Deep learning-based activity recognition and fine motor identification using 2D skeletons of cynomolgus monkeys.

Video-based action recognition is becoming a vital tool in clinical research and neuroscientific study for disorder detection and prediction. However, action recognition currently used in non-human primate (NHP) research relies heavily on intense manual labor and lacks standardized assessment. In this work, we established two standard benchmark datasets of NHPs in the laboratory: MonkeyinLab (MiL), which includes 13 categories of actions and postures, and MiL2D, which includes sequences of two-dimensional (2D) skeleton features. Furthermore, based on recent methodological advances in deep learning and skeleton visualization, we introduced the MonkeyMonitorKit (MonKit) toolbox for automatic action recognition, posture estimation, and identification of fine motor activity in monkeys. Using the datasets and MonKit, we evaluated the daily behaviors of wild-type cynomolgus monkeys within their home cages and experimental environments and compared these observations with the behaviors exhibited by cynomolgus monkeys possessing mutations in the MECP2 gene as a disease model of Rett syndrome (RTT). MonKit was used to assess motor function, stereotyped behaviors, and depressive phenotypes, with the outcomes compared with human manual detection. MonKit established consistent criteria for identifying behavior in NHPs with high accuracy and efficiency, thus providing a novel and comprehensive tool for assessing phenotypic behavior in monkeys.

Association between vmPFC gray matter volume and smoking initiation in adolescents.

Smoking of cigarettes among young adolescents is a pressing public health issue. However, the neural mechanisms underlying smoking initiation and sustenance during adolescence, especially the potential causal interactions between altered brain development and smoking behaviour, remain elusive. Here, using large longitudinal adolescence imaging genetic cohorts, we identify associations between left ventromedial prefrontal cortex (vmPFC) gray matter volume (GMV) and subsequent self-reported smoking initiation, and between right vmPFC GMV and the maintenance of smoking behaviour. Rule-breaking behaviour mediates the association between smaller left vmPFC GMV and smoking behaviour based on longitudinal cross-lagged analysis and Mendelian randomisation. In contrast, smoking behaviour associated longitudinal covariation of right vmPFC GMV and sensation seeking (especially hedonic experience) highlights a potential reward-based mechanism for sustaining addictive behaviour. Taken together, our findings reveal vmPFC GMV as a possible biomarker for the early stages of nicotine addiction, with implications for its prevention and treatment.

Role of adenosine A2A receptors in hot and cold cognition: Effects of single-dose istradefylline in healthy volunteers.

The role of the adenosine neurochemical system in human cognition is under-studied, despite such receptors being distributed throughout the brain. The aim of this study was to shed light on the role of the adenosine A2A receptors in human cognition using single-dose istradefylline. Twenty healthy male participants, aged 19-49, received 20 mg istradefylline and placebo, in a randomized, double-blind, placebo-controlled cross-over design. Cognition was assessed using computerized cognitive tests, covering both cold (non-emotional) and hot (emotion-laden) domains. Cardiovascular data were recorded serially. Cognitive effects of istradefylline were explored using repeated measures analysis of variance and paired t-tests as appropriate. On the EMOTICOM battery, there was a significant effect of istradefylline versus placebo on the Social Information Preference task (t = 2.50, p = 0.02, d=-0.59), indicating that subjects on istradefylline interpreted social situations more positively. No other significant effects were observed on other cognitive tasks, nor in terms of cardiovascular measures (pulse and blood pressure). De-briefing indicated that blinding was successful, both for participants and the research team. Further exploration of the role of adenosine A2A receptors in emotional processing may be valuable, given that abnormalities in related cognitive functions are implicated in neuropsychiatric disorders. The role of adenosine systems in human cognition requires further clarification, including with different doses of istradefylline and over different schedules of administration.

Early-life stress and inflammation: A systematic review of a key experimental approach in rodents.

Repeated maternal separation is the most widely used pre-clinical approach to investigate the relationship between early-life chronic stress and its neuropsychiatric and physical consequences. In this systematic review, we identified 46 studies that conducted repeated maternal separation or single-episode maternal separation and reported measurements of interleukin-1b, interleukin-6, interleukin-10, tumour necrosis factor-alpha, or microglia activation and density. We report that in the short-term and in the context of later-life stress, repeated maternal separation has pro-inflammatory immune consequences in diverse tissues. Repeated maternal separation animals exhibit greater microglial activation and elevated pro-inflammatory cytokine signalling in key brain regions implicated in human psychiatric disorders. Notably, repeated maternal separation generally has no long-term effect on cytokine expression in any tissue in the absence of later-life stress. These observations suggest that the elevated inflammatory signalling that has been reported in humans with a history of early-life stress may be the joint consequence of ongoing stressor exposure together with potentiated neural and/or immune responsiveness to stressors. Finally, our findings provide detailed guidance for future studies interrogating the causal roles of early-life stress and inflammation in disorders such as major depression.

Goal-Directed and Habitual Control in Smokers.

INTRODUCTION: Harmful behavior such as smoking may reflect a disturbance in the balance of goal-directed and habitual control. Animal models suggest that habitual control develops after prolonged substance use. In this study, we investigated whether smokers (N = 49) differ from controls (N = 46) in the regulation of goal-directed and habitual behavior. It was also investigated whether individual differences in nicotine dependence levels were associated with habitual responding. METHODS: We used two different multistage instrumental learning tasks that consist of an instrumental learning phase, subsequent outcome devaluation, and a testing phase to measure the balance between goal-directed and habitual responding. The testing phases of these tasks occurred after either appetitive versus avoidance instrumental learning. The appetitive versus aversive instrumental learning stages in the two different tasks modeled positive versus negative reinforcement, respectively. RESULTS: Smokers and nonsmoking controls did not differ on habitual versus goal-directed control in either task. Individual differences in nicotine dependence within the group of smokers, however, were positively associated with habitual responding after appetitive instrumental learning. This effect seems to be due to impaired stimulus-outcome learning, thereby hampering goal-directed task performance and tipping the balance to habitual responding. CONCLUSIONS: The current finding highlights the importance of individual differences within smokers. For future research, neuroimaging studies are suggested to further unravel the nature of the imbalance between goal-directed versus habitual control in severely dependent smokers by directly measuring activity in the corresponding brain systems. IMPLICATIONS: Goal-directed versus habitual behavior in substance use and addiction is highly debated. This study investigated goal-directed versus habitual control in smokers. The findings suggest that smokers do not differ from controls in goal-directed versus habitual control. Individual differences in nicotine dependence within smokers, however, were positively associated with habitual responding after appetitive instrumental learning. This effect seems to be due to impaired stimulus-outcome learning, thereby hampering goal-directed task performance and tipping the balance to habitual responding. These findings add to the ongoing debate on habitual versus goal-directed control in addiction and emphasize the importance of individual differences within smokers.

Decreased brain connectivity in smoking contrasts with increased connectivity in drinking.

In a group of 831 participants from the general population in the Human Connectome Project, smokers exhibited low overall functional connectivity, and more specifically of the lateral orbitofrontal cortex which is associated with non-reward mechanisms, the adjacent inferior frontal gyrus, and the precuneus. Participants who drank a high amount had overall increases in resting state functional connectivity, and specific increases in reward-related systems including the medial orbitofrontal cortex and the cingulate cortex. Increased impulsivity was found in smokers, associated with decreased functional connectivity of the non-reward-related lateral orbitofrontal cortex; and increased impulsivity was found in high amount drinkers, associated with increased functional connectivity of the reward-related medial orbitofrontal cortex. The main findings were cross-validated in an independent longitudinal dataset with 1176 participants, IMAGEN. Further, the functional connectivities in 14-year-old non-smokers (and also in female low-drinkers) were related to who would smoke or drink at age 19. An implication is that these differences in brain functional connectivities play a role in smoking and drinking, together with other factors.

Distinct risk factors for obsessive and compulsive symptoms in chronic schizophrenia.

BACKGROUND: Obsessive-compulsive disorder (OCD) is common in clozapine-treated patients although the actual prevalence, phenomenology and risk factors remain unclear. The aim of the present study was to address the three aforementioned questions. METHODS: The electronic records of a large cohort of clozapine-medicated schizophrenia patients routinely screened for OCD were used. The Obsessive Compulsive Inventory Revised version (OCI-R) was available from 118 cases and a 21 points cut-off threshold for OCD was defined. RESULTS: OCD prevalence was 47%, higher in patients on poly-pharmacy than on monotherapy (64% vs 31%; p = 0.001). Two OCI-R factors had significantly higher scores and distinct risk factors: checking behaviour (mean = 5.1; SD = 3.6) correlated with length of clozapine treatment (r = 0.21; p = 0.026), and obsessing factor (mean = 4.8; SD = 3.6) correlated with psychosis severity (r = 0.59; p = 0.001). These factors along with total OCI-R, did not correlate with either clozapine dose or plasma levels, after correcting for psychosis severity. CONCLUSIONS: Screening for OCD in clozapine patients, and probably in those treated with structurally similar drugs with potent antiserotoninergic properties, should be widely adopted by clinicians. Further research is needed to understand the pathophysiology underlying repetitive behavior onset in clozapine-treated patients.

Effective Use of Animal Models for Therapeutic Development in Psychiatric and Substance Use Disorders.

Athina Markou and others argue forcefully for the adoption of a "translational-back translational strategy" for central nervous system drug discovery involving novel application of drugs with established safety profiles in proof-of-principle studies in humans, which in turn encourage parallel studies using experimental animals to provide vital data on the neural systems and neuropharmacological mechanisms related to the actions of the candidate drugs. Encouraged by the increasing adoption of drug-development strategies involving reciprocal information exchange between preclinical animal studies and related clinical research programs, this review presents additional compelling examples related to the following: 1) the treatment of cognitive deficits that define attention-deficit/hyperactivity disorder; 2) the development of fast-acting antidepressants based on promising clinical effects with low doses of the anesthetic ketamine; and 3) new and effective medications for the treatment of substance misuse. In the context of addressing the unmet medical need for new and effective drugs for treatment of mental ill health, now may be the time to launch major new academic-industry consortia committed to open access of all preclinical and clinical data generated by this research.

Selective and interactive effects of D2 receptor antagonism and positive allosteric mGluR4 modulation on waiting impulsivity.

BACKGROUND: Metabotropic glutamate receptor 4 (mGluR4) and dopamine D2 receptors are specifically expressed within the indirect pathway neurons of the striato-pallidal-subthalamic pathway. This unique expression profile suggests that mGluR4 and D2 receptors may play a cooperative role in the regulation and inhibitory control of behaviour. We investigated this possibility by testing the effects of a functionally-characterised positive allosteric mGluR4 modulator, 4-((E)-styryl)-pyrimidin-2-ylamine (Cpd11), both alone and in combination with the D2 receptor antagonist eticlopride, on two distinct forms of impulsivity. METHODS: Rats were trained on the five-choice serial reaction time task (5-CSRTT) of sustained visual attention and segregated according to low, mid, and high levels of motor impulsivity (LI, MI and HI, respectively), with unscreened rats used as an additional control group. A separate group of rats was trained on a delay discounting task (DDT) to assess choice impulsivity. RESULTS: Systemic administration of Cpd11 dose-dependently increased motor impulsivity and impaired attentional accuracy on the 5-CSRTT in all groups tested. Eticlopride selectively attenuated the increase in impulsivity induced by Cpd11, but not the accompanying attentional impairment, at doses that had no significant effect on behavioural performance when administered alone. Cpd11 also decreased choice impulsivity on the DDT (i.e. increased preference for the large, delayed reward) and decreased locomotor activity. CONCLUSIONS: These findings demonstrate that mGluR4s, in conjunction with D2 receptors, affect motor- and choice-based measures of impulsivity, and therefore may be novel targets to modulate impulsive behaviour associated with a number of neuropsychiatric syndromes.

Iowa gambling task impairment in Parkinson's disease can be normalised by reduction of dopaminergic medication after subthalamic stimulation.

BACKGROUND: Impulse control disorders (ICD), including pathological gambling, are common in Parkinson's disease (PD) and tend to improve after subthalamic (STN) stimulation after a marked reduction of dopaminergic medication. In order to investigate the effect of STN stimulation on impulsive decision making, we used the Iowa Gambling task (IGT). METHODS: We investigated IGT performance in 20 patients with PD before STN surgery with and without dopaminergic treatment and in 24 age-matched controls. All patients underwent an extensive neuropsychological interview screening for behavioural disorders. Assessment in patients was repeated 3 months after surgery without dopaminergic treatment with and without stimulation. RESULTS: Chronic antiparkinsonian treatment was drastically reduced after surgery (-74%). At baseline, on high chronic dopaminergic treatment 8/20 patients with PD presented with pathological hyperdopaminergic behaviours, which had resolved in 7/8 patients 3 months after surgery on low chronic dopaminergic treatment. Preoperative performance on the IGT was significantly impaired compared to after surgery. CONCLUSIONS: Dopaminergic medication likely contributes to the impairment in decision making underlying ICDs. Deep brain stimulation allows drastic reduction of dopaminergic medication and, thus, concomitant remediation of medication-induced impairment in decision making.

Neuropsychosocial profiles of current and future adolescent alcohol misusers.

A comprehensive account of the causes of alcohol misuse must accommodate individual differences in biology, psychology and environment, and must disentangle cause and effect. Animal models can demonstrate the effects of neurotoxic substances; however, they provide limited insight into the psycho-social and higher cognitive factors involved in the initiation of substance use and progression to misuse. One can search for pre-existing risk factors by testing for endophenotypic biomarkers in non-using relatives; however, these relatives may have personality or neural resilience factors that protect them from developing dependence. A longitudinal study has potential to identify predictors of adolescent substance misuse, particularly if it can incorporate a wide range of potential causal factors, both proximal and distal, and their influence on numerous social, psychological and biological mechanisms. Here we apply machine learning to a wide range of data from a large sample of adolescents (n = 692) to generate models of current and future adolescent alcohol misuse that incorporate brain structure and function, individual personality and cognitive differences, environmental factors (including gestational cigarette and alcohol exposure), life experiences, and candidate genes. These models were accurate and generalized to novel data, and point to life experiences, neurobiological differences and personality as important antecedents of binge drinking. By identifying the vulnerability factors underlying individual differences in alcohol misuse, these models shed light on the aetiology of alcohol misuse and suggest targets for prevention.

Lower ventral striatal activation during reward anticipation in adolescent smokers.

OBJECTIVE: Adolescents are particularly vulnerable to addiction, and in the case of smoking, this often leads to long-lasting nicotine dependence. The authors investigated a possible neural mechanism underlying this vulnerability. METHOD: Functional MRI was performed during reward anticipation in 43 adolescent smokers and 43 subjects matched on age, gender, and IQ. The authors also assessed group differences in novelty seeking, impulsivity, and reward delay discounting. RESULTS: In relation to the comparison subjects, the adolescent smokers showed greater reward delay discounting and higher scores for novelty seeking. Neural responses in the ventral striatum during reward anticipation were significantly lower in the smokers than in the comparison subjects, and in the smokers this response was correlated with smoking frequency. Notably, the lower response to reward anticipation in the ventral striatum was also observed in smokers (N=14) who had smoked on fewer than 10 occasions. CONCLUSIONS: The present findings suggest that a lower response to reward anticipation in the ventral striatum may be a vulnerability factor for the development of early nicotine use.

Trait-like impulsivity does not predict escalation of heroin self-administration in the rat.

RATIONALE: The neural and psychological mechanisms underlying vulnerability to drug addiction are poorly understood. Although a number of animal models have been developed to investigate vulnerability to stimulant addiction, few have considered how vulnerability traits such as impulsivity predict hallmark features of heroin addiction including the escalation of drug intake and increased propensity for relapse following protracted abstinence. OBJECTIVE: The aim of this study was to investigate whether high impulsivity in rats predicts the propensity to escalate intravenous heroin self-administration and to relapse following an extended withdrawal period from heroin. METHODS: High (HI)- and low (LI)-impulsive rats, defined by the extent of premature responding on the 5-choice serial reaction time test (5-CSRTT), were catheterized and allowed to self-administer heroin (40 µg/100 µl/infusion). After 5 days of short access (1 h/day) to heroin, rats were then given extended (6 h/day) access to heroin for 18 consecutive days. RESULTS: High impulsivity predicted neither a greater tendency to acquire heroin SA nor an increased escalation of heroin self-administration. Moreover, high impulsivity was not associated with an increased propensity to relapse after protracted withdrawal from heroin. Nevertheless, marked inter-individual differences in the escalation of heroin self-administration were observed. CONCLUSIONS: Although high impulsivity on the 5-CSRTT has been shown to predict loss of control over cocaine intake, this does not generalize to a loss of control over heroin self-administration. These findings suggest important distinctions in vulnerability mechanisms underlying cocaine and heroin addiction with trait-like impulsivity playing a role in stimulant but not opiate addiction.

The role of the orbitofrontal cortex in human discrimination learning.

Several lines of evidence implicate the prefrontal cortex in learning but there is little evidence from studies of human lesion patients to demonstrate the critical role of this structure. To this end, we tested patients with lesions of the frontal lobe (n=36) and healthy controls (n=35) on two learning tasks: the weather prediction task (WPT), and an eight-pair concurrent visual discrimination task ('Choose'). Performance of both tasks was previously shown to be disrupted in patients with Parkinson's disease; the Choose deficit was only present when patients were medicated. Patients with damage to the orbitofrontal cortex (OFC) were significantly impaired on Choose, compared to both healthy controls and non-OFC lesion patients. The OFC lesion patients showed a mild deficit on the first 50 trials of the WPT, compared to the control subjects but not non-OFC lesion patients. The selective deficit in the OFC patients on Choose performance could not be attributed to the larger lesion size in this group, and the deficit was not correlated with the volume of damage to adjacent prefrontal subregions (e.g. anterior cingulate cortex). These data support the notion that the OFC play a role in normal discrimination learning, and suggest qualitative similarities in learning performance of patients with OFC damage and medicated PD patients.

Differences in orbitofrontal activation during decision-making between methadone-maintained opiate users, heroin users and healthy volunteers.

OBJECTIVE: Previously, we reported that opiate users enrolled in methadone treatment made 'risky' choices on a decision-making task following a loss of points compared with heroin users and healthy volunteers. One possible explanation for this behaviour is that methadone users were less sensitive to punishment on immediately preceding unsuccessful trials. METHODS: We sought to explore this finding from a neural perspective by performing a post hoc analysis of data from a previous [see text] positron emission tomography study. We restricted the analysis to the opiate groups and controls, assessing differences between opiate users on methadone and those on heroin. RESULTS: We found significant over-activation in the lateral orbitofrontal cortex (OFC) in methadone users compared with both heroin users and controls concomitant with the greatest overall tendency to 'play risky'. Heroin users showed significant under-activation in this area compared with the other two groups whilst exhibiting the greatest overall tendency to 'play safe'. Correlational analysis revealed that abnormal task-related activation of the left OFC was associated with the dose of methadone in methadone users and with the duration of intravenous heroin use in heroin users. 'Playing safe' following a loss of points was also negatively correlated with the activation of pregenual anterior cingulate and insula cortex in controls, but not in opiate users. CONCLUSION: Our findings suggest that the interplay between processes involved in integrating penalty information for the purpose of response selection may be altered in opiate users. This change was reflected differentially in task-related pattern of OFC activation depending on the opiate used.

Effects of levodopa and subthalamic nucleus stimulation on cognitive and affective functioning in Parkinson's disease.

In Parkinson's disease (PD), levodopa and subthalamic nucleus (STN) stimulation lead to major improvement in motor symptoms. Effects of both treatments on cognition and affective status are less well understood. Motor, cognitive, and affective symptoms may relate to the dysfunctioning of parallel cortico-striatal loops. The aim of this study was to assess cognition, behavior, and mood, with and without both treatments in the same group of PD patients. A group of 22 nondemented PD patients was included in this study. Patients were tested twice before surgery (off and on levodopa) and twice 3 months after surgery (OFF and ON STN stimulation, off levodopa). Cognitive and affective effects of STN stimulation and levodopa had some common, but also different, effects. STN stimulation improved performance on the planning test, associated with the dorsolateral prefrontal cortex. However, the treatments had opposite effects on tests associated with the orbitofrontal cortex; specifically, levodopa impaired while STN stimulation improved performance on the extinction phase of a reversal/extinction task. Acutely, both treatments improved motivation and decreased fatigue and anxiety. On chronic treatment (3 months after surgery), depression improved, whereas apathy worsened 3 months after surgery. To conclude, there were significant but contrasting effects of levodopa and STN stimulation on cognition and affective functions.

The hippocampus and appetitive Pavlovian conditioning: effects of excitotoxic hippocampal lesions on conditioned locomotor activity and autoshaping.

The hippocampus (HPC) is known to be critically involved in the formation of associations between contextual/spatial stimuli and behaviorally significant events, playing a pivotal role in learning and memory. However, increasing evidence indicates that the HPC is also essential for more basic motivational processes. The amygdala, by contrast, is important for learning about the motivational significance of discrete cues. This study investigated the effects of excitotoxic lesions of the rat HPC and the basolateral amygdala (BLA) on the acquisition of a number of appetitive behaviors known to be dependent on the formation of Pavlovian associations between a reward (food) and discrete stimuli or contexts: (1) conditioned/anticipatory locomotor activity to food delivered in a specific context and (2) autoshaping, where rats learn to show conditioned discriminated approach to a discrete visual CS+. While BLA lesions had minimal effects on conditioned locomotor activity, hippocampal lesions facilitated the development of both conditioned activity to food and autoshaping behavior, suggesting that hippocampal lesions may have increased the incentive motivational properties of food and associated conditioned stimuli, consistent with the hypothesis that the HPC is involved in inhibitory processes in appetitive conditioning.

Interactions between serotonin and dopamine in the control of impulsive choice in rats: therapeutic implications for impulse control disorders.

Forebrain serotonergic lesions attenuate the ability of d-amphetamine to decrease impulsivity in a delay-discounting paradigm, potentially through interactions between the serotonin (5-HT) and dopamine (DA) systems. Nucleus accumbens (NAC) lesions increase impulsivity, but the extent to which accumbal DA is involved in regulating impulsive choice is unknown. In the current study, the effects of intra-accumbal infusions of 6-hydroxydopamine (6-OHDA) on impulsive choice were evaluated, in combination with d-amphetamine and serotonergic drugs, in order to investigate the importance of 5-HT : DA interactions in the control of impulsive behavior. Following training on a delay-discounting task, animals received intra-NAC 6-OHDA or sham surgery. Postoperatively, subjects received systemic injections of d-amphetamine (0, 0.3, 1.0, 1.5 mg/kg) and the 5-HT(1A) receptor agonist 8-OH-DPAT (0, 0.1, 0.3, 1.0 mg/kg). Intra-NAC 6-OHDA, which reduced local DA and NA levels by 70-75%, had no effect on delay-discounting, but transiently potentiated the d-amphetamine-induced decrease in impulsive choice. 8-OH-DPAT (1.0 mg/kg) increased impulsivity in sham-operated controls, an effect which was blocked by the 5-HT(1A) receptor antagonist WAY 100635. However, 8-OH-DPAT had no effect on impulsivity in 6-OHDA NAC lesioned rats. 8-OH-DPAT (0.3 mg/kg), which did not itself alter task performance, blocked the effect of d-amphetamine in sham-operated controls, while WAY 100635 augmented the effect of amphetamine in all subjects. In an additional experiment, intracerebroventricular administration of the selective serotonergic toxin 5,7-dihydroxytryptamine, which decreased forebrain 5-HT levels by 85-90%, did not block 8-OH-DPAT's ability to increase impulsive choice. These data suggest a significant role for 5-HT : DA interactions within the NAC in the control of impulsivity, and in the mechanism by which amphetamine decreases impulsive choice.

Role of the anterior cingulate cortex in the control over behavior by Pavlovian conditioned stimuli in rats.

To investigate the contribution of the anterior cingulate cortex (ACC) to stimulus-reward learning, rats with lesions of peri- and postgenual ACC were tested on a variety of Pavlovian conditioning tasks. Lesioned rats learned to approach a food alcove during a stimulus predicting food, and responded normally for conditioned reinforcement. They also exhibited normal conditioned freezing and Pavlovian-instrumental transfer, yet were impaired at autoshaping. To resolve this apparent discrepancy, a further task was developed in which approach to the food alcove was under the control of 2 stimuli, only 1 of which was followed by reward. Lesioned rats were impaired, approaching during both stimuli. It is suggested that the ACC is not critical for stimulus-reward learning per se, but is required to discriminate multiple stimuli on the basis of their association with reward.

Distractibility during selection-for-action: differential deficits in Huntington's disease and following frontal lobe damage.

Selective attention can be measured through analysis of errors and reaction time (RT) for trials in which targets are presented alone compared with trials in which targets and distractors are presented. This study investigated selective attention using a reaching task, in which subjects made rapid reaches to targets. Thirty-seven patients with lesions of the prefrontal cortex (PFC) were compared with 19 healthy age- and IQ-matched volunteers and 18 patients with early-stage Huntington's disease (HD), a neurodegenerative disease primarily affecting the basal ganglia. It was hypothesised that, if fronto-striatal circuits as a whole support selection-for-action, then the pattern of behavioural performance of both patient groups would be similar. Alternatively, if the functional roles of PFC and basal ganglia in selection-for-action are dissociable, then two different patterns would emerge. It was found that that both HD and frontal groups were significantly more distractible than controls for RT, but they had a different pattern of errors. Frontal patients made significantly more touches of the distractor location itself than did controls, while this was not the case for HD. It is argued that a reactive-inhibition mechanism, required in the circumstance of strong distractor activation, is affected by frontal damage, while a lateral-inhibition mechanism, invoked during the recruitment of selective attention, is affected in HD. Additionally, there were significant correlations between the degree of distractibility for RT and the extent of lateral PFC damage, and between cue-generated preparation and lateral PFC damage, thus highlighting the critical importance of lateral, rather than orbital or medial, PFC for attention to action.