Evidence from comprehensive independent validation studies for smooth pursuit dysfunction as a sensorimotor biomarker for psychosis.

Smooth pursuit eye movements are considered a well-established and quantifiable biomarker of sensorimotor function in psychosis research. Identifying psychotic syndromes on an individual level based on neurobiological markers is limited by heterogeneity and requires comprehensive external validation to avoid overestimation of prediction models. Here, we studied quantifiable sensorimotor measures derived from smooth pursuit eye movements in a large sample of psychosis probands (N = 674) and healthy controls (N = 305) using multivariate pattern analysis. Balanced accuracies of 64% for the prediction of psychosis status are in line with recent results from other large heterogenous psychiatric samples. They are confirmed by external validation in independent large samples including probands with (1) psychosis (N = 727) versus healthy controls (N = 292), (2) psychotic (N = 49) and non-psychotic bipolar disorder (N = 36), and (3) non-psychotic affective disorders (N = 119) and psychosis (N = 51) yielding accuracies of 65%, 66% and 58%, respectively, albeit slightly different psychosis syndromes. Our findings make a significant contribution to the identification of biologically defined profiles of heterogeneous psychosis syndromes on an individual level underlining the impact of sensorimotor dysfunction in psychosis.

Double dissociation between P300 components and task switch error type in healthy but not psychosis participants.

Event-related potentials (ERPs) during oddball tasks and the behavioral performance on the Penn Conditional Exclusion Task (PCET) measure context-appropriate responding: P300 ERPs to oddball targets reflect detection of input changes and context updating in working memory, and PCET performance indexes detection, adherence, and maintenance of mental set changes. More specifically, PCET variables quantify cognitive functions including inductive reasoning (set 1 completion), mental flexibility (perseverative errors), and working memory maintenance (regressive errors). Past research showed that both P300 ERPs and PCET performance are disrupted in psychosis. This study probed the possible neural correlates of 3 PCET abnormalities that occur in participants with psychosis via the overlapping cognitive demands of the two study paradigms. In a two-tiered analysis, psychosis (n = 492) and healthy participants (n = 244) were first divided based on completion of set 1 - which measures subjects' ability to use inductive reasoning to arrive at the correct set. Results showed that participants who failed set 1 produced lower parietal P300, independent of clinical status. In the second tier of analysis, a double dissociation was found among healthy set 1 completers: frontal P300 amplitudes were negatively associated with perseverative errors, and parietal P300 was negatively associated with regressive errors. In contrast, psychosis participants showed global P300 reductions regardless of PCET performance. From this we conclude that in psychosis, overall activations evoked by the oddball task are reduced while the cognitive functions required by PCET are still somewhat supported, showing some level of independence or compensatory physiology in psychosis between neural activities underlying the two tasks.

Antisaccade error rates and gap effects in psychosis syndromes from bipolar-schizophrenia network for intermediate phenotypes 2 (B-SNIP2).

BACKGROUND: Antisaccade tasks can be used to index cognitive control processes, e.g. attention, behavioral inhibition, working memory, and goal maintenance in people with brain disorders. Though diagnoses of schizophrenia (SZ), schizoaffective (SAD), and bipolar I with psychosis (BDP) are typically considered to be distinct entities, previous work shows patterns of cognitive deficits differing in degree, rather than in kind, across these syndromes. METHODS: Large samples of individuals with psychotic disorders were recruited through the Bipolar-Schizophrenia Network on Intermediate Phenotypes 2 (B-SNIP2) study. Anti- and pro-saccade task performances were evaluated in 189 people with SZ, 185 people with SAD, 96 people with BDP, and 279 healthy comparison participants. Logistic functions were fitted to each group's antisaccade speed-performance tradeoff patterns. RESULTS: Psychosis groups had higher antisaccade error rates than the healthy group, with SZ and SAD participants committing 2 times as many errors, and BDP participants committing 1.5 times as many errors. Latencies on correctly performed antisaccade trials in SZ and SAD were longer than in healthy participants, although error trial latencies were preserved. Parameters of speed-performance tradeoff functions indicated that compared to the healthy group, SZ and SAD groups had optimal performance characterized by more errors, as well as less benefit from prolonged response latencies. Prosaccade metrics did not differ between groups. CONCLUSIONS: With basic prosaccade mechanisms intact, the higher speed-performance tradeoff cost for antisaccade performance in psychosis cases indicates a deficit that is specific to the higher-order cognitive aspects of saccade generation.

Reduced white matter microstructure in bipolar disorder with and without psychosis.

OBJECTIVES: Affective and psychotic features overlap considerably in bipolar I disorder, complicating efforts to determine its etiology and develop targeted treatments. In order to clarify whether mechanisms are similar or divergent for bipolar disorder with psychosis (BDP) and bipolar disorder with no psychosis (BDNP), neurobiological profiles for both the groups must first be established. This study examines white matter structure in the BDP and BDNP groups, in an effort to identify portions of white matter that may differ between the bipolar and healthy groups or between the bipolar subgroups themselves. METHODS: Diffusion-weighted imaging data were acquired from participants with BDP (n = 45), BDNP (n = 40), and healthy comparisons (HC) (n = 66). Fractional anisotropy (FA), radial diffusivity (RD), and spin distribution function (SDF) values indexing white matter diffusivity or spin density were calculated and compared between the groups. RESULTS: In comparisons between both the bipolar groups and HC, FA (FDR < 0.00001) and RD (FDR = 0.0037) differed minimally, in localized portions of the left cingulum and corpus callosum, while reductions in SDF (FDR = 0.0002) were more widespread. The bipolar subgroups did not differ from each other on FA, RD, or SDF metrics. CONCLUSIONS: Together, these results demonstrate a novel profile of white matter differences in bipolar disorder and suggest that this white matter pathology is associated with the affective disturbance common to those with bipolar disorder rather than the psychotic features unique to some. The white matter alterations identified in this study may provide substrates for future studies examining specific mechanisms that target affective domains of illness.

Smooth pursuit eye movement deficits as a biomarker for psychotic features in bipolar disorder-Findings from the PARDIP study.

OBJECTIVES: Smooth pursuit eye movement deficits are an established psychosis biomarker across schizophrenia, schizoaffective and psychotic bipolar disorder (BPwP). Whether smooth pursuit deficits are also seen in bipolar disorder without psychosis (BPwoP) is unclear. Here we present data from the Psychosis and Affective Research Domains and Intermediate Phenotypes (PARDIP) study comparing bipolar patients with and without psychotic features. METHODS: Probands with BPwP (N = 49) and BPwoP (N = 36), and healthy controls (HC, N = 71) performed eye tracking tasks designed to evaluate specific sensorimotor components relevant for pursuit initiation and pursuit maintenance. RESULTS: While BPwoP did not differ from either BPwP or HC on initial eye acceleration, they performed significantly better than BPwP on early (P < .01) and predictive (P = .02) pursuit maintenance measures, both without differing from HC. BPwP were impaired compared to HC on initial eye acceleration, and on early and predictive pursuit maintenance (all P < .01). In contrast to the three pursuit measures, BPwP and BPwoP were both impaired on general neurocognitive assessments in relation to HC (both P < .001), without a significant difference between the two bipolar patient groups. CONCLUSIONS: Our findings support the model that impairments of sensorimotor and cognitive processing as required for early and later predictive smooth pursuit maintenance are relatively specific to those bipolar patients with a history of psychosis. This suggests that the neural circuitry for developing feed-forward predictive models for accurate pursuit maintenance is associated with the occurrence of psychotic features in bipolar patients. In contrast, generalized neuropsychological impairments did not differentiate the two bipolar patient groups.