Tina Gupta

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.

When Does Stress Help or Harm? The Effects of Stress Controllability and Subjective Stress Response on Stroop Performance

The ability to engage in goal-directed behavior despite exposure to stress is critical to resilience. Questions of how stress can impair or improve behavioral functioning are important in diverse settings, from athletic competitions to academic testing. Previous research suggests that controllability is a key factor in the impact of stress on behavior: learning how to control stressors buffers people from the negative effects of stress on subsequent cognitively demanding tasks. In addition, research suggests that the impact of stress on cognitive functioning depends on an individual’s response to stressors: moderate responses to stress can lead to improved performance while extreme (high or low) responses can lead to impaired performance. The present studies tested the hypothesis that (1) learning to behaviorally control stressors leads to improved performance on a test of general executive functioning, the color-word Stroop, and that (2) this improvement emerges specifically for people who report moderate (subjective) responses to stress. Experiment 1: Stroop performance, measured before and after a stress manipulation, was compared across groups of undergraduate participants (n = 109). People who learned to control a noise stressor and received accurate performance feedback demonstrated reduced Stroop interference compared with people exposed to uncontrollable noise stress and feedback indicating an exaggerated rate of failure. In the group who learned behavioral control, those who reported moderate levels of stress showed the greatest reduction in Stroop interference. In contrast, in the group exposed to uncontrollable events, self-reported stress failed to predict performance. Experiment 2: In a second sample (n = 90), we specifically investigated the role of controllability by keeping the rate of failure feedback constant across groups. In the group who learned behavioral control, those who reported moderate levels of stress showed the greatest Stroop improvement. Once again, this pattern was not demonstrated in the group exposed to uncontrollable events. These results suggest that stress controllability and subjective response interact to affect high-level cognitive abilities. Specifically, exposure to moderate, controllable stress benefits performance, but exposure to uncontrollable stress or having a more extreme response to stress tends to harm performance. These findings may provide insights on how to leverage the beneficial effects of stress in a range of settings.

Sleep dysfunction and thalamic abnormalities in adolescents at ultra high-risk for psychosis.

BACKGROUND Sleep dysfunction is a pervasive, distressing characteristic of psychosis, yet little is known regarding sleep quality prior to illness onset. At present, it is unclear whether sleep dysfunction precedes the emergence of psychotic symptoms, signifying a core feature of the disorder, or if it represents a consequence of prolonged contact with aspects of schizophrenia and its treatment (e.g., medication use or neurotoxicity) or co-morbid symptoms (e.g., depressive and manic symptomatology). The current study examined sleep dysfunction in adolescents at ultra high-risk (UHR) for psychosis, relationships between sleep disturbances and psychosis symptoms, volume of an integral sleep-structure (thalamus), and associations between thalamic abnormalities and sleep impairment in UHR youth. METHOD Thirty-three UHR youth and 33 healthy controls (HC) participated in a self-assessment of sleep functioning (Pittsburgh Sleep Quality Index; PSQI), self and parent-report clinical interviews, and structural magnetic resonance imaging (MRI). RESULTS UHR adolescents displayed increased latency to sleep onset and greater sleep disturbances/disrupted continuity compared to HC youth, over and above concurrent mood symptoms. Among UHR youth, increased sleep dysfunction was associated with greater negative symptom severity but not positive symptoms. Compared to HC adolescents, UHR participants displayed decreased bilateral thalamus volume, which was associated with increased sleep dysfunction. CONCLUSIONS Sleep dysfunction occurs during the pre-psychotic period, and may play a role in the etiology and pathophysiology of psychosis. In addition, the relationship of disrupted sleep to psychosis symptoms in UHR youth indicates that prevention and intervention strategies may be improved by targeting sleep stabilization in the pre-psychotic period.

Actigraphic-measured sleep disturbance predicts increased positive symptoms in adolescents at ultra high-risk for psychosis: A longitudinal study.

BACKGROUND Sleep disturbance is prevalent among patients with psychosis, yet little is known about sleep health during the ultra high-risk (UHR) period. This study used actigraphy to evaluate sleep in healthy control (HC) and UHR adolescents to examine the relationship between sleep disturbance and psychosis symptoms at baseline and 12-month follow-up, as well as comparisons between objective and subjective measurements of sleep functioning in UHR youth. METHOD Thirty-six UHR and 31 HC youth participated in a baseline evaluation including 5 nights of actigraphy, subjective measurement of sleep health (Pittsburgh Sleep Quality Index; PSQI), and clinical interviews. Clinical measures were repeated with UHR youth (N=23) at a 12-month follow-up. RESULTS The actigraphy data indicated that UHR youth displayed increased wake time after onset (WASO), increased movements during sleep, and decreased efficiency compared to HC, and several markers of sleep disturbance including decreased efficiency, increased WASO, number of awakenings, and increased movements were associated with symptomatology in the UHR group. Interestingly, there were associations between actigraph and self-report indices of sleep duration and efficiency (at the trend level) but not awakenings. Several objective measures of sleep disturbance and one self-reported measure (disrupted continuity) predicted the longitudinal course of symptoms over 12 months in the UHR group. CONCLUSIONS Taken together, the results suggest a potential role for sleep problems in the etiology of schizophrenia, and highlight sleep health as a possible target for prevention/intervention efforts. Additionally, actigraphy represents an inexpensive, sensitive measurement providing unique information not captured by self-report, and may be an informative adjunct to UHR assessments.

Physical Activity Level and Medial Temporal Health in Youth at Ultra High-Risk for Psychosis

A growing body of evidence suggests that moderate to vigorous activity levels can affect quality of life, cognition, and brain structure in patients diagnosed with schizophrenia. However, physical activity has not been systematically studied during the period immediately preceding the onset of psychosis. Given reports of exercise-based neurogenesis in schizophrenia, understanding naturalistic physical activity levels in the prodrome may provide valuable information for early intervention efforts. The present study examined 29 ultra high-risk (UHR) and 27 matched controls to determine relationships between physical activity level, brain structure (hippocampus and parahippocampal gyrus), and symptoms. Participants were assessed with actigraphy for a 5-day period, MRI, and structured clinical interviews. UHR participants showed a greater percentage of time in sedentary behavior while healthy controls spent more time engaged in light to vigorous activity. There was a strong trend to suggest the UHR group showed less total physical activity. The UHR group exhibited smaller medial temporal volumes when compared with healthy controls. Total level of physical activity in the UHR group was moderately correlated with parahippocampal gyri bilaterally (right: r = .44, left: r = .55) and with occupational functioning (r = -.36; of negative symptom domain), but not positive symptomatology. Results suggest that inactivity is associated with medial temporal lobe health. Future studies are needed to determine if symptoms are driving inactivity, which in turn may be affecting the health of the parahippocampal structure and progression of illness. Although causality cannot be determined from the present design, these findings hold important implications for etiological conceptions and suggest promise for an experimental trial.

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.

Cerebellar Morphology and Procedural Learning Impairment in Neuroleptic-Naive Youth at Ultrahigh Risk of Psychosis

Despite evidence suggesting a role for cerebellar abnormalities in the pathogenesis of psychosis, the structure has yet to receive attention in individuals at ultrahigh risk for psychosis (UHR). Accumulating research has suggested that the cerebellum helps modulate cognition and movement, domains in which UHR individuals show impairment; understanding putative markers of risk, such as structural abnormalities and behavioral correlates, is essential. In this study, participants underwent a high-resolution structural brain scan and participated in a pursuit rotor experiment. Cerebellar regions associated with movement (anterior cerebellum) and cognition (crus I) were subsequently analyzed. UHR participants showed impaired performance on the pursuit rotor task, learned at a slower rate, and showed smaller cerebellar volumes compared with control participants. Left crus I volume was significantly associated with poor rate of learning. The present results suggest that cerebellar abnormalities and their behavioral correlates (poor learning and motor control) precede the onset of psychosis.

Hippocampal Shape Abnormalities Predict Symptom Progression in Neuroleptic-Free Youth at Ultrahigh Risk for Psychosis

INTRODUCTION Hippocampal abnormalities have been widely studied in schizophrenia spectrum populations including those at ultrahigh risk (UHR) for psychosis. There have been inconsistent findings concerning hippocampal morphology prior to and during the transition to psychosis, and little is known about how specific subregions are related to the symptom progression. METHODS A total of 80 participants (38 UHR and 42 healthy controls) underwent a 3T MRI scan, as well as structured clinical interviews. Shape analysis of hippocampi was conducted with FSL/FIRST vertex analysis to yield a localized measure of shape differences between groups. A subgroup of the sample (24 UHR and 24 controls) also returned for a 12-month clinical follow-up assessment. RESULTS The UHR group exhibited smaller hippocampal volumes bilaterally, and shape analysis revealed significant inversion in the left ventral posterior hippocampus in the UHR group. Greater inversion in this subregion was related to elevated symptomatology at baseline and increased positive symptoms, negative symptoms, and impaired tolerance to normal stress 12 months later. These results did not hold when left hippocampal volume was used as a predictor instead. DISCUSSION This represents the first study to use vertex analysis in a UHR sample and results suggest that abnormalities in hippocampal shape appear to reflect underlying pathogenic processes driving the progression of illness. These findings suggest that examining shape and volume may provide an important new perspective for our conception of brain alterations in the UHR period.

Striatal Abnormalities and Spontaneous Dyskinesias in Non-Clinical Psychosis

BACKGROUND Accumulating evidence suggests that individuals experiencing non-clinical psychosis (NCP) represent a critical group for improving understanding of etiological factors underlying the broader psychosis continuum. Although a wealth of evidence supports widespread neural dysfunction in formal psychosis, there has been little empirical evidence to inform our understanding of putative vulnerability markers or brain structure in NCP. In this study, we examined the neural correlates of spontaneous movement abnormalities, a biomarker previously detected in NCP that is linked to abnormalities in the striatal dopamine. METHODS We screened a total of 1285 adolescents/young adults, and those scoring in the upper 15th percentile on a NCP scale were invited to participate; 20 of those invited agreed and these individuals were matched with healthy controls. Participants were administered a structural scan, clinical interviews, and an instrumental motor assessment. RESULTS The NCP group showed elevated force variability and smaller putamen (but not caudate), and there was a significant relationship between motor dysfunction and striatal abnormalities for the sample. Elevated force variability was associated with both higher positive and negative symptoms, and there was a strong trend (p=.06) to suggest that smaller left putamen volumes were associated with elevated positive symptoms. CONCLUSIONS The results are among the first to suggest an association between neural structure and a risk marker in NCP. Findings indicate that vulnerabilities seen in schizophrenia also characterize the lower end of the psychosis spectrum.

Mismatch and lexical retrieval gestures are associated with visual information processing, verbal production, and symptomatology in youth at high risk for psychosis

INTRODUCTION Gesture is integrally linked with language and cognitive systems, and recent years have seen a growing attention to these movements in patients with schizophrenia. To date, however, there have been no investigations of gesture in youth at ultra high risk (UHR) for psychosis. Examining gesture in UHR individuals may help to elucidate other widely recognized communicative and cognitive deficits in this population and yield new clues for treatment development. METHOD In this study, mismatch (indicating semantic incongruency between the content of speech and a given gesture) and retrieval (used during pauses in speech while a person appears to be searching for a word or idea) gestures were evaluated in 42 UHR individuals and 36 matched healthy controls. Cognitive functions relevant to gesture production (i.e., speed of visual information processing and verbal production) as well as positive and negative symptomatologies were assessed. RESULTS Although the overall frequency of cases exhibiting these behaviors was low, UHR individuals produced substantially more mismatch and retrieval gestures than controls. The UHR group also exhibited significantly poorer verbal production performance when compared with controls. In the patient group, mismatch gestures were associated with poorer visual processing speed and elevated negative symptoms, while retrieval gestures were associated with higher speed of visual information-processing and verbal production, but not symptoms. CONCLUSIONS Taken together these findings indicate that gesture abnormalities are present in individuals at high risk for psychosis. While mismatch gestures may be closely related to disease processes, retrieval gestures may be employed as a compensatory mechanism.