Showing papers by "Trevor W. Robbins published in 2007"

Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement.

Abstract: Stimulant addiction is often linked to excessive risk taking, sensation seeking, and impulsivity, but in ways that are poorly understood. We report here that a form of impulsivity in rats predicts high rates of intravenous cocaine self-administration and is associated with changes in dopamine (DA) function before drug exposure. Using positron emission tomography, we demonstrated that D2/3 receptor availability is significantly reduced in the nucleus accumbens of impulsive rats that were never exposed to cocaine and that such effects are independent of DA release. These data demonstrate that trait impulsivity predicts cocaine reinforcement and that D2 receptor dysfunction in abstinent cocaine addicts may, in part, be determined by premorbid influences.

Evolution of cognitive dysfunction in an incident Parkinson's disease cohort

Abstract: We have previously performed detailed clinical and neuropsychological assessments in a community-based cohort of patients with newly diagnosed parkinsonism, and through analysis of a subcohort with idiopathic Parkinson's disease (PD), we have demonstrated that cognitive dysfunction occurs even at the time of PD diagnosis and is heterogeneous. Longitudinal follow-up of the cohort has now been performed to examine the evolution of cognitive dysfunction within the early years of the disease. One hundred and eighty (79%) eligible patients from the original cohort with parkinsonism were available for re-assessment at between 3 and 5 years from their initial baseline assessments. PD diagnoses were re-validated with repeated application of the UKPDS Brain Bank criteria in order to maximize sensitivity and specificity, following which a diagnosis of idiopathic PD was confirmed in 126 patients. Thirteen out of 126 (10%) had developed dementia at a mean (SD) of 3.5 (0.7) years from diagnosis, corresponding to an annual dementia incidence of 30.0 (16.4-52.9) per 1000 person-years. A further 57% of PD patients showed evidence of cognitive impairment, with frontostriatal deficits being most common amongst the non-demented group. However, the most important clinical predictors of global cognitive decline following correction for age were neuropsychological tasks with a more posterior cortical basis, including semantic fluency and ability to copy an intersecting pentagons figure, as well as a non-tremor dominant motor phenotype at the baseline assessment. This work clarifies the profile of cognitive dysfunction in early PD and demonstrates that the dementing process in this illness is heralded by both postural and gait dysfunction and cognitive deficits with a posterior cortical basis, reflecting probable non-dopaminergic cortical Lewy body pathology. Furthermore, given that these predictors of dementia are readily measurable within just a few minutes in a clinical setting, our work may ultimately have practical implications in terms of guiding prognosis in individual patients.

Neurocognitive endophenotypes of obsessive-compulsive disorder

Abstract: Endophenotypes (intermediate phenotypes) are objective, heritable, quantitative traits hypothesized to represent genetic risk for polygenic disorders at more biologically tractable levels than distal behavioural and clinical phenotypes. It is theorized that endophenotype models of disease will help to clarify both diagnostic classification and aetiological understanding of complex brain disorders such as obsessive-compulsive disorder (OCD). To investigate endophenotypes in OCD, we measured brain structure using magnetic resonance imaging (MRI), and behavioural performance on a response inhibition task (Stop-Signal) in 31 OCD patients, 31 of their unaffected first-degree relatives, and 31 unrelated matched controls. Both patients and relatives had delayed response inhibition on the Stop-Signal task compared with healthy controls. We used a multivoxel analysis method (partial least squares) to identify large-scale brain systems in which anatomical variation was associated with variation in performance on the response inhibition task. Behavioural impairment on the Stop-Signal task, occurring predominantly in patients and relatives, was significantly associated with reduced grey matter in orbitofrontal and right inferior frontal regions and increased grey matter in cingulate, parietal and striatal regions. A novel permutation test indicated significant familial effects on variation of the MRI markers of inhibitory processing, supporting the candidacy of these brain structural systems as endophenotypes of OCD. In summary, structural variation in large-scale brain systems related to motor inhibitory control may mediate genetic risk for OCD, representing the first evidence for a neurocognitive endophenotype of OCD.

Shifting and stopping: fronto-striatal substrates, neurochemical modulation and clinical implications

Abstract: The neuropsychological basis of attentional set-shifting, task-set switching and stop-signal inhibition is reviewed through comparative studies of humans and experimental animals. Using human functional neuroimaging, plus neuropsychological investigation of patients with frontal damage quantified by structural magnetic resonance imaging, and through parallels with effects of specific lesions of the prefrontal cortex (PFC) and striatum in rats and marmosets, it is possible to define both distinct and overlapping loci for tasks such as extra-dimensional shifting and reversal learning, stop-signal reaction time and task-set switching. Notably, most of the paradigms implicate a locus in the right PFC, specifically the right inferior frontal gyrus, possibly associated with processes of response inhibition. The neurochemical modulation of fronto-striatal circuitry in parallel with effects on task performance has been investigated using specific neuropharmacological agents in animals and by human psychopharmacological investigations, sometimes in conjunction with functional imaging. Evidence is provided for double dissociations of effects of manipulations of prefrontal cortical catecholamine and indoleamine (5-HT) systems that have considerable implications in the treatment of disorders such as Parkinson's disease, attention deficit/hyperactivity disorder and depression, as well as in theoretical notions of how ‘fronto-executive’ functions are subject to state-dependent influences, probably related to stress, arousal and motivation.

Disrupted prediction-error signal in psychosis: evidence for an associative account of delusions.

Abstract: Delusions are maladaptive beliefs about the world. Based upon experimental evidence that prediction error—a mismatch between expectancy and outcome—drives belief formation, this study examined the possibility that delusions form because of disrupted prediction-error processing. We used fMRI to determine prediction-error-related brain responses in 12 healthy subjects and 12 individuals (7 males) with delusional beliefs. Frontal cortex responses in the patient group were suggestive of disrupted prediction-error processing. Furthermore, across subjects, the extent of disruption was significantly related to an individual's propensity to delusion formation. Our results support a neurobiological theory of delusion formation that implicates aberrant prediction-error signalling, disrupted attentional allocation and associative learning in the formation of delusional beliefs.

Impaired cognitive flexibility and motor inhibition in unaffected first-degree relatives of patients with obsessive-compulsive disorder

Abstract: Objective: Obsessive-compulsive disorder (OCD) is highly heritable. Attempts to delineate precise genetic contributions have met with limited success. There is an ongoing search for intermediate cognitive brain markers (endophenotypes) that may help clarify genetic contributions. The aim was to assess inhibitory control processes in unaffected first-degree relatives of OCD patients for the first time with objective tests. Method: The Intradimensional/Extradimensional Shift, Stop-Signal, and Cambridge Gamble tasks were administered to 20 unaffected first-degree relatives, 20 OCD patient probands with washing/checking symptoms, and 20 healthy matched comparison subjects without a family history of OCD. Results: Unaffected first-degree relatives and OCD patient probands showed cognitive inflexibility (extradimensional set shifting) and motor impulsivity (stop-signal reaction times). Decision making (Cambridge Gamble task) was intact. Conclusions: Deficits in cognitive flexibility and motor inhibition may rep...

Differential Regulation of Fronto-Executive Function by the Monoamines and Acetylcholine

Abstract: The prefrontal cortex (PFC) is innervated by the monoamines, dopamine (DA), noradrenaline (NA), and serotonin, as well as acetylcholine, and the marked influence of these neurochemical systems on prefrontal working memory processes has been widely described. However, their potentially, differential contribution to prefrontal functioning is less well understood. This paper reviews evidence to support the hypothesis that these neurochemical systems recruit distinct fronto-executive operations. Direct comparison of the effects of manipulations of these neuromodulators within PFC on performance of an attentional set-shifting paradigm reveals their differential contribution to distinct task stages. Depletion of prefrontal serotonin selectively disrupts reversal learning but not attentional set formation or set shifting. In contrast, depletion of prefrontal DA disrupts set formation but not reversal learning. NA depletion on the other hand specifically impairs set-shifting, whereas its effects on reversal learning remain unclear. Finally, depletion of prefrontal acetylcholine has no effect on either set formation or set shifting but impairs serial reversal learning. Because these neurochemical systems are known to represent distinct states of stress, arousal, attention, and affect, it is postulated that they augment the different types of executive operation that are recruited and performed within these states via a synergistic interaction with the PFC.

A role for mesencephalic dopamine in activation: commentary on Berridge (2006)

Abstract: Ideas about the functions of the central dopamine (DA) system may seem to have evolved quite considerably in the last decade. While the theoretical debate based on classic neuropsychopharmacological approaches has become much more sophisticated and refined, perhaps the major new concepts have derived from (1) electrophysiological observations that fast phasic firing of cells in the ventral tegmental area appear to model an error prediction signal relevant to Pavlovian or temporal difference learning models (Schultz 2002), and from (2) the relative contributions of such phasic responses with the tonic mode of action of the same DA systems (Goto and Grace 2005). Both of these empirical advances were also matched by theoretical refinement; for example, in the domain of human cognitive neuroscience, the study of the role of DA in reinforcement learning and “error prediction” learning has become highly fashionable (see, e.g., Montague et al. 2004; Frank and O’Reilly 2006) and the tonic–phasic distinction has been a major new construct for modeling psychopathology, including genomic approaches (Bilder et al. 2004). One of the main thrusts of Berridge’s article is a critical analysis of the role of DA in reinforcement learning, and we particularly appreciate his attempt to differentiate his account from a learning standpoint, for example, by his experiments with serial conditioned stimuli (CSs). We are graciously assigned one of the competing perspectives to Berridge’s “incentive sensitization” hypothesis in terms of our speculations about the role of DA in habit learning. However, our position is a much more general one that in many ways is in harmony with that of Berridge, although on the basis of very different evidence. His discussion of a “motivational” role for the ascending DA system reminds us in many ways of notions that we have entertained in several previous articles (Robbins and Everitt 1982, 1987, 1992, 1995; Robbins et al. 1989). Thus, we suggested that functions of the central DA systems could be explained in terms of an “energetic” construct (i.e., one that accounts for the vigor and frequency of behavioral output) of “activation.” This activational state, which is particularly important in the modulation of behavioral (and cognitive) output, has to be distinguished from concepts of arousal that affect the efficiency of cortical processing. As posited in our 1992 review of the considerable empirical data already then available, activation (sometimes confusingly called “behavioral arousal”) is induced by many related states or stimuli, including food deprivation, “stress,” psychomotor stimulant drugs, aversive stimuli such as tail-pinch and foot-shock, novelty, CSs, including predictors of appetitive events such as food, and also of aversive events (Robbins and Everitt 1992). The range of these stimuli and states, incidentally goes far beyond the hypothesis that the midbrain DA system responds simply to error prediction signals, especially as the class of activating stimuli also includes novel stimuli under certain conditions (c.f. Bardo et al. 1990). However, we acknowledge that there is controversy about the relative sensitivity of the midbrain DA neurons to different states and stimuli—often arising from differences in the methods for indexing such changes, for example, electrophysiological, which are more sensitive to phasic Psychopharmacology (2007) 191:433–437 DOI 10.1007/s00213-006-0528-7

Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls.

Abstract: The catechol-O-methyltransferase (COMT) Val158Met polymorphism is hypothesized to affect executive function in patient and control populations. Studies inconsistently report better performance on the Wisconsin Card Sort Test (WCST) in individuals with one or more Met alleles. We conducted a meta-analysis of studies published until August 2006 that reported WCST perseverative errors from healthy volunteers or patients with schizophrenia-spectrum disorders. Twelve studies met inclusion criteria (total n=1910) providing 10 samples each of patients and controls. In healthy controls, individuals with the Met/Met genotype performed better than those with the Val/Val genotype (d=0.29; 95% confidence interval (CI) 0.02–0.55; P=0.03), but this was not supported in the patient sample (d=−0.07; 95% CI −0.40 to 0.26; P=0.68). Post hoc analyses suggested that Val and Met alleles are codominant in their effects on cognition. Effect size was greater in studies published at an earlier date and may also be larger in non-Caucasian samples. Gender did not affect the results. There was no evidence of publication bias. We conclude that there is small but significant relationship between Val158Met genotype and executive function in healthy individuals but not in schizophrenia.

Differential effects of modafinil and methylphenidate on stop-signal reaction time task performance in the rat, and interactions with the dopamine receptor antagonist cis-flupenthixol.

Abstract: Rationale The stop-signal reaction time (SSRT) task measures inhibition of a response that has already been initiated, i.e. the ability to stop. ‘Impulsive’ human subjects, e.g. with attention deficit and hyperactivity disorder (ADHD), have longer SSRTs. Both SSRT and go-trial reaction time (GoRT) may be sensitive to drugs such as d-amphetamine, methylphenidate and modafinil, both in normal subjects and those with ADHD.

Catechol O-Methyltransferase val158met Genotype Influences Frontoparietal Activity during Planning in Patients with Parkinson's Disease

Abstract: Cognitive dysfunction commonly occurs even in the early stages of Parkinson9s disease (PD). Impairment on frontostriatally based executive tasks is particularly well described but affects only a proportion of early PD patients. Our previous work suggests that a common functional polymorphism (val 158 met) within the catechol O -methyltransferase ( COMT ) gene underlies some of this executive heterogeneity. In particular, an increasing number of methionine alleles, resulting in lower enzyme activity, is associated with impaired performance on the “Tower of London” planning task. The main objective of this study was to investigate the underlying neural basis of this genotype–phenotype effect in PD using functional magnetic resonance imaging. We scanned 31 patients with early PD who were homozygous for either valine (val) ( n = 16) or methionine (met) ( n = 15) at the COMT val 158 met polymorphism during performance of an executive task comprising both Tower of London (planning) and simple subtracting (“control”) problems. A cross-group comparison between genetic subgroups revealed that response times for planning problems were significantly longer in met compared with val homozygotes, whereas response times for control problems did not differ. Furthermore, imaging data revealed a significant reduction in blood oxygen level-dependent signal across the frontoparietal network involved in planning in met/met compared with val/val patients. Hence, we have demonstrated that COMT genotype impacts on executive function in PD through directly influencing frontoparietal activation. Furthermore, the directionality of the genotype–phenotype effect observed in this study, when interpreted in the context of the existing literature, adds weight to the hypothesis that the relationship between prefrontal function and dopamine levels follows as an inverted U-shaped curve.

Lesions of the dorsal noradrenergic bundle impair attentional set-shifting in the rat.

Abstract: Rats with medial prefrontal cortex (mPFC) lesions are impaired in attentional set-shifting, when it is required to shift to a previously irrelevant perceptual dimension. The main source of noradrenergic input to the mPFC is from the locus coeruleus via the dorsal noradrenergic ascending bundle (DNAB). This study examined the effects of selective cortical noradrenaline depletion following 6-hydroxydopamine-induced lesions of the DNAB on attentional set-shifting and other aspects of discrimination learning and performance. Rats learned to dig in baited bowls, and then acquired discriminations based on one of two aspects of a bowl--odour or digging medium. The task tested acquisition of novel discriminations (both intra- and extra-dimensional) and reversal learning when contingencies were reversed with the same stimuli. At the conclusion of testing, the DNAB-lesioned rats were shown to have a selective depletion of noradrenaline of approximately 70% within the mPFC (cingulate and prelimbic cortex subregions), with no other significant changes in dopamine or 5-hydroxytryptamine. Rats required more trials to learn new discriminations when attentional shifting was required [extra-dimensional (ED)-shift]. Rats with dorsal noradrenergic ascending bundle (DNAB) lesions were impaired in novel acquisitions when an ED-shift was required, but were unimpaired in reversal learning and other aspects of discrimination learning, relative to controls. These data are consistent with other evidence implicating noradrenaline (NA) in attentional set-shifting, and contrast with effects of manipulations of 5-hydroxytryptamine (5-HT) and acetylcholine within the medial prefrontal cortex (mPFC). The findings are also relevant to recent theorizing about the functions of the coeruleo-cortical noradrenergic system.

Forebrain connectivity of the prefrontal cortex in the marmoset monkey (Callithrix jacchus): an anterograde and retrograde tract-tracing study.

Abstract: The cortical and subcortical forebrain connections of the marmoset prefrontal cortex (PFC) were examined by injecting the retrograde tracer, choleratoxin, and the anterograde tracer, biotin dextran amine, into four sites within the PFC. Two of the sites, the lateral and orbital regions, had previously been shown to provide functionally dissociable contributions to distinct forms of behavioral flexibility, attentional set-shifting and discrimination reversal learning, respectively. The dysgranular and agranular regions lying on the orbital and medial surfaces of the frontal lobes were most closely connected with limbic structures including cingulate cortex, amygdala, parahippocampal cortex, subiculum, hippocampus, hypothalamus, medial caudate nucleus, and nucleus accumbens as well as the magnocellular division of the mediodorsal nucleus of the thalamus and midline thalamic nuclei, consistent with findings in the rhesus monkey. In contrast, the granular region on the dorsal surface closely resembled area 8Ad in macaques and had connections restricted to posterior parietal cortex primarily associated with visuospatial functions. However, it also had connections with limbic cortex, including retrosplenial and caudal cingulate cortex as well as auditory processing regions in the superior temporal cortex. The granular region on the lateral convexity had the most extensive connections. Based on its architectonics and functionality, it resembled areas 12/45 in macaques. It had connections with high-order visual processing regions in the inferotemporal cortex and posterior parietal cortex, higher-order auditory and polymodal processing regions in the superior temporal cortex. In addition it had extensive connections with limbic regions including the amygdala, parahippocampal cortex, cingulate, and retrosplenial cortex.

The Orbital Prefrontal Cortex and Drug Addiction in Laboratory Animals and Humans

Abstract: In this chapter, we review evidence implicating the orbitofrontal cortex (OFC) in drug addiction. We show that the orbital cortex is involved in conditioned reinforcement and is thereby important for the acquisition of cocaine-seeking behavior studied in a way that provides an animal experimental homologue of orbital cortex activation and craving upon exposure of addicts to drug-associated stimuli. We discuss the evidence indicating orbital prefrontal cortex dysfunction in human drug addicts, reviewing both neuropsychological and neuroimaging studies. Finally, we consider animal experimental evidence suggesting that addictive drugs may cause orbital cortex dysfunction and thereby contribute to the transition to drug addiction. Reconciling the observations that even brief periods of drug exposure can lead to long-lasting functional and structural deficits associated with the OFC together with those suggesting interactions between a vulnerable phenotype and chronic drug-self-administration will be an important topic of future research.

Selective depletion of cortical noradrenaline by anti-dopamine beta-hydroxylase-saporin impairs attentional function and enhances the effects of guanfacine in the rat.

Abstract: Rationale Previous data indicate that depletion of cortical noradrenaline (NA) impairs performance of an attentional five-choice serial reaction time task (5CSRT) under certain conditions. This study employed a novel immunotoxin, anti-dopamine-beta hydroylase (DβH)–saporin, to make relatively selective lesions of the noradrenergic projections to the prefrontal cortex (PFC) in rats trained to perform the 5CSRT.

Bilateral high-frequency stimulation of the subthalamic nucleus on attentional performance: transient deleterious effects and enhanced motivation in both intact and parkinsonian rats.

Abstract: It is now well established that subthalamic nucleus high-frequency stimulation (STN HFS) alleviates motor problems in Parkinson's disease. However, its efficacy for cognitive function remains a matter of debate. The aim of this study was to assess the effects of STN HFS in rats performing a visual attentional task. Bilateral STN HFS was applied in intact and in bilaterally dopamine (DA)-depleted rats. In all animals, STN HFS had a transient debilitating effect on all the variables measured in the task. In DA-depleted rats, STN HFS did not alleviate the deficits induced by the DA lesion such as omissions and latency to make correct responses, but induced perseverative approaches to the food magazine, an indicator of enhanced motivation. In sham-operated controls, STN HFS significantly reduced accuracy and induced perseverative behaviour, mimicking partially the effects of bilateral STN lesions in the same task. These results are in line with the hypothesis that STN HFS only partially mimics inactivation of STN produced by lesioning and confirm the motivational exacerbation induced by STN inactivation.

Delay discounting and impulsive choice in the rat.

Abstract: Delay discounting refers to the degree to which immediate outcomes exhibit more influence over behavior than outcomes which are delayed. Impulsive choice, in the context of delay discounting, is generally considered as an increased preference for immediate over delayed outcomes, even where the delayed outcomes are more advantageous. In the past decade, there has been increasing use of delay-discounting paradigms to elucidate the physiological, pharmacological, and behavioral aspects of the putative neural circuitry underlying impulsive choice. This unit describes the assessment of impulsive choice in the rat using a delay-discounting procedure involving an operant response choice between a small reinforcer delivered immediately and a larger reinforcer delivered after a delay, which is progressively increased within a session. Variations of some of the main task parameters are also discussed, as well as their significance and interpretation.

Atomoxetine increases salivary cortisol in healthy volunteers.

Abstract: It has been proposed that acute hypothalamo-pituitary-adrenal (HPA) axis challenge using noradrenergic drugs may be of utility in assessing the functional integrity of central noradrenaline pathways. Atomoxetine (formerly tomoxetine) is a highly selective noradrenaline reuptake inhibitor, which has recently been licensed for the treatment of attention deficit hyperactivity disorder (ADHD). The aim of this study was to assess the effects of acute atomoxetine on salivary cortisol levels for the first time.A total of 60 healthy male volunteers received 60 mg atomoxetine, 30 mg citalopram, or placebo per os in a double-blind parallel groups design (n = 20 per group). Salivary cortisol, blood pressure and pulse rates were recorded at baseline and at +1.0, +1.5, +2.5 and +3.5 hours after capsule administration.60 mg atomoxetine led to highly significant increases in salivary cortisol and a moderate increase in pulse rate, in the absence of significant effects on blood pressure. 30 mg citalopram had no significant effects on cortisol or cardiovascular parameters. These data support the utility of atomoxetine neuroendocrine challenge for evaluating central noradrenaline pathways, which may be of future use in neuropsychiatric patient studies. Furthermore, the effects of atomoxetine on HPA axis function may have clinical implications given the use of this agent in the treatment of ADHD.

Neuroscience of Drugs and Addiction

Abstract: Publisher Summary Brain science is at the core of future understanding of how drugs affect behavior and their consequent impact the society. Extraordinary advances in the past three decades have meant that now much is understood about the connectivity of the brain and how its functionality depends on chemical messages passing among nerve cells, or neurons, in the form of neurotransmitters they release that bind to receptors. Psychoactive substances exert their effects by affecting the regulation of neurotransmitters or simulating their actions at their receptors, and subsequently within the nerve cell itself, often in highly specific ways. It is now understood that many drugs work in molecular terms and they may work, at least initially, in the brain. Moreover, one now knows in broad terms how different parts of the brain work at a systems level to produce behavioral and cognitive output. A complementary advance is the application of some aspects of neural decision making theory to the explanation of the behavior of individual substance abusers. Vulnerability or susceptibility to some actions of psychoactive substances, including both cognitive enhancement and dependence, depends on individual differences based on genetic or environmental, including developmental factors. Although in the society drug abuse is viewed as a social or moral problem best handled through the criminal justice system, the growing scientific evidence suggests instead that addiction is a chronic, relapsing, and treatable brain disorder that can result from prolonged effects of drugs on the brain.

Drugs Futures 2025

Abstract: Publisher Summary Significant advances in the understanding of areas such as neuroscience, genetics, pharmacology, psychology, and social policy have taken place in recent years This new knowledge has moved one to a new level in the understanding of how the brain work, how chemicals affect the brain's performance and, in turn, how this affects human behavior At the same time, more is expected from the human brain The knowledge of the way the human brain and behavior work is growing at pace This knowledge has brought significant gains through better treatments for many mental health disorders and the diagnosis of new conditions such as attention deficit hyperactivity disorder (ADHD) There is a significant investment in the research on drugs and the brain and it is starting to bear fruit Many of the advances are unexpected and are still not understood In particular, new approaches are being developed for medicines for mental health Preventative treatments are being trialed for Alzheimer's disease and one may be able to develop them for schizophrenia At the same time, pharmacogenetics is allowing one to identify people at higher risk of adverse or in some cases even beneficial drug side effects This chapter enlists the support of academic experts ranging from neuroscientists to economists and presents some reviews of the science that are the most thorough analyses ever written of the issues faced by the United Kingdom and other countries in the sphere of legal and illegal drug use and their interaction with brain science