An integrated brain-behavior model for working memory.

Working memory (WM) is a central construct in cognitive neuroscience because it comprises mechanisms of active information maintenance and cognitive control that underpin most complex cognitive behavior. Individual variation in WM has been associated with multiple behavioral and health features including demographic characteristics, cognitive and physical traits and lifestyle choices. In this context, we used sparse canonical correlation analyses (sCCAs) to determine the covariation between brain imaging metrics of WM-network activation and connectivity and nonimaging measures relating to sensorimotor processing, affective and nonaffective cognition, mental health and personality, physical health and lifestyle choices derived from 823 healthy participants derived from the Human Connectome Project. We conducted sCCAs at two levels: a global level, testing the overall association between the entire imaging and behavioral-health data sets; and a modular level, testing associations between subsets of the two data sets. The behavioral-health and neuroimaging data sets showed significant interdependency. Variables with positive correlation to the neuroimaging variate represented higher physical endurance and fluid intelligence as well as better function in multiple higher-order cognitive domains. Negatively correlated variables represented indicators of suboptimal cardiovascular and metabolic control and lifestyle choices such as alcohol and nicotine use. These results underscore the importance of accounting for behavioral-health factors in neuroimaging studies of WM and provide a neuroscience-informed framework for personalized and public health interventions to promote and maintain the integrity of the WM network.

Neural correlates of affective and non-affective cognition in obsessive compulsive disorder: A meta-analysis of functional imaging studies.

Obsessive compulsive disorder (OCD) is characterized by intrusive thoughts and repetitive ritualistic behaviors and has been associated with diverse functional brain abnormalities. We sought to synthesize current evidence from functional magnetic resonance imaging (fMRI) studies and examine their alignment to pathogenetic models of OCD. Following systematic review, we identified 54 task-fMRI studies published in the last decade comparing adults with OCD (n=1186) to healthy adults (n=1159) using tasks of affective and non-affective cognition. We used voxel-based quantitative meta-analytic methods to combine primary data on anatomical coordinates of case-control differences, separately for affective and non-affective tasks. We found that functional abnormalities in OCD cluster within cortico-striatal thalamic circuits. Within these circuits, the abnormalities identified showed significant dependence on the affective or non-affective nature of the tasks employed as circuit probes. In studies using affective tasks, patients overactivated regions involved in salience, arousal and habitual responding (anterior cingulate cortex, insula, caudate head and putamen) and underactivated regions implicated in cognitive and behavioral control (medial prefrontal cortex, posterior caudate). In studies using non-affective cognitive tasks, patients overactivated regions involved in self-referential processing (precuneus, posterior cingulate cortex) and underactivated subcortical regions that support goal-directed cognition and motor control (pallidum, ventral anterior thalamus, posterior caudate). The overall pattern suggests that OCD-related brain dysfunction involves increased affective and self-referential processing, enhanced habitual responding and blunted cognitive control.

Early-life metal exposure and schizophrenia: A proof-of-concept study using novel tooth-matrix biomarkers.

BACKGROUND: Despite evidence for the effects of metals on neurodevelopment, the long-term effects on mental health remain unclear due to methodological limitations. Our objective was to determine the feasibility of studying metal exposure during critical neurodevelopmental periods and to explore the association between early-life metal exposure and adult schizophrenia. METHODS: We analyzed childhood-shed teeth from nine individuals with schizophrenia and five healthy controls. We investigated the association between exposure to lead (Pb(2+)), manganese (Mn(2+)), cadmium (Cd(2+)), copper (Cu(2+)), magnesium (Mg(2+)), and zinc (Zn(2+)), and schizophrenia, psychotic experiences, and intelligence quotient (IQ). We reconstructed the dose and timing of early-life metal exposures using laser ablation inductively coupled plasma mass spectrometry. RESULTS: We found higher early-life Pb(2+) exposure among patients with schizophrenia than controls. The differences in log Mn(2+) and log Cu(2+) changed relatively linearly over time to postnatal negative values. There was a positive correlation between early-life Pb(2+) levels and psychotic experiences in adulthood. Moreover, we found a negative correlation between Pb(2+) levels and adult IQ. CONCLUSIONS: In our proof-of-concept study, using tooth-matrix biomarker that provides direct measurement of exposure in the fetus and newborn, we provide support for the role of metal exposure during critical neurodevelopmental periods in psychosis.

Subcortical volumetric abnormalities in bipolar disorder.

Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case-control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen's d=-0.232; P=3.50 × 10-7) and thalamus (d=-0.148; P=4.27 × 10-3) and enlarged lateral ventricles (d=-0.260; P=3.93 × 10-5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

Connectomic markers of disease expression, genetic risk and resilience in bipolar disorder.

Bipolar disorder (BD) is characterized by emotional dysregulation and cognitive deficits associated with abnormal connectivity between subcortical-primarily emotional processing regions-and prefrontal regulatory areas. Given the significant contribution of genetic factors to BD, studies in unaffected first-degree relatives can identify neural mechanisms of genetic risk but also resilience, thus paving the way for preventive interventions. Dynamic causal modeling (DCM) and random-effects Bayesian model selection were used to define and assess connectomic phenotypes linked to facial affect processing and working memory in a demographically matched sample of first-degree relatives carefully selected for resilience (n=25), euthymic patients with BD (n=41) and unrelated healthy controls (n=46). During facial affect processing, patients and relatives showed similarly increased frontolimbic connectivity; resilient relatives, however, evidenced additional adaptive hyperconnectivity within the ventral visual stream. During working memory processing, patients displayed widespread hypoconnectivity within the corresponding network. In contrast, working memory network connectivity in resilient relatives was comparable to that of controls. Our results indicate that frontolimbic dysfunction during affect processing could represent a marker of genetic risk to BD, and diffuse hypoconnectivity within the working memory network a marker of disease expression. The association of hyperconnectivity within the affect-processing network with resilience to BD suggests adaptive plasticity that allows for compensatory changes and encourages further investigation of this phenotype in genetic and early intervention studies.

Increased affective reactivity to neutral stimuli and decreased maintenance of affective responses in bipolar disorder.

BACKGROUND: Affective dysregulation is a core feature of bipolar disorder (BD) and a significant predictor of clinical and functional outcome. Affective dysregulation can arise from abnormalities in multiple processes. This study addresses the knowledge gap regarding the precise nature of the processes that may be dysregulated in BD and their relationship to the clinical expression of the disorder. METHODS: Patients with BD (n=45) who were either in remission or in a depressive or manic state and healthy individuals (n=101) were compared in terms of the intensity, duration and physiological response (measured using inter-beat intervals and skin conductance) to affective and neutral pictures during passive viewing and during experiential suppression. RESULTS: Compared to healthy individuals, patients with BD evidenced increased affective reactivity to neutral pictures and reduced maintenance of subjective affective responses to all pictures. This pattern was present irrespective of clinical state but was more pronounced in symptomatic patients, regardless of polarity. Patients, regardless of symptomatic status, were comparable to healthy individuals in terms of physiological arousal and voluntary control of affective responses. CONCLUSION: Our study demonstrates that increased affective reactivity to neutral stimuli and decreased maintenance of affective responses are key dimensions of affective dysregulation in BD.

Is avolition in schizophrenia associated with a deficit of dorsal caudate activity? A functional magnetic resonance imaging study during reward anticipation and feedback.

BACKGROUND: The neurobiological underpinnings of avolition in schizophrenia remain unclear. Most brain imaging research has focused on reward prediction deficit and on ventral striatum dysfunction, but findings are not consistent. In the light of accumulating evidence that both ventral striatum and dorsal caudate play a key role in motivation, we investigated ventral striatum and dorsal caudate activation during processing of reward or loss in patients with schizophrenia. METHOD: We used functional magnetic resonance imaging to study brain activation during a Monetary Incentive Delay task in patients with schizophrenia, treated with second-generation antipsychotics only, and in healthy controls (HC). We also assessed the relationships of ventral striatum and dorsal caudate activation with measures of hedonic experience and motivation. RESULTS: The whole patient group had lower motivation but comparable hedonic experience and striatal activation than HC. Patients with high avolition scores showed lower dorsal caudate activation than both HC and patients with low avolition scores. A lower dorsal caudate activation was also observed in patients with deficit schizophrenia compared to HC and patients with non-deficit schizophrenia. Dorsal caudate activity during reward anticipation was significantly associated with avolition, but not with anhedonia in the patient group. CONCLUSIONS: These findings suggest that avolition in schizophrenia is linked to dorsal caudate hypoactivation.

Empirical evidence for discrete neurocognitive subgroups in bipolar disorder: clinical implications.

BACKGROUND: Recent data suggest trait-like neurocognitive impairments in bipolar disorder (BPD), with deficits about 1 s.d. below average, less severe than deficits noted in schizophrenia. The frequency of significant impairment in BPD is approximately 60%, with 40% of patients characterized as cognitively spared. This contrasts with a more homogeneous presentation in schizophrenia. It is not understood why some BPD patients develop deficits while others do not. METHOD: A total of 136 patients with BPD completed the MATRICS Consensus Cognitive Battery and data were entered into hierarchical cluster analyses to: (1) determine the optimal number of clusters (subgroups) that fit the sample; and (2) assign subjects to a specific cluster based on individual profiles. We then compared subgroups on several clinical factors and real-world community functioning. RESULTS: Three distinct neurocognitive subgroups were found: (1) an intact group with performance comparable with healthy controls on all domains but with superior social cognition; (2) a selective impairment group with moderate deficits on processing speed, attention, verbal learning and social cognition and normal functioning in other domains; and (3) a global impairment group with severe deficits across all cognitive domains comparable with deficits in schizophrenia. CONCLUSIONS: These results suggest the presence of multiple cognitive subgroups in BPD with unique profiles and begin to address the relationships between these subgroups, several clinical factors and functional outcome. Next steps will include using these data to help guide future efforts to target these disabling symptoms with treatment.

Staging systems in bipolar disorder: an International Society for Bipolar Disorders Task Force Report.

OBJECTIVE: We discuss the rationale behind staging systems described specifically for bipolar disorders. Current applications, future directions and research gaps in clinical staging models for bipolar disorders are outlined. METHOD: We reviewed the literature pertaining to bipolar disorders, focusing on the first episode onwards. We systematically searched data on staging models for bipolar disorders and allied studies that could inform the concept of staging. RESULTS: We report on several dimensions that are relevant to staging concepts in bipolar disorder. We consider whether staging offers a refinement to current diagnoses by reviewing clinical studies of treatment and functioning and the potential utility of neurocognitive, neuroimaging and peripheral biomarkers. CONCLUSION: Most studies to date indicate that globally defined late-stage patients have a worse overall prognosis and poorer response to standard treatment, consistent with patterns for end-stage medical disorders. We believe it is possible at this juncture to speak broadly of 'early'- and 'late'-stage bipolar disorder. Next steps require further collaborative efforts to consider the details of preillness onset and intermediary stages, and how many additional stages are optimal.

Systematic review of the efficacy and tolerability of clozapine in the treatment of youth with early onset schizophrenia.

BACKGROUND: The use of clozapine (CLZ) for treatment-resistant schizophrenia is well established in adults. However, it is seldom used in youth with early onset schizophrenia (EOS) largely because of lack of clarity about its risk benefit ratio. This review synthesises and evaluates available evidence regarding the efficacy and tolerability of CLZ in EOS with the aim to assist clinical decision-making. METHODS: We conducted a systematic review of the primary literature on the clinical efficacy and adverse drug reactions (ADRs) observed during CLZ treatment in EOS. We also identified relevant practice guidelines and summarised current guidance. RESULTS: CLZ showed superior efficacy than other antipsychotics in treating refractory EOS patients; short-term clinical trials suggest an average improvement of 69% on the Brief Psychiatric Rating Scale that was sustained during long-term follow-up (up to 9 years). No fatalities linked to CLZ treatment were reported. Sedation and hypersalivation were the most common complaints, reported by over 90% of patients. Other common ADRs (reported in 10-60% of patients) were enuresis, constipation, weight gain, and non-specific EEG changes. Less common ADRs (reported in 10-30% of patients) were akathisia, tachycardia and changes in blood pressure. Neutropenia was reported in 6-15% of cases but was usually transient while agranulocytosis was rare (<0.1%). Seizures were also uncommon (<3%). Metabolic changes were relatively common (8-22%) but emergent diabetes was not frequently observed (<6%). Overall the rate of discontinuation was low (3-6%). Current guidelines recommend the use of CLZ in EOS patients who have failed to respond to two adequate trials with different antipsychotics and provide detailed schedules of assessments to evaluate and assess potential ADRs both prior to initiation and throughout CLZ treatment. CONCLUSION: Available data although limited in terms of number of studies are consistent in demonstrating that CLZ is effective and generally safe in the treatment of refractory EOS provided patients are regularly monitored.

Examination of the predictive value of structural magnetic resonance scans in bipolar disorder: a pattern classification approach.

BACKGROUND: Bipolar disorder (BD) is one of the leading causes of disability worldwide. Patients are further disadvantaged by delays in accurate diagnosis ranging between 5 and 10 years. We applied Gaussian process classifiers (GPCs) to structural magnetic resonance imaging (sMRI) data to evaluate the feasibility of using pattern recognition techniques for the diagnostic classification of patients with BD. METHOD: GPCs were applied to gray (GM) and white matter (WM) sMRI data derived from two independent samples of patients with BD (cohort 1: n = 26; cohort 2: n = 14). Within each cohort patients were matched on age, sex and IQ to an equal number of healthy controls. RESULTS: The diagnostic accuracy of the GPC for GM was 73% in cohort 1 and 72% in cohort 2; the sensitivity and specificity of the GM classification were respectively 69% and 77% in cohort 1 and 64% and 99% in cohort 2. The diagnostic accuracy of the GPC for WM was 69% in cohort 1 and 78% in cohort 2; the sensitivity and specificity of the WM classification were both 69% in cohort 1 and 71% and 86% respectively in cohort 2. In both samples, GM and WM clusters discriminating between patients and controls were localized within cortical and subcortical structures implicated in BD. CONCLUSIONS: Our results demonstrate the predictive value of neuroanatomical data in discriminating patients with BD from healthy individuals. The overlap between discriminative networks and regions implicated in the pathophysiology of BD supports the biological plausibility of the classifiers.

Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta-analysis.

OBJECTIVE: An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and previous meta-analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view. METHOD: Individual patient and control data were obtained from original authors for 11 measures from four common neuropsychological tests: California or Rey Verbal Learning Task (VLT), Trail Making Test (TMT), Digit Span and/or Wisconsin Card Sorting Task. RESULTS: Impairments were found for all 11 test-measures in the bipolar group after controlling for age, IQ and gender (Ps ≤ 0.001, E.S. = 0.26-0.63). Residual mood symptoms confound this result but cannot account for the effect sizes found. Impairments also seem unrelated to drug treatment. Some test-measures were weakly correlated with illness severity measures suggesting that some impairments may track illness progression. CONCLUSION: This reanalysis supports VLT, Digit Span and TMT as robust measures of cognitive impairments in bipolar disorder patients. The heterogeneity of some test results explains previous differences in meta-analyses. Better controlling for confounds suggests deficits may be smaller than previously reported but should be tracked longitudinally across illness progression and treatment.

Evidence of diagnostic specificity in the neural correlates of facial affect processing in bipolar disorder and schizophrenia: a meta-analysis of functional imaging studies.

BACKGROUND: Schizophrenia (SZ) and bipolar disorder (BD) may overlap in etiology and phenomenology but differ with regard to emotional processing. We used facial affect as a probe for emotional processing to determine whether there are diagnosis-related differences between SZ and BD in the function of the underlying neural circuitry. METHOD: Functional magnetic resonance imaging (fMRI) studies published up to 30 April 2012 investigating facial affect processing in patients with SZ or BD were identified through computerized and manual literature searches. Activation foci from 29 studies encompassing 483 healthy individuals, 268 patients with SZ and 267 patients with BD were subjected to voxel-based quantitative meta-analysis using activation likelihood estimation (ALE). RESULTS: Compared to healthy individuals, when emotional facial stimuli were contrasted to neutral stimuli, patients with BD showed overactivation within the parahippocampus/amygdala and thalamus and reduced engagement within the ventrolateral prefrontal cortex (PFC) whereas patients with SZ showed underactivation throughout the entire facial affect processing network and increased activation in visual processing regions within the cuneus. Patients with BD showed greater thalamic engagement compared to patients with SZ; in the reverse comparison, patients with SZ showed greater engagement in posterior associative visual cortices. CONCLUSIONS: During facial affect processing, patients with BD show overactivation in subcortical regions and underactivation in prefrontal regions of the facial affect processing network, consistent with the notion of reduced emotional regulation. By contrast, overactivation within visual processing regions coupled with reduced engagement of facial affect processing regions points to abnormal visual integration as the core underlying deficit in SZ.

Increased salience of gains versus decreased associative learning differentiate bipolar disorder from schizophrenia during incentive decision making.

BACKGROUND: Abnormalities in incentive decision making, typically assessed using the Iowa Gambling Task (IGT), have been reported in both schizophrenia (SZ) and bipolar disorder (BD). We applied the Expectancy-Valence (E-V) model to determine whether motivational, cognitive and response selection component processes of IGT performance are differentially affected in SZ and BD. METHOD: Performance on the IGT was assessed in 280 individuals comprising 70 remitted patients with SZ, 70 remitted patients with BD and 140 age-, sex- and IQ-matched healthy individuals. Based on the E-V model, we extracted three parameters, 'attention to gains or loses', 'expectancy learning' and 'response consistency', that respectively reflect motivational, cognitive and response selection influences on IGT performance. RESULTS: Both patient groups underperformed in the IGT compared to healthy individuals. However, the source of these deficits was diagnosis specific. Associative learning underlying the representation of expectancies was disrupted in SZ whereas BD was associated with increased incentive salience of gains. These findings were not attributable to non-specific effects of sex, IQ, psychopathology or medication. CONCLUSIONS: Our results point to dissociable processes underlying abnormal incentive decision making in BD and SZ that could potentially be mapped to different neural circuits.

Cross-cultural standardization of the South Texas Assessment of Neurocognition in India.

BACKGROUND & OBJECTIVES: Despite the central role of cognition for mental disorders most studies have been conducted in western countries. Similar research from other parts of the world, particularly India, is very limited. As a first step in closing this gap this cross-cultural comparability study of the South Texas Assessment of Neurocognition (STAN) battery was conducted between USA and India. METHODS: One hundred healthy adults from Kerala, India, were administered six language independent subtests of the Java Neuropsychological Test (JANET) version of the STAN, assessing aspects of general intellectual ability (Matrix Reasoning), attention (Identical Pairs Continuous Performance, 3 Symbol Version Test; IPCPTS), working memory (Spatial Capacity Delayed Response Test; SCAP), response inhibition (Stop Signal Reaction Time; SSRT), Emotional Recognition and Risk taking (Balloon Analogue Risk Task; BART). Test results were compared to a demographically matched US sample. RESULTS: Overall test performance in the Kerala sample was comparable to that of the US sample and commensurate to that generally described in studies from western countries. INTERPRETATION & CONCLUSIONS: Our results support the metric equivalence of currently available cognitive test batteries developed in western countries for use in India. However, the sample was restricted to individuals who were literate and had completed basic primary and secondary education.

Abnormal intrinsic and extrinsic connectivity within the magnetic mismatch negativity brain network in schizophrenia: a preliminary study.

Altered neuroplasticity is increasingly invoked as a mechanism underpinning dysconnectivity in schizophrenia. We used Dynamic Causal Modelling to compare connectivity during the magnetic auditory Mismatch Negativity (MMN), an index of error prediction, between schizophrenia patients and controls. Patients showed reduced intrinsic connectivity within the primary auditory cortex suggestive of impaired local neuronal adaptation and disrupted forward and backward extrinsic connectivity throughout the MMN network indicative of reduced higher order input in disambiguating activity in lower network nodes. Our study provides the first empirical description of the dysplastic changes underpinning dysconnectivity between primary sensory and higher order cortical areas in schizophrenia.

Initial evidence for the role of CACNA1C on subcortical brain morphology in patients with bipolar disorder.

BACKGROUND: The polymorphism rs1006737 within the CACNA1C gene is associated with increased risk for bipolar disorder (BD) and variations in brain morphology and function of subcortical regions. Here we sought to investigate the influence of CACNA1C polymorphism on key subcortical brain structures implicated in the pathophysiology of BD. METHODS: Structural magnetic resonance imaging scans were acquired from 41 euthymic patients with BD and 40 healthy controls, who were also genotyped for the CACNA1C rs1006737 polymorphism. The effect of diagnosis, genotype and their interaction was examined in predefined volumes of interest in the basal ganglia, hypothalamus and amygdala extracted using SPM5. RESULTS: Carriers of the CACNA1C rs1006737 risk allele showed increased grey matter density in the right amygdala and right hypothalamus irrespective of diagnosis. An interaction between genotype and diagnosis was observed in the left putamen which was smaller in BD patients carrying the risk allele than in healthy controls. CONCLUSIONS: The CACNA1C rs1006737 polymorphism influences anatomical variation within subcortical regions involved in emotional processing.

The impact of the Val158Met catechol-O-methyltransferase genotype on neural correlates of sad facial affect processing in patients with bipolar disorder and their relatives.

BACKGROUND: The Met allele of the catechol-O-methyltransferase (COMT) valine-to-methionine (Val158Met) polymorphism is known to affect dopamine-dependent affective regulation within amygdala-prefrontal cortical (PFC) networks. It is also thought to increase the risk of a number of disorders characterized by affective morbidity including bipolar disorder (BD), major depressive disorder (MDD) and anxiety disorders. The disease risk conferred is small, suggesting that this polymorphism represents a modifier locus. Therefore our aim was to investigate how the COMT Val158Met may contribute to phenotypic variation in clinical diagnosis using sad facial affect processing as a probe for its neural action. METHOD: We employed functional magnetic resonance imaging to measure activation in the amygdala, ventromedial PFC (vmPFC) and ventrolateral PFC (vlPFC) during sad facial affect processing in family members with BD (n=40), MDD and anxiety disorders (n=22) or no psychiatric diagnosis (n=25) and 50 healthy controls. RESULTS: Irrespective of clinical phenotype, the Val158 allele was associated with greater amygdala activation and the Met158 allele with greater signal change in the vmPFC and vlPFC. Signal changes in the amygdala and vmPFC were not associated with disease expression. However, in the right vlPFC the Met158 allele was associated with greater activation in all family members with affective morbidity compared with relatives without a psychiatric diagnosis and healthy controls. CONCLUSIONS: Our results suggest that the COMT Val158Met polymorphism has a pleiotropic effect within the neural networks subserving emotional processing. Furthermore the Met158 allele further reduces cortical efficiency in the vlPFC in individuals with affective morbidity.