8.4 Ways to Enhance Memory

Learning objectives.

By the end of this section, you will be able to:

  • Recognize and apply memory-enhancing strategies
  • Recognize and apply effective study techniques

   Most of us suffer from memory failures of one kind or another, and most of us would like to improve our memories so that we don’t forget where we put the car keys or, more importantly, the material we need to know for an exam. Of course it is impossible to remember everything that has happened to you exactly as it had originally played out. The previous section specifically emphasized examples of how memory can be distorted and in some cased completely fabricated. In this section, we’ll look at some ways to help you remember better, and at some strategies for more effective studying.

MEMORY-ENHANCING STRATEGIES

   What are some everyday ways we can improve our memory, including recall? To help make sure information goes from short-term memory to long-term memory, you can use memory-enhancing strategies. One strategy is  rehearsal , or the conscious repetition of information to be remembered (Craik & Watkins, 1973). Think about how you learned your multiplication tables as a child. You may recall that 6 x 6 = 36, 6 x 7 = 42, and 6 x 8 = 48. Memorizing these facts is rehearsal.

Another strategy is chunking: you organize information into manageable bits or chunks (Bodie, Powers, & Fitch-Hauser, 2006). Chunking is useful when trying to remember information like dates and phone numbers. Instead of trying to remember 5205550467, you remember the number as 520-555-0467. So, if you met an interesting person at a party and you wanted to remember his phone number, you would naturally chunk it, and you could repeat the number over and over, which is the rehearsal strategy.

Try this  fun activity  that employs a memory-enhancing strategy.

   You could also enhance memory by using elaborative rehearsal: a technique in which you think about the meaning of the new information and its relation to knowledge already stored in your memory (Tigner, 1999). For example, in this case, you could remember that 520 is an area code for Arizona and the person you met is from Arizona. This would help you better remember the 520 prefix. If the information is retained, it goes into long-term memory.

Mnemonic devices are memory aids that help us organize information for encoding. They are especially useful when we want to recall larger bits of information such as steps, stages, phases, and parts of a system (Bellezza, 1981). Brian needs to learn the order of the planets in the solar system, but he’s having a hard time remembering the correct order. His friend Kelly suggests a mnemonic device that can help him remember. Kelly tells Brian to simply remember the name Mr. VEM J. SUN, and he can easily recall the correct order of the planets:  M ercury,  V enus,  E arth,  M ars,  J upiter,  S aturn,  U ranus, and  N eptune. You might use a mnemonic device to help you remember someone’s name, a mathematical formula, or the order of mathematical operations.

This is a knuckle mnemonic to help you remember the number of days in each month. Months with 31 days are represented by the protruding knuckles and shorter months fall in the spots between knuckles. (credit: modification of work by Cory Zanker)

If you have ever watched the television show  Modern Family , you might have seen Phil Dunphy explain how he remembers names:

The other day I met this guy named Carl. Now, I might forget that name, but he was wearing a Grateful Dead t-shirt. What’s a band like the Grateful Dead? Phish. Where do fish live? The ocean. What else lives in the ocean? Coral. Hello, Co-arl. (Wrubel & Spiller, 2010)

It seems the more vivid or unusual the mnemonic, the easier it is to remember. The key to using any mnemonic successfully is to find a strategy that works for you.

   Some other strategies that are used to improve memory include expressive writing and saying words aloud. Expressive writing helps boost your short-term memory, particularly if you write about a traumatic experience in your life. Masao Yogo and Shuji Fujihara (2008) had participants write for 20-minute intervals several times per month. The participants were instructed to write about a traumatic experience, their best possible future selves, or a trivial topic. The researchers found that this simple writing task increased short-term memory capacity after five weeks, but only for the participants who wrote about traumatic experiences. Psychologists can’t explain why this writing task works, but it does.

What if you want to remember items you need to pick up at the store? Simply say them out loud to yourself. A series of studies (MacLeod, Gopie, Hourihan, Neary, & Ozubko, 2010) found that saying a word out loud improves your memory for the word because it increases the word’s distinctiveness. Feel silly, saying random grocery items aloud? This technique works equally well if you just mouth the words. Using these techniques increased participants’ memory for the words by more than 10%. These techniques can also be used to help you study.

In some of the previous sections, depth of processing has been discussed to suggest that information that is encoded in a deeper way by associating the information to be remembered with something that is important to you on a personal level or personally identifying with the information can create a stronger trace for the information to be later recalled (Craik & Tulving, 1975). Further studies implementing these theories in terms of enhancing memory have demonstrated that by encoding the information with an emotional valence, the information may be efficiently recalled and the memory trace may be more vivid allowing for more details to be accurately remembered (Kensigner & Corkin, 2003). Comparing memory for neutrally valence words compared to words encoded with a negative valence indicated that participants were statistically more likely to accurately remember words with a valence or emotional arousal associated. Additionally, words that were encoded with both emotional arousal (words related to cultural taboos) and negative valence were more accurate and had higher recall rates compared to words with just emotional valence. This suggests that systems in the brain that create emotional responses such as the amygdala and hypothalamus can be recruited by attaching emotional reactions to information to be remembered in order to enhance encoding procedures and build a stronger trace for later recall.

HOW TO STUDY EFFECTIVELY

   Based on the information presented in this chapter, here are some strategies and suggestions to help you hone your study techniques. The key with any of these strategies is to figure out what works best for you.

Memory techniques can be useful when studying for class. (credit: Barry Pousman)

  • Use elaborative rehearsal : In a famous article, Craik and Lockhart (1972) discussed their belief that information we process more deeply goes into long-term memory. Their theory is called levels of processing. If we want to remember a piece of information, we should think about it more deeply and link it to other information and memories to make it more meaningful. For example, if we are trying to remember that the hippocampus is involved with memory processing, we might envision a hippopotamus with excellent memory and then we could better remember the hippocampus.
  • Apply the self-reference effect : As you go through the process of elaborative rehearsal, it would be even more beneficial to make the material you are trying to memorize personally meaningful to you. In other words, make use of the self-reference effect. Write notes in your own words. Write definitions from the text, and then rewrite them in your own words. Relate the material to something you have already learned for another class, or think how you can apply the concepts to your own life. When you do this, you are building a web of retrieval cues that will help you access the material when you want to remember it.
  • Don’t forget the forgetting curve : As you know, the information you learn drops off rapidly with time. Even if you think you know the material, study it again right before test time to increase the likelihood the information will remain in your memory. Overlearning can help prevent storage decay.
  • Rehearse, rehearse, rehearse : Review the material over time, in spaced and organized study sessions. Organize and study your notes, and take practice quizzes/exams. Link the new information to other information you already know well.
  • Be aware of interference : To reduce the likelihood of interference, study during a quiet time without interruptions or distractions (like television or music).
  • Keep moving : Of course you already know that exercise is good for your body, but did you also know it’s also good for your mind? Research suggests that regular aerobic exercise (anything that gets your heart rate elevated) is beneficial for memory (van Praag, 2008). Aerobic exercise promotes neurogenesis: the growth of new brain cells in the hippocampus, an area of the brain known to play a role in memory and learning.
  • Get enough sleep : While you are sleeping, your brain is still at work. During sleep the brain organizes and consolidates information to be stored in long-term memory (Abel & Bäuml, 2013).
  • Make use of mnemonic devices : As you learned earlier in this chapter, mnemonic devices often help us to remember and recall information. There are different types of mnemonic devices, such as the acronym. An acronym is a word formed by the first letter of each of the words you want to remember. For example, even if you live near one, you might have difficulty recalling the names of all five Great Lakes. What if I told you to think of the word Homes? HOMES is an acronym that represents Huron, Ontario, Michigan, Erie, and Superior: the five Great Lakes. Another type of mnemonic device is an acrostic: you make a phrase of all the first letters of the words. For example, if you are taking a math test and you are having difficulty remembering  the order of operations , recalling the following sentence will help you: “Please Excuse My Dear Aunt Sally,” because the order of mathematical operations is Parentheses, Exponents, Multiplication, Division, Addition, Subtraction. There also are jingles, which are rhyming tunes that contain key words related to the concept, such as  i before e, except after c .

THE METHOD OF LOCI – CREATING INSTRUCTIONS TO ASSIST MEMORY RETRIEVAL

The World Memory Competitions represent a series of events where people from all over the world compete in ten different disciplines of memory in order to memorize as much information as possible within a given period of time and then are judged on what they are able to remember and the accuracy of their memory. One of the key strategies individuals have reported using in order to master their encoding ability and compete with some of the worlds leading memory performers is known as the method of loci, a strategy of memory enhancement which uses visualizations, spatial memory, and familiarity with the environment to quickly and efficiently recall information. Also known as the memory journey, memory palace, or the memory palace technique, this mnemonic device dates back to ancient Greece and Rome where orators and story tellers would use this method to memorize grandiose speeches and pass down epic stories through oral history such as the Homer’s Iliad and The Odyssey. The method of loci is an imaging technique where a person memorizes the layout of a building or some environment they are familiar with, and information that is needed to be remembered is arranged throughout the environment. The person trying to recall the information then uses this spatial map they have created to mentally walk through the environment to encounter each piece of information along the way. This mnemonic has been widely used throughout the history of humans and modern brain imaging techniques have demonstrated activation of areas of the brain related to spatial memory during method of loci recall including the medial prefrontal cortex and areas of the posterior hippocampus (Maguire et al., 2003). Additionally recent research using virtual reality has demonstrated that the method of loci appears to be equally useful in environments that are novel compared to familiar, as well as extremely detailed compared to less detailed (Legge et al., 2012). Additionally the method of loci was demonstrated to be effective for participants that had previously been naive to the technique compared to participants that did not use the method of loci. Overall, the method of loci represents a historically practiced and scientifically validated technique which can create a stronger process of encoding and lead to more accurate and efficient information recall.

   There are many ways to combat the inevitable failures of our memory system. Some common strategies that can be used in everyday situations include mnemonic devices, rehearsal, self-referencing, and adequate sleep. These same strategies also can help you to study more effectively.

References:

Openstax Psychology text by Kathryn Dumper, William Jenkins, Arlene Lacombe, Marilyn Lovett and Marion Perlmutter licensed under CC BY v4.0. https://openstax.org/details/books/psychology

Review Questions:

1. When you are learning how to play the piano, the statement “Every good boy does fine” can help you remember the notes E, G, B, D, and F for the lines of the treble clef. This is an example of a (an) ________.

c. acrostic

d. acoustic

2. According to a study by Yogo and Fujihara (2008), if you want to improve your short-term memory, you should spend time writing about ________.

your best possible future self

a. a traumatic life experience

b. a trivial topic

c. your grocery list

3. The self-referencing effect refers to ________.

a. making the material you are trying to memorize personally meaningful to you

b. making a phrase of all the first letters of the words you are trying to memorize

c. making a word formed by the first letter of each of the words you are trying to memorize

d. saying words you want to remember out loud to yourself

4. What type of memory enhancer requires you to organize units into manageable units?

a. rehearsal

b. chunking

c. elaborative rehearsal

d. none of the above

5. Memory aids that help organize information for encoding are ________.

a. mnemonic devices

b. memory-enhancing strategies

d. effortful processing

Critical Thinking Questions:

1. What is the self-reference effect, and how can it help you study more effectively?

2. You and your roommate spent all of last night studying for your psychology test. You think you know the material; however, you suggest that you study again the next morning an hour prior to the test. Your roommate asks you to explain why you think this is a good idea. What do you tell her?

3.  Describe three different ways you could enhance your memory when studying for an exam. Which strategies do you think are more effective in enhancing memory than others?

Personal Application Questions:

1. Create a mnemonic device to help you remember a term or concept from this chapter.

2. What is an effective study technique that you have used? How is it similar to/different from the strategies suggested in this chapter?

elaborative rehearsal

levels of processing

memory-enhancing strategy

mnemonic device

Answers to Exercises

1. The self-reference effect is the tendency an individual to have better memory for information that relates to oneself than information that is not personally relevant. You can use the self-reference effect to relate the material to something you have already learned for another class, or think how you can apply the concepts to your life. When you do this, you are building a web of retrieval cues that will help you access the material when you want to remember it.

2. You remind her about Ebbinghaus’s forgetting curve: the information you learn drops off rapidly with time. Even if you think you know the material, you should study it again right before test time to increase the likelihood the information will remain in your memory. Overlearning can help prevent storage decay.

chunking:  organizing information into manageable bits or chunks

elaborative rehearsal:  thinking about the meaning of the new information and its relation to knowledge already stored in your memory

levels of processing:  information that is thought of more deeply becomes more meaningful and thus better committed to memory

memory-enhancing strategy:  technique to help make sure information goes from short-term memory to long-term memory

mnemonic device:  memory aids that help organize information for encoding

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Mechanisms of memory enhancement

Affiliation.

  • 1 Center for Neural Science, New York University, New York, NY, USA.
  • PMID: 23151999
  • PMCID: PMC3527655
  • DOI: 10.1002/wsbm.1196

The ongoing quest for memory enhancement is one that grows necessary as the global population increasingly ages. The extraordinary progress that has been made in the past few decades elucidating the underlying mechanisms of how long-term memories are formed has provided insight into how memories might also be enhanced. Capitalizing on this knowledge, it has been postulated that targeting many of the same mechanisms, including CREB activation, AMPA/NMDA receptor trafficking, neuromodulation (e.g., via dopamine, adrenaline, cortisol, or acetylcholine) and metabolic processes (e.g., via glucose and insulin) may all lead to the enhancement of memory. These and other mechanisms and/or approaches have been tested via genetic or pharmacological methods in animal models, and several have been investigated in humans as well. In addition, a number of behavioral methods, including exercise and reconsolidation, may also serve to strengthen and enhance memories. By utilizing this information and continuing to investigate these promising avenues, memory enhancement may indeed be achieved in the future.

Copyright © 2012 Wiley Periodicals, Inc.

Publication types

  • Research Support, N.I.H., Extramural
  • Cognitive Behavioral Therapy / methods*
  • Exercise Therapy / methods*
  • Memory / drug effects*
  • Memory Disorders / physiopathology*
  • Memory Disorders / prevention & control*
  • Neurotransmitter Agents / administration & dosage*
  • Neurotransmitter Agents

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  • R37 MH065635/MH/NIMH NIH HHS/United States
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How to Improve Memory

Reviewed by Psychology Today Staff

It doesn’t take an extraordinary brain to get smarter about remembering. From techniques used by memory champions to fundamentals like securing enough sleep and maintaining healthy behaviors, just about anyone who wants to learn more efficiently has a variety of tools at their disposal—some of which they have likely already used.

On This Page

  • Memory Tricks
  • Everyday Memory Boosts

While simply revisiting a newly learned fact, the definition of a word, or some other information can help reinforce someone’s memory for it, additional tools and processes can help make the effort to retain those details more powerful.

  • Mnemonic devices are ways of enhancing memory that can involve elaboration—connecting what one is trying to remember to other information in memory—organizing to-be-remembered details more efficiently in memory, and making use of mental visualization. Examples of mnemonics include:
• forming a series of word s into an acronym (such as ROY G BIV, for the colors of the rainbow) or a series of letters into an acrostic (Elephants And Donkeys Got Big Ears, for the notes of each string on a guitar, E-A-D-G-B) • grouping to-be-remembered items together into categories (such as several types of food, when remembering what to buy at the grocery store) • creating a memory palace : visualizing a series of objects, events, or other things appearing in a familiar physical space (such as a room at home), where each one represents something to be remembered; also called the method of loci
  • Paying closer attention to details in the moment can make it easier to remember them later. People can learn to focus better; mindfulness techniques may help. Minimizing distractions and avoiding multitasking while learning information could also help with remembering.
  • Spacing apart the time spent studying , rather than massing it together, tends to lead to better learning, according to research on the spacing effect . An example of spaced practice would be studying a topic once every day for relatively small blocks of time rather than spending a longer block of time studying on Friday. Accordingly, “cramming”—studying in one long, continuous period— can be an unhelpful study habit.
  • Testing memory of learned material , such as a passage of text, can enhance memory for that material—above and beyond re-reading, research indicates. The findings suggest that self-testing can help with learning , whether a person responds to self-generated questions or flashcards related to that information or questions provided by someone else (such as sample test questions in textbooks). Explaining a newly learned concept to oneself or someone else may also help reinforce memory for it.
  • Chunking is the combination of to-be-remembered pieces of information, such as numbers or letters, into a smaller number of units (or “chunks”), making them easier to remember. A simple example is the reduction of a phone number into three parts (which one might repeat to oneself in three bursts), though more complex forms of chunking are thought to help account for experts’ superior memory for certain kinds of information (such as chess positions).

Can someone deliberately improve their ability to remember over the long-term? While factors such as well-timed and sufficient sleep and physical activity can aid a neurologically healthy person’s memory ability, the evidence for approaches such as supplements or brain games is often mixed.

In addition to a variety of strategies (such mnemonic devices and others mentioned above) to enhance your memory in the short term , striving to live a healthy and active lifestyle can help preserve memory ability over time. That means engaging in regular mental challenges, exercising routinely, getting enough sleep, and eating well. Reducing stress in daily life may also help to boost memory.

Sleep is thought to play an important role in the consolidation of memories. There is evidence that people who sleep soon after studying new information are more likely to recall it later than those who study it and remain awake. Procedural memories (memory for physical skills, for example) as well as memories for experiences and for new knowledge, seem to benefit from sleep. Consequently, failing to prioritize sleep (or struggling with sleep for other reasons) may mean a missed chance for optimal memory consolidation.

In addition to having longer-term benefits for memory ability, well-timed exercise may immediately boost memory for new information under some conditions. Research has found that moderate-to-high-intensity cardiovascular workout just before or after a learning period enhanced recall for the information learned.

Vegetables, nuts, berries, beans, olive oil, whole grains, fish, and other nutritious foods are elements of the Mediterranean diet and the DASH (Dietary Approaches to Stop Hypertension) Diet, which have been studied for their potential positive long-term effects on brain health. People who, over the course of several years, followed a diet blending elements of both showed reduced risk of Alzheimer’s disease , of which memory loss is one component. The same diet advises limiting consumption of red meat, butter and margarine, cheese, sweets, and fried or fast food.

There is reason to be skeptical about “brain training” programs based on inconsistent evidence of their effectiveness at improving memory or other cognitive abilities. Apps that purport to train the brain often feature tasks used to exercise working memory, with the aim of increasing working memory capacity (which has been linked to intelligence) in order to produce broader cognitive improvements. While working memory training may at least temporarily enhance performance on working memory-related tasks, however, that does not mean the improvement carries over to other mental abilities.

A range of substances, both synthetic and naturally occurring, have been studied for their potential to improve cognitive function, including memory ability. There are certain kinds of medications that can be prescribed to help treat memory loss due to a disease. Supplements proposed to enhance memory in healthy people , however, which have varying degrees of evidence in their favor—often based on small studies—may have a modest impact, if any, on memory.

write a term paper of enhancement of memory

Technology has made our brains more machine-like. What are we losing when they act as human routers rather than for reading, contemplating, critiquing, synthesizing, and retaining?

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The interplay between genes and lifestyle choices: How proactive habits can empower you to shape your brain's resilience over time.

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An interview with neuroscientist Daniela Schiller about the mechanisms underlying trauma and how trauma experiences can differ.

write a term paper of enhancement of memory

Alzheimer's was first described over a century ago, but the term wasn't in common use until recently.

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Have you ever tried to get rid of a memory of an unpleasant experience? Our survey respondents provided many creative techniques used to eliminate such problematic recollections.

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Art appreciation emerges as a valuable tool for fostering mental well-being and cognitive resilience.

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Consider these 3 ways you probably didn't realize you used your memory.

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Earworms—when a catchy piece of music plays on repeat in your head.

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Screens are replacing paper when it comes to nearly every aspect of communication, including reading books. But is it good for our mental health? Here's why paper books are better.

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Habit replacement and development is a process by which new behaviors effectively become automatic. Automatic means that you have succeeded in establishing a new normal.

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Ways to Enhance Memory

OpenStaxCollege

[latexpage]

Learning Objectives

By the end of this section, you will be able to:

  • Recognize and apply memory-enhancing strategies
  • Recognize and apply effective study techniques

Most of us suffer from memory failures of one kind or another, and most of us would like to improve our memories so that we don’t forget where we put the car keys or, more importantly, the material we need to know for an exam. In this section, we’ll look at some ways to help you remember better, and at some strategies for more effective studying.

MEMORY-ENHANCING STRATEGIES

What are some everyday ways we can improve our memory, including recall? To help make sure information goes from short-term memory to long-term memory, you can use memory-enhancing strategies . One strategy is rehearsal , or the conscious repetition of information to be remembered (Craik & Watkins, 1973). Think about how you learned your multiplication tables as a child. You may recall that 6 x 6 = 36, 6 x 7 = 42, and 6 x 8 = 48. Memorizing these facts is rehearsal.

Another strategy is chunking : you organize information into manageable bits or chunks (Bodie, Powers, & Fitch-Hauser, 2006). Chunking is useful when trying to remember information like dates and phone numbers. Instead of trying to remember 5205550467, you remember the number as 520-555-0467. So, if you met an interesting person at a party and you wanted to remember his phone number, you would naturally chunk it, and you could repeat the number over and over, which is the rehearsal strategy.

write a term paper of enhancement of memory

Try this fun activity that employs a memory-enhancing strategy.

You could also enhance memory by using elaborative rehearsal : a technique in which you think about the meaning of the new information and its relation to knowledge already stored in your memory (Tigner, 1999). For example, in this case, you could remember that 520 is an area code for Arizona and the person you met is from Arizona. This would help you better remember the 520 prefix. If the information is retained, it goes into long-term memory.

Mnemonic devices are memory aids that help us organize information for encoding ( [link] ). They are especially useful when we want to recall larger bits of information such as steps, stages, phases, and parts of a system (Bellezza, 1981). Brian needs to learn the order of the planets in the solar system, but he’s having a hard time remembering the correct order. His friend Kelly suggests a mnemonic device that can help him remember. Kelly tells Brian to simply remember the name Mr. VEM J. SUN, and he can easily recall the correct order of the planets: M ercury, V enus, E arth, M ars, J upiter, S aturn, U ranus, and N eptune. You might use a mnemonic device to help you remember someone’s name, a mathematical formula, or the seven levels of Bloom’s taxonomy.

A photograph shows a person’s two hands clenched into fists so the knuckles show. The knuckles are labeled with the months and the number of days in each month, with the knuckle protrusions corresponding to the months with 31 days, and the indentations between knuckles corresponding to February and the months with 30 days.

If you have ever watched the television show Modern Family , you might have seen Phil Dunphy explain how he remembers names:

The other day I met this guy named Carl. Now, I might forget that name, but he was wearing a Grateful Dead t-shirt. What’s a band like the Grateful Dead? Phish. Where do fish live? The ocean. What else lives in the ocean? Coral. Hello, Co-arl. (Wrubel & Spiller, 2010)

It seems the more vivid or unusual the mnemonic, the easier it is to remember. The key to using any mnemonic successfully is to find a strategy that works for you.

Watch this fascinating TED Talks lecture titled “Feats of Memory Anyone Can Do.” The lecture is given by Joshua Foer, a science writer who “accidentally” won the U. S. Memory Championships. He explains a mnemonic device called the memory palace.

Some other strategies that are used to improve memory include expressive writing and saying words aloud. Expressive writing helps boost your short-term memory, particularly if you write about a traumatic experience in your life. Masao Yogo and Shuji Fujihara (2008) had participants write for 20-minute intervals several times per month. The participants were instructed to write about a traumatic experience, their best possible future selves, or a trivial topic. The researchers found that this simple writing task increased short-term memory capacity after five weeks, but only for the participants who wrote about traumatic experiences. Psychologists can’t explain why this writing task works, but it does.

What if you want to remember items you need to pick up at the store? Simply say them out loud to yourself. A series of studies (MacLeod, Gopie, Hourihan, Neary, & Ozubko, 2010) found that saying a word out loud improves your memory for the word because it increases the word’s distinctiveness. Feel silly, saying random grocery items aloud? This technique works equally well if you just mouth the words. Using these techniques increased participants’ memory for the words by more than 10%. These techniques can also be used to help you study.

HOW TO STUDY EFFECTIVELY

Based on the information presented in this chapter, here are some strategies and suggestions to help you hone your study techniques ( [link] ). The key with any of these strategies is to figure out what works best for you.

A photograph shows students studying.

  • Use elaborative rehearsal : In a famous article, Craik and Lockhart (1972) discussed their belief that information we process more deeply goes into long-term memory. Their theory is called levels of processing . If we want to remember a piece of information, we should think about it more deeply and link it to other information and memories to make it more meaningful. For example, if we are trying to remember that the hippocampus is involved with memory processing, we might envision a hippopotamus with excellent memory and then we could better remember the hippocampus.
  • Apply the self-reference effect : As you go through the process of elaborative rehearsal, it would be even more beneficial to make the material you are trying to memorize personally meaningful to you. In other words, make use of the self-reference effect. Write notes in your own words. Write definitions from the text, and then rewrite them in your own words. Relate the material to something you have already learned for another class, or think how you can apply the concepts to your own life. When you do this, you are building a web of retrieval cues that will help you access the material when you want to remember it.
  • Don’t forget the forgetting curve : As you know, the information you learn drops off rapidly with time. Even if you think you know the material, study it again right before test time to increase the likelihood the information will remain in your memory. Overlearning can help prevent storage decay.
  • Rehearse, rehearse, rehearse : Review the material over time, in spaced and organized study sessions. Organize and study your notes, and take practice quizzes/exams. Link the new information to other information you already know well.
  • Be aware of interference : To reduce the likelihood of interference, study during a quiet time without interruptions or distractions (like television or music).
  • Keep moving : Of course you already know that exercise is good for your body, but did you also know it’s also good for your mind? Research suggests that regular aerobic exercise (anything that gets your heart rate elevated) is beneficial for memory (van Praag, 2008). Aerobic exercise promotes neurogenesis: the growth of new brain cells in the hippocampus, an area of the brain known to play a role in memory and learning.
  • Get enough sleep : While you are sleeping, your brain is still at work. During sleep the brain organizes and consolidates information to be stored in long-term memory (Abel & Bäuml, 2013).
  • Make use of mnemonic devices : As you learned earlier in this chapter, mnemonic devices often help us to remember and recall information. There are different types of mnemonic devices, such as the acronym. An acronym is a word formed by the first letter of each of the words you want to remember. For example, even if you live near one, you might have difficulty recalling the names of all five Great Lakes. What if I told you to think of the word Homes? HOMES is an acronym that represents Huron, Ontario, Michigan, Erie, and Superior: the five Great Lakes. Another type of mnemonic device is an acrostic: you make a phrase of all the first letters of the words. For example, if you are taking a math test and you are having difficulty remembering the order of operations , recalling the following sentence will help you: “Please Excuse My Dear Aunt Sally,” because the order of mathematical operations is Parentheses, Exponents, Multiplication, Division, Addition, Subtraction. There also are jingles, which are rhyming tunes that contain key words related to the concept, such as i before e, except after c .

There are many ways to combat the inevitable failures of our memory system. Some common strategies that can be used in everyday situations include mnemonic devices, rehearsal, self-referencing, and adequate sleep. These same strategies also can help you to study more effectively.

Review Questions

When you are learning how to play the piano, the statement “Every good boy does fine” can help you remember the notes E, G, B, D, and F for the lines of the treble clef. This is an example of a (an) ________.

According to a study by Yogo and Fujihara (2008), if you want to improve your short-term memory, you should spend time writing about ________.

  • your best possible future self
  • a traumatic life experience
  • a trivial topic
  • your grocery list

The self-referencing effect refers to ________.

  • making the material you are trying to memorize personally meaningful to you
  • making a phrase of all the first letters of the words you are trying to memorize
  • making a word formed by the first letter of each of the words you are trying to memorize
  • saying words you want to remember out loud to yourself

Memory aids that help organize information for encoding are ________.

  • mnemonic devices
  • memory-enhancing strategies
  • elaborative rehearsal
  • effortful processing

Critical Thinking Questions

What is the self-reference effect, and how can it help you study more effectively?

The self-reference effect is the tendency an individual to have better memory for information that relates to oneself than information that is not personally relevant. You can use the self-reference effect to relate the material to something you have already learned for another class, or think how you can apply the concepts to your life. When you do this, you are building a web of retrieval cues that will help you access the material when you want to remember it.

You and your roommate spent all of last night studying for your psychology test. You think you know the material; however, you suggest that you study again the next morning an hour prior to the test. Your roommate asks you to explain why you think this is a good idea. What do you tell her?

You remind her about Ebbinghaus’s forgetting curve: the information you learn drops off rapidly with time. Even if you think you know the material, you should study it again right before test time to increase the likelihood the information will remain in your memory. Overlearning can help prevent storage decay.

Personal Application Questions

Create a mnemonic device to help you remember a term or concept from this chapter.

What is an effective study technique that you have used? How is it similar to/different from the strategies suggested in this chapter?

Ways to Enhance Memory Copyright © 2014 by OpenStaxCollege is licensed under a Creative Commons Attribution 4.0 International License , except where otherwise noted.

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10 Influential Memory Theories and Studies in Psychology

Discover the experiments and theories that shaped our understanding of how we develop and recall memories..

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10 Influential Memory Theories and Studies in Psychology

How do our memories store information? Why is it that we can recall a memory at will from decades ago, and what purpose does forgetting information serve?

The human memory has been the subject of investigation among many 20th Century psychologists and remains an active area of study for today’s cognitive scientists. Below we take a look at some of the most influential studies, experiments and theories that continue to guide our understanding of the function of memory.

1 Multi-Store Model

(atkinson & shiffrin, 1968).

An influential theory of memory known as the multi-store model was proposed by Richard Atkinson and Richard Shiffrin in 1968. This model suggested that information exists in one of 3 states of memory: the sensory, short-term and long-term stores . Information passes from one stage to the next the more we rehearse it in our minds, but can fade away if we do not pay enough attention to it. Read More

Information enters the memory from the senses - for instance, the eyes observe a picture, olfactory receptors in the nose might smell coffee or we might hear a piece of music. This stream of information is held in the sensory memory store , and because it consists of a huge amount of data describing our surroundings, we only need to remember a small portion of it. As a result, most sensory information ‘ decays ’ and is forgotten after a short period of time. A sight or sound that we might find interesting captures our attention, and our contemplation of this information - known as rehearsal - leads to the data being promoted to the short-term memory store , where it will be held for a few hours or even days in case we need access to it.

The short-term memory gives us access to information that is salient to our current situation, but is limited in its capacity.

Therefore, we need to further rehearse information in the short-term memory to remember it for longer. This may involve merely recalling and thinking about a past event, or remembering a fact by rote - by thinking or writing about it repeatedly. Rehearsal then further promotes this significant information to the long-term memory store, where Atkinson and Shiffrin believed that it could survive for years, decades or even a lifetime.

Key information regarding people that we have met, important life events and other important facts makes it through the sensory and short-term memory stores to reach the long-term memory .

Learn more about Atkinson and Shiffrin’s Multi-Store Model

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2 Levels of Processing

(craik & lockhart, 1972).

Fergus Craik and Robert Lockhart were critical of explanation for memory provided by the multi-store model, so in 1972 they proposed an alternative explanation known as the levels of processing effect . According to this model, memories do not reside in 3 stores; instead, the strength of a memory trace depends upon the quality of processing , or rehearsal , of a stimulus . In other words, the more we think about something, the more long-lasting the memory we have of it ( Craik & Lockhart , 1972). Read More

Craik and Lockhart distinguished between two types of processing that take place when we make an observation : shallow and deep processing. Shallow processing - considering the overall appearance or sound of something - generally leads to a stimuli being forgotten. This explains why we may walk past many people in the street on a morning commute, but not remember a single face by lunch time.

Deep (or semantic) processing , on the other hand, involves elaborative rehearsal - focusing on a stimulus in a more considered way, such as thinking about the meaning of a word or the consequences of an event. For example, merely reading a news story involves shallow processing, but thinking about the repercussions of the story - how it will affect people - requires deep processing, which increases the likelihood of details of the story being memorized.

In 1975, Craik and another psychologist, Endel Tulving , published the findings of an experiment which sought to test the levels of processing effect.

Participants were shown a list of 60 words, which they then answered a question about which required either shallow processing or more elaborative rehearsal. When the original words were placed amongst a longer list of words, participants who had conducted deeper processing of words and their meanings were able to pick them out more efficiently than those who had processed the mere appearance or sound of words ( Craik & Tulving , 1975).

Learn more about Levels of Processing here

write a term paper of enhancement of memory

3 Working Memory Model

(baddeley & hitch, 1974).

Whilst the Multi-Store Model (see above) provided a compelling insight into how sensory information is filtered and made available for recall according to its importance to us, Alan Baddeley and Graham Hitch viewed the short-term memory (STM) store as being over-simplistic and proposed a working memory model (Baddeley & Hitch, 1974), which replace the STM.

The working memory model proposed 2 components - a visuo-spatial sketchpad (the ‘inner eye’) and an articulatory-phonological loop (the ‘inner ear’), which focus on a different types of sensory information. Both work independently of one another, but are regulated by a central executive , which collects and processes information from the other components similarly to how a computer processor handles data held separately on a hard disk. Read More

According to Baddeley and Hitch, the visuo-spatial sketchpad handles visual data - our observations of our surroundings - and spatial information - our understanding of objects’ size and location in our environment and their position in relation to ourselves. This enables us to interact with objects: to pick up a drink or avoid walking into a door, for example.

The visuo-spatial sketchpad also enables a person to recall and consider visual information stored in the long-term memory. When you try to recall a friend’s face, your ability to visualize their appearance involves the visuo-spatial sketchpad.

The articulatory-phonological loop handles the sounds and voices that we hear. Auditory memory traces are normally forgotten but may be rehearsed using the ‘inner voice’; a process which can strengthen our memory of a particular sound.

Learn more about Baddeley and Hitch’s working memory model here

write a term paper of enhancement of memory

4 Miller’s Magic Number

(miller, 1956).

Prior to the working memory model, U.S. cognitive psychologist George A. Miller questioned the limits of the short-term memory’s capacity. In a renowned 1956 paper published in the journal Psychological Review , Miller cited the results of previous memory experiments, concluding that people tend only to be able to hold, on average, 7 chunks of information (plus or minus two) in the short-term memory before needing to further process them for longer storage. For instance, most people would be able to remember a 7-digit phone number but would struggle to remember a 10-digit number. This led to Miller describing the number 7 +/- 2 as a “magical” number in our understanding of memory. Read More

But why are we able to remember the whole sentence that a friend has just uttered, when it consists of dozens of individual chunks in the form of letters? With a background in linguistics, having studied speech at the University of Alabama, Miller understood that the brain was able to ‘chunk’ items of information together and that these chunks counted towards the 7-chunk limit of the STM. A long word, for example, consists of many letters, which in turn form numerous phonemes. Instead of only being able to remember a 7-letter word, the mind “recodes” it, chunking the individual items of data together. This process allows us to boost the limits of recollection to a list of 7 separate words.

Miller’s understanding of the limits of human memory applies to both the short-term store in the multi-store model and Baddeley and Hitch’s working memory. Only through sustained effort of rehearsing information are we able to memorize data for longer than a short period of time.

Read more about Miller’s Magic Number here

write a term paper of enhancement of memory

5 Memory Decay

(peterson and peterson, 1959).

Following Miller’s ‘magic number’ paper regarding the capacity of the short-term memory, Peterson and Peterson set out to measure memories’ longevity - how long will a memory last without being rehearsed before it is forgotten completely?

In an experiment employing a Brown-Peterson task, participants were given a list of trigrams - meaningless lists of 3 letters (e.g. GRT, PXM, RBZ) - to remember. After the trigrams had been shown, participants were asked to count down from a number, and to recall the trigrams at various periods after remembering them. Read More

The use of such trigrams makes it impracticable for participants to assign meaning to the data to help encode them more easily, while the interference task prevented rehearsal, enabling the researchers to measure the duration of short-term memories more accurately.

Whilst almost all participants were initially able to recall the trigrams, after 18 seconds recall accuracy fell to around just 10%. Peterson and Peterson’s study demonstrated the surprising brevity of memories in the short-term store, before decay affects our ability to recall them.

Learn more about memory decay here

write a term paper of enhancement of memory

6 Flashbulb Memories

(brown & kulik, 1977).

There are particular moments in living history that vast numbers of people seem to hold vivid recollections of. You will likely be able to recall such an event that you hold unusually detailed memories of yourself. When many people learned that JFK, Elvis Presley or Princess Diana died, or they heard of the terrorist attacks taking place in New York City in 2001, a detailed memory seems to have formed of what they were doing at the particular moment that they heard such news.

Psychologists Roger Brown and James Kulik recognized this memory phenomenon as early as 1977, when they published a paper describing flashbulb memories - vivid and highly detailed snapshots created often (but not necessarily) at times of shock or trauma. Read More

We are able to recall minute details of our personal circumstances whilst engaging in otherwise mundane activities when we learnt of such events. Moreover, we do not need to be personally connected to an event for it to affect us, and for it lead to the creation of a flashbulb memory.

Learn more about Flashbulb Memories here

write a term paper of enhancement of memory

7 Memory and Smell

The link between memory and sense of smell helps many species - not just humans - to survive. The ability to remember and later recognize smells enables animals to detect the nearby presence of members of the same group, potential prey and predators. But how has this evolutionary advantage survived in modern-day humans?

Researchers at the University of North Carolina tested the olfactory effects on memory encoding and retrieval in a 1989 experiment. Male college students were shown a series of slides of pictures of females, whose attractiveness they were asked to rate on a scale. Whilst viewing the slides, the participants were exposed to pleasant odor of aftershave or an unpleasant smell. Their recollection of the faces in the slides was later tested in an environment containing either the same or a different scent. Read More

The results showed that participants were better able to recall memories when the scent at the time of encoding matched that at the time of recall (Cann and Ross, 1989). These findings suggest that a link between our sense of smell and memories remains, even if it provides less of a survival advantage than it did for our more primitive ancestors.

8 Interference

Interference theory postulates that we forget memories due to other memories interfering with our recall. Interference can be either retroactive or proactive: new information can interfere with older memories (retroactive interference), whilst information we already know can affect our ability to memorize new information (proactive interference).

Both types of interference are more likely to occur when two memories are semantically related, as demonstrated in a 1960 experiment in which two groups of participants were given a list of word pairs to remember, so that they could recall the second ‘response’ word when given the first as a stimulus. A second group was also given a list to learn, but afterwards was asked to memorize a second list of word pairs. When both groups were asked to recall the words from the first list, those who had just learnt that list were able to recall more words than the group that had learnt a second list (Underwood & Postman, 1960). This supported the concept of retroactive interference: the second list impacted upon memories of words from the first list. Read More

Interference also works in the opposite direction: existing memories sometimes inhibit our ability to memorize new information. This might occur when you receive a work schedule, for instance. When you are given a new schedule a few months later, you may find yourself adhering to the original times. The schedule that you already knew interferes with your memory of the new schedule.

9 False Memories

Can false memories be implanted in our minds? The idea may sound like the basis of a dystopian science fiction story, but evidence suggests that memories that we already hold can be manipulated long after their encoding. Moreover, we can even be coerced into believing invented accounts of events to be true, creating false memories that we then accept as our own.

Cognitive psychologist Elizabeth Loftus has spent much of her life researching the reliability of our memories; particularly in circumstances when their accuracy has wider consequences, such as the testimonials of eyewitness in criminal trials. Loftus found that the phrasing of questions used to extract accounts of events can lead witnesses to attest to events inaccurately. Read More

In one experiment, Loftus showed a group of participants a video of a car collision, where the vehicle was travelling at a one of a variety of speeds. She then asked them the car’s speed using a sentence whose depiction of the crash was adjusted from mild to severe using different verbs. Loftus found when the question suggested that the crash had been severe, participants disregarded their video observation and vouched that the car had been travelling faster than if the crash had been more of a gentle bump (Loftus and Palmer, 1974). The use of framed questions, as demonstrated by Loftus, can retroactively interfere with existing memories of events.

James Coan (1997) demonstrated that false memories can even be produced of entire events. He produced booklets detailing various childhood events and gave them to family members to read. The booklet given to his brother contained a false account of him being lost in a shopping mall, being found by an older man and then finding his family. When asked to recall the events, Coan’s brother believed the lost in a mall story to have actually occurred, and even embellished the account with his own details (Coan, 1997).

Read more about false memories here

write a term paper of enhancement of memory

10 The Weapon Effect on Eyewitness Testimonies

(johnson & scott, 1976).

A person’s ability to memorize an event inevitably depends not just on rehearsal but also on the attention paid to it at the time it occurred. In a situation such as an bank robbery, you may have other things on your mind besides memorizing the appearance of the perpetrator. But witness’s ability to produce a testimony can sometimes be affected by whether or not a gun was involved in a crime. This phenomenon is known as the weapon effect - when a witness is involved in a situation in which a weapon is present, they have been found to remember details less accurately than a similar situation without a weapon. Read More

The weapon effect on eyewitness testimonies was the subject of a 1976 experiment in which participants situated in a waiting room watched as a man left a room carrying a pen in one hand. Another group of participants heard an aggressive argument, and then saw a man leave a room carrying a blood-stained knife.

Later, when asked to identify the man in a line-up, participants who saw the man carrying a weapon were less able to identify him than those who had seen the man carrying a pen (Johnson & Scott, 1976). Witnesses’ focus of attention had been distracted by a weapon, impeding their ability to remember other details of the event.

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Understand & Improve Memory Using Science-Based Tools

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write a term paper of enhancement of memory

This episode I explain the mechanisms by which different types of memories are established in our brain and how to leverage the amount and timing of key neurochemicals and hormones, such as adrenaline (aka epinephrine) and cortisol, to improve your learning and memory abilities. I describe multiple science-based protocols to do this, including repetition, caffeine, emotional states, deliberate cold exposure, sleep, meditation, and the role of vision, including taking “mental snapshots.” I also describe how exercise and an associated hormone, osteocalcin, can improve cognitive ability and memory formation. I also describe unique aspects and forms of memory such as photographic memory, extreme facial recognition (aka super recognition), and the phenomenon known as déjà vu. 

  • A Novel Demonstration of Enhanced Memory Associated with Emotional Arousal  ( Consciousness and Cognition )
  • Mechanisms of memory under stress  ( Neuron )
  • Photographic Memory: The Effects of Volitional Photo Taking on Memory for Visual and Auditory Aspects of an Experience  ( Psychological Science )
  • Brief, daily meditation enhances attention, memory, mood, and emotional regulation in non-experienced meditators  ( Behavioural Brain Research )
  • 00:00:00 Memory, Improving Memory
  • 00:02:45 Eight Sleep, Thesis, InsideTracker
  • 00:07:54 Sensory Stimuli, Nervous System & Encoding Memory
  • 00:11:12 Context & Memory Formation
  • 00:13:46 Tool: Repetition, Improving Learning & Memory
  • 00:17:11 Co-Activation and intensity Neuron Activation
  • 00:20:50 Different Types of Memory
  • 00:25:40 Memory Formation in the Brain, Hippocampus
  • 00:28:00 Hippocampus, Role in Memory & Learning, Explicit vs. Implicit Memory
  • 00:31:49 Emotion & Memory Enhancement
  • 00:36:44 Tool: Emotion Saliency & Improved Memory
  • 00:41:42 Conditioned-Placed Avoidance/Preference, Adrenaline
  • 00:47:14 Adrenaline & Cortisol
  • 00:49:35 Accelerating the Repetition Curve & Adrenaline
  • 00:53:03 Tool: Enhancing Learning & Memory – Caffeine, Alpha-GPC & Stimulant Timing
  • 01:00:50 Tool: Enhancing Learning & Memory – Sleep, Non-Sleep Deep Rest (NSDR)
  • 01:04:48 Tool: Enhancing Learning & Memory – Deliberate Cold Exposure, Adrenaline
  • 01:08:42 Timing of Adrenaline Release & Memory Formation
  • 01:12:36 Chronically High Adrenaline & Cortisol, Impact on Learning & Memory
  • 01:15:12 Adrenaline Linked with Learning: Not a New Principle
  • 01:17:25 Amygdala, Adrenaline & Memory Formation, Generalization of Memories
  • 01:22:20 Tool: Cardiovascular Exercise & Neurogenesis
  • 01:27:00 Cardiovascular Exercise, Osteocalcin & Improved Hippocampal Function
  • 01:29:59 Load-Bearing Exercise, Osteocalcin & Cognitive Ability
  • 01:34:41 Tool: Timing of Exercise, Learning & Memory Enhancement
  • 01:37:29 Photographic Memory
  • 01:38:49 “Super Recognizers,” Facial Recognition
  • 01:41:46 Tool: Mental Snapshots, Photographs & Memory Enhancement
  • 01:49:12 Déjà Vu
  • 01:53:24 Tool: Meditation, Daily Timing of Meditation
  • 02:02:21 How to Enhance Memory
  • 02:05:51 Zero-Cost Support, YouTube Feedback, Spotify & Apple Reviews, Sponsors, Patreon, Momentous Supplements, Instagram, Twitter, Neural Network Newsletter

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Andrew Huberman:

Welcome to the Huberman Lab podcast, where we discuss science and science-based tools for everyday life.

I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today we are discussing memory, in particular, how to improve your memory. Now, the study of memory is one that dates back many decades, and by now there's a pretty good understanding of how memories are formed in the brain, the different structures involved, and some of the neurochemicals involved, and we will talk about some of that today. Often overlooked, however, is that memories are not just about learning. Memories are also about placing your entire life into a context. And that's because what's really special about the brain, and in particular the human brain, is its ability to place events in the context of past events, the present and future events, and sometimes even combinations of the past and present, or present and future, and so on. So when we talk about memory, what we're really talking about is how your immediate experiences relate to previous and future experiences.

Today I'm going to make clear how that process occurs. Even if you don't have a background in biology or psychology, I promise to put it into language that anyone can access and understand. And we are going to talk about the science that points to specific tools for enhancing learning and memory. We're also going to talk about unlearning and forgetting. There are, of course, instances in which we would like to forget things, and that, too, is a biological process for which great tools exist to, for instance, eliminate, or at least reduce the emotional load of a previous experience that you really did not like, or that perhaps even was traumatic to you.

So today you're going to learn about the systems in the brain and body that establish memories, you're going to learn why certain memories are easier to form than others, and I'm going to talk about specific tools that are grounded in not just one, not just a dozen, but well over a hundred studies in animals and humans that point to specific protocols that you can use in order to stamp down learning of particular things more easily. And you can also leverage that same knowledge to better forget, or unload the emotional weight of experiences that you did not like.

We are also going to discuss topics like déjà vu and photographic memory. And for those of you that do not have a photographic memory, and I should point out that I do not have a photographic memory either, well, you will learn how to use your visual system in order to better learn visual and auditory information. There are protocols to do this grounded in excellent peer-reviewed research, so while you may not have a true photographic memory, by the end of the episode, you will have tools in hand, or I should say tools in mind, or in eyes and mind, to be able to encode and remember specific events better than you would otherwise.

Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero-cost-to-consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast.

Okay, let's talk about memory. And let's talk about how to get better at remembering things. Now, in order to address both of those things, we need to do a little bit of brain science 101 review, and I promise this will only take two minutes, and I promise that even if you don't have a background in biology, it will make sense. We are constantly being bombarded with physical stimuli: patterns of touch on our skin, light to our eyes — light to our skin, for that matter — smells, taste, and sound waves. In fact, if you can hear me saying this right now, well that's the consequence of sound waves arriving into your ears through headphones, a computer, or some other speaker device. Each one of and all of those sensory stimuli are converted into electricity and chemical signals by your so-called nervous system: your brain, your spinal cord, and all their connections with the organs of the body, and all the connections of your organs of the body back to your brain and spinal cord.

One of the primary jobs of your nervous system, in fact, is to convert physical events in the world that are nonnegotiable. Photons of light are photons of light, sound waves are sound waves. There's no changing that. But your nervous system does change that. It converts those things into electrical signals and chemical signals, which are the language of your nervous system. Now, just because you're being bombarded with all this sensory information and it's being converted into a language that neurons and the rest of your nervous system can understand does not mean that you are aware of it all. In fact, you are only going to perceive a small amount of that sensory information. For instance, if you can hear me speaking right now, you are perceiving my voice, but you are also most likely neglecting the feeling of the contact of your skin with whichever surface you happen to be sitting or standing on.

It is only by perceiving a subset, a small fraction of the sensory events in our environment, that we can make sense of the world around us. Otherwise, we would just be overwhelmed with all the things that are happening in any one given moment. Now, memory is simply a bias in which perceptions will be replayed again in the future. Anytime you experience something, that is the consequence of specific chains of neurons, that we call neural circuits, being activated. And memory is simply a bias in the likelihood that that specific chain of neurons will be activated again. For instance, if you can remember your name, and I certainly hope that you can, well, that means that there are specific chains of neurons in your brain that represent your name, and when those neurons connect with one another and communicate electrically with one another in a particular sequence, you remember your name. Were that particular chain of neurons to be disrupted, you would not be able to remember your name.

Now, this might seem immensely simple, but it raises this really interesting question, which we talked about before, which is why do we remember certain things and not others? Because according to what I've just said, as you go through life, you're experiencing things all the time. You're constantly being bombarded with sensory stimuli; some of those sensory stimuli you perceive, and only some of those perceptions get stamped down as memories. Today I'm going to teach you how certain things get stamped down as memories, and I'm going to teach you how to leverage that process in order to remember the information that you want far better. Now, even though I've told you that a memory is simply a bias in the likelihood that a particular chain of neurons will be activated in a particular sequence again and again, it doesn't operate on its own. In fact, most of what we remember takes place in a context of other events.

For instance, you can most likely remember your name, and yet you're probably not thinking about when it was that you first learned your name. This generally happens when we are very, very young children. And yet, I'm guessing you could probably remember a time when someone mispronounced your name, or made fun of your name, or, as the case was for me, I got to the third grade and there were two Andrews. And sadly for me, I lost the coin flip that allowed me to keep Andrew, and from about third grade until about 12th grade, people called me Andy, which I really did not prefer. So if you call me Andy in the comments, I'll delete your comment. Just kidding, it doesn't bother me that much. But eventually, I reclaimed Andrew as my name. Well, it was mine to begin with and throughout, but I started going by Andrew again.

Why do I say this? Well, there's a whole context to my name for me. And there may or may not be a whole context to your name for you, but presumably if you ask your parents why they named you your given name, you'll get a context, et cetera. That context reflects the activation of other neural circuits that are also related to other events in your life, not just your name, but probably your siblings' names and who your parents are, and on, and on, and on. And so, the way memory works is that each individual thing that we remember or that we want to remember is linked to something by either a close, a medium, or a very distant association.

This turns out to be immensely important. I know many of you will read or will encounter programs that are designed to help you enhance your memory. You have these phenoms that can remember 50 names in a room full of people, or they can remember a bunch of names of novel objects, or maybe even in different languages. And oftentimes that's done by association, so people will come up with little mental tricks to either link the sound of a word or the meaning of a word in some way that's meaningful for them and will enhance their memory. That can be done, and is impressive when we see it, and for those of you who can do that, congratulations. Most of us can't do that, or at least it requires a lot of effort and training.

However, there are things that we can do that leverage the natural biology of our nervous system to enhance learning and memory of particular perceptions and particular information. Let's first just talk about the most basic ways that we learn and remember things and how to improve learning and memory. And the most basic one is repetition. Now, the study of memory and the role of repetition actually dates back to the late 1800s, early 1900s, when Ebbinghaus developed the first so-called learning curves. Now, learning curves are simply what results when you quantify how many repetitions of something are required in order to remember something. In fact, it's been said that Ebbinghaus liberated the understanding of learning from the philosophers by generating these learning curves. What do we mean by that? Well, before Ebbinghaus came along, learning and memory were thought to be philosophical ideas. Ebbinghaus came along and said, "Well, let's actually take some measurements. Let's measure how well I can remember a sequence of words or a sequence of numbers if I just repeat them."

What Ebbinghaus did is he would take a sequence of numbers or words on a page, and he would read them. And then, he would take a separate sheet of paper, and we have to presume he didn't cheat, and he would write down as many of them as he could, and he would try and keep them in the same sequence. Then he would compare to the original list, and he would see how many errors he made. And you do this over, and over, and over again. And as you would expect, early in the training and the learning, it took a lot more repetitions to get the sequence correct, and over time, it took fewer sequences. And he referred to that difference in the initial number of repetitions that he had to perform versus the later number of repetitions that he had to perform as a so-called "savings."

So he literally thought of the brain as having to generate a kind of a currency of effort. And he talked about savings as the reduction in the amount of effort that he had to put forward in order to learn information. And what he got was a learning curve, and you can imagine what that learning curve looked like; it had a very sharp peak at the beginning that dropped off over time. And of course, he remembered all this meaningless information. But even though the information might have been meaningless, the experiment itself and what Ebbinghaus demonstrated was immensely meaningful. Because what it said was that with repetition, we can activate particular sequences of neurons, and that repeated activation lays down what we call a memory.

And that might all seem like a big duh, but prior to Ebbinghaus, none of that was known. Now, I should also say Ebbinghaus, because of when he was alive, was not aware of these things that we call neural circuits. It was in 1906 that Golgi and Cajal got the Nobel Prize for actually showing that neurons are independent cells connected by synapses, these little gaps between them where they communicate. So he may have been aware of that, but the whole notion of neural circuits hadn't really come about. Nevertheless, what the Ebbinghaus learning curves really established was that sheer repetition, just repeating things over, and over, and over again, is sufficient to learn. Something that no doubt had been observed before, but had never been formally quantified.

Now, if we look at that result, there's something really important that lies a little bit cryptic, that's not so obvious to most people, which is the information that he was trying to learn wasn't any more interesting the second time than it was the first, it probably was even less interesting, and less and less interesting with each repetition, and yet it was sheer repetition that allowed him to remember. Now, sometime later in the early- to mid-1920s, a psychologist in Canada named Donald Hebb came up with what was called Hebb's Postulate. And Hebb's postulate, broadly speaking, is this idea that if a sequence of neurons is active at roughly the same time, that that would lead to a strengthening of the connections between those neurons. And many, many decades of experimentation later, we now know that postulate to be true.

Neurons themselves are not smart — they don't have knowledge, so every memory is the consequence, as I told you before, of the repeated activation of a particular chain of neurons. And what Ebbinghaus showed through repetition, and what Donald Hebb proposed, and it was eventually verified through experimentation on animals and humans, was that if you encourage the coactivation of neurons, meaning, have neurons fire at roughly the same time, they will strengthen their connections. It leads to a bias in the probability that those neurons will be active again.

Now, this is vitally important, because nowadays we hear a lot about how memories are the consequence of new neurons added in the brain. Or that every time you learn something, a new connection in your brain forms. Well, sorry to break it to you, but that's simply not the case. Most of the time, and I want to emphasize most, not all, but most of the time when we learn something, it's because existing neurons, not new neurons, strengthen their connection through coactivation over, and over, and over, through repetition. Or, and this is a very important or, through very strong activation once, and only once. In fact, there's something called one-trial learning, whereby we experience something and we will remember that thing forever. This is often most associated with negative events, and I'll explain why in a few minutes, but it can also be associated with positive events, like the first time you saw your romantic partner, or something that happened with that romantic partner, or the first time that you saw your child, or any other positive event, as well as any other extremely negative event.

Again, both repetition, and I guess we could label it intensity — but what we really mean when we say intensity is strong activation of neurons — can lay down these traces, these circuits that are far more likely to be active again than had there not been repetition, or not some strong activation of those circuits. With that in mind, let's return to the original contrarian question that I raised before, which is why do we remember anything? Every day you wake up, your neurons in your brain and body are active, different neural circuits are active, and yet you only remember a small fraction of the things that happen each day. And yet, you retain a lot of information from previous days, and the days before those, and so on. It is only with a lot of repetition, or with extremely strong activation of a given neural circuit, that we will create new memories.

And so, in a few minutes, I'll explain how to get extremely strong activation of particular neural circuits. Repetition is pretty obvious, repetition is repetition. But in a few minutes, I'll illustrate a whole set of experiments, and a whole set of tools that point to how you can get extra strong activation of a given neural circuit as it relates to learning, so that you will remember that information, perhaps not just with one trial of learning, but certainly with far fewer repetitions than would be required otherwise. Before we go any further, I want to preface the discussion by saying that there are a lot of different kinds of memory. In fact, were you to take a voyage into the neuroscience and/or psychology of memory, you would find an immense number of different terms to describe the immense number of different types of memory that researchers focus on. But for sake of today's discussion, really just want to focus on short-term memory, medium-term memory, and long-term memory. And while there's still debate, as is always the case with scientists, frankly, about the exact divisions between short-term, medium- and long-term memory, we can broadly define short-term memory and long-term memory, and we can describe a couple different types of those that I think you can relate to in your everyday life.

The most common form of short-term memory that we're going to focus on is called working memory. Working memory is your ability to keep a chain of numbers in mind for some period of time, but the expectation really isn't that you would remember those numbers the next day, and certainly not the next week. So a good example would be a phone number. If I were to tell you a phone number, 493-2938, well, you could probably remember it, 493-2938. But if I came back tomorrow and asked you to repeat that chain of numbers, most likely you would not. Unless, of course, we used a particular tool to stamp down that memory into your mind and commit it to long-term memory.

Now, of course, in this day and age, most people have phone numbers programmed into their phone; they don't really have to remember the exact numbers, it's usually done by contact identity and so forth. A different example that some of you are probably more familiar with would be those security codes. So you try and log on to an app or a website, and it asks you for a security code that's been sent to your text messages, and then you can either plug that in directly in some cases, or you have to remember that short sequence of anywhere, usually, from six to seven, sometimes eight numbers. Your ability to do that, to switch back and forth between webpages or apps, and plug in that number by remembering the sequence and plugging it in by keying it in on your keyboard, that's a really good example of working memory.

Long-term memory of the sort that we're going to be talking a lot about today is your ability to commit certain patterns of information, either cognitive information or motor information — the ability to move your limbs in a particular sequence — over long periods of time, such that you could remember it a day, or a week, or a month, or maybe even a year, or several years later. So we've got short-term memory and long-term memory, and we've got this working memory, which is keeping something online, but then discarding it. Not online on a computer, but online within your brain.

There are also two major categories of memory that I'd like you to know about. One is explicit memory, this is not necessarily explicit of the sort that you're used to thinking about, but rather the fact that you can declare you know something. So you have an explicit memory of your name, presumably you have an explicit memory of the house or the apartment that you grew up in. You know something, and you know you know it. And you can declare it, so I can ask you, "What was the color of the first car that you owned?" Or, "What is the color of your romantic partner's hair?" These sorts of things, that's an explicit declarative memory. But you also have explicit procedural memories. Procedural memories, as the name suggests, involve action sequences.

The simplest one, it's almost ridiculously simple, is walking. If I say, "How is it that you walk from one room to the other?" You'd probably say, "Well, I go that direction, then I turn left." I say, "No, no, no, no. How is it exactly that you do it?" You say, "Well, I move my left foot, then my right foot, then my left foot," and you could describe that. So it's an explicit procedural memory, so much so that if you were going to teach a young toddler how to walk, you would probably say, "Okay, good, try ..." Probably, that's going to be prelanguage for the toddler, but you're going to encourage them to move one leg, then the other, and you're going to encourage and reward them for moving one leg, then the other, because you have an explicit procedural memory of how to walk. Almost ridiculously simple, maybe even truly ridiculously simple. But nonetheless, when you think about it in the context of neural circuits and neural firing, pretty amazing.

Even more amazing is the fact that all explicit memories, both declarative and procedural explicit memories, can be moved from explicit to implicit. What do I mean by that? Well, in the example of walking, you might have chuckled a little bit, or shook your head and said, "That's a ridiculous thing to ask — how do I walk from one room to the next? I just walk, I just do it." Ah, well, what is just do it? What it is, is that you have an implicit understanding, meaning your nervous system knows how to walk without you actually having to think about what you know about how to walk. You just get up out of your chair, or you get up out of bed, and you walk.

In the brain, you have a structure. In fact, you have one on each side of your brain, it's called the hippocampus. The hippocampus literally means seahorse. Anatomists like to name brain structures after things that they think those brain structures resemble. When I look at the hippocampus, frankly, it doesn't look like a seahorse, which either reflects my lack of understanding of what a seahorse really looks like, a visual deficit, or, I think it's fair to say that those anatomists were using a little bit of creative elaboration when thinking about what the hippocampus looks like.

Nonetheless, it is a curved structure, it has many layers. It's been described by my colleague Robert Sapolsky, and by others, as looking more like a jelly roll, or a cinnamon roll is what it looks like to me. And if you were to take one cinnamon roll, chop it down the middle — so now you've got two half cinnamon rolls, and rather than put them back together in the configuration they were before, you just slide one down so that you've got essentially two Cs, two C-shaped halves of the cinnamon roll, and you push them together, slightly offset from one another, well, that's what the hippocampus looks like to me. And I think that's a far better description of its actual physical structure, but I guess if you were to use that physical structure as the name, well, then you'd have to open up a brain atlas, and it would be called "Two half-C cinnamon rolls stuffed halfway together," so that's not very good, so I guess seahorse will work.

Hippocampus is the name of this structure, and it is the site in your brain — and again, you have one on each side of your brain — in which explicit declarative memories are formed. It is not where those memories are stored and maintained, it is where they are established in the first place. In contrast, implicit memories, these subconscious memories, are formed and stored elsewhere in the brain, mainly by areas like the cerebellum, but also the neocortex, the outer shell of your brain. The cerebellum literally means mini brain, and it does in fact look like a mini brain, and is in the back of the brain. And the neocortex is the outer part of the brain that covers all the other stuff.

So the hippocampus is vitally important for establishing these new declarative memories of what you know, and what you know how to do. Now, in order to really understand the role of the hippocampus in memory, in particular, explicit declarative and explicit procedural memory, and to really understand how that's distinct from implicit declarative and implicit procedural memories, we have to look to a clinical case. And the clinical case that I'm referring to is a patient who went by the name H.M. Patients go by their initials in order to maintain confidentiality of their real identity. H.M. had what's called intractable epilepsy, so he would have these really dramatic so-called grand mal seizures, or drop seizures. For those of you that know somebody with epilepsy, or that have epilepsy, you might be familiar with this. You can have petit mal seizures, which are minor seizures; you can have tonic-clonic seizures, which are sometimes not even detectable; you can have absent seizures where people will just stop, it's almost as if their brain goes on pause, and they'll just stop there. It was reported, actually, that Einstein had absent seizures, although I don't know that that's ever really been confirmed neurologically.

Grand mal seizures are extremely severe, and that's what H.M. had. So he could just be going about his day, and maybe even cooking, or doing something, driving, operating any kind of machinery, and then all of a sudden, he would just have a drop seizure. He would just physically drop and go into a grand mal seizure, convulsing of the whole body, loss of consciousness, et cetera. Or he would feel it coming on. Oftentimes, people with epilepsy can feel the seizure coming on, kind of like a wave from the back of the brain. And sometimes they can get to a safe circumstance, but not always. And so, the frequency and the intensity of his seizures were so robust that the neurosurgeons and neurologists decided that they needed to locate the origin, what they call the foci of those seizures, and remove that brain tissue. Because the way seizures work is they spread out from that foci of brain tissue.

And unfortunately for H.M., the focus of his seizures was the hippocampus. So after a lot of deliberation, a neurosurgeon, in fact, one of the most famous neurosurgeons in the world at that time, made what are called electrolytic lesions, actually burned out the hippocampus in the brain of H.M. And as a consequence, he lost all explicit memory. Now, the consequence of this was that he couldn't exist in normal everyday life like most people, so he had to live mostly, not entirely, in a hospital setting. And I've talked to several people who met H.M. directly, because he's no longer alive, but an interaction with him might look like the following:

He would walk up to you just fine, you wouldn't know that he had any kind of brain damage. He could walk fine, he could speak fine. And you'd say, "Hi, I'm Andrew," and he'd say, "Hi, I'm ..." whatever his name happened to be. He wouldn't say, "H.M.," but he'd probably say his real name. And then, perhaps someone new would walk into the room, he might turn around, look at that person, as any of us might do, then turn around back to me and say, "Hi, what's your name?" And if I were to say, "Well, I just told you my name, and you just told me your name, do you remember that?" He'd say, "I'm sorry, I don't remember any of that. What's your name?" So you had to go through this over and over again.

So a complete lack of explicit declarative memory. Now, he did have some memory for previous events in his life that dated way back. Again, hinting at the idea that memories aren't not necessarily stored in the hippocampus, they're just formed in the hippocampus. So once they've moved out of the hippocampus to other brain areas, he could still keep those memories. They're in a different database, if you will. They're in a different pattern of firing of other neural circuits, but he couldn't form new memories. Now, there's some very important and interesting twists on what H.M. could and could not do, in terms of learning and memory, that teach us a lot about the brain. In fact, I think most neuroscientists would agree that this unfortunate case of H.M.'s epilepsy, and the subsequent neurosurgery that he had, taught us much of what we know, or at least think about in terms of human learning and memory.

For instance, as I mentioned before, he still had implicit knowledge. He knew how to walk, he knew how to do certain things like make a cup of coffee, he knew the names of people that he had met much earlier in his life, and so on. And yet, he couldn't form new memories. Now, in violation to that last statement, there were some elements of H.M.'s emotionality that suggests that there was some sort of residual capacity to learn new information, but it wasn't what we normally think of as explicit declarative or procedural memory. For instance, it's been said, I don't know that the studies were ever done with intense physiological measurements, that if you were to tell H.M. a joke, and he thought it was funny, he would laugh really hard. He liked jokes, so you'd say, "H.M., I want to tell you a joke," you'd tell him a joke, and he'd laugh really hard. Then you could leave the room, come back and tell him the same joke again. Now, keep in mind, he did not remember that you told him the joke previously. And the second time, he would laugh a little bit less. And then you'd leave the room, come back again, say, "Hi, I'm Andrew," and he'd say, "Oh, nice to meet you," because as you recall, because you can recall things, but he couldn't recall things, he didn't know that he just met you, or at least he couldn't remember it.

You tell him the joke a third time, or a fourth time, and with each subsequent telling of the joke, he found it a little less funny. Just as, keep this in mind, folks, if you tell a joke and you get a big laugh, don't tell it again. At least not immediately, not to the same person or the same crowd, because the second time it's a little less funny, and the third time, it's a little less funny. And that actually has to do with the whole element of dopamine and its relationship to surprise, and that's the topic of a future podcast where we talk all about humor and novelty in the brain. But the point being that certain forms of memory seemed to exist in a phantom-like way within H.M.'s brain.

What do I mean by that? Well, this underscores the fact that he had an implicit memory of having heard the joke before. And it suggests that humor, or at least what we find funny, is somehow more related to procedures, similar to walking or a motor ability, than it is to the precise content of that joke. That's a little bit of an abstract concept, but the point is that H.M. lacked explicit declarative memory. He couldn't tell you what he had just heard. He could not learn new information, and he couldn't tell you how to do something unless he had learned how to do that something many years prior.

Now, there have been a lot of other patients besides H.M. that have had brain lesions due to epilepsy, or I should say due to surgeries to treat epilepsy, due to strokes, due to, sadly, gunshot wounds, and other forms of what we call infarct, I-N-F-A-R-C-T. Infarct is the word we use to describe damage to a particular brain region. And many different patients with many different patterns of infarct have taught us a lot about how memory and other aspects of the brain work. H.M. really teaches us that what we know and what we are able to do is the consequence of things that we are aware of and learnings that have been passed off into subconscious knowledge, that our body knows, our brain knows, but we don't know exactly how we know that thing.

And I tell you the story about H.M.'s ability to understand a joke, but that with repeated telling of a joke, it has less, and less, and less of an impact in creating a sense of laughter, of humor in H.M., not as just an anecdote to flesh out his story, but because emotion itself turns out to be the way in which we can enhance memories, even if those are memories for things that are not funny, are not intensely sad, are not immensely happy, or don't evoke a really strong emotional response, or even emotional response. And the reason for that is that emotions, just like perception, just like sensation, are the consequence of particular neurochemicals being present in our brain and body. And as I'm going to tell you next, there are particular neurochemicals that you can leverage in order to learn specific information faster, and to remember it for a much longer period of time, maybe even forever. And you can do that by leveraging the relationship in your nervous system between your brain and your body, and your body back to your brain.

Let's talk about tools for enhancing memory. Now, there's one tool that is absolutely-

Enhancing memory. Now there's one tool that is absolutely clear works and it's always worked. It works now and it will work forever. And that's repetition. The more often that you perform something or that you recite something, the more likely you are to remember it in the future. And while that might seem obvious, it's worth thinking about what's happening when you repeat something. But when I say what's happening, I mean at the neural level. What's happening is that you are encouraging the firing of particular chains of neurons that reside in a particular circuit. Right? So a particular sequence of neurons playing, neuron A, B, C, D, played in that particular sequence over and over and over again. And with more repetitions you get more strengthening of those nerve connections.

Now, repetition works, but the problem for most people is that they either don't have the patience, they don't have the time, and sometimes they literally don't have the time because they've got a deadline on something that they're trying to remember and learn, or they simply would like to be able to remember things better in general and remember them more quickly.

This process of accelerating repetition-based learning so that your learning curve doesn't go from having to perform something 1,000 times and then gradually, over time, it's 1,000, 750 times a day, 500 times a day, 300 times a day, and down to no repetitions. Right? You can just perform that thing the first time and every time. Well there is a way to shift that curve so that you can essentially establish stronger connections between the neurons that are involved in generating that memory or behavior more quickly. How do you do that? Well in order to answer that we have to look at the beautiful work of James McGaugh and Larry Cahill. James McGaugh and Larry Cahill did a number of experiments, over several decades really, based on a lot of animal literature but mainly focused on humans that really established what's required to get better at remembering things and to do so very quickly.

I want to talk about one experiment that they did that was particularly important, and we will provide a link to this paper. It's some years old now, but the results still hold up. In fact, the results establish an entire field of memory in neuroscience and psychology. What they did is they had human subjects come into the laboratory and to read a short paragraph of about 12 sentences. And the key thing is that some subjects read a paragraph that was pretty mundane. The content, the information within the paragraph was all related to the content of the previous sentence. So it was a cogent paragraph. Right? It just wasn't a meaningless scramble of words, but it described a kind of mundane set of circumstances.

Maybe it would be a story about someone who walked into a room, sat down at a desk, wrote for a little bit, then got up and had lunch. You know, just kind of mundane information. Not very interesting. Another group of subjects read also a 12-sentence paragraph, but that paragraph included a subset of sentences that had a lot of emotionally intense language or that had language that could evoke an emotionally intense response in the person reading it.

So it might have talked about a car accident or a very intense surgery, but it also could be positive stuff. Things like a birthday party or a celebration of some other kind or a big sports win. So in other words you have two conditions of this study. People either read a boring paragraph or they read a really emotionally laden paragraph, and again the emotions could either be positive or negative emotions. Subjects left the laboratory and sometime later they were called back to the laboratory. And I should say at no point in the experiment did they know they were part of a memory experiment. They don't know why they're reading this. They came in either for class credit or to get paid. That's typically how these things are done on college campuses or elsewhere. They come back into the lab and they would get a pop quiz.

They would be asked to recall the content of the paragraph that they had read previously. Now, as is probably expected, perhaps even obvious to you, the subjects that read the emotionally intense paragraph remembered far more of the content of that paragraph and were far more accurate in the remembering of that information. Now that particular finding wasn't very novel. Many people had previously described how emotionally intense events are better remembered than nonemotionally intense events. In fact, way back in the 1600s, Francis Bacon, who's largely credited with developing the scientific method, said "Memory is assisted by anything that makes an impression on a powerful passion, inspiring fear, for example, or wonder, shame or joy." Francis Bacon said that in 1620. So Jim McGaugh and Larry Cahill were certainly not the first to demonstrate or to conceive of the idea that emotionally laden experiences are more easily remembered than other experiences.

However, what they did next was immensely important for our understanding of memory and for our building of tools to enhance learning and memory. What they did was they evaluated the capacity for stress, and for particular neurochemicals associated with stress, to improve our ability to learn information. Not just information that is emotional, but information of all kinds. So I'm going to describe some experiments done in animal models just very briefly, and then experiments done on human subjects, because McGaugh worked mainly on animals, also human subjects. Larry Cahill, almost exclusively on human subjects. If you take a rat or a mouse and put it in an arena where at one location the animal receives an electrical shock, and then you come back the next day, you remove the shock-evoking device and you let the animal move around that arena, that animal will quite understandably avoid the location where it was shocked, so-called conditioned place aversion.

That effect of avoiding that particular location occurs in one trial. That's a good example of one-trial learning. So somehow the animal knows that it was shocked at that location. It remembers that. It is a hippocampal-dependent learning. So animals that lack a hippocampus or who have their hippocampus pharmacologically or otherwise incapacitated will not learn that new bit of information. But for animals that do, they remember it after the first time and every time, unless you are to block the release of certain chemicals in the brain and body. And the chemicals I'm referring to are epinephrine/adrenaline, and to some extent the corticosteroids, things like cortisol.

Now, we know that the effect of getting one-trial learning somehow involves epinephrine, at least in this particular experimental scenario, because if researchers do the exact same experiment, and they have done the exact same experiment, but they introduce a pharmacological blocker of epinephrine so that epinephrine is released in response to the shock, but it cannot actually bind to its receptors and have all of its biological effects, well then the animal is perfectly happy to tread back into the area where it received the shock. It's almost as if it didn't know, or we have to assume it didn't remember that it received the shock at that location. So it all seems pretty obvious when you hear it, something bad happens in the location, you don't go back to that location. So that's conditioned place avoidance. But it turns out that the opposite is also true, meaning for something called conditioned place preference, you can take an animal, put it into an arena, feed it or reward it somehow at one location in that arena.

So you can give a hungry rat or mouse food at one particular location, take the animal out, come back the next day, no food is introduced, but it'll go back to the location where it received the food. Or you can do any variant of this. You can make the arena a little bit chilly and provide warmth at that location. Or you can take a male animal — and turns out male rats and mice will mate at any point — or a female animal that's at the particular so-called receptive phase of her mating cycle and give them an opportunity to mate at a given location. They'll go back to that location and wait and wait.

This is perhaps why people go back to the same bar or the seat at the bar or the same restaurant and wait, because of the one time things worked out for them, whatever the context was. Conditioned place preference. Conditioned place preference, as with conditioned place avoidance, depends on the release of adrenaline, right? It's not just about stress, it's about a heightened emotional state in the brain and body. Okay? This is really important. It's not just about stress. You can get one-trial learning for positive events, conditioned place preference, and you can get one-trial learning for negative events.

Here I say positive, negative. I'm putting what's called valence on. I'm making a value judgment about whether or not the animal liked it or didn't like it, and we have to presume what the animal liked or didn't like and how it felt. But this turns out all to be true for humans as well. We know that because McGaugh and Cahill did experiments where they gave people a boring paragraph to read, and only a boring paragraph to read, but one group of subjects was asked to read the paragraph and then to place their arm into very, very cold water. In fact, it was ice water. We know that placing one's arm into ice water, especially if it's up to the shoulder or near to it, evokes the release of adrenaline in the body. It's not an enormous release, but it's a significant increase.

And yes, they measured adrenaline release. In some cases they also measured for things like cortisol, et cetera. And what they found is that if one evokes the release of adrenaline through this arm-into-ice-water approach, the information that they read previously just a few minutes before was remembered. It was retained as well as emotionally intense information. But keep in mind that information that they read was not interesting at all, or at least it wasn't emotionally laden. This had to be the effect of adrenaline released into the brain and body, because if they blocked the release or the function of adrenaline in the brain and/or body, they could block this effect. Now, the biology of epinephrine and cortisol are a little bit complex, but there's some nuance there that's actually interesting and important to us. First of all, adrenaline is released in the body and in the brain.

It's released in the body from the adrenals. Remember, epinephrine and adrenaline are the same thing. Cortisol is also released from the adrenal glands, these two little glands that ride atop our kidneys, but it can't cross into the brain. It only has what we call peripheral effects. Quickening of the heart rate, right? Changes the patterns of blood flow. Changes our patterns of breathing. In general, makes our breathing more shallow and faster. In general, makes our heart beat more quickly, et cetera.

Within our brain, we have a little brain area called locus coeruleus, which is in the back of the brain, which has the opportunity to sprinkler the rest of the brain with the neuromodulator epinephrine/adrenaline, as well as norepinephrine, a related neuromodulator, and to essentially wake up or create a state of alertness throughout the brain. So it's a very general effect. The reason we have two sites of release is because these neurochemicals do not cross the blood-brain barrier. And so waking up the body with adrenaline, and waking up the brain, are two separate so-called parallel phenomena. Cortisol can cross the blood-brain barrier because it's lipophilic, meaning it can move through fatty tissue, and we'll get into the biology of that in another episode. But cortisol, in general, is released and has much longer-term effects. And, as I've just told you, can permeate throughout the brain and body. Adrenaline has more local effects, or at least is segregated between the brain and the body. This will turn out to be important later.

The important thing to keep in mind is that it is the emotionality evoked by an experience or, to be more precise, it is the emotional state that you were in after you experience something that dictates whether or not you will learn it quickly or not. This is absolutely important in terms of thinking about tools to improve your memory. And no, I am not going to suggest that every time you want to learn something, you plunge your arm into ice water. Why won't I suggest that? Well, it will induce the release of adrenaline, but there are better ways to get that adrenaline release. Before I explain exactly what those tools are, I want to tamp down the biology of how all this works because in that understanding, you will have access to the best possible tools to improve your memory.

First of all, McGaugh and Cahill were excellent experimentalists. They did not just establish that you could quicken the formation of a memory by accessing material that was very emotionally laden or creating an emotional high-adrenaline state after interacting with some thing, some words, some person, some information. They also tested whether or not that whole effect could be blocked by blocking the emotional state or by blocking adrenaline. So what they did is they had people read paragraphs that either had a lot of emotional content, or they had people read paragraphs that were pretty boring, but then had them put their arm into ice water. And I should say they did other experiments too to increase adrenaline. There were even some shock experiments that were done by other groups. Any number of things to evoke the release of adrenaline. Even people taking drugs that increase adrenaline.

But then they also did what are called blocking experiments. They did experiments where they had people get into a highly emotional state from reading highly emotional material, or they got people to get into a highly emotional neurochemical state by reading boring material and then taking a drug to increase adrenaline or ice bath or a shock, and then they also administered a drug called a beta blocker to block the effect of adrenaline and related chemicals in the brain and body.

And what they found is that even if people were exposed to something really emotional or had a lot of adrenaline in their system because they received a drug to increase the amount of adrenaline, two manipulations that normally would increase memory, keep that in mind if they gave them a beta blocker, which reduced the response to that adrenaline, right? So no quickening of the heart rate, no quickening of the breathing, no increase in the activity of locus coeruleus, and these kind of wake-up signals to the rest of the brain. Well then the material wasn't remembered better at all. What this tells us is that, yes, Francis Bacon was right. McGaugh and Cahill were right. Hundreds, if not thousands, of philosophers and psychologists and neuroscientists were right in stating and in thinking that high emotional states help you learn things. But what McGaugh and Cahill really showed, and what's most important to know is that it is the presence of high adrenaline, high amounts of norepinephrine and epinephrine, and perhaps cortisol as well, as you'll soon see, that allows a memory to be stamped down quickly.

It is not the emotion. It is the neurochemical state that you go into as a consequence of the emotion. And it's very important to understand that while those two things are related, they are not one and the same thing. Because what that means is that were you to evoke the release of epinephrine, norepinephrine, and cortisol, or even just one or two of those chemicals after experiencing something, you are stamping down the experience that you just previously had. Now, this is fundamentally important and far and away different than the idea that we remember things because they're important to us or because they evoke emotion.

That's true. But the real reason, the neurochemical reason, the mechanism behind all that is these neurochemicals have the ability to strengthen neural connections by making them active just once. There's something truly magic about that neurochemical cocktail that removes the need for repetition. Okay, so let's apply this knowledge. Let's establish a scientifically grounded set of tools, meaning tools that take into account the identity of the neurochemicals that are important for enhancing learning and the timing of the release of those chemicals in order to enhance learning. When I first learned about the results of McGaugh and Cahill, I was just blown away. I was also pretty upset, but not with them. I was upset with myself because I realized that the way that I had been approaching learning and memory was not optimal. In fact, it was probably in the opposite direction to the enhanced protocol for learning and memory that I'm going to teach you today.

My typical mode of trying to learn something while I was in college, or while I was in graduate school, or as a junior professor, or even a tenured professor, was to sit down to whatever it is I was going to try and learn, perhaps even memorize, or if it was a physical skill, move to whatever environment I was going to learn that physical skill in. And prior to that to make sure that I was hydrated, because that's important to me and certainly can contribute to your brain's ability to function and your body's ability to function and general patterns of alertness, but also to caffeinate. I would have a nice strong cup of coffee or espresso. I would have a nice strong cup of yerba maté. And I still drink coffee or yerba maté very regularly. I drink them in moderation, I think, certainly for me. But typically I would drink those things before I would engage in any kind of attempt to learn or memorize or to acquire a new skill.

Now, caffeine in the form of coffee or yerba maté or any other form of caffeine does create a sense of alertness in our brain and body, and it does that through two major mechanisms. The first mechanism is by blocking the effects of adenosine. Adenosine is a molecule that builds up in the brain and body the longer that we are awake. And it's largely what's responsible for our feelings of sleepiness and fatigue when we've been awake for a very long time. Caffeine essentially acts to block the effects of adenosine. It's a competing agonist, not to get technical, but it binds to the receptor for adenosine for some period of time and prevents adenosine from having its normal pattern of action, and thereby reduces our feelings of fatigue, but it also increases state of alertness.

So while it's reducing fatigue, it's also pushing on neurochemical systems in order to directly increase our alertness. And it does that in large part by increasing the transmission of epinephrine/adrenaline in the brain and body. It also has this interesting effect of upregulating the number and/or efficiency, or we say the efficacy, of dopamine receptors such that when dopamine is present, and as a molecule that increases motivation and craving and pursuit, that dopamine can have a more potent effect than it would otherwise. So caffeine really hits these three systems. It hits other systems too, but it mainly reduces fatigue by reducing adenosine, increases alertness by increasing epinephrine release, or adrenaline release, I should say, both from the adrenals in your body and from locus coeruleus within the brain, and it can, in parallel to all that, increase the action or the efficacy of the action of dopamine.

So my typical way of approaching learning and memory would be to drink some caffeine and then focus really hard on whatever it is that I'm trying to learn, try and eliminate distractions, and then hope, hope, hope, or try, try, try to remember that information as best as I could. Frankly, I felt like it was working pretty well for me. And typically, if I leveraged other forms of pharmacology in order to enhance learning and memory, things like Alpha-GPC, or phosphatidylserine, I would do that by taking those things before I sat down to learn a particular set of information or before I went off to learn a particular physical skill. Now, for those of you out there listening to this, you're probably thinking, well, okay, the results of McGaugh and Cahill pointed to the fact that having adrenaline released after learning something enhanced learning of that thing. But a lot of these things like caffeine or Alpha-GPC can increase epinephrine and adrenaline or dopamine or other molecules in the brain and body that can enhance memory for a long period of time.

So it makes sense to take it first or even during learning and then allow that increase to occur, and the increase will occur over a long period of time and will enhance learning and memory. And while that is partially true, it is not entirely true, and it turns out it's not optimal. Work that was done by the McGaugh Laboratory and other laboratories evaluated the precise temporal relationship between neurochemical activation of these pathways and learning and memory. What they did is they had animals and/or people, depending on the experiment, take a drug, could be caffeine, could be in pill form, something that would increase adrenaline or related molecules that create this state of alertness that are related to emotionality. And they had them do it either an hour before, 30 minutes before, 10 minutes before, 5 minutes before learning, or during the bout of learning — right? — the reading of the information or the performing of the skill that one is trying to learn, or 5 minutes, 10 minutes, 15 minutes, 30 minutes, et cetera afterwards.

So they looked very precisely at when exactly is best to evoke this adrenaline release. And it turns out that the best time window to evoke the release of these chemicals if the goal is to enhance learning and memory of the material, is either immediately after or just a few minutes, 5, 10, maybe 15 minutes, after you're repeating that information, you're trying to learn that information. Again, this could be cognitive information or this could be a physical skill. Now, this really spits in the face of the way that most of us approach learning and memory. Most of us, if we use stimulants like caffeine or Alpha-GPC, we're taking those before or during an attempt to learn, not afterwards. These results point to the fact that it is after the learning and memory that you really want to get that big increase in epinephrine and the related molecules that will tamp down memory.

So what this means is that if you are currently using caffeine or other compounds, and we'll talk about what those are and safety issues and so forth in a moment, if you're using those compounds in order to enhance learning and memory by taking them before or during a learning episode, well then I encourage you to try and take them either late in the learning episode or immediately after the learning episode. Now, given everything I've told you up until now, why would I say late in the learning episode or immediately after? Well, when you ingest something by drinking it, or you take it in capsule form, there's a period of time before that gets absorbed into the body, and different substances, such as caffeine, Alpha-GPC, et cetera are absorbed from the gut and into the bloodstream and reach the brain and trigger these effects in the brain of body at different rates.

So it's not instantaneous. Some have effects within minutes, others within tens of minutes and so on. It's really going to depend on the pharmacology of those things. And it's also going to depend on whether or not you have food in your gut, what else you happen to have circulating in your bloodstream, et cetera. But at a very basic level, we can confidently say that there are not one, not dozens, but, as I mentioned before, hundreds of studies in animals and in humans that point to the fact that triggering the increase of adrenaline late in learning or immediately after learning is going to be most beneficial if your goal is to retain that information for some period of time and to reduce the number of repetitions required in order to learn that information. Now, I want to acknowledge that on previous episodes of this podcast and in appearing on other podcasts, I've talked a lot about things like non-sleep deep rest and naps and sleep as vital to the learning process.

And I want to emphasize that none of that information has changed, right? I don't look at any of that information differently as the consequence of what I'm talking about today. It is still true that the strengthening of connections in the brain, the literal neuroplasticity, the changing of the circuits occurs during deep sleep and non-sleep deep rest. And it is also true, and I've mentioned these results earlier, that two papers were published in Cell Reports, Cell Press journal, excellent journal, over the last few years, showing that brief naps of about 20 to up to 90 minutes in some period of time after an attempt to learn, can enhance the rate of learning and memory. However, those bouts of sleep, the deep sleep that night, I should say, or those brief naps, or even the so-called NSDR, as we call it, non-sleep deep rest, that was used to enhance the learning and memory of particular pieces of information, either cognitive or physical information or both, that still can be performed, but it can be performed some hours later, even an hour later, it can be performed two hours later, four hours later.

Remember, it's in these naps and in deep sleep that the actual reconfiguration of the neural circuits occurs, the strengthening of those neural circuits occurs. It is not the case that you need to finish a bout of learning and drop immediately into a nap or sleep. Some people might do that, but if you're really trying to optimize and enhance and improve your memory, the data from McGaugh and Cahill and many other laboratories that stemmed out from their initial work really point to the fact that the ideal protocol would be focus on the thing you're trying to learn very intensely. There are also some other things like error rates, et cetera. Please see our episodes on learning. We have a newsletter on how to learn better. You can access that at hubermanlab.com. It's a zero-cost newsletter. You can grab that PDF. It lists out the things to do during the learning bout.

Still try and get excellent sleep. Again, fundamentally important for mental health, physical health and performance. And we can now extend from performance to saying including learning and memory. Nap if it doesn't interrupt your nighttime sleep. Naps of anywhere from 10 to 90 minutes, or non-sleep deep rest protocols will enhance learning and memory. But we can now add to that that spiking adrenaline, provided it can be done in a safe way, is going to reduce the number of repetitions required to learn, and that should be done at the very tail end or immediately after a learning bout. Which is compatible with all the other protocols that I mentioned.

And the reason I'm revisiting the stuff about sleep and non-sleep deep rest is I think that some people got the impression that they need to do that immediately after learning. And today, I'm saying to the contrary. Immediately after learning, you need to go into a heightened state of emotionality and alertness. Now, it's vitally important to point out that you do not need pharmacology. You don't need caffeine, you don't need Alpha-GPC. You don't need any pharmacologic substance to spike adrenaline unless that's something that you already are doing or that you can do safely or that you know you can do safely. And I always say, and I'll say it again, I'm not a physician, so I'm not prescribing anything. I'm a professor, so I profess things you need to do what's safe for you.

So if you're somebody who's not used to drinking caffeine and you suddenly drink four espresso after trying to learn something, you are going to have a severe increase in alertness and probably even anxiety. If you're panic attack prone, please don't start taking stimulants in order to learn things better. Please be safe. I don't just say that to protect me. I say that to protect you. And I should mention that if you're not accustomed to taking something, you always want to first check with your doctor, of course, but also move into that gradually, right? Start with the lowest effective dose. The minimal effective dose. And sometimes the minimal effective dose is zero milligrams. It's nothing. Why do I say that? Well, we already talked about results where they put people's arms into an ice bath in order to evoke adrenaline release. You are welcome to do that if you want.

In fact, that's a pretty low-cost, zero pharmacology, at least exogenous pharmacology, way to approach this whole thing. That's a way of evoking your own natural epinephrine. And it turns out also dopamine release. You could take a cold shower. You could do an ice bath or get into a cold circulating bath. We've done several episodes on the utility of cold for health and performance. You can find those episodes at hubermanlab.com. Also, the episode with my colleague at Stanford from the Biology Department, Dr. Craig Heller, lots of protocols, in particular in the episode on cold for health and performance that describe how best to use the cold shower or the ice bath or the circulating cold bath in order to evoke epinephrine and dopamine release.

The point is that the time in which you would want to do those protocols is after, ideally, immediately after your learning bout. Meaning when you're sitting down to learn new information or after trying to learn some new physical skill. Now, whether or not that's compatible with the other reasons you're doing deliberate cold exposure, and whether or not that's compatible with the other things you're doing, that depends on the contour of your lifestyle, your training, your academic goals, your learning goals, et cetera. But if your specific purpose is to enhance learning and memory, you want to spike adrenaline afterwards. And so what I'm telling you is you can do that with caffeine, you can do that with Alpha-GPC. You can do that with a combination of caffeine and Alpha-GPC, if you can do that safely.

Some of you I know are using other forms of pharmacology. I did a long episode all about ADHD. I have to just really declare my stance very clearly that I am not a fan. I am actually opposed to people using prescription drugs who are not prescribed those drugs in order to enhance alertness. I think there's a big addictive potential. There also is a potential to really disrupt one's own pharmacology around the dopaminergic system. However, some of you I know are prescribed things like Ritalin, Adderall, and modafinil and things of that sort in order to increase alertness and focus. So for those of you that are prescribed those things from a board-certified physician, you're going to have to decide if you're going to take them before trying to learn or after trying to learn. You also have to take into consideration that some of those drugs are very long acting, some are shorter acting, and time that according to what you're trying to learn and when.

So that's pharmacology. But as I've mentioned, there are the behavioral protocols. You can use cold, and cold is an excellent stimulus because first of all, it doesn't involve pharmacology. Second of all, you can generally access it at low to zero cost, especially the cold shower approach. And third, you can titrate it. You can start with warmer water. You can make it very, very cold. If that's your thing and you're able to tolerate that safely. You can make it moderately cold. How cold should it be in order to evoke adrenaline release? Well, it should be uncomfortably cold, but cold enough that you feel like you really want to get out, but can stay in safely. That's going to evoke adrenaline release. If it quickens your breathing, if it makes you go wide-eyed, that's increasing adrenaline release. In fact, those effects of going wide-eyed and quickening of the breathing and the challenges and thinking clearly, those are the direct effects of adrenaline on your brain and body.

And of course, there are other ways to increase adrenaline. You could go out for a hard run. You could do any number of things that would increase adrenaline in your body. Which things you choose is up to you. But from a very clear, solid grounding in research data, we can confidently say that spiking adrenaline after interacting with some material, physical or cognitive material that you're trying to learn, is going to be the best time to spike that adrenaline. Now, I realize that I'm being a bit redundant today, or perhaps a lot redundant in repeating over and over that the increase.

PART 1 OF 3 ENDS [00:32:04]

And in repeating over and over that the increase in epinephrine should occur either very late in an attempt to learn something, or immediately after an attempt to learn something. I also want to emphasize the general contour of pharmacologic effects and of behavioral tools to create adrenaline. What do I mean by that sentence? What I mean is that McGaugh and colleagues explored a huge number of different compounds and approaches, everything from the hand into the ice bath to injecting adrenaline, to caffeine, to drugs that block the effects of adrenaline and caffeine, drugs like muscimol and picrotoxin — please don't take those, these are drugs that reduce or enhance the amount of adrenaline. And the overall takeaway is that anything that increases adrenaline will increase learning and memory and will reduce the number of repetitions required to learn something, regardless of whether or not that something has an emotional intensity or not.

Provided that that spike in adrenaline occurs late in the learning or immediately after. And anything that reduces epinephrine and adrenaline will impair learning. And that's the key and novel piece of information that I'm adding now, which is if you're taking beta blockers, for instance, or if you're trying to learn something and it's not evoking much of an emotional response, and you're not using any pharmacology or other methods to enhance adrenaline release after learning that thing, well, you're not going to learn it very well. In fact, McGaugh and Cahill did beautiful experiments in humans looking at how much adrenaline is increased by varying the emotional intensity of different things that they were trying to get people to learn, or by changing the dosage of epinephrine, or by changing the amount of epinephrine blocker that they injected, lots and lots of studies. The key thing to take away from those studies is that for some people, adrenaline was increased 600% to 700%, so six to sevenfold over baseline in the amount of circulating epinephrine or adrenaline.

And keep in mind, sometimes that increase was due to the actual thing they were trying to learn being very emotional, positive or negative emotion, and sometimes it was because they were using a pharmacologic approach or the ice bath approach. I don't think they ever used a cold shower approach, but that would've been a very effective one, we can be sure. However, other people had a zero to 10% increase, so a very small increase in epinephrine. What we can confidently say on the basis of all those data is that the more epinephrine release, the better that people remembered the material over and over again. This was shown whether or not it was for cognitive material, so learning a language, learning a passage of words, learning mathematics, or whether or not it was for physical learning. I want to emphasize something about physical learning because I know a number of you are probably drinking a cup of coffee or having a cup of yerba maté or maybe even an energy drink and taking some Alpha-GPC or something before physical exercise.

I'm not saying that's a bad thing to do or that you wouldn't want to do that, but that's really to increase alertness. It won't enhance learning, at least not as well as doing those things after the physical exercise. Now, again, many of you, including myself, exercise for sake of the physical benefits of that exercise of cardiovascular or resistance training, but we're not really focused on learning and memory. So I emphasize this just so it's immensely clear to everybody, if you want to use those approaches of increasing adrenaline prior to or during physical training or cognitive work for that matter, be my guest, I think that's perfectly fine, provided that safe for you.

It's only by moving it to late or after the learning that you're really shifting the role of that adrenaline increase to enhancing memory specifically. And as a cautionary note, don't think that you can push this entire system to the extreme over and over again, or chronically, as we say, and get away with it.

In other words, you're not going to be able to take an Alpha-GPC and a double espresso, do your focused bout of work, cognitive or physical work, and then spike adrenaline again afterwards and remember that stuff even better, right? I'm not encouraging you, in fact, I'm discouraging you from chronically increasing adrenaline both during and after a given bout of work. If the goal is to learn, why do I say that? Well, work from McGaugh and Cahill and others has shown that it's not the absolute amount of adrenaline that you release in your brain and body that matters for enhancing memory. It's the amount of adrenaline that you release relative to the amount of adrenaline that was in your system just prior, in particular in the hour or two prior. So again, it's the delta as we say, it's the difference. So if you're going to chronically increase adrenaline, you're not going to learn as well.

The real key is to have adrenaline modestly low, perhaps even just as much as you need in order to be able to focus on something, pay attention to it, and then spike it afterwards. This is immensely important because while much of what we're talking about is actually a form of inducing a neurochemical acute stress, meaning a brief and rapid onset of stress, well chronic stress, the chronic elevation of epinephrine and cortisol, is actually detrimental to learning. And there's an entire category of literature, mainly from the work of the great, and sadly, the late Bruce McEwen from the Rockefeller University, and some of his scientific offspring like the great Robert Sapolsky, showing that chronic stress, chronic elevation of epinephrine actually inhibits learning and memory and also can inhibit immune system function. Whereas acute, right, sharp increases in adrenaline and cortisol actually can enhance learning, and indeed can enhance the immune system.

So if you really want to leverage this information, you might consider getting your brain and body into a very calm and yet alert state. So a high attentional state that will allow you to focus on what it is that you're trying to learn. We know focus is vital for encoding information and for triggering neuroplasticity, but remaining calm throughout that time, and then afterwards spiking adrenaline and allowing adrenaline to have these incredible effects on reducing the number of repetitions required to learn. So if you're like me, you're learning about this information, this beautiful work of McGaugh and Cahill and others, and thinking, "Wow, I should perhaps consider spiking my adrenaline in one form or another at the tail end or immediately following an attempt to learn something." And yet, we are not the first to have this conversation, nor were McGaugh and Cahill or any other researchers that I've discussed today.

The first to start using this technique, in fact, there is a beautiful review that was published just this year, May of 2022, in the journal Neuron, Cell Press journal, excellent journal, called "Mechanisms of memory under stress." And I just want to read to you the first opening paragraph of this review, which is, as the name suggests, all about memory and stress. So here I'm reading, and I quote, "In medieval times, communities threw young children in the river when they wanted them to remember important events. They believed that throwing a child in the water after witnessing historic proceedings would leave a lifelong memory for the events in the child."

And believe it or not, this is true. This is a practice that somehow people arrived at. I don't know if they were aware of what adrenaline was, probably not. But somehow in medieval times it was understood that spiking adrenaline, or creating a robust emotional experience after an experience that one hoped a child would learn, would encourage the child's nervous system, and they didn't even know what a nervous system was, but would encourage the brain and body of that child to remember those particular events.

Very counterintuitive, if you ask me. I would've thought that the kid would remember only being thrown into the river. My guess is that they remember that, but that they, the idea here anyway is that they also remember the things that preceded being thrown into the river. So both interesting and amusing and somewhat, I should say, thought-stimulating, really, that this is a practice that has been going on for many hundreds of years, and we are not the first to start thinking about using cold water as an adrenaline stimulus, nor are we the first to start thinking about using cold water-induced adrenaline as a way to enhance learning and memory. This has been happening since medieval times. So up until now, I've been talking about pretty broad contour of these experiments. I've been talking about the underlying pharmacology, the role of epinephrine and so forth.

I haven't really talked a lot about the underlying neural mechanisms, so I'm just going to take a minute or two and describe those for you because they are informative. We all have a brain structure called the amygdala. A lot of people think it's associated with fear, but it's actually associated with threat detection, and, more generally, and I should say more specifically, with detecting what sorts of events in the environment are novel and are linked to particular emotional states, both positive emotional states and negative emotional states. So the neurons in the amygdala are exquisitely good at figuring out, right, they don't have their own mind, but at detecting correlations between sensory events in the environment that trigger the release of adrenaline and what's going on in the brain. And because the amygdala is so extensively interconnected with other areas of the brain, it basically connects to everything and everything connects back to it.

The amygdala is in a position to strengthen particular connections in the brain very easily provided certain conditions are met, and those conditions are the ones we've been talking about up until now, emotional saliency that results in increases in epinephrine and cortisol, or circulating epinephrine and cortisol, being much higher than it was 10 minutes or 15 minutes before. And the net effect of the amygdala in this context is to take whatever patterns of neural activity preceded that increase in adrenaline and corticosteroid and strengthen those synapses that were involved in that neural activity. So the amygdala doesn't have knowledge; it's not a thinking area — it's a correlation detector, and it's correlating neurochemical states of the brain and body with different patterns of electrical activity in the brain. This is important because it really emphasizes the fact that both negative and positive emotional states, and the different but somewhat overlapping chemical states that they create, are the conditions, as we say, the endgates through which memory is laid down.

Endgates will be familiar to those of you who have done a bit of computer programming. An endgate is simply a condition in which you need one thing and another to happen in order for a third thing to happen. So you need epinephrine elevated and you need robust activity in a particular brain circuit if, in fact, that brain circuit is going to be strengthened; it's not sufficient to have one or the other. You need both, hence the name "endgate," and the amygdala is very good at establishing these endgate contingencies. It's also a very generic brain structure, in the sense that it doesn't really care what sorts of sensory events are involved provided they correlated in time with that increase in adrenaline and corticosteroid. This has a wonderful side and a kind of dark side. The dark side is that PTSD and traumas of various kinds often involve an increase in adrenaline because whatever it was that caused the PTSD was indeed very stressful, caused these big increases in these chemicals.

And because the amygdala is rather general in its functions, right, it's not tuned or designed in any kind of way to be specifically active in response to particular types of sensory events or perceptions, well, then what it means is that we can start to become afraid of entire city blocks where one bad thing happened, in a particular room of a particular building in a city block. We can become fearful of any place that contains a lot of people if something bad happened to us in a place that contained a lot of people. The amygdala is not so much of a splitter, as we say in science. We talk about lumpers and splitters. Lumpers are kind of generalizers, if that's even a word, and I think it is — someone will tell me one way or the other. And splitters are people that are ultraprecise and specific and nuanced about every little detail.

The amygdala is more of a lumper than a splitter when it comes to sensory events. Other areas of the brain only become active under very, very specific conditions, and only those conditions. And similarly, epinephrine is just a molecule. It's just a chemical that's circulating in our brain and body. There's no epinephrine specifically for a cold shower that is distinct from the epinephrine associated with a bad event, which is distinct from the epinephrine associated with a really exciting event that makes you really alert. Epinephrine is just a molecule, it's generic. And so these systems have a lot of overlap, and that can explain in large part why when good things happen in particular locations and in the company of particular people, we often generalize to large categories of people, places and things. And when negative things happen in particular circumstances, we often generalize about people, places, and things associated with that negative event.

So now I'd like to talk about other tools that you can leverage that have been shown in quality peer-reviewed studies to enhance learning and memory, and perhaps one of the most potent of those tools is exercise. There are numerous studies on this in both animal models and fortunately now also in humans, thanks to the beautiful work of people like Wendy Suzuki from New York University. Wendy's lab has identified how exercise works to enhance learning and memory, and other forms of cognition I should mention, as well as things that can augment, can enhance the effects of exercise on learning and memory and other forms of cognition. Wendy's going to be a guest on this podcast. It's actually the episode that follows this episode and includes a lot of material that we have not covered today, and she's an incredible scientist and has some incredible findings that I know everyone is going to find immensely useful.

In the meantime, I want to talk about some of the general effects of exercise on learning a memory that she's discovered and that other laboratories have discovered. If you recall, earlier I mentioned that learning and memory almost always involves the strengthening of particular synapses and neural circuits in the brain and not so much the increase in the number of neurons in the brain. There is one exception, however, and we now have both animal data and some human data to support the fact that cardiovascular exercise seems to increase what we call dentate gyrus neurogenesis. Neurogenesis is the creation of new neurons. The dentate gyrus is a subregion of the hippocampus that's involved in learning and memory of particular kinds, right? Certain types of events, in particular contextual learning, but some other things as well, sometimes involved in spatial learning. There's a lot of debate about exactly what the dentate gyrus does, but for sake of this discussion, and I think everyone in the neuroscience community would agree that the dentate gyrus is important for memory formation and consolidation.

The dentate gyrus does seem to be one region of the brain, certainly in the rodent brain, but more and more, it's seeming, also in the human brain where at least some new neurons are added throughout the lifespan. And as it turns out, that cardiovascular exercise can increase the proliferation of new neurons in this structure, and that those new neurons are important for the formation of certain types of new memories. There are wonderful data showing that if you use X-irradiation, which is a way to eliminate the formation of those new cells, or other tools and tricks to eliminate the formation of those cells, that you block the formation of certain kinds of learning and memory.

What does this mean? Well, there are a lot of reasons for the statement I'm about to make that extend far beyond neurogenesis in the hippocampus, learning and memory, but it's very clear that getting anywhere from 180, I should say a minimum of 180, to 200 minutes of so-called zone 2 cardiovascular exercise — so this is cardiovascular exercise that can be performed at a pretty steady state, which would allow you to just barely hold a conversation. So breathing hard, but not super hard. This isn't sprints or high-intensity-interval training. But doing that for 180 to 200 minutes per week total is, it appears, the minimum threshold for enhancing some of the longevity effects associated with improvements in cardiovascular fitness. And we believe that it is indirectly, I should say, indirectly through enhancements in cardiovascular fitness that there are improvements in hippocampal dentate gyrus neurogenesis. What does that mean? The improvements in cardiovascular function are indirectly impacting the ability of the dentate gyrus to create these new neurons. To my knowledge, there's no direct relationship between exercise and stimulating the production of new neurons in the brain.

It seems that it's the improvements in blood flow that also relate to improvements in things like lymphatic flow, the circulation of lymph fluid within the brain, that are enhancing neurogenesis, and that neurogenesis is, it appears, important. Now, in fairness to the landscape of neuroscience and my colleagues at Stanford and elsewhere, there is a lot of debate as to whether or not there is much, if any, neurogenesis in the adult human brain. But regardless, I think the data are quite clear that the 180 to 200 minutes minimum of cardiovascular exercise is going to be important for other health metrics. Now, it is clear that exercise can impact learning and memory through other nonneurogenesis, nonnew-neuron-type mechanisms. And one of the more exciting ones that has been studied over the years is this notion of hormones from bone traveling in the bloodstream to the brain and enhancing the function of the hippocampus.

The words hormones from bones is surprising to you. I'm here to tell you that, yes, indeed, your bones make hormones. We call these endocrine effects. So in biology, we hear about autocrine, paracrine, and endocrine, and those different terms refer to over what distance a given chemical has an effect on a cell. For instance, a cell can have an effect on itself, it can have an effect on immediately neighboring cells, or it can have an effect on both itself, immediately neighboring cells, and cells far, far away in the body. And that last example of a given chemical or substance having an effect on the cell that produced it plus neighboring cells, plus cells far away, is an endocrine effect. And a lot of hormones, not all, work in this fashion. Hence, why we sometimes hear about endocrine and hormone as kind of synonymous terms.

Your bones make chemicals that travel in the bloodstream and have these endocrine effects, so they're effectively acting as hormones, and one such chemical is something called osteocalcin. Now, these findings arrive to us through various labs, but one of the more important labs, for sake of this discussion today, is the laboratory of Eric Kandel at Columbia Medical School. Eric is now, I believe, in his mid to late nineties, still very sharp, and has studied learning and memory. It also turns out that he is an avid swimmer. Now, I happen to know that Eric swims anywhere from a half a mile to a mile a day. And again, this is anecdata, I'm not referring to the published data just yet, but he credits that exercise as one of the ways in which he keeps his brain sharp and has indeed kept his brain sharp for many, many decades. And as I mentioned before, he's well into his nineties, so pretty impressive. His laboratory has studied the effects of exercise on hippocampal function and memory, and other laboratories have done that as well.

And what they found is that cardiovascular exercise and perhaps other forms of exercise too, but mainly cardiovascular exercise, creates the release of osteocalcin from the bones that travels to the brain and to subregions of the hippocampus and encourages the electrical activity and the formation and maintenance of connections within the hippocampus, and keeps the hippocampus functioning well in order to lay down new memories. Now, osteocalcin has a lot of effects besides just improving the function of the hippocampus. Osteocalcin is involved in bone growth itself; it's involved in hormone regulation — in fact, there's really nice evidence that it can regulate testosterone and estrogen production by the testes and ovaries, and a bunch of other effects in other organs of the body, because again, it's acting in this endocrine manner. It's arriving from bone to a lot of different organs to have effects.

Load-bearing exercise in particular turns out to be important for inducing the release of osteocalcin, and when you think about this, it makes sense. A nervous system exists for a lot of reasons, to sense, perceive, et cetera. You've got taste, you've got smell, got hearing, But the vast majority of brain real estate, especially in humans, is dedicated to two things. One, vision — we have an enormous amount of brain real estate devoted to vision, certainly compared to other senses. And to movement, the ability to generate fine movements to the body like the digits, or to wink one eye, or to tilt your head in a particular way, or move your lips, or move your face, and do all sorts of different things in a very nuanced and detailed way.

So much of our brain real estate is devoted to movement that it's been hypothesized for more than a half century, but especially in recent years as we've learned more about the function of the brain at a really detailed circuit level, that the relationship between the brain and body and the maintenance and perhaps even the improvement of neural circuitry in the brain depends on our body movements and the signal from the body that our brain is still moving.

So think about that. How would your brain know if your body was moving regularly, and how would it know how much it was moving? How would it know which limbs it was moving? Well, you could say if the heart rate is increased, then the blood flow will be increased, and then the brain will know. But how does your brain know that it's increased blood flow due to movement and not to, for instance, just stress, right? Maybe you actually can't move and you're very stressed about that. And so the increased blood flow is simply a consequence of increased stress. The fact that osteocalcin is released from bone and in particular can be released in response to load-bearing exercise. So this would be running; again, weightlifting hasn't been tested directly, but one would imagine anything that involves jumping and landing or weight lifting or body weight movements and things of that sort.

That's a signal to release osteocalcin — and we know that signal occurs — that is directly reflective of the fact that the body was moving, and moving in particular ways. In fact, you could imagine that big bones, like your femur, are going to release more osteocalcin or be in a position to release more osteocalcin than fine movements, like the movements of the digits. And this idea that the body is constantly signaling to the brain about the status of the body and the varying needs of the brain to update its brain circuitry is a really attractive idea that fits entirely with the biology of exercise osteocalcin and hippocampal function. I do want to mention that I'm not the first to raise this hypothesis. This hypothesis actually was discussed in a fair amount of detail by John Ratey, who's a professor in Harvard Medical School. He wrote a book called "Spark," which was one of the early books, at least from an academic, about brain plasticity and the relationship between exercise and movement and plasticity.

And John, who I have the good fortune to know, has described to me experiments, or I should say observations of species, of ocean-dwelling animals that have, at least for the early part of their life, a very robust and complicated nervous system. But then these particular animals are in the habit of plopping down onto a rock, they find a kind of a safe, comfy space, and they actually stick to that rock, and they don't move anymore for a certain portion, I should say the late portion of their life. And it is at the transition between moving a lot and being stationary that those animals actually digest their own brain. They literally metabolize a good portion of their nervous system because they decide, "Hmm, don't need this anymore," and gobble it up, use it for its nutritional value, and then sit there like a moron version of themselves with a limited amount of brain tissue because they don't need to move anymore.

Now, I certainly don't want to give the message that just moving, just exercise is sufficient to keep the neural architecture of your brain healthy, young, and able to learn. While that might be true, it's also important to actually engage in attempts to learn new material, either physical material, so new types of movements and skills and/or new types of cognitive information: languages, mathematics, history, current events, all sorts of things that involve your brain.

Nonetheless, it's clear that physical movement and cognitive ability and the potential to enhance cognitive ability and the ability to learn new physical skills are intimately connected. And osteocalcin appears to be at least one way in which that brain-body relationship is established and maintained. So given the information about osteocalcin and movement and given the information about spiking adrenaline late or after a period of attempt to learn, you might be asking, "When is the best time to exercise?"

Now, unfortunately, that has not been addressed in a lot of varying detail where every sort of variation on the theme has been carried out. And yet Wendy Suzuki's lab has done really beautiful experiments where they have people exercise, generally it was in the morning, but at other periods of the day as well. And what they find is that at least as late as two hours after that exercise, there's an enhancement in learning and memory. Now, I want to be clear, we don't know whether or not that exercise led to big increases in adrenaline. It may be that those forms of exercise were modest enough or didn't challenge people enough that they merely got a lot of blood flow going, and that the improvements in learning and memory were related to blood flow and, we presume, increases in osteocalcin. However, you could imagine a couple of different logical protocols based on what we've talked about.

Let's say you were going to do a form of exercise that was going to spike adrenaline a lot. So this would be exercise that really challenges your system and forces you to push through a burn, right? So here I'm mainly thinking about cardiovascular exercise, but it could even be yoga, it could be resistance training. If it's going to give you a big spike in adrenaline, it's going to take some serious effort. Then logically speaking, you would want to place that after a learning bout in order to increase learning and memory. However, if you are using the exercise in order to enhance blood flow and to enhance osteocalcin release in efforts to augment the function of your hippocampus, I think it stands to reason that doing that exercise sometime within the hour to three hours preceding an attempt to learn makes a lot of sense. And there I'm basing it on the human data from Wendy Suzuki's lab.

I'm basing it on the studies from Eric Kandel and from others labs. Again, right now, there hasn't been an evaluation of a lot of different protocols to arrive at the peer-reviewed laboratory super protocol. However, since what we're talking about is using activities like exercise that most of us, probably, perhaps all of us, should be doing regularly anyway, and I do believe most, if not all of us should probably regularly be trying to learn and keep our brain functioning well and acquire new knowledge because it's just a wonderful part of life. And there is evidence that that actually can keep your brain young, so to speak. Well, then exercising either before or after a learning bout makes a lot of sense, with the emphasis on after a learning bout if the form of exercise spikes a lot of adrenaline, for all the reasons we talked about before.

Okay, so we've talked about two major categories of protocols to improve memory that are grounded in quality, peer-reviewed science, and there is yet another third protocol that we'll talk about in a few minutes. But before we do that, I want to briefly touch on an aspect of memory. In fact, two aspects of memory that I get a lot of questions about.

The first one is photographic memory. To be clear, there are people out there who have a true photographic memory. They can look at a page of text, they can scan it with their eyes, and they can essentially commit that to memory with very little if any effort. While it might seem that having a photographic memory is a very attractive skill to have, I should caution you against believing that because it turns out that people with true photographic memory are often very challenged at remembering things that they hear and oftentimes are not so good at learning physical skills. It's not always the case, but often that's the case. So be careful what you wish for. If you do have a photographic memory, there are certain professions that lend themselves particularly well to you. And indeed, a lot of people with photographic memory have to find a profession and have to move through life in a way that is in concert with that photographic memory. So again, it's a super ability, it's a hyper ability, and yet it's not necessarily one that is desirable for most people.

There's also this category of what are called super recognizers. These people are, I should mention, highly employable by government agencies. These are people that have an absolutely astonishing ability to recognize faces and to match faces to templates. They can look at a photograph of, say, somebody on a most-wanted list, and then they can look at video footage of, let's say, an airport or a mall or a city street at fairly low resolution, and they can spot the person whose face matches that photograph that they looked at, even if that video or other footage is of people, profiles, or even the tops of their heads and just a portion of their forehead. These people have just an incredible ability to recognize faces and to template match. And again, these people often will take jobs with agencies where this sort of thing is important.

Some of you out there probably are super recognizers and may or may not notice it. If you ever had the experience of watching a movie and thought to yourself, "Wow, her mouth looks so much like my cousin's mouth," or you look at a character in a movie or a television show and you think how they look almost like the younger sister of so-and-so, well, then it's very likely that you have this, or at least a mild form of the super-recognizer ability that is not memory per se. That is the hyperfunctioning of an area of the brain that we call the fusiform gyrus.

The fusiform gyrus is literally a face recognition area and a face template matching area, and it harbors neurons that respond to faces generally. So as humans and other nonhuman primates care a lot about faces and their emotional content, and the identity of faces is super important to us for all the kinds of reasons that are probably obvious — knowing who's friend, who's foe, who do you know well, who's famous, who's not famous, et cetera. That is not memory per se. And yet, if you're a super recognizer, or I guess we could call it-

PART 2 OF 3 ENDS [01:04:04]

And yet if you're a super recognizer, or I guess we could call it a moderate face recognizer, or not very good at recognizing faces, because indeed there are some people that are face blind, they don't actually recognize people when they walk in the room. I used to work with somebody like this. I'd walk into his office and he'd say, "Are you Rich or are you Andrew?" I'd say, "Well, am I rich, rich? Like wealth rich? No." And he'd say, "No. Are you Richard or are you Andrew?" And I'd say, "I'm Andrew. We know each other really well." And he'd say, "Oh, I'm sorry I'm kind of face blind." And it actually tended to be better or worse depending on how much he was working. Ironically, the more rested he was, the more face blind he would become. So it wasn't a sleep deprivation thing.

That exists, that's out there. There's the full constellation of people's ability to recognize faces. That's not really memory, and yet visual function is a profoundly powerful way in which we can enhance our memory. So whether or not you're a super recognizer of faces, whether or not you are face blind or anything in between, next I'm going to tell you about a study which points out the immense value of visual images for laying down memories. And you can leverage this information, and this involves both the taking of photographs, something that's actually quite easily done these days with your phone, as well as your ability to take mental photographs, by literally snapping your eyelids shut. So I just briefly want to describe this paper because it provides a tool that you can leverage in your attempt to learn and remember things better. The title of this paper is "Photographic memory: The effects of our volitional photo taking on memory for visual and auditory aspects of an experience."

I really like this paper because it refers to photographic memory, not in the context of photographic memory that we normally hear about, where people are truly photographic, look at a page and somehow absorb all that information and commit it to memory. But rather the use of camera photographs, or the use of mental camera photographs. Literally looking at something and deciding, blink, and snapping a, so to speak, snapping a snapshot of whatever it is that you were looking at, and remembering the content. The reason I like this paper and the reason I'm attracted to this issue of mental snapshots is this is something that I've been doing since I was a kid. I don't know why I started doing it, but every once in a while, I would say maybe twice a year, I would look at something and decide to just snap a mental snapshot of it.

And I've maintained very clear memories of those visual scenes. Two years ago I was in an Uber, and I looked out the window and it was a street scene. I was actually in New York at the time, and I decided, for reasons that are still unclear to me, to take a mental snapshot of this city street image, even though nothing interesting in particular was happening. And I do recall that there was a guy wearing a yellow shirt, walking, there was some construction, et cetera. I can still see that image in my mind's eye because I took this mental snapshot. This paper addresses whether or not this mental snapshotting thing is real, and, this is something that I think a lot of people will resonate with, whether or not the constant taking of pictures on our phones, or with other devices, is either improving or degrading our memory.

You could imagine an argument for both. A lot of people are taking pictures that they never look at again. And so in a sense, they're outsourcing their visual memory of events into their phone or to some other device, and they're not ever accessing the actual imaging, and they're not looking at it, right? You're not printing out those photos, you're not scanning through your phone again. Sometimes you might do that, but most of the time people don't. Most of the photographs that people are taking, they're not revisiting again. So the motivation for this study was that previous experiments had shown that if people take photos of a scene, or a person, or an object, that they are actually less good at remembering the details of that scene or object, et cetera.

This study challenged that idea and raised the hypothesis that if people are allowed to choose what they take photos of, that taking photos ... again, this is with a camera, not mental snapshotting ... that taking those photos would actually enhance their memory for those objects, those places, those people, and, in fact, details of those objects, places, and people. And indeed that's what they found. So in contrast to previous studies where people had been more or less told, take photos of these following objects, or these following people, or these following places, and then they were given a memory test at some point later, in this study, people were given volitional control, right? They were given agency in making the decision of what to take photos of. And I'll just summarize the results; we'll provide a link to this study. Should say that some of the stuff that they tested was actually pretty challenging. Some of them were pottery and other forms of ceramics that are of the sort that you see if you go to a big museum in a big city.

And if you've ever done that and you see all the different objects, there are a lot of details in those objects, and a lot of those objects look a lot alike. And so some will have two handles, some will have one handle, the position of the handles, how broad or narrow these things are. A lot of this is pretty detailed stuff. They also took photos of other things. So basically what they found was that if people take pictures of things, and they choose which things they are taking pictures of, right? It's up to them. It's volitional. That there's enhanced memory for those objects later on. However, it degraded their ability to remember auditory information. So what this means is that when we take a picture of something, or a person, we are stamping down a visual memory of that thing, and that makes sense. It's a photograph after all.

But we are actually inhibiting our ability to remember the auditory, the sound component of that visual scene, or what the person was saying. Very interesting, and points to the fact that the visual system can outcompete the auditory system, at least in terms of how the hippocampus is encoding this information. The other finding I find particularly interesting within this study is that it didn't matter whether or not they ever looked at the photos again. So they actually had people take photos, or not take photos, of different objects. They had some people keep their photos and they had other people delete their photos. And it turns out that whether or not people kept the photos or deleted those photos had no bearing on whether or not they were better or worse at remembering things. They were always better at remembering them as compared to not taking photos of them. What does this mean?

It means if you really want to remember something or somebody, take a photo of that thing or person. Pay attention while you take the photo. But it doesn't really matter if you look at the photo again. Somehow the process of taking that photo, probably looking at it in a camera — typically, we'd say through the view finder, now because of digital cameras, on the screen on the back of that camera, or on your phone — that framing up of the photograph stamps down a visual image in your mind that is more robust at serving a memory than had you just looked at that thing with your own eyes.

Very interesting, and it raises all sorts of questions for me about whether or not it's because you're framing up a small aperture, or a small portion of the visual scene. That's one logical interpretation, although they didn't test that. I should also say that they found that whether or not you looked at a photo that you took, or whether or not you deleted it and never looked at it again, didn't just enhance visual memory or the memory for the visual components of that image, but it always reduced your ability to remember sounds associated with that experience. So that's interesting. And then last but not least, and perhaps most interesting, at least to me, was the fact that you didn't even need a camera to see this effect.

If subjects looked at something and took a mental photograph of that thing, it enhanced their visual memory of that thing significantly more than had they not taken a mental picture. In fact, it increased their memory of that thing almost as much as taking an actual photograph with an actual camera. And the reason I find this so interesting is that a lot of what we try and learn is visual, and for a lot of people the ability to learn visual information feels challenging. And we'll look at something, and we'll try and create some detailed understanding of it, we'll try and understand the relationships between things in that scene. It does appear, based on the study, that the mere decision to take a mental snapshot like, "Okay, I'm going to blink my eyelids and I'm going to take a snapshot of whatever it is I see," can actually stamp down a visual memory, much in the same way that a camera can stamp down a visual memory. Of course, through vastly distinct mechanisms.

No discussion of memory would be complete without a discussion of the ever intriguing phenomenon known as déjà vu. This sense that we've experienced something, before, but we can't quite put our finger on it. Where and when did it happen? Or the sense that we've been someplace before, or that we are in a familiar state, or place, or context of some kind. Now I've talked about this on the podcast before, at least I think I have. And the way this works has been defined largely by the wonderful work of Susumu Tonegawa at Massachusetts Institute of Technology, MIT. Susumu collected a Nobel Prize, quite appropriately, for his beautiful work on immunology. And he's also a highly accomplished neuroscientist who studies memory and learning and déjà vu. And I should also mention the beautiful work of Mark Mayford at the Scripps Institute and UC San Diego, beautiful work on this notion of déjà vu.

Here's what they discovered. They evaluated the patterns of neural firing in the hippocampus as subjects learn new things, okay? So neuron A fires, then neuron B fires, then neuron C fires, in a particular sequence. Again, the firing of neurons in a particular sequence, like the playing of keys on a piano in a particular sequence, leads to a particular song on the piano, and leads to a particular memory of an experience within the brain. They then used some molecular tools and tricks to label and capture those neurons such that they could go back later and activate those neurons in either the same sequence or in a different sequence to the one that occurred during the formation of the memory.

And to make a long story short and to summarize, multiple papers published in incredibly high-tier journals, journals like Nature and Science, which are extremely stringent, found that whether or not those particular neurons were played in the precise sequence that happened when they encoded the memory, or whether or not those neurons were played in a different sequence, or even if those neurons were played, activated that is, all at once with no temporal sequence, all firing in concert all at once, evoked the same behavior and in some sense the same memory. So at a neural circuit level, this is déjà vu. This is a different pattern of firing of neurons in the brain leading to the same sense of what happened, leading to a particular emotional state or behavior.

Now, whether or not this same sort of phenomenon occurs when you're walking down the street, and suddenly you feel as if, "Wow, I feel like I've been here before." You meet someone and you feel like, "Wow, I feel like I know you, I feel like there's some familiarity here that I can't quite put my finger on," we don't know for sure that that's what's happening. But this is the most mechanistic and logical explanation for what has for many decades, if not hundreds of years, been described as déjà vu. So for those of you that experience déjà vu often, just know that this reflects a normal pattern of encoding experiences and events within your hippocampus.

I'm not aware of any pathological situations where the presence of déjà vu inhibits daily life. Some people like the sensation of déjà vu, other people don't. Almost everybody, however, describes it as somewhat eerie. This idea that even though you're in a very different place, even though you're interacting with a very different person, that you could somehow feel as if this has happened before. And just realize this: that your hippocampus, while it is exquisitely good at encoding new types of perceptions, new experiences, new emotions, new contingencies and relationships of life events, it is not infinitely large, nor does it have an infinite bucket full of different options of different sequences for those neurons to play. So in a lot of ways it makes perfect sense that sometimes we would feel as if a given experience had happened previously. I'd like to cover one additional tool that you can use to improve learning and memory.

And I should mention this is a particularly powerful one, and it's one that I'm definitely going to employ myself. This is based on a paper from none other than Wendy Suzuki at New York University. We've talked about her a little bit earlier, and again, she's going to be on the podcast in our next episode and is just an incredible researcher. I've known Wendy for a number of years, and it's only in the last, I would say, five or six years that she's really shifted her laboratory toward generating protocols that human beings can use. And she's putting that to great effect, great positive effect, I should say, publishing papers of the sort that I'm about to describe. But also incorporating some of these tools and protocols into the learning curriculum, and the lifestyle curriculum, of students at NYU, which I think is a terrific initiative. So you don't need to be an NYU student in order to benefit from her work.

I'm going to tell you about some of that work now, and she'll tell you about this much more in the episode that follows this one. The title of this paper will tell you a lot about where we're going. The title is "Brief daily meditation enhances attention, memory, mood and emotional regulation in non-experienced meditators." If ever there was an incentive to meditate, it is the data contained within this paper. I want to briefly describe the study, and then I also want to emphasize that when you meditate is absolutely critical. I'll talk about that just at the end. This is a study that involved subjects aged 18 to 45, none of whom were experienced meditators prior to this study. There were two general groups in this study. One group did a 13-minute-long meditation, and this meditation was a fairly conventional meditation. They would sit or lie down, they would do somewhat of a body scan, evaluating, for instance, how tense or relaxed they felt throughout their body, and they would focus on their breathing, trying to bring their attention back to their breathing and to the state of their body as the meditation progressed.

The other group, which we can call the control group, listened to, of all things, a podcast. They did not listen to this podcast. They listened to "Radiolab," which is a popular podcast, for an equivalent amount of time, but they were not instructed to do any kind of body scan or pay attention to their breathing. Every subject in the study either meditated daily or listened to an equivalent duration podcast daily for a period of eight weeks. And the experimenters measured a large number of things, of variables, as we say. They looked at measures of emotion regulation. They actually measured cortisol, a stress hormone. They measured, as the title suggests, attention and memory, and so forth. And the basic takeaway of the study is that eight weeks, but not four weeks, of this daily 13-minute-a-day meditation had a significant effect in improving attention, memory, mood and emotion regulation.

I find this study to be very interesting, and, in fact, important, because most of us have heard about the positive effects of meditation on things like stress reduction, or on things such as improving sleep. And I want to come back to sleep in a few moments, because it turns out to be a very important feature of this study. This particular study I like so much because they used a really broad array of measurements for cognitive function. Things like the Wisconsin Card Sorting Task. I'm not going to go into this. Things like the Stroop Task. And they also, as I mentioned, measured cortisol and many other things, including, not surprisingly, memory and people's ability to remember certain types of information — in fact, varied types of information. And the basic takeaway was, again, that you could get really robust improvements in learning and memory, mood and attention from just 13 minutes a day of meditation.

Now there's an important twist in this study that I want to emphasize. If you read into the discussion of this study, it's mentioned that somehow meditation did not improve, but actually impaired, sleep quality compared to the control subjects. You might think, "Wow, why would that be?" I mean, meditation is supposed to reduce our stress; stress is supposed to inhibit sleep, and therefore why would sleep get worse? Well, what's interesting is the time of day when most of these subjects tended to do their meditation. Most of the subjects in this study did their meditation late in the day. This is often the case in experiments. I know this because we run experiments with human subjects in my laboratory, and people are paid some amount of money in order to participate, or they're given something as compensation for being in the study. But oftentimes the meditation, or in the case of my lab, the respiration work, or other kinds of things that they're assigned to do are not their top-top priority, and we understand this.

But in this study, the majority of subjects — here I'm reading — completed their meditation sessions from somewhere between 8:00 and 11:00 p.m. and sometimes even between 12:00 and 3:00 a.m. I think there probably were a lot of college students enrolled in this study, and their hours often are late shifted. That impaired sleep. And this raises a bigger theme that I think is important. Many times before on this podcast, and certainly in the episode on mastering sleep, and conquering or mastering stress, those episodes we talked about the value, again, of these non-sleep deep rest protocols, NSDR, for reducing the activity of your sympathetic nervous system. The alertness, so-called stress arm, of your autonomic nervous system that makes you feel really alert, and NSDR is superb for reducing your level of alertness, increasing your level of calmness, and putting you into a so-called more parasympathetic relaxed state.

Meditation does that too, but it also increases attention. If you think about meditation, meditation involves focusing on your breath, and constantly focusing back on your breath, and trying to avoid the distraction of things you're thinking, or things that you're hearing, and coming so-called back to your body, back to your breath. So meditation actually has a high attentional load. It requires a lot of prefrontal cortical activity that's involved in attention, which then logically relates to one of the outcomes of this study, which is that attention abilities improved in daily meditators. It also points out that increasing the level of attention and the activity of your prefrontal cortex may — and I want to emphasize may, because here, I'm speculating about the underlying mechanism — inhibit your ability to fall asleep.

So while we have meditation, on the one hand, that does tend to put us into a calm state, but it is a calm, very focused state; in fact, attention and focus are inherent to most forms of meditation. Non-sleep deep rest such as yoga nidra, as some of you know it to be, or NSDR. There's a terrific NSDR script that's available free online that's put out by Madefor, so you can go to YouTube: "NSDR Madefor." You can also just do a search for NSDR; there are a number of these available out there, again at no cost. Those NSDR protocols tend to put people into a state of deep relaxation but also very low attention, and we have to assume very low activation of the prefrontal cortex. So the takeaways from the study are severalfold. First of all, that daily meditation of 13 minutes can enhance your ability to pay attention and to learn. It can truly enhance memory. However, you need to do that for at least eight weeks in order to start to see the effects to occur.

And we have to presume that you have to continue those meditation training sessions. In fact, they found that if people only did four weeks of meditation, these effects didn't show up. Now, eight weeks might seem like a long time, but I think that 13 minutes a day is not actually that big of a time commitment. And the results of this study certainly incentivized me to start adopting a ... I'm going for 15 minutes a day now. I've been an on-and-off meditator for a number of years. I've been pretty good about it lately, but I confess I've been doing far shorter meditations of anywhere from three to five, or maybe 10 minutes. I'm going to ramp that up to 15 minutes a day. And I'm doing that specifically to try and access these improvements in cognitive ability, and our abilities to learn. Also, based on the data in this paper, I'm going to do those meditation sessions either early in the day, such as immediately after waking, or close to it. So I might get my sunshine first. I'm, as you all know, very big on getting sunlight in the eyes early in the day, as much as one can, and as early as one can, once the sun is out. But certainly doing it early in the day and not past 5:00 p.m. or so, in order to make sure that I don't inhibit sleep. Because I think this result that they describe of meditation inhibiting quality sleep compared to controls is an important one to pay attention to, no pun intended.

Today we covered a lot of aspects of memory and how to improve your memory. We talked about the different forms of memory, and we talked about some of the underlying neural circuitry of memory formation. And we talked about how the emotional saliency and intensity of what you're trying to learn has a profound impact on whether or not you learn in response to some sort of experience.

Whether or not that experience is reading, or mathematics, or music, or language, or a physical skill, it doesn't matter. The more intense of an emotional state that you're in the period immediately following that learning, the more likely you are to remember whatever it is that you're trying to learn. And we talked about the neurochemicals that explain that effect, about epinephrine, and corticosterones like cortisol, and how adjusting the timing of those is so key to enhancing your memory. And we talked about the different ways to enhance those chemicals. Everything ranging from cold water to pharmacology, and even just adjusting the emotional state within your mind in order to stamp down and remember experiences better. We also talked about how to leverage exercise, in particular load-bearing exercise, in order to evoke the release of hormones like osteocalcin, which can travel from your bones to your brain and enhance your ability to learn.

And we talked about a new form of photographic memory, not the traditional type of photographic memory in which people can remember everything they look at very easily, but rather taking mental snapshots of things that you see. Again, emphasizing that that will create a better memory of what you see when you take that mental snapshot, but will actually reduce your memory for the things that you hear at that moment. And we discussed the really exciting data looking at how particular meditation protocols can enhance memory, but also attention and mood. However, if done too late in the day, it can actually disrupt sleep precisely because those meditation protocols can enhance attention. Now, I know that many of you are interested in neurochemicals that can enhance learning and memory, and I intend to cover those in deep detail in a future episode. However, for the sake of what was discussed today, please understand that any number of different neurochemicals can evoke or can increase the amount of adrenaline that's circulating in your brain and body.

And it's less important how one accesses that increase in adrenaline, right? Again, this can be done through behavioral protocols or through pharmacology. Assuming that those behavioral protocols and pharmacology are safe for you, it really doesn't matter how you evoke the adrenaline release, because remember, adrenaline is the final common pathway by which particular experiences, particular perceptions are stamped into memory, which answers our very first question raised at the beginning of the episode. Which is, why do we remember anything at all, right? That was the question that we raised. Why is it that from morning till night and throughout your entire life, you have tons of sensory experience, tons of perceptions? Why is it that some are remembered and others are not? While I would never want to distill an important question such as that down to a one-molecule type of answer, I think we can confidently say, based on the vast amount of animal and human research data, that epinephrine/adrenaline and some of the other chemicals that it acts with in concert is, in fact, the way that we remember particular events, and not all events.

If you're learning from and/or enjoying this podcast, please subscribe to our YouTube channel. That's a terrific zero-cost way to support us. In addition, please subscribe to our podcast on Spotify and on Apple, and now on both Spotify and Apple you can leave us up to a five-star review. Please also leave us comments and feedback in the comments section on our YouTube channel. You can also suggest future guests that you'd like us to cover. We do read all those comments. Please also check out the sponsors mentioned at the beginning of today's podcast. That's a terrific, perhaps the best way to support this podcast. We also have a Patreon, it's patreon.com/andrewhuberman, and there you can support this podcast at any level that you like. During today's episode, and on many previous episodes of the Huberman Lab podcast, we discussed supplements. While supplements aren't necessary for everybody, many people derive tremendous benefit from them for things like enhancing sleep and focus, and indeed for learning and memory.

For that reason, the Huberman Lab podcast is now partnered with Momentous Supplements. The reason we partnered with Momentous is severalfold. First of all, we wanted to have one location where people could go to access single ingredient, high-quality versions of the supplements that we were discussing on this podcast. This is a critical issue. A lot of supplement companies out there sell excellent supplements, but they combine different ingredients into different formulations, which make it very hard to figure out exactly what works for you, and to arrive at the minimal effective dose of the various compounds that are best for you, which we think is extremely important. And that's certainly the most scientific way or rigorous way to approach any kind of supplementation regimen. So Momentous has made these single-ingredient formulations on the basis of what we suggested to them, and I'm happy to say they also ship internationally.

So whether or not you're in the U.S. or abroad, they'll ship to you. If you'd like to see the supplements recommended on the Huberman Lab podcast, you can go to livemomentous.com/huberman. They've started to assemble the supplements that we've talked about on the podcast, and in the upcoming weeks, they will be adding many more supplements, such that in a brief period of time, most if not all of the compounds that are discussed on this podcast will be there. Again, in single-ingredient, extremely high-quality formulations that you can use to arrive at the best supplement protocols for you. We also include behavioral protocols that can be combined with supplementation protocols in order to deliver the maximum effect. Once again, that's livemomentous.com/huberman. And if you're not already following us on Twitter and Instagram, it's Huberman Lab on both Twitter and Instagram.

There I describe science and science-related tools, some of which overlap with the content of the Huberman Lab podcast, but much of which is distinct from the content of the Huberman Lab podcast. We also have a newsletter called the Huberman Lab Neural Network. That newsletter provides summary protocols and information from our various podcast episodes. It does not cost anything to sign up. You can go to hubermanlab.com, go to the menu and click on newsletter. You just provide your email, and I should point out, we do not share your email with anyone else. We have a very clear privacy policy that you can read there, and that newsletter comes out about once a month. You can also see some sample newsletters, things like the "Toolkit for Sleep," or for neuroplasticity, and for various other topics covered on the Huberman Lab podcast.

Once again, thank you for joining me today to discuss the neurobiology of learning and memory and how to improve your memory using science-based tools. And last but certainly not least, thank you for your interest in science.

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ScienceDaily

Study shows stronger brain activity after writing on paper than on tablet or smartphone

Unique, complex information in analog methods likely gives brain more details to trigger memory.

A study of Japanese university students and recent graduates has revealed that writing on physical paper can lead to more brain activity when remembering the information an hour later. Researchers say that the unique, complex, spatial and tactile information associated with writing by hand on physical paper is likely what leads to improved memory.

"Actually, paper is more advanced and useful compared to electronic documents because paper contains more one-of-a-kind information for stronger memory recall," said Professor Kuniyoshi L. Sakai, a neuroscientist at the University of Tokyo and corresponding author of the research recently published in Frontiers in Behavioral Neuroscience . The research was completed with collaborators from the NTT Data Institute of Management Consulting.

Contrary to the popular belief that digital tools increase efficiency, volunteers who used paper completed the note-taking task about 25% faster than those who used digital tablets or smartphones.

Although volunteers wrote by hand both with pen and paper or stylus and digital tablet, researchers say paper notebooks contain more complex spatial information than digital paper. Physical paper allows for tangible permanence, irregular strokes, and uneven shape, like folded corners. In contrast, digital paper is uniform, has no fixed position when scrolling, and disappears when you close the app.

"Our take-home message is to use paper notebooks for information we need to learn or memorize," said Sakai.

In the study, a total of 48 volunteers read a fictional conversation between characters discussing their plans for two months in the near future, including 14 different class times, assignment due dates and personal appointments. Researchers performed pre-test analyses to ensure that the volunteers, all 18-29 years old and recruited from university campuses or NTT offices, were equally sorted into three groups based on memory skills, personal preference for digital or analog methods, gender, age and other aspects.

Volunteers then recorded the fictional schedule using a paper datebook and pen, a calendar app on a digital tablet and a stylus, or a calendar app on a large smartphone and a touch-screen keyboard. There was no time limit and volunteers were asked to record the fictional events in the same way as they would for their real-life schedules, without spending extra time to memorize the schedule.

After one hour, including a break and an interference task to distract them from thinking about the calendar, volunteers answered a range of simple (When is the assignment due?) and complex (Which is the earlier due date for the assignments?) multiple choice questions to test their memory of the schedule. While they completed the test, volunteers were inside a magnetic resonance imaging (MRI) scanner, which measures blood flow around the brain. This is a technique called functional MRI (fMRI), and increased blood flow observed in a specific region of the brain is a sign of increased neuronal activity in that area.

Participants who used a paper datebook filled in the calendar within about 11 minutes. Tablet users took 14 minutes and smartphone users took about 16 minutes. Volunteers who used analog methods in their personal life were just as slow at using the devices as volunteers who regularly use digital tools, so researchers are confident that the difference in speed was related to memorization or associated encoding in the brain, not just differences in the habitual use of the tools.

Volunteers who used analog methods scored better than other volunteers only on simple test questions. However, researchers say that the brain activation data revealed significant differences.

Volunteers who used paper had more brain activity in areas associated with language, imaginary visualization, and in the hippocampus -- an area known to be important for memory and navigation. Researchers say that the activation of the hippocampus indicates that analog methods contain richer spatial details that can be recalled and navigated in the mind's eye.

"Digital tools have uniform scrolling up and down and standardized arrangement of text and picture size, like on a webpage. But if you remember a physical textbook printed on paper, you can close your eyes and visualize the photo one-third of the way down on the left-side page, as well as the notes you added in the bottom margin," Sakai explained.

Researchers say that personalizing digital documents by highlighting, underlining, circling, drawing arrows, handwriting color-coded notes in the margins, adding virtual sticky notes, or other types of unique mark-ups can mimic analog-style spatial enrichment that may enhance memory.

Although they have no data from younger volunteers, researchers suspect that the difference in brain activation between analog and digital methods is likely to be stronger in younger people.

"High school students' brains are still developing and are so much more sensitive than adult brains," said Sakai.

Although the current research focused on learning and memorization, the researchers encourage using paper for creative pursuits as well.

"It is reasonable that one's creativity will likely become more fruitful if prior knowledge is stored with stronger learning and more precisely retrieved from memory. For art, composing music, or other creative works, I would emphasize the use of paper instead of digital methods," said Sakai.

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Materials provided by University of Tokyo . Note: Content may be edited for style and length.

Journal Reference :

  • Keita Umejima, Takuya Ibaraki, Takahiro Yamazaki, Kuniyoshi L. Sakai. Paper Notebooks vs. Mobile Devices: Brain Activation Differences During Memory Retrieval . Frontiers in Behavioral Neuroscience , 2021; 15 DOI: 10.3389/fnbeh.2021.634158

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Learning and memory

Anna-katharine brem.

1 Berenson-Allen Center for Noninvasive Brain Stimulation, Division of Cognitive Neurology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

ALVARO PASCUAL-LEONE

2 Institut Guttman de Neurorehabilitació, Universitat Autonoma, Barcelona, Spain

INTRODUCTION

A fairly large number of studies to date have investigated the nature of learning and memory processes in brain-injured and healthy subjects with noninvasive brain stimulation (NBS) methods. NBS techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), can alter brain activity in targeted cortical areas and distributed brain networks. The effects depend on the stimulation parameters. TMS and tDCS can be used to interfere with ongoing brain activity (“virtual lesion”) and thus help to characterize brain–behavior relations, give information about the chronometry of cognitive processes, and reveal causal relationships. Particularly in real-time combination with electroencephalography (EEG) or functional magnetic resonance imaging (fMRI), TMS and tDCS are valuable tools for neuropsychological research. They offer the combination of interference methods (TMS, tDCS) with techniques to record ongoing brain activity with high temporal (EEG) and spatial (MRI) resolution. This can: (1) shed unique insights into physiological and behavioral interactions, and (2) test, refine, and improve cognitive models; and (3) might ultimately lead to better neurorehabilitative methods.

The main goals of research with NBS in learning and memory have been to: (1) identify underlying neuropsychological processes and neurobiological components; (2) find out how this knowledge can be used to diagnose and restore dysfunctions of learning and memory in various patient populations; and (3) assess the use of NBS for enhancement purposes in healthy subjects.

In the present chapter, we first review and define memory and learning processes from a neuropsychological perspective. Then we provide a systematic and comprehensive summary of available research that investigates the neurobiological substrates of memory and aims to improve memory functions in patient populations, as well as in healthy subjects. Finally, we discuss methodological considerations and limitations, as well as the promise of the approach.

FRAMING APPLICATION OF NONINVASIVE BRAIN STIMULATION IN THE CONTEXT OF NEUROPSYCHOLOGICAL DEFINITIONS

Learning and memory are cognitive functions that encompass a variety of subcomponents. These components can be structured in different ways. For example, we can focus on their temporal dimension, or differentiate various forms of memory by virtue of their content or mechanisms of acquisition ( Fig. 55.1 ). It seems clear that the cognitive structure of learning and memory is complex, and that, given the many interactions and overlaps between key subcomponents, neither neuropsychological nor neurobiological models can give us a fully satisfying taxonomy.

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Classification of different types of memory process.

A key advance in the study of the neurobiological substrates of memory was Squire’s (1987 , 2004 ) distinction between declarative and nondeclarative memory functions related to their differential reliance on distinct neural structures ( Cohen and Squire, 1980 ). Declarative memory incorporates semantic and episodic memory, and refers to everyday memory functions, which are typically impaired in amnesic patients. Declarative memory is thought to rely primarily on medial temporal lobe structures, including the hippocampus. Nondeclarative memory includes various subcomponents, of which procedural memory or formation of motor memories is the most prominent. Nondeclarative memory is thought to depend mostly on striatum, cerebellum, and cortical association areas ( Cohen and Squire, 1980 ). However, procedural memory also includes associative learning forms, such as classical and operant conditioning, and nonassociative learning forms such as priming, habituation, and learning of perceptual and cognitive routines. Notably, motor learning has been regarded as a less cognitive form of memory functions, and most research makes a clear distinction between motor and nonmotor memory functions. Thus, it seems clear that declarative and nondeclarative memory processes are interactive and partly overlapping domains.

Historically, the distinction between explicit and implicit memory has been associated with declarative and nondeclarative memory. It is often argued that declarative memory (semantic and episodic memory) corresponds to explicit memories that are conscious and verbally transmittable. On the other hand, nondeclarative memory is thought to represent an implicit and nonverbal type of memory that is acquired subconsciously. Although most declarative memory contents seem to be acquired explicitly, and most nondeclarative memory contents appear to be acquired implicitly, this dichotomy is an oversimplification and ultimately not accurate. For example, declarative memories can be acquired subconsciously (e.g., memories of an emotionally intense event or subliminal priming effects), and nondeclarative memories can be acquired with conscious engagement (e.g., learning of motor movements playing sports or a musical instrument).

Another important dichotomy, first proposed by William James (1890) , differentiates memory subcomponents along a temporal dimension of duration (short-versus long-term memory, STM versus LTM). Since then researchers have proposed that STM and LTM are dependent on different neural substrates. More recently, however, it has been argued that the same representations that are active during encoding are also active during STM or during retrieval from LTM. According to these models, medial temporal lobe structures are responsible for the establishment of new representations independent of their duration, and the same binding processes are active in both STM and LTM ( Wheeler et al., 2000 ; Jonides et al., 2008 ). A related temporal dichotomy separates retrograde and anterograde memory processes ( Hartje and Poeck, 2002 ; Markowitsch and Staniloiu, 2013 ). Access to memories of the past enables us to improve current decisions, while mental time traveling and the imagination of future experiences helps us to follow long-term goals ( Boyer, 2008 ).

These are some of the complex and not mutually exclusive dichotomies of memory processes that NBS could help link to specific neural substrates. For example, one can conceive of experiments aimed at assessing whether disruption of specific brain regions affects one type of memory process and not another (e.g., Basso et al., 2010 ), or experiments evaluating the time at which disruption of a given brain region interferes with a specific memory step (e.g., Oliveri et al., 2001 ). One can use NBS to explore the nature of the relation between different processes within or across different dichotomies. Finally, one can compare the effects of NBS in healthy individuals and those with deficits in specific memory processes, and evaluate the impact on the deficit or even on other, apparently unaffected, memory and learning types.

It is also apparent that memory is tightly connected to time perception, attention, and emotional valence of memory contents, and there is evidence that brain circuits implicated with these functions are overlapping with areas involved in processing of memory functions. For example, with an increasing load of varying experiences stored in memory, time intervals are perceived to be longer ( Bailey and Areni, 2006 ), and the subjective perception of a long time interval recruits areas such as the medial temporal cortex, which is known to be involved in binding episodic memory features ( Noulhiane et al., 2007 ). State-dependent models have proposed that there is no “centralized clock,” but that there are time-dependent neural changes, such as short-term synaptic plasticity, accounting for the decoding of temporal information ( Karmarkar and Buonomano, 2007 ). It has been suggested that there is no linear metric of time, but that short time intervals are rather encoded in the context of (memory) events and therefore a state of local neural networks. In the same way as long-term plasticity may provide a memory of a learning experience ( Martin et al., 2000 ), state-dependent networks may use short-term plasticity to provide a memory trace of the recent stimulus history of a network ( Buonomano, 2000 ). These are further examples of questions that NBS can help address. Pharmacological experimental interventions suggest that affecting working memory (WM) also interferes with temporal processing ( Rammsayer et al., 2001 ). However, NBS offers a promise of spatial and temporal precision that pharmacological agents lack.

Currently, researchers are trying to integrate findings in the memory domain into comprehensive models aiming to account for the wealth of data on functional characteristics of memory networks. There are debates over the implication of attention functions to memory and specifically, for example, of the role of parietal regions to retrieval of episodic memory. For instance, the Attention to Memory (AtoM) model postulates that the dorsal parietal cortex mediates top-down attention processes guided by retrieval goals (orienting), while ventral parietal cortex mediates automatic bottom-up attention processes captured by retrieved memory output (detection) ( Ciaramelli et al., 2008 ; Cabeza et al., 2011 ). Cabeza and colleagues (2011) have proposed that parietal regions control attention in a similar way to perception processes. While orienting-related activity for memory and perception are thought to overlap in dorsoparietal cortex (DPC), detection-related activity is believed to overlap in ventroparietal cortex (VPC). Furthermore, both DPC and VPC show strong connectivity with medial–temporal lobe (MTL) during a memory task, which can, however, shift to strong connectivity with visual cortex during a perception task. Accordingly, the DPC appears to be collaborating with the prefrontal cortex (PFC) to induce top-down attention to salient retrieval paths, while the VPC seems to be involved in the activation of episodic features in alliance with the MTL. Thus, current models of memory processes integrate dynamic concepts of distributed network interactions and plasticity. These and other conclusions are derived from brain imaging studies, which, although extremely valuable, cannot offer insights into causality ( Silvanto and Pascual-Leone, 2012 ). Here again, NBS offers the promise of a transformative approach.

Procedural memory

Motor learning and the formation of motor memories can be defined as an improvement of motor skills through practice, which are associated with long-lasting neuronal changes. They rely primarily on the primary motor cortex, premotor and supplementary motor cortices, cerebellum, thalamus, and striatal areas ( Karni et al., 1998 ; Muellbacher et al., 2002 ; Seidler et al., 2002 ; Ungerleider et al., 2002 ). As learned from patients with apraxia, the parietal cortex is furthermore implicated in accessing long-term stored motor skills and contributes to visuospatial processing during motor learning ( Halsband and Lange, 2006 ). Frontoparietal networks may become important after learning has been established, and play key roles in consolidation and storage of skill ( Wheaton and Hallett, 2007 ).

Motor learning and memory take a special place within the memory domain and have been studied extensively. However, procedural memories build on subprocesses similar to those of nonmotor memories: they are divided into encoding, consolidation and long-term stability, retrieval ( Karni et al., 1998 ; Robertson et al., 2005 ), and even a short-term memory system has been suggested to exist in the primary motor cortex ( Classen et al., 1998 ). Robertson (2009) has further proposed that motor and nonmotor memory processes may be fully or partially supported by the same neuronal resources during wakefulness, but not during sleep. Indeed, the MTL – which is known to support declarative memory formation – also contributes to implicit procedural learning ( Schendan et al., 2003 ; Robertson, 2007 ; Albouy et al., 2008 ). During sleep, motor and nonmotor memory systems may be functionally disengaged, which may promote independent offline consolidation within systems ( Robertson, 2009 ). As we shall see, key aspects of such insights have been derived from recent studies using NBS.

Short-term memory

STM is an essential component of cognition and is defined as the maintenance of information over a short period of time (seconds). Multistore models differentiate between STM and LTM. STM can remain unimpaired in amnesic patients who show distinct LTM impairments ( Scoville and Milner, 1957 ; Cave and Squire, 1992 ). However, STM can be impaired while LTM functions remain intact ( Shallice and Warrington, 1970 ). According to William James (1890) , STM (primary memory) involves a conscious maintenance of sensory stimuli over a short period of time after which they are not present anymore. On the other hand, LTM (secondary memory) involves the reactivation of past experiences that were not consciously available between the time of encoding and retrieval. This led to the assumption, going back to Hebb (1940s), that STM and LTM are based on separate neural systems. While STM engages repeated excitation of a cellular compound, LTM leads to structural changes on the synaptic level, which are preceded by consolidation processes that are thought to be highly dependent on hippocampal functions. NBS, particularly TMS combined with EEG, MRI, or other brain imaging methods, has provided valuable insights on such neurobiological questions.

Baddeley also proposed a multistore architecture of STM and LTM ( Baddeley and Hitch, 1974 ; Baddeley, 1986 ). In his model, STM consists of a “verbal buffer” (phonological loop) and a “visuospatial sketchpad” (maintenance of visual information). He later added an “episodic buffer” that is supposed to draw on the other buffers and LTM ( Baddeley, 2000 ). Finally, a “central executive” is argued to be responsible for orchestrating all components. As we shall see, such cognitive models lend themselves exquisitely well to hypothesis testing with NBS.

Unitary store models assume that the MTL is engaged in both STM and LTM, and that its function is the establishment of new representations independent of their duration. Accordingly, information that does not require binding processes can be preserved in amnesic patients, which might also explain often preserved retrieval of consolidated preinjury memories. In a comprehensive review, Jonides and colleagues (2008) concluded that STM and LTM are not separable, but that STM consists of temporarily activated LTM representations. Several studies have confirmed these assumptions ( Ranganath and D’Esposito, 2001 ; Hannula et al., 2006 ; Olson et al., 2006a , b ). According to their assumptions, initial neural representations are also the repository of long-term representations, as they are active during encoding, as well as during STM, or the retrieval from LTM into STM ( Wheeler et al., 2000 ). Chronometric brain stimulation experimental designs can be applied to explore such questions (e.g., Mottaghy et al., 2003a ).

Long-term memory

LTM refers to the mechanism by which acquired memories gain stability or are strengthened over time, and become resistant to interference ( Brashers-Krug et al., 1996 ; McGaugh, 2000 ; Dudai, 2004 ). Consolidation is assessed as a change in performance between testing and retesting ( Robertson et al., 2004 ; Walker, 2005 ) and provides a direct measure of “offline” changes.

Mainly two components of LTM are described in the literature and frequently included under the term “declarative memory” – episodic and semantic memory. They rely mostly on MTL structures. Episodic memory refers to contents that can be located within a spatiotemporal context, such as holiday memories or autobiographical events. On the other hand, semantic memories are independent of context and are not personally relevant. They consist of general and factual world knowledge, such as “Dakar is the capital city of Senegal.” However, “nondeclarative” memory functions, such as procedural memory (see above), also involve LTM consolidation processes, such as knowing how to ride a bike.

Successful long-term storage includes several steps starting with the encoding of information, followed by short-term storage and consolidation from STM to LTM, as well as repeated reconsolidation. Consolidation is thought to occur in a structured way allowing for prompt and precise retrieval. Elegant work from Muellbacher and colleagues (2002) pioneered the use of NBS approaches to explore the neurobiology of such processes in humans. During consolidation, memories can undergo changes that can be quantitative (enhancement, strengthening) as well as qualitative in nature (e.g., awareness of underlying sequences) ( Wagner et al., 2004 ; Walker, 2005 ; Robertson and Cohen, 2006 ). Chronometric brain stimulation paradigms are contributing to clarify some of these issues. Consolidation mechanisms may depend on neuronal reactivation (signal increase), on the removal of noise-inducing synaptic changes (noise decrease), or their combination, all of which can be examined with NBS. For example, offline performance changes seem to be causally associated with neuronal reactivation ( Rasch et al., 2007 ). However, it remains to be shown that disruption of reactivation would impair consolidation processes, a problem that seems experimentally approachable with TMS.

It has been shown that sleep plays an important role in the consolidation of memories ( Walker et al., 2002 ; Korman et al., 2007 ), and it has been argued (synaptic homeostasis hypothesis) that a net increase in the efficacy and number of synapses during wakefulness may add noise to the network. The reduction of noise would therefore improve the signal-to-noise ratio. Slow-wave sleep is thought to be responsible for downscaling synaptic strength and therefore noise reduction ( Tononi and Cirelli, 2003 , 2006 ), and has been associated with learning and the induction of brain plasticity ( Huber et al., 2004 , 2006 ; De Gennaro et al., 2008 ). NBS, in this case, particularly tDCS, is being elegantly employed to test some of these notions, while TMS–EEG studies are providing experimental support for the underlying hypotheses (e.g., Marshall et al., 2004 , 2011 ).

Encoding and retrieval

During encoding, various event features distributed across neocortical areas are held actively online through processes guided by the PFC ( Miller and Cohen, 2001 ; D’Esposito, 2007 ). TMS and tDCS lend themselves well to experimentally test such notions and evaluate precise spatial and temporal aspects of the hypothesized neural substrates.

The MTL is thought to be responsible for binding these representations in a highly structured way to enable optimal retrieval at a later timepoint ( Cohen and Eichenbaum, 1991 ; Squire and Zola, 1998 ), and activity in PFC and MTL during encoding is correlated with successful retrieval ( Paller and Wagner, 2002 ). Moreover, intermediate processes such as additional encoding or consolidation processes, are relevant for further stabilization of memories ( Squire, 1984 ; Nadel et al., 2000 ; Paller, 2002 ). Critical encoding components include bottom-up sensory processes as well as top-down processes that select/engage, maintain, and update relevant features ( Shimamura, 2011 ). Here again, NBS is a valuable experimental tool, thanks to the opportunity of interference with ongoing neural activity in a spatially and temporally controlled manner.

Retrieval of episodic memories depends on the recollection of encoded contextual features of a past event, such as time, place, people, sights, thoughts, and emotions ( Mitchell and Johnson, 2009 ). Source memory is therefore an important element of episodic memory ( Tulving, 2002 ; Shimamura and Wickens, 2009 ). MTL plays its part in memory retrieval by reinstating these features ( Eldridge et al., 2005 ; Moscovitch et al, 2006 ). Successful retrieval has also been associated with the PFC ( Buckner et al., 1998 ; Dobbins et al., 2002 ; Simons and Spiers, 2003 ), which is involved in top-down executive control. The HERA (Hemispheric Encoding/Retrieval Asymmetry) model proposed by Tulving and colleagues (1994) postulates that both prefrontal lobes subserve memory processes, but play different roles. While the left PFC is believed to be more involved in encoding and semantic retrieval, the right PFC is thought to be more important in episodic memory retrieval. Early functional imaging studies proposed an asymmetry in memory processes irrespective of modality, with encoding and retrieval being associated with left and right/bilateral PFC respectively ( Cabeza and Nyberg, 2000 ; Haxby et al., 2000 ; Fletcher and Henson, 2001 ). The HAROLD (Hemispheric Asymmetry Reduction in OLDer adults) model suggests that prefrontal activity during cognitive performance becomes less lateralized with advancing age ( Cabeza, 2002 ). In particular, the role of the PFC can be evaluated with TMS or tDCS, as the PFC is easily accessible to modulation with NBS (e.g., Gagnon et al., 2010 , 2011 ).

Besides MTL, PFC, and cortical sites that store contextual features, brain imaging studies suggest that parietal areas also play an important role in episodic memory retrieval ( Wagner et al., 2005 ; Cabeza et al., 2008 ). For instance, according to a recently proposed theory (“COrtical Binding of Relational Activity”, CoBRA), the VPC acts as a binding zone for episodic features and linking these to long-term memory networks ( Shimamura, 2011 ). Both the CoBRA model and the AtoM model (see above) share some similarities, as both suggest that MTL and VPC are linked. Although the role assigned to the VPC differs between the AtoM model (bottom-up processes) and the CoBRA model (integration of event-related activity), they might complement each other. Paired-pulse TMS and the combination of TMS with brain imaging are well suited to examine such notions of corticocortical interactions.

Prospective memory

Prospective memory involves an intention to carry out a psychological or physical act and is related to future-oriented behaviors. In order to realize a goal in the future, it is necessary to retain intentions and activate them at the right time and/or in the appropriate context ( Ellis et al., 1999 ). Depending on the time that passes in between the creation of the intention and the action, and depending on whether the action is triggered externally (context feature) or internally (internal pacemaker), prospective memory involves working and long-term memory processes, as well as attentional processes ( Wittmann, 2009 ). Within this context it has been proposed that, during encoding, prospective memory contents obtain a special status, where they are tagged as not being achieved yet. During the presentation of prospective memory cues, temporal areas are active, possibly representing stimulus-driven attentional processes ( Reynolds et al., 2009 ). The delay period between encoding the intention and the actual act is filled with cognitive activity that prevents active and conscious rehearsal, which differentiates prospective memory from WM or vigilance ( Reynolds et al., 2009 ; Burgess et al., 2011 ). Prospective memory and WM take a special place within the memory domain as they rely strongly on executive processes. However, prospective memory and WM engage different brain areas. Whereas WM demands dorsolateral prefrontal cortex (DLPFC) activity, prospective memory has been associated mainly with activation in the rostral PFC ( Okuda et al., 1998 , 2007 ; Reynolds et al., 2009 ), which is implicated in “future thinking” ( Atance and O’Neill, 2001 ). Such, largely theoretical, considerations derived from careful task analysis and psychological and cognitive model formation can be tested experimentally using NBS.

Working memory

WM refers to the temporary, active maintenance and manipulation of information necessary for complex tasks, while ignoring irrelevant information. It involves the temporary manipulation of external (experienced) or internal (retrieved) stimuli. Like other memory components, it also involves an encoding and retrieval stage. The PFC is an integral component for successful WM performance ( Missonnier et al., 2003 , 2004 ; Jaeggi et al., 2007 ), and NBS offers experimental approaches that were previously limited to animal models.

WM takes a special place within the memory functions, as it is highly dependent on top-down processing and selective attention. Top-down modulation allows us to focus attention on relevant stimuli and ignore irrelevant distractors. This is achieved through an improvement of the signal-to-noise ratio by increasing sensory activity for relevant items and decreasing activity for irrelevant items ( Gazzaley and Nobre, 2012 ). Successful manipulation of information is necessary for encoding as well as the integration of memory functions with other so-called higher cognitive functions associated with conscious processing, such as decision-making, mental imagery, interference control, or language functions. State-dependency experimental designs with NBS ( Silvanto and Pascual-Leone, 2008 ) might allow selective modulation of different items of information and thus shifting of the signal-to-noise ratio. This offers intriguing promises for translational applications of such NBS to populations with WM deficits, such as the elderly or patients with attention-deficit disorders, Parkinson’s disease, or schizophrenia.

UNDERSTANDING THE NEURAL MECHANISMS OF LEARNING AND MEMORY

Learning and memory processes are investigated with a wealth of methods. In the literature we find studies that use brain imaging during memory tasks, analyze the number of remembered items correlated with EEG activity, look at the influence of state changes as captured by various brain imaging and neurophysiological measures, or “borrow patients’ illnesses” to investigate the impact of serendipitous lesions. The application of all these methods has led to valuable information about the neural mechanisms of memory. However, cause–effect relationships are difficult to establish. NBS is uniquely suited to provide this ( Silvanto and Pascual-Leone, 2012 ).

Although TMS and tDCS both promote changes in excitability, they do not rely on the same processes ( Wagner et al., 2007 ; Nitsche et al., 2008 ) and behavioral effects can be different. Neuronavigated TMS can serve to probe the spatio-temporal contribution of certain structures and processes important for learning and memory. It can reveal where and when certain memory processes happen and can shed light on the interplay of multiple processes. On the other hand, the temporal and spatial resolution is lower for tDCS, which is a reason why the utility of tDCS to study spatiotemporal properties of learning and memory is limited. In the following section we concentrate on studies applying TMS as a means to induce so-called “virtual lesions” in the healthy brain ( Pascual-Leone et al., 2000 ). In recent years, research in this field has grown immensely.

Assessing memory functions by induction of virtual lesions in healthy subjects

The first systematic investigation of the contribution of certain brain areas to cognitive functions took place during World War I. Soldiers with circumscribed brain lesions after gunshots provided information about how certain brain regions are associated with cognitive functions ( Lepore, 1994 ). Later, Luria’s work with brain-damaged war veterans contributed strongly to rekindling of the interest in neuropsychology during World War II ( Luria, 1972 ).

Although lesion studies with patients have been widely used since then to investigate learning and memory, they have some disadvantages. Important variables, such as, for example, lesion size, comorbidities, and age, cannot be controlled easily. On the other hand, modern brain imaging methods, such as positron emission tomography (PET) and fMRI, are able to detect regional activation changes with an excellent spatial resolution, and allow for controlled, test–retest experimental designs, but their low temporal resolution does not allow investigation of the organization of distributed memory networks, and they cannot provide information on facilitatory or inhibitory effects or cause–effect relationships. EEG offers a direct measure of brain activity with exquisite temporal resolution, but spatial resolution is in turn limited.

Many of these disadvantages can be overcome when using TMS to induce a “virtual lesion” in an otherwise healthy brain ( Pascual-Leone et al., 1999 ; Walsh and Pascual-Leone, 2003 ). Instead of studying cognitive functions in patients with brain lesions, we can use TMS as a means to induce virtual lesions in healthy subjects and, therefore, reproduce neurobehavioral patterns of patients with brain lesions. TMS is a method that interferes with brain activity and thereby allows probing the chronological contribution of underlying cortical areas. However, it is important to note that our understanding on the neural mechanisms underlying such “virtual lesions” is rather limited, and that a functional disruption is not simply dependent on a mere modification of cortical excitability in the targeted brain area, but appears to involve a complex interplay of inhibitory and excitatory mechanisms, disruption of oscillators, and modification of functional connectivity and synaptic efficacy across distributed neural networks.

TMS has been used in a vast number of studies investigating mechanisms of motor learning and memory ( Bütefisch et al., 2004 ; Censor and Cohen, 2011 ), whereas studies looking at nonmotor memory functions are less numerous. However, recent technical advances allowing the combination of TMS with EEG and fMRI are promising and will allow further exploration of nonmotor memory processes ( Miniussi and Thut, 2010 ; Thut and Pascual-Leone, 2010 ). The combination of methods has, furthermore, the advantage of helping to unravel local and distant effects of brain stimulation and give us insights into functional connectivity.

Most research groups that study WM or STM with NBS methods have focused on the DLPFC or the parietal cortex, believed to be core cortical structures for memory processes. Typically, these studies have used delayed response tasks or n -back tasks to measure STM or WM performance, respectively. A classical example of a delayed match-to-sample task is the Sternberg task ( Sternberg, 1966 ), where the subject is shown a list of numbers or letters and is asked to memorize them. After the delay period, a probe number or letter is shown and the subject has to indicate whether the probe was in the list. Researchers have used several versions of this test using different stimuli and parameters. In “ n -back tasks” a string of visual or auditory stimuli is presented, and subjects have to compare each new stimulus with a stimulus presented n trials back. n -back tasks with n = 1 involve a continuous maintenance and matching of stimuli, whereas n -back tasks with n > 1 furthermore require concurrent engagement of manipulation processes. The reallocation of attention and processing capacity away from mere matching to actual WM processes (by increasing n ) is reflected in decreasing P300 amplitudes ( Watter et al., 2001 ). As these tasks draw on different processes, we will address them in separate sections. Studies using delayed match-to-sample tasks will therefore be summarized under the STM section, whereas studies using the n -back task, or other tasks requiring the online manipulation and integration of stimuli, will be summarized under the WM section. Another major section gives an overview for studies that have investigated encoding, consolidation, and retrieval.

The number of studies that apply TMS and tDCS to address questions regarding the underlying neurobiological structure and modulation of memory functions has grown rapidly in past years. The studies presented in Table 55.1 have applied single-pulse TMS, paired-pulse TMS, repetitive TMS (rTMS), and theta-burst stimulation (TBS). The tasks that were used draw on various processes (attentional, sensory, motor, verbal/nonverbal, spatial/nonspatial, maintenance/manipulation) and stimulation parameters, such as pattern, timing, duration, intensity, and location, vary across studies. It is important to realize that memory tasks vary greatly regarding their specific cognitive demands. In addition, it is important to recognize TMS methodological factors. For example, online stimulation differs from offline stimulation in that underlying brain areas are concomitantly activated through TMS as well as through task performance. This combined activation may affect stimulation outcome. Finally, note that some studies report effects on accuracy, whereas others focus on response times (see Table 55.1 ). It is important to note, though, that the amount of time it takes to recognize an already encountered stimulus or to recall a memorized representation is far less important than the accuracy of this process. Finally, we have to keep in mind that the act of receiving TMS may have an influence on attentional processes that should be carefully controlled for.

Synopsis of peer-reviewed, published studies applying noninvasive brain stimulation in the memory domain

A, C, S, anodal, cathodal, sham; ADAS-Cog, Alzheimer’s Disease Assessment Scale – Cognitive subscale; aMT, active motor threshold; ATL, anterior temporal lobe; BA, Brodmann’s area; BBR, brain-behavior relationship; Cb, cerebellum; CGIC, Clinical Global Impression of Change; CPM, colored progressive matrices; cTBS, continuous theta-burst stimulation; Cz, vertex; DLPFC, dorsolateral prefrontal cortex; DMS, delayed match-to-sample; DMPFC, dorsomedial prefrontal cortex; DR, discrimination rate; EF, executive functions; ERP, event-related potential; Exp., experiment; FEF, frontal eye fields; FL, frontal lobe; fO, frontal operculum; Fz, frontal midline; GDS, Geriatric Depression Scale; HF, high frequency; HVOT, Hooper Visual Organization Test; IADL, Instrumental Activities of Daily Living; IFG, inferior frontal gyrus; IFJ, inferior frontal junction; IPL, inferior parietal lobule; IPS, intraparietal sulcus; ITI, intertrain interval; L, left; LA/RA, left anodal/right anodal; LC/RC, left cathodal/ right cathodal; LF, low frequency; LH, left hemisphere; LOC, lateral occipital cortex; M1, primary motor cortex; MFG, middle frontal gyrus; MMSE, Mini Mental State Examination; MSO, maximum stimulator output; NP, neuropsychological; NPI, neuropsychiatric inventory; OC, occipital cortex; OFC, orbitofrontal cortex; p, pulse; PANAS, positive and negative symptoms scale; PC, parietal cortex; PCG, postcentral gyrus; PD, Parkinson’s disease; PFC, prefrontal cortex; PL, parietal lobule; PM, prospective memory; PMC, premotor cortex; PPC, posterior parietal cortex; ppTMS, paired-pulse transcranial magnetic stimulation; R, right; RBMT, Rivermead Behavioural Memory Test; rCBF, regional cerebral blood flow; ref, reference; RH, right hemisphere; rMT, resting motor threshold; R-pSAC and L-pSAC, right and left parietal somatosensory association cortex; RT, reaction time; rTMS, repetitive transcranial magnetic stimulation; S1, primary somatosensory cortex; SFG, superior frontal gyrus; sign., significant; SMG, supramarginal gyrus; SOA, supraorbital area; sp, single pulse; SPL, superior parietal lobule; stim, stimulation; STM, short-term memory; T, tesla; TL, temporal lobe; TMT, trail making test; TPC, temporoparietal cortex; tRNS, transcranial random noise stimulation; TSOS, transcranial slow oscillation stimulation; VAT, visual attention task; VLPFC, ventrolateral prefrontal cortex; VPFC, ventral prefrontal cortex; VFT, verbal fluency test; VRT, visual recognition task; WAIS, Wechsler Adult Intelligence Scale; WCST, Wisconsin Card Sorting Test; WM, working memory; y, years.

Despite the many differences between studies, the growing literature summarized in Table 55.1 is providing important novel insights in the neurobiology of human learning and memory, and illustrates the power of NBS in this area of cognitive neuroscience.

S hort-term memory

Prefrontal areas undoubtedly play an important role in STM processes. However, one of the questions that NBS studies are helping address relates to the organization of information processing streams. Is processing of STM supported through a domain-specific segregation (spatial, object, verbal processing) or rather through a processing segregation (encoding, maintenance, storage)?

Processing segregation

Most studies examining this question have used a delayed match-to-sample task and applied stimulation during either the delay period or the decision period ( Fig. 55.2 ). High-frequency TMS applied over the parietal cortex during the delay period can improve STM function ( Kessels et al., 2000 ; Kirschen et al., 2006 ; Luber et al., 2007 ; Yamanaka et al., 2010 ), but some studies found it to impair STM ( Koch et al., 2005 ; Postle et al., 2006 ). In either case, the effects seem specific to the delay period, since parietal TMS during the decision phase has not been found to impact STM ( Luber et al., 2007 ; Hamidi et al., 2009 ). The question whether DLPFC also plays a role during the delay phase has not been answered yet. Although some TMS studies support DLPFC participation ( Pascual-Leone and Hallett, 1994 ; Koch et al., 2005 ), others have found no impact when stimulating DLPFC during the delay phase ( Herwig et al., 2003 ; Postle et al., 2006 ; Hamidi et al., 2008 ; Sandrini et al., 2008 ). On the other hand, high-frequency TMS over the DLPFC during the decision period impairs STM functions ( Koch et al., 2005 ; Hamidi et al., 2009 ). Therefore, although further studies are needed, findings suggest a dissociation between parietal and prefrontal areas, playing primary roles in delay and decision phases, respectively. These findings are supportive of the notions of posteroanterior temporal gradient in memory processing: parietal regions coming online first and prefrontal regions contributing to later subprocesses. Chronometric TMS experimental designs enable such notions to be directly tested further.

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Schematic summary of findings from studies investigating the impact on short-term memory after stimulation over the left or right prefrontal cortex, parietal areas, or the cerebellum during the delay (green) or the decision period (orange).

Mottaghy et al. (2003a) conducted the first such experiment ( Fig. 55.3 ), albeit focusing on verbal WM. They used single-pulse TMS to explore the temporal dynamics of left and right inferior parietal and DLPFC involvement in verbal WM in six healthy volunteers. TMS was applied at 10 different time points 140–500 ms into the delay period of a 2-back verbal WM task. Precise and consistent targeting of a given cortical brain region was assured by using frameless stereotactic neuronavigation. A choice reaction task was used as a control task. Interference with task accuracy was induced by TMS earlier in the parietal cortex than in the PFC, and earlier over the right than the left hemisphere. This suggests a propagation of information flow from posterior to anterior cortical sites, converging in the left PFC. Significant interference with reaction time was observed after 180 ms with left PFC stimulation. These effects were not observed in the control task, underlining the task specificity of our results. Hamidi and colleagues (2009) also examined the roles of right and left DLPFC in recall and recognition. They found that right DLPFC stimulation impaired accuracy in delayed recall, while enhancing accuracy in delayed recognition. On the other hand, left DLPFC stimulation impaired delayed recognition. Therefore, it seems clear that TMS, in repetitive and chronometric single-pulse experimental designs, can provide valuable insights into the functional segregation of core subprocesses of STM.

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Accuracy in the 2-back task as a function of the time of transcranial magnetic stimulation (TMS). TMS interference peaked at 180 ms at the right inferior parietal cortex, at 220 ms at the left inferior parietal cortex and right middle frontal gyrus (MFG), and at 260 ms at the left MFG (all p < 0.05). This study illustrates the chronometry of causal contributions of different brain regions to memory processing. (Modified from Mottaghy et al., 2003a , by permission of the authors.)

Domain-specific segregation

Mottaghy et al. (2002b) , in another pioneering study ( Fig. 55.4 ) used TMS to show that functional and modality-specific segregation need not be mutually exclusive. They applied low-frequency rTMS to explore the functional organization of STM by selectively disrupting the left dorsomedial PFC (DMPFC), DLPFC, or ventral PFC (VPFC). They applied a 10-min 1-Hz rTMS train before assessing spatial or nonspatial (face recognition) delayed-response performance. Spatial task performance was impaired after rTMS to DMPFC, whereas nonspatial task performance was impaired after rTMS to VPFC. Disruption of the DLPFC affected the performance in both tasks. This finding reveals a task-related segregation of processing streams along prefrontal structures. More recent studies have confirmed the utility of TMS to offer empirical support for modality-specific segregation. For example, Soto et al. (2012) combined evidence from fMRI and rTMS to demonstrate that verbal and nonverbal memories interact with attention functions independently: whereas rTMS to the superior frontal gyrus disrupted STM effects from colored shapes, rTMS to the lateral occipital cortex disrupted effects from written words. Finally, Morgan and colleagues (2013) used TMS to reveal the neural substrates for integration of segregated features of STM processes. They investigated STM for colors, orientations, and combinations of these, and found that continuous TBS (cTBS) over the right parietal cortex or left inferior frontal gyrus selectively impaired STM for combinations but not for single features. Therefore, functional coupling between frontal and parietal areas appears to be critical to bind modality-specific segregated processes.

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Study exploring the segregation of memory processes in prefrontal cortex. Two alternative models were proposed based on the data. ( A ) There might be two different, nonoverlapping, functionally segregated regions within the prefrontal cortex (PFC) that are domain-specific (S, spatial domain; F, face domain). Repetitive transcranial magnetic stimulation (TMS) over the dorsomedial PFC (DMPFC) interferes only with the processing of the spatial information. Dorsolateral PFC (DLPFC) stimulation might have induced overlapping interference of two adjacent domain-specific areas, whereas the ventral PFC (VPFC) led only to interference with the processing of the face stimuli. ( B ) The DMPFC and the VPFC interference effects can be explained in the same manner as in proposal ( A ); however, the performance deterioration over the DLPFC in this model might be explained by the interference with information processing of a common module (C) that is employed during both types of stimulus. (Modified from Mottaghy et al., 2002b , by permission of the authors.)

Frontoparietal binding

Frontoparietal interactions in memory formation and maintenance appear to be dynamic and NBS studies – particularly studies combining TMS with MRI or EEG – help gaining critical insights in this regard.

In the motor domain, frontoparietal interactions seem to be particularly important in the early phase of learning, as has been shown in a recent study combining TMS and EEG ( Karabanov et al., 2012 ). In the nonmotor domain, a recent TMS–fMRI study ( Feredoes et al., 2011 ) found that DLPFC contribution to maintenance of stimuli in STM is highly dynamic depending on the presence or absence of distractors. In the presence of distractors, DLPFC changes its communication with posterior regions to support maintenance. These results are supported by tDCS studies that assign the DLPFC an important role in STM in the presence of distractors ( Gladwin et al., 2012 ; Meiron and Lavidor, 2013 ). Zanto and colleagues (2011) combined EEG with 1-Hz rTMS to the right inferior frontal junction to investigate the contribution of the prefrontal cortex in top-down modulation of visual processing and STM in a delayed-match-to-sample task. They found that EEG patterns from posterior electrodes, which are associated with the distinction of task-relevant and -irrelevant stimuli during early encoding, were diminished after TMS, which again predicted a subsequent decrease in STM accuracy. Subjects with stronger frontoposterior functional connectivity furthermore showed greater disruption. Higo and colleagues (2011) combined offline TMS over the frontal junction with subsequent fMRI to explore the same question. They also observed a TMS-induced decrease of effects in posterior regions depending on task relevance/irrelevance. The inferior frontal junction may therefore control the causal connection between early attentional processes and subsequent STM performance, and may regulate the level of activity of representations in posterior brain areas depending on their relevance/irrelevance for response selection.

It could be hypothesized that the interaction between frontal and posterior areas during the delay period secures the maintenance of information, especially if this information needs to be protected from distracting information. These processes may be related to the regulation and reactivation of patterns that were active during encoding. Accordingly, frontal areas might recruit neuronal assemblies and regulate their activity in posterior areas in order to protect and actively maintain information. Such activations may be most prominent at the beginning of the delay period and decrease gradually.

Other brain regions involved in STM

Frontal and parietal areas are undoubtedly the most explored areas in STM. Although it has been debated in the literature, there is some evidence that the cerebellum may also be involved in STM. When Desmond and colleagues (2005) applied single-pulse TMS (at 120% resting motor threshold) over the right superior cerebellum at the beginning of the delay phase, they found an increased reaction time but no change in accuracy for correct trials in the Sternberg task. This is in agreement with a tDCS study that probed the cerebellum and found an abolishment of practice-dependent improvements in reaction time after anodal as well as cathodal tDCS in a Sternberg task ( Ferrucci et al., 2008 ).

Last, but not least, cortical areas implied in sensory processing are also believed to be involved in STM of sensory information, which may be guided through attentional processes. A number of TMS studies have shown a role of visual cortex with visual STM and WM (see review by Postle et al., 2006 ). A few studies have furthermore investigated the tactile domain. Application of TMS to the visual cortex during the delay phase of STM tasks results in a decrease of accuracy in the targeted visual field for high memory loads ( Van de Ven et al., 2012 ) or a decrease in memory scanning rates ( Beckers and Hömberg, 1991 ). The effect of TMS was furthermore shown to be different if applied at the beginning (inhibitory) or at the end (facilitatory) of the delay period in both a visual STM task and imagery ( Cattaneo et al., 2009 ). This is an elegant application of state-dependency TMS experimental designs ( Silvanto and Pascual-Leone, 2008 ). Although neurons implicated in encoding are highly active at the onset of the retention period, TMS might preferentially activate neurons not involved in encoding, thereby reducing the signal-to-noise ratio of the memory trace, and impair behavior.

In the tactile domain, a TMS study using single-pulse stimulation over the middle frontal gyrus (MFG) during the early maintenance period led to a decrease in reaction time in a tactile STM task, even in the presence of a distracting stimulus ( Hannula et al., 2010 ). In a follow-up study, the same group investigated whether this improvement only occurs when the interference is tactile, or whether MFG creates a more general top-down suppression ( Savolainen et al., 2011 ). Their results showed that TMS did not lead to facilitation when a visual interference was presented, but only when the interfering stimulus was also tactile.

These and other findings (e.g., Silvanto and Cattaneo, 2010 ) suggest that sensory brain areas involved in early, modality-specific, processing of perceptual stimuli contribute to the formation and maintenance of STM representations through an interaction with the attentional system. In this context, TMS can help elaborate the chronology of memory processes and contributions of state-dependent processes.

W orking memory

WM has been investigated with NBS in a growing number of studies. As for STM, most of these studies have explored the roles of DLPFC and parietal areas, trying to find an answer to the question of whether information is separately processed with regard to domain or functional subprocess ( Fig. 55.5 ). In addition, some studies have examined the question of whether the same areas that participate in STM are also active in WM tasks.

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Schematic summary of findings from studies investigating the impact on verbal (red) or nonverbal (blue) working memory (WM) after stimulation over the left or right prefrontal cortex (PFC), parietal areas, or cerebellum.

Verbal and nonverbal WM in DLPFC

Again building on pioneering work from Mottaghy et al. (2000) , most researchers have found an impairment of verbal WM after stimulation of the left DLPFC ( Mull and Seyal, 2001 ; Mottaghy et al., 2000 , 2003a ; Postle et al., 2006 ; Osaka et al., 2007 ) and after stimulation of the right DLPFC ( Mottaghy et al., 2003a ; Postle et al., 2006 ; Sandrini et al., 2008 ). However, some studies failed to find such effects ( Mull and Seyal, 2001 ; Rami et al., 2003 ; Imm et al., 2008 ; Sandrini et al., 2008 ).

The role of DLPFC in nonverbal WM has been studied much less ( Oliveri et al., 2001 ; Imm et al., 2008 ; Sandrini et al., 2008 ). Sandrini and colleagues (2008) tried to clarify domain- and process-specific contributions of the DLPFC. They presented physically identical stimuli (letters in different spatial locations) in a 1-back task (STM) and a 2-back task (WM). Furthermore, they presented the 2-back task with stimuli of both or just one domain. A short train of 10-Hz rTMS was applied at the end of the delay period between stimuli. They found interference only during the 2-back task, and only when stimuli from both domains were presented. Interestingly, performance in the letter task was impaired after rTMS over the right DLPFC, whereas performance in the location task was impaired after rTMS over the left DLPFC. These results were interpreted as an interference effect on control mechanisms (central executive) in the sense of the suppression of task-irrelevant information. The same hypothesis has been put forward with regard to the protection of memory contents in STM ( Feredoes et al., 2011 ; Higo et al., 2011 ; Zanto et al., 2011 ), according to which an interaction between frontal and posterior areas during the delay period secures the maintenance of information, especially in the presence of distractors.

Further experiments have aimed at dissecting the role of DLPFC in WM in order to find out whether domain- or process-specific models should be favored, and others have examined the role of interactions between DLPFC and other brain areas. Combination of TMS with brain imaging has proven quite valuable in this context. Mottaghy and colleagues (2000) found that performance in a verbal WM (2-back) task was significantly diminished after rTMS (30-second train of 4-Hz rTMS) to the left but also the right DLPFC (F3/F4). Importantly, by combining TMS with PET, they showed that TMS-altered performance in the WM task was associated with a reduction in regional cerebral blood flow (rCBF) at the stimulation site and in distant areas as assessed with PET. In an elegant follow-up TMS–PET study, the same authors ( Mottaghy et al., 2003b ) showed that at baseline (in the absence of TMS) there was a negative correlation between rCBF in the left (but not the right) DLPFC and WM task performance. Application of rTMS to the left or the right DLPFC could disrupt WM performance, but appeared to do so on the basis of different distributed impact on a bihemispheric network of frontal and parietal regions: whereas rTMS over the left DLPFC led to changes in rCBF in the directly targeted left DLPFC and the contralateral right PFC, rTMS over the right DLPFC led to more distributed changes involving not only bihemispheric prefrontal, but also parietal areas ( Fig. 55.6B ). Regardless of the differential network impact of the right or left stimulation, the behavioral consequences of rTMS were always related to the impact onto left DLPFC rCBF. This study highlights a number of important findings of relevance for future studies on NBS in memory and learning. First, it shows that rTMS to different nodes of a given brain network can exert differential impact onto said brain network. More recently, Eldaief et al. (2011) have expanded on this line of inquiry combining resting-state fMRI with TMS to examine brain network dynamics. Second, the study shows that network dynamics are modified by behavioral engagement. In other words, it might be possible to learn about mechanisms of memory and learning by examining how the impact of TMS onto a given brain network is modulated by the behavioral state. Finally, the study illustrates that brain stimulation can affect behavior by disrupting a computation in the targeted brain region (as in the case of left DLPFC rTMS) or by disrupting function of a brain regions reached via trans-synaptic network impact (as in the case of rTMS to the right DLPFC altering left DLPFC via interhemispheric connections). This later finding is important in the interpretation of brain stimulation results in general, and illustrates the power of studies integrating brain stimulation with neuroimaging in exploring causal relations between brain activity and behavior ( Fig. 55.6A ). In a later study, Mottaghy and colleagues (2003a) applied single-pulse TMS at different time points after stimulus presentation to probe the temporal dynamics of parietal and prefrontal contributions in verbal WM. With this approach they were able to add chronometric information to their prior findings. They showed that single-pulse TMS could interfere with task accuracy earlier in the parietal than in the PFC, and earlier over the right than left hemisphere. This indicates an information flow from posterior to anterior converging in the left PFC. These series of studies reveal that both hemispheres contribute to WM, but that the computation performed by the left PFC is critical in verbal WM.

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Transcranial magnetic stimulation–positron emission tomography (TMS–PET) study of the neurobiological substrates of working memory. ( A ) The impact of TMS on behavior relies on activity changes in local and distributed brain networks. The combination of TMS with brain imaging techniques, such as EEG, fMRI, PET, and EMG, allows us to detect correlations between these activity changes and behavior. Moreover, it allows study of the impact of state dependency on stimulation outcome. ( B ) Positive (green) and negative (red) correlation between regional cerebral blood flow (rCBF) and performance in the 2-back working memory (WM) task (1) without application of repetitive TMS (rTMS), (2) with rTMS delivered over the left middle frontal gyrus (MFG), and (3) with rTMS applied over the right MFG. While rTMS over the left MFG has a local impact, which is correlated with behavior, rTMS over the right MFG has an impact on a distributed network, including homologous areas. Importantly, also in the case of stimulation over the right MFG, activity changes in the left MFG but not right MFG are correlated with behavioral output. This key finding shows that the effect of TMS can be achieved by a direct effect on underlying areas, but also through trans-synaptic effects (e.g., in homologous areas). The combination of TMS with imaging techniques is crucial in order to identify neural substrates associated with behavioral output. (Modified from Mottaghy et al., 2003b , by permission of the authors.)

Interestingly, involvement of DLPFC, regardless of stimulus modality, has been shown in an often-cited study using bilateral single-pulse stimulation during a 2-back task ( Oliveri et al., 2001 ). Early temporal stimulation (300 ms) increased reaction time for object-related WM, whereas early parietal stimulation and late stimulation (600 ms) over the superior frontal gyrus increased reaction time for spatial WM. However, late DLPFC stimulation interfered with both tasks and not only with RT, but also with accuracy. These results relate to the discrimination of a dorsal (“where”) and ventral (“what”) pathway and again information flow from parietotemporal to frontal areas. They indicate that there might not only exist a bilateral involvement of the DLPFC in verbal WM, but that DLPFC might be active irrespective of stimulus material, unlike other prefrontal regions that may be segregated (see e.g., Mottaghy et al., 2002b ). Segregation in posterior areas seems to be easier to pinpoint, and is concordant with the view that both hemispheres are implicated in spatial and object WM tasks ( Smith and Jonides, 1997 ). The research that has been done up to date generally points into the direction of favoring a process-specific model for DLPFC, whereas other areas of the prefrontal or parietal cortex may be modality-based. Possibly, WM operations relying on DLPFC, such as selective attention and other executive processes (e.g., the inhibition of task-irrelevant stimuli), are independent of modality ( Smith and Jonides, 1999 ) and play a role in both STM and WM. The combination of fMRI and EEG with TMS may help us to disentangle further the interactions of DLPFC and other prefrontal and parietal areas to WM functions.

P rospective memory

Prospective memory is tightly connected with other memory subcomponents (see Fig. 55.1 ), which makes it difficult to single out its processes. Perhaps this challenge accounts for the fact that few studies to date have explored prospective memory using NBS. One study ( Basso et al., 2010 ) investigated whether verbal WM and prospective memory are based on common or separate processes. In a first experiment participants had to accomplish tasks with low, medium, or high WM load. In the prospective condition, subjects had to react whenever a specific word appeared. In a second experiment the prospective conditions included 1 or 3 prospective words. A higher prospective memory demand interfered with the WM task only at higher loads, whereas WM activity did not affect prospective memory performance. If both processes were part of the same system one might expect a trade-off. In a third experiment single-pulse TMS was applied to the left and right DLPFC in order to test the notion that WM and prospective memory rely on distinct systems. TMS to the DLPFC increased error rates in the prospective memory task, whereas the effect on the WM task was only marginal. No difference between hemispheres was detected. The authors concluded that WM and prospective memory may not be based on the same memory system. However, it is hard to rule out that prospective memory may require resources (including in part WM resources) and may thus be easier to disrupt with TMS. More complex TMS designs, such as input–output designs with TMS applied at various intensity and timings, seem necessary to explore this issue further.

Costa and coworkers (2011) investigated the effects of cTBS (80% active motor threshold) on prospective memory. Stimulation over left Brodmann area (BA) 10 (frontal pole) resulted in impaired accuracy as compared with stimulation over Cz. In a second experiment they did not find a significant difference after cTBS over left BA46 (DLPFC) and Cz. They concluded that the left BA10 is important for prospective memory processes. This is in accordance with a neuroimaging study ( Koechlin et al., 1999 ) that tried to dissociate the roles of frontopolar and DLPF cortices in prospective memory. Costa and colleagues employed a fairly novel TMS paradigm (cTBS) and tackled a complicated memory construct (prospective memory). However, this important, innovative study also illustrates one important challenge for all studies using NBS in memory: it is ultimately critical to have separate empirical demonstration of the impact of brain stimulation on brain function, and on behavior. In fact, ideally, one would want to apply TMS, measure the behavioral impact and the impact on brain physiology, and then correlate one with the other (see Fig. 55.6A ). Costa and coworkers (like most investigators using TMS or tDCS in studies of memory) placed the TMS coil over the scalp overlaying the brain regions they wanted to target (frontal pole or DLPFC). They then assumed that the TMS impact on brain activity would be maximal in the underlying cortex. They assessed the impact of TMS onto prospective memory and assumed that said impact must reflect the consequence of TMS-induced change in activity in the targeted brain region. There is a risk of circular logic in this approach: “If TMS over a given region has a predicted impact onto a given memory process, then I have shown that said brain region was affected by TMS and that it plays said role in memory.” Obviously, independent empirical demonstration of these two steps would be important and the use of NBS in studies of memory, or studies of cognitive functions in general, should aim to achieve such experimental discrimination.

E ncoding, consolidation, retrieval

Some studies have applied rTMS during the encoding phase and support the critical role of the PFC in such memory processes. Stimulation of the left DLPFC during the encoding phase has been found to affect both verbal ( Grafman et al., 1994 ; Rami et al., 2003 ; Sandrini et al., 2003 ; Flöel et al., 2004 ; Skrdlantová et al., 2005 ; Blanchet et al., 2010 ; Gagnon et al., 2010 , 2011 ) and nonverbal ( Rossi et al., 2001 , 2004 ; Blanchet et al., 2010 ; Gagnon et al., 2010 , 2011 ) memory. However, a few studies have reported an impact on memory functions after stimulating right frontal areas during the encoding phase of verbal ( Grafman et al., 1994 ; Sandrini et al., 2003 ; Kahn et al., 2005 ; Blanchet et al., 2010 ; Machizawa et al., 2010 ) or nonverbal ( Epstein et al., 2002 ; Flöel et al., 2004 ; Blanchet et al., 2010 ) memory functions. Some investigators did not find any effects after stimulating right frontal cortex ( Rami et al., 2003 ; Köhler et al., 2004 ). No effects have been found after stimulating parietal ( Köhler et al., 2004 ; Rossi et al., 2006 ) or occipital cortex ( Grafman et al., 1994 ). Only one study reported impairment after stimulating the temporal cortex ( Grafman et al., 1994 ).

Fewer studies have applied TMS during the retrieval phase of memories. Stimulation of the right DLPFC during the retrieval phase appears to be associated with an impact on both verbal ( Sandrini et al., 2003 ; Gagnon et al., 2010 , 2011 ) and nonverbal ( Rossi et al., 2001 , 2004 ; Gagnon et al., 2010 , 2011 ) memory. No studies have reported an effect after stimulation of the left hemisphere during the retrieval phase.

Several studies have used NBS to reveal the important role of the ventrolateral PFC (VLPFC) in the formation of long-term memory ( Grafman et al., 1994 ; Flöel et al., 2004 ; Köhler et al., 2004 ; Machizawa et al., 2010 ), and it has been suggested that VLPFC may be material-specific whereas DLPFC is not. Further studies are needed to shed light on these mechanisms.

Recent studies by Gagnon and colleagues explicitly addressed the assumptions of the HERA model ( Blanchet et al., 2010 ; Gagnon et al., 2010 , 2011 ) and tried to shed light on the contribution of left and right DLPFC in encoding and retrieval of verbal as well as nonverbal information. These are particularly important studies as they illustrate the value of TMS in the systematic testing of key aspects of a well formulated cognitive conceptual model. It is this type of experimental approach that can fully leverage the advantages of TMS in studies of memory and learning. In a first study, Gagnon et al. (2010) applied paired-pulse TMS (interstimulus interval (ISI) 3 ms) over the left or right DLPFC during encoding or retrieval of verbal (words) and nonverbal stimuli (random shapes). They found that left and right DLPFC play different roles in encoding and retrieval irrespective of stimulus type: stimulation of the left DLPFC during encoding resulted in discrimination deficits, whereas stimulation of the right DLFPC during retrieval resulted in a reduced hit and disrimination rate. In a follow-up study they applied paired-pulse TMS with a longer ISI (15 ms) to promote facilitation (rather than cortical suppression) to the left and right DLPFC during encoding or retrieval of verbal (words) and nonverbal stimuli (random shapes) ( Gagnon et al., 2011 ). They found a facilitation of reaction times during encoding (left DLPFC) and retrieval (right DLPFC) regardless of the type of material presented. These results are consistent with other TMS studies ( Rossi et al., 2001 , 2006 ; Rami et al., 2003 ) and provide experimental support for the HERA model, which proposes that the left PFC is more involved in semantic retrieval and episodic encoding than the right PFC, whereas the right PFC is involved in episodic retrieval ( Tulving et al., 1994 ). This hemispheric asymmetry seems to uphold for both verbal and nonverbal material ( Haxby et al., 2000 ; Blanchet et al., 2010 ).

USING NONINVASIVE BRAIN STIMULATION AS A DIAGNOSTIC TOOL

In addition to uses in cognitive neuroscience, it is worth considering the potential utility of NBS in clinical neuroscience as a diagnostic tool. Diagnostic applications of NBS are appealing as they are noninvasive and can be applied safely to various patient populations across the lifespan, if appropriate precautions are taken and guidelines are followed ( Rossi et al., 2009 ). TMS has an excellent temporal resolution and its spatial resolution is superior to tDCS, which are important advantages in diagnostic applications and make TMS a superior tool to probe brain reactivity and brain connectivity.

To date, TMS has not been established as a diagnostic tool. However, if we define carefully the areas of need in specific patient populations, we may be able to complement currently used test measures, which rely mainly on behavioral assessments ( Rost et al., 2008 ; Sigurdardottir et al., 2009 ; Gialanella, 2011 ; Wagle et al., 2011 ).

As for motor dysfunctions, nonmotor memory functions could be characterized by changes in the excitation/inhibition (E/I) balance and cortical plasticity in specific brain areas, which could be assessed with TMS–EEG measures ( Thut and Pascual-Leone, 2010 ). Changes of such neurophysiological measures over the time-course of cognitive rehabilitation, during normal and pathological aging, or in response to treatment of disease could help us establishing neurophysiological biomarkers indicative of functional improvements. Such measures could not only be helpful to differentiate across pathological entities, but may also disentangle underlying causes of memory dysfunctions on an individual level. Finally, this information could help develop novel and improve existing interventions in order to improve memory functions.

In the memory domain there are several questions worth exploring with TMS as a diagnostic tool: (1) What is the pathogenesis of present memory problems? (2) Who is at risk of developing memory problems and what kind of memory problems? (3) Who is likely to benefit from a given behavioral/physiologic/pharmacological intervention?

Identify the pathogenesis of memory problems

Depending on the etiology, the pathogenesis of an individual patient’s memory problem can be vastly different and be affected by many factors including age, environmental, and genetic predispositions. Regardless of etiology, though, one can also aim to identify the proximal, neural dysfunction that accounts for a given memory deficit. TMS can be applied to gain insights at both these levels of inquiry.

Single- and paired-pulse TMS measures may reveal changes in connectivity or altered network dynamics and link those to specific memory functions. Advanced combined technologies such as TMS–EEG or TMS–MRI allow us to utilize TMS-induced cortical evoked potentials or TMS-induced blood oxygen level-dependent (BOLD) fMRI changes as neural measures of brain activity in specific brain regions or networks to relate to behavioral memory measures.

rTMS paradigms, for example intermittent and continuous TBS stimulation (iTBS and cTBS), can be used to obtain indices of cortical plasticity that appear related to long-term potentiation and depression (LTP and LTD)- like induction of synaptic plasticity. Such paradigms can be used to evaluate cortical plasticity in neural structures thought to support memory processes and may allow us to draw conclusions regarding the pathogenesis of a memory problem. For example, a cortical lesion within a widespread memory network could not only have a direct impact on memory functions caused by this particular lesion but could also lead to indirect deficits due to disconnection of the lesioned area with another memory hub. TMS measures could inform us about acute processes as well as adaptive or maladaptive changes characteristic of chronic processes that lead to memory dysfunctions ( Pascual-Leone et al., 2011 ).

Identify risk for developing memory problems

Another major area of interest lies in the possible use of TMS as a physiological biomarker, which could indicate the individual risk of developing memory dysfunctions with age and predict what kind of memory problems could be expected in certain populations. Cognitive decline including memory functions presents a critical hallmark of aging ( Morrison and Baxter, 2012 ). Early changes in neuroplasticity and neurophysiological circuits indicated by TMS measures, such as short-latency afferent inhibition (SAI), could constitute biomarkers for the development of neurodegenerative disorders ( Freitas et al., 2011b ). Risk identification with this approach requires the integration of numerous factors associated with causal and formal pathomechanisms, including age-related changes, but also, for example, changes related to systemic diseases, such as diabetes mellitus, that may indirectly have an impact on brain physiology and plasticity. TMS could be a valuable tool to identify these factors and consequently help guide and implement early interventions in populations at risk.

Another approach is using TMS measures to identify risks related to interventions that could result in brain lesions or dysfunctions. For example, consider neurosurgical interventions: presurgical detailed knowledge about functional contributions of brain areas to be resected can critically inform surgical approaches and minimize the risk. In this context, the Wada test can be used to determine hemispheric language dominance prior to brain surgery ( Wada and Rasmussen, 1960 ). However, this test has a non-negligible risk of complications and discomfort for the patient and does not allow precise functional localization. Neuronavigated TMS can provide detailed information regarding functional anatomy of the targeted brain area and is potentially valuable for presurgical planning not only in regard to language dominance ( Pascual-Leone et al., 1991 ; Devlin and Watkins, 2007 ), but also in regard to memory ( Grafman et al., 1994 ). Such noninvasive neuronavigated TMS cortical mapping appears to correlate well with direct cortical stimulation (DCS) results and seems to be more precise than fMRI, which is the most widely used technique today ( Krieg et al., 2012 ). As DCS is limited to intraoperative use, presurgical TMS might also save operation time by guiding intraoperative DCS.

Predicting benefit from a given intervention/medication

Cognitive rehabilitation consists in assessment-based therapeutic interventions aiming to reduce disability and promote functional recovery. Functional changes are achieved through various intervention methods targeting restitution, compensation, and adaptation ( Cicerone et al., 2000 ). But how can we determine whether a given therapeutic intervention will have a beneficial effect for an individual patient?

TMS measures may be used not only to track but also to predict intervention-related neuroplastic changes within memory networks. Moreover, TMS measures can inform us about the functionality of specific neurophysiological circuits implicated in memory functions and may be indicative of how well an individual will profit from a given pharmacological intervention. For instance, acetylcholine (ACh) is a neurotransmitter that plays a crucial role in synaptic plasticity and memory functions, and ACh imbalances have been associated with memory deficits in patients with Alzheimer’s disease (AD) ( Davies and Maloney, 1976 ; Coyle et al., 1983 ). Deficits in cholinergic circuits can be counteracted with pharmacological interventions involving acetylcholine esterase (AChE) inhibitors. SAI is a TMS measure that is indicative of cholinergic circuits in the motor cortex ( Di Lazzaro et al., 2000 ) and is altered in patients with AD (for a review see Freitas et al., 2011a ). SAI may even be useful to differentiate dementia subtypes ( Di Lazzaro et al., 2006 , 2008 ) and may be used as an indicator of who will profit from AChE inhibitors. Short-latency intracortical inhibition (SICI) and the cortical silent period (cSP) are thought to reflect the excitability of inhibitory γ-aminobutyric acid (GABA)ergic circuits ( Hallett, 2000 ) and were also found to be abnormal in patients with AD. However, the relationship of these TMS measures with specific memory dysfunctions is less clear ( Freitas et al., 2011a ). Notably, studies up to date have relied on TMS measures from the motor cortex. However, the combination of TMS with EEG may enable us to find more precise TMS biomarkers by exploring neurophysiological changes outside the motor cortex.

MODULATING LEARNING AND MEMORY

The interest in the augmentation of cognitive functions reaches far back into the history of modern humanity. The use of memory techniques, for instance in order to improve rhetorical skills, was already promoted by Marcus Tullius Cicero (“De Oratore”, Book II, 55 bc ). One of these methods, the “Cicero Memory Method” (Method of loci), a simple memory enhancement method that uses visualization to structure information, is still in use today. The pursuit of cognitive augmentation has since led researchers to take advantage of technical developments in order to achieve a better outcome. In the past decade, scientists have therefore started investigating the impact of various NBS techniques on memory functions.

Learning is a prerequisite for the formation of memory traces and is thought to be dependent on synaptic plasticity mediated by LTP and LTD, which also represent key mechanisms in the effects of NBS on brain functions. This has not only rendered NBS valuable for the investigation of neuroplastic processes associated with learning and memory but also promotes it as a valuable tool to enhance memory functions.

Although TMS is used mostly for diagnostic purposes and the investigation of brain structures contributing to specific functions, tDCS is more often applied to enhance brain functions.

Healthy subjects

In the past decade, researchers have begun examining the effects of WM training on neural correlates and concomitant performance ( Jaeggi et al., 2008 ). These studies have shown that not only can WM capacity be increased via constructive training but also that said training increases the density of cortical D1 dopamine receptors in prefrontal regions ( McNab et al., 2009 ). The neurobiological substrate of WM is an ongoing topic of research; however, prefrontal regions are believed to be critically involved. Consistent with such notions, studies exploring the potential for NBS to enhance WM have focused on the prefrontal cortex, generally the DLPFC, and the majority have used verbal WM tasks. In most studies subjects were asked to practice STM or WM tasks concurrently to tDCS, and their WM abilities were assessed either during or afterwards.

Compared with sham stimulation, tDCS with the anode over the left DLPFC (and the cathode right supraorbitally) has been repeatedly reported to enhance WM in healthy subjects ( Fregni et al., 2005 ; Ohn et al., 2008 ; Mulquiney et al., 2011 ; Teo et al., 2011 ; Zaehle et al., 2011 ). Some researchers have suggested that increasing stimulation intensity ( Teo et al., 2011 ) or duration ( Ohn et al., 2008 ) might lead to more robust effects. Only one study has reported no memory improvement following tDCS with the anode over the left DLPFC ( Mylius et al., 2012 ), and one study reported improvement in STM but not in WM ( Andrews et al., 2011 ). The only study applying tDCS with the anode over the right DLPFC showed no WM effect ( Mylius et al., 2012 ). On the other hand, tDCS with the cathode over the left DLPFC (and the anode right supraorbitally) yielded diverse results in different studies, ranging from memory benefits ( Mylius et al., 2012 ), to no effects ( Fregni et al., 2005 ), and even negative effects ( Zaehle et al., 2011 ). The study by Zaehle et al. (2011) is of particular interest as the authors reported that the negative effects of tDCS with the cathode over the left DLPFC were associated with decreased electroencephalographic power in theta and alpha bands over posterior (parietal) regions. On the other hand, the authors found that improved WM following tDCS with the anode over the left DLPFC was associated with increased power in alpha and theta EEG bands over parietal regions. This study illustrates the potential of studies combining behavioral and neurophysiological outcome measures, and suggests the critical role of corticocortical interactions in memory enhancement. It has been proposed that a more distributed network may subserve WM functions with the posterior parietal cortex (PPC) playing an important role ( Mottaghy et al., 2002a ; Collette et al., 2006 ). Stimulation might disrupt activity in a given cortical region and thus release activity in a distant connected node, resulting in paradoxical facilitation ( Najib and Pascual-Leone, 2011 ). The specific nature of the stimulation seems important, although, for example, random noise stimulation over the left DLPFC showed no effects ( Mulquiney et al., 2011 ).

In order to explore further the role of parietal structures in WM, Sandrini and colleagues (2012) applied bilateral stimulation over the PPC during a 1-back (STM) or a 2-back (WM) task. They found a double dissociation, with STM being impaired after left-anodal/right-cathodal and WM being impaired after left-cathodal/right-anodal stimulation. They concluded that this dissociation might be due to differential processing strategies in STM and WM. However, the effects might have been mediated by impact on attentional (rather than memory) processes given the fact that only response time, and not accuracy, was affected. Future studies will need to investigate further the contribution of parietal areas and their interaction with prefrontal areas to WM enhancement.

Further studies could examine the duration of effects, the likely synergistic effect of cognitive training with tDCS, or the applicability of tDCS or other NBS methods to enhance WM across the age span, from children to elderly. However, all such studies need carefully to weigh risk–benefit considerations, and should be informed by a thoughtful discussion of the ethical connotations of such enhancement approaches ( Rossi et al., 2009 ; Hamilton et al, 2011 ; Horvath et al., 2011 ).

Whether NBS can enhance STM in normal subjects is less clear. Studies show less consistent results. This could in part be due to the fact that basic STM tasks are easy for healthy subjects, which leads to ceiling effects. More recent studies have applied adapted tasks, which, however, makes it difficult to compare across studies. Most studies, similar to the literature on WM, have targeted the DLPFC. Two recent studies reported beneficial effects of tDCS with the anode over the DLPFC for an STM task with additional distractors ( Gladwin et al., 2012 ; Meiron and Lavidor, 2013 ). One study found a gender-dependent improvement in accuracy, with male subjects profiting more from left DLPFC stimulation and female subjects profiting more from right DLPFC stimulation, but only if distractor loads were high ( Meiron and Lavidor, 2013 ). The other study used a modified Sternberg task, which introduced additional distractor stimuli during the delay period ( Gladwin et al., 2012 ). These workers found significant reaction time improvements after stimulation of the left DLPFC. Compared with these studies, Marshall et al. (2005) applied tDCS with either two anodes or two cathodes over DLPFC, with the reference electrodes positioned over the mastoids, and found deleterious effects of STM. This may indicate that the introduction of distractors to an STM task changes underlying neurobiological processes and enables enhancement effects. Improvements after tDCS may be due to either improved selective attention or more successful inhibition of distracting information. Indeed, a recent TMS study has shown that the role of the DLPFC in STM tasks seems to be dependent on the presence of distractors. The stronger the distraction, the more prominent the frontoparietal interactions become, in order to protect relevant memory representations ( Feredoes et al., 2011 ).

Studies in which investigators stimulated parietal areas have yielded partly opposing results. This is true of studies using tDCS and those employing TMS. Regarding TMS experiments, some show worsened STM ( Koch et al., 2005 ; Postle et al, 2006 ), while the other report improved STM ( Hamidi et al., 2008 ; Yamanaka et al., 2010 ) after high-frequency parietal stimulation during the delay period. As for tDCS experiments, Berryhill et al. (2010) found impairment in recognition, but not free recall, after tDCS with the cathode over the right parietal cortex (and the anode over the left cheek), whereas Heimrath and coworkers (2012) , positioning the cathode over the right parietal cortex (and the anode over the contralateral homologous area), found an improved capacity in a delayed match-to-sample task after tDCS when stimuli were presented in the left visual hemifield (STM for stimuli presented in the left hemifield decreased). Interestingly, Heimrath et al. used concurrent tDCS and EEG, and found a decrease in oscillatory power in the alpha band after cathodal stimulation. As alpha activity is assumed to reflect inhibition of distractors ( Klimesch, 1999 ), the authors suggested that this measure might indicate memory performance. This study again illustrates the potential of experiments combining behavioral and neurophysiological outcome measures with NBS.

Finally, one study probed the cerebellum and found an abolishment of practice-dependent improvements in response time in a Sternberg task, regardless of whether the anode or the cathode was placed over the cerebellum (and the other electrode over the vertex) ( Ferrucci et al., 2008 ). The contribution of the cerebellum to STM was also probed with single-pulse TMS by Desmond and colleagues (2005) , who also found a negative effect on response time in the Sternberg task. Whether other cerebellar stimulation paradigms can induce an enhancement of STM remains unexplored.

G eneral memory and learning

Researchers attempting to enhance learning processes have targeted various neural regions. Such diverse approaches again render it difficult to single out a pattern regarding stimulatory condition, mechanisms, and outcome. Most studies have applied tDCS during the learning phase, and most have targeted the left DLPFC or other left prefrontal areas. Generally, studies report memory improvement following tDCS with the anode over DLPFC ( Kincses et al., 2004 ; Javadi and Walsh, 2012 ; Javadi et al., 2012 ) or other prefrontal areas ( De Vries et al., 2010 ), and worsening memory after tDCS with the cathode over DLPFC ( Elmer et al., 2009 ; Hammer et al., 2011 ; Javadi and Walsh, 2012 ; Javadi et al., 2012 ) or other prefrontal areas ( Vines et al., 2006 ). However, in interpreting their results, investigators have often made the overly simplistic assumption that the effects of tDCS can be accounted for by the neurobiological effect of one of the electrodes, the anode enhancing and the cathode suppressing activity in the brain area under them. Yet, it is important to remember that tDCS is not monopolar and that all electrodes are active. Thus the brain is exposed to a flow of current with opposite faradizing effects of the anode and the cathode. Therefore, to speak of anodal tDCS or cathodal tDCS is inaccurate.

Few studies have targeted right prefrontal areas. One study reported no effects in an episodic verbal memory task after tDCS with either anode or cathode over the right prefrontal region ( Elmer et al., 2009 ). Two studies showed that the learning process of threat detection in a virtual reality environment and the time required to learn this skill can be improved following tDCS with the anode over the right prefrontal ( Bullard et al., 2011 ; Clark et al., 2012 ) or right parietal region ( Clark et al., 2012 ). Furthermore, Bullard and colleagues (2011) found that applying tDCS at the beginning of the learning phase significantly enhanced learning in comparison with findings in experienced learners (after 1 hour of training).

Bilateral stimulation (anode and cathode over homologous areas of either hemisphere) has been applied in a few studies ( Marshall et al., 2004 , 2011 ; Boggio et al., 2009 ; Chi et al., 2010 ; Cohen Kadosh et al., 2010 ; Penolazzi et al., 2010 ; Jacobson et al., 2012 ). Jacobson and coworkers (2012) applied bilateral tDCS (anodal left, cathodal right, or vice versa) over the parietal lobe during encoding. They found improved verbal memory only when the anode was placed over the left hemisphere and the cathode over the right hemisphere. Another study investigating the contribution of the parietal cortex to numerical learning applied bilateral tDCS during a training phase of 6 days ( Cohen Kadosh et al., 2010 ). While right-anodal/left-cathodal stimulation improved learning significantly, right-cathodal/left-anodal stimulation decreased learning compared with sham tDCS.

Penolazzi and colleagues (2010) applied bilateral tDCS (anode left and cathode right, or vice versa) over the frontotemporal cortex during encoding and found facilitated recall of pleasant images after right-anodal/left-cathodal tDCS, whereas left-anodal/right-cathodal tDCS facilitated recall of unpleasant images. These results support a theoretical model (specific valence hypothesis) according to which the right and left hemispheres are specialized in the processing of unpleasant and pleasant stimuli respectively. Another group applying bilateral stimulation (anodal left, cathodal right, or vice versa) over the anterior temporal lobe assessed visual memory ( Chi et al., 2010 ) and also reported an improvement in memorizing different types of shape after right-anodal/left-cathodal stimulation, but no effects when applying an inverse stimulation pattern.

One set of studies has investigated effects of bilateral anodal stimulation over DLPFC during sleep and wakefulness. In their first study, Marshall and colleagues (2004) reported an improvement of memory consolidation when applying intermittent (on/off 15 seconds) anodal tDCS simultaneously over both DLPFCs during slow-wave (nonrapid eye movement, non-REM) sleep but not during wakefulness. In a second study they investigated state-dependent effects, and found enhanced theta activity when transcranial slow oscillation stimulation (tSOS) was applied during wakefulness ( Kirov et al., 2009 ). Memory enhancement occurred only when tSOS was applied during learning, but not after learning. In their third study, Marshall and colleagues (2011) applied anodal theta-tDCS (tDCS oscillating at 5 Hz) during REM sleep and non-REM sleep, which led to increased gamma-band activity and decreased memory consolidation respectively. The data from these studies illustrate the potential of transcranial current stimulation at specific stimulation frequencies selectively to modulate specific brain oscillations. This NBS method provides an interesting approach for investigating the relation between cortical brain rhythms, sleep-related processes, and memory functions.

Some studies have reported apparently contradictory results, highlighting the need for further investigation of the mechanisms of action underlying tDCS and TMS. Boggio et al. (2009) found decreased “false memories” utilizing anodal tDCS over the left anterior temporal lobe, or bilateral (left-anodal/right-cathodal) tDCS. However, the same researchers reported a nearly identical effect after applying 1-Hz rTMS over the same region, a protocol that is believed to suppress activity of the targeted brain area ( Gallate et al., 2009 ). Of course, it is possible that the behavioral effect might be related to trans-synaptic network effects, rather than being mediated by the targeted brain region. Indeed, a study using single-pulse TMS reported a facilitatory effect on verbal memory after stimulating the right inferior PFC ( Kahn et al., 2005 ), presumably due to interhemispheric paradoxical facilitation effects. This would be consistent with another study that found an improvement in verbal memory after stimulating the left inferior PFC with 7-Hz rTMS bursts ( Köhler et al., 2004 ). Furthermore, a paired-pulse protocol known to induce facilitatory effects led to memory improvements after stimulation of the left and right DLPFC in verbal as well as nonverbal episodic memory. The combination of stimulation techniques and other methods, such as EEG and fMRI, allows their inherent advantages to be combined to help answer these open questions.

Elderly healthy subjects

Basic memory research includes mostly young and healthy subjects. However, one of the key topics in the domain of NBS research concerns the changes of interhemispheric balance and the increased compensatory recruitment of brain areas with aging. As memory represents an overarching topic for the elderly, it is crucial to promote research that investigates these changes and provides information as to how to enhance memory functions. Furthermore, research with healthy elderly subjects is vital if we want to translate it into the clinical setting, as patients with memory deficits are mostly older. A newly emerging field has started to investigate memory enhancement in elderly subjects and underlying models ( Rossi et al., 2004 ; Solé-Padullés et al., 2006 ; Manenti et al., 2011 ; Flöel et al., 2012 ).

The “Hemispheric Asymmetry Reduction in Older Adults” (HAROLD) model states that prefrontal activity during cognitive performance becomes less lateralized with advancing age ( Cabeza, 2002 ). Manenti and colleagues investigated the differential assumptions of the HERA model (young subjects) and the HAROLD model (elderly subjects), suggesting that hemispheric asymmetry is reduced with age. Interestingly, they could show that low-performing elderly subjects continue showing prefrontal asymmetry, whereas high-performing elderly individuals show reduced asymmetry indicative of compensatory mechanisms ( Manenti et al., 2011 ).

Although lateralized activations within the PFC can be observed in younger subjects during episodic memory tasks ( Rossi et al., 2001 ), this asymmetry vanishes progressively with advancing age, as indicated by bilateral interference effects ( Rossi et al., 2004 ).

Conversely, the predominance of left DLPFC effect during encoding was not abolished in older subjects, indicating its causal role for encoding along the lifespan. However, this study did not differentiate between high- and low-performing subjects. Another study supported the assumption that higher performance is associated with more bilateral recruitment of brain areas and that stimulation may be able to promote the recruitment of additional brain areas to compensate for age-related decline. Solé-Padullés and colleagues (2006) found improved performance in associative learning after 5-Hz offline rTMS, which was accompanied by additional recruitment of right prefrontal and bilateral posterior brain regions.

A tDCS study showed improvements in spatial learning and memory in elderly subjects (mean 62 years) when stimulating during encoding ( Flöel et al., 2012 ). Anodal stimulation over the right temporoparietal cortex improved free recall 1 week later compared with sham stimulation. No immediate learning differences were observed, which indicates that retention (less decay) rather than encoding was affected by the stimulation.

To summarize, several studies have found different results following the stimulation of the DLPFC in young and elderly healthy subjects in accordance with the HAROLD model ( Cabeza, 2002 ). These differences could be due to changes in interhemispheric balance and recruitment of different brain areas for the same tasks, which could arise due to compensatory mechanisms. It remains to be further elucidated whether these changes reflect local or distributed mechanisms, whether compensatory recruitment of additional brain areas is associated with higher performance levels and could be enhanced by NBS.

Compared with the wealth of studies that have been done with healthy and mostly young subjects, studies on patients are rather sparse (see Table 55.1 ). The evidence is encouraging and calls for further investigation of the combined application of NBS and neuropsychological therapy. Besides behavioral measures, these studies should ideally include other measurements, such as assessment of brain plasticity or memory-specific neurophysiological outcomes. The work on patients with stroke is very preliminary, and more studies with larger patient numbers and better control of lesion location are needed. In one crossover, sham-controlled study, Jo et al. (2009) applied tDCS with the anode over the left DLPFC (and the cathode over the contralateral supraorbital area) in a 2-back task to 10 patients with unilateral, right-hemispheric, ischemic, or hemorrhagic strokes (1–4 months poststroke). After a single stimulation session, performance accuracy but not reaction time improved significantly. Enhancement of memory functions has been more extensively investigated in patients with AD and Parkinson’s disease (PD). These findings provide evidence that NBS could be a safe and useful tool in restoring/compensating brain functions through activation of primary and compensatory networks that underlie memory functions.

A lzheimer’s disease

A few studies have demonstrated effects of NBS on cognitive functions in AD (6 TMS, 3 tDCS). The first studies that used NBS in AD looked primarily at language and not memory functions. Cotelli and colleagues used rTMS (20 Hz) over the left and right DLPFC and reported positive effects for both hemispheres. They applied a single online session of rTMS in two crossover, sham-controlled studies ( Cotelli et al., 2006 , 2008 ). In the first study they reported improved accuracy in action naming, but not object naming, for all patients ( Cotelli et al., 2006 ). In the second study they could replicate the positive results for action naming; however, object naming also improved significantly, although only in moderately to severely impaired patients ( Cotelli et al., 2008 ). The authors hypothesized that the lack of improvement in object naming may be due to a ceiling effect. Furthermore, the bilateral effect could have been due to compensatory activation of right hemispheric resources.

In a third placebo-controlled study the same authors tested various functions, including memory, executive functions, and language in patients with moderate AD ( Cotelli et al., 2011 ). This study entailed 4 weeks of daily sessions of 20-Hz rTMS to the left DLPFC. Although they found significant improvements in sentence comprehension after 10 sessions (with no further improvement after 20 sessions), they did not find any improvements in memory and executive functions ( Cotelli et al., 2011 ). This lack of improvement could be due to the fact that the patients were not doing any specific concomitant cognitive training. Alternatively, the lack of memory effects could be related to the targeted brain region.

Bentwich and colleagues (2011) interleaved cognitive training and rTMS (10 Hz) during 30 sessions while stimulating six different brain regions (Broca, Wernicke, right and left DLPFC and parietal cortices). During each session three of these regions were stimulated while patients did cognitive tasks that were developed to fit each of these regions. Improvements in cognitive functions were significant, as measured using the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog), and were maintained for 4.5 months after the training. A case report ( Haffen et al., 2012 ) showed an improvement in episodic memory (free recall) and processing speed following 10 sessions of rTMS (10 Hz) over the left DLPFC. These are open trials and, obviously, sham-controlled interventions are needed. However, the results are promising and warrant follow-up. In a sham-controlled trial, Ahmed and colleagues (2012) assigned 45 patients with AD to three different treatment groups to study the effects of high- or low-frequency rTMS (20 Hz, 1 Hz), or sham stimulation. Patients received treatment on 5 consecutive days without combined cognitive training. Mildly to moderately impaired patients receiving high-frequency rTMS improved significantly on all scales (Mini Mental State Examination (MMSE), Instrumental Daily Living Activity Scale, Geriatric Depression Scale), and maintained these improvements for 3 months. However, severely impaired patients did not respond to the treatment.

Two crossover studies applied tDCS for one session and reported improvements in visual recognition memory following stimulation of the left DLPFC and temporoparietal cortex (TPC) ( Boggio et al., 2009 ), and in word recognition following stimulation of the bilateral TPC ( Ferrucci et al., 2008 ). In the first study, the authors applied 15 minutes of anodal, cathodal, and sham stimulation over bilateral TPC on three different sessions in patients with mild AD. While anodal tDCS led to an improvement, cathodal stimulation led to impairments in word recognition. No effects were observed in a visual attention task ( Ferrucci et al., 2008 ). In the second study, mildly to moderately impaired AD patients received anodal tDCS over the left DLPFC, the left TPC, or sham stimulation. Stimulation over both DLFPC and TPC resulted in a significant improvement in visual recognition. No effects were observed on selective attention or a visual delayed match-to-sample task.

Possibly, tDCS-induced changes in cholinergic activity contributed to these improvements. A recent study reported a significant change of SAI (ISI 2 ms) in the motor cortex of healthy subjects after anodal stimulation, while the resting motor threshold and amplitudes of motor evoked potentials did not change ( Scelzo et al., 2011 ). This could explain the positive impact of tDCS on memory functions in the above-mentioned studies. Future studies measuring behavioral along with neurophysiological effects and exploring correlations between them would be desirable.

P arkinson’s disease

Two studies have applied TMS or tDCS with the aim of improving cognitive functioning in PD. The first study compared the effects of active or sham rTMS and fluoxetine or placebo in patients with PD with concurrent depression ( Boggio et al., 2005 ). The authors applied 15-Hz rTMS over the left DLPFC for 10 daily sessions, and assessed cognitive functions at baseline, and 2 and 8 weeks after the treatment. Treatments were not combined with cognitive training or psychotherapy. After 2 weeks both interventions led to similar improvements in the Stroop Test and the Wisconsin Card Sorting Test (executive functions), and the Hooper (visuospatial functions). Furthermore, depression rates improved significantly in both groups. However, no improvements were reported in STM or WM (digits forward and backward). Eight weeks after treatment, these improvements declined slightly but remained significant.

The second study found improved accuracy in a 3-back task during a single session of anodal tDCS over the left DLPFC. Improvement was significant at a stimulation intensity of 2 mA but not at 1 mA ( Boggio et al., 2006 ).

Cognitive impairments in PD are often associated with depression symptoms, which occur in about 35% of patients. Furthermore, dementia is common in these patients with a point prevalence of 30% ( Aarsland and Kurz, 2010 ). Further studies are needed to investigate underlying processes leading to cognitive impairments. Moreover, studies should evaluate the efficacy of repetitive NBS in combination with cognitive training for this patient population.

A quickly growing number of studies is using NBS applications to study the underlying neurobiological substrates of memory functions, to investigate the use of TMS as a diagnostic tool, and the application of NBS to enhance memory functions. To date, most studies have used TMS to probe underlying memory processes and their causal and temporal relationships, whereas TMS, tDCS, and other forms of transcranial current stimulation are being used to enhance memory functions in healthy as well as patient populations. The combination of NBS with other methods, such as EEG and fMRI, enables the measurement of behavioral along with neurophysiological effects; the exploration of correlations between them is desirable to advance our neurobiological understanding and optimize future interventions.

ACKNOWLEDGMENTS

A.P.-L. serves on the scientific advisory boards for Nexstim, Neuronix, Starlab Neuroscience, Neosync, and Novavision, and is listed as an inventor on several issued and pending patents on the real-time integration of transcranial magnetic stimulation (TMS) with electroencephalography (EEG) and magnetic resonance imaging (MRI). Work on this study was supported by grants from the National Center for Research Resources: Harvard Clinical and Translational Science Center/Harvard Catalyst (UL1 RR025758), and investigator-initiated grants from Nexstim Inc. and Neuronix. A.-K.B. was supported by the Young Academics Support of the University of Zurich, Switzerland. K.R. was supported by the Dean’s Summer Research Award Grant, Harvard University.

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COMMENTS

  1. Mechanisms of Memory Enhancement

    Go to: Abstract The ongoing quest for memory enhancement is one that grows necessary as the global population increasingly ages. The extraordinary progress that has been made in the past few decades elucidating the underlying mechanisms of how long-term memories are formed has provided insight into how memories might also be enhanced.

  2. Cognitive neuroscience perspective on memory: overview and summary

    This paper explores memory from a cognitive neuroscience perspective and examines associated neural mechanisms. It examines the different types of memory: working, declarative, and non-declarative, and the brain regions involved in each type. The paper highlights the role of different brain regions, such as the prefrontal cortex in working ...

  3. (PDF) Memory Types and Mechanisms

    This paper discusses three essential items: the different types of memory, their molecular physiology and their corresponding dysfunctions. Discover the world's research Content uploaded by...

  4. Metamemory: Metacognitive Strategies for Improved Memory Operations and

    1. Introduction Memory is one of the most vital cognitive functions, affecting almost all aspects of human life. A strong, active memory is the foundation of our whole mental functioning, ensuring survival, learning, and achievement. Even self-identity is dependent on our memories.

  5. Mechanisms of memory enhancement

    Short-term memory (STM) thus refers to memories that are held in mind for a relatively short period of time—seconds to minutes (i.e., remembering a phone-number until you can write it down).7 This differs from long-term memory, which can hold information for long periods of time, without a predefined limit on the quantity of information held.

  6. Strategies to Enhance Memory Based on Brain Research

    Semantic memory, also called conceptual knowledge or declarative memory, is a type of long-term memory, which contains general knowledge about objects, word meanings, facts and concepts, rules ...

  7. 8.4 Ways to Enhance Memory

    You may recall that 6 x 6 = 36, 6 x 7 = 42, and 6 x 8 = 48. Memorizing these facts is rehearsal. Another strategy is chunking: you organize information into manageable bits or chunks (Bodie, Powers, & Fitch-Hauser, 2006). Chunking is useful when trying to remember information like dates and phone numbers.

  8. Mechanisms of memory enhancement

    The ongoing quest for memory enhancement is one that grows necessary as the global population increasingly ages. The extraordinary progress that has been made in the past few decades elucidating the underlying mechanisms of how long-term memories are formed has provided insight into how memories might also be enhanced.

  9. PDF Improving Memory Strategies

    Teach someone (even yourself!): Try teaching someone the concept you're trying to remember. You can even try to talk to yourself about it! Vocalizing helps activate different sensory processes, which enhance memory. Interleave: We often think we'll do best if we study one subject for long periods of time, but research contradicts this.

  10. How to Improve Memory

    Accordingly, "cramming"—studying in one long, continuous period—can be an unhelpful study habit. Testing memory of learned material, such as a passage of text, can enhance memory for that...

  11. Enhance your memory

    Psychologists are finding strategies to help people adapt to memory problems, including: Take mental snapshots. Good memory is actually good learning, say rehabilitation experts. That means forming a strong association with new information as you learn it. Systematically take note of things. When you put down your keys, for instance, take a ...

  12. The Influence of Colour on Memory Performance: A Review

    Similarly, a high level of arousal leads to enhancement of both short-term and long-term memory. In an experiment conducted by Corteen (cited in 27), which used aurally presented words, it was reported that higher recall was found after 20 minutes and two week delays. The same result was reported in an experiment which used a single arousing word.

  13. Ways to Enhance Memory

    Some other strategies that are used to improve memory include expressive writing and saying words aloud. Expressive writing helps boost your short-term memory, particularly if you write about a traumatic experience in your life. Masao Yogo and Shuji Fujihara (2008) had participants write for 20-minute intervals several times per month.

  14. Term Paper: Memory Enhancement

    👤 Memory Enhancement Term Paper Pages: 4 (1193 words) · Bibliography Sources: ≈ 2 · File: .docx · Topic: Psychology ¶ … Wagner, U., Gais, S., Haider, H., Verleger, R., & Born, J. (2004). Sleep inspires insight. Nature, Research area The notion of insight is difficult to quantify but psychologists have attempted to do so for many years.

  15. Mechanisms of memory enhancement

    The ongoing quest for memory enhancement is one that grows necessary as the global population increasingly ages. The extraordinary progress that has been made in the past few decades elucidating the underlying mechanisms of how long-term memories are formed has provided insight into how memories might also be enhanced.

  16. 10 Influential Memory Theories and Studies in Psychology

    An influential theory of memory known as the multi-store model was proposed by Richard Atkinson and Richard Shiffrin in 1968. This model suggested that information exists in one of 3 states of memory: the sensory, short-term and long-term stores. Information passes from one stage to the next the more we rehearse it in our minds, but can fade ...

  17. Evidence-Based Strategies to Improve Memory and Learning

    In the book Make it Stick: The Science of Successful Learning, authors Henry Roediger and Mark McDaniel, cognitive scientists specializing in the study of learning and memory, together with novelist Peter Brown, tell engaging stories of how people learn in a way that allows them to successfully apply their knowledge and skills.

  18. Understand & Improve Memory Using Science-Based Tools

    01:34:41 Tool: Timing of Exercise, Learning & Memory Enhancement; 01:37:29 Photographic Memory; 01:38:49 "Super Recognizers," Facial ... really just want to focus on short-term memory, medium-term memory, and long-term memory. And while there's still debate, as is always the case with scientists, frankly, about the exact divisions between ...

  19. PDF Effects of Visual Communication on Memory Enhancement of Thai ...

    can increase memory performance in terms of the recall rates (Smilek et al., 2002; Pan, 2012). In addition, the human brain quickly recognizes, stores and recalls images, seamlessly and subconsciously cementing ideas in long-term memory (Wulandari, 2018) because images contain two codes, that is, one visual and the other one verbal.

  20. Term Paper

    Term Paper. Definition: Term paper is a type of academic writing assignment that is typically assigned to students at the end of a semester or term. It is usually a research-based paper that is meant to demonstrate the student's understanding of a particular topic, as well as their ability to analyze and synthesize information from various sources.. Term papers are usually longer than other ...

  21. Memory enhancing drugs and Alzheimer's Disease: Enhancing the self or

    Rephrased and focused on the subject of this paper, the crucial problem can be stated as follows. The term 'memory enhancing drugs' suggests that these drugs do indeed enhance memory. Apart from the problem what 'memory' and 'enhancement' then mean, the question is whether MEDs also enhance the self?

  22. Study shows stronger brain activity after writing on paper than on

    Summary: A study of university students and recent graduates has revealed that writing on physical paper can lead to more brain activity when remembering the information an hour later....

  23. Learning and memory

    The main goals of research with NBS in learning and memory have been to: (1) identify underlying neuropsychological processes and neurobiological components; (2) find out how this knowledge can be used to diagnose and restore dysfunctions of learning and memory in various patient populations; and (3) assess the use of NBS for enhancement purpose...