Samuel R. Chamberlain

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

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.

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

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.

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

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, Tourettes syndrome, and trichotillomania (compulsive hair pulling).

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

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.

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

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.

The neuropsychiatry of impulsivity.

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 with 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.

The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorder.

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.

Neurocognitive mechanisms in depression: implications for treatment.

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.

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

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 and 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.

Atomoxetine Modulates Right Inferior Frontal Activation During Inhibitory Control: A Pharmacological Functional Magnetic Resonance Imaging Study

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 patients. 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.