Jerillyn S. Kent

Cerebellar networks in individuals at ultra high-risk of psychosis: impact on postural sway and symptom severity.

Despite known deficits in postural control in patients with schizophrenia, this domain has not been investigated in youth at ultra high‐risk (UHR) for psychosis. This is particularly relevant as postural control implicates dysfunction in the cerebellum‐a region implicated in cognitive dysmetria conceptions of schizophrenia but poorly understood in the prodrome. Here, we extended our understanding of movement abnormalities in UHR individuals to include postural control, and have linked these deficits to both symptom severity and cerebello‐cortical network connectivity. UHR and healthy control participants completed an instrumentally based balance task to quantify postural control along with a resting state brain imaging scan to investigate cerebellar networks. We also quantified positive and negative symptom severity with structured clinical interviews. The UHR group showed overall increased postural sway and decreased cerebello‐cortical resting state connectivity, relative to controls. The decreased cerebello‐cortical connectivity was seen across multiple networks. Postural sway was also correlated with cerebellar connectivity in this population and uniquely positively correlated with the severity of negative symptoms. Finally, symptom severity was also associated with cerebellar connectivity. Together, our results point to a potential deficit in sensory integration as an underlying contributor to the increased postural sway, and provide evidence of cerebellar abnormalities in UHR individuals. These results extend our understanding of the motor abnormalities of UHR individuals beyond striatum‐based dyskinesias to include postural control and sensory integration deficits, and implicate the cerebellum as a distinct neural substrate preceding the onset of psychosis. Taken together, our results extend the cognitive dysmetria framework to UHR populations. Hum Brain Mapp 35:4064–4078, 2014.

Motor Deficits in Schizophrenia Quantified by Nonlinear Analysis of Postural Sway

Motor dysfunction is a consistently reported but understudied aspect of schizophrenia. Postural sway area was examined in individuals with schizophrenia under four conditions with different amounts of visual and proprioceptive feedback: eyes open or closed and feet together or shoulder width apart. The nonlinear complexity of postural sway was assessed by detrended fluctuation analysis (DFA). The schizophrenia group (n = 27) exhibited greater sway area compared to controls (n = 37). Participants with schizophrenia showed increased sway area following the removal of visual input, while this pattern was absent in controls. Examination of DFA revealed decreased complexity of postural sway and abnormal changes in complexity upon removal of visual input in individuals with schizophrenia. Additionally, less complex postural sway was associated with increased symptom severity in participants with schizophrenia. Given the critical involvement of the cerebellum and related circuits in postural stability and sensorimotor integration, these results are consistent with growing evidence of motor, cerebellar, and sensory integration dysfunction in the disorder, and with theoretical models that implicate cerebellar deficits and more general disconnection of function in schizophrenia.

Postural control in bipolar disorder: increased sway area and decreased dynamical complexity.

Structural, neurochemical, and functional abnormalities have been identified in the brains of individuals with bipolar disorder, including in key brain structures implicated in postural control, i.e. the cerebellum, brainstem, and basal ganglia. Given these findings, we tested the hypothesis that postural control deficits are present in individuals with bipolar disorder. Sixteen participants with bipolar disorder (BD) and 16 age-matched non-psychiatric healthy controls were asked to stand as still as possible on a force platform for 2 minutes under 4 conditions: (1) eyes open-open base; (2) eyes closed-open base; (3) eyes open-closed base; and (4) eyes closed-closed base. Postural sway data were submitted to conventional quantitative analyses of the magnitude of sway area using the center of pressure measurement. In addition, data were submitted to detrended fluctuation analysis, a nonlinear dynamical systems analytic technique that measures complexity of a time-series, on both the anterior-posterior and medio-lateral directions. The bipolar disorder group had increased sway area, indicative of reduced postural control. Decreased complexity in the medio-lateral direction was also observed for the bipolar disorder group, suggesting both a reduction in dynamic range available to them for postural control, and that their postural corrections were primarily dominated by longer time-scales. On both of these measures, significant interactions between diagnostic group and visual condition were also observed, suggesting that the BD participants were impaired in their ability to make corrections to their sway pattern when no visual information was available. Greater sway magnitude and reduced complexity suggest that individuals with bipolar disorder have deficits in sensorimotor integration and a reduced range of timescales available on which to make postural corrections.

Paced finger-tapping abnormalities in bipolar disorder indicate timing dysfunction

OBJECTIVES Theoretical and empirical evidence suggests that impaired time perception and the neural circuitry contributing to internal timing mechanisms may contribute to severe psychiatric disorders, including mood disorders. The structures that are involved in subsecond timing, i.e., cerebellum and basal ganglia, have also been implicated in the pathophysiology of bipolar disorder. However, the timing of subsecond intervals has infrequently been studied in this population. METHODS Paced finger-tapping tasks have been used to characterize internal timing processes in neuropsychiatric disorders. A total of 42 bipolar disorder patients (25 euthymic, 17 manic) and 42 age-matched healthy controls completed a finger-tapping task in which they tapped in time with a paced (500-ms intertap interval) auditory stimulus (synchronization), then continued tapping without auditory input while attempting to maintain the same pace (continuation). This procedure was followed using the dominant index finger, then with alternating thumbs. RESULTS Bipolar disorder participants showed greater timing variability relative to controls regardless of pacing stimulus (synchronization versus continuation) or condition (dominant index finger versus alternating thumbs). Decomposition of timing variance into internal clock versus motor implementation components using the Wing-Kristofferson model showed higher clock variability in the bipolar disorder groups compared to controls, with no differences between groups on motor implementation variability. CONCLUSIONS These findings suggest that internal timing mechanisms are disrupted in bipolar disorder patients, independent of symptom status. Increased clock variability in bipolar disorder may be related to abnormalities in cerebellar function.

Increased postural sway predicts negative symptom progression in youth at ultrahigh risk for psychosis

Impaired ability to maintain an upright posture may reflect impairment in the cerebellum, a critical structure for the fluid coordination of neural information, thought to be disrupted in psychosis. The current study utilized an instrumental measure of posture in individuals at ultrahigh risk (UHR) for psychosis (n=43) and healthy controls (n=44). Positive and negative symptoms were assessed twice over 12months. Results showed that increased postural sway in the UHR group predicted changes in negative symptoms. This study provides an important prospective view on the relationship between cerebellar-sensitive behavior and integral symptoms, which until now has received limited biomarker research.

Disrupted Modular Architecture of Cerebellum in Schizophrenia: A Graph Theoretic Analysis

Recent studies of schizophrenia have revealed cognitive and memory deficits that are accompanied by disruptions of neuronal connectivity in cortical and subcortical brain regions. More recently, alterations of topological organization of structural networks in schizophrenia are also being identified using graph theoretical analysis. However, the role of the cerebellum in this network structure remains largely unknown. In this study, global network measures obtained from diffusion tensor imaging were computed in the cerebella of 25 patients with schizophrenia and 36 healthy volunteers. While cerebellar global network characteristics were slightly altered in schizophrenia patients compared with healthy controls, the patients showed a retained small-world network organization. The modular architecture, however, was changed mainly in crus II. Furthermore, schizophrenia patients had reduced correlations between modularity and microstructural integrity, as measured by fractional anisotropy (FA) in lobules I-IV and X. Finally, FA alterations were significantly correlated with the Positive and Negative Syndrome Scale symptom scores in schizophrenia patients. Taken together, our data suggest that schizophrenia patients have altered network architecture in the cerebellum with reduced local microstructural connectivity and that cerebellar structural abnormalities are associated symptoms of the disorder.

The clinical and prognostic value of motor abnormalities in psychosis, and the importance of instrumental assessment.

HIGHLIGHTSMotor abnormalities should be considered as a prodrome of psychotic disorders.Motor abnormalities can be quantified with innovative instruments, yielding sensitive, valid and reliable data and will become the new standard.Motor symptoms have a predictive value for the development and course of psychosis and should be added to the symptomatology of psychotic disorders besides the other psychotic symptoms.Motor abnormalities may become the first relevant non‐mental sign in psychotic spectrum disorders in particular because of its objective assessment with electronic and software‐based instruments. ABSTRACT Motor abnormalities comprise several clinical signs intrinsic to psychosis. Critically, these features are of prognostic value in individuals at‐risk for psychosis, and for those in early stages of psychotic disorders. Motor abnormalities such as tremor, rigidity, and neurological soft signs often go unrecognized. Currently, advances in this area are limited by a paucity of theoretical conceptions categorizing or linking these behaviours to underlying neurobiology affected in psychosis. However, emerging technological advances have significantly improved the ability to detect and assess motor abnormalities with objective instruments in a timely and reliable manner. Further, converging evidence has laid the groundwork for theoretically and empirically derived categorization and conceptualization. This review summarizes these advances, stressing the importance of motor abnormalities for understanding vulnerability across different stages of psychosis and introducing these innovative instrumental approaches. Patients, researchers and clinicians will benefit from these new developments, as better assessment aids the development of targeted interventions to ultimately improve the care for individuals experiencing psychosis.

Nodal centrality of functional network in the differentiation of schizophrenia.

A disturbance in the integration of information during mental processing has been implicated in schizophrenia, possibly due to faulty communication within and between brain regions. Graph theoretic measures allow quantification of functional brain networks. Functional networks are derived from correlations between time courses of brain regions. Group differences between SZ and control groups have been reported for functional network properties, but the potential of such measures to classify individual cases has been little explored. We tested whether the network measure of betweenness centrality could classify persons with schizophrenia and normal controls. Functional networks were constructed for 19 schizophrenic patients and 29 non-psychiatric controls based on resting state functional MRI scans. The betweenness centrality of each node, or fraction of shortest-paths that pass through it, was calculated in order to characterize the centrality of the different regions. The nodes with high betweenness centrality agreed well with hub nodes reported in previous studies of structural and functional networks. Using a linear support vector machine algorithm, the schizophrenia group was differentiated from non-psychiatric controls using the ten nodes with the highest betweenness centrality. The classification accuracy was around 80%, and stable against connectivity thresholding. Better performance was achieved when using the ranks as feature space as opposed to the actual values of betweenness centrality. Overall, our findings suggest that changes in functional hubs are associated with schizophrenia, reflecting a variation of the underlying functional network and neuronal communications. In addition, a specific network property, betweenness centrality, can classify persons with SZ with a high level of accuracy.

A magnetic resonance imaging-safe method for the study of human eyeblink conditioning

Eyeblink conditioning (EBC) is a widely used translational probe of cerebellar function in both humans and non-human animals. Decades of animal research have identified the cerebellum as critical for EBC. While there is evidence for the involvement of the cerebellum in human EBC, the neural circuitry of EBC in healthy humans has yet to be fully elucidated. The purpose of this study was to design and validate a highly customisable system for EBC stimulus presentation and response recording using infrared (IR) reflectance suitable for use in magnetic resonance imaging (MRI) environments; in this way, the neural activity of EBC could be investigated using fMRI in humans. Four participants underwent delay EBC and simultaneous fMRI. The results indicate (1) a high signal-to-noise ratio in the IR reflectance data that effectively quantifies the eyeblink morphology and timing and (2) evidence of conditioning in the fMRI environment. The quality of the data, the feasibility of conducting EBC experiments in the fMRI environment, and the customisability of the current system to fit a variety of EBC experimental design parameters are discussed.