Jessica R. Lunsford-Avery

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.

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.

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.

Sleep impairment, mood symptoms, and psychosocial functioning in adolescent bipolar disorder

Few empirical studies have investigated the role of sleep impairment in the course of adolescent bipolar spectrum disorders (BSD). The present study examined the longitudinal associations between sleep disruption, mood symptom severity, and psychosocial functioning in a 2-year follow-up of patients with adolescent BSD. Fifty-three adolescents with BSD (mean [S.D.] age: 14.6 [1.6]) participated in a two-site randomized trial of family focused treatment for adolescents (FFT-A) or enhanced care, a briefer psychoeducational treatment; both treatments were administered with pharmacotherapy. Sleep disturbance was assessed with the Adolescent Sleep Habits Questionnaire (ASHQ) filled out by patients every 6 weeks in the first study year and every 3 months in the second year. Main outcomes included clinician-rated measures of mania, depression and psychosocial impairment over 2 years. Sleep impairment was significantly associated with mania and depression severity scores and psychosocial impairment ratings across the 2-year follow-up. Despite its efficaciousness in reducing mood symptoms, FFT-A was not more effective than enhanced care in improving sleep habits. Sleep impairment may play a substantial role in the course of adolescent BSD. Youth with BSDs may benefit from targeted psychosocial interventions that emphasize sleep regularity.

Hypothalamic–pituitary–adrenal axis dysfunction in non-clinical psychosis

While studies have examined psychosocial stress in non-clinical psychosis (NCP), it is unclear if the elevated cortisol seen in schizophrenia also occurs in this group. Cortisol was sampled in High- and Low-NCP groups, and findings of elevated resting cortisol in the former suggest that hypothalamic-pituitary-adrenal-axis dysfunction underlies a psychosis continuum.

Emotion recognition and social/role dysfunction in non-clinical psychosis

As researchers continue to understand non-clinical psychosis (NCP-brief psychotic-like experiences occurring in 5-7% of the general population; van Os et al., 2009), it is becoming evident that functioning deficits and facial emotion recognition (FER) impairment characterize this phenomenon. However, the extent to which these domains are related remains unclear. Social/role functioning and FER were assessed in 65 adolescents/young adults exhibiting low and high-NCP. Results indicate that FER and social/role functioning deficits were present in the High-NCP group, and that the domains were associated in this group alone. Taken together, findings suggest that a core emotive deficit is tied to broader social/role dysfunction in NCP.

BDNF Val66Met and spontaneous dyskinesias in non-clinical psychosis

BACKGROUND Evidence indicating that symptoms of non-clinical psychosis (NCP) occur in 6-8% of the general population suggests that psychosis may occur across a continuum. Although a number of studies have examined environmental contributors, to date there have been few investigations of biological/genetic factors in this integral population. A recent study observed spontaneous dyskinetic movements (reflecting an innervated striatal system) in individuals reporting NCP. The present investigation is designed to replicate this finding and determine if brain-derived neurotrophic factor (BDNF) (implicated in striatal dopamine function) is associated with dyskinesias. METHOD A total of 68 young-adult participants reporting High and Low-NCP were assessed for dyskinetic movements using a sensitive instrumental measure of force variability. Saliva from the participants was genotyped for val66met (rs6265), a common functional polymorphism of the BDNF gene (the Met allele is associated with lower activity-dependent release of BDNF). RESULTS Participants in the High-NCP group showed significantly elevated levels of force variability. Met allele carriers exhibited significantly higher levels of force variability when compared with the Val homozygotes. Logistic regression indicated that the odds of membership in the High-NCP group were significantly higher given the presence of dyskinesias (OR=2.32; CI: 1.25-4.28). CONCLUSION Findings of elevated force variability suggest that individuals with NCP exhibit subtle signs of striatal vulnerability, reflected more dramatically as jerking and hyperkinetic movements in patients with formal psychosis. The results are consistent with a larger literature implicating BDNF as a critical factor underlying abnormal movements, and suggest that specific candidate genes underlie putative markers across a psychosis continuum.

Adolescents at clinical-high risk for psychosis: Circadian rhythm disturbances predict worsened prognosis at 1-year follow-up

BACKGROUND Individuals with psychotic disorders experience disruptions to both the sleep and circadian components of the sleep/wake cycle. Recent evidence has supported a role of sleep disturbances in emerging psychosis. However, less is known about how circadian rhythm disruptions may relate to psychosis symptoms and prognosis for adolescents with clinical high-risk (CHR) syndromes. The present study examines circadian rest/activity rhythms in CHR and healthy control (HC) youth to clarify the relationships among circadian rhythm disturbance, psychosis symptoms, psychosocial functioning, and the longitudinal course of illness. METHODS Thirty-four CHR and 32 HC participants were administered a baseline evaluation, which included clinical interviews, 5days of actigraphy, and a sleep/activity diary. CHR (n=29) participants were re-administered clinical interviews at a 1-year follow-up assessment. RESULTS Relative to HC, CHR youth exhibited more fragmented circadian rhythms and later onset of nocturnal rest. Circadian disturbances (fragmented rhythms, low daily activity) were associated with increased psychotic symptom severity among CHR participants at baseline. Circadian disruptions (lower daily activity, rhythms that were more fragmented and/or desynchronized with the light/dark cycle) also predicted severity of psychosis symptoms and psychosocial impairment at 1-year follow-up among CHR youth. CONCLUSIONS Circadian rhythm disturbances may represent a potential vulnerability marker for emergence of psychosis, and thus, rest/activity rhythm stabilization has promise to inform early-identification and prevention/intervention strategies for CHR youth. Future studies with longer study designs are necessary to further examine circadian rhythms in the prodromal period and rates of conversion to psychosis among CHR teens.