Development and Validation of the Negative Symptom Inventory-Psychosis Risk.

BACKGROUND AND HYPOTHESES: Early identification and prevention of psychosis is limited by the availability of tools designed to assess negative symptoms in those at clinical high-risk for psychosis (CHR). To address this critical need, a multi-site study was established to develop and validate a clinical rating scale designed specifically for individuals at CHR: The Negative Symptom Inventory-Psychosis Risk (NSI-PR). STUDY DESIGN: The measure was developed according to guidelines recommended by the NIMH Consensus Conference on Negative Symptoms using a transparent, iterative, and data-driven process. A 16-item version of the NSI-PR was designed to have an overly inclusive set of items and lengthier interview to support the ultimate intention of creating a new briefer measure. Psychometric properties of the 16-item NSI-PR were evaluated in a sample of 218 CHR participants. STUDY RESULTS: Item-level analyses indicated that men had higher scores than women. Reliability analyses supported internal consistency, inter-rater agreement, and temporal stability. Associations with measures of negative symptoms and functioning supported convergent validity. Small correlations with positive, disorganized, and general symptoms supported discriminant validity. Structural analyses indicated a 5-factor structure (anhedonia, avolition, asociality, alogia, and blunted affect). Item response theory identified items for removal and indicated that the anchor range could be reduced. Factor loadings, item-level correlations, item-total correlations, and skew further supported removal of certain items. CONCLUSIONS: These findings support the psychometric properties of the NSI-PR and guided the creation of a new 11-item NSI-PR that will be validated in the next phase of this multi-site scale development project.

Negative Symptom Inventory-Self-Report (NSI-SR): Initial development and validation.

Negative symptoms (i.e., anhedonia, avolition, asociality, blunted affect, alogia) are frequently observed in the schizophrenia-spectrum (SZ) and associated with functional disability. While semi-structured interviews of negative symptoms represent a gold-standard approach, they require specialized training and may be vulnerable to rater biases. Thus, brief self-report questionnaires measuring negative symptoms may be useful. Existing negative symptom questionnaires demonstrate that this approach may be promising in schizophrenia, but no measure has been devised for use across stages of psychotic illness. The present study reports initial psychometric validation of the Negative Symptom Inventory-Self-Report (NSI-SR), the self-report counterpart of the Negative Symptom Inventory-Psychosis Risk clinical interview. The NSI-SR is a novel transphasic negative symptoms measure assessing the domains of anhedonia, avolition, and asociality. The NSI-SR and related measures were administered to two samples: 1) undergraduates (n = 335), 2) community participants, including: SZ (n = 32), clinical-high risk for psychosis (CHR, n = 25), and healthy controls matched to SZ (n = 31) and CHR (n = 30). The psychometrically trimmed 11-item NSI-SR showed good internal consistency and a three-factor solution reflecting avolition, asociality, and anhedonia. The NSI-SR demonstrated convergent validity via moderate to large correlations with clinician-rated negative symptoms and related constructs in both samples. Discriminant validity was supported by lower correlations with positive symptoms in both samples; however, correlations with positive symptoms were still significant. These initial psychometric findings suggest that the NSI-SR is a reliable and valid brief questionnaire capable of measuring negative symptoms across phases of psychotic illness.

Hippocampal subfields, daily stressors, and resting cortisol in individuals at clinical high-risk for psychosis.

INTRODUCTION: The hippocampus, comprised of functionally distinct subfields, both regulates stress and is affected by it during psychosis pathogenesis. Hippocampal abnormalities are evident across psychosis spectrum and are associated with aberrant cortisol levels and greater environmental stressors exposure. These associations, particularly at the subfield-level, are poorly understood in individuals at clinical high-risk (CHR) for psychosis. This represents a significant literature gap given this critical pathogenetic period is characterized by an interplay between environmental stressors and biological susceptibility. METHODS: A total of 121 participants including 51 CHR (mean age=18.61) and 70 healthy controls (HC; mean age=18.3) were enrolled in the study. Participants completed a structural scan, salivary cortisol assays, and a self-report measure assessing distress from daily stressors exposure (DSI). Hippocampal subfield segmentation was conducted using Freesurfer. RESULTS: Smaller hippocampal subfields were associated with greater stress levels. Greater DSI was associated with lower volumes in CA1 (r = -0.38) and CA2/3 (r = -0.29), but not in CA4/DG (r = -0.28), presubiculum (r = -0.09), or subiculum (r = -0.17). Higher resting cortisol was associated with lower volumes in presubiculum (r = -0.4) but not subiculum (r = -0.22), CA1 (r = 0.08), CA2/3 (r = 0.1), or CA4/DG (r = -0.005). Regressions indicated effects for CA1 and DSI (ß = 0.57, p = .03) and presubiculum and cortisol (ß = 0.61, p = .02) are specific to CHR participants relative to HCs. CONCLUSIONS: The findings provided insights into links between stress and brain vulnerability during psychosis-risk period. Regional differences highlighted potentially different mechanisms by which stress impacts specific subfields. Presubiculum may be more susceptible to the impact of early stress on HPA-axis and cornu amonis to acute stressors.

Exercise Intervention in Individuals at Clinical High Risk for Psychosis: Benefits to Fitness, Symptoms, Hippocampal Volumes, and Functional Connectivity.

BACKGROUND AND HYPOTHESIS: Individuals at clinical high risk for psychosis (CHR-p) are less fit than nonclinical peers and show hippocampal abnormalities that relate to clinical symptoms. Exercise generates hippocampal neurogenesis that may ameliorate these hippocampal abnormalities and related cognitive/clinical symptoms. This study examines the impact of exercise on deficits in fitness, cognitive deficits, attenuated psychotic symptoms, hippocampal volumes, and hippocampal connectivity in individuals at CHR-p. STUDY DESIGN: In a randomized controlled trial, 32 individuals at CHR-p participated in either an exercise (n = 17) or waitlist (no exercise) (n = 15) condition. All participants were sedentary at use and absent of current antipsychotic medication, psychosis diagnoses, or a substance use disorder. The participants completed a series of fitness, cognitive tasks, clinical assessments, and an MRI session preintervention and postintervention. The exercise intervention included a high-intensity interval exercise (80% of VO2max) with 1-minute high-intensity intervals (95% of VO2max) every 10 minutes) protocol twice a week over 3 months. STUDY RESULTS: The exercise intervention was well tolerated (83.78% retention; 81.25% completion). The exercising CHR-p group showed that improved fitness (pre/post-d = 0.53), increased in cognitive performance (pre/post-d = 0.49), decrease in positive symptoms (pre/post-d = 1.12) compared with the waitlist group. Exercising individuals showed stable hippocampal volumes; waitlist CHR-p individuals showed 3.57% decreased hippocampal subfield volume. Exercising individuals showed that increased exercise-related hippocampal connectivity compared to the waitlist individuals. CONCLUSIONS: The exercise intervention had excellent adherence, and there were clear signs of mechanism engagement. Taken together, evidence suggests that high-intensity exercise can be a beneficial therapeutic tool in the psychosis risk period.

The relationship between stress responding in family context and stress sensitivity with sleep dysfunction in individuals at clinical high-risk for psychosis.

Stress and sleep have been implicated in the etiology of psychosis, and literature suggests they are closely related. Two distinct domains of stress associated with sleep dysfunction in the general population are responsivity to environmental stressors and stress sensitivity. However, to date, no research has examined relationships between these stress domains and sleep dysfunction in individuals at clinical high-risk (CHR) for psychosis. A total of 57 CHR (mean age = 18.89, SD = 1.82) and 61 healthy control (HC; mean age = 18.34, SD = 2.41) adolescents and young adults completed a measure of emerging stress intolerance. A subset of participants (CHR = 50, HC = 49) completed a measure indexing responsivity to family stressors - an integral context for this developmental stage overlapping with the psychosis-risk period. Sleep efficiency, continuity, and duration were objectively assessed by actigraphy (CHR = 38, HC = 36). Partial correlations with age and sex as covariates were conducted in both groups separately to examine relationships between stress and sleep. Results indicated that automatic maladaptive responsivity to family stressors was associated with disrupted sleep in the CHR but not HC group. Specifically, greater involuntary engagement was associated with poorer sleep efficiency (r = -.42) but not sleep continuity (r = 0.31) and duration (r = .-19). Interestingly, both adaptative and maladaptive voluntary responses to stressors (engagement and disengagement coping) were not associated with sleep. Finally, impaired stress tolerance was associated with sleep efficiency (r = -0.47), continuity (r = 0.37), and duration (r = -0.43). Taken together, findings provided important groundwork for understanding the role of the relationship between involuntary maladaptive responsivity to family stressors and stress sensitivity with sleep in psychosis etiology.

Cannabis use, self-perceived risk, perceived peer approval and parental attitudes among youth at clinical high-risk for psychosis.

AIM: Cannabis use is associated with greater likelihood of psychosis. The relationship between attitudes about cannabis and use has not been examined in youth at clinical high-risk (CHR) for psychosis. Additionally, the shifting legal landscape can provide a valuable context for evaluating use and related attitudes. METHODS: This study included 174 participants (44 CHR, 43 healthy control [HC] youth-parent dyads). Youth completed measures of self-reported cannabis use confirmed with a urinalysis, self-perceived risk and perceived peer attitudes. Parents reported attitudes about youth use. Legalization occurred halfway during a 5-year study in Colorado, providing an opportunity to cross-sectionally examine its role in use and attitudes. RESULTS: Frequency of youth reporting cannabis use was significantly higher in CHR (69%) than control group (30%). Use in CHR group was associated with higher perceived peer approval (r = .57), increased parental permissiveness (r = .28) and lower self-perceived risk (r = -.26). Comparing samples participating pre and post-legalization, use remained stable within each group. Group differences in parental permissiveness shifted; trend toward decrease in permissiveness in CHR group (η2partial  = .07) and a significant increase in HCs (η2partial  = .16) were observed. Post-legalization, use in CHR group correlated with higher perceived peer approval (r = .64), lower self-perceived risk (r = -.51) and higher parental permissiveness (r = .35, trend). CONCLUSIONS: Taken together, results indicate a relationship between self and peer/parental attitudes about cannabis and use in youth at CHR for psychosis. These factors are important to consider within the legalization context given the changes in parental attitudes and a stronger association between use and attitudes in this group post-legalization.

Timing of menarche and abnormal hippocampal connectivity in youth at clinical-high risk for psychosis.

The "estrogen hypothesis" suggests that estrogen is a protective factor against psychotic disorders such as schizophrenia. Although the precise protective mechanisms are still unclear, one potential explanation lies in the role that increased estrogens play in mediating hippocampal plasticity, as this may reduce hippocampal dysconnectivity that is characteristically observed in psychosis. In support of this view, later age at menarche- less available estrogen during critical early adolescent development- is related to earlier onset of psychosis and increased symptom severity. Furthermore, if estrogens have protective effects, then we should see this effect in the psychosis risk period in those at clinical high-risk (CHR) for psychosis - i.e., individuals showing attenuated symptoms at imminent risk for transitioning to a psychotic diagnosis. This study examined whether earlier age at menarche would result in more normative hippocampal connectivity in CHR youth; menarche is an easily assessed, developmental marker associated with the availability of estrogens. Resting-state connectivity was examined in sixty female participants (26 CHR and 34 healthy control; age 12-21) using a cross-sectional approach; hippocampal connectivity was found to relate to age at menarche. Later age at menarche in the CHR group related to increased hippocampal dysconnectivity to the occipital cortex (a region with a neurotrophic response to estrogen) compared to the controls. Results suggest that earlier availability of estrogens may have neuroprotective effects on hippocampal plasticity. Findings have relevance for understanding sex differences and etiology, as well as guiding novel treatments.

Consistent Exposure to Psychosocial Stressors and Progressive Intolerance to Stress in Individuals at Clinical High Risk for Psychosis.

A body of evidence suggests that exposure to psychosocial stressors and stress sensitivity are involved in psychosis pathogenesis. However, little is known about the temporal course of these domains in those with psychosis-risk syndromes. Furthermore, to date, there have been no studies examining associations between psychosocial stressors and impaired stress tolerance, or how these factors might be implicated in symptom progression prior to psychosis onset. A total of 73 clinical high-risk (CHR) participants and 78 healthy controls (HCs) completed baseline measures of life event (LE) exposure and impaired stress tolerance. Additionally, 54 CHR and 57 HC participants returned to complete the same procedures at a 12-month follow-up assessment. Results indicated that when compared to HCs, CHR individuals exhibited increased LE exposure and impaired stress tolerance at baseline. Longitudinal analyses compared subgroups of CHR participants who exhibited positive symptoms worsening over the 1-year course (CHR-Prog), improved or steady (CHR-Remiss/Persist), and HCs. CHR-Prog individuals showed consistently elevated independent LEs exposure while CHR-Remiss/Persist reported a decline and HCs a steady low level across time. Furthermore, CHR-Prog exhibited increased stress intolerance, while the CHR-Remiss/Persist improved and HCs displayed consistently low levels over time. Analyses examining interrelationships between these domains showed a trend level interaction effect predicting follow-up symptoms. Taken together, results from the present study indicate an important role for exposure to stressors and increasing stress intolerance during psychosis pathogenesis. Additionally, findings indicating that decreases in stress exposure may lead to more favorable outcomes provide a promising target for novel targeted interventions.

Postural Control and Verbal and Visual Working Memory Correlates in Nonclinical Psychosis.

INTRODUCTION: Motor and cognitive abnormalities are well documented in psychosis spectrum disorders. Evidence suggests these deficits could be pronounced because of disruptions in the cerebellar-thalamic-cortical-cerebellar (CTCC) circuit, a network thought to be heavily implicated in motor and higher cognitive functioning. Although significant research has been done on this topic in individuals with schizophrenia and those at a clinical high risk for psychosis, much less is known about deficits at the lower end of the spectrum. METHODS: In this study, we extended the understanding of motor abnormalities across the psychosis continuum by examining postural sway deficits in the nonclinical psychosis (NCP) population. Furthermore, we linked these deficits to verbal and visual working memory. High-NCP (n = 37) and low-NCP control (n = 31) participants completed an instrumental balance task, highly sensitive to subtle variations in postural sway, along with a brief working memory battery. RESULTS: We found that high-NCP participants presented with increased postural sway area (i.e., worse postural control) relative to low-NCP controls on a difficult condition (with limited proprioceptive cues), but not on an easier condition. Furthermore, results indicated that the sway area was correlated with poorer performance on working memory tasks in the high-NCP group. CONCLUSION: These findings suggest that CTCC circuit abnormalities are present across the lower end of the psychosis spectrum and that they may be contributing to a range of motor and cognitive behaviors seen in the population. However, evidence suggests that the signs are subtle, and that sensitive assessment devices and challenging conditions may be necessary for detection.

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.

Exercise Treatments for Psychosis: A Review.

Schizophrenia is a devastating mental illness that has profound effects on a person's health and quality of life. Exercise represents a promising new treatment option that may supplement current psychosocial and pharmacological interventions for psychosis. A large body of work suggests that exercise can improve cardio-metabolic and health behavior and facilitate neurogenesis in areas of the brain that are notably impacted by psychosis. Recent efforts to incorporate exercise as either stand-alone or adjunctive treatment for individuals with schizophrenia range from yoga and light stretching to moderately intense walking, bike riding, or team sports. These interventions suggest that moderately intense exercise may be beneficial for improving both positive and negative symptomatology, cognition and functioning. Indeed, exercise may be beneficial for decreasing risk factors for a wide range of health problems often observed in patients with schizophrenia, including weight gain and metabolic syndrome as well as tobacco and substance use. Given the positive results from interventions in schizophrenia patients, there is an impetus for incorporating exercise in the early stages of the disorder. Notably, individuals at ultrahigh risk (UHR) for psychosis report more sedentary behavior and perceive less benefit from exercise; interventions prior to the onset of the disorder may be helpful for increasing health behaviors, perhaps delaying or preventing the onset of psychosis. Taken together, for individuals with psychosis, exercise may provide holistic benefits for the neural to the social impairments.

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.

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.