Julie M. McCarthy

Abnormal Medial Prefrontal Cortex Resting-State Connectivity in Bipolar Disorder and Schizophrenia

Bipolar disorder and schizophrenia overlap in symptoms and may share some underlying neural substrates. The medial prefrontal cortex (MPFC) may have a crucial role in the psychophysiology of both these disorders. In this study, we examined the functional connectivity between MPFC and other brain regions in bipolar disorder and schizophrenia using resting-state functional magnetic resonance imaging (fMRI). Resting-state fMRI data were collected from 14 patients with bipolar disorder, 16 patients with schizophrenia, and 15 healthy control subjects. Functional connectivity maps from the MPFC were computed for each subject and compared across the three groups. The three groups showed distinctive patterns of functional connectivity between MPFC and anterior insula, and between MPFC and ventral lateral prefrontal cortex (VLPFC). The bipolar disorder group exhibited positive correlations between MPFC and insula, and between MPFC and VLPFC, whereas the control group exhibited anticorrelations between these regions. The schizophrenia group did not exhibit any resting-state correlation or anticorrelation between the MPFC and the VLPFC or insula. In contrast, neither patient group exhibited the significant anticorrelation between dorsal lateral prefrontal cortex (DLPFC) and MPFC that was exhibited by the control group. The decoupling of DLPFC with MPFC in bipolar disorder and schizophrenia is consistent with the impaired executive functioning seen in these disorders. Functional connectivity between MPFC and insula/VLPFC distinguished bipolar disorder from schizophrenia, and may reflect differences in the affective disturbances typical of each illness.

Elevated Gamma-Aminobutyric Acid Levels in Chronic Schizophrenia

BACKGROUND Despite widely replicated abnormalities of gamma-aminobutyric acid (GABA) neurons in schizophrenia postmortem, few studies have measured tissue GABA levels in vivo. We used proton magnetic resonance spectroscopy to measure tissue GABA levels in participants with schizophrenia and healthy control subjects in the anterior cingulate cortex and parieto-occipital cortex. METHODS Twenty-one schizophrenia participants effectively treated on a stable medication regimen (mean age 39.0, 14 male) and 19 healthy control subjects (mean age 36.3, 12 male) underwent a proton magnetic resonance spectroscopy scan using GABA-selective editing at 4 Tesla after providing informed consent. Data were collected from two 16.7-mL voxels and analyzed using LCModel. RESULTS We found elevations in GABA/creatine in the schizophrenia group compared with control subjects [F(1,65) = 4.149, p = .046] in both brain areas (15.5% elevation in anterior cingulate cortex, 11.9% in parieto-occipital cortex). We also found a positive correlation between GABA/creatine and glutamate/creatine, which was not accounted for by % GM or brain region. CONCLUSIONS We found elevated GABA/creatinine in participants with chronically treated schizophrenia. Postmortem studies report evidence for dysfunctional GABAergic neurotransmission in schizophrenia. Elevated GABA levels, whether primary to illness or compensatory to another process, may be associated with dysfunctional GABAergic neurotransmission in chronic schizophrenia.

The Motivation and Pleasure Scale–Self-Report (MAP-SR): Reliability and validity of a self-report measure of negative symptoms

The Clinical Assessment Interview for Negative Symptoms (CAINS) is an empirically developed interview measure of negative symptoms. Building on prior work, this study examined the reliability and validity of a self-report measure based on the CAINS-the Motivation and Pleasure Scale-Self-Report (MAP-SR)-that assesses the motivation and pleasure domain of negative symptoms. Thirty-seven participants with schizophrenia or schizoaffective disorder completed the 18-item MAP-SR, the CAINS, and other measures of functional outcome. Item analyses revealed three items that performed poorly. The revised 15-item MAP-SR demonstrated good internal consistency and convergent validity with the clinician-rated Motivation and Pleasure scale of the CAINS, as well as good discriminant validity, with little association with psychotic symptoms or depression/anxiety. MAP-SR scores were related to social anhedonia, social closeness, and clinician-rated social functioning. The MAP-SR is a promising self-report measure of severity of negative symptoms.

Brain gamma-aminobutyric acid (GABA) abnormalities in bipolar disorder.

OBJECTIVES Gamma-aminobutyric acid (GABA) abnormalities have been implicated in bipolar disorder. However, due to discrepant studies measuring postmortem, cerebrospinal fluid, plasma, and in vivo brain levels of GABA, the nature of these abnormalities is unclear. Using proton magnetic resonance spectroscopy, we investigated tissue levels of GABA in the anterior cingulate cortex and parieto-occipital cortex of participants with bipolar disorder and healthy controls. METHODS Fourteen stably medicated euthymic outpatients with bipolar disorder type I (mean age 32.6 years, eight male) and 14 healthy control participants (mean age 36.9 years, 10 male) completed a proton magnetic resonance spectroscopy scan at 4-Tesla after providing informed consent. We collected data from two 16.7-mL voxels using MEGAPRESS, and they were analyzed using LCModel. RESULTS GABA/creatine ratios were elevated in bipolar disorder participants compared to healthy controls [F(1,21) = 4.4, p = 0.048] in the anterior cingulate cortex (25.1% elevation) and the parieto-occipital cortex (14.6% elevation). Bipolar disorder participants not taking GABA-modulating medications demonstrated greater GABA/creatine elevations than patients taking GABA-modulating medications. CONCLUSIONS We found higher GABA/creatine levels in euthymic bipolar disorder outpatients compared to healthy controls, and the extent of this elevation may be affected by the use of GABA-modulating medications. Our findings suggest that elevated brain GABA levels in bipolar disorder may be associated with GABAergic dysfunction and that GABA-modulating medications reduce GABA levels in this condition.

Inefficient effort allocation and negative symptoms in individuals with schizophrenia.

Negative symptoms like avolition and anhedonia are thought to involve difficulties with reward processing and motivation. The current study aimed to replicate and extend prior findings that individuals with schizophrenia display reduced willingness to expend effort for rewards and that such reduced effort is associated with negative symptoms, poor functioning, and cognitive impairment. The present study compared the effortful decision making of individuals with schizophrenia (n=48) and healthy controls (n=27) on the Effort Expenditure for Rewards Task (EEfRT). Individuals with schizophrenia chose a smaller proportion of hard tasks than healthy controls across all probability and reward levels with the exception of trials with a 12% probability and low or medium reward magnitude wherein both groups chose similarly few hard tasks. Contrary to expectations, in individuals with schizophrenia, greater negative symptoms were associated with making more effortful choices. Effortful decision making was unrelated to positive symptoms, depression, cognition, and functioning in individuals with schizophrenia. Our results are consistent with prior findings that revealed a pattern of inefficient decision making in individuals with schizophrenia relative to healthy controls. However the results did not support the hypothesized association of negative symptoms and reduced effort in schizophrenia and highlight prior inconsistencies in this literature. Future research is needed to understand what factors may be related to diminished effortful decision making in schizophrenia and the clinical significance of such performance deficits.

Gray matter volume in schizophrenia and bipolar disorder with psychotic features

There is growing evidence that schizophrenia (SZ) and bipolar disorder (BD) overlap significantly in risk factors, neurobiological features, clinical presentations, and outcomes. SZ is characterized by well documented gray matter (GM) abnormalities in multiple frontal, temporal and subcortical structures. Recent voxel-based morphometry (VBM) studies and meta-analyses in BD also report GM reductions in overlapping, albeit less widespread, brain regions. Psychosis, a hallmark of SZ, is also experienced by a significant proportion of BD patients and there is evidence that psychotic BD may be characterized by specific clinical and pathophysiological features. However, there are few studies comparing GM between SZ and psychotic BD. In this study we compared GM volumes in a sample of 58 SZ patients, 28 BD patients experiencing psychotic symptoms and 43 healthy controls using whole-brain voxel-based morphometry. SZ patients had GM reductions in multiple frontal and temporal regions compared to healthy controls and in the subgenual cortex compared to psychotic BD patients. GM volume was increased in the right posterior cerebellum in SZ patients compared to controls. However, psychotic BD patients did not show significant GM deficits compared to healthy controls or SZ patients. We conclude that GM abnormality as measured by VBM analysis is less pronounced in psychotic BD compared to SZ. This may be due to disease-specific factors or medications used more commonly in BD.

Screening for negative symptoms: Preliminary results from the self-report version of the Clinical Assessment Interview for Negative Symptoms

Though negative symptoms in schizophrenia are associated with a host of deleterious outcomes (e.g., White et al., 2009), not all individuals with schizophrenia suffer from negative symptoms (e.g., Blanchard et al., 2005). Thus, methods to quickly screen and identify patients for more intensive clinical interview assessments may have significant clinical and research utility. The present study is a preliminary examination of the reliability and validity of a self-report version of the newly developed Clinical Assessment Interview for Negative Symptoms (CAINS; Blanchard et al., 2011; Forbes et al., 2010; Horan et al., 2011). The CAINS-SR is a 30-item self-report measure that assesses Experiential (avolition, anhedonia, asociality) and Expressive (blunted affect, alogia) domains of negative symptoms. Participants (N = 69) completed the CAINS-SR questionnaire and were evaluated with symptom interviews using the CAINS and other non-negative symptom interviews that assessed psychotic, affective, and other symptoms. The Experience subscale of the CAINS-SR demonstrated good internal consistency, convergent validity, and discriminant validity, while the poorer psychometric properties of the Expression subscale suggest that self-report of negative symptoms should focus on the experiential domain. Overall, preliminary findings indicate that the CAINS-SR (addressing experiential deficits) may be a useful complement to the clinician-rated interview measure. Future research on the sensitivity and specificity of the CAINS-SR will determine its suitability as a screening measure.

Motivation and effort in individuals with social anhedonia.

It has been proposed that anhedonia may, in part, reflect difficulties in reward processing and effortful decision making. The current study aimed to replicate previous findings of effortful decision making deficits associated with elevated anhedonia and expand upon these findings by investigating whether these decision making deficits are specific to elevated social anhedonia or are also associated with elevated positive schizotypy characteristics. The current study compared controls (n=40) to individuals elevated on social anhedonia (n=30), and individuals elevated on perceptual aberration/magical ideation (n=30) on the Effort Expenditure for Rewards Task (EEfRT). Across groups, participants chose a higher proportion of hard tasks with increasing probability of reward and reward magnitude, demonstrating sensitivity to probability and reward values. Contrary to our expectations, when the probability of reward was most uncertain (50% probability), at low and medium reward values, the social anhedonia group demonstrated more effortful decision making than either individuals high in positive schizotypy or controls. The positive schizotypy group only differed from controls (making less effortful choices than controls) when reward probability was lowest (12%) and the magnitude of reward was the smallest. Our results suggest that social anhedonia is related to intact motivation and effort for monetary rewards, but that individuals with this characteristic display a unique and perhaps inefficient pattern of effort allocation when the probability of reward is most uncertain. Future research is needed to better understand effortful decision making and the processing of reward across a range of individual difference characteristics.

Negative symptoms and the formation of social affiliative bonds in schizophrenia

Negative symptoms in schizophrenia are characterized by deficits in normative experiences and expression of emotion, and they are associated with poor social functioning. Negative symptoms relating to deficits in motivation and pleasure may hinder the development of affiliative bonds. The current study used a novel procedure to examine the relation between negative symptoms and the development of social affiliation within a laboratory setting. Fifty-five men (35 controls; 20 with a schizophrenia spectrum disorder) completed three Social Affiliation Enhancement Tasks with an experimenter partner. Self-reported affiliation and affect ratings were assessed before and after the affiliative interaction. Across groups, social affiliation and positive affect increased following the interactive tasks. However, the schizophrenia group reported less positive and more negative affect than controls. Within individuals with schizophrenia, negative symptoms reflecting motivation and pleasure deficits and self-reported social anhedonia were associated with less affiliative feelings of interpersonal closeness and less willingness to interact. Additionally, these self-reported reactions to the interaction partner were significantly related to social functioning in the community. These findings indicate that though individuals with schizophrenia can form affiliative bonds, the extent to which this is possible may be limited by negative symptoms relating to motivation and pleasure. Additional research will be necessary to examine just how these negative symptoms interfere with social affiliation.

Reduced interhemispheric executive control network coupling in men during early cocaine abstinence: A pilot study

BACKGROUND Individuals who use cocaine have fewer cognitive resources needed to maintain abstinence. This is evidenced by blunted brain function during cognitive control tasks and reduced communication between brain regions associated with cognitive function. For instance, relapse vulnerability is heightened in individuals with less communication between the right and left frontoparietal executive control network (ECN). Given that recent cocaine use enhances such communication, it is plausible that recency of cocaine use influences interhemispheric ECN communication. However, it is unclear whether ECN communication weakens over the course of early cocaine abstinence, which may then enhance relapse risk. METHODS In ten men with cocaine use disorder, we conducted a preliminary assessment of the relationship between the number of days since last cocaine use (1-3days) and interhemispheric ECN coupling using resting state functional magnetic resonance imaging (fMRI). RESULTS Reduced interhemispheric ECN coupling was associated with increasing days since last cocaine use; weaker coupling was also associated with lower urine cocaine metabolite concentrations. This association was more prominent in prefrontal than parietal ECN-subregions. CONCLUSIONS Preliminary results indicate that resting state interhemispheric ECN coupling weakens within the first few days following last cocaine use. Because of the known link between reduced ECN interhemispheric coupling and relapse vulnerability, these results suggest that relapse risk may increase the longer an individual abstains during an early quit attempt. Treatments focused on reversing this coupling deficit may facilitate abstinence.