Catecholamine influences on prefrontal cortical function: relevance to treatment of attention deficit/hyperactivity disorder and related disorders.
TL;DR: Studies in animals show that norepinephrine and dopamine enhance PFC function through actions at postsynaptic α(2A)-adrenoceptors and dopamine D1-receptors, respectively, which likely contributes to the therapeutic effects of these medications for the treatment of ADHD.
Abstract: The primary symptoms of attention deficit/hyperactivity disorder (ADHD) include poor impulse control and impaired regulation of attention. Research has shown that the prefrontal cortex (PFC) is essential for the "top-down" regulation of attention, behavior, and emotion, and that this brain region is underactive in many patients with ADHD. The PFC is known to be especially sensitive to its neurochemical environment; relatively small changes in the levels of norepinephrine and dopamine can produce significant changes in its function. Therefore, alterations in the pathways mediating catecholamine transmission can impair PFC function, while medications that optimize catecholamine actions can improve PFC regulation of attention, behavior, and emotion. This article reviews studies in animals showing that norepinephrine and dopamine enhance PFC function through actions at postsynaptic α(2A)-adrenoceptors and dopamine D1-receptors, respectively. Stimulant medications and atomoxetine appear to enhance PFC function through increasing endogenous adrenergic and dopaminergic stimulation of α(2A)-receptors and D1-receptors. In contrast, guanfacine mimics the enhancing effects of norepinephrine at postsynaptic α(2A)-receptors in the PFC, strengthening network connectivity. Stronger PFC regulation of attention, behavior, and emotion likely contributes to the therapeutic effects of these medications for the treatment of ADHD.
Citations
More filters
01 Jan 2002
TL;DR: This paper investigated changes in regional cerebral blood flow (rCBF) induced by methylphenidate during performance of a self-ordered spatial working memory task to define the neuroanatomical loci of the beneficial effect of the drug.
Abstract: The indirect catecholamine agonist methylphenidate (Ritalin) is the drug treatment of choice in attention deficit/hyperactivity disorder (AD/HD), one of the most common behavioral disorders of childhood (DSM-IV), although symptoms may persist into adulthood. Methylphenidate can enhance cognitive performance in adults and children diagnosed with AD/HD (Kempton et al., 1999; Riordan et al., 1999) and also in normal human volunteers on tasks sensitive to frontal lobe damage, including aspects of spatial working memory (SWM) performance (Elliott et al., 1997). The present study investigated changes in regional cerebral blood flow (rCBF) induced by methylphenidate during performance of a self-ordered SWM task to define the neuroanatomical loci of the beneficial effect of the drug. The results show that the methylphenidate-induced improvements in working memory performance occur with task-related reductions in rCBF in the dorsolateral prefrontal cortex and posterior parietal cortex. The beneficial effects of methylphenidate on working memory were greatest in the subjects with lower baseline working memory capacity. This is to our knowledge the first demonstration of a localization of a drug-induced improvement in SWM performance in humans and has relevance for understanding the treatment of AD/HD.
547 citations
TL;DR: This review focuses on the pathophysiology, etiology, and treatment of ADHD and details the adverse effects and drug interaction profiles of the drugs used to treat it.
Abstract: Objective: To review the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD). Data Sources and Data Extraction: A literature search was conducted in PubMed and EMBASE using the terms attention deficit hyperactive disorder, ADHD, pathophysiology, etiology, and neurobiology. Limits applied were the following: published in the past 10 years (January 2003 to August 2013), humans, review, meta-analysis, and English language. These yielded 63 articles in PubMed and 74 in EMBASE. After removing duplicate/irrelevant articles, 86 articles and their relevant reference citations were reviewed. Data Synthesis: ADHD is a neurological disorder that affects children, but symptoms may persist into adulthood. Individuals suffering from this disorder exhibit hyperactivity, inattention, impulsivity, and problems in social interaction and academic performance. Medications used to treat ADHD such as methylphenidate, amphetamine, and atomoxetine indicate a dopamine/norepinephrine deficit...
366 citations
Cites background or result from "Catecholamine influences on prefron..."
...For example, methylphenidate, amphetamine, and atomoxetine enhance DA and NE transmission in PFC, whereas guanfacine stimulates postsynaptic α 2A receptors directly.(9) However, several studies pointed toward a hyperactive DA and/or NE system in ADHD....
[...]
...Studies in ADHD patients have shown slower maturation of PFC(11) or a smaller volume and reduced activity of the PFC, caudate, or cerebellum.(9) The network activity between these areas is “extremely sensitive to the neurochemical environment,”(9) and is maintained by neurotransmitters (NTs), dopamine (DA), and norepinephrine (NE) acting in conjunction with each other via multiple receptors(12-15) that may be either presynaptic or postsynaptic (Figure 1)....
[...]
...Whereas a decreased receptor density or genetic polymorphisms related to the NE system in ADHD has not been determined,(20) disruption of α 2A receptor function leads to impaired attention and impulse control and hyperactivity.(9) Taken together, these studies pointed to a reduced DA and/ or NE function hypothesis in ADHD, which was in perfect agreement with the mechanism of action of the medications used to treat ADHD....
[...]
...These areas are interconnected by a network of neurons and together regulate attention, thoughts, emotions, behavior, and actions.(9,10) Studies in ADHD patients have shown slower maturation of PFC(11) or a smaller volume and reduced activity of the PFC, caudate, or cerebellum....
[...]
TL;DR: It is suggested that interventions aimed at restoring the balance between the reward and anti-reward networks in patients with chronic pain may help decreasing their suicide risk.
173 citations
TL;DR: It is found that dorsomedial prefrontal cortical areas are important for inhibiting an already initiated response in the rat and that they are differentially modulated by noradrenergic and dopaminergic neurotransmission.
Abstract: Defining the neural and neurochemical substrates of response inhibition is of crucial importance for the study and treatment of pathologies characterized by impulsivity such as attention-deficit/hyperactivity disorder and addiction. The stop-signal task (SST) is one of the most popular paradigms used to study the speed and efficacy of inhibitory processes in humans and other animals. Here we investigated the effect of temporarily inactivating different prefrontal subregions in the rat by means of muscimol microinfusions on SST performance. We found that dorsomedial prefrontal cortical areas are important for inhibiting an already initiated response. We also investigated the possible neural substrates of the selective noradrenaline reuptake inhibitor atomoxetine via its local microinfusion into different subregions of the rat prefrontal cortex. Our results show that both orbitofrontal and dorsal prelimbic cortices mediate the beneficial effects of atomoxetine on SST performance. To assess the neurochemical specificity of these effects, we infused the α2-adrenergic agonist guanfacine and the D1/D2 antagonist α-flupenthixol in dorsal prelimbic cortex to interfere with noradrenergic and dopaminergic neurotransmission, respectively. Guanfacine, which modulates noradrenergic neurotransmission, selectively impaired stopping, whereas blocking dopaminergic receptors by α-flupenthixol infusion prolonged go reaction time only, confirming the important role of noradrenergic neurotransmission in response inhibition. These results show that, similar to humans, distinct networks play important roles during SST performance in the rat and that they are differentially modulated by noradrenergic and dopaminergic neurotransmission. This study advances our understanding of the neuroanatomical and neurochemical determinants of impulsivity, which are relevant for a range of psychiatric disorders.
154 citations
Cites background from "Catecholamine influences on prefron..."
...Guanfacine produces beneficial effects on working memory (Arnsten and Pliszka, 2011) in tasks possibly necessitating a different level of PFC activation compared with the SST....
[...]
TL;DR: A systematic overview of drugs that may induce distinct cardiovascular toxicity of illicit sympathomimetic drugs, drugs that prolong the QT interval, antidysrhythmic drugs, digoxin and other cardioactive steroids, beta‐blockers, calcium channel blockers, female hormones, nonsteroidal anti‐inflammatory, and anticancer compounds are discussed.
Abstract: Cardiovascular diseases are a leading cause of morbidity and mortality in most developed countries of the world. Pharmaceuticals, illicit drugs, and toxins can significantly contribute to the overall cardiovascular burden and thus deserve attention. The present article is a systematic overview of drugs that may induce distinct cardiovascular toxicity. The compounds are classified into agents that have significant effects on the heart, blood vessels, or both. The mechanism(s) of toxic action are discussed and treatment modalities are briefly mentioned in relevant cases. Due to the large number of clinically relevant compounds discussed, this article could be of interest to a broad audience including pharmacologists and toxicologists, pharmacists, physicians, and medicinal chemists. Particular emphasis is given to clinically relevant topics including the cardiovascular toxicity of illicit sympathomimetic drugs (e.g., cocaine, amphetamines, cathinones), drugs that prolong the QT interval, antidysrhythmic drugs, digoxin and other cardioactive steroids, beta-blockers, calcium channel blockers, female hormones, nonsteroidal anti-inflammatory, and anticancer compounds encompassing anthracyclines and novel targeted therapy interfering with the HER2 or the vascular endothelial growth factor pathway.
154 citations
References
More filters
TL;DR: Advances in human lesion-mapping support the functional localization of such inhibition to right IFC alone, and future research should investigate the generality of this proposed inhibitory function to other task domains, and its interaction within a wider network.
2,920 citations
"Catecholamine influences on prefron..." refers background in this paper
...The right inferior PFC is especially important for reducing impulsive behavior and inhibiting inappropriate actions (Aron et al., 2004), while the orbital and ventromedial PFC is essential for the regulation of emotion, such as the inhibition of aggressive impulses (Best et al., 2002; Izquierdo et…...
[...]
...The right inferior PFC is especially important for reducing impulsive behavior and inhibiting inappropriate actions (Aron et al., 2004), while the orbital and ventromedial PFC is essential for the regulation of emotion, such as the inhibition of aggressive impulses (Best et al....
[...]
TL;DR: The special nature of working memory was first identified in studies of human cognition, and modern neurobiological methods have identified a specific population of neurons, patterns of their intrinsic and extrinsic circuitry, and signaling molecules that are engaged in this process in animals.
2,413 citations
"Catecholamine influences on prefron..." refers background in this paper
...The cellular networks of the PFC are able to maintain representations of goals and rules and use remembered information to guide attention, actions, and emotion (Goldman-Rakic, 1995)....
[...]
...PFC networks are able to excite each other in the absence of external environmental stimulation, thus representing information such as goals for behavior, our “mental sketch pad” (Goldman-Rakic, 1995)....
[...]
TL;DR: The result indicates that top-down and bottom-up signals arise from the frontal and sensory cortex, respectively, and different modes of attention may emphasize synchrony at different frequencies.
Abstract: Attention can be focused volitionally by "top-down" signals derived from task demands and automatically by "bottom-up" signals from salient stimuli. The frontal and parietal cortices are involved, but their neural activity has not been directly compared. Therefore, we recorded from them simultaneously in monkeys. Prefrontal neurons reflected the target location first during top-down attention, whereas parietal neurons signaled it earlier during bottom-up attention. Synchrony between frontal and parietal areas was stronger in lower frequencies during top-down attention and in higher frequencies during bottom-up attention. This result indicates that top-down and bottom-up signals arise from the frontal and sensory cortex, respectively, and different modes of attention may emphasize synchrony at different frequencies.
2,086 citations
TL;DR: Maturation to progress in a similar manner regionally in both children with and without ADHD, with primary sensory areas attaining peak cortical thickness before polymodal, high-order association areas, and there was a marked delay in ADHD in attainingpeak thickness throughout most of the cerebrum.
Abstract: There is controversy over the nature of the disturbance in brain development that underpins attention-deficit/hyperactivity disorder (ADHD). In particular, it is unclear whether the disorder results from a delay in brain maturation or whether it represents a complete deviation from the template of typical development. Using computational neuroanatomic techniques, we estimated cortical thickness at >40,000 cerebral points from 824 magnetic resonance scans acquired prospectively on 223 children with ADHD and 223 typically developing controls. With this sample size, we could define the growth trajectory of each cortical point, delineating a phase of childhood increase followed by adolescent decrease in cortical thickness (a quadratic growth model). From these trajectories, the age of attaining peak cortical thickness was derived and used as an index of cortical maturation. We found maturation to progress in a similar manner regionally in both children with and without ADHD, with primary sensory areas attaining peak cortical thickness before polymodal, high-order association areas. However, there was a marked delay in ADHD in attaining peak thickness throughout most of the cerebrum: the median age by which 50% of the cortical points attained peak thickness for this group was 10.5 years (SE 0.01), which was significantly later than the median age of 7.5 years (SE 0.02) for typically developing controls (log rank test χ(1)2 = 5,609, P < 1.0 × 10−20). The delay was most prominent in prefrontal regions important for control of cognitive processes including attention and motor planning. Neuroanatomic documentation of a delay in regional cortical maturation in ADHD has not been previously reported.
1,515 citations
"Catecholamine influences on prefron..." refers background in this paper
...There is evidence of delayed maturation of the PFC in children with ADHD (Shaw et al., 2007)....
[...]
TL;DR: Developmental trajectories for all structures, except caudate, remain roughly parallel for patients and controls during childhood and adolescence, suggesting that genetic and/or early environmental influences on brain development in ADHD are fixed, nonprogressive, and unrelated to stimulant treatment.
Abstract: ContextVarious anatomic brain abnormalities have been reported for attention-deficit/hyperactivity
disorder (ADHD), with varying methods, small samples, cross-sectional designs,
and without accounting for stimulant drug exposure.ObjectiveTo compare regional brain volumes at initial scan and their change over
time in medicated and previously unmedicated male and female patients with
ADHD and healthy controls.Design, Setting, and ParticipantsCase-control study conducted from 1991-2001 at the National Institute
of Mental Health, Bethesda, Md, of 152 children and adolescents with ADHD
(age range, 5-18 years) and 139 age- and sex-matched controls (age range,
4.5-19 years) recruited from the local community, who contributed 544 anatomic
magnetic resonance images.Main Outcome MeasuresUsing completely automated methods, initial volumes and prospective
age-related changes of total cerebrum, cerebellum, gray and white matter for
the 4 major lobes, and caudate nucleus of the brain were compared in patients
and controls.ResultsOn initial scan, patients with ADHD had significantly smaller brain
volumes in all regions, even after adjustment for significant covariates.
This global difference was reflected in smaller total cerebral volumes (−3.2%,
adjusted F1,280 = 8.30, P = .004) and
in significantly smaller cerebellar volumes (−3.5%, adjusted F1,280 = 12.29, P = .001). Compared with controls,
previously unmedicated children with ADHD demonstrated significantly smaller
total cerebral volumes (overall F2,288 = 6.65; all pairwise comparisons
Bonferroni corrected, −5.8%; P = .002) and
cerebellar volumes (−6.2%, F2,288 = 8.97, P<.001). Unmedicated children with ADHD also exhibited strikingly
smaller total white matter volumes (F2,288 = 11.65) compared with
controls (−10.7%, P<.001) and with medicated
children with ADHD (−8.9%, P<.001). Volumetric
abnormalities persisted with age in total and regional cerebral measures (P = .002) and in the cerebellum (P =
.003). Caudate nucleus volumes were initially abnormal for patients with ADHD
(P = .05), but diagnostic differences disappeared
as caudate volumes decreased for patients and controls during adolescence.
Results were comparable for male and female patients on all measures. Frontal
and temporal gray matter, caudate, and cerebellar volumes correlated significantly
with parent- and clinician-rated severity measures within the ADHD sample
(Pearson coefficients between −0.16 and −0.26; all P values were <.05).ConclusionsDevelopmental trajectories for all structures, except caudate, remain
roughly parallel for patients and controls during childhood and adolescence,
suggesting that genetic and/or early environmental influences on brain development
in ADHD are fixed, nonprogressive, and unrelated to stimulant treatment.
1,511 citations
"Catecholamine influences on prefron..." refers background or result in this paper
...In addition, the volumes of other brain regions, such as the caudate and cerebellum, which have reciprocal connections with the PFC, have been reported to be smaller in children with ADHD than in control subjects in some studies (Castellanos et al., 2002)....
[...]
...Several imaging studies have shown that the dorsolateral PFC has a smaller volume and reduced activity in patients with ADHD compared with controls (Castellanos et al., 2002; Castellanos et al., 2008; Mostofsky et al., 2002; Rubia et al., 1999; Seidman et al., 2005)....
[...]