Neurobiology of Executive Functions: Catecholamine Influences on Prefrontal Cortical Functions

doi:10.1016/j.biopsych.2004.08.019

Biological Psychiatry

Volume 57, Issue 11, 1 June 2005, Pages 1377-1384

https://doi.org/10.1016/j.biopsych.2004.08.019 Get rights and content

The prefrontal cortex guides behaviors, thoughts, and feelings using representational knowledge, i.e., working memory. These fundamental cognitive abilities subserve the so-called executive functions: the ability to inhibit inappropriate behaviors and thoughts, regulate our attention, monitor our actions, and plan and organize for the future. Neuropsychological and imaging studies indicate that these prefrontal cortex functions are weaker in patients with attention-deficit/hyperactivity disorder and contribute substantially to attention-deficit/hyperactivity disorder symptomology. Research in animals indicates that the prefrontal cortex is very sensitive to its neurochemical environment and that small changes in catecholamine modulation of prefrontal cortex cells can have profound effects on the ability of the prefrontal cortex to guide behavior. Optimal levels of norepinephrine acting at postsynaptic α-2A-adrenoceptors and dopamine acting at D1 receptors are essential to prefrontal cortex function. Blockade of norepinephrine α-2-adrenoceptors in prefrontal cortex markedly impairs prefrontal cortex function and mimics most of the symptoms of attention-deficit/hyperactivity disorder, including impulsivity and locomotor hyperactivity. Conversely, stimulation of α-2-adrenoceptors in prefrontal cortex strengthens prefrontal cortex regulation of behavior and reduces distractibility. Most effective treatments for attention-deficit/hyperactivity disorder facilitate catecholamine transmission and likely have their therapeutic actions by optimizing catecholamine actions in prefrontal cortex.

Section snippets

The Role of the PFC in Executive Functions

The PFC guides behavior, thought, and affect using working memory, i.e., the ability to keep in mind an event that has just happened or bring to mind information from long-term stores and use this representational knowledge to inhibit inappropriate actions or thoughts and to plan effective actions. These processes are the basis of the so-called executive functions, including regulation of attention, planning, impulse control, mental flexibility, and the initiation and monitoring of action,

The Role of the PFC Dysfunction in ADHD

Neuropsychological and imaging studies have long established that PFC abilities are inadequate in patients with ADHD (reviewed in Arnsten et al 1996; Barkley 1997). Attention-deficit/hyperactivity disorder patients are impaired on tasks of behavioral inhibition, reward reversal, and working memory, which require PFC function (e.g., Bedard et al 2003; Itami and Uno 2002; McLean et al 2004) but not on those requiring parietal cortical regulation of attention (Swanson et al 1991). Numerous

Catecholamines Have an Essential Influence on PFC Function

The landmark study by Brozoski et al (1979) established that catecholamines have a critical influence on PFC working memory function. Depletion of both DA and NE from the PFC was as detrimental to performance as removing the cortex itself. Although the original paper emphasized the importance of DA mechanisms in PFC, it is now known that both DA and NE are critical to PFC function.

Relevance to Pharmacological Treatment of ADHD

Most effective treatments for ADHD facilitate catecholamine transmission. For example, methylphenidate (Ritalin) blocks DA and NE transporters; amphetamines (e.g., Adderall) block DA and NE transporters and increase catecholamine release; atomoxetine blocks NE transporters (which take up DA in PFC, thus effectively increasing the concentration of both catecholamines in the synapse and extrasynaptic space) (Bymaster et al 2002); and guanfacine mimics NE at α-2A-adrenoceptors. Oral, low-dose

References (94)

A.F.T. Arnsten et al.
The selective dopamine D4 receptor antagonist, PNU-101387G, prevents stress-induced cognitive deficits in monkeys
Neuropsychopharmacology
(2000)
A.R. Aron et al.
Methylphenidate improves response inhibition in adults with attention-deficit/hyperactivity disorder
Biol Psychiatry
(2003)
A.R. Aron et al.
Inhibition and the right inferior frontal cortex
Trends Cogn Sci
(2004)
R.A. Avery et al.
The alpha-2A-adenoceptor agonist, guanfacine, increases regional cerebral blood flow in dorsolateral prefrontal cortex of monkeys performing a spatial working memory task
Neuropsychopharmacology
(2000)
R.T. Bartus et al.
Frontal decortication in rhesus monkeysA test of the interference hypothesis
Brain Res
(1977)
S.G. Birnbaum et al.
A role for norepinephrine in stress-induced cognitive deficitsAlpha-1-adrenoceptor mediation in prefrontal cortex
Biol Psychiatry
(1999)
S.G. Birnbaum et al.
Noradrenergic alpha-2 receptor agonists reverse working memory deficits induced by the anxiogenic drug, FG7142, in rats
Pharmacol Biochem Behav
(2000)
F.P. Bymaster et al.
Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of ratA potential mechanism for efficacy in attention deficit/hyperactivity disorder
Neuropsychopharmacology
(2002)
B.J. Casey et al.
Implication of right frontostriatal circuitry in response inhibition and attention-deficit/hyperactivity disorder
J Am Acad Child Adolesc Psychiatry
(1997)
P.B. Chappell et al.
Guanfacine treatment of comorbid attention deficit hyperactivity disorder and Tourette’s syndromePreliminary clinical experience
J Am Acad Child Adolesc Psychiatry
(1995)

O. Godefroy et al.

Divided and focused attention in patients with lesion of the prefrontal cortex

Brain Cogn

(1996)

P.S. Goldman-Rakic

Cellular basis of working memory

Neuron

(1995)

J.P. Horrigan

Guanfacine for PTSD nightmares

J Am Acad Child Adolesc Psychiatry

(1996)

R.D. Hunt et al.

An open trial of guanfacine in the treatment of attention deficit hyperactivity disorder

J Am Acad Child Adolesc Psychiatry

(1995)

P. Jakala et al.

Guanfacine, but not clonidine, improves planning and working memory performance in humans

Neuropsychopharmacology

(1999)

P. Jakala et al.

Guanfacine and clonidine, alpha-2 agonists, improve paired associates learning, but not delayed matching to sample, in humans

Neuropsychopharmacology

(1999)

W.R. Kates et al.

MRI parcellation of the frontal lobe in boys with attention deficit hyperactivity disorder or Tourette syndrome

Psychiatry Res

(2002)

R.T. Knight et al.

Prefrontal cortex gating of auditory transmission in humans

Brain Res

(1989)

B.-M. Li et al.

Alpha-2 adrenergic modulation of prefrontal cortical neuronal activity related to spatial working memory in monkeys

Neuropsychopharmacology

(1999)

B.-M. Li et al.

Delayed response deficit induced by local injection of the alpha-2 adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys

Behav Neural Biol

(1994)

C.-L. Ma et al.

Locomotor hyperactivity induced by blockade of prefrontal cortical alpha-2-adrenoceptors in monkeys

Biol Psychiatry

(2005)

E. MacDonald et al.

Gene targeting-homing in on alpha-2-adrenoceptor subtype function

Trends Pharmacol Sci

(1997)

Z.-M. Mao et al.

Local infusion of alpha-1 adrenergic agonist into the prefrontal cortex impairs spatial working memory performance in monkeys

Biol Psychiatry

(1999)

M. Morita et al.

A rapid presentation event-related functional magnetic resonance imaging study of response inhibition in macaque monkeys

Neurosci Lett

(2004)

K. Rubia et al.

Right inferior prefrontal cortex mediates response inhibition while mesial prefrontal cortex is responsible for error detection

Neuroimage

(2003)

T. Sawaguchi et al.

Dopamine enhances the neuronal activity of spatial short-term memory task in the primate prefrontal cortex

Neurosci Res

(1988)

M.V. Solanto

Dopamine dysfunction in AD/HDIntegrating clinical and basic neuroscience research

Behav Brain Res

(2002)

E.R. Sowell et al.

Cortical abnormalities in children and adolescents with attention-deficit hyperactivity disorder

Lancet

(2003)

H. Tanila et al.

The effects of prefrontal intracortical microinjections of an alpha-2 agonist, alpha-2 antagonist and lidocaine on the delayed alternation performance of aged rats

Brain Res Bull

(1996)

M. Watanabe

Prefrontal unit activity during delayed conditional go/no-go discrimination in the monkey. I. Relation to the stimulus

Brain Res Brain Res Rev

(1986)

A.J. Wilkins et al.

Frontal lesions and sustained attention

Neuropsychologia

(1987)

S. Yamaguchi et al.

Gating of somatosensory input by human prefrontal cortex

Brain Res

(1990)

S.W. Anderson et al.

Impairment of social and moral behavior related to early damage in human prefrontal cortex

Nat Neurosci

(1999)

C. Aoki et al.

Cellular and subcellular sites for noradrenergic action in the monkey dorsolateral prefrontal cortex as revealed by the immunocytochemical localization of noradrenergic receptors and axons

Cereb Cortex

(1998)

A.F.T. Arnsten et al.

The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects

J Neurosci

(1988)

A.F.T. Arnsten et al.

Alpha-2 adrenergic agonists decrease distractability in aged monkeys performing a delayed response task

Psychopharmacology

(1992)

A.F.T. Arnsten et al.

Alpha-2 adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates

Science

(1985)

A.F.T. Arnsten et al.

Noise stress impairs prefrontal cortical cognitive function in monkeysEvidence for a hyperdopaminergic mechanism

Arch Gen Psychiatry

(1998)

A.F.T. Arnsten et al.

The contribution of alpha-2 noradrenergic mechanisms to prefrontal cortical cognitive functionPotential significance to attention deficit hyperactivity disorder

Arch Gen Psychiatry

(1996)

R.A. Barkley

ADHD and the Nature of Self-Control

(1997)

A.C. Bedard et al.

Selective inhibition in children with attention-deficit hyperactivity disorder off and on stimulant medication

J Abnorm Child Psychol

(2003)

T. Brozoski et al.

Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey

Science

(1979)

S.A. Bunge et al.

Prefrontal regions involved in keeping information in and out of mind

Brain

(2001)

J.X. Cai et al.

Dose-dependent effects of the dopamine D1 receptor agonists A77636 or SKF81297 on spatial working memory in aged monkeys

J Pharmacol Exp Ther

(1997)

J.X. Cai et al.

Reserpine impairs spatial working memory performance in monkeysReversal by the alpha-2 adrenergic agonist clonidine

Brain Res

(1993)

F.X. Castellanos et al.

Quantitative brain magnetic resonance imaging in attention deficit/hyperactivity disorder

Arch Gen Psychiatry

(1996)

R. Dias et al.

Dissociation in prefrontal cortex of affective and attentional shifts

Nature

(1996)

Cited by (742)

Maternal choline supplementation lessens the behavioral dysfunction produced by developmental manganese exposure in a rodent model of ADHD
2024, Neurotoxicology and Teratology
Studies in children have reported associations between elevated manganese (Mn) exposure and ADHD-related symptoms of inattention, impulsivity/hyperactivity, and psychomotor impairment. Maternal choline supplementation (MCS) during pregnancy/lactation may hold promise as a protective strategy because it has been shown to lessen cognitive dysfunction caused by numerous early insults. Our objectives were to determine whether (1) developmental Mn exposure alters behavioral reactivity/emotion regulation, in addition to impairing learning, attention, impulse control, and sensorimotor function, and (2) MCS protects against these Mn-induced impairments. Pregnant Long-Evans rats were given standard diet, or a diet supplemented with additional choline throughout gestation and lactation (GD 3 - PND 21). Male offspring were exposed orally to 0 or 50 mg Mn/kg/day over PND 1–21. In adulthood, animals were tested in a series of learning, attention, impulse control, and sensorimotor tasks. Mn exposure caused lasting dysfunction in attention, reactivity to errors and reward omission, learning, and sensorimotor function, recapitulating the constellation of symptoms seen in ADHD children. MCS lessened Mn-induced attentional dysfunction and partially normalized reactivity to committing an error or not receiving an expected reward but provided no protection against Mn-induced learning or sensorimotor dysfunction. In the absence of Mn exposure, MCS produces lasting offspring benefits in learning, attention, and reactivity to errors. To conclude, developmental Mn exposure produces a constellation of deficits consistent with ADHD symptomology, and MCS offered some protection against the adverse Mn effects, adding to the evidence that maternal choline supplementation is neuroprotective for offspring and improves offspring cognitive functioning.
The effects of sleep deprivation, acute hypoxia, and exercise on cognitive performance: A multi-experiment combined stressors study
2024, Physiology and Behavior
Both sleep deprivation and hypoxia have been shown to impair executive function. Conversely, moderate intensity exercise is known to improve executive function. In a multi-experiment study, we tested the hypotheses that moderate intensity exercise would ameliorate any decline in executive function after i) three consecutive nights of partial sleep deprivation (PSD) (Experiment 1) and ii) the isolated and combined effects of a single night of total sleep deprivation (TSD) and acute hypoxia (Experiment 2).
Using a rigorous randomised controlled crossover design, 12 healthy participants volunteered in each experiment (24 total, 5 females). In both experiments seven executive function tasks (2-choice reaction time, logical relations, manikin, mathematical processing, 1-back, 2-back, 3-back) were completed at rest and during 20 min semi-recumbent, moderate intensity cycling. Tasks were completed in the following conditions: before and after three consecutive nights of PSD and habitual sleep (Experiment 1) and in normoxia and acute hypoxia (F_IO₂ = 0.12) following one night of habitual sleep and one night of TSD (Experiment 2).
Although the effects of three nights of PSD on executive functions were inconsistent, one night of TSD (regardless of hypoxic status) reduced executive functions. Significantly, regardless of sleep or hypoxic status, executive functions are improved during an acute bout of moderate intensity exercise.
These novel data indicate that moderate intensity exercise improves executive function performance after both PSD and TSD, regardless of hypoxic status. The key determinants and/or mechanism(s) responsible for this improvement still need to be elucidated. Future work should seek to identify these mechanisms and translate these significant findings into occupational and skilled performance settings.
How a pilot's brain copes with stress and mental load? Insights from the executive control network
2024, Behavioural Brain Research
In aviation, mental workload and stress are two major factors that can considerably impact a pilot’s flight performance and decisions. Their consequences can be even more dramatic in single-pilot aircraft or with the forthcoming single-pilot operations where the pilot will fly alone and will not be able to be assisted in case of difficulty. An accurate and automatic monitoring of the pilot’s mental state could help to prevent the potentially dangerous effects of an excess mental workload and stress. For example, some tasks could be allocated to automation or to a ground-based flight crew if a mental overload or significant stress is detected. In the current study, the brain activity of 20 private pilots was recorded with a fNIRS device during two realistic flight simulator scenarios. The mental workload was manipulated with the added difficulty of a secondary task and stress was induced by a social stressor. Our results confirmed the sensitivity of the fNIRS readings to variations in the mental workload, with increased HbO2 concentration in regions of the executive control network (ECN), in particular in the dorsolateral prefrontal cortex and in lateral parietal regions, when the difficulty of the secondary task was high. The social stressor also triggered an HbO2 increase in the ECN, especially when it was combined with high mental workload. This latter result suggests that mental workload and stress together can have cumulative effects, and coping with both factors is possible at the expense of an extra recruitment of the ECN. Finally, results also revealed a time-on-task effect, with a progressive reduction of the HbO2 signal in the ECN during the flight scenario, suggesting that these regions are sensitive to short term habituation to the tasks. Overall, fNIRS efficiently indexed mental load, stress, and practice effects.
Polygenic risk for neuroticism is associated with less efficient control in more difficult situations
2023, Psychiatry Research - Neuroimaging
Neuroticism is a heritable trait and a risk factor for mental health due to its relevance to poor control of negative events. To examine the relationship between genetic propensity for neuroticism and control processing, we used the polygenic risk score (PRS) approach and a stop signal task during fMRI. We hypothesized that genetic propensity for neuroticism may moderate control processing as a function of control difficulty. PRSs for neuroticism were computed from a transdiagnostic group of individuals (n=406) who completed the stop signal task. The level of control difficulty was a function of the stop signal asynchrony: shorter asynchrony allows easier stopping whereas longer asynchrony makes stopping difficult. The relationship between PRS for neuroticism and neural activity for controlling responses was examined by the stop signal asynchrony. Although PRS for neuroticism did not relate to the overall inhibitory control, individuals with high PRS for neuroticism showed greater activity in left dorsal prefrontal cortex, middle temporal gyrus, and dorsal posterior cingulate cortex for difficult control. Thus, the genetic propensity for neuroticism affects neural processing in a difficult control context, which may help to explain why individuals with high levels of neuroticism exert poor control of negative events in difficult situations.
Past and current drug repurposing clinical trials to treat cognition in methamphetamine use: a scoping review of pharmacotherapy candidates
2023, Addiction Neuroscience
Globally, methamphetamine is one of the most widely used illicit substances. Despite this, there are no Food and Drug Administration (FDA)-approved pharmacotherapies for treating methamphetamine use disorder. Accumulating evidence suggests consistent cognitive impairments in people with methamphetamine use disorder, which are also associated with neural dysfunction. Importantly, improving cognition may be highly beneficial in reducing methamphetamine use. Indeed, there are medications that have been or are currently being assessed in clinical trials as repurposing drugs to treat methamphetamine use disorder and associated cognitive deficits. Given the known safety profiles and bioavailability, as well as established manufacturing processes, drug repurposing can bypass some steps of conventional drug discovery. This shortens the timeline from bench to bedside translation with lower cost and less risk. Hence, drug repurposing to find pharmacotherapies to treat methamphetamine use disorder should be highly encouraged. The aim of the present review is to scope all repurposed medications in past and current clinical trials in people with methamphetamine use disorder that also assess cognitive function. Medications were selected from publicly available clinical trials registration databases. Based on human and animal literature, we will describe their putative mechanism of action, pharmacological properties, and their potential to improve cognitive functioning in people who use methamphetamine. We hope this scoping review will stimulate drug repurposing and promote rigorous neuroscience-based rationale in future clinical trials to treat methamphetamine use disorder.
Neurophysiology of sustained attention in early infancy: Investigating longitudinal relations with recognition memory outcomes
2023, Infant Behavior and Development
The ability to sustain attention is a critical cognitive domain that emerges in infancy and is predictive of a multitude of cognitive processes. Here, we used a heart rate (HR) defined measure of sustained attention to assess corresponding changes in frontal electroencephalography (EEG) power at 3 months of age. Second, we examined how the neural underpinnings of HR-defined sustained attention were associated with sustained attention engagement. Third, we evaluated if neural or behavioral sustained attention measures at 3-months predicted subsequent recognition memory scores at 9 months of age. Seventy-five infants were included at 3 months of age and provided usable attention and EEG data and 25 infants returned to the lab at 9 months and provided usable recognition memory data. The current study focuses on oscillatory power in the theta (4–6 Hz) frequency band during phases of HR-defined sustained attention and inattention phases. Results revealed that theta power was significantly higher during phases of sustained attention. Second, higher theta power during sustained attention was positively associated with proportion of time in sustained attention. Third, longitudinal analyses indicated a significant positive association between theta power during sustained attention on 9-month visual paired comparison scores such that higher theta power predicted higher visual paired comparison scores at 9-months. These results highlight the interrelation of the attention and arousal systems which have longitudinal implications for subsequent recognition memory processes.

View all citing articles on Scopus

View full text

Advancing the neuroscience of ADHDNeurobiology of Executive Functions: Catecholamine Influences on Prefrontal Cortical Functions

Section snippets

The Role of the PFC in Executive Functions

The Role of the PFC Dysfunction in ADHD

Catecholamines Have an Essential Influence on PFC Function

Relevance to Pharmacological Treatment of ADHD

Neuropsychopharmacology

Biol Psychiatry

Trends Cogn Sci

Neuropsychopharmacology

Brain Res

Biol Psychiatry

Pharmacol Biochem Behav

Neuropsychopharmacology

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

Brain Cogn

Neuron

J Am Acad Child Adolesc Psychiatry

J Am Acad Child Adolesc Psychiatry

Neuropsychopharmacology

Neuropsychopharmacology

Psychiatry Res

Brain Res

Neuropsychopharmacology

Behav Neural Biol

Biol Psychiatry

Trends Pharmacol Sci

Biol Psychiatry

Neurosci Lett

Neuroimage

Neurosci Res

Behav Brain Res

Lancet

Brain Res Bull

Brain Res Brain Res Rev

Neuropsychologia

Brain Res

Impairment of social and moral behavior related to early damage in human prefrontal cortex

Nat Neurosci

Cellular and subcellular sites for noradrenergic action in the monkey dorsolateral prefrontal cortex as revealed by the immunocytochemical localization of noradrenergic receptors and axons

Cereb Cortex

The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects

J Neurosci

Alpha-2 adrenergic agonists decrease distractability in aged monkeys performing a delayed response task

Psychopharmacology

Alpha-2 adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates

Science

Noise stress impairs prefrontal cortical cognitive function in monkeysEvidence for a hyperdopaminergic mechanism

Arch Gen Psychiatry

The contribution of alpha-2 noradrenergic mechanisms to prefrontal cortical cognitive functionPotential significance to attention deficit hyperactivity disorder

Arch Gen Psychiatry

ADHD and the Nature of Self-Control

Selective inhibition in children with attention-deficit hyperactivity disorder off and on stimulant medication

J Abnorm Child Psychol

Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey

Science

Prefrontal regions involved in keeping information in and out of mind

Brain

Dose-dependent effects of the dopamine D1 receptor agonists A77636 or SKF81297 on spatial working memory in aged monkeys

J Pharmacol Exp Ther

Reserpine impairs spatial working memory performance in monkeysReversal by the alpha-2 adrenergic agonist clonidine

Brain Res

Quantitative brain magnetic resonance imaging in attention deficit/hyperactivity disorder

Arch Gen Psychiatry

Dissociation in prefrontal cortex of affective and attentional shifts

Nature

Advancing the neuroscience of ADHD
Neurobiology of Executive Functions: Catecholamine Influences on Prefrontal Cortical Functions