Memory

Table of Contents

Neurobiology of Memory

Memory is essential for learning. Learning and memory are complicated processes of the brain in which information from our experiences (i.e., our senses) can be stored and then retrieved later. Memory and learning are important evolutionarily but also for everyday functioning. When these processes fail, as in neurodegenerative diseases, simple tasks become very difficult.

Much of our understanding about learning comes from studies on individuals with brain lesions. The most famous case was a man named H.M. with intractable epilepsy who underwent surgery to remove both of his medial temporal lobes. After the surgery, H.M. had significant memory deficits. He could not form new memories. He could not remember what happened the day prior, could not remember anyone he met, but was able to recall remote events in his life. Remarkably, H.M. retained his ability to improve his performance on procedural tasks despite being completely unaware that he had learned it previously. What H.M. taught us was that forming new declarative memories require structures in the medial temporal lobes (hippocampus and related structures), but over time memories become stored in other areas of the brain and are independent of the medial temporal lobe structures.

In humans, storing information involves two systems: declarative (also called explicit or conscious memory) and non-declarative (also called implicit or unconscious memory).

  • Declarative memory is memory that can be “declared” by language and is within the realm of our consciousness. Declarative memory is further divided into Episodic memory (i.e. memory for events and experiences) and Semantic memory (i.e. memory of facts).
  • Non-declarative or implicit memory or “procedural” memory is within the realm of the unconscious. That is, when we learn to ride a bike or play an instrument, it is very difficult to explain in words “how” we do it. In fact, focusing on every detail of how we are riding a bike may make riding a bike more difficult.  Non-declarative memory does not require us to be aware that we are “remembering” what it is we are trying to remember. Some people call this “muscle memory.” Non-declarative memory is further divided into Skills and Habits, Priming, Classic Conditioning, and Non-associative learning (also called habituation).

Memory can be classified by time

Learning and Memory can be thought of as processes that occur in stages over time:

  1. Acquisition is the first stage where information is acquired through our primary sensory organs and “registered.” This first stage has also been called registration and occurs within fractions of seconds. The primary structure involved is the prefrontal cortex
  2. After information is registered, the information then moves into the next processing stage called Short Term Memory (also called working memory or immediate memory). Information can be retained in this form of short term memory for seconds or minutes and the primary structures involved include the Prefrontal Cortex and Hippocampal Formation (within the temporal lobe). Short term memory is easily disrupted by distraction and can be enhanced with rehearsal. For example, when told a phone number, if someone diverts your attention while trying to remember the number, you will likely forget it. However, repeating the number over and over in your head will improve your ability to remember it. 
  3. If we were only able to remember things for a few minutes, we would have a very difficult time surviving. We would injure ourselves or repeat the same mistakes over and over again. Therefore, the ability to store information for longer than a few minutes is essential to an organism’s ability to survive. This is where Long Term Memory comes into play. Long term memory occurs when short term memory is “consolidated” into a more permanent form that may last for days to years. The primary structures involved include the Association Cortices and Hippocampus and requires changes in the synaptic connections between neurons (e.g., Long Term Potentiation/Long Term Depression). Long-Term Potentiation (LTP) is a process that occurs between neurons whereby their connection become “stronger” and/or more efficient. This requires NMDA/AMPA/Ca++ mediated changes that are not discussed here. 
  4. The final stage is Retrieval, the process in which the stored information is brought to awareness when needed. 

It is important to note that this process is not necessarily linear. This is a dynamic process involving multiple stages occurring simultaneously as new information is added to old information in ways that are still poorly understood. 

Below we review the various components of memory as well as the mechanisms responsible for remembering things.

DECLARATIVE MEMORY

Declarative memory is memory that can be “declared” by language and is within the realm of our consciousness. Declarative memory is further divided into Episodic memory (i.e. memory for events and experiences) and Semantic memory (i.e. memory of facts). Declarative memory is more recent phylogenetically and is available to multiple response systems. 

Structures involved in Declarative memory:

Medial temporal lobe structures

  •   Hippocampus 
  •   Perirhinal Cortex
  •   Parahippocampal cortex
  •   Amygdala

Midline diencephalic structures

  •   Midline thalamic nuclei
  •   Dorsomedial thalamus
  •   Anterior thalamus
  •   Mammillary nuclei

Neocortex

  •   Frontal Association Cortex
  •   Sensory Association Cortex

HIPPOCAMPUS INPUTS AND OUTPUTS FOR DECLARATIVE MEMORY FORMATION

  • Inputs and outputs to and from the hippocampus are bundled together in the same paths. This makes learning the pathways a little easier. If you know the outputs then you know the inputs.
  • The fornix and the entorhinal cortex are the two major “roadways” to and from the hippocampus.

 

Fornix

The fornix is a C-shaped white matter tract that connects the hippocampus with other important structures in the brain. The fornix begins as a bundle of fibers called the alveus and splits into many pathways before and after the anterior commissure. The section of the fornix located before the anterior commissure splits off and connects to the septal nuclei, preoptic nuclei, ventral striatum, orbital cortex and anterior cingulate cortex. The section of the fornix located after the anterior commissure splits off and connects to the anterior nucleus of the thalamus and the mammillary bodies of the hypothalamus. 

The anterior thalamic nuclei in turn connect to the cingulate cortex. The cingulate cortex projects back to the entorhinal cortex of parahippocampal gyrus, completing the Papez circuit, named after James Papez who originally discovered the circuit and thought it to be the location of emotional experience. It is now well known that the amygdala, along with neocortical areas, are involved in emotional experience.

In addition to receiving inputs from the mammillary bodies of the hypothalamus, the hippocampus also receives inputs from the nucleus basalis of Meynert (NBM) via the fornix. The NBM is a portion of the substantia innominata which is itself part of the many septal nuclei.

The Entorhinal Cortex

The entorhinal cortex is a major source of inputs to the hippocampus. The cingulate cortex, temporal lobe cortex, amygdala, orbital cortex, and olfactory bulb all converge onto the entorhinal cortex, which then relays information to the hippocampus. 

The hippocampus has direct connections to the entorhinal cortex (via the subiculum) and the amygdala which connect to other brain regions. Because the entorhinal cortex projects to the cingulate cortex, the hippocampus can affect the cingulate cortex through either the anterior thalamic nucleus or the entorhinal cortex. The cingulate cortex, in turn, projects to the temporal lobe cortex, orbital cortex, and olfactory bulb. 

The Frontal Lobe And Declarative Memory

Lesions of the frontal lobe result in the following deficits:

  1. Poor memory for context in which info was acquired
  2. Difficulty in unaided recall
  3. Difficulty implementing memory retrieval strategies
  4. Difficulty evaluating and monitoring memory performance (unable to assess own memory dysfunction)

It appears that information is first processed in the cortical association areas and then sent to the hippocampus for consolidation. Long term memories are not stored in the hippocampus but redistributed throughout the cortex and become independent of medial temporal lobe structures.

NON-DECLARATIVE MEMORY

Non-declarative or implicit memory or “procedural” memory is within the realm of the unconscious. That is, when we learn to ride a bike or play an instrument, it is very difficult to explain in words “how” we do it. In fact, focusing on every detail of how we are riding a bike may make riding a bike more difficult.  Non-declarative memory does not require us to be aware that we are “remembering” what it is we are trying to remember. Some people call this “muscle memory.” Non-declarative memory is further divided into Skills and Habits, Priming, Classic Conditioning, and Nonassociative learning (also called habituation).  Retrieval of nondeclarative memories requires engaging specific processing systems (i.e., you have to do it to remember it) whereas declarative memories are available to multiple systems. 

Primary structures involved in non-declarative memories:

 

  • Neocortex: Priming, Habits, Extinction
  • Basal Ganglia: Habits
  • Cerebellum: Conditioning (especially of skeletal musculature), Extinction
  • Amygdala: Emotional learning
  • Hippocampus: Contextual Features

Priming

  • Priming refers to the ability to detect or to identify a particular stimulus based on recent experience. It is an unconscious process. For example, if we set up an experiment whereby we talked about the hippocampus and the next day I asked you to pick three animals, you might choose hippopotamus as one of them simply because “hippo” was discussed earlier and your brain was “primed” for this. Many “Mentalists” use priming to “predict” how people will respond. Priming is usually intact in patients with amnesia. Why? Likely because priming is independent of medial temporal lobe structures which are often affected in amnesia disorders. There are two main types of priming:
  • Perceptual priming: Naming pictures of previously presented objects much faster than naming pictures of new objects. The word stem completion test is an example of a test of perceptual priming.
  • Conceptual priming: Meaning rather than precepts (e.g. remembering doctor much quicker after being primed with nurse

ASSOCIATIVE LEARNING (CLASSIC CONDITIONING) AND EMOTIONAL RESPONSES

  • Classical Conditioning: Classical Conditioning involves pairing an unconditioned stimulus with a conditioned stimulus to elicit a conditioned response. For example, in rabbits, air puffs to the eye (unconditioned stimulus) elicits a blink response (unconditioned response). If the air puff is then paired with a sound (conditioned stimulus) then over time the conditioned stimulus evokes the same response. That is, the sound causes the rabbit to blink even without the air puff to the eye (unconditioned stimulus). The blinking in response to the sound (without the air puff) is the conditioned response. Interestingly, when deep nuclei of cerebellum are reversibly disrupted, the conditioned response is eliminated without affecting the unconditioned response (blinking after air puff). However, these lesions also prevent initial learning from occurring.
  • Fear conditioning and fear-potentiated startle: Mice exhibit freezing behavior when returned to a situation (like a cage) in which an adverse stimulus (e.g., an electric shock) was given previously. This learning depends on the encoding of contextual features of the environment at the time of the adverse stimulus/event. Acquiring and expressing this type of learning requires neural circuits that include both the amygdala (associating negative affect with new stimuli) and hippocampus (representing the context).
  • Extinction: Extinction is the gradual reduction in the response to a feared stimulus when the stimulus is repeatedly encountered without an adverse experience (also called extinction training). Extinction is likely accomplished through the development of new memories rather than “erasing” the old memories. That is, “forgetting” is an active process. The frontal cortex is a key player in extinction. Exposure therapies, such as Exposure Response Prevention, are based upon this concept. 
  • Forgetting is an active process: For efficiency (and lack of enough brain matter), Memories are stored as broad outlines rather than details. As time goes on, we lose memories due to weaker synaptic connections. The brain removes old material in an active process to make room for new memories. Neurogenesis in the hippocampus has been correlated with more “forgetting.” This suggests “new memories” are required to “forget” old memories

METAMEMORY

  • Metamemory is the ability to judge one’s memory abilities. Metamemory tests are helpful in distinguishing amnesia/dementia from memory deficits of depression.

TRAUMA AND MEMORY

  • Traumatic experiences are known to produce long-lasting, intense (but not necessarily accurate) memories. It appears that chronic stress corrupts the memory-storage process. Studies have shown that humans who were given stress levels of cortisol demonstrate impaired declarative memory within days. The hypothesized mechanism is excess glucocorticoids causing atrophy of hippocampal dendrites which shrinks the hippocampus and decreases hippocampal neurogenesis

SLEEP AND MEMORY

  • A group at University of California, Riverside, postulated that episodic memories acquired during the day are temporarily stored in the hippocampus and relayed up to the cortex during the night for long-term storage. Investigators found evidence that alternating electrical activity between the hippocampus and cortical neurons during deep sleep strengthens synaptic connections that are believed to be the physical manifestation of memory storage. Maybe this is why we spend 1/3 of our lives sleeping? Interestingly, memory storage is enhanced by the processing that occurs during deep sleep (slow wave sleep) within a few hours after learning. TIP: Maybe studying this and then sleeping well will help you remember this. Research suggests that declarative memory (not non-declarative memory) storage occurs during slow wave sleep.

“HIPPOCAMPAL REPLAY”: This is a concept whereby declarative memories acquired during waking hours can be processed again, or “replayed,” during sleep and this can influence the likelihood of subsequent memory retrieval when awake.

PSYCHOGENIC AMNESIA

  • Psychogenic amnesia results when the amnesia is not explained by structural/neurological changes or lesions but instead due to psychological influences. Individuals with psychogenic amnesia usually don’t have deficits in new-learning but have severe retrograde amnesia with inability to recall specific events with emotional significance and often will report forgetting their name (which is very uncommon even in severe neurological amnesia). Neurological amnesia patients rarely forget their name and their remote memories are intact (unless there is damage to lateral temporal or frontal lobes).

NEUROTRANSMITTERS INVOLVED IN MEMORY

Acetylcholine

Much of our understanding of the neurotransmitters involved in memory come from post-mortem studies of patients diagnosed with Alzheimer disease (AD). In the 1970s, researchers found a common pattern in post-mortem brain samples of AD patients: Significant loss of choline acetyltransferase (CAT) in the cortex and hippocampus. CAT is an enzyme responsible for the synthesis of acetylcholine (from acetyl CoA and Choline) and was used as a marker of cholinergic activity.

Acetyl CoA + Choline —— Choline Acetyltransferase (CAT) ——–> Acetylcholine + CoA 

It was later discovered that about 70% of acetylcholine producing nerve terminals in the cerebral cortex have cell bodies located in the medial forebrain. This group of acetylcholine (ACh) producing neuron cell bodies in the medial forebrain is called the nucleus basalis of Meynert. These ACh neurons project throughout the cortex. The remaining ACh producing neurons in the cortex are interneurons. In addition to decreased acetylcholine in the cortex, post-mortem brain studies of AD patients also show decrease ACh in the hippocampus, which receives cholinergic input from cholinergic projections that “begin” in the medial septal nucleus.  

Through numerous experiments carried out in rats, the general theory (simplified) at present is that cortical acetylcholine plays an important role in long term memory whereas hippocampal acetylcholine plays an important role in short term memory.

Acetylcholine is rapidly metabolized by Acetylcholinesterase (AChE) after released from ACh neurons. Therefore, AChE inhibitors such as rivastigmine, galantamine, and donepezil are used with some success to improve memory and cognition in patients with dementia. 

Glutamate

Glutamate is the most abundant neurotransmitter in the human brain. It turns out that glutamate can also be toxic at high doses. When glutamate neurons die, they release glutamate into the extracellular environment and act on nearby glutamate receptors on other neurons. When NMDA receptors are over-activated by glutamate, calcium channels within the NMDA receptor open and allow large influx of calcium into the neuron which then induces apoptosis and neuron cell death via biocehmical mechanisms that are beyond this discussion. Therefore, NMDA receptor antagonist medications like the noncompetitive NMDA receptor antagonist Memantine (Namenda) have been developed to “protect” neurons from NMDA receptor over activation and destruction. Unfortunately, Memantine has shown mixed results in clinical trials. 

 

Neurobiology of Attention

What is Attention?

Attention is a cognitive function. Attention describes the mechanism that weighs the importance of various stimuli and selects the one that will receive the brain’s focus. Attention is an important component of our consciousness. There are two major functions of attention: 1) Selective/directed Attention (which is best tested using the stroop task) and 2) Sustained Attention (which is best tested using the n-back test). The capacity to concentrate and maintain one’s attention correlates with the ability to ignore extraneous stimuli. Continuous Performance Tests (CPTs) give an objective estimate of an individuals attention and impulsivity. An individual’s ability to focus or stay attentive appears to increase with age (based on reduction in number of errors on a standardized attention task) until approximately age 50 years.

Brain Areas involved in Attention:

 

What is Working Memory?

Working memory describes what is actively being considered at any moment. Working memory and attention are closely related and interdependent. Working memory and attention are important components of executive functioning. The Executive functions include working memory, attention, and other higher-level cognitive skills such as organizing priorities and planning. We know a lot about the functioning of the prefrontal cortex thanks to the famous case of Phineas Gage (PG). PG was a railroad worker who had a tempering iron explode through his frontal cortex. He went from being responsible and organized to impulsive and inattentive. His personality also changed. We now know that trauma to the Prefrontal Cortex (PFC) impairs working memory.

In the 1970s, neuroscientists began measuring working memory in monkeys. They implanted microelectrodes into individual neurons in the PFC and measured activity in these neurons while monkeys performed a delayed response task (DRT). It turned out that individual neurons responded differently during the DRT such that some neurons were active only during the cue/response part of the task while other neurons responded only during the delay period.

 

Catecholamines (Dopamine, Norepinephrine) and Working Memory

Dopamine and norepinephrine appear to be two very important neurotransmitters involved in attention. This was demonstrated in rats. Rats were subjected to a delayed response task (i.e., radial maze). By measuring the amount of dopamine in the PFC, investigators were able to demonstrate an inverse correlation between extracellular dopamine concentration in the PFC and the number of errors during the task. The length of the delay period was also inversely correlated with extracellular DA concentration in PFC and the number of errors.

 

Reward and Impulse Control

Controlling the impulse to take an immediate, smaller reward rather than waiting for the larger, delayed reward is essential for completing any project. People who cannot control these impulses perpetually fall behind. In the famous Stanford Marshmallow Experiments of the 1970s, Walter Mischel, a psychologist, conducted a very interesting experiment. 4 year old children were given one marshmallow and told they could either eat the marshmallow now or wait until the research assistant returned from an errand and receive two marshmallows. Some children couldn’t wait for the assistant to return and decided to eat the marshmellow in front of them. Others waited it out a little but then ate the marshmellow. And yet others waited until the assistant returned and were rewarded with TWO marshmellows. These same children were followed into adolescence and adulthood. In turned out that the children who were better at inhibiting the impulse to immediately eat the one marshmallow were more resilient, confident, and dependable as adolescents. They also scored higher on standardized tests (e.g., SAT). 

 

The Nucleus accumbens (NAc) and Dopamine Transporter (DAT) density

Attention and impulsivity are partially controlled by dopamine (DA) in the NAc. People are less distracted when pursuing activities they enjoy. Stimulant medications increase DA at the NAc and improve impulse control. Interestingly, rats with damaged NAc become more impulsive and choose the immediate reward in impulse control experiments. In younger individuals and patients with ADHD, there appears to be a higher density of dopamine transporters (DAT) in the striatum. Higher striatal DAT density has been correlated with more impulsive behavior (Drug-naïve patients with ADHD have a slightly higher density in DAT). 

 

Dysfunctions in the PFC and striatum are the most common abnormal brain findings reported for ADHD. Judith Rapoport’s (NIMH) neuroimaging studies have revealed interesting findings in children with ADHD. Children w/ ADHD have smaller brain volumes by approx 5%, have smaller volumes of all four cerebral lobes (including white/gray matter) and smaller cerebellums. The trajectory of brain volumes did not change as the children aged, nor was it affected by the use of stimulant medication. Regions of significantly greater activation in healthy subjects relative to the attention deficit hyperactivity disorder (ADHD) group during a target detection task included areas of the parietal lobe and frontal lobe. 

 

What is Attention Deficit Hyperactivity Disorder (ADHD)?

ADHD is a neurodevelopmental disorder characterized by inattention, impulsivity, and/or hyperactivity. It is one of the most heritable psychiatric disorders. Although historically conceptualized as a disorder of childhood, we now know that approximately 2/3 of children diagnosed with ADHD experience impairing symptoms in adulthood. In School-Aged Children/Adolescents, the prevalence is about 5-7% with the combined type most common. Males are more likely diagnosed in childhood and adolescence (3:1), likely because males display more hyperactive symptoms than females, who usually have more inattentive symptoms and aren’t diagnosed until later in life. This is supported by the more equal prevalence of ADHD in adult males and females (1:1). The inattentive type is the most prevalent type in adults (about 47% of cases). The decline in hyperactivity-impulsivity as individual’s with ADHD age is likely related to cortical and subcortical maturation. 

 

DSM-5 Criteria

(A) A persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development, as characterized by Inattention and/or Hyperactivity (see below)

Inattention: Six (or more) symptoms present for at least 6 months and are not solely a manifestation of oppositional behavior, defiance, hostility, or failure to understand tasks or instructions. For older adolescents and adults (Age 17 and older), at least five symptoms are required.

  1. Inattention to detail, careless mistakes
  2. Often does not seem to listen when spoken to directly (e.g., mind seems to wander elsewhere).
  3. Doesn’t follow directions
  4. Difficulty organizing tasks and activities
  5. Often avoids tasks requiring sustained mental effort
  6. Often loses things
  7. Often easily distracted
  8. Often forgetful in daily activities
  9. Often has difficulty sustaining attention in tasks or play activities

Hyperactivity/Impulsivity: Six (or more) symptoms present for at least 6 months and are not solely a manifestation of oppositional behavior, defiance, hostility, or failure to understand tasks or instructions. For older adolescents and adults (Age 17 and older), at least five symptoms are required.

  1. Often fidgets or squirms in seat
  2. Often leaves seat in situations when remaining seated is expected
  3. Often runs about or climbs in situations where it is inappropriate
  4. Often unable to play or engage in leisure activities quietly
  5. Internal restlessness, always on the go
  6. Often talks excessively
  7. Often finishes sentences or blurts out answers
  8. Often has difficulty waiting his or her turn
  9. Often interrupts or intrudes on others

(B) Several symptoms present prior to age 12 years

(C) Several symptoms present in two or more settings (home, school, work, etc)

(D) Significant dysfunction

(E) Symptoms do not occur exclusively during the course of another mental disorder 

Specify whether:

Combined Presentation (A1 + A2 for the past 6 months)

Predominantly Inattentive presentation (A1 for the past 6 months)

Predominantly hyperactive/impulsive presentation (A2 for the past 6 months)

 

ADHD & Gender Differences

 

FemalesMales
Onset at/after pubertyOnset before puberty
Less likely to be diagnosedMore likely to be diagnosed
Internalizing behaviorsExternalizing behaviors
Inattentiveness more difficult to identifyInattentiveness easier to identify
Show distress by crying/sadnessShow distress through agitation
Impatience: complaints > actionImpatience: aggression/hostility
>comorbid conduct disorder or ODD
>comorbid depressive/anxiety dxsHigher rates of substance use dxs
Shyness/shame is commonShyness/shame less common
More empathicOften lacks empathy
Hormonal fluctuations can affect sxs

 

Consequences of ADHD

 

Young adults diagnosed with ADHD are less likely to enroll in college and/or graduate from college. Students with ADHD are more likely to be on academic probation and have a lower grade point average. Adults with ADHD experience difficulties in all aspects related to employment. Employment problems include poor job performance, lower occupational status, increased absence days, more workplace accidents and job instability. A World Health Organization survey estimated that 3.5% of all workers suffer from ADHD (only a minority of these workers received treatment). ~20% of parents of children with ADHD have ADHD themselves (Faraone et al. 2000). Risky behaviors (traffic tickets, MVAs, injuries) and Substance use problems (earlier onset; greater severity).

ADHD and Criminality: Studies have estimated the prevalence of ADHD among male prison inmates to be around 40% (Rösler et al. 2004; Ginsberg et al. 2010). Other studies found that in the absence of comorbid conduct disorder, ADHD patients had no higher risk for later delinquency than adults with other childhood psychiatric disorders (Gjervan et al. 2012).

 

ADHD Symptoms/Complaints in Adults

Hyperactivity: Inner restlessness, Talkativeness, Excessive fidgeting (lectures, movies, etc)

Impulsivity: Impatience – “acting/talking without thinking”, Difficulty keeping a job, Difficulty maintaining relationships, Attention seeking behavior

Inattentiveness: Feeling bored, Indecisive, Procrastination, Disorganization, Easily distracted

Common complaints in adults with ADHD:

Mood swings, Difficulties dealing with stressful situations, Frequent irritability and frustration, Emotional excitability (anger over minor things), Relationship problems (short-lived, divorce), Coping with one or more children with ADHD

 

ADHD vs Bipolar Disorder

Differentiating ADHD from Bipolar Disorder can be difficult as many symptoms overlap. It doesn’t help that the two disorders often co-occur. Here is a table to help differentiate the two.

 

Signs/SymptomsADHD AloneBipolar Disorder Alone
Hyperactivity If present, a constant problemAppears only during mania
Mood swingsRapid and briefSustained, lasts days to weeks
Difficulty with concentrationConstant problem Intermittent problem
Euphoric moodsNot presentPresent with mania
DelusionsNot presentMay present with mania
Chronic irritability Usually not presentPresent
Frequently losing itemsCommonNot common
HallucinationsNot present May occur with mania
Sleep DisturbancesChronic periods of insomnia and/or hypersomniaInsomnia common in mania
DisorganizationA key and persistent featureNot common unless manic
Distractibility A key and persistent featureNot common unless manic
GrandiosityNot present Common, especially during mania
Self-EsteemUsually poorInappropriately high during mania
Racing ThoughtsOften chronically present Present, especially during mania
Impulsivity Common featurePresent only during mania
High-risk behaviors May Occur, but reason generally prevails Present during mania, may be extreme and life-threatening

 

Treatment Options For ADHD

 

Stimulants

Generic NameBrand NameUsual Starting DoseTypical Daily Dose Range
Amphetamine-dextroamphetamine (Mixed Salts)Adderall5-10mg q4-5hrs10-120mg
Adderall XR10mg QAM
DextroamphetamineDexedrine5mg q4-6hrs10-100mg
LisdexamfetamineDexedrine spansules5-15mg q6-8hrs5-100mg
Dextrostat5-10mg q4-6hrs5-80mg
Vyvanse20-30mg QAM20-70mg
Methamphetamine Desoxyn5-10mg QAM20-45mg
Long-acting MPHRitalin SR20mg QAM10-140mg
Ritalin LA20mg QAM20-120mg
Concerta18mg QAM18-144mg
Metadate CD10-20mg QAM10-120mg
Short-acting MPHMethylphenidate 10mg q4hrs10-140mg
Methylin10mg q4hrs10-140mg
Ritalin10mg q4hrs10-140mg
D-methylphenidate Focalin5mg q4-6hrs10-80mg
Focalin XR5-10mg QAM10-80mg

Methylphenidate (Ritalin, Concerta, Focalin) and Amphetamines (Vyvanse, Dexedrine, Adderall)

Both amphetamine (AMPH) and methylphenidate (MPH) target the dopamine and norepinephrine systems by increasing the concentration of these neurotransmitters in the synaptic cleft. AMPH has additional properties of promoting release by reversing the dopamine and norepinephrine transporters. Stimulants have been shown to be more effective than nonstimulants (atomoxetine) in treating core symptoms of ADHD. Prescription stimulants do not pose significant health risks to individuals when used as prescribed (Findling & Dogin, 1998). Side effects of prescription stimulants are dose-dependent (Solanto, 2001, Weyandt et al., 2014). Psychosis, seizures, and cardiac events such as tachycardia, hypertension, myocardial infarction, and sudden death are rarely reported in individuals taking therapeutic oral doses of prescription stimulants (Greenhill et al. 2002; Graham & Coghill 2008). While pre-existing cardiac disease is a relative contraindication, many patients with cardiac histories are safely treated with stimulants. 

Review of the Pharmacology of Methylphenidate and Amphetamines (PDF) by Stephen Faraone 2018

 

Modafinil (Provigil)

Both modafinil (Provigil) and Armodafinil (Nuvigil) are medications used to treat excessive daytime sleepiness in Narcolepsy. Both modafinil (Provigil) and Armodafinil (Nuvigil) promote histamine release throughout the cortex. Histamine neurons located in the tuberomamillary nucleus of the hypothalamus have widespread projections throughout the cortex and brain stem and play an important role in wakefulness and arousal.

 

Psychostimulants Explained, Simply:

In individuals with attention and/or concentration problems, there may be a problem with how the brain is processing sensory input. Our brains spend an enormous amount of energy (up to 20-30% of all energy used by your body) processing information below our level of awareness. In fact only a very small percentage of brain activity contributes to our conscious awareness, about 15% (rough estimate). The rest of the activity is all the unconscious processing, integrating, and analyzing of information that ultimately results in complex behavior. Much of the brain’s energy is spent “deciding” which signals are relevant and need to be brought to conscious awareness. Think of all the activities we do that we aren’t even aware of. While walking down the street talking with someone, do you actively feel your left big toe? Well, no, not unless you have pain or stub your toe. We aren’t aware of our left big toe because it’s irrelevant to what we are doing. But this doesn’t mean those signals aren’t physiologically absent.

Dopamine, serotonin, and norepinephrine are monoamine neurotransmitters in the brain that act like the tuners of a piano. The actual piano itself can be thought of as the glutamate neurons, GABA neurons, and supporting cells within the brain that play the music. Glutamate and GABA neurons make up the majority of the neurons in the mammalian brain and only a small fraction are dopamine, norepinephrine, and serotonin. The monoamines, especially norepinephrine and dopamine (and many others including steroid hormones, etc) are there to tighten the strings so the music sounds good. No one likes a song that is off beat or out of tune. Dopamine and norepinephrine are like those “tuners” of the brain–they modulate communication between neurons. They help your brain decide what you should ignore and what you should focus on. Interestingly, ignoring and focusing may be two separate processes or systems in the brain. Medications like amphetamines (vyvanse, adderall), methylphenidate (Ritalin, concerta), bupropion (Wellbutrin), atomoxetine (strattera), and other medications modulate these monoamines (“tuners”) to help us tune out the extraneous signals coming in that we just don’t need while allowing the important relevant signals flowing smoothly.

Like a garden hose with holes in it, one monoamine system increases the water pressure while the other plugs the holes so the water gets to where it’s supposed to go. Obviously the brain is much more complex than this example, but it gives us a framework for why our psychiatric medications might work. Medications (or illicit drugs) that enhance dopamine too much in certain regions of the brain may cause us to “hyperfocus” or “fixate” our attention such that we find ourselves overly “motivated” to do things that might not yield a large reward at all. On the other hand, too little dopamine in certain areas of the brain and we might lack motivation altogether and find ourselves apathetic or indifferent to doing anything because most tasks don’t seem “worth it” because the perceived reward isn’t big enough.

 

 

Nonstimulants

Generic NameBrand NameUsual Starting DoseTypical Daily Dose Range
AtomoxetineStrattera40mg/day40-140mg
ModafinilProvigil200mg/day100-400mg
ArmodafinilNuvigil50-150mg/day150-250mg
BupropionWellbutrin IR37.5mg/day75-300mg
Wellbutrin SR100mg/day100-400mg
Wellbutrin XL150mg/day150-450mg
ClonidineCatapres0.1mg BID
Guanfacine Tenex1mg/day

Atamoxetine (Strattera)

Potent norepinephrine Reuptake inhibitor (NRI)

 

Clonidine, Guanfacine

Alpha-2 Receptors agonists

Bupropion (Wellbutrin)

Dopamine and Norepinephrine reuptake inhibitor (see above)