Carrie E. Bearden

Beyond hypofrontality: A quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia

Although there is considerable evidence that patients with schizophrenia fail to activate the dorsolateral prefrontal cortex (DLPFC) to the degree seen in normal comparison subjects when performing working memory or executive tasks, hypofrontality may be coupled with relatively increased activity in other brain regions. However, most imaging studies of working memory in schizophrenia have focused on DLPFC activity. The goal of this work is to review functional neuroimaging studies that contrasted patients with schizophrenia and healthy comparison subjects during a prototypical working memory task, the n‐back paradigm, to highlight areas of hyper‐ and hypoactivation in schizophrenia. We utilize a quantitative meta‐analysis method to review 12 imaging studies where patients with schizophrenia were contrasted with healthy comparison subjects while performing the n‐back paradigm. Although we find clear support for hypofrontality, we also document consistently increased activation in anterior cingulate and left frontal pole regions in patients with schizophrenia compared to that in controls. These data suggest that whereas reduced DLPFC activation is reported consistently in patients with schizophrenia relative to healthy subjects, abnormal activation patterns are not restricted to this region, raising questions as to whether the pathophysiological dysfunction in schizophrenia is specific to the DLPFC and about the relationship between impaired performance and aberrant activation patterns. The complex pattern of hyper‐ and hypoactivation consistently found across studies implies that rather than focusing on DLPFC dysregulation, researchers should consider the entire network of regions involved in a given task when making inferences about the biological mechanisms of schizophrenia. Hum Brain Mapp 25:60–69, 2005.

Diffusion Tensor Imaging of the Superior Longitudinal Fasciculus and Working Memory in Recent-Onset Schizophrenia

BACKGROUND Structural and functional abnormalities in frontal-parietal circuitry are thought to be associated with working memory (WM) deficits in patients with schizophrenia. This study examines whether recent-onset schizophrenia is associated with anatomical changes in the superior longitudinal fasciculus (SLF), the main frontal-parietal white matter connection, and whether the integrity of the SLF is related to WM performance. METHODS We applied a novel registration approach (Tract-Based Spatial Statistics [TBSS]) to diffusion tensor imaging data to examine fractional anisotropy (FA) in the left and right SLF in 12 young adult patients with recent-onset schizophrenia and 17 matched control subjects. RESULTS Schizophrenia patients showed lower FA values than control subjects across the entire SLF, with particular deficits on the left SLF. Fractional anisotropy values were correlated with performance on a verbal WM task in both patient and control groups in the left but not right SLF. CONCLUSIONS Recent-onset schizophrenia patients show deficits in frontal-parietal connections, key components of WM circuitry. Moreover, the integrity of this physiological connection predicted performance on a verbal WM task, indicating that this structural change may have important functional implications. These findings support the view that schizophrenia is a disorder of brain connectivity and implicate white matter changes detectable in the early phases of the illness as one source of this dysfunction.

Social Cognition in Schizophrenia, Part 1: Performance Across Phase of Illness

Social cognitive impairments are consistently reported in schizophrenia and are associated with functional outcome. We currently know very little about whether these impairments are stable over the course of illness. In the current study, 3 different aspects of social cognition were assessed (emotion processing, Theory of Mind [ToM], and social relationship perception) at 3 distinct developmental phases of illness: prodromal, first episode, and chronic. In this cross-sectional study, participants included 50 individuals with the prodromal risk syndrome for psychosis and 34 demographically comparable controls, 81 first-episode schizophrenia patients and 46 demographically comparable controls, and 53 chronic schizophrenia patients and 47 demographically comparable controls. Outcome measures included total and subtest scores on 3 specialized measures of social cognition: (1) emotion processing assessed with the Mayer-Salovey-Caruso Emotional Intelligence Test, (2) ToM assessed with The Awareness of Social Inference Test, and (3) social relationship perception assessed the Relationships Across Domains Test. Social cognitive performance was impaired across all domains of social cognition and in all clinical samples. Group differences in performance were comparable across phase of illness, with no evidence of progression or improvement. Age had no significant effect on performance for either the clinical or the comparison groups. The findings suggest that social cognition in these 3 domains fits a stable pattern that has outcome and treatment implications. An accompanying article prospectively examines the longitudinal stability of social cognition and prediction of functional outcome in the first-episode sample.

Greater cortical gray matter density in lithium-treated patients with bipolar disorder.

BACKGROUND The neurobiological underpinnings of bipolar disorder are not well understood. Previous neuroimaging findings have been inconsistent; however, new methods for three-dimensional (3-D) computational image analysis may better characterize neuroanatomic changes than standard volumetric measures. METHODS We used high-resolution magnetic resonance imaging and cortical pattern matching methods to map gray matter differences in 28 adults with bipolar disorder, 70% of whom were lithium-treated (mean age = 36.1 +/- 10.5; 13 female subject), and 28 healthy control subjects (mean age = 35.9 +/- 8.5; 11 female subjects). Detailed spatial analyses of gray matter density (GMD) were conducted by measuring local proportions of gray matter at thousands of homologous cortical locations. RESULTS Gray matter density was significantly greater in bipolar patients relative to control subjects in diffuse cortical regions. Greatest differences were found in bilateral cingulate and paralimbic cortices, brain regions critical for attentional, motivational, and emotional modulation. Secondary region of interest (ROI) analyses indicated significantly greater GMD in the right anterior cingulate among lithium-treated bipolar patients (n = 20) relative to those not taking lithium (n = 8). CONCLUSIONS These brain maps are consistent with previous voxel-based morphometry reports of greater GMD in portions of the anterior limbic network in bipolar patients and suggest neurotrophic effects of lithium as a possible etiology of these neuroanatomic differences.

Neurocognitive performance and functional disability in the psychosis prodrome

OBJECTIVE This study evaluates the pattern of neuropsychological deficits and their association with clinical symptomatology and social functioning in individuals identified as ultra-high-risk (UHR) for psychosis. METHODS A sample of 45 UHR individuals was identified using the Structured Interview for Prodromal Syndromes (SIPS) from consecutive referrals to the Staglin Music Festival Center for the Assessment and Prevention of Prodromal States (CAPPS) at UCLA. Participants were administered a neurocognitive test battery, as well as measures of global (Strauss-Carpenter Outcome Scale) and social functioning (UCLA Social Attainment Survey). RESULTS Participants showed significant deficits in speed of processing, verbal learning and memory, and motor speed. Poorer verbal learning and memory performance was significantly associated with poorer social functioning, and there was a trend for poorer performance on reasoning and problem solving to be associated with poorer global functioning. Verbal memory independently predicted social functioning over and above severity of negative symptoms. Cognitive deficits were not associated with severity of clinical symptomatology. CONCLUSIONS Despite the absence of fully psychotic symptoms, UHR individuals experience significant cognitive deficits, particularly on tasks requiring speeded information-processing and efficient recall from memory, and these deficits appear to be associated with functional disability in a manner parallel to that observed in patients with established psychotic illness.

The Neurocognitive Phenotype of the 22Q11.2 Deletion Syndrome: Selective Deficit in Visual-Spatial Memory

The 22q11.2 deletion syndrome (velocardiofacial/DiGeorge syndrome) is associated with a high frequency of learning disabilities. Although previous work has demonstrated that verbal skills are typically better preserved than non-verbal skills on both IQ and academic achievement testing in children with this syndrome, such measures are not sufficiently specific to determine a selective cognitive deficit. As part of an ongoing prospective study of patients with this syndrome, 29 children aged 517 with confirmed 22q11.2 deletions were assessed with a comprehensive neuropsychological test battery, including matched tasks of verbal and visuospatial memory. Results indicate that 22q patients displayed a selective deficit in visual-spatial memory, which was mirrored by deficits in arithmetic and general visual-spatial cognition. Further, a dissociation between visual-spatial and object memory was observed, indicating further selectivity of this pattern of deficit, and providing evidence for the dissociability of these components of visual cognition. These results indicate that children with 22q11.2 deletions display a specific neurocognitive phenotype, and suggest that this region of Chromosome 22q11 may harbor a gene or genes relevant to the etiology of nonverbal learning deficits.

The neurocognitive signature of psychotic bipolar disorder.

BACKGROUND Psychotic bipolar disorder may represent a neurobiologically distinct subgroup of bipolar affective illness. We sought to ascertain the profile of cognitive impairment in patients with bipolar disorder and to determine whether a distinct profile of cognitive deficits characterizes bipolar patients with a history of psychosis. METHODS Sixty-nine outpatients with bipolar I disorder (34 with a history of psychotic symptoms and 35 with no history of psychosis) and 35 healthy comparison subjects underwent a comprehensive neurocognitive battery. All three groups were demographically matched. RESULTS Despite preserved general intellectual function, bipolar I patients overall showed moderate impairments on tests of episodic memory and specific executive measures (average effect size = .58), and moderate to severe deficits on attentional and processing speed tasks (average effect size = .82). Bipolar I patients with a history of psychosis were impaired on measures of executive functioning and spatial working memory compared with bipolar patients without history of psychosis. CONCLUSIONS Psychotic bipolar disorder was associated with differential impairment on tasks requiring frontal/executive processing, suggesting that psychotic symptoms may have neural correlates that are at least partially independent of those associated with bipolar I disorder more generally. However, deficits in attention, psychomotor speed, and memory appear to be part of the broader disease phenotype in patients with bipolar disorder.

Progressive Reduction in Cortical Thickness as Psychosis Develops: A Multisite Longitudinal Neuroimaging Study of Youth at Elevated Clinical Risk

BACKGROUND Individuals at clinical high risk (CHR) who progress to fully psychotic symptoms have been observed to show a steeper rate of cortical gray matter reduction compared with individuals without symptomatic progression and with healthy control subjects. Whether such changes reflect processes associated with the pathophysiology of schizophrenia or exposure to antipsychotic drugs is unknown. METHODS In this multisite study, 274 CHR cases, including 35 individuals who converted to psychosis, and 135 healthy comparison subjects were scanned with magnetic resonance imaging at baseline, 12-month follow-up, or the point of conversion for the subjects who developed fully psychotic symptoms. RESULTS In a traveling subjects substudy, excellent reliability was observed for measures of cortical thickness and subcortical volumes. Controlling for multiple comparisons throughout the brain, CHR subjects who converted to psychosis showed a steeper rate of gray matter loss in the right superior frontal, middle frontal, and medial orbitofrontal cortical regions as well as a greater rate of expansion of the third ventricle compared with CHR subjects who did not convert to psychosis and healthy control subjects. Differential tissue loss was present in subjects who had not received antipsychotic medications during the interscan interval and was predicted by baseline levels of an aggregate measure of proinflammatory cytokines in plasma. CONCLUSIONS These findings demonstrate that the brain changes are not explained by exposure to antipsychotic drugs but likely play a role in psychosis pathophysiology. Given that the cortical changes were more pronounced in subjects with briefer durations of prodromal symptoms, contributing factors may predominantly play a role in acute-onset forms of psychosis.

White Matter Integrity and Prediction of Social and Role Functioning in Subjects at Ultra-High Risk for Psychosis

BACKGROUND White matter microstructural disruptions have been observed in patients with schizophrenia. However, whether changes exist prior to disease onset or in high-risk individuals is unclear. Here, we investigated white matter integrity, as assessed by diffusion tensor imaging (DTI), in individuals at ultra-high risk for psychosis (UHR) relative to healthy control subjects (HC) and the relationship between baseline DTI measures and functional outcome over time. METHODS Thirty-six UHR participants and 25 HCs completed baseline DTI scans. Subjects also completed clinical follow-up assessments approximately 6 months (26 subjects) and 15 months (13 subjects) later. We used a rigorous registration approach (Tract-Based Spatial Statistics [TBSS]) to examine fractional anisotropy (FA) in six major white matter tracts. RESULTS Relative to the HC group, UHR subjects showed lower baseline FA in the superior longitudinal fasciculus, the major frontoparietal white matter connection. Cross-sectional analyses demonstrated that UHR youth failed to show the same age-associated increases in FA in the medial temporal lobe (MTL) and inferior longitudinal fasciculus as HCs. Finally, lower baseline FA in the MTL and inferior longitudinal fasciculus predicted deterioration in social and role functioning in UHR participants at 15-month follow-up. CONCLUSIONS This is the first investigation of white matter microstructural alterations in a clinical high-risk sample. Our findings indicate that white matter development may be altered in youth at risk for psychosis, possibly due to disrupted developmental mechanisms, and further, that white matter integrity may be predictive of functional outcome.

The prodromal questionnaire (PQ): Preliminary validation of a self-report screening measure for prodromal and psychotic syndromes

This study aims to establish preliminary validity of the Prodromal Questionnaire (PQ), a 92-item self-report screening measure for prodromal and psychotic symptoms. Adolescents and young adults (N = 113) referred to a prodromal psychosis research clinic completed the PQ and the Structured Interview for Prodromal Syndromes (SIPS [Miller, T.J., McGlashan, T.H., Woods, S.W., Stein, K., Driesen, N., Corcoran, C.M., Hoffman, R., Davidson, L., 1999. Symptom assessment in schizophrenic prodromal states. Psychiatric Quarterly 70(4), 273-287]), an interview with established validity for predicting future psychosis. When maximizing selection of true positive cases, scores on a subset of PQ items that assess positive symptoms predicted a concurrent prodromal or psychotic SIPS diagnosis with 90% sensitivity and 49% specificity. The PQ shows good preliminary validity in detecting individuals with an interview-diagnosed prodromal or psychotic syndrome, but it is less sensitive to the threshold between prodromal and full-blown psychosis.