Exercise and Markers of Medial Temporal Health in Youth At-risk for Psychosis

The goal of this proposal is to test the feasibility and effectiveness of cardiovascular exercise in promoting brain health and improving related symptoms (e.g., hearing sounds that are not there, feeling emotionally detached from self and others), cognitive difficulties (troubles with memory and learning), and every day social-occupational functioning in youth at imminent risk for developing a psychotic disorder such as schizophrenia. Understanding how exercise may protect or improve the health of a brain area that is implicated as a major contributing factor to the onset of psychosis may lead to a path-breaking new intervention that does not suffer from many of the side effects, costs, and other barriers that characterize treatments that are currently available for this group. Because a significant portion of high-risk youth go on to develop a psychotic disorder in a short period, intervening at this stage may help to improve the clinical course and ultimately prevent the onset of a devastating and prevalent mental illness.

Accumulating evidence from the animal literature, healthy populations, and schizophrenia studies suggests that regular exercise positively affects integral functions such as neurogenesis, synaptic plasticity and cognition. Likewise, preliminary evidence suggests that aerobic activity has been associated with improved quality of life and a lower level of symptoms in patients with schizophrenia. Because exercise has been found to stimulate human medial temporal neurogenesis, and related abnormalities have been widely observed in studies of schizophrenia, physical activity may be in an important intervention. During the psychosis prodrome, a period immediately proceeding formal onset of psychotic disorders, adolescents experience subtle attenuated symptoms coupled with cognitive deterioration and a global decline in socio-occupational functioning and anywhere between 10-35% go on to transition to a psychotic disorder such as schizophrenia in a two-year period. Despite the promise of exercise interventions, and the critical role medial temporal lobe abnormalities play in etiological models of psychosis, there have been no experimental studies of aerobic exercise in ultra-high risk youth (UHR). Understanding the potential benefits of aerobic exercise in UHR youth is integral as the prodrome is a viable period of intervention in which considerable brain development is still occurring. Further, as there have been challenges associated with many of the available interventions, and an increasing level of potential found in neuroplasticity-based interventions, understanding the effect of exercise on respective brain-behavior holds considerable promise. Experimental research is sorely needed to determine if prescribed aerobic exercise can stimulate medial-temporal neurogenesis and ameliorate cognition and symptoms/functioning in this vital group. In the proposed study, an expert team of experienced prodromal and exercise investigators will follow a group of 15 UHR adolescent and young adults (ages 16-24) through a 12 week exercise trial to determine which level of exercise intensity/frequency is tolerable for participants and optimal for improving aerobic fitness (65% of VO2max and 2 sessions per week versus 85% intensity and 3 sessions per peek) and if improvements in aerobic fitness (i.e., VO2max, VO2peak, ventilatory threshold) are associated with increases in medial temporal structure volume (hippocampus and parahippocampal gyrus) and accompanying improvements in cognitive function (i.e., including tasks known to recruit heavily on medial temporal structures) as well as symptomatology and social/role functioning. If the benchmarks are met, this data will be used to streamline a three-year rater-blind controlled trial (15 UHR-exercise, 15 UHR waitlist-control) to determine the efficacy of the intervention in promoting medial temporal health as well as accompanying cognitive, clinical, and socio-occupational function improvement. Participants will be followed up to 24-months to determine if the intervention has an affect on clinical course and transition to psychosis. Taken together, this study is important for understanding the lessons necessary for planning a future large-scale trial, and has the potential to shed light on a promising new treatment for UHR youth.

Medial temporal structures (hippocampus and parahippocampal gyrus) will be delineated automatically using the FMRIB's Integrated Registration and Segmentation Tool algorithm within the FMRIB's Software Library (FSL) image-processing suite (Patenaude, 2007). Secondly, the structures will be evaluated with vertex analyses (assessing changes in shape post trial on a per-vertex basis), which will also be carried out utilizing FIRST. Shape/appearance models used in FIRST are constructed from manually segmented images provided by the Center for Morphometric Analysis (CMA, Boston). This approach is different from using a whole-structure summary measure like volume, as it allows visualization of the region of the shape that is changing as well as the type of shape change.

Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, Relational and Item Specific Encoding and Retrieval (RISE) task.

The MATRICS battery (Green & Nuechterlein, 2004) includes: the Brief Assessment of Cognition in Schizophrenia (BACS), Symbol-Coding, Animal Naming, Trail Making Test A, Continuous Performance Test-Identical Pairs, Spatial Span, Letter-Number Span, Hopkins Verbal Learning Test-Revised™ (HVLT-R™), Brief Visuospatial Memory Test-Revised (BVMT-R), Neuropsychological Assessment Battery (NAB): Mazes, and the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT): Managing Emotions. Standard T-scores will be evaluated for each test. The RISE (Ragland et al., 2012) task includes visual object representations of word stimuli. Subjects make a two-button "yes/no" response to indicate whether items in each pair had been presented "together." To prevent additional encoding of the relational object pairs the item recognition task precedes the associated recognition task. Scores reflect the familiarity and recollection performance as well as hit rates and false alarm rates following encoding.

The Structured Interview for Prodromal Symptoms (SIPS) (Miller et al., 1999) will be administered to formally assess attenuated positive, negative and disorganized symptoms after inclusion in the study. It will also be administered post-trial to track changes in clinical symptoms post intervention trial. The SIPS rates the severity of relevant dimensions including positive, negative and disorganized symptoms along a 7-point scale ranging from absent to severe and psychotic. Role and social functioning will be assessed with the Global Functioning Scale: Role (GFS-R) (Niendam et al., 2006), and the Global Functioning Scale: Social (GFS-S) (Auther et al., 2006), which provide ratings on two separate 10-point Likert scales. The SIPS and GFS-R/S will be administered at annual clinical assessments following completion of the study to track changes in clinical course and determine any cases of transition to psychosis.

Inclusion Criteria: age 16-24 no history of brain injury or neurological disease no contraindications to exercise training (as assessed by a Clinical Translational Research Center CTRC physician) no history or current treatment with antipsychotics no contraindications for being in an magnetic resonance imaging scanner. meet criteria for a prodromal syndrome based upon the Structure Interview for Prodromal Syndromes (SIPS) interview. Exclusion Criteria: people who are extremely claustrophobic have a history of significant head injury other physical disorder that could affect brain functioning mental retardation history of substance use disorder within 6 months of screening interview have a psychotic disorder (at study entry) and/or have exhibited serious self-harm behaviors pregnant females people who have contraindications to magnetic resonance (MR) scanning including intracranial, intraorbital or intraspinal metal, pacemakers, cochlear implants or other non-MR-compatible devices inability of the subject or their parent/guardian to understand the informed consent document meeting criteria for an Axis I psychotic disorder

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Dean DJ, Bryan AD, Newberry R, Gupta T, Carol E, Mittal VA. A Supervised Exercise Intervention for Youth at Risk for Psychosis: An Open-Label Pilot Study. J Clin Psychiatry. 2017 Nov-Dec;78(9):e1167-e1173. doi: 10.4088/JCP.16m11365.