Emily E. Carol

A Pilot Study of Cognitive Training in Clinical High Risk for Psychosis: Initial evidence of cognitive benefit

Individuals at clinical high risk (CHR) for psychosis have cognitive deficits that are associated with functional impairment and psychosis conversion (Giuliano et al., 2012). Targeted cognitive training (TCT) (i.e., intense, progressively difficult practice of a cognitive skill) improves cognition and daily functioning in schizophrenia (Wykes et al., 2011). TCT has been proposed as a preventive intervention for CHR, but research is minimal and optimal training parameters, including dose, intensity, and setting, are unknown. Because prolonged duration of untreated CHR symptoms can compromise outcome, rapid treatment response is essential (Fusar-Poli et al., 2009). However, ambiguous risk status, psychosis-related stigma, and practical scheduling problems can reduce treatment motivation and compliance. Without pilot data to guide intervention development, the randomized-controlled trials necessary to show efficacy of cognitive training in CHRmay be unsuccessful. This study investigated the feasibility and potential behavioral benefits of 40 h/8 weeks of computer-based TCT in a single group of CHR participants. Cognitive and functional outcome were assessed with measures recommended for clinical trials, including the MATRICS Consensus Cognitive Battery (MCCB) and Global Functioning (GF): Role and Social scales (Cornblatt et al., 2007). Training performance was analyzed to: verify the relationship between training engagement and treatment outcome; identify an early predictor of treatment response; and evaluate intervention dose.

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.

Resting cortisol level, self-concept, and putative familial environment in adolescents at ultra high-risk for psychotic disorders

A growing body of evidence suggests that resting cortisol levels are elevated in patients with schizophrenia and closely tied to symptom severity. However, there is limited research on the biological stress system during the ultra high-risk (UHR) period immediately preceding the onset of psychosis, and cortisol has not been examined in relation to individual characteristics such as self-concept or potential stressors such as putative familial environment in this critical population. In the present study, salivary cortisol samples were collected on 37 UHR and 42 matched control adolescents, and these individuals were assessed with clinical interviews as well as a measure of self-concept. For a subsection of the sample (23 UHR and 20 control adolescents), a participating relative/caretaker was also assessed with an expressed emotion interview designed to gauge psychosocial environment. Consistent with previous studies, UHR participants exhibited elevated resting cortisol levels when compared with controls. In addition, UHR adolescents exhibited increased negative self-concept and their relatives/caretakers endorsed significantly fewer initial positive statements about the participant. Interestingly, a strong trend in the UHR group suggests that higher cortisol levels are associated with higher rates of critical statements from relatives/caretakers. Furthermore, elevated cortisol levels in the participants were associated with increased negative self-concept as well as fewer initial positive comments from relatives/caretakers. Results suggest that hypothalamic-pituitary-adrenal axis (HPA) dysfunction is closely associated with both individual and environmental-level characteristics. Taken together, these findings support a neural diathesis-stress model of psychosis and future studies, designed to examine causal relationships, stand to inform both our understanding of pathogenic processes in the high-risk period as well as early intervention efforts.

Self-reported cannabis use is inconsistent with the results from drug-screening in youth at ultra high-risk for psychosis in Colorado ☆

Given recent high profile attention to cannabis use during the prodromal psychosis period (Auther et al., 2012), it is increasingly important to insure that the field is incorporating appropriate assessment methodologies. As researchers have expressed concerns with the validity of self reported health-risk behaviors (including drug use) in adolescents and young adults (Addington et al., 2013), and a large majority of published cannabis studies in the prodrome rely solely on self-report, we were concerned. In a study of ultra high-risk (UHR) youth examining differences between rates of self-reported cannabis use and results from a drug screen, we predicted that these youth would under-report use when compared with the outcome from the urine panel. A total of 33 ultrahigh-risk (UHR) (12 female/21 male) adolescents (mean = 18.76; SD = 1.278) were recruited; inclusion criteria included the presence of a prodromal syndrome and exclusion criteria included an Axis I psychotic disorder diagnosis. Cannabis usagewasmeasured utilizing the Alcohol/Drug Use Scale (AUS/DUS) (Drake et al., 1996). This scale is among the most widely used in UHR programs (Woods et al., 2009) and found to be highly reliable in psychosis populations (ICCs ≥ .93) (Brunette et al., 2006). The scale has good convergent (Wüsthoff et al., 2011) as well as face validity, directly asking “Please rate your use of cannabis in the past 1 month according to the following scale: 0 = “no use” to 5 = “almost daily”.” A urine sample was screened for the presence of tetrahydrocannabinol (THC cutoff 50 ng/ml) utilizing Instant Technologies iCup (Norfolk, VA). The rapid drug screen has detection times up to one month and is commonly used in drug research (McRae-Clark et al., 2013). A study examining concordance between self-report and on-site urine screening for cannabis (using the same 50 ng/ml cutoff as the present investigation) in adolescents meeting criteria for abuse/dependence observed good consistency between urine panel results and self reported use in the last seven days (up to 94%) but noted that for reported use past one week, agreement dropped considerably (Buchan et al., 2002). Twenty participants reported cannabis use (60.1%): 6 (18.2%) indicated occasional use (1–4× per month) and 14 (42.4%) reported heavy-use (1–2× per week-daily). However, the urine panel identified 12 (36.4%) as positive (urine was unavailable for 1 participant). There were 13 inconsistent cases and of these, 3 participants (9.4%) did not report drug use but the urine screen detected THC. Surprisingly, 10 participants (31.3%) reported usage in the past month but the urine

The relationship between cannabis use and cortisol levels in youth at ultra high-risk for psychosis

Recent studies have posited a relationship between cannabis use and the biological stress system, but this critical relationship has not been evaluated during the ultra high-risk (UHR) period immediately preceding the onset of psychotic disorders. Salivary cortisol samples were collected on 46 UHR and 29 control adolescents; these individuals were assessed for current cannabis use with a urine panel and self-report. UHR participants where separated into two groups: Current Cannabis Use (UHR-CU) and No Current Cannabis Use (UHR-NC). Healthy Control participants (HC) were free of cannabis use. Consistent with the literature, results indicate UHR individuals showed elevated cortisol levels when compared to HC participants. Further, we also observed that UHR-CU participants exhibited elevated levels when compared to both the non-using UHR and HC groups. Findings suggest that cannabis use may interact with underlying biological vulnerability associated with the hypothalamic-pituitary-adrenal (HPA) axis system.

Sex differences in morning cortisol in youth at ultra-high-risk for psychosis

Research suggests abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function play an important role in the pathophysiology of psychosis. However, there is limited research on the biological stress system in young people at ultra high risk (UHR) for psychosis. Morning cortisol levels are particularly relevant to study in this context, as these markers reflect HPA regulation. This is the first examination of sex differences in morning cortisol levels in UHR individuals. Twenty-eight UHR and 22 matched healthy control participants were assessed in respect to symptoms and had home-based collection of salivary cortisol over three time points in the morning. It was predicted that the UHR participants would exhibit lower morning cortisol levels and lower cortisol would be associated with greater symptomatology (i.e. higher positive, negative, and depressive symptoms). Additionally, sex differences in morning cortisol levels were explored based on recent evidence suggesting that sex differences may play an important role in the exacerbation of psychosis. While there were no group differences in morning salivary cortisol secretion, there was a sex by time interaction among UHR individuals, such that only UHR males exhibited flat cortisol levels across two hours after awakening, whereas UHR females had a pattern of cortisol secretion similar to healthy controls, even among medication-free individuals (F=6.34, p=0.004). Cortisol AUC (area under the curve) across the three time points had a trend association (medium effect size; r=0.34, p=0.08) with depressive, but not positive or negative, symptom severity. These results stress the importance of considering sex differences in the psychosis-risk period, as they improve understanding of pathogenic processes.

Normative adolescent experiences may confound assessment of positive symptoms in youth at ultra-high risk for psychosis

Adolescents who are at ultra high-risk (UHR) for psychosis are primarily identified by attenuated positive symptoms (APS) and global decline in functioning. Suspiciousness and grandiosity are twoprominent symptoms (Miller et al., 2003; Yung et al., 2012), and include thoughts about being watched, singled out, and/or criticized (suspiciousness) and exaggerated self-opinion and unrealistic sense of superiority (grandiose ideas). These are highly important diagnostic indicators; indeed, Cannon et al. (2008) observed that suspiciousness was one of strongest prognostic indicators of eventual conversion to psychosis. However, it is also important to consider that the UHR period overlaps with adolescence, a developmental stage characterized by some normative behaviors that at first glance may appear unusual. Within this context, it is possible that clinicians and researchers unaware of common adolescent developmental phases may misattribute normative developmental experiences with these particular APS symptoms. Elkind and Bowen (1979) was the first to define and categorize two aspects of adolescent development, imaginary audience (IA) and personal fable (PF), that are particularly relevant to this issue. IA is defined as an adolescents belief that he/she is the focus of attention and everyone around them is as concerned and critical about their behavior as they are (Elkind and Bowen, 1979). These beliefs result in heightened self-consciousness, an over concern with the thoughts of others, and a tendency to anticipate the reactions of others in real and imagined situations. PF is defined as the adolescent experience of feeling unique, invulnerable, and omnipotent (Elkind and Bowen, 1979). Both IA and FP emerge during adolescent development and are experienced most strongly between the ages 11 and 18 years old (Galanaki, 2012), a period that matches very closely to the age when UHR youth start experiencing attenuated positive symptoms (Cannon et al., 2008). It is important to stress that the available evidence suggest that both IA and PF are common and a normative component of healthy adolescent development (Adams and Jones, 1981). In addition, because IA and PF emerge over time, related behaviors and thoughts may occur or increase in frequency in a similar fashion to suspiciousness and grandiose ideas in UHR youth (Lapsley et al., 1989). IA and PF aremost commonlymeasured through theNew Imaginary Audience Scale (NIAS) and the New Personal Fable Scale (NPFS; Lapsley et al., 1989). Table 1 outlines characteristics from these inventories that are similar to items on the Structured Interview for Prodromal Syndromes (SIPS; Miller et al., 1999), a common diagnostic measure in wide use for prodromal studies. As seen in the table, aspects of IA match closely to symptoms of suspiciousness and PF closely resembles symptoms of grandiose ideas in UHR adolescents. For example, a

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.