Ivy F. Tso

Meta-Analysis of Functional Neuroimaging Studies of Emotion Perception and Experience in Schizophrenia

BACKGROUND Neuroimaging studies of emotion in schizophrenia have reported abnormalities in amygdala and other regions, although divergent results and heterogeneous paradigms complicate conclusions from single experiments. To identify more consistent patterns of dysfunction, a meta-analysis of functional imaging studies of emotion was undertaken. METHODS Searching Medline and PsycINFO databases through January 2011, 88 potential articles were identified, of which 26 met inclusion criteria, comprising 450 patients with schizophrenia and 422 healthy comparison subjects. Contrasts were selected to include emotion perception and emotion experience. Foci from individual studies were subjected to a voxelwise meta-analysis using multilevel kernel density analysis. RESULTS For emotional experience, comparison subjects showed greater activation in the left occipital pole. For emotional perception, schizophrenia subjects showed reduced activation in bilateral amygdala, visual processing areas, anterior cingulate cortex, dorsolateral frontal cortex, medial frontal cortex, and subcortical structures. Schizophrenia subjects showed greater activation in the cuneus, parietal lobule, precentral gyrus, and superior temporal gyrus. Combining across studies and eliminating studies that did not balance on effort and stimulus complexity eliminated most differences in visual processing regions as well as most areas where schizophrenia subjects showed a greater signal. Reduced reactivity of the amygdala appeared primarily in implicit studies of emotion, whereas deficits in anterior cingulate cortex activity appeared throughout all contrasts. CONCLUSIONS Processing emotional stimuli, schizophrenia patients show reduced activation in areas engaged by emotional stimuli, although in some conditions, schizophrenia patients exhibit increased activation in areas outside those traditionally associated with emotion, possibly representing compensatory processing.

GABA abnormalities in schizophrenia: A methodological review of in vivo studies

Abnormalities of GABAergic interneurons are some of the most consistent findings from post-mortem studies of schizophrenia. However, linking these molecular deficits with in vivo observations in patients - a critical goal in order to evaluate interventions that would target GABAergic deficits - presents a challenge. Explanatory models have been developed based on animal work and the emerging experimental literature in schizophrenia patients. This literature includes: neuroimaging ligands to GABA receptors, magnetic resonance spectroscopy (MRS) of GABA concentration, transcranial magnetic stimulation of cortical inhibitory circuits and pharmacologic probes of GABA receptors to dynamically challenge the GABA system, usually in combination with neuroimaging studies. Pharmacologic challenges have elicited behavioral changes, and preliminary studies of therapeutic GABAergic interventions have been conducted. This article critically reviews the evidence for GABAergic dysfunction from each of these areas. These methods remain indirect measures of GABAergic function, and a broad array of dysfunction is linked with the putative GABAergic measures, including positive symptoms, cognition, emotion, motor processing and sensory processing, covering diverse brain areas. Measures of receptor binding have not shown replicable group differences in binding, and MRS assays of GABA concentration have yielded equivocal evidence of large-scale alteration in GABA concentration. Overall, the experimental base remains sparse, and much remains to be learned about the role of GABAergic interneurons in healthy brains. Challenges with pharmacologic and functional probes show promise, and may yet enable a better characterization of GABAergic deficits in schizophrenia.

Eye-contact perception in schizophrenia: Relationship with symptoms and socioemotional functioning

Accurately perceiving self-referential social signals, particularly eye contact, is critical to social adaptation. Schizophrenia is often accompanied by deficits in social cognition, but it is unclear whether this includes gaze discrimination deficits. This study investigated whether eye-contact perception is preserved or impaired and if it is related to symptoms and broader socioemotional functioning in schizophrenia. Twenty-six participants with schizophrenia (SCZ) and 23 healthy controls (HC) made eye-contact judgments for faces in varying gaze direction (from averted to direct in ten 10% increments), head orientation (forward, 30° averted), and emotion (neutral, fearful). Psychophysical analyses for forward faces showed that SCZ began endorsing eye contact with weaker eye-contact signal and their eye-contact perception was less of a dichotomous function, as compared with HC. SCZ were more likely than HC to endorse eye contact when gaze was ambiguous, and this overperception of eye contact was modulated by head orientation and emotion. Overperception of eye contact was associated with more severe negative symptoms. Decreased categorical gaze perception explained variance of socioemotional deficits in schizophrenia after taking basic neurocognition into consideration, suggesting the relationship was not solely due to a general deficit problem. These results were discussed in relation to the nature of categorical gaze perception and its significance to clinical and functional presentations of schizophrenia.

Emotional experience predicts social adjustment independent of neurocognition and social cognition in schizophrenia.

BACKGROUND Emotional abnormalities are prominent features of schizophrenia. While the capacity for emotions is essential to social adaptation, little is known about the role of emotional experience in the social dysfunction observed in schizophrenia. OBJECTIVE This study examined the contribution of emotional experience, neurocognition, and social cognition to functional outcome in schizophrenia. METHOD Self-reported emotional experience (anhedonia, affect intensity, and emotion frequency) was assessed in 33 stable schizophrenic/schizoaffective patients and 33 healthy controls. Symptoms, neurocognition, social cognition, and functional outcome were also assessed. RESULTS Patients and controls exhibited good internal reliability on all self-report scales, except for negative affect intensity. Patients reported equally intense but less frequent positive emotions, more intense and frequent negative emotions, and more anhedonia. Results of hierarchical regression analyses showed that emotional experience accounted for significant amounts of variance of social adjustment independent of neurocognition and social cognition. CONCLUSION These data show that emotional experience can be reliably assessed and is an important determinant of functional outcome in schizophrenia.

Can P300 distinguish among schizophrenia, schizoaffective and bipolar I disorders? An ERP study of response inhibition.

Research utilizing visual event-related brain potentials (ERPs) has demonstrated that reduced P300 amplitude and prolonged latency may qualify as a biological marker (biomarker) for schizophrenia (SZ). We examined P300 characteristics in response inhibition among three putatively distinct psychopathology groups including schizophrenia (SZ), bipolar I disorder (BD) and schizoaffective disorder (SA) in comparison with healthy controls (CT) to determine their electrophysiological distinctiveness. In two separate studies, deficits in response inhibition indexed by the P300 component were investigated using a lateralized Go/NoGo task. We hypothesized that deficits in response inhibition would be present and distinctive among the groups. In both studies, SZ showed response inhibition deficits as measured by P300 when stimuli were presented to the right visual field. In Study 2, delayed cognitive stimulus evaluation was observed in BD as indexed by prolonged P300 latency for NoGo trials. Six selected NoGo P300 variables out of thirty six NoGo P300 variables (18 amplitude, 18 latency) correctly classified SZ (79%), SA (64%) in Study 1 and seven variables selected in Study 2 classified CT (80%), and SZ (61%), BD (67%) and CT (68%) with the accuracy higher than chance level (33%). The findings suggest that distinct P300 features in response inhibition may be biomarkers with the capacity to distinguish BD and SZ, although SA was not clearly distinguishable from SZ and CT.

Social appraisal in chronic psychosis: Role of medial frontal and occipital networks.

Persons with schizophrenia often appraise other individuals as threatening or persecutory. To evaluate social appraisal in schizophrenia, we probed brain networks with a task in which subjects judged whether or not they liked face stimuli with emotional expressions. We predicted that appraising negative expressions would engage patients, more than controls, and negative faces would be related to higher levels of negative affect and produce increased activity in the medial frontal cortex, an area involved in social appraisal. Twenty-one stable outpatients with chronic non-affective psychosis (16 schizophrenic, 5 schizoaffective) and 21 healthy subjects underwent functional magnetic resonance imaging. Compared with the control subjects, patients were slower to respond, but particularly slow when they judged negatively-valenced faces, a slowness correlated with negative affect in the psychosis patients. Appraisal activated the medial prefrontal cortex (mPFC) across all face valences. For negative expressions, patients exhibited greater activation of the dorsal anterior cingulate cortex (dACC). A psychophysiological interaction analysis of the dACC revealed co-modulation of the mPFC in controls, significantly less in patients, and a trend for co-modulation of occipital cortex in the patients. Activity in occipital cortex correlated with poor social adjustment and impaired social cognition, and co-modulation of the occipital gyrus by the dACC was correlated with poorer social cognition. The findings link appraisal of negative affect with aberrant activation of the medial frontal cortex, while early sensory processing of this social cognitive task was linked with poor social function, reflecting either top-down or bottom-up influences.

Abnormal GABAergic Function and Negative Affect in Schizophrenia

Deficits in the γ-aminobutyric acid (GABA) system have been reported in postmortem studies of schizophrenia, and therapeutic interventions in schizophrenia often involve potentiation of GABA receptors (GABAR) to augment antipsychotic therapy and treat negative affect such as anxiety. To map GABAergic mechanisms associated with processing affect, we used a benzodiazepine challenge while subjects viewed salient visual stimuli. Fourteen stable, medicated schizophrenia/schizoaffective patients and 13 healthy comparison subjects underwent functional magnetic resonance imaging using the blood oxygenation level-dependent (BOLD) technique while they viewed salient emotional images. Subjects received intravenous lorazepam (LRZ; 0.01 mg/kg) or saline in a single-blinded, cross-over design (two sessions separated by 1–3 weeks). A predicted group by drug interaction was noted in the dorsal medial prefrontal cortex (dmPFC) as well as right superior frontal gyrus and left and right occipital regions, such that psychosis patients showed an increased BOLD signal to LRZ challenge, rather than the decreased signal exhibited by the comparison group. A main effect of reduced BOLD signal in bilateral occipital areas was noted across groups. Consistent with the role of the dmPFC in processing emotion, state negative affect positively correlated with the response to the LRZ challenge in the dmPFC for the patients and comparison subjects. The altered response to LRZ challenge is consistent with altered inhibition predicted by postmortem findings of altered GABAR in schizophrenia. These results also suggest that negative affect in schizophrenia/schizoaffective disorder is associated—directly or indirectly—with GABAergic function on a continuum with normal behavior.

Differential hedonic experience and behavioral activation in schizophrenia and bipolar disorder

The Kraepelinian distinction between schizophrenia (SZ) and bipolar disorder (BP) emphasizes affective and volitional impairment in the former, but data directly comparing the two disorders for hedonic experience are scarce. This study examined whether hedonic experience and behavioral activation may be useful phenotypes distinguishing SZ and BP. Participants were 39 SZ and 24 BP patients without current mood episode matched for demographics and negative affect, along with 36 healthy controls (HC). They completed the Chapman Physical and Social Anhedonia Scales, Temporal Experience of Pleasure Scale (TEPS), and Behavioral Activation Scale (BAS). SZ and BP showed equally elevated levels of self-report negative affect and trait anhedonia compared to HC. However, SZ reported significantly lower pleasure experience (TEPS) and behavioral activation (BAS) than BP, who did not differ from HC. SZ and BP showed differential patterns of relationships between the hedonic experience and behavioral activation measures. Overall, the results suggest that reduced hedonic experience and behavioral activation may be effective phenotypes distinguishing SZ from BP even when affective symptoms are minimal. However, hedonic experience differences between SZ and BP are sensitive to measurement strategy, calling for further research on the nature of anhedonia and its relation to motivation in these disorders.

Self-assessment of psychological stress in schizophrenia: Preliminary evidence of reliability and validity

Heightened stress sensitivity is a common characteristic of schizophrenia and may be predictive of clinical and functional outcomes. However, systematic assessment is not part of routine clinical practice. This study investigated the reliability and predictive values of two versions of a new scale for the assessment of psychological stress in psychosis (Psychological Stress Index; PSI). Thirty-seven patients with schizophrenia/schizoaffective disorder and 30 healthy controls completed a battery of self-report measures at baseline and 4-8 weeks for test-retest. Thirty-four patients were followed up at 12 months. Both of the 18-item and 9-item PSI demonstrated good levels of reliability and could significantly discriminate patients from healthy controls. Both versions showed moderate convergence with self-report and clinician ratings of depression and anxiety, and superior predictive validity of 12-month follow-up clinical and functional outcomes compared to an existing measure of stress (Perceived Stress Scale). The clinical usefulness of the PSI is supported by its predictive power on cross-sectional and longitudinal outcome. The PSI-9 performed as well as, if not better than, the PSI-18 in this study, but further evaluation is warranted for more conclusive comparison.

Role of Visual Integration in Gaze Perception and Emotional Intelligence in Schizophrenia

BACKGROUND Individuals with schizophrenia demonstrate a wide range of social cognitive deficits that significantly compromise functioning. Early visual processing is frequently disrupted in schizophrenia, and growing evidence suggests a role of perceptual dysfunctions in socioemotional functioning in the disorder. This study examined visual integration (the ability to effectively integrate individual, local visual features into a holistic representation), a target construct of basic perception identified by the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia initiative, and its relationship with eye- contact perception and emotional intelligence in schizophrenia. METHODS Twenty-nine participants with schizophrenia (SCZ) and 23 healthy controls (HC) completed tasks measuring visual integration (Coherent Motion Task, Contour Integration Task), an eye-contact perception task, and a measure of emotional intelligence. RESULTS SCZ participants showed compromised visual integration as suggested by poorer performance on the Contour Integration Task relative to HC. Visual integration was a significant predictor of eye-contact perception and emotional intelligence among SCZ. The amounts of variances in these 2 social cognitive areas accounted for by visual integration were comparable to and overlapped with those accounted for by the diagnosis of schizophrenia. CONCLUSIONS Individuals with schizophrenia showed compromised visual integration, and this may play a significant role in the observed deficits in higher level processing of social information in the disorder.