Mehdi Tehrani-Doost, M.D.Tehran University of Medical Sciences

Neural network in ADHDMany of the symptoms of

attention-deficit/hyperactivity disorder (ADHD) are thought to arise from dysfunction of the prefrontal cortex (PFC) and its connections with cortical and subcortical brain regions

Current data suggest that the lateral PFC regions regulating attention and behavior are especially sensitive to the influence of norepinephrine (NE) and dopamine (DA) (

Top-Down Regulation by Prefrontal CortexThe PFC intelligently regulates our thoughts,

actions, and emotions through extensive connections with other brain regions, including projections to the association cortices for the regulation of sensory processing and extensive projections to the basal ganglia and cerebellum for the regulation of motor, cognitive, and emotional responses

Top-Down Regulation by Prefrontal CortexThe PFC creates a mental sketch pad through

networks of neurons that maintain information in the absence of environmental stimulation.

This process is sometimes referred to as working memory: the ability to keep in mind an event that has just occurred or bring to mind information from long-term storage and use this representational knowledge to regulate behavior, thought, and emotion

Top-Down Regulation by Prefrontal CortexThe PFC is able to protect these

fragile representations from the interference of external or internal distractions and is key for inhibiting inappropriate actions and promoting task-relevant operations (so-called top-down regulation)

Top-Down Regulation by Prefrontal CortexPrefrontal cortex operations allow the

flexible regulation of behavior to properly respond to a changing environment, e.g., the ability to shift attentional set to new dimensions and to alter decision making as reward contingencies shift .

The PFC also monitors errors, giving us the insight that we are incorrect and need to shift strategies

Top-Down Regulation by Prefrontal CortexThere are regional specializations for

these functions,, with dorsolateral PFC regions often involved in the regulation of attention and the right inferior PFC being especially important for the inhibition of inappropriate behaviors .

All of these abilities depend on proper PFC neuronal network connections,

CatecholaminesThe arousal pathways (e.g., norepinephrine,

dopamine, acetylcholine, serotonin,) all project to the PFC

It is now known that both NE and DA have an inverted-U dose effect on PFC function, whereby either too little (e.g., fatigue) or too much (e.g., uncontrollable stress) impairs PFC function,

while moderate levels of catecholamine released when a subject is alert

CatecholaminesThe NE and DA neurons in the

brainstem change their firing rate according to our arousal state, as well as the relevance of events in the environment.

Norepinephrine neurons in the locus coeruleus fire to relevant stimuli during alert waking but can fire to distracters during fatigue or stress

CatecholaminesDopamine neurons have not been

followed with regard to states of arousal but have been shown to fire related to prediction of reward

However, recent studies suggest that a subset of midbrain DA neurons can increase their firing to aversive stimuli ,and these neurons may contribute to increased DA release in the PFC during stress

CatecholaminesThe levels of catecholamine release in PFC

may rapidly alter the strength of PFC network connections to coordinate cognitive state with physiological demands

Under optimal arousal conditions, phasic cate-cholamine release appears to regulate the strength and breadth of network inputs in a manner that is essential to PFC cognitive function.

Thus, precise regulation of NE and DA is needed for appropriate PFC regulation

NorepinephrineNorepinephrine has the highest

affinity for alpha 2 adrenergic receptors and lower affinity for alpha 1 and beta receptors. Therefore, the type of receptor engaged may be determined by the amount of NE release

NorepinephrineModerate levels of NE released

during alert, nonstressed waking improve working memory performance by engaging postsynaptic, alpha 2A receptors ,

whereas high levels of NE released during stress impair PFC function via stimulation of lower affinity alpha1 and beta 1 receptors

NorepinephrineA variety of behavioral evidence indicates that

NE stimulation of alpha2A receptors in dorsolateral PFC is critical for working memory

Either depletion of NE or blockade of alpha2A receptors in PFC impairs working memory performance

Conversely, stimulation of postsynaptic alpha2A receptors in dorsolateral PFC, e.g., with guanfacine infusions directly into this region, improves working memory performance

NorepinephrineSystemic guanfacine administration

in humans also can improve dorsolateral PFC functions, such as working memory and planning

Guanfacine has also been shown to improve working memory performance in patients with epilepsy and schizotypal disorder

NorepinephrineIn contrast to alpha 2A receptors, infusion of an alpha 1 agonist directly into the dorsolateral PFC impairs working memory performance .

Norepinephrineinfusions of guanfacine into the ventrolateral

PFC—a region altered in ADHD—improved response flexibility and conditional associative motor learning in monkeys.

As orbital circuits are important for the control of aggression ,guanfacine strengthening of orbital function may underlie the reduced aggression observed in monkeys and ADHD patients taking this medication

NorepinephrineImportantly, blockade of alpha 2

receptors selectively within the monkey PFC can recreate many of the key symptoms of ADHD.

Infusions of yohimbine into this same region induce locomotor hyperactivity ,errors of commission on no-go trials in a go/no-go task, and impaired working memory performance

NorepinephrineThese data suggest that genetic

insults that similarly weaken alpha 2A receptor signaling may also impair PFC regulation of attention and behavior.

Genetic alterations in the 2A receptor also have been associated with ADHD and with impaired PFC executive function.

NE Mechanisms and ADHD MedicationsAll medications currently approved for the

treatment of ADHD influence NE transmission and all can improve at least some aspects of PFC function.

A common misconception is that methylphenidate is a selective DA transporter blocker, when in actuality it blocks both NE and DA transporters.

Indeed, methylphenidate has more potent effects on NE than DA in the rat PFC

NE Mechanisms and ADHD MedicationsBehavioral data in rats and monkeys

indicate that methylphenidate can improve working memory performance by indirectly enhancing both NE alpha 2A receptor and DA D1 receptor actions .

Methylphenidate has also been shown to improve working memory and stop signal performance in both normal volunteers and patients with ADHD

NE Mechanisms and ADHD MedicationsAtomoxetine also blocks the NE

transporter and as the NE transporter clears both NE and DA in the PFC,

However, higher doses of atomoxetine reduce dorsolateral PFC firing during working memory.

Atomoxetine has been shown to improve stop signal performance in normal volunteers, as well as in patients with ADHD

NE Mechanisms and ADHD MedicationsImportantly, atomoxetine (40 mg)

has been shown to increase right inferior PFC activity during performance of this task ,a brain region often shown to be underactive in patients with ADHD.

NE Mechanisms and ADHD MedicationsHowever, a much higher dose of atomoxetine

impaired go/no-go performance .It is possible that atomoxetine’s effects on

PFC functions will be dose-related, with low doses producing moderate NE release that engages alpha 2A receptors, improving working memory and go/no-go performance ,

while higher doses produce greater NE release that engages receptors, improving stop signal reactive inhibition.

NE Mechanisms and ADHD Medications Guanfacine directly mimics NE

stimulation of alpha 2A receptors, Guanfacine administration to

children with ADHD and tics improved performance of a Conners’ Continuous Performance Test task that requires sustained attention, working memory, and behavioral inhibition

D1/5 Receptor MechanismsDopamine has an inverted U-shaped

influence on working memory abilities via actions at the D1 receptor family in both animals and humans .

Cognitive studies in animals have shown that either blockade of D1/5 receptors or excessive stimulation of D1/5 receptors in the PFC impairs spatial working memory

D1/5 Receptor Mechanismshigh doses of D1/5 agonist suppress

all neuronal firing. These actions likely contribute to

impaired working memory abilities during uncontrollable stress exposure, when high levels of DA are released in PFC

Animal studies have also shown that the enhancing effects of methylphenidate and atomoxetine on working memory performance involve D1/5 receptor stimulation, as well as the NE 2 receptor actions described above.

However, higher doses of these agents impaired working memory, consistent with the D1 inverted-U response

Psychostimulants and motivated behavior: Arousal and cognition

Motivated behavior toward a goal requires arousal, motivation, and reward as well as associative and executive processes. Dysregulation in the integration of these processes likely underlies a variety of behavioral disorders, including addiction (Kelley and Berridge, 2002).

Psychostimulants and motivated behavior: Arousal and cognitionPsychostimulants are a class of drugs

defined by their potent arousal-enhancing, motor-activating and reinforcing effects

Neurochemically, psychostimulants block dopamine (DA), norepinephrine (NE), elevating extracellular levelsof these transmitters (Kuczenski and Segal, 1994).

Psychostimulants and motivated behavior: Arousal and cognitionThe locus coeruleus (LC)is the major

source of brain NE, providing particularly prominent input to regions associated with cognition and arousal (e.g. neo-cortex, hippocampus, thalamus, basal forebrain( Foote et al., 1983;Espa˜na and Berridge, 2006).

Neurobiology of psychostimulant-induced arousalNoradrenergic systems exert potent

arousal-promoting actions LC neurons increase tonic discharge rates immediately prior to the transition from sleep to waking(Hobson et al., 1975; Foote et al., 1980).

Within waking, LC neurons increases in discharge rates during periods of elevated arousal (Foote et al., 1980; Aston-Jones and Bloom,1981).

Neurobiology of psychostimulant-induced arousalpsychostimulant-induced waking is closely

aligned with drug-induced increases in extracellular NE levels (Berridge and Stalnaker, 2002).

Thus, the arousal promoting actions of psychostimulants involve, at least in part, elevated NE signaling within an array of cortical and subcortical sites.

Neurobiology of psychostimulant-induced arousallimited observations demonstrate

that the selective activation of DA D1 and D2 receptors globally within the brain increases waking (Isaacand Berridge, 2003).

Within the waking state, DA neurons display phasic discharge related to reward prediction errors (Schultz,1998).

Neurobiology of psychostimulant-induced arousalThere is a close relationship between

arousal and cognitive function .PFC-dependent cognitive function is also

highly sensitive to catecholamines located within the PFC.

Thus, psychostimulant-induced elevations in catecholamine signaling may influence PFC-dependent function via direct (within the PFC) and indirect (via arousal-modulation) mechanisms.

Psychostimulant-induced alterations in executive functionThe qualitative differences in the

electrophysiological effects of varying levels of NE and DA within the PFC likely contribute to the diverse behavioral effects of varying doses of psychostimulants in humans, with therapeutic actions occurring at low doses and loss of self-regulation at high and abused doses.

Consistent with this, high doses of psychostimulants impair PFC-dependent function(Berridge et al., 2006; Devilbiss and Berridge, 2008; Arnsten andPliszka, 2011)

Neurobiology of psychostimulant-induced arousalIn contrast to the effects of high and motor-

activating doses of psychostimulants, low doses exert behavioral-calming and cognition-enhancing actions that make these drugs a first-line treatment for ADHD

low doses of methylphenidate improve working memory, attention and response inhibition in healthy adult subjects similar to that seen in ADHD patients (Mehta et al., 2001; Pauls et al., 2012)

Neurobiology of psychostimulant-induced arousallow and cognition-enhancing doses of psy-

chostimulants preferentially target PFC catecholamines, eliciting relatively large increases in extracellular levels of NE and DA in the PFC and modest increases outside the PFC

Thus, as with catecholamines, psychostimulants exert an inverted-U shaped modulation of signal processing properties of PFC neurons.

Neurobiology of psychostimulant-induced arousalLow-dose psychostimulants do not uniformly

modulate PFC-dependent cognitive processes. Specifically, working memory performance and behavioral inhibition, display a narrow inverted-U shaped facilitation by psychostimulants

while others, including sustained attention, attention set shifting, and classroom behavior display broader and/or right-shifted dose sensitivity (Berridgeet al., 2012 )

Neurobiology of psychostimulant-induced arousalFor example, in rats, 0.5 mg/kg

methylphenidate maximally improves working memory performance, whereas a slightly higher dose of2.0 mg/kg impairs performance (Berridge et al., 2006; Devilbiss andBerridge, 2008).

In contrast, sustained attention and attention set shifting are maximally improved by 2.0 mg/kg methylphenidate (Berridge et al., 2012 )

Neurobiology of psychostimulant-induced arousalThe facilitation of working memory

by low-dose methylphenidate is dependent on activation of D1 and alpha 2 receptors while the facilitation of attention-related processes involves alpha1 receptors and not alpha 2 receptors (Berridge et al., 2012)

Arousal and dysregulated motivated behavior Arousal exerts a strong modulatory influence

on behavioral processes associated with goal-directed behavior.

Thus, at low levels of arousal (sedation), motivation and executive function are impaired.

Moreover, high arousal states (e.g. stress), similar to high-dose psychostimulants, are associated with an impairment in PFC-dependent, top-down regulation of motivated behavior(Schwabe and Wolf, 2011).