Emotional scene processing in biotypes of psychosis.

Social-emotional deficits in psychosis may be indexed by deviations in emotional scene processing, but event-related potential (ERP) studies indicate such deviations may not map cleanly to diagnostic categories. Neurobiologically defined psychosis subgroups offer an alternative that may better capture neurophysiological correlates of social-emotional deficits. The current study investigates emotional scene-elicited ERPs in Biotypes of psychosis in a large (N = 622), well-characterized sample. Electroencephalography was recorded in healthy persons (N = 129), Biotype-1 (N = 195), Biotype-2 (N = 131), and Biotype-3 (N = 167) psychosis cases. ERPs were measured from posterior and centroparietal scalp locations. Neural responses to emotional scenes were compared between healthy and psychosis groups. Multivariate group discrimination analyses resulted in two composite variates that differentiated groups. The first variate displayed large differences between low-cognition (Biotype-1, Biotype-2) and intact-cognition groups (Biotype-3, healthy persons). The second indicated a small-to-moderate distinction of Biotypes-2 and -3 from Biotype-1 and healthy persons. Two multivariate correlations were identified indicating associations between 1) self-reported emotional experience and generalized cognition and 2) socio-occupational functioning and late-stage emotional processing. Psychosis Biotypes displayed emotional processing deficits not apparent in DSM psychosis subgroups. Future translational research may benefit from exploring emotional scene processing in such neurobiologically-defined psychosis groups.

Genome-wide association studies of smooth pursuit and antisaccade eye movements in psychotic disorders: findings from the B-SNIP study.

Eye movement deviations, particularly deficits of initial sensorimotor processing and sustained pursuit maintenance, and antisaccade inhibition errors, are established intermediate phenotypes for psychotic disorders. We here studied eye movement measures of 849 participants from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study (schizophrenia N=230, schizoaffective disorder N=155, psychotic bipolar disorder N=206 and healthy controls N=258) as quantitative phenotypes in relation to genetic data, while controlling for genetically derived ancestry measures, age and sex. A mixed-modeling genome-wide association studies approach was used including ~4.4 million genotypes (PsychChip and 1000 Genomes imputation). Across participants, sensorimotor processing at pursuit initiation was significantly associated with a single nucleotide polymorphism in IPO8 (12p11.21, P=8 × 10-11), whereas suggestive associations with sustained pursuit maintenance were identified with SNPs in SH3GL2 (9p22.2, P=3 × 10-8). In participants of predominantly African ancestry, sensorimotor processing was also significantly associated with SNPs in PCDH12 (5q31.3, P=1.6 × 10-10), and suggestive associations were observed with NRSN1 (6p22.3, P=5.4 × 10-8) and LMO7 (13q22.2, P=7.3x10-8), whereas antisaccade error rate was significantly associated with a non-coding region at chromosome 7 (P=6.5 × 10-9). Exploratory pathway analyses revealed associations with nervous system development and function for 40 top genes with sensorimotor processing and pursuit maintenance (P=4.9 × 10-2-9.8 × 10-4). Our findings suggest novel patterns of genetic variation relevant for brain systems subserving eye movement control known to be impaired in psychotic disorders. They include genes involved in nuclear trafficking and gene silencing (IPO8), fast axonal guidance and synaptic specificity (PCDH12), transduction of nerve signals (NRSN1), retinal degeneration (LMO7), synaptic glutamate release (SH3GL2), and broader nervous system development and function.

Brain activation differences in schizophrenia during context-dependent processing of saccade tasks.

BACKGROUND: Brain function in schizophrenia has been probed using saccade paradigms and functional magnetic resonance imaging, but little information exists about how changing task context impacts saccade related brain activation and behavioral performance. We recruited schizophrenia and comparison subjects to perform saccade tasks in differing contexts: (1) two single task runs (anti- or pro-saccades alternating with fixation) and (2) one dual task run (antisaccades alternating with prosaccades). RESULTS: Context-dependent differences in saccade circuitry were evaluated using ROI analyses. Distinction between anti- and pro-saccade activation across contexts (single versus dual task) suggests that the schizophrenia group did not respond to context in the same way as the comparison group. CONCLUSIONS: Further investigation of context processing effects on brain activation and saccade performance measures informs models of cognitive deficits in the disorder and enhances understanding of antisaccades as a potential endophenotype for schizophrenia.

An eight month randomized controlled exercise intervention alters resting state synchrony in overweight children.

Children with low aerobic fitness have altered brain function compared to higher-fit children. This study examined the effect of an 8-month exercise intervention on resting state synchrony. Twenty-two sedentary, overweight (body mass index ≥85th percentile) children 8-11 years old were randomly assigned to one of two after-school programs: aerobic exercise (n=13) or sedentary attention control (n=9). Before and after the 8-month programs, all subjects participated in resting state functional magnetic resonance imaging scans. Independent components analysis identified several networks, with four chosen for between-group analysis: salience, default mode, cognitive control, and motor networks. The default mode, cognitive control, and motor networks showed more spatial refinement over time in the exercise group compared to controls. The motor network showed increased synchrony in the exercise group with the right medial frontal gyrus compared to controls. Exercise behavior may enhance brain development in children.

Timing and magnitude of frontal activity differentiates refixation and anti-saccade performance.

EEG data were recorded while 10 subjects generated refixation saccades towards a visual target and antisaccades away from a visual cue. Theoretically, the same basic neural circuitry supports refixation and correct anti-saccade performances, with additional activity in primarily dorsolateral prefrontal cortex circuitry supporting antisaccade-associated inhibitory processes. Analyses demonstrated that sensory registration of visual stimuli is similar for refixation and anti-saccade conditions. Increased frontal brain activity at 5 and 15 Hz was observed preceding correct antisaccades when compared to refixation saccades. These analyses provide specific information suggesting that 160-60 ms before saccade generation is the critical period for response inhibition.

Behavioral and brain imaging studies of saccadic performance in schizophrenia.

Data are reviewed from a series of saccadic studies demonstrating that schizophrenia subjects have normal performance on some types, and abnormal performance on other types, of tasks. Normal refixation saccade characteristics and BOLD signal change among schizophrenia subjects suggest that basic saccade generating circuitry is functionally intact among these subjects. Schizophrenia patients and their relatives, however, demonstrate difficulty with saccadic inhibition, a function ostensibly mediated by DLPFC circuitry. We review additional evidence for saccadic inhibition being associated with prefrontal circuitry provided by EEG and fMRI data. Minimum norm analysis of EEG data suggests that dipolar activity preceding correct antisaccades occurred preferentially in prefrontal cortex. Furthermore, there is an indication from the fMRI data that prefrontal activity may be increased in normal, but not in schizophrenia, subjects during antisaccade tasks. These data suggest that a research program relying on multiple functional imaging technologies may be helpful for furthering our understanding of schizophrenia's essential neuropathology.

Saccadic inhibition among schizotypal personality disorder subjects.

Schizotypal personality disorder (SPD) is theoretically part of the schizophrenia spectrum both clinically and neurobiologically. A liability for developing schizophrenia may be associated with dysfunction of dorsolateral prefrontal cortex (DLPFC) and its cortical and/or subcortical circuitry. If so, abnormalities on tasks associated with DLPFC functioning among SPD subjects would support the thesis that SPD is neurobiologically related to schizophrenia. Antisaccade and ocular motor delayed response performance, both of which are ostensibly supported by DLPFC circuitry, were assessed among 29 SPD, 17 schizophrenia, and 25 normal subjects. Generally, the SPD subjects' performance was more similar to normal than to schizophrenia groups. There was evidence, however, for inhibition abnormalities in a subgroup of SPD subjects. Antisaccade performance identified more SPD subjects as "abnormal" than delayed response measures.

Ocular motor delayed-response task performance among patients with schizophrenia and their biological relatives.

Schizophrenia patients and their relatives have saccadic abnormalities characterized by problems inhibiting a response. The dorsolateral prefrontal cortex and its associated circuitry ostensibly mediate inhibition and support correct delayed response performance. In this context, two components of delayed response task performance are of interest: memory saccade metrics and error saccades made during the delay. To evaluate these variables, an ocular motor delayed response task was presented to 23 schizophrenia patients, 25 of their first-degree biological relatives, and 19 normal subjects. The measure that best differentiated groups was an increased frequency of error saccades generated during the delay by schizophrenia subjects and relatives. Decreased memory saccade gain also characterized patients and relatives. The similar pattern of results demonstrated by the patients with schizophrenia and their relatives suggests that performance on ocular motor delayed response tasks, either alone or in combination with other saccadic variables, may provide useful information about neural substrates associated with a liability for developing schizophrenia.

Prefrontal, parietal, and temporal cortex networks underlie decision-making in the presence of uncertainty.

Decision-making in the presence of uncertainty, i.e., selecting a sequence of responses in an uncertain environment according to a self-generated plan of action, is a complex activity that involves both cognitive and noncognitive processes. Using functional magnetic resonance imaging, the neural substrates of decision-making in the presence of uncertainty are examined. Normal control subjects show a significant activation of a frontoparietal and limbic neural system during a two-choice prediction task relative to a two-choice response task. The most prevalent response strategy during the two-choice prediction task was "win-stay/lose-shift," where subjects will repeat the previous response if it successfully predicted the stimulus and switch to the alternative response otherwise. Increased frequency of responses that are consistent with this strategy is associated with activation in the superior temporal gyrus. In comparison, increased frequency of response inconsistent with win-stay/lose-shift is associated with parietal cortex activation. These results support the hypothesis that subjects use a frontoparietal neural system to establish a contingency based decision-making strategy even in the presence of random reinforcement.

Measuring liability for schizophrenia using optimized antisaccade stimulus parameters.

The ability to identify unaffected gene carriers within families may be crucial to the success of schizophrenia genetics studies. Data collected from three family samples (N = 365) demonstrated that poor antisaccade performance is an exceptionally promising indicator of liability for schizophrenia. A particular antisaccade task version provides large separations (5-6 sigma) between proband and normal groups. Poor antisaccade performance alone correctly identified 70% of patients in California, Utah, and Micronesia schizophrenia samples. Twenty-five to 50% of these patients' nonpsychotic first-degree relatives also had poor antisaccade performance, yielding risk ratios around 20:1 for simplex and 50:1 for multiplex schizophrenia families. Poor antisaccade performance is associated with dorsolateral prefrontal cortex pathology, suggesting that dysfunction of this circuitry also may predispose individuals to developing this disease.

The effect of fixation condition manipulations on antisaccade performance in schizophrenia: studies of diagnostic specificity.

This series of studies evaluated (1) hypotheses that poor antisaccade performance is attributable to confounding variables (e.g., visual attention deficits, incomplete understanding of task demands) and (2) the specificity of poor antisaccade performance to schizophrenia. In addition to self-correcting errors before being cued to do so, schizophrenia patients also showed the expected saccadic reaction time changes to fixation condition manipulations: decreased latencies for gap and increased latencies for overlap trials. These data suggest that schizophrenia patients are adequately engaged in and understand the antisaccade task. Schizophrenia patients made fewer correct antisaccade responses than other psychiatric patients (obsessive-compulsive and bipolar disorder) and normal subjects. The first-degree relatives of schizophrenia patients also generated a decreased proportion of correct antisaccade responses compared with normal subjects. For schizophrenia patients who performed below the range of normal subjects, 26% of their relatives also performed below the normal range. Conversely, patients who performed normally did not have a single poor-performing relative. These data suggest that increased antisaccade error rates may index a liability for schizophrenia within a subset of families.

Timing and amplitude of saccades during predictive saccadic tracking in schizophrenia.

Schizophrenia patients have ocular motor abnormalities. It has been hypothesized that these abnormalities are associated with frontal eye field pathology. If so, schizophrenia patients should have difficulties decreasing saccadic reaction times in response to predictably moving targets. To evaluate the frontal eye field hypothesis, 25 schizophrenic and 26 nonpsychiatric subjects completed predictive saccadic tracking tasks. The groups demonstrated equivalent decreases in saccadic reaction times over consecutive trials. Schizophrenia patients, however, had faster reaction times and shorter amplitude saccades than nonpsychiatric subjects. The shorter amplitude saccades were made regardless of reaction time, perhaps an antipsychotic medication effect. The reaction time results are unlikely to be an effect of treatment with antipsychotic medication and are inconsistent with the hypothesis that schizophrenia patients have frontal eye field pathology.

Ocular-motor delayed-response task performance among schizophrenia patients.

Twenty schizophrenia patients and 20 nonpsychiatric subjects were presented with an ocular-motor delayed-response task. Schizophrenia patients generated fewer memory-guided saccades which were characterized by increased latency and decreased gain relative to the nonpsychiatric subjects. In addition, the patients generated an increased frequency of reflexive (made to the initial cue) and anticipatory (made during the delay period) errors. The results are most consistent with hypothesized pathology of prefrontal cortex among schizophrenia patients.

Abnormality of smooth pursuit eye movement initiation: specificity to the schizophrenia spectrum?

Schizophrenia patients have a deficiency of smooth pursuit eye movement initiation. We addressed whether this deficit is specifically related to a predisposition for schizophrenia. Thirty-two relatives of schizophrenia patients, eight schizotypals, 13 psychiatric comparison, and 33 nonpsychiatric subjects were assessed on smooth pursuit initiation. The nonpsychiatric subjects had significantly higher eye accelerations than did subjects in the other three groups, who did not significantly differ. The relatives were subdivided into three groups: (a) those with a schizophrenia spectrum disorder (n = 4) performed similarly to the schizotypals; (b) those with a major depression history (n = 7) were similar to the psychiatric comparison subjects; and (c) those with no psychiatric history differed from the nonpsychiatric subjects only on 30 degrees/s targets. There was also a significant relationship between offspring and parent eye accelerations to 30 degrees/s targets (r = .476). These results suggest that pursuit initiation deficits may be associated with a nonspecific, genetically transmitted neurological abnormality among schizophrenia spectrum disorder subjects.

Saccadic system functioning among schizophrenia patients and their first-degree biological relatives.

In Study 1, 30 schizophrenia Ss and 27 nonpsychiatric comparison Ss were presented with a fixation task, a visually guided reflexive saccade (prosaccade) task, a predictive tracking task (0.4-Hz square wave), and an antisaccade task. The 2 groups did not differ on either the fixation or prosaccade tasks. Schizophrenia Ss had an increased number of errors on the antisaccade task and had decreased rightward visually guided saccade amplitudes during the predictive tracking task. In Study 2, 13 psychiatric comparison Ss and 32 first-degree biological relatives of the schizophrenia Ss were compared with the schizophrenia Ss and a larger and older sample of nonpsychiatric Ss (n = 33) on the predictive tracking and antisaccade tasks. The groups did not differ on predictive saccadic tracking. The schizophrenia Ss and their first-degree biological relatives made more errors on the antisaccade task than both the nonpsychiatric and psychiatric comparison groups (who did not significantly differ). Results are consistent with the notion that dysfunction of dorsolateral prefrontal cortex, caudate nucleus, or both is related to liability for schizophrenia.

Smooth pursuit in schizophrenia: abnormalities of open- and closed-loop responses.

A sample of 29 schizophrenia patients and 27 nonpsychiatric subjects were tested on measures of open- and closed-loop smooth-pursuit performance. Rashbass step-ramps were used to measure pursuit latency and open-loop gain. Regular ramps were used to calculate frequency and amplitude of both catch-up saccades and square-wave jerks, frequency of anticipatory saccades, and steady-state gain. Schizophrenia patients demonstrated lower open-loop gain than did nonpsychiatric subjects, an effect that was accentuated at faster target velocities. They also showed reduced steady-state gain, but only to 30 degrees/s right-moving targets. There was no evidence of saccadic abnormalities during smooth pursuit among the schizophrenia patients. These patients generated fewer square-wave jerks than did nonpsychiatric subjects for 10 degrees /s left-moving targets. These results suggest an abnormality of smooth-pursuit initiation among patients with schizophrenia.