Transcript Top-Down Regulation by Prefrontal Cortex

Mehdi Tehrani-Doost, M.D.
Tehran University of Medical Sciences
Neural network in ADHD
 Many 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 Cortex
 The 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 Cortex
 The 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 longterm storage and use this representational knowledge
to regulate behavior, thought, and emotion
Top-Down Regulation by
Prefrontal Cortex
 The 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 (socalled top-down regulation)
Top-Down Regulation by
Prefrontal Cortex
 Prefrontal 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 Cortex
 There 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,
Catecholamines
 The 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
Catecholamines
 The 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
Catecholamines
 Dopamine 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
Catecholamines
 The 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 catecholamine 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
Norepinephrine
 Norepinephrine 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
Norepinephrine
 Moderate 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
Norepinephrine
 A 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
Norepinephrine
 Systemic 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
Norepinephrine
 In contrast to alpha 2A receptors,
infusion of an alpha 1 agonist directly
into the dorsolateral PFC impairs
working memory performance .
Norepinephrine
 infusions 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
Norepinephrine
 Importantly, 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
Norepinephrine
 These 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
Medications
 All 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
Medications
 Behavioral 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
Medications
 Atomoxetine 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
Medications
 Importantly, 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
Medications
 However, 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 Mechanisms
 Dopamine 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 Mechanisms
 high 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 cognition
 Psychostimulants 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 cognition
 The 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 psychostimulantinduced arousal
 Noradrenergic 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 psychostimulantinduced arousal
 psychostimulant-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 psychostimulantinduced arousal
 limited 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 psychostimulantinduced arousal
 There 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 PFCdependent function via direct (within the PFC)
and indirect (via arousal-modulation)
mechanisms.
Psychostimulant-induced
alterations in executive function
 The 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 psychostimulantinduced arousal
 In contrast to the effects of high and motor-activating
doses of psychostimulants, low doses exert behavioralcalming 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 psychostimulantinduced arousal
 low 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 psychostimulantinduced arousal
 Low-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 psychostimulantinduced arousal
 For 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 psychostimulantinduced arousal
 The 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).