A Double-Blind, Placebo-Controlled Trial of Lamotrigine for Pathological Skin Picking: Treatment Efficacy and Neurocognitive Predictors of Response.

Grant JE, Odlaug BL, Chamberlain SR, Kim SW

Journal of clinical psychopharmacology 2010 Jun;

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 tre... expand abstractatment 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 >/=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. collapse abstract

The role of the right inferior frontal gyrus: inhibition and attentional control.

Hampshire A, Chamberlain SR, Monti MM, Duncan J, Owen AM

NeuroImage 2010 Apr; 50(3)

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 inhibiti... expand abstracton 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. collapse abstract

Probing compulsive and impulsive behaviors, from animal models to endophenotypes: a narrative review.

Fineberg NA, Potenza MN, Chamberlain SR, Berlin HA, Menzies L, Bechara A, Sahakian BJ, Robbins TW, Bullmore ET, Hollander E

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2010 Feb; 35(3)

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 proc... expand abstractesses 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. collapse abstract

Motor inhibition and cognitive flexibility in pathologic skin picking.

Odlaug BL, Chamberlain SR, Grant JE

Progress in neuro-psychopharmacology & biological psychiatry 2010 Feb; 34(1)

BACKGROUND: 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 subject... expand abstracts 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. METHOD: Twenty subjects with PSP (mean age 33.1+/-14.3 years; 85% female) and 20 healthy controls (mean age 31.6+/-9.1 years; 85% female) underwent cognitive assessments using the Stop-signal and Intra-dimensional/Extra-dimensional (ID/ED) set-shift tasks. Groups were matched for age, gender, and education. RESULTS: PSP was associated with significantly impaired stop-signal reaction times but intact ID/ED cognitive flexibility compared to controls. Measures of disease severity in the PSP subjects did not covary significantly with stop-signal performance. CONCLUSION: The finding of impaired inhibitory control but intact set-shift cognitive flexibility draws remarkable parallels with findings in trichotillomania but differs from obsessive compulsive disorder. These findings have important implications for understanding potential neurobiological dysfunction in PSP, how the disorder should be classified, and suggest new potential treatment directions. collapse abstract

Cross-species models of OCD spectrum disorders.

Boulougouris V, Chamberlain SR, Robbins TW

Psychiatry research 2009 Nov; 170(1)

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-com... expand abstractpulsive 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. collapse abstract

Cognitive event-related potentials differentiate schizophrenia with obsessive-compulsive disorder (schizo-OCD) from OCD and schizophrenia without OC symptoms.

Pallanti S, Castellini G, Chamberlain SR, Quercioli L, Zaccara G, Fineberg NA

Psychiatry research 2009 Nov; 170(1)

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 b... expand abstracteen 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. collapse abstract

Endophenotypes of obsessive-compulsive disorder: rationale, evidence and future potential.

Chamberlain SR, Menzies L

Expert review of neurotherapeutics 2009 Aug; 9(8)

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 ... expand abstractrooted 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. collapse abstract

Trichotillomania: neurobiology and treatment.

Chamberlain SR, Odlaug BL, Boulougouris V, Fineberg NA, Grant JE

Neuroscience and biobehavioral reviews 2009 Jun; 33(6)

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 considerin... expand abstractg 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. collapse abstract

Neurocognitive mechanisms in depression: implications for treatment.

Clark L, Chamberlain SR, Sahakian BJ

Annual review of neuroscience 2009 Apr; 32

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 mecha... expand abstractnisms 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. collapse abstract

Atomoxetine modulates right inferior frontal activation during inhibitory control: a pharmacological functional magnetic resonance imaging study.

Chamberlain SR, Hampshire A, Müller U, Rubia K, Del campo N, Craig K, Regenthal R, Suckling J, Roiser JP, Grant JE, Bullmore ET, Robbins TW, Sahakian BJ

Biological psychiatry 2009 Apr; 65(7)

BACKGROUND: 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 patien... expand abstractts. However, the mechanisms by which atomoxetine improves inhibitory control have yet to be determined. METHODS: The effects of atomoxetine (40 mg) were measured with a stop-signal functional magnetic resonance imaging (fMRI) paradigm in 19 healthy volunteers, in a within-subject, double-blind, placebo-controlled design. RESULTS: Atomoxetine improved inhibitory control and increased activation in the right inferior frontal gyrus when volunteers attempted to inhibit their responses (irrespective of success). Plasma levels of drug correlated significantly with right inferior frontal gyrus activation only during successful inhibition. CONCLUSIONS: These results show that atomoxetine exerts its beneficial effects on inhibitory control via modulation of right inferior frontal function, with implications for understanding and treating inhibitory dysfunction of ADHD and other disorders. collapse abstract

Grey matter abnormalities in trichotillomania: morphometric magnetic resonance imaging study.

Chamberlain SR, Menzies LA, Fineberg NA, Del campo N, Suckling J, Craig K, Müller U, Robbins TW, Bullmore ET, Sahakian BJ

The British journal of psychiatry : the journal of mental science 2008 Sep; 193(3)

BACKGROUND: Trichotillomania (repetitive hair-pulling) is an Axis I psychiatric disorder whose neurobiological basis is incompletely understood. Whole-brain trichotillomania neuroimaging studies are lacking. AIMS: To investigate grey and white matter... expand abstract abnormalities over the whole brain in patients with trichotillomania. METHOD: Eighteen patients with DSM-IV trichotillomania and 19 healthy controls undertook structural magnetic resonance imaging after providing written informed consent. Differences in grey and white matter were investigated using computational morphometry. RESULTS: Patients with trichotillomania showed increased grey matter densities in the left striatum, left amygdalo-hippocampal formation, and multiple (including cingulate, supplementary motor, and frontal) cortical regions bilaterally. CONCLUSIONS: Trichotillomania was associated with structural grey matter changes in neural circuitry implicated in habit learning, cognition and affect regulation. These findings inform animal models of the disorder and highlight key regions of interest for future translational research. collapse abstract

Orbitofrontal dysfunction in patients with obsessive-compulsive disorder and their unaffected relatives.

Chamberlain SR, Menzies L, Hampshire A, Suckling J, Fineberg NA, Del campo N, Aitken M, Craig K, Owen AM, Bullmore ET, Robbins TW, Sahakian BJ

Science (New York, N.Y.) 2008 Jul; 321(5887)

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... expand abstract 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. collapse abstract

White matter abnormalities in patients with obsessive-compulsive disorder and their first-degree relatives.

Menzies L, Williams GB, Chamberlain SR, Ooi C, Fineberg N, Suckling J, Sahakian BJ, Robbins TW, Bullmore ET

The American journal of psychiatry 2008 Oct; 165(10)

OBJECTIVE: 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 b... expand abstractasis 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. METHOD: The authors used diffusion tensor imaging to measure fractional anisotropy of white matter in 30 patients with OCD, 30 unaffected first-degree relatives, and 30 matched healthy comparison subjects. Regions of significantly abnormal fractional anisotropy in patients in relation to healthy comparison subjects were identified by permutation tests. The authors assessed whether these abnormalities were also evident in the first-degree relatives. A secondary region-of-interest analysis was undertaken to assess the extent of replication between our data and previous relevant literature. RESULTS: Patients with OCD demonstrated significantly reduced fractional anisotropy in a large region of right inferior parietal white matter and significantly increased fractional anisotropy in a right medial frontal region. Relatives also exhibited significant abnormalities of fractional anisotropy in these regions. CONCLUSIONS: These findings indicate that OCD is associated with white matter abnormalities in parietal and frontal regions. Similar abnormalities in unaffected first-degree relatives suggest these may be white matter endophenotypes for OCD. collapse abstract

Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: the orbitofronto-striatal model revisited.

Menzies L, Chamberlain SR, Laird AR, Thelen SM, Sahakian BJ, Bullmore ET

Neuroscience and biobehavioral reviews 2008 Jan; 32(3)

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 cogniti... expand abstractve 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. collapse abstract

Neurocognitive endophenotypes of obsessive-compulsive disorder.

Menzies L, Achard S, Chamberlain SR, Fineberg N, Chen CH, Del campo N, Sahakian BJ, Robbins TW, Bullmore E

Brain : a journal of neurology 2007 Dec; 130(Pt 12)

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 theoriz... expand abstracted 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. collapse abstract

Atomoxetine improved response inhibition in adults with attention deficit/hyperactivity disorder.

Chamberlain SR, Del campo N, Dowson J, Müller U, Clark L, Robbins TW, Sahakian BJ

Biological psychiatry 2007 Nov; 62(9)

BACKGROUND: 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 a... expand abstractnd potentially lower addictive potential. Studies have yet to assess whether atomoxetine improves cognition following a single oral dose in ADHD. METHODS: Twenty-two adults with DSM-IV ADHD were administered a single oral dose of atomoxetine (60 mg) in a placebo-controlled double-blind crossover design. Cognitive effects were assessed using stop-signal, sustained attention, spatial working memory, and set-shifting paradigms. Normative cognitive data from 20 healthy volunteers were collected for comparison. RESULTS: The ADHD patients under placebo conditions showed response inhibition and working memory deficits compared with healthy volunteers. Atomoxetine treatment in the ADHD patients was associated with shorter stop-signal reaction times and lower numbers of commission errors on the sustained attention task. CONCLUSIONS: Atomoxetine improved inhibitory control, most likely via noradrenergically mediated augmentation of prefrontal cortex function. These results have implications for understanding the mechanisms by which atomoxetine exerts beneficial clinical effects and suggest novel treatment directions for other disorders of impulsivity. collapse abstract

The neurobiology of attention-deficit/hyperactivity disorder.

Chamberlain SR, Robbins TW, Sahakian BJ

Biological psychiatry 2007 Jun; 61(12)

Does obsessive-compulsive personality disorder belong within the obsessive-compulsive spectrum?

Fineberg NA, Sharma P, Sivakumaran T, Sahakian B, Chamberlain SR, Chamberlain S

CNS spectrums 2007 Jun; 12(6)

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" spec... expand abstracttrum. 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. collapse abstract

The neuropsychiatry of impulsivity.

Chamberlain SR, Sahakian BJ

Current opinion in psychiatry 2007 May; 20(3)

PURPOSE OF REVIEW: 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 w... expand abstractith a focus on the ability to suppress motor responses (response inhibition). RECENT FINDINGS: Using objective tests, response inhibition deficits were identified in several neuropsychiatric conditions associated with impulsivity, namely attention deficit hyperactivity disorder, trichotillomania, obsessive-compulsive disorder, and chronic substance abuse. Deficits were also found in unaffected first-degree relatives of attention deficit hyperactivity disorder and obsessive-compulsive disorder patients. Evidence from patients with focal brain lesions and from healthy volunteers using functional MRI and transcranial stimulation implicated the right inferior frontal gyrus in response inhibition. Pharmacological manipulations of the serotonin system had no detectable behavioural effects on response inhibition, whereas manipulations of the noradrenaline system did. SUMMARY: Neuropsychological assessment shows great promise in the investigation of impulsivity and its brain substrates. These results support a key role for response inhibition, a function linked to the right inferior frontal gyrus, in the manifestation of impulsivity. Measures of response inhibition will contribute to the search for psychiatric endophenotypes, novel treatments, and more optimal diagnostic classification systems for neuropsychiatric disorders. collapse abstract

Atomoxetine increases salivary cortisol in healthy volunteers.

Chamberlain SR, Müller U, Cleary S, Robbins TW, Sahakian BJ

Journal of psychopharmacology (Oxford, England) 2007 Jul; 21(5)

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 sele... expand abstractctive 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. collapse abstract

Lifting the veil on trichotillomania.

Chamberlain SR, Menzies L, Sahakian BJ, Fineberg NA

The American journal of psychiatry 2007 Apr; 164(4)

Lack of deleterious effects of buspirone on cognition in healthy male volunteers.

Chamberlain SR, Müller U, Deakin JB, Corlett PR, Dowson J, Cardinal RN, Aitken MR, Robbins TW, Sahakian BJ

Journal of psychopharmacology (Oxford, England) 2007 Mar; 21(2)

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 cognit... expand abstractive 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. collapse abstract

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

Chamberlain SR, Fineberg NA, Menzies LA, Blackwell AD, Bullmore ET, Robbins TW, Sahakian BJ

The American journal of psychiatry 2007 Feb; 164(2)

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 ... expand abstractclarify 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 represent cognitive endophenotypes for OCD. Such measures will play a key role in understanding genotype/phenotype associations for OCD and related spectrum conditions. collapse abstract

The neuropsychology of mood disorders.

Chamberlain SR, Sahakian BJ

Current psychiatry reports 2006 Dec; 8(6)

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... expand abstract 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. collapse abstract

Neuropharmacological modulation of cognition.

Chamberlain SR, Müller U, Robbins TW, Sahakian BJ

Current opinion in neurology 2006 Dec; 19(6)

PURPOSE OF REVIEW: 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 neuropharmac... expand abstractological manipulation studies in humans relating to these domains. RECENT FINDINGS: Serotonin manipulations in healthy volunteers did not affect response inhibition, a cognitive function implicated in impulsive symptoms of attention deficit hyperactivity disorder, trichotillomania, and substance abuse. Serotonin manipulations did affect performance on cognitive tests involving emotionally salient rewards and feedback, suggesting involvement of this neurochemical in affective aspects of impulsivity. Attentional deficits in attention deficit hyperactivity disorder and visuospatial neglect were ameliorated by noradrenergic drugs. Noradrenergic beta-blockade suppressed the encoding of emotionally arousing unpleasant stimuli and reduced amygdala activation in healthy volunteers, with potential implications for posttraumatic stress disorder. Dopaminergic manipulations affected aspects of working memory in healthy volunteers and in patients with Parkinson's disease, with evidence for bidirectional effects depending on baseline performance. SUMMARY: Recent findings raise exciting prospects for modulating impulsivity, attention, and working memory in a variety of neuropsychiatric disorders. Future studies should use computerized cognitive assessment, measures of functional genetic polymorphisms, and neuroimaging techniques, in order to further elucidate the neurochemical substrates of cognition and optimize treatment approaches. collapse abstract

An A-B-C model of habit disorders: hair-pulling, skin-picking, and other stereotypic conditions.

Stein DJ, Chamberlain SR, Fineberg N

CNS spectrums 2006 Nov; 11(11)

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 stereotyp... expand abstractic 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. collapse abstract

A neuropsychological comparison of obsessive-compulsive disorder and trichotillomania.

Chamberlain SR, Fineberg NA, Blackwell AD, Clark L, Robbins TW, Sahakian BJ

Neuropsychologia 2007 Mar; 45(4)

BACKGROUND: 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 h... expand abstractas yet to be elucidated using patients without confounding co-morbidities. AIM: To compare neurocognitive functioning in co-morbidity-free patients with OCD and trichotillomania, focusing on domains of learning and memory, executive function, affective processing, reflection-impulsivity and decision-making. METHOD: Twenty patients with OCD, 20 patients with trichotillomania, and 20 matched controls undertook neuropsychological assessment after meeting stringent inclusion criteria. RESULTS: Groups were matched for age, education, verbal IQ, and gender. The OCD and trichotillomania groups were impaired on spatial working memory. Only OCD patients showed additional impairments on executive planning and visual pattern recognition memory, and missed more responses to sad target words than other groups on an affective go/no-go task. Furthermore, OCD patients failed to modulate their behaviour between conditions on the reflection-impulsivity test, suggestive of cognitive inflexibility. Both clinical groups showed intact decision-making and probabilistic reversal learning. CONCLUSIONS: OCD and trichotillomania shared overlapping spatial working memory problems, but neuropsychological dysfunction in OCD spanned additional domains that were intact in trichotillomania. Findings are discussed in relation to likely fronto-striatal neural substrates and future research directions. collapse abstract

Motor inhibition and cognitive flexibility in obsessive-compulsive disorder and trichotillomania.

Chamberlain SR, Fineberg NA, Blackwell AD, Robbins TW, Sahakian BJ

The American journal of psychiatry 2006 Jul; 163(7)

OBJECTIVE: 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 a... expand abstractnd cognitive flexibility in OCD and trichotillomania for the first time, to their knowledge. METHOD: The Stop-Signal Task and the Intradimensiona/Extradimensional Shift Task were administered to 20 patients with OCD, 17 patients with trichotillomania, and 20 healthy comparison subjects. RESULTS: Both OCD and trichotillomania showed impaired inhibition of motor responses. For trichotillomania, the deficit was worse than for OCD, and the degree of the deficit correlated significantly with symptom severity. Only patients with OCD showed deficits in cognitive flexibility. CONCLUSIONS: Impaired inhibition of motor responses (impulsivity) was found in OCD and trichotillomania, whereas cognitive inflexibility (thought to contribute to compulsivity) was limited to OCD. This assessment will advance the characterization and classification of obsessive-compulsive spectrum disorders and aid the development of novel treatments. collapse abstract

Noradrenergic modulation of working memory and emotional memory in humans.

Chamberlain SR, Müller U, Blackwell AD, Robbins TW, Sahakian BJ

Psychopharmacology 2006 Nov; 188(4)

RATIONALE: 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 e... expand abstractngage 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. OBJECTIVES: The authors provide a concise overview of pharmacological studies that have investigated effects of selective NA manipulations on working memory and emotional memory functions in healthy human volunteers. MATERIALS AND METHODS: Selection of relevant peer-reviewed publications was based on a PubMed search. RESULTS: Studies to date indicate that: (1) the beta-blocker propranolol impaired working and emotional memory, (2) clonidine frequently impaired working memory, and (3) reboxetine, a selective noradrenaline reuptake inhibitor, enhanced emotional memory for positive material. CONCLUSIONS: Improved understanding of coupling between NA, cortico-subcortical circuitry and human mnemonic functions will suggest novel therapeutic directions for the treatment of neuropsychiatric conditions, such as attention deficit hyperactivity disorder and post-traumatic stress disorder. Future research directions are discussed in relation to neuroimaging techniques, functional central nervous system polymorphisms and study designs. collapse abstract

Neurochemical modulation of response inhibition and probabilistic learning in humans.

Chamberlain SR, Müller U, Blackwell AD, Clark L, Robbins TW, Sahakian BJ

Science (New York, N.Y.) 2006 Feb; 311(5762)

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 dif... expand abstractferent 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. collapse abstract

Strategy implementation in obsessive-compulsive disorder and trichotillomania.

Chamberlain SR, Blackwell AD, Fineberg NA, Robbins TW, Sahakian BJ

Psychological medicine 2006 Jan; 36(1)

BACKGROUND: 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-compulsiv... expand abstracte 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). METHOD: The ability to generate novel visuospatial sequences using a computer interface was examined before and after undertaking optimal strategy training in 20 OCD patients, 17 trichotillomania patients, and 20 controls (matched for age, education, and IQ). RESULTS: OCD patients failed to improve ability to generate novel sequences above baseline despite successfully completing strategy training to the same extent as other groups. In contrast, performance of trichotillomania patients improved significantly after training to the same extent as controls. Groups did not differ on memory span, trial-by-trial action monitoring, or ability to generate novel visuospatial sequences prior to strategy training. CONCLUSIONS: Strategy implementation deficits, suggestive of cognitive inflexibility and fronto-striatal dysfunction, appear integral to the neurocognitive profile of OCD but not trichotillomania. Future research should investigate cognitive flexibility in obsessive-compulsive spectrum disorders using a variety of paradigms, and clarify the contribution of specific neural structures and transmitter systems to deficits reported. collapse abstract

The neuropsychology of obsessive compulsive disorder: the importance of failures in cognitive and behavioural inhibition as candidate endophenotypic markers.

Chamberlain SR, Blackwell AD, Fineberg NA, Robbins TW, Sahakian BJ

Neuroscience and biobehavioral reviews 2005 May; 29(3)

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 le... expand abstractsser 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). collapse abstract

Cognition in mania and depression: psychological models and clinical implications.

Chamberlain SR, Sahakian BJ

Current psychiatry reports 2004 Dec; 6(6)

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 dys... expand abstractfunctions 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. collapse abstract