Abstract: Background: There is evidence to suggest that obsessive-compulsive disorder (OCD) is associated with structural abnormalities in cortico-striato-thalamic circuits, yet the extent of white matter abnormalities is not well established. In this study, we used diffusion tensor imaging (DTI) to examine white matter integrity in specific regions of interest (ROIs) in patients with OCD. Methods: Patients with OCD and sex-, age- and IQ-matched healthy controls underwent DTI. The primary objective was to explore whether patients with OCD had white matter abnormalities in the anterior limb of the internal capsule (ALIC), the uncinate fasciculus, the genu of the corpus callosum and the cingulum. The secondary objective was to evaluate the relation between fractional anisotropy and mean diffusivity in these ROIs and other clinical variables (including age at onset of OCD, OCD severity and levels of depressive and anxiety symptomatology) in patients with OCD. Results: There were 15 patients and 17 controls enrolled in our study. Compared with healthy controls, patients with OCD showed increased fractional anisotropy in bilateral regions of the ALIC adjacent to the body of the caudate, as well as decreased fractional anisotropy in the right anterior limb near the head of the caudate. Patients also had decreased mean diffusivity in the body of the right cingulum and the left anterior cingulum compared with controls. Correlational analyses revealed significant associations of fractional anisotropy and mean diffusivity in select circuits with OCD, depression and anxiety severity scores. Limitations: Inclusion of patients with OCD receiving pharmacotherapy may have been a limitation. In addition, the patients were heterogeneous in terms of their obsessive-compulsive symptom profiles; we did not distinguish between different obsessive-compulsive symptom dimensions. Conclusion: The study results provide further evidence for OCD-related white matter abnormalities in the ALIC and cingulum, consistent with a cortico striatal model of OCD.
Abstract: Literature on the ability of patients with obsessive-compulsive disorder (OCD) to recognize static facial expressions of disgust is not consistent. We aimed to investigate whether OCD is associated with deficits in the recognition of disgust in a dynamic task, and if so, whether the acute administration of the selective serotonin reuptake inhibitor (SSRI) escitalopram would result in the normalization of such deficits.
Abstract: BACKGROUND: Cannabis is the most widely used illicit substance and has been associated with cognitive impairment. It is unclear whether such impairment can occur in the absence of potential confounding influences of co-morbid axis-I disorders and use of other illicit substances. METHOD: Young adult volunteers (18-29 years) were recruited from the general community on the basis of having no axis-I disorders or history of illicit substance use other than cannabis use. Subjects were then grouped according to presence or absence of cannabis use (>1 time/week over past 12 months). Cognition was compared between groups using selected paradigms from the CANTAB. RESULTS: Cannabis users (N=16) and controls (N=214) did not differ significantly on salient demographic characteristics. Compared to controls, cannabis users showed significant impairments on quality of decision-making (Cambridge Gamble task), and executive planning (One Touch Stockings of Cambridge task). Response inhibition, spatial working memory, and sustained attention were intact. CONCLUSIONS: This study identified cognitive deficits in cannabis users even in the absence of axis-I disorders and a history of using other illicit drugs. Future work should use longitudinal designs to track whether these deficits predate cannabis use or are due to its consumption.
Abstract: Attention-deficit/hyperactivity disorder (ADHD) is a prevalent condition associated with cognitive dysfunction. The Cambridge Neuropsychological Test Automated Battery is a computerized set of tests that has been widely used in ADHD and in translation/back-translation. Following a survey of translational research relevant to ADHD in experimental animals, a comprehensive literature review was conducted of studies that had used core Cambridge Neuropsychological Test Automated Battery tests 1) to evaluate cognitive dysfunction in ADHD and 2) to evaluate effects of salient drugs in patients and in volunteers. Meta-analysis was conducted where four or more independent datasets were available. Meta-analysis revealed medium-large decrements in ADHD for response inhibition (d = .790, p < .001), working memory (d = .883, p < .001), executive planning (d = .491, p < .001), and a small decrement in attentional set shifting (d = .160, p = .040). Qualitative review of the literature showed some consistent patterns. In ADHD, methylphenidate improved working memory, modafinil improved planning, and methylphenidate, modafinil, and atomoxetine improved inhibition. Meta-analysis of modafinil healthy volunteer studies showed no effects on sustained attention or set shifting. Results were paralleled by findings in experimental animals on comparable tests, enabling further analysis of drug mechanisms. Substantial cognitive deficits are present in ADHD, which can be remediated somewhat with current medications and which can readily be modeled in experimental animals using back-translational methodology. The findings suggest overlapping but also distinct early cognitive effects of ADHD medications and have important implications for understanding the pathophysiology of ADHD and for future trials.
Abstract: Trichotillomania is characterized by repetitive pulling causing noticeable hair loss. Pharmacological treatment data for trichotillomania are limited.
Abstract: The ability to predict cognitive deterioration in patients with dementia holds valuable potential for clinical trials and early intervention. This study identified cognitive domains deteriorating differentially over time as well as baseline predictors of subsequent cognitive decline in patients referred to a memory clinic. Twenty-six subjects with Alzheimer's disease (AD) and 43 subjects with Subjective Memory Impairment (SMI) were entered into a longitudinal study in which cognitive function was assessed at baseline and at 8-monthly intervals for 2 years, using a range of well-validated measures. Thirty-seven patients with depression and 39 healthy controls were also longitudinally assessed. AD was associated with disproportionate deterioration over time on general measures of cognitive function, multiple measures of mnemonic processing, mental fluency (letter and category), and aspects of motor speed. SMI showed restricted relative cognitive deterioration on general measures of cognitive function, on a subset of memory measures, and on letter but not category fluency. Secondary analysis showed that earliest detectable ADAS-cog and MMSE decline in AD was at 16 months, while several specific neuropsychological indices were sensitive as early as 8 months (graded naming test, semantic naming, and the category/letter fluency tests). In combination, baseline/early changes in cognitive performance, alongside clinical measures, predicted 48% of disease progression over two years in memory impaired patients as a whole. These findings have implications for identifying patients likely to benefit from disease modifying agents, and for designing, powering, enriching, and implementing future clinical trials. Follow-up studies in independent populations are needed to validate predictive algorithms identified.
Abstract: Impairments in working memory are present in many psychiatric illnesses such as attention-deficit hyperactivity disorder (ADHD) and schizophrenia. The dopamine transporter and catechol-O-methyltransferase (COMT) are proteins involved in dopamine clearance and the dopamine system is implicated in the modulation of working memory (WM) processes and neurochemical models of psychiatric diseases. The effects of functional polymorphisms of the dopamine transporter gene (DAT1) and the COMT gene were investigated using a visuospatial and numerical n-back working memory paradigm. Our n-back task was designed to reflect WM alone, and made no demands on higher executive functioning.
Abstract: Obsessive-compulsive disorder (OCD) is characterized by obsessions (intrusive thoughts) and compulsions (repetitive ritualistic behaviours) leading to functional impairment. Accumulating evidence links these conditions with underlying dysregulation of fronto-striatal circuitry and monoamine systems. These abnormalities represent key targets for existing and novel treatment interventions. However, the brain bases of these conditions and treatment mechanisms are still not fully elucidated. Animal models simulating the behavioural and clinical manifestations of the disorder show great potential for augmenting our understanding of the pathophysiology and treatment of OCD. This paper provides an overview of what is known about OCD from several perspectives. We begin by describing the clinical features of OCD and the criteria used to assess the validity of animal models of symptomatology; namely, face validity (phenomenological similarity between inducing conditions and specific symptoms of the human phenomenon), predictive validity (similarity in response to treatment) and construct validity (similarity in underlying physiological or psychological mechanisms). We then survey animal models of OC spectrum conditions within this framework, focusing on (i) ethological models; (ii) genetic and pharmacological models; and (iii) neurobehavioural models. We also discuss their advantages and shortcomings in relation to their capacity to identify potentially efficacious new compounds. It is of interest that there has been rather little evidence of 'false alarms' for therapeutic drug effects in OCD models which actually fail in the clinic. While it is more difficult to model obsessive cognition than compulsive behaviour in experimental animals, it is feasible to infer cognitive inflexibility in certain animal paradigms. Finally, key future neurobiological and treatment research areas are highlighted.
Abstract: As a behavioral addiction with clinical and phenomenological similarities to substance addiction, recreational and pathological gambling represent models for studying the neurobiology of addiction, without the confounding deleterious brain effects which may occur from chronic substance abuse.
Abstract: Pathological Skin Picking (PSP) and Trichotillomania (TTM) share overlapping comorbidity and phenomenology. The extent to which these disorders share a common cognitive phenotype, however, has yet to be examined. This study sought to compare inhibitory control processes in individuals with PSP or TTM.
Abstract: Despite reasonable knowledge of pathological gambling (PG), little is known of its cognitive antecedents. We evaluated decision-making and impulsivity characteristics in people at risk of developing PG using neuropsychological tests. Non-treatment seeking volunteers (18-29 years) who gamble ≥ 5 times/year were recruited from the general community, and split into two groups: those "at risk" of developing PG (n=74) and those social, non-problem gamblers (n=112). Participants undertook the Cambridge Gamble and Stop-signal tasks and were assessed with the Mini-International Neuropsychiatric Interview and the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling. On the Cambridge Gamble task, the at-risk subjects gambled more points overall, were more likely to go bankrupt, and made more irrational decisions under situations of relative risk ambiguity. On the Stop-signal task, at-risk gamblers did not differ from the social, non-problem gamblers in terms of motor impulse control (stop-signal reaction times). Findings suggest that selective cognitive dysfunction may already be present in terms of decision-making in at-risk gamblers, even before psychopathology arises. These findings implicate selective decision-making deficits and dysfunction of orbitofronto-limbic circuitry in the chain of pathogenesis between social, non-problematic and pathological gambling.
Abstract: Through neuromodulatory influences over fronto-striato-cerebellar circuits, dopamine and noradrenaline play important roles in high-level executive functions often reported to be impaired in attention-deficit/hyperactivity disorder (ADHD). Medications used in the treatment of ADHD (including methylphenidate, dextroamphetamine and atomoxetine) act to increase brain catecholamine levels. However, the precise prefrontal cortical and subcortical mechanisms by which these agents exert their therapeutic effects remain to be fully specified. Herein, we review and discuss the present state of knowledge regarding the roles of dopamine (DA) and noradrenaline in the regulation of corticostriatal circuits, with a focus on the molecular neuroimaging literature (both in ADHD patients and in healthy subjects). Recent positron emission tomography evidence has highlighted the utility of quantifying DA markers, at baseline or following drug administration, in striatal subregions governed by differential cortical connectivity. This approach opens the possibility of characterizing the neurobiological underpinnings of ADHD (and associated cognitive dysfunction) and its treatment by targeting specific neural circuits. It is anticipated that the application of refined and novel positron emission tomography methodology will help to disentangle the overlapping and dissociable contributions of DA and noradrenaline in the prefrontal cortex, thereby aiding our understanding of ADHD and facilitating new treatments.
Abstract: Although pathological gambling (PG) is relatively common, pharmacotherapy research for PG is limited. Memantine, an N-methyl D-aspartate receptor antagonist, appears to reduce glutamate excitability and improve impulsive decision making, suggesting it may help individuals with PG.
Abstract: Although a relatively common behavior, treatment data for pathological skin picking (PSP) are limited. The current study sought to examine the efficacy and tolerability of lamotrigine in adults with PSP and to examine neurocognitive predictors of treatment response. Thirty-two subjects (29 female subjects [90.6%]; mean age, 32.8 +/- 13.3 years) with PSP were treated in a 12-week randomized, double-blind, placebo-controlled trial of lamotrigine as monotherapy. Baseline cognitive assessment comprised the stop signal and intradimensional/extradimensional set shift tasks. Lamotrigine dosing ranged from 12.5 to 300 mg/d. The primary outcome measure was picking symptoms measured by the Yale-Brown Obsessive Compulsive scale Modified for Neurotic Excoriation. Subjects also were assessed with measures of psychosocial functioning. No significant overall differences were noted between lamotrigine and placebo on the primary or secondary end points. Seven subjects assigned to lamotrigine (43.8%) were considered responders (defined as >or=35% n the Yale-Brown Obsessive Compulsive scale Modified for Neurotic Excoriation) compared with 5 (31.3%) assigned to placebo. Those who ultimately responded to lamotrigine exhibited impaired cognitive flexibility (extradimensional shifting) at baseline compared with lamotrigine nonresponders. These findings suggest that, although safe and well tolerated, lamotrigine treatment may not be efficacious in patients with PSP as a whole, compared with placebo. However, these neurocognitive data suggest that lamotrigine may be valuable in a subset of patients who exhibit relatively impaired cognitive flexibility.
Abstract: Background. Impairments in working memory are present in many psychiatric illnesses such as attention-deficit
hyperactivity disorder (ADHD) and schizophrenia. The dopamine transporter and catechol-O-methyltransferase
(COMT) are proteins involved in dopamine clearance and the dopamine system is implicated in the modulation of
working memory (WM) processes and neurochemical models of psychiatric diseases. The effects of functional
polymorphisms of the dopamine transporter gene (DAT1) and the COMT gene were investigated using a visuospatial
and numerical n-back working memory paradigm. Our n-back task was designed to reflect WM alone, and made no
demands on higher executive functioning.
Method. A total of 291 healthy volunteers (aged 18–45 years) were genotyped and matched for age, sex, and Barratt
Impulsivity Scale (BIS) and National Adult Reading Test (NART) scores. To assess individual gene effects on WM,
factorial mixed model analysis of variances (ANOVAs) were conducted with the between-subjects factor as genotype
and difficulty level (0-, 1-, 2- and 3-back) entered as the within-subjects factor.
Results. The analysis revealed that the DAT1 or COMT genotype alone or in combination did not predict
performance on the n-back task in our sample of healthy volunteers.
Conclusions. Behavioral effects of DAT1 and COMT polymorphisms on WM in healthy volunteers may be nonexistent,
or too subtle to identify without exceedingly large sample sizes. It is proposed that neuroimaging may
provide more powerful means of elucidating the modulatory influences of these polymorphisms.
Abstract: Previous research has demonstrated cognitive-enhancing effects of modafinil in humans and generated evidence for its therapeutic potential in psychiatric disorders. The neurochemical basis of these effects remains unresolved although a role for α1-adrenoceptors has been hypothesised. In this within-subject, double-blind, placebo-controlled study, 12 healthy male adults received modafinil (300 mg), the α1-adrenoceptor antagonist prazosin (3 mg), both together and placebo on separate occasions at least 5 days apart. Cognitive effects were assessed using a well-validated testing battery focusing on executive and working memory functions. Blood pressure, heart rate and salivary α-amylase (sAA) were measured at hourly intervals. Cognitive effects of modafinil and prazosin were identified at the difficult levels of the One-Touch Stockings of Cambridge (OTSOC) planning task. Prazosin antagonized the error-reducing effect of modafinil when the agents were given together. In contrast, the combined agents acted synergistically to increase time taken to complete OTSOC problems compared with placebo. The tachycardic and sAA-elevating effects of prazosin were also potentiated by concurrent modafinil administration. The current data suggest that the cognitive effects of modafinil on performance accuracy and latency are dissociable in terms of their neurochemical mechanisms. Our findings support the hypothesised involvement of α1-adrenoceptors in some of the cognitive-enhancing effects of modafinil and warrant further investigation.
Abstract: Individuals with pathologic skin picking (PSP) often report significant difficulty resisting the urges and drive to engage in picking behavior. Studies have shown significant inhibitory deficiencies (i.e. increased impulsivity) in subjects with other putative obsessive-compulsive spectrum disorders, such as trichotillomania, using objective tests. This study sought to assess motor inhibitory control and aspects of cognitive flexibility in a sample of individuals with PSP.
Abstract: Failures in cortical control of fronto-striatal neural circuits may underpin impulsive and compulsive acts. In this narrative review, we explore these behaviors from the perspective of neural processes and consider how these behaviors and neural processes contribute to mental disorders such as obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder, and impulse-control disorders such as trichotillomania and pathological gambling. We present findings from a broad range of data, comprising translational and human endophenotypes research and clinical treatment trials, focussing on the parallel, functionally segregated, cortico-striatal neural projections, from orbitofrontal cortex (OFC) to medial striatum (caudate nucleus), proposed to drive compulsive activity, and from the anterior cingulate/ventromedial prefrontal cortex to the ventral striatum (nucleus accumbens shell), proposed to drive impulsive activity, and the interaction between them. We suggest that impulsivity and compulsivity each seem to be multidimensional. Impulsive or compulsive behaviors are mediated by overlapping as well as distinct neural substrates. Trichotillomania may stand apart as a disorder of motor-impulse control, whereas pathological gambling involves abnormal ventral reward circuitry that identifies it more closely with substance addiction. OCD shows motor impulsivity and compulsivity, probably mediated through disruption of OFC-caudate circuitry, as well as other frontal, cingulate, and parietal connections. Serotonin and dopamine interact across these circuits to modulate aspects of both impulsive and compulsive responding and as yet unidentified brain-based systems may also have important functions. Targeted application of neurocognitive tasks, receptor-specific neurochemical probes, and brain systems neuroimaging techniques have potential for future research in this field.
Abstract: There is growing interest regarding the role of the right inferior frontal gyrus (RIFG) during a particular form of executive control referred to as response inhibition. However, tasks used to examine neural activity at the point of response inhibition have rarely controlled for the potentially confounding effects of attentional demand. In particular, it is unclear whether the RIFG is specifically involved in inhibitory control, or is involved more generally in the detection of salient or task relevant cues. The current fMRI study sought to clarify the role of the RIFG in executive control by holding the stimulus conditions of one of the most popular response inhibition tasks-the Stop Signal Task-constant, whilst varying the response that was required on reception of the stop signal cue. Our results reveal that the RIFG is recruited when important cues are detected, regardless of whether that detection is followed by the inhibition of a motor response, the generation of a motor response, or no external response at all.
Abstract: Mood disorders collectively account for a substantial proportion of disease burden across the globe and have a devastating impact on quality of life and occupational function. Here we evaluate recent progress in understanding the neurocognitive mechanisms involved in the manifestation of mood disorders. We focus on four domains of cognitive function that are altered in patients with depression: executive control, memory, affective processing, and feedback sensitivity. These alterations implicate a distributed neural circuit composed of multiple sectors of the prefrontal cortex in interaction with subcortical regions (striatum, thalamus) and temporal lobe structures (amygdala, hippocampus). Affective processing and feedback sensitivity are highly sensitive to serotonergic manipulation and are targeted by antidepressant treatments. By drawing together cognitive, neuroanatomical, and pharmacological tiers of research, we identify treatment targets and directions for future investigation to identify people at risk, minimize relapse, and maximize long-term beneficial outcomes for those suffering from depression.
Abstract: Several axis-I neuropsychiatric disorders are characterised by repetitive motor habits suggestive of underlying inhibitory dyscontrol, and may constitute members of a putative obsessive-compulsive (OC) spectrum. Notable examples include obsessive-compulsive disorder (OCD) and trichotillomania (repetitive hair-pulling). Multiple tiers of evidence link these conditions with underlying dysregulation of fronto-striatal circuitry and monoamine systems. These abnormalities represent key targets for existing and novel treatment interventions. Nonetheless, the brain bases of these conditions, and treatment mechanisms, remain poorly characterised. Animal models of repetitive habits and inhibitory control problems show great potential for augmenting our understanding of the pathophysiology and treatment of OC spectrum conditions. Here, we begin by describing clinical features of OC spectrum disorders, and criteria used to assess the validity of animal models of symptomatology. Namely, face validity (phenomenological similarity between inducing conditions and specific symptoms of the human phenomenon), predictive validity (similarity in response to treatment) and construct validity (similarity in underlying physiological or psychological mechanisms). We then survey animal models of OC spectrum conditions within this framework, focusing on (i) ethological models; (ii) genetic and pharmacological models; and (iii) behavioral models. Key future research directions are highlighted.
Abstract: Clinical and neurobiological evidence suggests that concurrent presentation of schizophrenia and obsessive-compulsive (schizo-OCD) symptoms represents a distinct clinical entity. Given that obsessive-compulsive disorder (OCD) and schizophrenia have been modeled as having different neurofunctional profiles, the overlap between them represents a heuristic challenge for cognitive and endophenotype research. Event-related potentials (ERPs) may be used to probe neurophysiological correlates of the cognitive, emotional and behavioral disturbances found in neuropsychiatric entities such as schizo-OCD. Here we measure ERPs during a discriminative response task (DRT) in patients presenting with the DSM-IV criteria for both schizophrenia and OCD. We also performed these measurements in patients with OCD without psychotic features, as well as in patients with schizophrenia without OC symptoms. Schizo-OCD patients showed a distinct ERP pattern, with abnormally increased target activation (akin to OCD patients, but unlike the pattern observed in schizophrenic patients) and reduced P300 amplitudes (akin to schizophrenic patients, but unlike OCD patients). Similar to the control subjects, schizo-OCD patients showed larger amplitudes in the non-target condition than in the target condition. These results suggest that schizo-OCD may not only be a distinct clinical entity from pure OCD and schizophrenia, but it may also be characterized by a distinguishable neurophysiologic pattern. Neurobiological underpinnings deserve further considerations and might drive to a definition of a distinctive endophenotype for schizo-OCD in the de-construction of the schizophrenia endophenotype.
Abstract: Obsessive-compulsive disorder (OCD) is a heritable and debilitating neuropsychiatric condition. Attempts to delineate genetic contributions have met with limited success, and there is an ongoing search for intermediate trait or vulnerability markers rooted in the neurosciences. Such markers would be valuable for detecting people at risk of developing the condition, clarifying etiological factors and targeting novel treatments. This review begins with brief coverage of the epidemiology of OCD, and presents a hierarchical model of the condition. The advantages of neuropsychological assessment and neuroimaging as objective measures of brain integrity and function are discussed. We describe the concept of endophenotypes and examples of their successful use in medicine and psychiatry. Key areas of focus in the search for OCD endophenotypes are identified, such as measures of inhibitory control and probes of the integrity of orbitofrontal and posterior parietal cortices. Finally, we discuss exciting findings in unaffected first-degree relatives of patients with OCD that have led to the identification of several candidate endophenotypes of the disorder, with important implications for neurobiological understanding and treatment of this and related conditions.
Abstract: Trichotillomania is a disorder characterized by repetitive hair pulling, leading to noticeable hair loss and functional impairment. This paper provides an overview of what is known of trichotillomania from several perspectives. We begin by considering historical descriptions of hair pulling that ultimately contributed to the inclusion of trichotillomania as a formal diagnostic entity in the Diagnostic and Statistical Manual. Psychological factors involved in the mediation of symptoms are examined, including positive and negative reinforcement. The relationships between trichotillomania, other body-focused repetitive behaviours, and disorders of the putative obsessive-compulsive (OC) spectrum are surveyed. The review then explores findings from the available controlled treatment trials that utilized psychotherapy, pharmacotherapy, or both. Neural circuitry involved in the manifestation of hair pulling is then identified by considering data from animal models of the condition, along with neurocognitive and neuroimaging results from patients. Finally, we highlight important areas for future neurobiological and treatment research.
Abstract: Atomoxetine, a selective noradrenaline reuptake inhibitor (SNRI) licensed for the treatment of attention-deficit/hyperactivity disorder (ADHD), has been shown to improve response inhibition in animals, healthy volunteers, and adult patients. However, the mechanisms by which atomoxetine improves inhibitory control have yet to be determined.
Abstract: Trichotillomania (repetitive hair-pulling) is an Axis I psychiatric disorder whose neurobiological basis is incompletely understood. Whole-brain trichotillomania neuroimaging studies are lacking.
Abstract: Obsessive-compulsive disorder (OCD) is characterized by repetitive thoughts and behaviors associated with underlying dysregulation of frontostriatal circuitry. Central to neurobiological models of OCD is the orbitofrontal cortex, a neural region that facilitates behavioral flexibility after negative feedback (reversal learning). We identified abnormally reduced activation of several cortical regions, including the lateral orbitofrontal cortex, during reversal learning in OCD patients and their clinically unaffected close relatives, supporting the existence of an underlying previously undiscovered endophenotype for this disorder.
Abstract: Obsessive-compulsive disorder (OCD) is a common, heritable neuropsychiatric disorder, hypothetically underpinned by dysconnectivity of large-scale brain systems. The extent of white matter abnormalities in OCD is unknown, and the genetic basis of this disorder is poorly understood. The authors used diffusion tensor imaging, a magnetic resonance imaging technique, for examining white matter abnormalities in brain structure through quantification of water diffusion, to confirm whether white matter abnormalities exist in OCD. They also explored whether such abnormalities occur in healthy first-degree relatives of patients, indicating they may be endophenotypes representing increased genetic risk for OCD.
Abstract: Obsessive-compulsive disorder (OCD) is a common, heritable and disabling neuropsychiatric disorder. Theoretical models suggest that OCD is underpinned by functional and structural abnormalities in orbitofronto-striatal circuits. Evidence from cognitive and neuroimaging studies (functional and structural magnetic resonance imaging (MRI) and positron emission tomography (PET)) have generally been taken to be supportive of these theoretical models; however, results from these studies have not been entirely congruent with each other. With the advent of whole brain-based structural imaging techniques, such as voxel-based morphometry and multivoxel analyses, we consider it timely to assess neuroimaging findings to date, and to examine their compatibility with cognitive studies and orbitofronto-striatal models. As part of this assessment, we performed a quantitative, voxel-level meta-analysis of functional MRI findings, which revealed consistent abnormalities in orbitofronto-striatal and other additional areas in OCD. This review also considers the evidence for involvement of other brain areas outside orbitofronto-striatal regions in OCD, the limitations of current imaging techniques, and how future developments in imaging may aid our understanding of OCD.
Abstract: Impulsive symptoms occur across neuropsychiatric disorders, with important ramifications for everyday functioning and quality of life. This article considers recent developments in the neuropsychological assessment of impulsivity with a focus on the ability to suppress motor responses (response inhibition).
Abstract: Obsessive-compulsive disorder (OCD) and trichotillomania (compulsive hair-pulling) share overlapping co-morbidity, familial transmission, and phenomenology. However, the extent to which these disorders share a common cognitive phenotype has yet to be elucidated using patients without confounding co-morbidities.
Abstract: Buspirone is a serotonin 5-HT(1A) receptor agonist licensed for the treatment of anxiety. Other anxiolytic drugs such as benzodiazepines show significant sedative and other unwanted effects on cognition. Studies to date have yet to investigate cognitive effects of buspirone using well-validated computerized tests. The aim of this study was to assess acute subjective and cognitive effects of buspirone in healthy volunteers. Sixty healthy male volunteers received 20 mg buspirone, 30 mg buspirone, or placebo per os in a double-blind parallel groups design (N=20 per group). Subjective ratings (visual analogue scales) were completed at baseline, and at 1.5 and 3.5 hours post-capsule. Cognitive assessment was undertaken between 1.5 and 3.5 hours post-capsule, including tests of memory, executive planning, impulse control, decision making and cognitive flexibility. The 30 mg buspirone group showed significantly higher subjective ratings of contentedness 3.5 hours after capsule relative to placebo. Treatment and placebo groups did not differ significantly on cognitive measures. In contrast to benzodiazepines, the anxiolytic buspirone appears to lack detectable deleterious effects on cognition when administered acutely at clinically meaningful doses. Future research directions are discussed in relation to acute and chronic studies in neuropsychiatric populations.
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.
Abstract: It has been proposed that certain Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Axis I disorders share overlapping clinical features, genetic contributions, and treatment response and fall within an "obsessive-compulsive" spectrum. Obsessive-compulsive personality disorder (OCPD) resembles obsessive-compulsive disorder (OCD) and other spectrum disorders in terms of phenomenology, comorbidity, neurocognition, and treatment response. This article critically examines the nosological profile of OCPD with special reference to OCD and related disorders. By viewing OCPD as a candidate member of the obsessive-compulsive spectrum, we gain a fresh approach to understanding its neurobiology, etiology, and potential treatments.
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.
Abstract: Atomoxetine, a highly selective noradrenaline reuptake inhibitor (SNRI), shows efficacy in the treatment of attention-deficit/hyperactivity disorder (ADHD). Compared with psychostimulants, atomoxetine has a distinct mode of brain action and potentially lower addictive potential. Studies have yet to assess whether atomoxetine improves cognition following a single oral dose in ADHD.
Abstract: 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.
Abstract: Problems relating to impulsivity, attention, and working memory occur in many neuropsychiatric disorders and represent important targets for pharmacological intervention. The purpose of this article is to review recent neuropharmacological manipulation studies in humans relating to these domains.
Abstract: The use of strategies to aid performance when undertaking neuropsychological tasks is dependent on intact fronto-striatal circuitry, and growing evidence suggests impaired spontaneous use of strategies in patients with obsessive-compulsive disorder (OCD). However, studies to date have not examined the effects of strategy training on task performance in OCD or in trichotillomania (compulsive hair-pulling, a condition that has been argued to share overlap with OCD in terms of phenomenology and co-morbidity).
Abstract: Cognitive functions dependent on the prefrontal cortex, such as the ability to suppress behavior (response inhibition) and to learn from complex feedback (probabilistic learning), play critical roles in activities of daily life. To what extent do different neurochemical systems modulate these two cognitive functions? Here, using stop-signal and probabilistic learning tasks, we show a double dissociation for the involvement of noradrenaline and serotonin in human cognition. In healthy volunteers, inhibition of central noradrenaline reuptake improved response inhibition but had no effect on probabilistic learning, whereas inhibition of central serotonin reuptake impaired probabilistic learning with no effect on response inhibition.
Abstract: Cognitive dysfunction is central to our understanding of mood disorders in terms of patient experiences, Diagnostic and Statistical Manual of Mental Disorders criteria, and psychological models. In this article, we highlight key findings from studies that have used neuropsychological tests and functional neuroimaging techniques to explore cognitive dysfunction in patients with depression and mania. In particular, we focus on affective processing bias, abnormal response to negative feedback, and decision making. Results are discussed in the context of current conceptualizations of dysfunctional neural circuitry, and in relation to important clinical research implications.
Abstract: Problems with inhibiting certain pathological behaviors are integral to obsessive-compulsive disorder (OCD), trichotillomania, and other putative obsessive-compulsive spectrum disorders. The authors assessed and compared motor inhibition and cognitive flexibility in OCD and trichotillomania for the first time, to their knowledge.
Abstract: Noradrenaline (NA) is implicated in arousal. Working memory is dependent upon prefrontal cortex, and moderate levels of NA are thought to facilitate working memory whereas higher levels during extreme stress may impair working memory and engage more posterior cortical and sub-cortical circuitry. The NA system also influences emotional memory via modulation of the amygdalae and related mediotemporal structures. NA dysfunction and abnormalities in arousal-dependent memory functions are evident in a variety of neuropsychiatric illnesses.
Abstract: Severe hair-pulling is characteristic of trichotillomania, an impulse control disorder not otherwise classified. Other pathological habits, including severe nail-biting and skin-picking, are also prevalent and are potentially diagnosable as stereotypic movement disorder. There is increasing awareness of the morbidity associated with these kind of habit disorders but, to date, relatively few randomized controlled trials of pharmacotherapy or psychotherapy have been undertaken. Advances in the understanding of the underlying cognitive-affective mechanisms driving stereotypies in animals and humans may ultimately lead to new approaches. An affect regulation, behavioral addiction, and cognitive control (A-B-C) approach is outlined to conceptualizing and managing these conditions.
Abstract: Obsessive compulsive disorder (OCD) is a highly debilitating neuropsychiatric condition with estimated lifetime prevalence of 2-3%, more than twice that of schizophrenia. However, in contrast to other neuropsychiatric conditions of a comparable or lesser prevalence, relatively little is understood about the aetiology, neural substrates and cognitive profile of OCD. Despite strong evidence for OCD being familial, with risk to first-degree relatives much greater than for the background population, its genetic underpinnings have not yet been adequately delineated. Although cognitive dysfunction is evident in the everyday behaviour of OCD sufferers and is central to contemporary psychological models, theory-based studies of neurocognitive function have yet to reveal a reliable cognitive signature, and interpretation has often been confounded by failures to control for co-morbidities. The neuroimaging findings in OCD are amongst the most robust reported in the psychiatric literature, with structural and functional abnormalities frequently reported in orbitofrontal cortex, anterior cingulate cortex, and caudate nucleus. In spite of this, our relative lack of understanding of OCD neurochemical processes continues to impede progress in the development of novel pharmacological treatment approaches. Integrating the neurobiological, cognitive, and clinical findings, we propose that OCD might usefully be conceptualised in terms of lateral orbitofrontal loop dysfunction, and that failures in cognitive and behavioural inhibitory processes appear to underlie many of the symptoms and neurocognitive findings. We highlight existing limitations in the literature, and the potential utility of endophenotypes in overcoming these limitations. We propose that neurocognitive indices of inhibitory functions may represent a useful heuristic in the search for endophenotypes in OCD. This has direct implications not only for OCD but also for putative obsessive-compulsive spectrum conditions including attention deficit hyperactivity disorder, Tourette's syndrome, and trichotillomania (compulsive hair pulling).
Abstract: Affective disorders, including bipolar disorder and major depressive disorder, are highly prevalent throughout the world and are extremely disabling. Diagnostic and Statistical Manual criteria and psychological models strongly implicate cognitive dysfunctions as being integral to our understanding of these disorders. We review the findings from studies that have used neurocognitive tests and functional imaging techniques to explore abnormal cognition in affective disorders. In particular, we highlight the evidence for cognitive dysfunctions that persist into full clinical remission, and the recent trend toward the use of "hot" processing tasks, involving emotionally charged stimuli, as a means of differentiating between the cognitive underpinnings of mania and depression. The clinical relevance of these developments is discussed.
