Andrew D. Blackwell

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).

Substantia nigra/ventral tegmental reward prediction error disruption in psychosis

While dopamine systems have been implicated in the pathophysiology of schizophrenia and psychosis for many years, how dopamine dysfunction generates psychotic symptoms remains unknown. Recent theoretical interest has been directed at relating the known role of midbrain dopamine neurons in reinforcement learning, motivational salience and prediction error to explain the abnormal mental experience of psychosis. However, this theoretical model has yet to be explored empirically. To examine a link between psychotic experience, reward learning and dysfunction of the dopaminergic midbrain and associated target regions, we asked a group of first episode psychosis patients suffering from active positive symptoms and a group of healthy control participants to perform an instrumental reward conditioning experiment. We characterized neural responses using functional magnetic resonance imaging. We observed that patients with psychosis exhibit abnormal physiological responses associated with reward prediction error in the dopaminergic midbrain, striatum and limbic system, and we demonstrated subtle abnormalities in the ability of psychosis patients to discriminate between motivationally salient and neutral stimuli. This study provides the first evidence linking abnormal mesolimbic activity, reward learning and psychosis.

Heterogeneity of Parkinson's disease in the early clinical stages using a data driven approach

Objective: To investigate the heterogeneity of idiopathic Parkinson’s disease (PD) in a data driven manner among a cohort of patients in the early clinical stages of the disease meeting established diagnostic criteria. Methods: Data on demographic, motor, mood, and cognitive measures were collected from 120 consecutive patients in the early stages of PD (Hoehn and Yahr I–III) attending a specialist PD research clinic. Statistical cluster analysis of the data allowed the existence of the patient subgroups generated to be explored. Results: The analysis revealed four main subgroups: (a) patients with a younger disease onset; (b) a tremor dominant subgroup of patients; (c) a non-tremor dominant subgroup with significant levels of cognitive impairment and mild depression; and (d) a subgroup with rapid disease progression but no cognitive impairment. Conclusions: This study complements and extends previous research by using a data driven approach to define the clinical heterogeneity of early PD. The approach adopted in this study for the identification of subgroups of patients within Parkinson’s disease has important implications for generating testable hypotheses on defining the heterogeneity of this common condition and its aetiopathological basis and thus its treatment.

Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline

Docosahexaenoic acid (DHA) plays an important role in neural function. Decreases in plasma DHA are associated with cognitive decline in healthy elderly adults and in patients with Alzheimers disease. Higher DHA intake is inversely correlated with relative risk of Alzheimers disease. The potential benefits of DHA supplementation in age‐related cognitive decline (ARCD) have not been fully examined.

Cognitive impairment in depression: a systematic review and meta-analysis

BACKGROUND This review aimed to address the question of whether cognitive impairment should be considered a core feature of depression that may be a valuable target for treatment. METHOD We conducted a systematic review and meta-analysis of cognitive function, assessed with a single neuropsychological test battery, the Cambridge Neuropsychological Test Automated Battery (CANTAB), in patients with depression during symptomatic and remitted states. Inclusion of studies comparing patients remitted from depression and controls enabled us to investigate whether cognitive impairment persists beyond episodes of low mood in depression. RESULTS Our meta-analysis revealed significant moderate cognitive deficits in executive function, memory and attention in patients with depression relative to controls (Cohens d effect sizes ranging from -0.34 to -0.65). Significant moderate deficits in executive function and attention (Cohens d ranging from -0.52 to -0.61) and non-significant small/moderate deficits in memory (Cohens d ranging from -0.22 to -0.54) were found to persist in patients whose depressive symptoms had remitted, indicating that cognitive impairment occurs separately from episodes of low mood in depression. CONCLUSIONS Both low mood and cognitive impairment are associated with poor psychosocial functioning. Therefore, we argue that remediation of cognitive impairment and alleviation of depressive symptoms each play an important role in improving outcome for patients with depression. In conclusion, this systematic review and meta-analysis demonstrates that cognitive impairment represents a core feature of depression that cannot be considered an epiphenomenon that is entirely secondary to symptoms of low mood and that may be a valuable target for future interventions.

Detecting dementia: Novel neuropsychological markers of preclinical Alzheimer's disease.

The results of a previous study have suggested that impaired performance on one neuropsychological test, CANTAB Paired Associates Learning (PAL), may serve as a marker for preclinical Alzheimer’s disease (AD). In a group of individuals with ‘questionable dementia’, the baseline PAL performance was found to correlate significantly with subsequent deterioration in global cognitive function over an 8-month period. The present paper reports diagnostic outcome data for the same individuals 32 months after the first assessment and evaluates the predictive diagnostic utility of baseline neuropsychological measures. Thirty-two months after joining the study, 11 of the 43 ‘questionable dementia’ patients met the criteria for probable AD diagnosis (‘converters’) and 29 remained free from AD (‘non-converters’). Logistic regression analysis revealed that two tests of memory, in combination, could be used to predict a later diagnosis of probable AD with a high level of accuracy [χ2(3) = 47.054, p < 0.0001]. As predicted, these tests are measures of visuospatial learning (CANTAB PAL) and, also, semantic memory (Graded Naming Test). These two tests in combination appear to be highly accurate in detecting cognitive dysfunction characteristic of preclinical AD. Using these tests, a simple algorithm is described for calculating, with 100% accuracy for this sample of 40 patients, the probability that an individual with mild memory impairments will go on to receive a diagnosis of probable AD.

Association Between Response Inhibition and Working Memory in Adult ADHD: A Link to Right Frontal Cortex Pathology?

BACKGROUND We sought to assess the relationship between response inhibition and working memory in adult patients with attention-deficit/hyperactivity disorder (ADHD) and neurosurgical patients with frontal lobe damage. METHODS The stop-signal reaction time (SSRT) test and a spatial working memory (SWM) task were administered to 20 adult patients with ADHD and a group of matched controls. The same tasks were administered to 21 patients with lesions to right frontal cortex and 19 patients with left frontal lesions. RESULTS The SSRT test, but not choice reaction time, was significantly associated with search errors on the SWM task in both the adult ADHD and right frontal patients. In the right frontal patients, impaired performance on both variables was correlated with the volume of damage to the inferior frontal gyrus. CONCLUSIONS Response inhibition and working memory impairments in ADHD may stem from a common pathologic process rather than being distinct deficits. Such pathology could relate to right frontal-cortex abnormalities in ADHD, consistent with prior reports, as well as with the demonstration here of a significant association between SSRT and SWM in right frontal patients.

A neuropsychological comparison of obsessive–compulsive disorder and trichotillomania

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 has 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.

Noradrenergic modulation of working memory and emotional memory in humans.

RationaleNoradrenaline (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.ObjectivesThe 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 methodsSelection of relevant peer-reviewed publications was based on a PubMed search.ResultsStudies 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.ConclusionsImproved 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.

Translational approaches to frontostriatal dysfunction in attention-deficit/hyperactivity disorder using a computerized neuropsychological battery.

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.