Attention Deficit Hyperactivity Disorder (ADHD)

What is 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. 

Symptoms of ADHD include inattention and/or hyperactivity-impulsivity that interferes with functioning or development. Below are some examples of symptoms common in ADHD:

Inattention: 

Inattention to detail, careless mistakes

Often does not seem to listen when spoken to directly (e.g., mind seems to wander elsewhere).

Doesn’t follow directions

Difficulty organizing tasks and activities

Often avoids tasks requiring sustained mental effort

Often loses things

Often easily distracted

Often forgetful in daily activities

Often has difficulty sustaining attention in tasks or play activities

Hyperactivity/Impulsivity:

Often fidgets or squirms in seat

Often leaves seat in situations when remaining seated is expected

Often runs about or climbs in situations where it is inappropriate

Often unable to play or engage in leisure activities quietly

Internal restlessness, always on the go

Often talks excessively

Often finishes sentences or blurts out answers

Often has difficulty waiting his or her turn

Often interrupts or intrudes on others

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 and 2) Sustained Attention. 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 (see graph below).

Brain Areas Involved in Attention/Working Memory:

Certain areas of the brain seem to have an important role in our ability to remain attentive. These areas include the prefrontal cortex (which is part of the frontal lobe) and the regions “underneath” or “embedded” in the frontal lobe (such as the cingulate cortex) play an important role in attention and working memory. 

So, 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 something we call executive functioning. The Executive functions include working memory, attention, and other higher-level cognitive skills such as organizing, planning, making decisions, and solving problems.

We know a lot about the functioning of the prefrontal cortex (PFC) thanks to the famous case of Phineas Gage (PG). PG was a railroad worker who had a tempering iron explode through his prefrontal 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). See the figure below. 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 (i.e., when the piece of fruit was covered requiring the monkey to remember where it was). This tells us that holding the memory of the fruit activates different neurons than the initial cue and/or response. Although many neurotransmitters have been implicated in this process, it appears that dopamine and norepinephrine play a major role in working memory. 

 

Dopamine, Norepinephrine and Working Memory

Dopamine and norepinephrine appear to be two very important neurotransmitters involved in attention and working memory. 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. 

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. 

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