Timing dysfunction and cerebellar resting state functional connectivity abnormalities in youth at clinical high-risk for psychosis.

BACKGROUND: Consistent with pathophysiological models of psychosis, temporal disturbances in schizophrenia spectrum populations may reflect abnormal cortical (e.g. prefrontal cortex) and subcortical (e.g. striatum) cerebellar connectivity. However, few studies have examined associations between cerebellar connectivity and timing dysfunction in psychosis populations, and none have been conducted in youth at clinical high-risk (CHR) for psychosis. Thus, it is currently unknown if impairments in temporal processes are present in CHR youth or how they may be associated with cerebellar connectivity and worsening of symptoms. METHODS: A total of 108 (56 CHR/52 controls) youth were administered an auditory temporal bisection task along with a resting state imaging scan to examine cerebellar resting state connectivity. Positive and negative symptoms at baseline and 12 months later were also quantified. RESULTS: Controlling for alcohol and cannabis use, CHR youth exhibited poorer temporal accuracy compared to controls, and temporal accuracy deficits were associated with abnormal connectivity between the bilateral anterior cerebellum and a right caudate/nucleus accumbens striatal cluster. Poor temporal accuracy accounted for 11% of the variance in worsening of negative symptoms over 12 months. CONCLUSIONS: Behavioral findings suggest CHR youth perceive durations of auditory tones as shortened compared to objective time, which may indicate a slower internal clock. Poorer temporal accuracy in CHR youth was associated with abnormalities in brain regions involved in an important cerebellar network implicated in prominent pathophysiological models of psychosis. Lastly, temporal accuracy was associated with worsening of negative symptoms across 12 months, suggesting temporal dysfunction may be sensitive to illness progression.

Ethical, Legal, and Clinical Considerations when Disclosing a High-Risk Syndrome for Psychosis.

There are complex considerations when planning to disclose an attenuated psychosis syndrome (APS) diagnosis. In this review, we evaluate ethical, legal, and clinical perspectives as well as caveats related to full, non- and partial disclosure strategies, discuss societal implications, and provide clinical suggestions. Each of the disclosure strategies is associated with benefits as well as costs/considerations. Full disclosure promotes autonomy, allows for the clearest psychoeducation about additional risk factors, helps to clarify and/or correct previous diagnoses/treatments, facilitates early intervention and bolsters communication between providers but there are important considerations involving heritability, comorbidity, culture, and stigma. Non-disclosure advances nonmaleficence by limiting stigma and stress (which may inadvertently exacerbate the condition), and confusion (related to the rapidly evolving diagnosis) in a sensitive developmental period but is complicated by varying patient preferences and the possibility that, as new treatments without adverse effects become available, the risk with false positives no longer justifies the accompanying loss of autonomy. Partial disclosure balances ethical considerations by focusing on symptoms instead of labels, but evidence that laypersons may interpret this information as a pseudo-diagnosis and that symptoms alone also contribute to stigma limits the efficacy of this approach. In addition, there are notable societal considerations relating to disclosure involving conservatorship, the reach of insurance companies, and discrimination. We advocate a hybrid approach to disclosure and recommend future research aimed at understanding the effects of stigma on clinical course and a renewed focus on those help-seeking cases that do not transition but remain clinically relevant.

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.

Interpersonal Coordination in Schizophrenia: A Scoping Review of the Literature.

Interpersonal coordination forms the natural bridge between the self and others. It arises from the dynamic and complex set of embodied processes that involve nonverbal behaviors, perceptions, movement, and emotions that support adaptive interactions. Disembodiment has been implicated in a myriad of core clinical phenomena that manifest in a "praecox feeling" in persons with schizophrenia during interpersonal interactions. To further understand mechanisms underlying aberrant interpersonal interactions in schizophrenia, recent research has focused on mimicry, imitation, and interactional synchrony. In this study, we conducted a Pubmed, Web of Science, and PsycInfo database review of the literature on interpersonal coordination in schizophrenia to evaluate the body of work in mimicry, imitation, and interactional synchrony in relation to schizophrenia-spectrum conditions. The results of the review suggest that the sensory-motor processes underlying interpersonal coordination may result in impaired abilities to mimic and synchronize nonverbal behavior during interactions. Opportunities for future progress lie in studies of interpersonal coordination at different developmental stages of psychosis, potential use of interpersonal coordination to improve treatment adherence and reduce stigma, as well as interventions to improve social functioning in people with a serious mental illness.

Cross-cultural comparisons of psychosocial distress in the USA, South Korea, France, and Hong Kong during the initial phase of COVID-19.

The COVID-19 crisis has resulted in disruption of everyday life worldwide but the impact and response to the pandemic have not been uniform. Many countries rapidly deployed physical-distancing mandates to curb the spread of the virus; others did not. Social distancing strategies are necessary to reduce the transmission of the virus but there may be unintended consequences. We examined psychological distress in four societies with distinct public health strategies (South Korea, Hong Kong, France and the United States) to identify common and region-specific factors that may contribute to mental health outcome during the pandemic. From March to July of 2020, a survey of demographics, general health, mental health, loneliness and social networks was conducted. Overall, younger age, greater concern for COVID, and more severe loneliness predicted worse psychological outcome but the magnitudes of these effects varied across the four regions. Objective measures of social isolation did not affect mental health. There were also notable differences in psychological outcome; Hong Kong, with very strict social distancing protocols plus ongoing political unrest, suffered the most drastic deterioration of mental health. To prepare for an impending mental health crisis, concerted efforts to reduce loneliness should be integrated into a comprehensive public health strategy.

Cognitive motor impairments and brain structure in schizophrenia spectrum disorder patients with a history of catatonia.

There is growing interest in understanding the behavioral and neural mechanisms of catatonia. Here, we examine cognition and brain structure in schizophrenia spectrum disorder (SSD) patients with a history of catatonia. A total of 172 subjects were selected from a data repository; these included SSD patients with (n = 43) and without (n = 43) a history of catatonia and healthy control subjects (n = 86). Cognitive functioning was assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP) and brain structure was assessed using voxel-based morphometry (VBM) in the CAT12 toolbox. SSD patients with a history of catatonia showed worse performance on tests of verbal fluency and processing speed compared to SSD patients without such a history, even after controlling for current antipsychotic and benzodiazepine use. No differences were found between patients with and without a history of catatonia in terms of brain structure. Both patient groups combined showed significantly smaller grey matter volumes compared to healthy control subjects in brain regions consistent with prior studies, including the anterior cingulate, insular, temporal, and medial frontal cortices. The results highlight a cognitive-motor impairment in SSD patients with a history of catatonia. Challenges and limitations of examining brain structure in patients with a history of catatonia are discussed.

Longitudinal Assessment and Functional Neuroimaging of Movement Variability Reveal Novel Insights Into Motor Dysfunction in Clinical High Risk for Psychosis.

Motor dysfunction in youth at clinical high risk (CHR) for psychosis is thought to reflect abnormal neurodevelopment within cortical-subcortical motor circuits and may be important for understanding clinical trajectories of CHR individuals. However, to date, our perspective of brain-behavior relationships has been informed solely by cross-sectional correlational studies linking behavior in the lab to brain structure or respective resting-state network connectivity. Here, we assess movement dysfunction from 2 perspectives: study 1 investigates the longitudinal progression of handwriting variability and positive symptoms in a sample of 91 CHR and healthy controls during a 12-month follow-up and study 2 involves a multiband functional magnetic resonance imaging task exploring the relationship between power grip force stability and motor network brain activation in a subset of participants. In study 1, we found that greater handwriting variability was a stable feature of CHR participants who experienced worse symptom progression. Study 2 results showed that CHR individuals had greater variability in their grip force and greater variability was related to decreased activation in the associative cortico-striatal network compared to controls. Motor variability may be a stable marker of vulnerability for psychosis risk and possible indicator of a vulnerable cortico-striatal brain network functioning in CHR participants, although the effects of antipsychotic medication should be considered.

The cerebellum and learning of non-motor associations in individuals at clinical-high risk for psychosis.

The cerebello-thalamo-cortical circuit (CTCC) has been implicated in schizophrenia. However, this work has been limited to structural and functional networks, or behavior, and to date, has not been evaluated in clinical high-risk (CHR) youth, a group at elevated risk for psychosis. Here, we used an innovative learning paradigm known to activate the CTCC (while limiting potential motor confounds) to evaluate CHR and healthy control individuals during functional magnetic resonance imaging (fMRI). 20 CHR and 21 healthy control individuals performed a second-order rule learning task while undergoing fMRI. This was preceded and followed by the paradigm under dual-task conditions. In addition, all participants underwent structured clinical interviews to confirm a prodromal syndrome and assess symptom severity. The rate of learning did not differ between groups. However, the CHR group consistently performed more poorly under dual-task conditions, and exhibited a higher dual-task cost after learning. Further, learning rate in the CHR group was significantly associated with symptom severity. Both groups showed activation in regions of the CTCC. During early learning, the CHR group exhibited greater engagement of regions of the default mode network, suggesting that they were less able to engage the appropriate task positive networks. During late learning, there were qualitative differences wherein controls showed more prefrontal cortical activation. Higher order cognitive rule learning is related to symptom severity in CHR individuals. fMRI revealed that CHR individuals may not reliably disengage the default mode network, and during late learning high-risk youth may not engage the prefrontal cortex as extensively as controls.

Motion energy analysis reveals altered body movement in youth at risk for psychosis.

BACKGROUND: Growing evidence suggests that movement abnormalities occur prior to the onset of psychosis. Innovations in technology and software provide the opportunity for a fine-tuned and sensitive measurement of observable behavior that may be particularly useful to detecting the subtle movement aberrations present during the prodromal period. METHODS: In the present study, 54 youth at ultrahigh risk (UHR) for psychosis and 62 healthy controls participated in structured clinical interviews to assess for an UHR syndrome. The initial 15min of the baseline clinical interview was assessed using Motion Energy Analysis (MEA) providing frame-by-frame measures of total movement, amplitude, speed, and variability of both head and body movement separately. RESULTS: Result showed region-specific group differences such that there were no differences in head movement but significant differences in body movement. Specifically, the UHR group showed greater total body movement and speed of body movements, and lower variation in body movement compared to healthy controls. However, there were no significant associations with positive, negative or disorganized symptom domains. CONCLUSION: This study represents an innovative perspective on gross motor function in the UHR group. Importantly, the automated approach used in this study provides a sensitive and objective measure of body movement abnormalities, potentially guiding novel assessment and prevention of symptom development in those at risk for psychosis.

What prevents youth at clinical high risk for psychosis from engaging in physical activity? An examination of the barriers to physical activity.

BACKGROUND: Exercise has increasingly been proposed as a healthful intervention prior to and after the onset of psychosis. There is some evidence to suggest that youth at clinical high risk (CHR) for psychosis are less physically active and report more barriers to engaging in exercise; however, there has been relatively limited empirical work documenting this phenomenon, and to date, relationships between physical activity, barriers, and clinical phenomenology have been unclear. METHODS: CHR (N = 51) and healthy control (N = 37) participants completed a structured clinical interview assessing attenuated psychotic symptoms and substance use, and an exercise survey that assessed current exercise practices, perceived physical fitness, and barriers related to engaging in exercise. RESULTS: CHR youth engaged in less physical activity, exhibited lower perception of fitness, and endorsed more barriers related to motivation for exercise. The CHR group showed significant negative correlations where lower perceptions of fitness were associated with increased negative, disorganized, and general symptoms. Decreased frequency of activity was related to more barriers of motivation. Interestingly, greater symptomatology in the CHR group was associated with more barriers of self-perception and motivation for engaging in exercise. However, findings suggested a nuanced relationship in this area; for example, increased physical activity was associated with increased substance use. CONCLUSIONS: The results of the current study support the notion that sedentary behavior is common in CHR youth, and more broadly, provide an impetus to target motivation through supervised exercise and fitness tracking to promote the health and well-being of CHR individuals.

Motor clusters reveal differences in risk for psychosis, cognitive functioning, and thalamocortical connectivity: evidence for vulnerability subtypes.

Abnormal development of parallel cortical-striatal networks may contribute to abnormal motor, cognitive, and affective behavior prior to the onset of psychosis. Partitioning individuals at clinical high-risk (CHR) using motor behavior may provide a novel perspective on different etiological pathways or patient subtypes. A K-means cluster analysis was conducted in CHR (N=69; 42% female, mean age=18.67 years) young adults using theoretically distinct measures of motor behavior. The resulting subtypes were then compared on positive and negative symptoms at baseline, and 2-year risk of psychosis conversion. CHR participants were followed for 2 years to determine conversion to psychosis. CHR subtypes and healthy controls (N=61; 57% female, mean age=18.58 years) were compared on multiple cognitive domains and cortical-striatal connectivity. Results suggest 3 vulnerability subtypes of CHR individuals with different profiles of motor performance, symptoms, risk for conversion to psychosis, cognition, and thalamocortical connectivity. This approach may reflect a novel strategy for promoting tailored risk assessment as well as future research developing individualized medicine.

Cerebellar Transcranial Direct Current Stimulation Improves Procedural Learning in Nonclinical Psychosis: A Double-Blind Crossover Study.

The present double-blind crossover study examines the effects of cerebellar transcranial direct current stimulation (tDCS) in controls and in an analogue population to psychosis: individuals reporting elevated symptoms of nonclinical psychosis (NCP). A total of 18 controls and 24 NCP individuals were randomized into conditions consisting of 25 minutes of anodal (active) or sham cerebellar tDCS. Following this, both groups completed a pursuit rotor task designed to measure procedural learning performance. Participants then returned 1-week later and received the corresponding condition (either active or sham) and repeated the pursuit rotor task. Results indicate that in the sham condition, control participants showed significantly greater rates of motor learning when compared with the NCP group. In the active condition, the NCP group exhibited significant improvements in the rate of motor learning and performed at a level that was comparable to controls; these data support the link between cerebellar dysfunction and motor learning. Taken together, tDCS may be a promising treatment mechanism for patient populations and a useful experimental approach in elucidating our understanding of psychosis.

Hippocampal Subregions Across the Psychosis Spectrum.

Introduction: Converging evidence suggests that hippocampal subregions subserve different functions, and are differentially affected by psychosis illness progression. Despite this fact, studies have not often studied subregions cross-sectionally across the psychosis spectrum. Furthermore, little is known about associations between subregion volumes and hippocampus-mediated cognition. Methods: A total of 222 participants (61 ultra high risk [UHR], 91 schizophrenia [SCZ], and 70 healthy volunteers) underwent a 3T MRI scan, as well as structured clinical interviews and a cognitive battery. Hippocampal subfield analysis was conducted with Freesurfer. We compared subregion volumes across groups, controlling for age, gender, and intracranial volume. We also examined associations in the UHR and SCZ groups between hippocampal subregion volumes and verbal learning, visual learning, and working memory. Results: We found a dose-dependent relationship such that the SCZ group showed significantly greater subfield volume reductions than the UHR group, which in turn showed significantly greater subfield volume reductions than the healthy volunteer group. We also found associations between subregion volume and cognitive performance in the visual memory, verbal memory, and working memory domains. Discussion: Our study examined hippocampal subregion volumes cross-sectionally in a large sample across the psychosis spectrum, as well as links with hippocampus-mediated cognitive function. Our findings suggest that hippocampal abnormalities emerge before first psychosis episode onset, and may be etiologically informative.

Self-reported sleep disturbances associated with procedural learning impairment in adolescents at ultra-high risk for psychosis.

Sleep disturbance contributes to impaired procedural learning in schizophrenia, yet little is known about this relationship prior to psychosis onset. Adolescents at ultra high-risk (UHR; N=62) for psychosis completed the Pittsburgh Sleep Quality Index (PSQI) and a procedural learning task (Pursuit Rotor). Increased self-reported problems with sleep latency, efficiency, and quality were associated with impaired procedural learning rate. Further, within-sample comparisons revealed that UHR youth reporting better sleep displayed a steeper learning curve than those with poorer sleep. Sleep disturbances appear to contribute to cognitive/motor deficits in the UHR period and may play a role in psychosis etiology.

A Supervised Exercise Intervention for Youth at Risk for Psychosis: An Open-Label Pilot Study.

OBJECTIVE: A rapidly accumulating body of research suggests that exercise can improve symptoms and well-being in patients suffering from psychosis. Exercise may also promote neurogenesis in the hippocampus, a structure that plays an important role in the pathophysiology of psychosis. To date, there has not been an intervention focused on exercise prior to the onset of psychosis, a critical time for prevention of more serious illness. METHODS: In this pilot study, 12 young adults at ultrahigh risk (UHR) for psychosis were enrolled in a 12-week open-label exercise intervention. Participants were randomly assigned to exercise 2 or 3 times each week and exercised between 65% and 85% of maximum oxygen capacity (Vo2max) for 30 minutes each session under the supervision of an exercise physiologist. Positive and negative symptoms, social and role functioning, performance on neurocognitive tests, cardiovascular fitness, and hippocampal structure and functional connectivity were evaluated before and after the trial. RESULTS: A total of 9 participants completed the exercise intervention. Participants showed improved positive and negative symptoms and social and role functioning; improvement in multiple areas of cognition; and increased functional connectivity between the left hippocampus and occipital cortex after 12 weeks of exercise. CONCLUSIONS: The results of this study suggest that exercise interventions are feasible in a UHR sample and may promote improvement in clinical, social, and cognitive domains as well as changes to brain function in regions impacted by the development of psychosis. These findings set the stage for an ongoing phase 2 randomized controlled trial. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02155699.

Beat gestures and postural control in youth at ultrahigh risk for psychosis.

Beat gestures, rhythmic hand movements that co-occur with speech, appear to be uniquely associated with the cerebellum in healthy individuals. This behavior may also have relevance for psychosis-risk youth, a group characterized by cerebellar dysfunction. This study examined beat gesture frequency and postural sway (a sensitive index of cerebellar functioning) in youth at ultrahigh risk (UHR) for psychosis. Results indicated that decreased beat gesture frequency, but not self-regulatory movement, is associated with elevated postural sway, suggesting that beat gestures may be an important biomarker in this critical population.

Motor behavior reflects reduced hemispheric asymmetry in the psychosis risk period.

BACKGROUND: A body of work focusing on brain connectivity, language dominance, and motor laterality research suggests that reduced hemispheric asymmetry is a core feature in schizophrenia. However, there is little consensus about whether reduced dominance is present in those at ultrahigh risk (UHR) for psychosis. METHODS: A total of 94 demonstrated right-handed neuroleptic free participants (38 UHR and 56 matched healthy controls) were assessed with structured clinical interviews and completed an innovative handwriting task using a digital tablet computer. A laterality quotient (LQ) was calculated using kinematic variables from the participant's left and right hands. A subset of the sample (26 UHR and 29 controls) returned after 12-months to complete clinical interviews in order to examine relationships between handwriting laterality and progression of psychosis risk symptoms. RESULTS: The UHR group showed decreased dextrality compared to healthy controls. At the 12-month follow-up, decreased dextrality accounted for 8% of the variance in worsened positive symptoms within the UHR group. CONCLUSION: The current results suggest that disrupted cerebral dominance is also present in the ultrahigh risk period and that decreased dextrality may serve as a novel biomarker for the progression of psychosis risk.

Fluctuating dermatoglyphic asymmetries in youth at ultrahigh-risk for psychotic disorders.

Fluctuating dermatoglyphic asymmetry represents one specific class of minor physical anomaly that has been proposed to reflect prenatal insult and vulnerability to psychosis. However, very little is known about fluctuating dermatoglyphic asymmetry in youth showing symptoms of ultrahigh risk (UHR) for psychosis. Using high-resolution photographs of fingerprints and clinical interviews, the UHR group in this study showed greater fluctuating dermatoglyphic asymmetry compared to controls; however, this was not further linked to symptomatology. The results of this study provide an important perspective on potential biomarkers and support neurodevelopmental conceptions 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.

Disruptions in neural connectivity associated with reduced susceptibility to a depth inversion illusion in youth at ultra high risk for psychosis.

Patients with psychosis exhibit a reduced susceptibility to depth inversion illusions (DII) in which a physically concave surface is perceived as convex (e.g., the hollow mask illusion). Here, we examined the extent to which lessened susceptibility to DII characterized youth at ultra high risk (UHR) for psychosis. In this study, 44 UHR participants and 29 healthy controls judged the apparent convexity of face-like human masks, two of which were concave and the other convex. One of the concave masks was painted with realistic texture to enhance the illusion; the other was shown without such texture. Networks involved with top-down and bottom-up processing were evaluated with resting state functional connectivity magnetic resonance imaging (fcMRI). We examined regions associated with the fronto-parietal network and the visual system and their relations with susceptibility to DII. Consistent with prior studies, the UHR group was less susceptible to DII (i.e., they were characterized by more veridical perception of the stimuli) than the healthy control group. Veridical responses were related to weaker connectivity within the fronto-parietal network, and this relationship was stronger in the UHR group, suggesting possible abnormalities of top-down modulation of sensory signals. This could serve as a vulnerability marker and a further clue to the pathogenesis of psychosis.