Jennifer Barrett

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.

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.

Global prefrontal and fronto-amygdala dysconnectivity in bipolar I disorder with psychosis history.

BACKGROUND Pathophysiological models of bipolar disorder postulate that mood dysregulation arises from fronto-limbic dysfunction, marked by reduced prefrontal cortex (PFC) inhibitory control. This might occur due to both disruptions within PFC networks and abnormal inhibition over subcortical structures involved in emotional processing. However, no study has examined global PFC dysconnectivity in bipolar disorder and tested whether regions with within-PFC dysconnectivity also exhibit fronto-limbic connectivity deficits. Furthermore, no study has investigated whether such connectivity disruptions differ for bipolar patients with psychosis history, who might exhibit a more severe clinical course. METHODS We collected resting-state functional magnetic resonance imaging at 3T in 68 remitted bipolar I patients (34 with psychosis history) and 51 demographically matched healthy participants. We employed a recently developed global brain connectivity method, restricted to PFC (rGBC). We also independently tested connectivity between anatomically defined amygdala and PFC. RESULTS Bipolar patients exhibited reduced medial prefrontal cortex (mPFC) rGBC, increased amygdala-mPFC connectivity, and reduced connectivity between amygdala and dorsolateral PFC. All effects were driven by psychosis history. Moreover, the magnitude of observed effects was significantly associated with lifetime psychotic symptom severity. CONCLUSIONS This convergence between rGBC, seed-based amygdala findings, and symptom severity analyses highlights that mPFC, a core emotion regulation region, exhibits both within-PFC dysconnectivity and connectivity abnormalities with limbic structures in bipolar illness. Furthermore, lateral PFC dysconnectivity in patients with psychosis history converges with published work in schizophrenia, indicating possible shared risk factors. Observed dysconnectivity in remitted patients suggests a bipolar trait characteristic and might constitute a risk factor for phasic features of the disorder.

Patterns of memory impairment in bipolar disorder and unipolar major depression

Unipolar and bipolar depression are known to exert detrimental effects on learning and memory processes. However, few comparisons have been undertaken between bipolar and unipolar patients with comparable illness histories, and predictors of impairment are not well understood. Adult outpatients with unipolar major depressive illness (UP, n = 30) and bipolar disorder (BP, n = 30), group-matched for illness duration and severity of depressive symptomatology (16% clinically remitted, 42% partially remitted, 42% depressed), and 30 demographically matched controls completed measures of general cognitive functioning and declarative memory. Despite comparable general intellectual abilities, BP and UP patients exhibited significant memory deficits relative to healthy controls. A similar deficit profile was observed in both patient groups, involving poorer verbal recall and recognition. Impairments were not secondary to strategic processing deficits or rapid forgetting. Although depression severity was not associated with neurocognitive performance, number of hospitalizations and family history of mood disorder significantly affected memory function in BP, but not UP, patients. Results suggest qualitatively similar patterns of memory impairment in BP and UP patients, consistent with a primary encoding deficit. These impairments do not appear to be secondary to clinical state, but rather suggest a similar underlying pathophysiology involving medial temporal dysfunction.

Adjudicating neurocognitive endophenotypes for schizophrenia.

Although genetic influences on schizophrenia are well established, localization of the genes responsible for this illness has proven extremely difficult. Given evidence that genes predisposing to schizophrenia may be transmitted without expression of the clinical phenotype, efforts have focused on developing endophenotypes. While several neuropsychological measures have been proposed to be endophenotypes, few studies have systematically assessed batteries of neurocognitive tests to determine which tests are most sensitive to liability for the illness. Two hundred sixty‐nine Latino individuals were administered a standard neuropsychological battery. Two hundred fourteen of these were members of families with at least two siblings diagnosed with schizophrenia or schizoaffective disorder. The remaining were community controls without history of major psychiatric illness. Neurocognitive measures found to be heritable were entered into analyses designed to determine which tests covary with the degree of genetic relationship to affected individuals. Although five measures were found to uniquely model genetic liability for schizophrenia, digit symbol coding was the most sensitive. To assess the specificity of these endophenotypes, performance on these measures were compared to family members with bipolar and unipolar affective disorders. These markers clearly distinguished between individuals with psychotic illnesses and those with major depression. As measures contributed uniquely to discriminate individuals at varying risk for schizophrenia, our findings imply multiple independently inherited elements to the liability for the illness. We present a practical model for adjudicating endophenotypes and determining which measures are best suited for use in linkage analyses.

Association of clinical symptoms and neurocognitive performance in bipolar disorder: a longitudinal study

OBJECTIVE Despite evidence that individuals with bipolar disorder have neurocognitive impairment that persists during euthymia, the impact of changes in affective symptoms on cognitive function has not been well established. Here, we sought to determine whether specific neurocognitive functions are sensitive to mood changes in individuals with bipolar disorder assessed three months apart without changes in treatment regimen. METHODS A total of 29 individuals with DSM-IV bipolar disorder and 30 healthy controls participated in the study. All participants received a comprehensive neuropsychological assessment and ratings of depressive [Hamilton Depression Rating Scale (HAMD)] and manic [Young Mania Rating Scale (YMRS)] symptoms at baseline and follow-up. Changes in symptoms over time were calculated and were examined in relation to changes in neurocognitive performance. RESULTS At baseline, clinically stable but symptomatic patients were impaired on measures of speed of processing and attention. Over the three-month follow-up period, HAMD scores changed by 6 points on average [range: -10 to +18] and YMRS scores changed by 5.31 points on average [range -11 to +15]. Changes in depressive symptoms were correlated with poorer verbal fluency, while no relationship between manic symptoms and neuropsychological performance was detected. CONCLUSIONS Individuals with bipolar disorder showed consistent impairment on speed of processing and attention over time, despite significant changes in mood.

Trait impulsivity as an endophenotype for bipolar I disorder

OBJECTIVE Impulsivity, conceptualized as impairment in planning and poor attentional and inhibitory control, is a key feature of bipolar disorder. Familial risk for bipolar disorder is known to affect inhibitory control but its impact on the attentional and planning dimensions of impulsivity is still unclear. METHODS We administered the Barratt Impulsiveness Scale, version 11 (BIS-11) to 54 euthymic individuals with DSM-IV bipolar I disorder, 57 of their clinically unaffected siblings, and 49 healthy comparison subjects. Groups were compared on the attentional (rapid shifts in attention/impatience with complexity), motor (acting impetuously), and non-planning (absence of weighing upon long-term consequences of actions) subscales of the BIS-11, and on total BIS-11 score. To investigate functional implications of trait impulsivity, total BIS-11 score was examined in relation to current psychosocial functioning and criminal history. RESULTS Individuals with bipolar I disorder had elevated scores compared to healthy comparison subjects on BIS-11 total score and all three subscales (p < 0.0001). Unaffected siblings had elevated BIS-11 total score (p = 0.0037), motor (p = 0.0027), and non-planning (p = 0.0379) subscales in comparison to unrelated healthy controls. Total BIS-11 score was negatively associated with global assessment of functioning (GAF) score (β = -0.32, p < 0.0001). CONCLUSIONS  Our results suggest that impulsivity is sensitive to familial liability for the illness, making it a potential endophenotype for bipolar disorder.

Reduced White Matter Integrity in Sibling Pairs Discordant for Bipolar Disorder

OBJECTIVE Several lines of evidence indicate that white matter integrity is compromised in bipolar disorder, but the nature, extent, and biological causes remain elusive. To determine the extent to which white matter deficits in bipolar disorder are familial, the authors investigated white matter integrity in a large sample of bipolar patients, unaffected siblings, and healthy comparison subjects. METHOD The authors collected diffusion imaging data for 64 adult bipolar patients, 60 unaffected siblings (including 54 discordant sibling pairs), and 46 demographically matched comparison subjects. Fractional anisotropy was compared between the groups using voxel-wise tract-based spatial statistics and by extracting mean fractional anisotropy from 10 regions of interest. Additionally, intraclass correlation coefficients were calculated between the sibling pairs as an index of familiality. RESULTS Widespread fractional anisotropy reductions in bipolar patients (>40,000 voxels) and more subtle reductions in their siblings, mainly restricted to the corpus callosum, posterior thalamic radiations, and left superior longitudinal fasciculus (>2,000 voxels) were observed. Similarly, region-of-interest analysis revealed significant reductions in most white matter regions in patients. In siblings, fractional anisotropy in the posterior thalamic radiation and the forceps was nominally reduced. Significant between-sibling correlations were found for mean fractional anisotropy across the tract-based spatial statistic skeleton, within significant clusters, and within nearly all regions of interest. CONCLUSIONS These findings emphasize the relevance of white matter to neuropathology and familiality of bipolar disorder and encourage further use of white matter integrity markers as endophenotypes in genetic studies.

Dissociable mechanisms for memory impairment in bipolar disorder and schizophrenia

BACKGROUND Although memory deficits are consistently reported in schizophrenia and bipolar disorder, the mechanisms underlying these impairments are poorly understood. Clarifying the nature and degree of overlap in memory deficits between the two illnesses could help to distinguish brain systems disrupted in these illnesses, and indicate cognitive remediation strategies to improve patient outcomes. METHOD We examined performance on a non-verbal memory task in clinically stable out-patients with bipolar disorder (n=40), schizophrenia (n=40), and healthy comparison subjects (n=40). This task includes conditions in which distinct mnemonic strategies -- namely, using context to organize familiar stimuli or using holistic representation of novel stimuli -- facilitate performance. RESULT When compared to a reference condition, bipolar patients had deficits consistent with organizational dysfunction and poor detection of novel information. Although patients with schizophrenia performed worse than the other groups, they were only differentially impaired when organizational demands were significant. Task performance was not correlated with severity of clinical symptomatology. CONCLUSIONS This pattern of distinct memory impairments implies disturbances in partially overlapping neural systems in bipolar disorder and schizophrenia. Evidence of impairment in detection of novel stimuli that is unique to bipolar disorder suggests that, while the absolute level of cognitive dysfunction is less severe in bipolar disorder as compared to schizophrenia, subtle disruptions in memory are present. These findings can be used to plan targeted cognitive remediation programs by helping patients to capitalize on intact functions and to learn new strategies that they do not employ without training.

A social cognitive approach to emotional intensity judgment deficits in schizophrenia

Patients with schizophrenia are impaired in both emotion perception and contextual processing, however these two processes have not been thoroughly assessed simultaneously in adults with schizophrenia. This study examined the impact of social contextual information upon the perception of emotional intensity in schizophrenia. 30 clinically stable outpatients with schizophrenia and 30 demographically matched healthy subjects assessed the intensity of a single emotion (anger, disgust, happiness, sadness or fear) from images of people presented under two conditions (context-free and context embedded). During the first assessment, a single person (face and body) was presented without any background (e.g., contextual) scenery. The second assessment included the same person but with the original background of the image. Differences between the first and second ratings provided an index of the extent to which contextual information was used to judge emotional intensity. Without contextual cues, patients with schizophrenia viewed scenes as having greater disgust and anger than healthy subjects. Furthermore, patients were less impacted by contextual cues as evidenced by the minute changes in their assessments. These results suggest that patients with schizophrenia differ from healthy subjects in both their ability to rate emotional intensity and the influence of contextual adjustment upon such ratings.