Julia M. Sheffield

Cognitive impairments in psychotic disorders: common mechanisms and measurement.

Decades of research have provided robust evidence of cognitive impairments in psychotic disorders. Individuals with schizophrenia appear to be impaired on the majority of neuropsychological tasks, leading some researchers to argue for a “generalized deficit”, in which the multitude of cognitive impairments are the result of a common neurobiological source. One such common mechanism may be an inability to actively represent goal information in working memory as a means to guide behavior, with the associated neurobiological impairment being a disturbance in the function of the dorsolateral prefrontal cortex. Here, we provide a discussion of the evidence for such impairment in schizophrenia, and how it manifests in domains typically referred to as cognitive control, working memory and episodic memory. We also briefly discuss cognitive impairment in affective psychoses, reporting that the degree of impairment is worse in schizophrenia than in bipolar disorder and psychotic major depression, but the profile of impairment is similar, possibly reflecting common mechanisms at the neural level. Given the recent release of the DSM‐5, we end with a brief discussion on assessing cognition in the context of diagnosis and treatment planning in psychotic disorders.

Reduced gray matter volume in psychotic disorder patients with a history of childhood sexual abuse.

Childhood trauma is associated with smaller gray matter volume, similar to the pattern seen in psychotic disorders. We explored the relationship between childhood abuse, psychosis, and brain volume in a group of 60 individuals with a psychotic disorder and 26 healthy control subjects. We used voxel-based morphometry (VBM) to quantify gray and white matter volume and the Childhood Trauma Questionnaire (CTQ) to measure childhood abuse. Within the psychotic disorder group, total gray matter volume was inversely correlated with the severity of childhood sexual abuse (r=-.34, p=.008), but not the other types of abuse. When the 24 patients with sexual abuse were compared with demographically matched samples of 23 patients without sexual abuse and 26 control subjects, only patients with a history of sexual abuse had reduced total gray matter volume (t(48)=2.3, p=.03; Cohens d=.63). Voxel-based analysis revealed a cluster in the prefrontal cortex where volume was negatively correlated with sexual abuse severity. Voxel based comparison of the three matched groups revealed a similar pattern of results, with widespread reductions in psychosis patients with sexual abuse relative to controls that were not found in psychosis patients without sexual abuse. These findings indicate that some of the variance of gray matter volume in psychotic disorders can be explained by a history of sexual abuse.

Fronto-parietal and cingulo-opercular network integrity and cognition in health and schizophrenia

Growing evidence suggests that coordinated activity within specific functional brain networks supports cognitive ability, and that abnormalities in brain connectivity may underlie cognitive deficits observed in neuropsychiatric diseases, such as schizophrenia. Two functional networks, the fronto-parietal network (FPN) and cingulo-opercular network (CON), are hypothesized to support top-down control of executive functioning, and have therefore emerged as potential drivers of cognitive impairment in disease-states. Graph theoretic analyses of functional connectivity data can characterize network topology, allowing the relationships between cognitive ability and network integrity to be examined. In the current study we applied graph analysis to pseudo-resting state data in 54 healthy subjects and 46 schizophrenia patients, and measured overall cognitive ability as the shared variance in performance from tasks of episodic memory, verbal memory, processing speed, goal maintenance, and visual integration. We found that, across all participants, cognitive ability was significantly positively associated with the local and global efficiency of the whole brain, FPN, and CON, but not with the efficiency of a comparison network, the auditory network. Additionally, the participation coefficient of the right anterior insula, a major hub within the CON, significantly predicted cognition, and this relationship was independent of CON global efficiency. Surprisingly, we did not observe strong evidence for group differences in any of our network metrics. These data suggest that functionally efficient task control networks support better cognitive ability in both health and schizophrenia, and that the right anterior insula may be a particularly important hub for successful cognitive performance across both health and disease.

Common and specific cognitive deficits in schizophrenia: relationships to function

The goals of the present study were to assess the interrelationships among tasks from the MATRICS and CNTRACS batteries, to determine the degree to which tasks from each battery capture unique variance in cognitive dysfunction in schizophrenia, and to determine the ability of tasks from each battery to predict functional outcome. Subjects were 104 schizophrenia patients and 132 healthy control subjects recruited as part of the CNTRACS initiative. All subjects completed four CNTRACS tasks and two tasks from the MATRICS battery: Brief Assessment of Cognition in Schizophrenia Symbol Coding and the Hopkins Verbal Learning Test. Functional outcome was also assessed in the schizophrenia subjects. In both the patient and control groups, we found significant intercorrelations between all higher order cognitive tasks (episodic memory, goal maintenance, processing speed, verbal learning) but minimal relationships with the visual task. For almost all tasks, scores were significantly related to measures of functional outcome, with higher associations between CNTRACS tasks and performance-based measures of function and between one of the MATRICS tasks and self-reported functioning, relative to the other functioning measures. After regressing out variance shared by other tasks, we continued to observe group differences in performance among task residuals, particularly for measures of episodic memory from both batteries, although these residuals did not correlate as robustly with functional outcome as raw test scores. These findings suggest that there exists both shared and specific variance across cognitive tasks related to cognitive and functional impairments in schizophrenia and that measures derived from cognitive neuroscience can predict functional capacity and status in schizophrenia.

Childhood sexual abuse increases risk of auditory hallucinations in psychotic disorders

BACKGROUND/AIMS Previous studies point to an association between childhood sexual abuse (CSA) and auditory hallucinations (AH). However, methodological issues limit the strength of these results. Here we compared childhood abuse between psychotic disorder patients and healthy control subjects using a reliable measure of abuse, and assessed the relationship between CSA and AH. METHODS 114 psychotic disorder patients and 81 healthy control subjects were administered the Structured Clinical Interview of the DSM-IV (SCID) and the Childhood Trauma Questionnaire (CTQ). We compared the severity of abuse between groups, and tested the relationship between different types of childhood abuse and specific psychotic symptoms. RESULTS Psychotic patients reported more childhood abuse than controls (p<.001). Psychotic patients with a history of AH reported significantly more sexual, emotional, and physical abuse than patients without a history of AH (p<.05). Emotional and physical abuse, in the absence of sexual abuse, did not lead to a higher rate of AH. Finally, reports of childhood abuse did not increase the risk of any form of hallucination other than AH or of any form of delusion. CONCLUSIONS These results suggest that childhood abuse, especially childhood sexual abuse, shapes the phenotype of psychotic disorders by conferring a specific risk for AH.

Transdiagnostic Associations Between Functional Brain Network Integrity and Cognition

Importance Cognitive impairment occurs across the psychosis spectrum and is associated with functional outcome. However, it is unknown whether these shared manifestations of cognitive dysfunction across diagnostic categories also reflect shared neurobiological mechanisms or whether the source of impairment differs. Objective To examine whether the general cognitive deficit observed across psychotic disorders is similarly associated with functional integrity of 2 brain networks widely implicated in supporting many cognitive domains. Design, Setting, and Participants A total of 201 healthy control participants and 375 patients with psychotic disorders from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium were studied from September 29, 2007, to May 31, 2011. The B-SNIP recruited healthy controls and stable outpatients from 6 sites: Baltimore, Maryland; Boston, Massachusetts; Chicago, Illinois; Dallas, Texas; Detroit, Michigan; and Hartford, Connecticut. All participants underwent cognitive testing and resting-state functional magnetic resonance imaging. Data analysis was performed from April 28, 2015, to February 21, 2017. Main Outcomes and Measures The Brief Assessment of Cognition in Schizophrenia was used to measure cognitive ability. A principal axis factor analysis on the Brief Assessment of Cognition in Schizophrenia battery yielded a single factor (54% variance explained) that served as the measure of general cognitive ability. Functional network integrity measures included global and local efficiency of the whole brain, cingulo-opercular network (CON), frontoparietal network, and auditory network and exploratory analyses of all networks from the Power atlas. Group differences in network measures, associations between cognition and network measures, and mediation models were tested. Results The final sample for the current study included 201 healthy controls, 143 patients with schizophrenia, 103 patients with schizoaffective disorder, and 129 patients with psychotic bipolar disorder (mean [SD] age, 35.1 [12.0] years; 281 male [48.8%] and 295 female [51.2%]; 181 white [31.4%], 348 black [60.4%], and 47 other [8.2%]). Patients with schizophrenia (Cohen d = 0.36, P < .001) and psychotic bipolar disorder (Cohen d = 0.33, P = .002) had significantly reduced CON global efficiency compared with healthy controls. All patients with psychotic disorders had significantly reduced CON local efficiency, but the clinical groups did not differ from one another. The CON global efficiency was significantly associated with general cognitive ability across all groups (&bgr; = 0.099, P = .009) and significantly mediated the association between psychotic disorder status and general cognition (&bgr; = −0.037; 95% CI, −0.076 to −0.014). Subcortical network global efficiency was also significantly reduced in psychotic disorders (F3,587 = 4.01, P = .008) and positively predicted cognitive ability (&bgr; = 0.094, P = .009). Conclusions and Relevance These findings provide evidence that reduced CON and subcortical network efficiency play a role in the general cognitive deficit observed across the psychosis spectrum. They provide new support for the dimensional hypothesis that a shared neurobiological mechanism underlies cognitive impairment in psychotic disorders.

Evidence for Accelerated Decline of Functional Brain Network Efficiency in Schizophrenia

Previous work suggests that individuals with schizophrenia display accelerated aging of white matter integrity, however, it is still unknown whether functional brain networks also decline at an elevated rate in schizophrenia. Given the known degradation of functional connectivity and the normal decline in cognitive functioning throughout healthy aging, we aimed to test the hypothesis that efficiency of large-scale functional brain networks supporting overall cognition, as well as integrity of hub nodes within those networks, show evidence of accelerated aging in schizophrenia. Using pseudo-resting state data in 54 healthy controls and 46 schizophrenia patients, in which task-dependent signal from 3 tasks was regressed out to approximate resting-state data, we observed a significant diagnosis by age interaction in the prediction of both global and local efficiency of the cingulo-opercular network, and of the local efficiency of the fronto-parietal network, but no interaction when predicting both default mode network and whole brain efficiency. We also observed a significant diagnosis by age interaction for the node degree of the right anterior insula, left dorsolateral prefrontal cortex, and dorsal anterior cingulate cortex. All interactions were driven by stronger negative associations between age and network metrics in the schizophrenia group than the healthy controls. These data provide evidence that is consistent with accelerated aging of large-scale functional brain networks in schizophrenia that support higher-order cognitive ability.

The WERCAP Screen and the WERC Stress Screen: psychometrics of self-rated instruments for assessing bipolar and psychotic disorder risk and perceived stress burden

BACKGROUND Identification of individuals in the prodromal phase of bipolar disorder and schizophrenia facilitates early intervention and promises an improved prognosis. There are no current assessment tools for clinical risk symptoms of bipolar disorder, and psychosis-risk assessment generally involves semi-structured interviews, which are time consuming and rater dependent. We present psychometric data on two novel quantitative questionnaires: the Washington Early Recognition Center Affectivity and Psychosis (WERCAP) Screen for assessing bipolar and psychotic disorder risk traits, and the accompanying WERC Stress Screen for assessing individual and total psychosocial stressor severities. METHODS Prevalence rates of the WERCAP Screen were evaluated among 171 community youth (aged 13-24 years); internal consistency was assessed and k-means cluster analysis was used to identify symptom groups. In 33 participants, test-retest reliability coefficients were assessed, and ROC curve analysis was used to determine the validity of the psychosis section of the WERCAP Screen (pWERCAP) against the Structured Interview of Psychosis-Risk Symptoms (SIPS). Correlations of the pWERCAP, the affectivity section of the WERCAP Screen (aWERCAP) and the WERC Stress Screen were examined to determine the relatedness of scores with cognition and clinical measures. RESULTS Cluster analysis identified three groups of participants: a normative (47%), a psychosis-affectivity (18%) and an affectivity only (35%) group. Internal consistency of the aWERCAP and pWERCAP resulted in alphas of 0.87 and 0.92, and test-retest reliabilities resulted in intraclass correlation coefficients of 0.76 and 0.86 respectively. ROC curve analysis showed the optimal cut-point on the pWERCAP as a score of >30 (sensitivity: 0.89; specificity: 1.0). There was a significant negative correlation between aWERCAP scores and total cognition (R=-0.42), and between pWERCAP scores and sensorimotor processing speed. Total stress scores correlated significantly with scores on the aWERCAP (R=0.88), pWERCAP (R=0.62) and total cognition (R=-0.44). CONCLUSIONS Our results show that the WERCAP Screen and the WERC Stress Screen are easy to administer and derived scores are related to cognitive and clinical traits. This suggests that their use could have particular benefits for epidemiologic studies and in busy clinical settings. Longitudinal studies would be required to evaluate clinical outcomes with high questionnaire scores.

Systematic Error in Hippocampal Volume Asymmetry Measurement is Minimal with a Manual Segmentation Protocol.

Hemispheric asymmetry of hippocampal volume is a common finding that has biological relevance, including associations with dementia and cognitive performance. However, a recent study has reported the possibility of systematic error in measurements of hippocampal asymmetry by magnetic resonance volumetry. We manually traced the volumes of the anterior and posterior hippocampus in 40 healthy people to measure systematic error related to image orientation. We found a bias due to the side of the screen on which the hippocampus was viewed, such that hippocampal volume was larger when traced on the left side of the screen than when traced on the right (p = 0.05). However, this bias was smaller than the anatomical right > left asymmetry of the anterior hippocampus. We found right > left asymmetry of hippocampal volume regardless of image presentation (radiological versus neurological). We conclude that manual segmentation protocols can minimize the effect of image orientation in the study of hippocampal volume asymmetry, but our confirmation that such bias exists suggests strategies to avoid it in future studies.

Rapid instruction-based task learning (RITL) in schizophrenia.

Individuals with schizophrenia demonstrate broad impairments in neurocognitive functioning as measured through laboratory-based tasks. Neuropsychological measures depend on rapid instruction-based task learning (RITL), the ability to rapidly translate task instruction into goal-directed behavior. Here, the authors present the first known investigation of RITL in schizophrenia and aim to test whether RITL deficits exist in schizophrenia, are associated with abnormal brain activation, and contribute to the generalized cognitive deficit. Twenty-nine schizophrenia participants and 31 healthy controls completed a previously established RITL task while in a functional magnetic resonance imaging (fMRI) scanner and completed a brief assessment of general cognition outside the scanner. Patients were significantly impaired in RITL accuracy and reaction time (RT). Compared to controls, patients had reduced activation of the caudate and left inferior frontal junction (LIFJ) while viewing task instructions, and across all subjects, lower activation in these regions was associated with worse RITL performance. During practice trials, activation in the anterior insula, LIFJ, and middle frontal gyrus also related to performance. RITL ability was robustly associated with general cognitive ability, explained a significant proportion of the variance in the generalized cognitive deficit, and was associated with LIFJ activity during RITL instructions. These results indicate that the ability to rapidly learn task instructions is impaired in schizophrenia and associated with abnormal activation of the caudate and LIFJ. Abnormalities in RITL represent a critical cognitive facet for understanding the broad profile of cognitive deficits in schizophrenia.