Exercise and Markers of Medial Temporal Health in Youth at Ultra High-risk for Psychosis
Phase: NA
Conditions: Attenuated Psychosis Syndrome
Sponsor: University of Colorado, Boulder

PROTOCOL TITLE: Exercise and markers of medial temporal health in youth at ultra high-
risk for psychosis, Phase 2  
 
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PROTOCOL TITLE: Exercise and markers of medial temporal health in youth at ultra 
high-risk for psychosis, Phase 2  
 
PRINCIPAL INVESTIGATOR: 
Name Vijay Anand Mittal 
Northwestern University 
Psychology, Swift Hall 102, 2029 Sheridan Road, Evanston, IL 60208 
Telephone Number 310-492-3303 
Email Address vijay.mittal@northwestern.edu 
 
 
CO INVESTIGATOR 
Name Daniel M. Corcos 
Northwestern University Feinberg School of Medicine 
Physical Therapy and Human Movement Sciences, 645 N Michigan Avenue, Suite 1100 
Chicago, IL 60611 
Telephone Number 312-908-8160 
Email Address Daniel.Corcos@northwestern.edu  
 
 
 
VERSION NUMBER: 
26 
 
VERSION DATE: 
12/13/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PROTOCOL TITLE: Exercise and markers of medial temporal health in youth at ultra high-
risk for psychosis, Phase 2  
 
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Objectives 
Based off of the success of the feasibility study completed at our University of Colorado Boulder 
lab named “Exercise and markers of medial temporal health in youth at ultra high-risk for 
psychosis” (protocol #14-0200), we have moved on to the second phase of the study, which is 
named the R33 phase. The goals of this study are to continue to look at the effectiveness of a 
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.  We call 
this population “Ultra High Risk (UHR)” or “Prodromal”.  Usually these individuals have a 
cluster of symptoms called positive symptoms that characterize what the field calls “Thought 
Disorder.”  Please see below and under “Background and Significance” for further discussions of 
UHR. 
 
“Ultra High-Risk” or “Prodromal” is the term that has been chosen by the field to describe 
individuals who may be experiencing symptoms that make them at risk for developing a 
psychotic illness such as schizophrenia, bipolar disorder with psychotic features, clinical 
depression with psychotic features. Thought disorder is characterized by unusual thoughts, 
suspiciousness/paranoia, a sense of having special powers or unrealistic plans for the future, 
and/or unusual experiences with seeing or hearings things that are not there.  
 
We currently have been working with this population for four years in our “Frontal-Subcortical 
Development, Movement Abnormalities, and Risk for Psychosis” study as well as our phase one 
study mentioned above, protocol 14-0200 at the University of Colorado Boulder before Professor 
Dr. Vijay Mittal became a new faculty member this year at Northwestern University. We will 
continue to use a measure called the Structured Interview for Prodromal Symptoms (SIPS), a 
widely used and well validated symptom measure, to see if a person is showing moderate 
attenuated positive symptoms (indicated by a score of a 3, 4, or 5 on positive symptoms of this 
scale) and a global decline in functioning which would make them UHR or prodromal. 
 
The study follows adolescents and young adults who may have a thought disorder and who may 
be at risk for developing psychosis.  
 
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.  
 
Specific Aim 1) If UHR subjects participating in the exercise condition show greater post-trial 
increases in medial temporal volume and improved cognitive, symptom and social/role 
functioning profiles when compared with the UHR waitlisted-controls.  We predict that the UHR 
exercise treatment group will show a strong trend to suggest larger effects for increases in 
hippocampal and parahippocampal gyral volume, and improvements in cognitive, 

PROTOCOL TITLE: Exercise and markers of medial temporal health in youth at ultra high-
risk for psychosis, Phase 2  
 
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social/functional, and symptom profiles after the trial as compared to the UHR waitlist controls. 
Any naturalistic aerobic activity seen in the UHR waitlisted-controls will be monitored by testing 
for changes in aerobic fitness between the pre-post 12-week assessments (although we do not 
anticipate a great deal of naturalistic aerobic activity in the UHR control group based on our pilot 
findings, any changes in fitness will be controlled for in the respective statistical analyses) 
 
Exploratory: Aim A) If the intervention has an influence on course of illness and conversion 
rates. An important ultimate consideration for UHR individuals relates to clinical outcome or 
conversion to formal psychotic disorders. Within-group analyses will focus on how varying 
degrees of aerobic fitness, brain, and cognitive changes post trial or wait-list predicts 12-month 
and 24-month symptoms levels and conversion status.  
 
Background 
Accumulating evidence from animal models (Wolf et al., 2011), healthy populations (Erickson et 
al., 2011), and schizophrenia studies (Farrow et al., 2005) suggests that regular exercise 
positively affects integral functions such as neurological maintenance and cognition.  Likewise, 
moderate to vigorous activity has been associated with improved quality of life and lower 
symptom levels in patients with schizophrenia (Gorczynski & Faulkner, 2010).  Because 
voluntary exercise has been found to stimulate adult medial temporal neurogenesis (Parker et al., 
2011), and the hippocampal and parahippocampal gyrus abnormalities have been widely 
observed in structural, functional, and neurocognitive studies of schizophrenia (Wible et al., 
1995, Walker et al., 2008, Allen et al., 2011), aerobic physical activity may be an important 
treatment in schizophrenia. The period immediately preceding the onset of schizophrenia is a 
viable point for intervention, and a critical phase for elucidating the pathophysiology of the 
disorder.  However, the available interventions have not been definitely effective, and these 
treatments have been met with significant challenges including costs, poor compliance, attrition, 
and side effects.  A new series of cognitive remediation trials promoting neuroplasticity have 
shown a great deal of potential for targeting specific symptoms and characteristics (Barlati et al., 
2012).  Despite the promise of exercise interventions in animal models as well as both healthy 
and clinical populations, to date there have been no trials in youth at ultra high-risk (UHR) for 
psychosis.  We propose an initial within-subject study to determine the effects of a 12-week 
exercise trial, comparing two different levels of exercise intensity in targeting specific neural, 
cognitive, symptom, and social/role function outcomes in UHR youth.  
 
The Prodromal Period and Research Priorities 
The onset of psychosis is usually preceded by a prodromal phase characterized by functional 
decline and subtle attenuated symptoms that include positive phenomena and a decline in socio-
occupational functioning (Haroun et al., 2006, Cannon et al., 2008).  The prodromal period is of 
interest both as a window for investigating processes involved in disease onset, and also as a 
potential point of intervention and prevention (Haroun et al., 2006, McGlashan et al., 2007, 
Mittal et al., 2010b).  More specifically, recent studies have suggested that adolescents with a 
prodromal syndrome (i.e., showing moderate attenuated positive symptoms accompanied by a 
global decline in functioning) (Miller et al., 1999, Miller et al., 2002, Miller et al., 2003b) are at 
imminent risk for conversion to a psychotic disorder; although successful early identification and 
other factors relating to heterogeneous assessment/inclusion criteria have yielded a global 
decrease in transition rates (Yung et al., 2007), a substantial proportion (anywhere from 10-35%) 

PROTOCOL TITLE: Exercise and markers of medial temporal health in youth at ultra high-
risk for psychosis, Phase 2  
 
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will convert to a psychotic disorder within a two-year period (Yung et al., 2007; Cannon et al., 
2008).  This is promising from a research perspective as prospective understanding of brain 
structure and function, in a period prior to when medications and neurotoxicity can confound 
research, is likely to significantly inform etiological conceptualizations of psychosis (Haroun et 
al., 2006, McGlashan, 2006).  It is also significant from a clinical perspective as better 
understanding of the high-risk period will help to implement early intervention and guide 
treatment decisions with the potential to reduce the duration of untreated psychosis (White et al., 
2006), ameliorate course of illness, and delay or potentially prevent onset of psychosis (McGorry 
et al., 2002, McGlashan et al., 2003, Woods et al., 2003, Morrison et al., 2004, Haroun et al., 
2006).  Because schizophrenia severely limits the most productive years of an individual's life, 
its costs to society are enormous (Wu et al., 2005), and this promise of early detection and 
intervention represents a major breakthrough.  
 
While existing cognitive-behavioral (Morrison et al., 2004), psychopharmacological (McGlashan 
et al., 2003, McGlashan et al., 2007), and supplemental treatments (Amminger et al., 2010) have 
shown noteworthy effects, to date there have been no conclusive empirically supported 
interventions for UHR youth (Corcoran et al., 2010).  Furthermore, there are significant 
treatment costs associated with psychotherapy, and serious adverse side effects accompanying 
pharmacological interventions (e.g. weight gain, related diabetes) (Gerbino-Rosen et al., 2005, 
Sporn et al., 2005).  There is a critical need for innovative new treatment options.  Recent 
cognitive remediation trials in psychosis have demonstrated benefits from neuroplasticity based 
interventions and that intensive trials engaging effortful activity are feasible in UHR samples 
(Fisher et al., 2013).  Because of its known effects on neuroplasticity, an exercise-based 
intervention holds significant potential as UHR youth show abnormalities in medial temporal 
structures as well as related cognitive impairments, symptoms and functional factors (Pantelis et 
al., 2007, Mittal & Walker, 2009, Walker et al., 2010, Mittal & Walker, 2011b, Mittal et al., 
2013).  
 
Mechanisms of Cardiovascular Exercise on Medial Temporal Health  
Animal models have been instrumental in establishing the effects of 
aerobic activity on medial temporal health.  This body of literature 
has suggested that aerobic activity promotes hippocampal growth 
and related function through several processes including promoting 
neurogenesis (process by which neurons are generated from neural 
stem and progenitor cells) (Cotman & Berchtold, 2002, Wolf et al., 
2011), cell proliferation (increase in the number of cells as a result 
of cell growth and cell division) (Koehl et al., 2008) and slowing 
apoptosis (programmed cell death) (Avula et al., 2001, Phaneuf & 
Leeuwenburgh, 2001).  For example, in an animal study examining 
the effects of treadmill exercise on cell proliferation in the 
hippocampus (dentate gyrus), Sprague-Dawley rats were classified 
into controls, an easy exercise group, and a moderate exercise group 
(Kim et al., 2002).  Results suggested a dose dependent response 
where easy and moderate exercise group rodents exhibited 
significant cell proliferation (increase in BrdU-positive cells) in the 
dentate gyrus compared to controls after 30 minutes of exercise a 
Figure 1. Photomicrographs of 5-
bromo-2′-deoxyuridine (BrdU)-
positive cells in the hippocampus 
(dentate gyrus). A and a, control 
group; B and b, easy exercise 
group; C and c, moderate 
exercise group. Black dots 
represent BrdU-positive cells. 
Scale bar in A, B, and C 
represents 100 μm. Scale bar in 
a, b, and c represents 12.5 μm.  

PROTOCOL TITLE: Exercise and markers of medial temporal health in youth at ultra high-
risk for psychosis, Phase 2  
 
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day for one week (see Figure 1).  Research also shows that exercise and fitness level can 
significantly alter blood oxygen level dependent (BOLD) activation in the parahippocampal 
gyrus (Janse Van Rensburg et al., 2009, Holzschneider et al., 2012), a grey matter cortical region 
that encapsulates the hippocampus and plays an integral role in memory coding and retrieval.  
Further, exercise-related brain plasticity has been shown in the increased temporal lobe 
connectivity between the bilateral parahippocampal gyrus and bilateral medial temporal gyrus in 
older adults (Voss et al., 2013).  With regard to the current proposal, its is important to note that 
several animal models have suggested that an aerobic exercise program promotes neuroplastic 
changes in the hippocampal formation (e.g., significant increase of protein level in the 
hippocampal formation and PV-immunoreactive neurons in CA1 and CA2/CA3) during 
adolescent period (Gomes da Silva et al., 2010).   
 
Accumulating evidence from a series of translational studies has indicated that the pattern of 
results seen in the animal research is also true for human populations. For example, aerobic 
exercise has been found to result in increased hippocampal blood volume in healthy individuals 
(Colcombe et al., 2004). There have also been several venues of research to suggest exercise 
counteracts declining medial temporal function in aging (Intlekofer & Cotman, 2012) and 
clinical populations such as those with Alzheimer’s disease (Yuede et al., 2009, Erickson et al., 
2011).  To date, there have been a small number of studies showing positive effects from 
exercise that are also seen in schizophrenia patients.  For example, researchers observed 
naturalistic activity levels over a 20-hour period (actigraphy) were positively associated with 
larger cortical volumes (Farrow et al., 2005).  In a landmark study, Pajonk and colleagues 
(Pajonk et al., 2010) found that after a brief cardiovascular exercise trial (12 weeks) in patients 
diagnosed with schizophrenia, those in the exercise group showed a significant increase in 
hippocampal volume (12%) when compared to a control group of schizophrenia patients in a 
non-aerobic activity (1%).  Further, the changes in volume were positively associated with 
improvement in aerobic fitness (measured by a change in maximum oxygen consumption) and 
improvement in verbal memory.  However, its important to note that while this work was 
instrumental in demonstrating trial-feasibility and a potentially effective treatment mechanism, 
the sample was small, analysis of structure involved a gross volume estimate (no consideration 
of shape), and the study included only a limited cognitive battery.  
 
Exercise and Cognitive Function 
There is good evidence to suggest that hippocampal neurogenesis is an important mechanism for 
learning and memory processes in healthy humans.  There have been several proposed 
mechanisms for explaining the relationship between increased neurogenesis and improved 
cognition, including computational theories demonstrating that new neurons improve memory 
capacity (Becker, 2005), reduce interference between memories (Wiskott et al., 2006), and add 
information about time to memories (Aimone et al., 2006).  The act of learning itself is 
associated with elevated neuronal survival (Gould et al., 1999).  Exercise has been found to 
improve cognitive functioning by promoting synaptic plasticity through a series of mechanisms 
that contribute to neuroreorganization processes (allowing neurons and respective networks to 
change connections and behavior in response to new information, stimulation, development, 
damage and dysfunction).  For example, research has shown that capacity of synaptic plasticity 
(the ability of the connection between two neurons to change in strength in response to either use 
or disuse of transmission over synaptic pathways) (Hughes, 1958) is positively associated with 

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aerobic activity; rats given access to a running wheel (aerobic exercise) exhibit significantly 
more short-term potentiation and long-term potentiation (LTP) with theta-patterned conditioning 
stimulation in vivo than do age-matched litter mate controls (Farmer et al., 2004). This increase 
in LTP appears to reflect an alteration in the induction threshold for synaptic plasticity that 
accompanies voluntary exercise (Farmer et al., 2004).  With particular relevance to the proposal, 
researchers have found that regular aerobic exercise (30 minutes of aerobic exercise for regular 
sessions over 8 weeks) increases the number of hippocampal CA1, CA3, and dentate gyrus 
neurons and enhances spatial memory in adolescent rats (Uysal et al., 2005). 
 
In a recent comprehensive review of the literature, researchers concluded that although more 
high-quality trials are needed to assess the effects of different types and intensities of exercise on 
cognitive function, beneficial effects of various exercise programs have been observed in studies 
among subjects with and without cognitive decline (van Uffelen et al., 2008).  Studies have 
shown cognitive improvements in Alzheimer’s patients (Kramer et al., 2006) and after an 8 week 
exercise trial, stroke survivors (stationary bike, 3 times a week for 45 minute sessions) showed 
significant improvement in VO2max (i.e., a widely used and accurate index of aerobic fitness), 
and cognitive function (Quaney et al., 2009).  As noted, a trial in patients with schizophrenia 
found improvements in verbal learning (Pajonk et al., 2010), an important process that is also 
affected in UHR groups (Brewer et al., 2005).  Several of the other neurocognitive deficits 
present in UHR individuals have also been positively affected by exercise interventions in other 
populations.  A large randomized controlled study with 120 individuals showed that exercise 
training increases the size of the anterior hippocampus and led to improvements in spatial 
memory in older adults (Erickson et al., 2011) and both this brain region and memory domain are 
affected in the prodrome (Wood et al., 2003, Pantelis et al., 2007).  This has been supported by 
the animal literature (rodent models) (Vaynman et al., 2004) and observed in investigations of 
healthy young adults (Stroth et al., 2009).  Hippocampal-dependent cognitive functioning such as 
the acquisition of new episodic memory is mediated in part by synaptic plasticity (Neves et al., 
2008) and also found to be improved in exercise trials in humans (Bunce & Murden, 2006).  
Episodic memory deficits are also prominent in UHR youth (Valli et al., 2012).  The medial 
temporal memory system (including the hippocampus and parahippocampal gyrus) governs 
broader declarative memory functions including episodic memory as well as verbal learning 
(Squire, 1992); as noted a successful trial in a small number of schizophrenia patients showed 
significant verbal learning improvement (Pajonk et al., 2010), and deficits in the verbal learning 
domain are both prominent in the prodrome (Fusar-Poli et al., 2012) and predictive of conversion 
(Walder et al., 2008, Mittal et al., 2010c, Seidman et al., 2010).  The cognitive targets in this 
proposal are based on the domains that have reliably been shown to be improved with exercise 
intervention in human populations, known to recruit heavily on medial temporal structures, and 
shown to be affected in UHR youth (i.e., spatial memory, episodic memory, verbal learning).  In 
addition, because of the central role medial temporal structures play in a wide range of high 
order cognitive functions (Voss et al., 2010), some research has shown exercise promotes 
improvements in domains such as executive function, although the specificity of this effect 
remains an empirical question. 
 
 
 
Exercise, Symptoms and Social/Role Functioning 

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Sedentary behavior has been widely associated with obesity and health problems in adolescent 
populations (Rosenberger et al., in press), and in addition to contributing to poor emotional well-
being and peer-support (Costigan et al., in press), it may also exacerbate the health related side-
effects of pharmacological treatment (Maayan & Correll, 2010) and potentially lead to poorer 
compliance in UHR adolescents.  Further, the nature of the prodrome may contribute to 
sedentary activity as prototypic characteristic symptoms such as avolition affect motivation and 
positive symptoms such as paranoia may lead to avoidance of social/peer involved activities, 
leading these patients to become increasingly prone to inactivity.  In contrast, moderate to 
vigorous activity has been found to have ameliorative effects, such as reduced cardio metabolic 
risk factors, regardless of the amount of time spent engaging in sedentary activities (Ekelund et 
al., 2012).  More broadly, physical activity decreases the risk of numerous deleterious physical 
outcomes among adults (Penedo & Dahn, 2005) and adolescents (Janssen & LeBlanc, 2010), and 
sedentary behavior has been identified as one of the leading preventable causes of death in the 
United States (Mokdad et al., 2004).  With regard to mental health, and consistent with studies in 
other populations (Dunn et al., 2001; Rangul et al., 2010), researchers have observed that 
exercise can improve symptoms of depression and social anhedonia in patients with 
schizophrenia (Gorczynski & Faulkner, 2010).  As noted, to date there have been no studies to 
determine how exercise may improve symptoms and social/role functioning in UHR youth.  
Because of studies showing that an active lifestyle promotes higher quality of life, better mental 
health outcomes (Rangul et al., 2010), and lower rates of depression (Brunet et al., 2013) and 
anxiety (Hallal et al., 2006) in adolescents and young adults, we predict that the exercise trial 
will improve social and role functioning (Aims 2). Further, based on the prominent role of the 
medial temporal lobe in etiological theories of schizophrenia (Walker & Diforio, 1997, Lipska, 
2002, Corcoran et al., 2003), and research noting significant relationships between the 
hippocampus and symptoms in psychosis (Benoit et al., 2012), we predict that aerobic exercise 
will also improve symptoms.  
 
Cortisol Sampling 
When accounting for the confluence of risk and disease progression in the prodromal period, a 
neural diathesis-stress model posits that one key pathogenic mechanism involves the 
hypothalamic pituitary adrenal (HPA) axis, which can trigger a cascade of events that culminates 
in expression of dysfunctional neural circuits that subserve psychotic symptoms (E. Walker, 
Mittal, & Tessner, 2008). This notion draws primarily on the extant evidence concerning the 
effects of HPA axis secretogues, especially cortisol, on brain and behavior.  Specifically, patients 
at-risk for schizophrenia manifest elevated levels of cortisol, and there is a synergistic 
relationship between activation of dopaminergic circuits that have been implicated in psychosis 
(Czyrak, Mackowiak, Chocyk, Fijal, & Wedzony, 2003). It is also of note that normative 
increases in the stress hormone cortisol, beginning at the onset of puberty, peak at the end of 
adolescence and this coincides precisely with the mean age of onset of psychotic disorders (E. 
Walker, et al., 2008). However, although studies have examined resting cortisol, little is known 
about the effect of acute stress in the prodrome, or how this may constitute risk for a poorer 
course of illness over time (E. Walker, et al., 2008). 
 
 
 
 

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Research Questions 
A neural diathesis-stress conceptualization is an established model used to understand 
pathogenic processes at play during the prodromal period and it predicts that an early 
vulnerability (the resulting confluence of genetic and/or 
early environmental factors) later interacts with 
neuromaturational processes and environmental stressors 
during adolescence, resulting in attenuated symptoms, 
cognitive and social/role dysfunction, and eventually 
psychosis (Walker & Diforio, 1997).  Within the context 
of the present study, we propose to investigate the 
potential for an exercise intervention to promote medial 
temporal health in the high-risk period and subsequently 
influence a series of related symptoms and deficits (see 
Figure 2).  If an exercise intervention is effective in 
promoting medial temporal health and facilitating 
synaptic plasticity in UHR youth, this can serve to 
improve several key features and characteristics strongly 
affected by hippocampal and parahippocampal gyral function including cognitive function, 
symptoms, and social/role function.  To address the research questions posited in Aims 1 and 2, 
we propose to assess medial temporal integrity, cognitive function (with tests that weigh heavily 
on medial temporal function as well as a broader battery), social/role functioning, and symptoms 
both pre and post an exercise trial (with two intensity groupings) in a group of UHR youth and a 
healthy controls (HC) group. 
 
Understanding the mechanisms and related effects of aerobic exercise in a developmentally 
sensitive period, characterized by significant neural-reorganization, symptom escalation, and 
cognitive functional decline, is both innovative and incredibly important.  Further, examining the 
period immediately preceding the onset of psychotic disorder, before the medications and/or 
neurotoxicity can cloud our understanding (McGlashan, 2006), represents a necessary step in 
elucidate the etiology of psychotic disorders and increasing our ability to refine target 
interventions high-risk individuals. The proposed investigation holds promise for improving the 
understanding of aerobic activity based changes in medial temporal structures. A body of 
evidence suggests that aerobic exercise increases hippocampal volume in clinical and healthy 
populations (Yuede et al., 2009, Berle et al., 2010, Pajonk et al., 2010, Erickson et al., 2011, 
Wolf et al., 2011).  Despite significant evidence to suggest medial temporal abnormalities in 
UHR youth (Fusar-Poli et al., 2007, Fusar-Poli et al., 2011, Mittal & Walker, 2011b), and 
prominent models implicating the hippocampus as an integral factor in the etiology of 
schizophrenia (Weinberger, 1995, Lipska, 2002, Corcoran et al., 2003, Walker et al., 2008), to 
date there have been no published studies that have examined an aerobic exercise mechanism in 
high-risk adolescents.  We propose to use the most promising and innovative aerobic fitness 
assessments, structural imaging methodologies (including size and shape based approaches), and 
tailored neurocognitive tests to accomplish this goal.   
 
 
 
 
Figure 2. Exercise Targets Key Pathogenic Factors Driving the 
Progression to Psychosis 

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Preliminary Studies 
UHR Participants exhibit deficits in cognitive functioning and smaller medial temporal 
lobe volume 
A group of UHR (n = 29) and healthy control (n = 27) adolescents (mean = 18.09; SD =2.3) 
were administered a structural scan and a brief cognitive battery.  Consistent with the 
broader literature, the ANCOVA analyses (controlling for age) 
indicated that UHR group showed poor performance across cognitive 
measures including verbal fluency F(1,50) = 2.25, p  .05, trail 
making, F(1,50) = 4.91, p  .01, and a trend for verbal learning, 
F(1,50) = 1.22, p = .14, when compared to healthy controls.  Analyses 
indicated that the UHR group showed significantly smaller right, 
F(1,51) = 10.17, p  .01, and left, F(1,51) = 4.44, p  .01, hippocampal 
volumes.  Likewise, the UHR group showed a non-significant trend 
towards smaller left, F(1,51) = .99, p = .18, and significantly smaller 
right, F(1,51) = 2.87, p  .05, parahippocampal gyral volumes (see 
Figure 3).  While these results serve to establish that cognitive and 
medial temporal lobe deficits are apparent in high-risk individuals, 
there has been little empirical work conducted to examine 
mechanisms that may contribute to these deficits, or interventions designed to target these 
specific domains.  As noted in the review above, a body of evidence suggests that moderate to 
vigorous aerobic activity promotes hippocampal cell growth and memory in healthy and 
clinical populations.  
Less activity is associated with smaller medial temporal volumes and cognitive deficits 
In this pilot investigation 29 UHR and 27 matched control participants were assessed to 
determine the relationship between naturalistic activity level (i.e., everyday behavior in a 
natural context that is not manipulated by instruction or intervention), medial temporal lobe 
structure (hippocampus and parahippocampal gyrus), and symptoms.  Participants were 
assessed with actigraphy for a 5-day period (participants wore an actigraph wristwatch), 
magnetic resonance imaging, and structured interviews.  We observed that UHR participants 
showed a greater percentage of time in sedentary behavior while healthy controls spent 
more time engaged in light, moderate and vigorous activity (Figure 4).  In addition, the total 
level of movement activity was moderately correlated with parahippocampal gyri bilaterally 
(right: r = .44, p  .01; left: r= .55, p  .01), a trend towards volume of the left hippocampus (r 
= .23, p = .09) and symptoms (r = -.35, p  .01).  The results suggest that more activity is 
linked to larger volumes and lower symptom levels.  Furthermore, activity was associated 
with performance in verbal fluency r = .35, p  .01), trail making (r= .28, p  .05), and verbal 
learning (r= .25, p  .05). Taken together, these data indicate that more activity is associated 
with improved cognition or conversely, lower activity is linked to a poorer cognitive 
performance on these measures. Finally, hippocampal volumes were bilaterally associated 
with performance on trail making (r= .27, p  .05) and a trend toward verbal fluency (r = .23, 
p = .08).   
Figure 3. The volumes of 
the hippocampus (red) 
and parahippocampal 
gyrus (green) were found 
to be smaller in the high-
risk group.  

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risk for psychosis, Phase 2  
 
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I. While collectively, this pilot data is 
instrumental in suggesting that inactivity 
is associated with medial temporal 
health, symptoms, and cognition, it is not 
possible to determine any causality (for 
example, it is unclear if symptoms are 
driving inactivity, which in turn may be 
affecting the health of the 
parahippocampal structure or if 
hippocampal deficits lead to lower 
levels of activity).  In our Aims, we 
propose to determine the optimal 
exercise prescription that balances 
intensity and tolerability in UHR 
youth, and whether prescribed 
physical activity will lead to changes 
in medial temporal volume, cognitive 
function and symptoms/function.  An experimental manipulation, focusing an aerobic fitness 
and tailoring level of activity to an individual’s initial level of cardiovascular fitness, will allow 
for stronger conclusions regarding the noted causality issue.  Taken together, the Aims for 
this phase hold important implications for etiological conceptions and the promise of 
exercise-based interventions for UHR youth.  
 
 
 
Inclusion and Exclusion Criteria 
Participants will be recruited from community health care providers or self-referred by flyers, 
electronic and paper advertisements. Participants will call into the ADAPT lab and a lab manager 
or trained graduate student will administer a phone screening. Based off of the phone screening, 
participants and the inclusion criteria, participants will be invited to participate in the study based 
off of “being a good fit” for the study. A phone screening will also be done to determine if the 
participant is eligible for the MRI scanning portion of the study (i.e. inquiring about 
claustrophobia, metal in their body, etc...). If participants are found not to be eligible based off of 
the phone screening and inclusion criteria, then participants will be excluded.  
 
If the participant is younger than the age of 18, and thus not considered an adult yet, a parent 
must call on (and this is indicated on recruitment material). The same phone screening will be 
completed with the parent and the questions will be about the child. 
 
Inclusion criteria for UHR participants are as follows: a) age 16-24, b) no history of brain injury 
or neurological disease, c) no contraindications to exercise training (as assessed in the phone 
screening) d.) do not meet for any MRI scanning exclusion criteria as assessed via the phone 
screen. During the phone screening, we will assess to make sure there is not a history of 
cardiovascular or respiratory disease. During the exercise study, the participant’s heart rate and 
EKG will be monitored to assure that they are not experiencing an adverse cardiac event and to 
assure they are healthy enough to participate.  The phone screening will also assess to make sure 
the participant is not obese, pre-diabetic/diabetic, has high cholesterol, or has high blood 
 
Figure 4. Note: Activity represents the percentage of time spent in four 
levels of activity based on actigraphy counts per minute. * p ≤ .05; † 
Indicates a trend level difference p ≤ .15;  Error bars represent standard 
error. 
*
*
*
†
0 
0.1 
0.2 
0.3 
0.4 
0.5 
0.6 
0.7 
Sedentary 
Light Activity 
Moderate Activity 
Vigorous Activity 
PercetageofTimeEngaagedinaGivenActivity
UltraHigh-Risk
Control

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pressure, and does not have a diagnosis of current substance dependence (this will be determined 
in the phone screen). Participants will be asked if they ever had a history of substance 
dependence or if they currently are diagnosed with substance dependence. Additionally, during 
the clinical evaluation, they will be asked if they have a current diagnosis of substance 
dependence and other related questions during the SCID) and d) no contraindications for being in 
an magnetic resonance imaging (MRI) scanner. As noted above, for inclusion in the study, the at-
risk group, participants must meet criteria for a prodromal syndrome based upon the Structure 
Interview for Prodromal Syndromes (SIPS) interview. Inclusion criteria for the HC group is as 
follows: a) age 16-24, b) no diagnosable psychotic disorder, c) no history of substance use 
disorder within 6 months of the screening interview, d) no history of head injury, tic disorder, 
neurological disorder. Substance use will be assessed during the prescreener, and the participants 
who consent to the study will be asked to provide a urine sample for drug testing (see Procedures 
Involved).  Exclusions criteria for all subjects include: a) less than 16 or greater than 24 years of 
age, people who are claustrophobic (people who have a fear of being in a closed space), b) have 
a history of significant head injury: This will be based off of the Childhood Brain Injury Scale to 
determine, if a head injury occurred, whether consciousness loss of consciousness.  If 
consciousness was lost between 2-30 minutes, and/or post-traumatic amnesia/confusion <1 hour 
and/or other symptoms (cognitive or behavior changes) lasting 1-24 hours, participants are not 
eligible to participate in the study (First, 2010), c) other neurological disorders that could affect 
brain functioning such as Multiple Sclerosis, Stroke, Tumors, Epilepsy, Alzheimer’s disease, 
Parkinson’s disease, d) mental retardation, e) history of substance use disorder within 6 months 
of screening interview, f) have a psychotic disorder, taking antipsychotic medication, and/or 
have exhibited serious self-harm behaviors, g) pregnant females (see scanner protection 
description below), h) people who have contraindications to magnetic resonance (MR) scanning 
including intracranial, intraoribital, or intraspinal metal, pacemakers, cochlear implants or other 
non-MR-compatible devices, face or neck tattoos, and i) inability of the subject or their 
parent/guardian to understand the informed consent document (see below), j) inability of the 
subject or parent/guardian to understand written or spoken English. For the at-risk group, 
participants meeting criteria for an Axis I psychotic disorder will be excluded (e.g., 
schizophrenia, schizoaffective disorder, psychosis NOS, brief psychotic disorder, mood disorder 
with psychotic features). Medications are not a basis for exclusion because of the sensitive nature 
of this research except for antipsychotics.  Similar studies have adopted a general policy 
allowing any outside treatment to remain because of ethical concerns that may arise.  During 
analyses, medications (individuals taking antipsychotics will be excluded.  All other medications 
are accepted) will be treated as covariates such as antidepressants and stimulants. Although this 
may limit statistical power, the exploratory nature of this study allows for such.  In Dr. Mittal’s 
current protocol, only 8% of prodromal participants are using medications, such as 
antipsychotics.  Consistent with past exercise studies, all participants will be sedentary (i.e., no 
more than 60 minutes of maximal heart output per week for at least the past six months).  This 
will not be the same as targeted treatment interventions at a high intensity and frequency of 2-3 
times a week for 65% or 85% of VO2max for 60-90 minutes.  Qualitative substance use will be 
evaluated by urine drug screening; urine drug screens which best document recent ingestion 
(which may have precipitated a worsening of symptoms).  
 
For the scan portion of the study, in order to protect the health and safety of the participants, 
exclusion criteria for this study will include any contraindication to magnetic resonance scanning 

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(e.g., metal in body, claustrophobia, pregnant). These exclusions are specific to MRI and are 
consistent with most studies involving MRI. Potential participants will be screened for the 
presence of any of these exclusion criteria prior to participating in this MRI study. Participants 
will be asked to complete the CTI required safety form prior to their scan.  
 
We will also exclude adults unable to consent, pregnant women (due to the scanning 
requirements), and prisoners because these populations are not relevant to our present research. 
We will be including individuals that are not yet adults (16-18 years of age). Specific procedures 
for these populations are described throughout this protocol. 
 
Study Timelines 
Participants will be enrolled in the study for two years. We will be doing 12 and 24 month follow 
ups so we do not expect this study to be complete until July 2021. We have made the 12 month 
follow up available to do on Zoom with an optional additional consent/assent form.  
 
Procedures Involved 
Overview 
Over a 2-year period, we hope to recruit 36 UHR youth (to yield 30 because of an expected 20% 
attenuation: 15 in the exercise and 15 in the waitlisted-control). Participants will first attend a 
screening session that will be roughly 1.5 hours (please see Table 1 below) and if they meet 
criteria for UHR, they will be invited to join. 
 
Then, participants will return for a longer assessment that will examine diagnosis (Table 2), 
cognition (Table 2), brain volume (Table 2), and cardiovascular fitness (Table 3). This baseline 
assessment can be completed in one visit but also broken into several short visits if the 
participant wishes. The screening, diagnosis, and cognitive assessment will take place in the 
ADAPT lab at 1801 Maple Avenue in Evanston, IL and the cardio fitness will take place in the 
Northwestern University Department of Physical Therapy and Human Movement Science 
located at 645 N. Michigan Avenue, 10th floor, Chicago IL 60611. In the table, we have 
referred to this as “Downtown” (this fitness portion takes 30 minutes pre and post exercise 
intervention and will be monitored by an exercise physiologist).   
 
After the baseline assessment, participants will be randomized into the following two conditions: 
exercise or waitlist control. The 15 UHR exercise group participants will be involved in a 3-
month exercise treatment 2x a week at moderate-vigorous levels. This will take place in the 
Evanston ADAPT lab and will be monitored by an exercise physiologist (Elizabeth Skender). 
For participants who are unable to come to Evanston twice a week, we will offer the downtown 
location as an alternative for one or both weekly exercise sessions.  
 
In total, this will result in 24 visits (each visit is 40 mintes). After, the 12 weeks are completed, 
participants will come back and simply repeat the baseline visit again (with the exception of the 
screening) (note: this is termed the post-exercise follow-up visit).  This will be a total of 5 hours, 
and can be broken down into shorter visits based on the individual needs of a participant.   
 

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Finally, after the post-exercise period, participants will be invited back at 1 year and 2 years later 
for a clinical assessment (this will include a 3 hour battery repeating the symptom and diagnostic 
measures that were noted at baseline).    
 
For the 15-waitlist control participants, the procedures are the same however they will 
NOT be undergoing the exercise intervention. They will simply be asked to come back after 3 
months to do all post intervention assessments. These participants will also be invited back 12 
months and 24 months later for follow up. The 12 month follow up interview will be optionally 
offered on Zoom secure video conferencing for CHR participants. The rationale is that the 
clinical group is the research priority during the remote work period before the return to 
Northwestern’s campus and the control group will be invited to follow up interviews normally in 
person at that time.  
 
 
The healthy control (HC) participants will only be invited to baseline, 12-month, and 24-month 
visits. We will not be inviting the HC group for the 3-month follow up because we do not 
anticipate any diagnostic or brain structure changes in this population. All procedures will be the 
same except for the cognitive battery (they will not complete MATRICS and RISE because these 
would not be a valid assessment of cognitive function in HC population) and the exercise 
assessment (because we are not looking at a 3-month change in HC group, they will not 
complete the VO2max). In addition, HC group will complete both fMRI tasks during the 
baseline visits.  
 
Below is a walk through of all visits: 
 
Table 1: Screening Visit 
Visit (1 visit) 
Time 
Location 
Time Point 
1. Screening 
1a. SIPS Positive 
1.5 hours 
ADAPT Lab 
Screening 
 
Table 2: Pre-Intervention (Both UHR groups) 
Visit (1-3 visits)* 
Time 
Location 
Time Point 
2. Clinical Assessment: 
2a. Cortisol Sampling-4 saliva 
samples and a hair sample 
2b. Optional Blood Sampling 
and a Health Behaviors 
Questionnaire and a Symptom 
Checklist 
2c. Food and Activity Log 
2d. Child Hood Brain Injury 
Scale 
2e. Drug and Alcohol Use Scale 
2f. Hospitalizations 
2g. Psychosocial Therapy 
2h. Medication Log 
 
 
 
1.5 hours 
 
 
 
ADAPT Lab 
 
 
 
Pre-Intervention 
 

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2i. Global Role/Social 
functioning 
2j. SIPS (negative, 
disorganized, general) 
2k. SCID 
2l. PINS 
2m. Exercise Survey 
2n.  Calgary Depression Scale 
2o. Beck Anxiety Scale 
2p. Beck Depression Inventory 
2q. 6 take home samples will be 
given  
2r. WRAT 
3. Cognitive Battery: 
3a. MATRICS 
3b. RISE Task 
3c. Urine Sample 
 
2 hour 
 
ADAPT Lab 
 
Pre-Intervention 
 
4. Scan 
4a. Structural Scan 
4b. fMRI Scan and MID task 
1.5 hours 
CTI 
Pre-Intervention 
 
5. Initial Exercise Assessment 
45 minutes 
Downtown 
Pre-Intervention 
 
 
Table 3: HC baseline visits  
Visit (1-3 visits)* 
Time 
Location 
Time Point 
2. Clinical Assessment: 
2a. Cortisol Sampling-4 saliva 
samples and a hair sample 
2b. Optional Blood Sampling 
and a Health Behaviors 
Questionnaire and a Symptom 
Checklist 
2c. Food and Activity Log 
2d. Child Hood Brain Injury 
Scale 
2e. Drug and Alcohol Use Scale 
2f. Hospitalizations 
2g. Psychosocial Therapy 
2h. Medication Log 
2i. Global Role/Social 
functioning 
2j. SIPS (negative, 
disorganized, general) 
2k. SCID 
2l. PINS 
2m. Exercise Survey 
 
 
 
1.5 hours 
 
 
 
ADAPT Lab 
 
 
 
Baseline 
 

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2n.  Calgary Depression Scale 
2o. Beck Anxiety Scale 
2p. Beck Depression Inventory 
2q. 6 take home samples will be 
given  
2r. WRAT 
2s. Urine sample 
4. Scan 
4a. Structural Scan 
4b. fMRI Scan and MID task 
4c. SOT task  
*2 hours or 2 
visits: 1.5 
hours and 30 
minutes 
CTI 
Baseline 
 
 
*depending on participant needs and preferences 
 
Table 4: Exercise Intervention (ONLY FOR THE 15 UHR exercise group) 
Visit (24 visits) 
Time 
Location 
Time Point 
6. Exercise Intervention 
(including the Orientation 
Tour and Affective 
Response Scales) 
 
PANAS and UFOV (will be 
given before and after 
exercise session 1, week 5 
sometime, week 9 
sometime, and week 12 
sometime) 
 
 
2x per week for 12 
weeks (40 minutes 
each session) 
 
Adapt Lab 
Or 
Downtown 
 
Intervention 
 
 
Table 5: Post Intervention (Both UHR groups) 
Visit (1-3 visits)* 
Time 
Location 
Time Point 
7. Clinical Assessment: 
7a. Cortisol Sampling-4 saliva 
samples and a hair sample 
7b. Optional Blood Sampling 
and a Health Behaviors 
Questionnaire and a Symptom 
Checklist 
7c. Food and Activity Log 
7d. Child Hood Brain Injury 
Scale 
7e. Drug and Alcohol Use 
Scale 
7f. Hospitalizations 
7g. Psychosocial Therapy 
 
 
 
 
 
1.5 
hours 
 
 
 
 
 
ADAPT Lab 
 
 
 
 
 
Post-Intervention 
 

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7h. Medication Log 
7i. Global Role/Social 
Functioning 
7j. SIPS (negative, 
disorganized, general) 
7k. SCID 
2l. PINS 
7m. Exercise Survey 
7n.  Calgary Depression Scale 
7o. Beck Anxiety Scale 
7p. Beck Depression Inventory 
7q. 4 take home samples will 
be given 
7r. WRAT 
8. Cognitive Battery: 
8a. MATRICS 
8b. RISE Task 
8c. Urine Sample 
 
 
2 hour 
 
 
ADAPT Lab 
 
 
Post-Intervention 
 
9. Scan 
9a. Structural Scan 
9b. fMRI Scan and SOT task 
1.5 hour CTI 
Post-Intervention 
 
10. Post Exercise Assessment 
and Feedback Session 
45 
minutes 
Downtown 
Post-Intervention 
 
*depending on participant needs and preferences 
 
 
Table 6: 12-month and 24-month Visits (All three groups) 
Visit (1 visit) 
Time 
Location 
Time Point 
2. Clinical Assessment: 
2a. Cortisol Sampling-4 saliva 
samples and a hair sample 
2b. Food and Activity Log  
2c. Child Hood Brain Injury 
Scale 
2d. Drug and Alcohol Use 
Scale 
2e. Hospitalizations 
2f. Psychosocial Therapy 
2g. Medication Log 
2h. Global Role/Social 
Functioning 
2i. SIPS (positive, negative, 
disorganized, general) 
2j. SCID 
2k. PINS 
2l. Exercise Survey 
 
 
 
 
3 hours 
 
 
 
 
ADAPT Lab  
Or  
Over the 
phone/Zoom 
 
 
 
 
12-month 
24-month 

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2m.  Calgary Depression Scale 
2n. Beck Anxiety Scale 
2o.4 take home samples will 
be given 
 
 
NOTE: Visits can be completed in 1-3 visits depending on what participants prefer. 
 
COVID-19 Symptom Checklist & Procedures 
If participating in person for any portion of the study, participants will be required to complete a 
COVID-19 pre-screening checklist within 24 hours before the appointment. This checklist will 
be sent via email to the participant upon confirmation of their in-person appointment. The form 
is brief and does not ask for vaccination status. If the individual answers “Yes” to any of the 
screening questions, the study team will cancel the study visit. If the individual is experiencing 
any of the above symptoms, study team members will recommend that they contact a doctor to 
determine if seeking medical care or being tested for COVID-19 is necessary. The study team 
member coordinating the visit will attempt to reschedule the session for a date at least 14 days 
later. However, the potential participant must pass pre-screening before proceeding with the in-
person study visit. COVID-19 prescreening checklists will be stored on Box SAFER, separate 
from study data. 
Participants will be asked to wear a mask for the duration of all study components in which the 
participant will be in the same room as research study team members. This is a requirement that 
will be included in the consent forms for all participants, and they will be informed that refusal to 
wear a mask or failure to comply can result in being removed from the study before it is 
completed. 
 
 
Design of the Proposed Study 
 
 
1. Screening Visit 
Participants will first attend a screening session (roughly 1.5 hours) and if they meet UHR 
criteria discussed throughout the protocol and in consent forms, they will be invited to join the 
study (note: we propose to screen 54 people to identify the 36 eligible UHR individuals). HC 
participants will be screened using the same measures to rule out UHR criteria. If potential HC 
participants present with the prodromal syndrome based on the SIPS scores, they will be 
informed that they cannot participate in the HC groups and provided with referrals to community 
mental health providers based on their specific needs. If they are still interested in participating 
in the study, they will be given an option to screen for the URH groups. At that point, we will 
follow the protocol outlined for UHR groups.  
 

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2. Clinical Assessment 
Background information will be obtained at the beginning of the clinical evaluation.  This will 
allow us to understand what the patient’s history is like in order to fully understand their current 
experiences.  This background packet will include questions about brain injury from the 
Childhood Brain Injury Scale, drugs and alcohol from the Drug and Alcohol Scale, 
hospitalizations from the Hospitalizations Questionnaire, therapy from the Psychosocial Therapy 
Questionnaire and medications from the Medication Log.  This will be given at baseline, 12 
month, and 24 month visits. 
 
The Structured Interview for Prodromal Symptoms (SIPS) (Miller et al., 1999) will be 
administered to initially detect the presence of a prodromal syndrome at the screening interview 
(the presence of a prodromal syndrome is necessary for inclusion in the at-risk group), and then 
to formally assess attenuated 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 contains an instrument, the Scale of Prodromal Symptoms (SOPS), which rates the 
severity of relevant dimensions including positive, negative, and disorganized symptoms along a 
7-point scale ranging from absent to severe and psychotic.  Prodromal or high-risk syndrome will 
defined by moderate levels of positive symptoms and/or a decline in global functioning 
accompanying the presence of schizotypal personality disorder and/or a family history of 
schizophrenia. The Structured Clinical Interview for DSM-IV (SCID-I) will be used to determine 
the presence of Axis I psychotic disorders (for rule-out) and to classify diagnostic status for non-
psychotic axis-I disorders (First et al., 1995).  It will also be administered post-trial to determine 
any changes in clinical status.  Each of the measures has been used with psychotic subjects and 
demonstrated reliability with adolescent populations (Martin et al., 2000, Miller et al., 2003a, 
Mittal et al., 2008b, Howes et al., 2009, Mittal et al., 2010c).  Advanced doctoral students and 
clinical psychologists will conduct the interviews.  As part of the ongoing ADAPT clinic, all 
interviewers in our program will participate in an in-depth training program regarding the 
administration and scoring of the SIPS and SCID and will be required to independently rate a 
minimum of six SIPS and SCID training videos, followed by four live supervised assessments 
(by the PI Mittal).  Interviewers will be required to achieve sensitivity and specificity Kappas of 
at least .80 regarding SIPS and SCID symptoms, as well as 90 percent agreement on all 
diagnostic classifications across assessments. Following this stage, ADAPT examiners will 
continue the training, observing and providing ratings of live interviews with high-risk 
adolescents specifically. ADAPT raters have been observed while conducting ratings on live 
interviews with high-risk adolescents; intraclass correlations (ICCS) over .80 for all symptom 
ratings and kappa of ≥ .80 for prodromal syndrome diagnoses will be met for each interviewer 
prior to participation in formal interviews. In addition, Prodromal Inventory of Negative 
Symptoms (PINS) will be administered to assess five dimensions of negative symptoms: 
avolition, asociality, anhedonia, transitionary distress, and blunted affect/alogia. The interview is 
comprised if 23 items and includes probes for the interviewer which assess areas of functioning 
reflected by these domenstions. Each item is rated on a scale from 0 (absent) to 6 (extremely 
severe).  
 
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.  On the GFS-R, a score of 10 

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indicates “Superior Role Functioning” (e.g., Independently maintains superior functioning in 
demanding roles), whereas a low score of 1 reflects “Extreme Role Dysfunction” (e.g., on 
disability, non-independent status).  A score of 10 on the GFS-S reflects “Superior 
Social/Interpersonal Functioning” (frequently seeks out others and has multiple satisfying 
interpersonal relationships including close and casual friends), whereas the lowest score of 1 
indicates “Extreme Social Isolation” (no social or family member contact at all).  The scales 
were designed for adolescents and have been found valid and reliable in assessing prodromal 
populations (Cornblatt et al., 2007) and our group is familiar in working with these measures 
(Mittal & Walker, 2011a, Pelletier et al., 2013).  
 
In addition, we may ask permission (participants to sign a release form) for us to speak to current 
therapists, psychiatrists, or other medical professionals involved in the mental health of 
participants. We ask to do this in order to fully understand the mental health history and 
background.  We can better rate various scales, measures, and interviews with this knowledge.  If 
participants choose not to give us permission to do so, they may still continue to participate in 
the study. This is considered additional material, but is not absolutely necessary. Detailed 
information regarding thoughts and experiences will be obtained during the clinical interview. 
Although information from current providers may provide useful supplementary information, 
this is not a requirement given the detailed structure of the interview. This has been the common 
and successful approach in our studies at the University of Colorado Boulder, and we will be 
extending this practice.  
 
We will also ask participants to complete an exercise survey. This survey is a short self-report 
questionnaire designed to capture exercise and activity practices of adolescents and young adults. 
The Exercise Survey was designed by and Deighton and Addington (2013) specifically for 
examining exercise in UHR samples, and uses items applicable to the adolescent and young adult 
age range from widely employed measures of exercise and recreation practices such as the 
International Physical Activity Questionnaire: Short, The World Health Organization (WHO) 
Quality of Life-BREF, Motivations for Physical Activities Measure-Revised, and the Physical 
Self Description Questionnaire. The survey is brief but highly informative (asking about the 
frequency, intensity, and duration of recent exercise activity; See Appendix 2) and will be 
administered pre and post exercise intervention, as well as during the yearly longitudinal follow-
up time points.   
 
We will also assess symptoms of depression and anxiety using the self report measures named 
the Beck Anxiety Scale (Beck et al., 1998), Beck Depression Inventory (Beck et al., 1998), and 
the Calgary Depression Scale developed by Addington, Addington,  and Schissel 1990, which is 
completed by the assessor based on interview. The scales will help supplement the questions 
given on the SCID noted above. This will be completed at pre and post exercise intervention, and 
12 and 24 month visits.  
 
We will ask participants to complete a puberty scale asking them to rate puberty milestones on a 
4 point likert scale (not yet started, barely started, seems complete) or “I don’t know”.  
 
Further, participants will be given a sheet with words listed on it ranging from simple to difficult. 
They will be asked to read the words and the assessor will keep track of incorrectly pronounced 

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words. This assessment called the Wide Range Achievement Test (WRAT) has been used in 
order to obtain a quick measure of general intelligence. Typically, general intelligence tests take 
several hours, and this is a quick and easy way to get this information. 
 
Cortisol  
Four saliva samples for cortisol assay will be collected in the ADAPT clinic at the pre and post 
exercise intervention, and at 12-month and 24-month assessment points. If participants choose to 
do the 12 and/or 24 month follow up over the phone, saliva sample tubes will be mailed to them 
to complete during the phone interview. A pre-labelled/prepaid package will be included for 
them to mail the completed samples back to ADAPT. Samples collected in the clinic will be 
collected at hourly intervals during the first morning of the initial and follow-up assessments 
while the diagnostic interviews and self-report measures are administered. Collection will begin 
around 9:30am, and subsequent samples will be obtained at hourly intervals, approximately 
10:30, 11:30 and 12:30. A timer-alarm will be used to signal collection times. Participants will 
provide each sample in a plastic specimen tube prelabeled with participant’s ID and sample 
number. Collection time is recorded on the label. Samples will be immediately stored at -20C in 
lab freezers, and kept frozen until assay. Because diet and activity affect cortisol, subjects will be 
given explicit instructions and provided a log to detail these activities.  On the evening before 
saliva sampling, they will be asked to avoid alcohol and caffeine after 6:00 PM. On the morning 
of the assessment, they will refrain from exercise, caffeinated beverages, and consume only 
grains (e.g., toast, cereal, pastry), milk, juice or water.  They will also avoid over-the-counter 
medications and physical exercise. Food, liquid, and medication consumption the previous 
evening and morning will be recorded (please see Food and Activity Log attached).  For salivary 
cortisol assay, the Salimetrics (Salimetrics, LLC, College Park, Pa) High Sensitivity Salivary 
Cortisol Enzyme Immunoassay Kit will be used. This assay captures the full range of salivary 
cortisol levels (0.003 to 3.0μg/dL) requiring only 25 uL of saliva per test. A built-in pH indicator 
detects acidic or basic samples.  
 
In addition to collecting salivary cortisol during pre and post exercise intervention, 12-month, 
and 24-month assessments, the participants will be asked to take home four plastic specimen 
tubes pre and post exercise intervention, 12-month and 24-month assessments. They will be 
given these tubes at the end of the clinical assessment (Please refer to tables 2, 4, and 5). These 
samples will be used to measure the Cortisol Awakening Response (CAR). The CAR is a new 
area of research that provides a good measure of HPA integrity (Wilhelm, Born, Kudielka, 
Schlotz, & Wüst, 2007). The participant will be instructed to give a saliva sample on any day 
prior to coming back for their next visit. Instructions on when to provide the samples will be 
given (see attached document, “Cortisol Sample Instructions”).  There is a section in the Sleep 
and Activity log for the participant to record the time and day that these samples are given as 
well as serve as a reminder to provide the samples. The participant is instructed to provide the 
samples immediately after waking, 30 minutes after awakening, 45 minutes after awakening, and 
immediately before going to sleep. The tubes will be labeled with their participant ID followed 
by a 01, 02, 03, 04 to denote the succession of samples.  The participant will be instructed to 
bring the samples back to the ADAPT office. Upon return to ADAPT, specimens will be stored 
in a freezer until ready for assay along with the other samples taken during the assessment. 
Please note that we do not request participants to store cortisol samples in a freezer when they 
take them home. If participants choose to do the 12 and/or 24 month follow up over the phone, 

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the take home saliva sample tubes will be mailed to participants to complete after the phone 
interview at the times noted above. A pre-labelled/prepaid package will be included for them to 
mail the completed samples back to ADAPT. 
 
In addition to saliva samples, participants will be asked to provide a hair sample for cortisol 
analysis. The assessor or lab manager will collect a hair sample from the participant. They will 
cut a small strand of hair from the crown of the participant’s head. They will also be asked the 
following questions: 
1) How frequently do you wash your hair? (times/week) 
2) Do you use a conditioner? (yes/no) 
3) Do you bleach your hair? (yes/no) 
4) Have you recently had a perm? (yes/no) 
5) Do you use hair straighteners? (yes/no) 
The strand of hair will be taped to a piece of foil and placed in a confidential, locked, cabinet. 
 
Blood Draw, RNA Extraction and BDNF and Inflammation Analysis:  
 
Before the blood draw, participants will be asked to complete a questionnaire asking about health 
behaviors (alcohol consumption, smoking, medication use, recreational activities, and 
reproductive health for female participants), a questionnaire about symptoms (e.g., headache, 
dizziness, chest pain), and questions about chronic illnesses and respiratory illnesses in the last 
two weeks. These questions are crucial for 1) data analysis because the blood sample can be 
affected by the health behaviors outlined above and 2) determining whether blood can be drawn 
on the scheduled day. If the participant had a respiratory illness (e.g., cold, flu) in the last two 
weeks, the blood draw will be rescheduled because the cell count would likely be impacted by 
the illness.  
In addition, if the participant agrees to the blood draw, the trained phlebotomist will take 
participants’ body measurements: weight, height, waist, and hip. These measures need to be 
factored in during the data analysis because they are related to inflammatory markers. Research 
suggests that BMI, waist circumference, and waist to hip ration are all associated with IL-6, 
TNF- α and CRP (O’Connor et al., 2009). During that procedure, the phlebotomist will ensure 
the participants’ privacy is protected by minimizing physical contact (having the participant hold 
the measurement tape during hip and waist measurement, keeping appropriate distance) and 
talking the participants though the steps. The participants will also be informed they may tell the 
phlebotomist if they are uncomfortable with the procedure and that they can stop at any point 
without penalty.  
 
Blood sampling will be optional, and the participant’s decision not to consent to the blood draw 
will not affect participation in any of the other procedures. For those participants who consent to 
the blood draw, less than 30 mL of blood will be taken via antecubital blood draw by a trained 
phlebotomist. Collected into 2 PAXGene tubes, stored (frozen at -80 degree Celcius) and 
shipped to Drs. Hutchison and Bryan at the University of Colorado Boulder.  There, blood will 
be collected into a 4 mL Vacutainer tube containing EDTA. A cell counter (Beckman Coulter 5-
part Hematology Analyzer) will be used to quantify the presence of different cell populations in 
whole blood, to determine whether gene expression values differ depending on blood cell 
composition. The mRNA will be extracted from blood samples using the Qiagen RNAeasy kit 

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and BDNF mRNA will be assayed using real time PCR and a commercially available assay from 
Applied Biosystems.EndFragment. Blood samples will be collected pre and post exercise 
intervention for the UHR Exercise group and pre and post waiting period for the UHR waitlist 
control.  
A sample of venous blood will be taken at the same time into a Vacutainer Serum Separation 
Tube (BD Biosciences), which is then centrifuged at 1200 rpm for 10 minutes (in the ADAPT 
lab Centrifuge). Samples will then be aliquoted into microfuge tubes and frozen at -80 degree 
Celsius until processing. These analyses will focus on inflammatory markers associated with 
exercising. Another sample will be processed at Dr. Gregory Miller and Dr. Edith Chen’s lab 
located at the same location as the ADAPT lab. Only trained and authorized lab members will be 
responsible for transporting the blood specimens for processing. During this process, blood will 
be collected into a 4 mL Vacutainer tube containing EDTA. A cell counter (Beckman Coulter 5-
part Hematology Analyzer) will be used to quantify the presence of different cell populations in 
whole blood, to determine whether gene expression values differ depending on blood cell 
composition.  
The total amount of blood drawn at each time point is less than 30mL between 4 tubes.  
 
Urine samples: 
We will ask participants to urinate in an icup. Icup is a brand of drug testing cups. If the results 
(which show up immediately) indicate that the participant is under the influence, they will be 
asked to reschedule their visit when they are not under the influence. With this information, we 
will include an appropriate referral.  
 
Audio and/or Video Recordings 
We will videotape the clinical interviews portion of the study. On the consent form, we included 
information about the video taping process, and whether or not participants agree to this.  
Participants will be informed that this is for educational purposes and this allows us to make sure 
we are doing everything correctly. Participants will be also informed that videotapes may be 
used for coding various portions of the study such as examining emotions. Additionally, this will 
allow us to have accurate consultation from the consultants involved.  If participants decide not 
to be videotaped, they still may participate in the study. 
Video tapes will be deleted upon participants’ request, although the participant will not be 
permitted to review the tape before doing so. Videotapes will be retained for research and/or 
training purposes for 30 years after which time they will be destroyed unless participant provide 
written permission for their continued use. In the future, the videotapes may be used for coding 
various components of the study (if consent is obtained). 
 
Participants who do not consent to be videotaped will not be videotaped. Participants who 
consent to be videotaped and then withdraw from the study or are ineligible will have their 
videotapes erased/deleted. 
 
3. Cognitive Battery 
The battery is designed to assess spatial memory, verbal learning, and episodic memory as well 
as broad cognitive function. This will include the Measurement and Treatment Research to 
Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (Green & 
Nuechterlein, 2004) which provides scores for domains of processing speed, attention/vigilance, 

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working memory, verbal learning, visual learning, problem solving, social cognition and an 
overall composite score.  The MATRICS includes the Brief Assessment of Cognition in 
Schizophrenia (BACS), Symbol-Coding (Timed paper-and-pencil test in which respondent uses 
a key to write digits that correspond to nonsense symbols), Category Fluency: Animal Naming 
(Oral test in which respondent names as many animals as she/he can in 1 minute), Trail Making 
Test: Part A (Timed paper-and-pencil test in which respondent draws a line to connect 
consecutively numbered circles placed irregularly on a sheet of paper), Continuous Performance 
Test—Identical Pairs (CPT-IP) (Computer-administered measure of sustained attention in which 
respondent presses a response button to consecutive matching numbers), Wechsler Memory 
Scale®—3rd Ed. (WMS®-III): Spatial Span (Using a board on which 10 cubes are irregularly 
spaced, respondent taps cubes in same (or reverse) sequence as test administrator), Letter-
Number Span (Orally administered test in which respondent mentally reorders strings of number 
and letters and repeats them to administrator), Hopkins Verbal Learning Test—Revised™ 
(HVLT-R™) (Orally administered test in which a list of 1 words from three taxonomic 
categories is presented and the respondent is asked to recall as many as possible after each of 
three learning trials), Brief Visuospatial Memory Test—Revised (BVMT-R™) (A test that 
involves reproducing six geometric figures from memory), Neuropsychological Assessment 
Battery® (NAB®): Mazes (Seven timed paper-and-pencil mazes of increasing difficulty that 
measure foresight and planning), and the Mayer-Salovey-Caruso Emotional Intelligence Test 
(MSCEIT™): Managing Emotions (Paper-and-pencil multiple-choice test that assesses how 
people manage their emotions).  This collective battery has been specifically designed, and 
validated for administration to psychosis spectrum individuals and is designed to take 60-90 
minutes to complete.  
 
Episodic memory is a critical cognitive process affected in the psychosis spectrum (Eastvold et 
al., 2007), and tied with aerobic fitness in other populations (Bunce & Murden, 2006).  Many of 
the common paradigms used to assess relational encoding and retrieval allow for the nature of 
the encoding strategy to be up to the participant, leaving open the possibility that poor task 
performance simply reflects a failure to apply relational processing, rather than a fundamental 
deficit in the ability to engage in such processing. In addition to the MATRICS consensus battery 
participants will also be administered the behavioral version of the Relational and Item Specific 
Encoding and Retrieval (RISE) task, which has been determined to gauge hippocampal mediated 
episodic memory function while explicitly controlling whether participants engage in item-
specific or relational memory processing (Ragland et al., 2012). The task is part of the final 
selection of CNTRICS initiative, and demonstrates excellent test-characteristics (Gold et al., 
2012).  Stimuli consist of visual object representations of word stimuli (selected from a 
standardized corpus of photographic images; http://cvcl.mit.edu/MM/). The RISE assessment 
includes several components and is administered with E-Prime® (version 2.0).  For the Item-
Specific encoding component, a total of 36 stimuli are presented for two seconds each, with a 
one second inter-stimulus-interval (ISI), and subjects make a two-button “yes/no” response to 
indicate whether the objects are “living” (this level-of-processing manipulation controls for 
potential group differences in strategy generation). For the Relational Encoding component 18 
pairs of visual objects are presented for 4 seconds each, with one second ISI and subjects make a 
two-button “yes/no” response to indicate whether one item could fit inside the other item. After 
the encoding conditions, two retrieval tasks are administered. For the Item Recognition 
component, all 72 objects studied during the encoding trials (36 item-specific and 36 relational 

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targets) are randomly intermixed and presented with 72 new unstudied foils, and participants 
indicate whether each test item was “old” (left hand response) or “new” (right hand response) 
and rate their confidence using one of three buttons (i.e., 3 = high, 2 = medium, 1 = low).  
Finally, the Associative Recognition component includes the 18 original objects pairs studied 
during the relational encoding, which are then randomly intermixed and presented with 18 
rearranged object pairs consisting of items presented during different encoding trials an not 
originally paired together. 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. The 
familiarity and recollection performance as well as hit rates and false alarm rates following 
encoding reflect the cognitive and neural mechanism underlying relational encoding and 
retrieval. The complete procedure, including practice, encoding, and retrieval required 20 
minutes to complete.  In addition to being highly innovative and amendable to administration in 
psychosis spectrum populations (the task uses visual objects rather than words to improve patient 
understanding of encoding instructions; because individuals with psychosis have prominent task-
switching difficulties, encoding conditions are alternated in a pseudo-random block design rather 
than in the fully randomized design; participants are presented with 3 second instruction screens 
to remind them of the encoding condition between blocks), the task specifically targets an NIMH 
prioritized construct as well (http://www.nimh.nih.gov/research-funding/rdoc/rdoc-
constructs.shtml#active_maintenance). Psychology Masters and Ph.D. level students will 
administer the entire battery under the supervision of Dr. Mittal. Taken together, this battery was 
kept brief to limit any potential participant strain over the multiple testing periods. 
 
We will also be measuring acute stress. We will do this using the the Positive and Negative 
Affect Scale (PANAS), which is a paper and pencil 20-item self-report questionnaire 
administered to the patients to assess their current mood state (Watson et al., 1988). The 
questionnaire takes approximately five minutes and will be repeated once monthly before and 
after exercise for the duration of the study. Additionally, we will use the Useful Field of View 
(UFOV), which is a computerized measure of selective attention and visual processing speed. 
Subjects will be asked to identify a central stimulus, as well as locate a peripheral target among 
distractors on the computer. Testing will last approximately five minutes and will be repeated 
once monthly before and after exercise for the duration of the study. Specifically, they will both 
be given before and after exercise session 1, week 5 sometime, week 9 sometime, and week 12 
sometime) 
 
4. Exercise Intervention 
VO2max Graded Treadmill Test: Participants will be asked to meet in downtown Chicago at the 
Northwestern University, Department of Physical Therapy and Human Movement Science, 645 
N. Michigan Ave. 10th Floor, 60611 for the initial exercise assessment pre and post exercise 
intervention. Prior to the initial exercise assessment, participants will be given information 
verbally on how to prepare for this test over the phone or during their last visit at ADAPT. We 
will inform participants to wear exercise clothes (comfortable clothing, tennis shoes, sports bra 
for women), bring water and water will also be provided if necessary, eat only very light meals 
before coming in for the assessments, and refrain from ingestion of caffeinated substances for at 
least 2 hours prior to the session  
 

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Once at the VO2max center, a trained exercise physiologist (Elizabeth Skender) will conduct the 
maximal exercise test. First, a resting 12-lead ECG will be recorded in the recumbent and upright 
positions immediately prior to the exercise test, as well as during the test. If the findings on the 
resting ECG do not contraindicate exercise, the exercise test will be performed.  Contraindicators 
include the following: (a) ST-segment depression of more than 0.2 mV that is either horizontal, 
downsloping, or slowly upsloping (less than 1 mV/sec) and lasts for 0.08 sec, or ST-segment 
elevation greater than 0.1 mV; (b) chest pain or discomfort; (c) serious arrhythmias, including 
multifocal PVCs, ventricular tachycardia, frequent (>10/min) PVCs or couplets, or sustained 
atrial tachyarrhythmias;  (d) A-V block or other conduction defects; (e) a fall of systolic blood 
pressure of 10 mmHg or greater from the peak level with increasing exercise intensity; (f) 
diastolic blood pressure above 110 mmHg or systolic above 220 mmHg; (g) dizziness; (h) ataxic 
gait; and (i) pallor or cyanosis. Elizabeth Skender, who is The American College of Sports 
Medicine certified exercise physiologist and has a successful completion of an American Heart 
Association-sponsored course in advanced cardiac life support, is qualified to conduct and 
monitor the ECG procedure. In addition, she has knowledge of appropriate indications and 
contraindications for exercise testing, competence in cardiopulmonary resuscitation, knowledge 
of cardiac arrhythmia and the ability to recognize and treat various arrhythmias, and knowledge 
of endpoints of exercise testing and indications to terminate exercise testing. As a part of her 
ACSM certification, she also qualified to take blood pressure and measure ratings of perceived 
exertion (RPE).   
  
Maximal aerobic power (VO2max) will be measured by indirect calorimetry (TruMax 2400, 
ParvoMedics, Sandy, UT) during the GXT. A warm-up period on the treadmill will be used to 
identify the walking speed that generates a HR that is 65-70% of the age- predicted HRmax. The 
speed of the treadmill will remain the same throughout the test but the incline of the treadmill 
belt will increase 2% every 2 min (or 2.5% for speeds 6 mph or greater). The ECG will 
continuously monitor the subject’s HR throughout the entire VO2 max test. Blood pressure will 
be taken every minute of the test, and the subject’s RPE will be recorded at each minute. The 
treadmill speed is determined using participant’s heart rate and RPE and can vary greatly 
between subjects (1.5-10+ mph). Because all participants will be sedentary, a speed that elicits 
70% of age-predicted max heart rate and an RPE rating of around 13 (“somewhat hard”) will be 
used to begin the test. Staying within these parameters generally yields an 8-12 min test; the 
recommended target for VO2max testing (Hollenberg et al., 1998). The determination of when a 
participant has reached VO2max is not without controversy, (Magnan, 2013) and will ultimately 
be up to the participant, who chooses when they can no longer continue. This study will 
determine a valid VO2max using both the primary criterion of having achieved a plateau in VO2 as 
well as secondary criteria outlined by Pimentel and colleagues (Pimentel et al., 2003) including 
respiratory exchange ratio (RER)max≥1.1, RPEmax≥18, and age predicted heart rate max 
±10bpm. VO2max will be used as a baseline measure of cardiovascular fitness and will serve as 
the basis for exercise prescriptions. There is ample evidence in the literature that VO2max is an 
appropriate measure for youth in this age range (Pheiffer et al., 2008). Additional measures of 
cardiovascular fitness obtained in the course of the assessment include ventilatory threshold (VT) 
(Ekkekakis et al., 2008) and VO2 peak (Cooper et al., 1984), both of which are related but 
distinct measures of cardiovascular fitness and have been used successfully in studies of 
adolescents and young adults. These variables will then serve as objective outcome measures to 

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determine whether participation in one of the aerobic exercise (moderate versus vigorous 
intensity) led to an increase in cardiovascular fitness. 
 
Exercise Intervention at Northwestern University in Evanston, IL 
 
Orientation Tour 
During the orientation tour, we will show participants the facility, share their exercise 
prescriptions with them, and work with them and their families to organize transportation for the 
sessions. We will also provide participants with more information about the incentives for 
participation and discuss factors relating to how to best keep them motivated. This will also be a 
great time for participants to meet the exercise staff (including an expert exercise physiologist) 
that will work with them to help meet aerobic fitness goals. This portion of the study will be 
apart from the exercise intervention. During the orientation tour, they will receive incentive 
flyers, exercise is fun flyer, and payment information forms (please see supporting documents). 
 
The exercise intervention will be tailored to each person’s current exercise fitness level. We will 
use 80% of VO2max and ask participants to exercise 2 times a week. The first 10 minutes of the 
visit will include warming up. Next, participants will be asked to run for 30 minutes. Every 10 
minutes they will be asked to run at a slightly higher intensity (a faster jog) for 3 1-minute 
intervals to get to 95% of VO2max. The purpose of adding brief sessions of high intensity 
interval training (HIIT) to participants’ exercise prescription is to increase rates of their fitness 
improvement. Recent studies suggest that HIIT is associated with higher improvements in 
adolescent and young adult aerobic fitness than more traditional continuous endurance training 
(Buchan, et al., 2012, Costigan et al., 2015, Logan et al., 2014, Matsuo, et al., 2014). Risks 
associated with brief spouts of HIIT are no greater than risks associated with aerobic exercise 
described in the Risks to subject portion of the protocol. In addition, individuals that are enrolled 
in the study will be asked not to partake in any physical activity outside of the exercise 
intervention. Based on our pilot data, which suggest that prodromal participants do not engage in 
physical activity but instead have more sedentary lifestyles, we do not think that excess physical 
activity will be a concern. Later in a different phase (which will be included in a separate 
application), the controls will be assessed for fitness before and after the exercise intervention 
and any increases in fitness will be considered outside physical activity. Increases in fitness will 
be treated as covariates.   
 
Most (if not all) exercise sessions will be monitored by the exercise physiologist. In an event the 
exercise physiologist is not available for the scheduled session, the research coordinator may step 
in to monitor the session to ensure participants are staying on the 2 session per week schedule. 
According to ACSM Guidelines for Exercise Testing and Prescription, 9th edition, “The 
health/fitness and clinical exercise professional may determine the level of supervision that is 
optimal for an individual by evaluating information derived from the pre-exercise evaluation as 
indicated by the individual’s exercise goals and health status” (the VO2max test in our case). 
“Supervision by an experienced exercise leader can enhance adherence to exercise and may 
improve safety for individuals with chronic disease and health conditions”. We are recruiting 
only low risk participants who do not have chronic diseases or health conditions that would put 
them at high risk for a detrimental event during exercise. Therefore, the supervision is not 
necessary (i.e., healthy adolescents and young adults could to the prescribed exercise regimen on 

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their own), and we monitor sessions to improve adherence, administer questionnaires, and to add 
a level of safety. However, we will be adding precautionary steps to ensure safety. Based off the 
VO2 max test and first few weeks of exercise sessions, the exercise physiologist will determine 
the level of supervision that is optimal for the individual. If for any reason the subject is severely 
deconditioned, or the exercise physiologist believes that they need an exercise professional’s 
supervision, they will only be supervised by an exercise physiologist. However, if based on the 
VO2 max test and the subject’s fitness level, the exercise physiologist determines that the 
research coordinator is an adequate level of supervision during certain exercise sessions, then 
that may be an option. Furthermore, we monitor heart rate and the perceived exertion every 5 
minutes throughout the sessions.  
 
Exercise Prescriptions. The initial exercise intensity will be 55% of VO2max. This is the baseline 
fitness threshold for the study to see what their baseline fitness level is prior to intervention. 
Then, the intensity will be gradually increased to peak intensity over the first 3 weeks. The initial 
exercise duration will be 15 minutes, and duration will be gradually increased to 30 minutes over 
the first 3 weeks. Intensity will be constantly monitored during exercise using heart rate (HR) 
monitors. Once at full training intensity, the goal will be to maintain HR within ±5% of the target 
intensity. The primary mode of exercise will be treadmill walking/running or elliptical. Adding 
variety will keep participants engaged and interested, allowing us to better test feasibility of this 
study. 
 
Feedback Session. At the end of the post exercise visits, participants will receive a feedback 
session with members that worked with them. This is an opportunity for participants to ask 
questions and receive appropriate recommendations and referrals, if needed. A feedback session 
is a great way to check in and get information regarding the participation. Additionally, it's a 
good way to wrap up the time in the lab and to remind the participant they will be asked to come 
in 12 and 24 months later. Additionally, participants will be given a take home packet consisting 
of a reminder of their next appointment and flyers. The first flyer will remind them about the 
opportunity to win incentives. The second flyer will be some information regarding the benefits 
of exercise, and other educational points. This allows participants to learn more about exercise 
throughout the process. Please see attached documents for more details. 
 
Affective Response Scales (Hardy and Rejeski, 1989; Svebak and Murgatroyd, 1985; Borg, 
1998): To check in with participants as they are exercising, we will be asking them questions 
about how they feel, how aroused they are, their thoughts, perceived exertion, and motivation. 
This will allow us to see how participants are able to handle the exercise intervention 
(contributing to the feasibility aims of the study).  
 
5. Imaging Assessment and Analysis 
PI Dr. Mittal and an experienced postdoctoral research assistant (PRA) will be responsible for 
preparing, analyzing, and interpreting the data. The entire imaging protocol including localizing 
images, gradient echo field mapping, arterial spin labeling scan, and BOLD weighted resting 
state scan takes approximately 30 minutes. Prior to scanning at each time point, each participant 
will be evaluated with a comprehensive screener detailed in the “Safety” section.   
 

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fMRI Monetary Incentive Delay (MID) Task. During the same session of the structural MRI 
scan, the participants will be asked to complete the MID task while undergoing an fMRI. They 
will complete 2 MID runs each lasting 9 minutes. On each trial, a cue will indicate whether 
participants can win money, lose money, or neither win nor lose money (neutral). Next 
they are instructed to press a response-box button as quickly as possible following the 
target stimulus. Finally, feedback will indicate whether participants won or lost that trial 
and whether or not they won/lost money for their response. Outcome probabilities are 
fixed by an adaptive algorithm by applying a sliding threshold that changes how quickly 
participants need to respond to receive win feedback. The algorithm tracks participants’ 
response times and adjusts the response time window to keep the task difficulty consistent 
(at approximately 66% success rate). This means that if the participant is below 66%, the 
target duration is lengthened, and if the participant is above 66%, the target duration is 
shortened. There will be 150 trials and the total task takes about 20 minutes to finish. In 
win trials, participants win 20 cents, and in lose trials, they lose 20 cents. Participants can 
earn an average of $20 during this task ($0 lowest and $30 highest amount) which will be 
added to the total payment for this session. The participants will be made aware that the 
difficulty of the task is changing depending on their performance and that they are most 
likely to earn $20 during the task. This taks will be completed only at the baseline (pre-
intervention).  
fMRI Self Ordered Working memory task (SOT). Participants will complete a Self Ordered 
Working memory class in the scanner. Eight line drawings of difficult-to-verbalize objects will 
be presented, and participants will be instructed to select each object once, in any order. After 
each object is selected, all objects will be pseudorandomly rearranged on the screen. Participants 
will then select an object not already selected so that at each step there is one more previously 
selected object to remember. A perceptual and motor control task will be used following 
identical procedures except that one object will be marked with an asterisk, and participants will 
be instructed to select the marked object, as a control condition. Participants will be paid $0.25 
per correct response for both tasks. The primary measure of performance will be working 
memory capacity. Participants are able to earn between $0.25 (one trial correct) and $36 (144 
trials correct) for an average of approximately $20. This task will only be completed at the 3 
month follow up (post-intervention). 
 
MRI Post Processing 
PI Dr. Mittal holds significant experience in utilizing structural imaging to understand grey 
matter changes both in early psychosis and neurodegenerative disease and will be responsible for 
preparing the images for analysis (registration and delineation) and analyzing the data and 
interpreting results. Medial temporal structures (hippocampus and parahippocampal gyrus) will 
be delineated automatically on MRI using the FMRIB’s Integrated Registration and 
Segmentation Tool (FIRST) algorithm within the FMRIB’s Software Library (FSL) image-
processing suite (Patenaude, 2007). Researchers have found close correspondences between 
FIRST and manually derived volume values (de Jong et al., 2008).  Dr. Mittal has also utilized 
this program in other recent studies of high-risk patients (e.g., Mittal et al., 2010a). To employ 
FIRST, each subject’s whole-brain IR-FSPGR will be converted from DICOM to Analyze 
format and cropped below the head.  The resulting volume will be resliced to an axial-oblique 
orientation aligned with the AC-PC plane. It will then be transformed into MNI152 space before 
being loaded into FIRST. FIRST was developed by the FMRIB Centre in the Department of 

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Clinical Neurology at Oxford and represents a cutting-edge addition to the widely used FSL 
medical image-processing package, incorporating several major advances in brain voluming of 
the last decade.  Briefly, the individual subject’s brain MRI is compared to a large database of 
standard brains maintained by Harvard/MGH. These brains have been carefully parcellated into 
numerous volumes-of-interest (VOIs), each representing a different brain anatomic structure, by 
hand.  A surface mesh is then applied to each candidate VOI in the subject’s brain, (i.e., the 
actual surface is approximated by a very complicated contiguous net of a large number of tiny 
polygons (e.g., triangles) each with vertices (mesh points) and an interior area (facet)). The shape 
formed by the points mesh is then described quantitatively as a 3D distribution in space, 
composed of varying amounts of a set of standard deformable distributions. The T1 MRI 
intensity at each facet of the mesh surface is normalized to correct for instrumental and other 
inter-subject differences in intensity. A separate 3D distribution is then derived for the intensity.  
A “training set” of standard VOIs is extracted from the database.  Iterative curve fitting is then 
applied until a linear combination of the standard VOIs is found that best reproduces the shape 
and intensity distributions of the subject’s VOI. That yields the final volume.  FIRST also returns 
values for each participant’s total intracranial volume (TICV; the sum of whole-brain grey matter 
plus white matter plus cerebrospinal fluid) and each structure is then divided by the TICV to 
control for whole brain volume. To confirm volumes derived using FIRST, results for each 
subject will be also checked by visual inspection by Dr. Mittal an experienced PRA. 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 (first_utils). Shape/appearance 
models used in FIRST are constructed from manually segmented images provided by the Center 
for Morphometric Analysis (CMA, MGH, 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 (changes in shape will be examined 
with exploratory analyses). Figure 5 illustrates a shape-based analysis of the hippocampus.  
Taken together, these analytic strategies will provide highly detailed information regarding 
longitudinal changes in the hippocampal structure. 
 
Data Analyses and Specific Hypotheses 
Preliminary analyses will be conducted to verify that demographics for the groups are 
adequately matched. If significant differences are found, these will be taken into 
consideration in subsequent analyses. Further, based on our previous studies indicating that 
target variables are normally distributed, we propose a parametric approach to data 
analysis; if any violations to parametric statistics are detected, we will employ corrections 
and/or non-parametric equivalent tests.  To control for development related changes in 
brain maturation between the ranges of subjects, each series of analyses will treat age as a 
covariate. With the exception of needing to control for any changes in aerobic fitness do to 
exercise activity from outside the trial (in the waitlist control) this will be the only covariate 
used in analyses.  For ROI based analyses, significance testing and adjustment for multiple 
comparisons will be calculated via modified Bonferroni correction.  Only participants with no 
history or current treatment with antipsychotics will be included in the study.  If participants 
begin treatment with neuroleptics during the 3-month trial period, they will be permitted to 
complete the trial, but excluded from the study. Our aim is If UHR subjects participating in 
the exercise condition show greater post-trial increases in medial temporal volume 
and improved cognitive, symptom and social/role functioning profiles when 

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compared with the UHR waitlisted-controls.  We predict that the UHR exercise treatment 
group will show a strong trend to suggest larger effects for increases in hippocampal and 
parahippocampal gyral volume, and improvements in cognitive, social/functional and 
symptom profiles after the trial as compared to the UHR waitlist controls. Any naturalistic 
aerobic activity seen in the UHR Waitlisted-Controls will be monitored by testing for changes 
in aerobic fitness between the pre-post 12-week assessments (although we do not anticipate 
a great deal of naturalistic aerobic activity in the UHR control group based on our pilot 
findings, any changes in fitness will be controlled for in the respective statistical analyses).  
Any participants in the UHR exercise group that are naturalistically being treated with 
psychotherapy will be matched with a wait-list control participant treated with a comparable 
modality.  All intervention analyses in the R33 phase will be conducted utilizing random 
coefficient regression that controls for variability in response across participants as well as 
the within-subjects nature of the fitness assessment data and cognitive assessment data.  
This flexible mixed models statistical approach (Cohen et al., 2003) allows for the inclusion of 
the age covariate, as well as the utilization of sophisticated approaches to the treatment of 
missing data (full information maximum likelihood (FIML) estimation) (Schafer & Graham, 
2002).  There are several important reasons for including a controlled trial phase.  First, a 
pilot controlled trial will provide opportunity to develop consistent practices to enhance data 
integrity and the protection of human subjects (e.g., informed consent procedures, data 
collection tools, regulatory reporting procedures, procedures for adverse event reporting).  
Second, it will be important to determine that any effects seen across the UHR-exercise group 
are due to the proposed intervention and not simply reflecting learning effects (for the 
cognitive measures) or developmental changes. Finally, the process of conducting a small 
clinical trial, before disseminating the findings or planning a larger multisite controlled trial 
will invariably provide a number of valuable insights and unforeseen factors.  This study will 
be instrumental in evaluating the feasibility of recruitment, retention, assessment and 
implementation of a novel intervention in a fully powered trial.  
 
Exploratory: Aim A) If the intervention has an influence on course of illness and 
conversion rates. An important ultimate consideration for UHR individuals relates to clinical 
outcome or conversion to formal psychotic disorders. Within-group analyses will focus on 
how varying degrees of aerobic fitness, brain, and cognitive changes post trial or wait-list 
predict 12-month and 24-month symptoms levels and conversion status.  In addition, it will 
be possible to compare the conversion incidence with that reported from extant well-
powered studies.  Finally, because there will be a small group of wait-list participants 
followed up (from years 3 and 4), it will be possible to run exploratory analyses to compare 
groups in course and outcome over time (note: those control UHR youth who elect to accept 
the offer to participate in the free exercise program following the wait-list period will be 
excluded from these analyses). Although the sample size prohibits any strong conclusions 
with regard to conversion (based on the current literature only 10-15% are likely to convert 
to psychosis), this approach will allow for us to track longitudinal changes symptoms, and 
social/role function and the data will be useful in determining the ultimate effects of the 
intervention on long-term clinical course and conversion.   
 
Timeline, Sample Size, and Power Analysis:  
Over the course of two years collecting data, 30 UHR participants (15 UHR-exercise, 15 UHR 

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waitlisted-control) and 15 controls will participate in the study.  Based on pilot data and 
observations for similar trials in other clinical populations, it is estimated that there will be a 
20% attrition rate among the participants.  To allow for a sufficient sample size to complete 
the Aims we propose to overall-sample at this rate a total of 36 subjects will be recruited for 
the R33 trial (an extra 3 in each group).   
Although the funding mechanism does not explicitly require a sample size sufficient to 
yield high- statistical power (PAR-11-177- “Pilot studies are not expected to be sufficiently 
powered to test efficacy, and inferential statistical test are not expected at this phase of 
development”), we projected the proposed numbers for each phase to provide a power level 
that is sufficient for detecting larger significant effects.  Following Cohen’s (1988) standard 
guidelines for power calculation (Cohen, 1988) and utilizing G*Power 3.0.3 (Faul et al., 
2007), we confirmed power estimates for each phase of the trial.  In the R33 phase we 
benefit significantly from the strength of the repeated measures design.  For the two-tailed 
multivariate tests comparing the two groups (UHR exercise, UHR waitlist-control) on target 
variables, with 15 participants per group and two measurement occasions, we should have 
observed power of .75 with =. 05 and for the detection of a moderate effect size (f = .25).  
Our observed power for the detection of a large effect (f = .40) should be well over .99.   Thus, 
while significant effects are not central to the aims of the investigation, there is still power to 
detect larger effects in both phases.  
 
The scanning portion of the study will take place at the Center for Translational Imaging 
(CTI) located at 737 N. Michigan Avenue, Suite 1600 Chicago IL 60611. The MRI device for 
these scans is FDA approved for research with human subjects and has all the safety 
inherent in a clinical MRI scanner.  The radio frequency fields conform to guidelines 
determined by the FDA and the FDA has designated MRI scanners to be a non-significant 
risk device. MR techniques non-invasively produce images and measurements from tissues 
in the intact, living human. The facility houses Tim Trio 3.0 Tesla Siemens Medical 
Solutions scanners.  
 
About the Subjects 
The participants in the proposed study will consist of 30 UHR youth (15 in the exercise and 
15 in the waitlisted-control) and 15 HC.  All participants (age 16 to 24) will be recruited into 
the study over a 5-year period through the established Adolescent Development and 
Preventive Treatment (ADAPT) program directed by Co-P.I. Mittal.  Potential UHR subjects 
undergo a telephone screen and those who screen positive will be invited to an in-person 
eligibility and consent evaluation.  Those screened participants who meet criteria for a 
prodromal syndrome based on the SIPS (Miller et al., 2003a) will be invited to participate in 
the study (help-seeking individuals who do not meet criteria will be referred to appropriate 
community resources).  This upper limit of 24 years was chosen as this age falls within the 
range for mean age of conversion to psychosis yet is still characterized by significant changes 
in neural organization (maximizing the potential for the trial to influence brain morphology) 
(Sowell et al., 1999). With regard to physical activity status, consistent with previous exercise 
studies, all participants will be sedentary. HC participants will be self-referred (responding to 
flyers and ads).  
 

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For the scan portion of the study, in order to protect the health and safety of the 
participants, exclusion criteria for this study will include any contraindication to magnetic 
resonance scanning (e.g., metal in body, claustrophobia, pregnant). These exclusions are 
specific to MRI and are consistent with most studies involving MRI. Potential participants 
will be screened for the presence of any of these exclusion criteria prior to participating in 
this MRI study.  
 
Financial Compensation 
Participants will be given $45.00 for 1.5 hour screening to decide whether they are a good fit for 
the study.  If found to be a good fit, participants will be given an additional $30 per hour for up 
to 3-hours of clinical assessments.  UHR participants will be given $45 for a 1.5-hour cognitive 
battery.  For the scan, UHR subjects will be given $45 for 1.5 hours and HC participants $60 for 
the 2 hour scan. For the fitness assessments, UHR subjects will be given $20.00.  For the 
exercise intervention trial, subjects who are exercising will be given $20.00 per 40 minutes of 
their time. Participants who consent to the blood draw will be receive $25 for each of the draws. 
Subjects will be asked to complete the clinical assessments, cognitive testing, and scan post 
exercise intervention, and they will receive the same reimbursement.  Additionally, they will 
receive this reimbursement at 12-month, and 24-month time points. Other compensations 
include: 1.) To improve compliance, the exercise group will be enrolled in a rewards system. For 
each completed exercise session, they will receive a ticket for the total of 24 tickets. For the first 
8 tickets, each participant in the exercise group will get a $50 gift card. For the next 8, they will 
get $100 gift card (Northwestern’s PNC Stored Value Card which will be explained to 
participants). For the last 8 tickets, they will get an iPad mini.  2.) Snacks will be available at any 
of the visits and any costs relating to parking will be reimbursed. $15 will be used to purchase 
snacks for participants. $10 dollars will be available to supplement travel/gas costs for the 
Pre/Post Exercise Assessment time points as well as both the 12 and 24-month follow-ups ($40 
total for participation in the duration of the study).  If participants would like to complete the 12 
and/or 24 month follow-up clinical assessments over the phone, they will be emailed a virtual 
Northwestern Stored Gift Card after completing the interview. Transportation/snack total costs 
will be $55. As noted earlier, we will also arrange for a free pick up and drop off service for each 
of the exercise sessions if requested.   
 
Withdrawal of Subjects* 
If a subject chooses to stop participating for any reason, his or her participation in the study will 
be terminated. Though highly unlikely, the circumstances under which a participant would be 
withdrawn without her consent include: (1) obviously not following study instructions or (2) 
behaving in a way that is verbally or physically abusive towards research staff. Those who 
experience early withdrawal will receive prorated payment based on the number of sessions they 
completed 
Risks to Subjects* 
Risks associated with breach of confidentiality: There is a potential risk that confidential health 
information collected during the course of the study may be disclosed to others.  
 
Risks associated with stigma: There is a potential risk that participants will be subjected to 
stigma and undue anxiety from identification as “at risk” of a serious mental disorder. 
 

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Risks associated with being distressed: There is a potential risk that the participants may find the 
study questions and procedures tedious, or that they may be distressed by the discussion of 
personal issues. 
 
Risks associated with the MRI Procedures:  
1. The magnetic field of the MR environment has the potential to cause burns or bodily injury if 
ferrous metal objects are implanted in the body, or if personal articles containing ferrous material 
are brought into the environment. 
2. The risk of MRI to pregnant women and fetuses is currently unknown.   
3. The MRI may cause discomfort due to scanner noise.  
4. There may be some discomfort from lying still and in one position for a long time 
5. Peripheral nerve stimulation (PNS/tingling). At sufficient exposure levels, peripheral nerve 
stimulation is perceptible as “tingling” or “tapping” sensations. PNS symptoms will usually 
subside shortly after the scan is completed. 
6. Participants may feel nervousness or feelings of claustrophobia. 
7. There is a risk that the image will reveal an observation concerning an individual research 
participant that has potential clinical importance but is beyond the aims of this protocol. In the 
event of the confirmation of a significant anomaly in a participant’s brain image, this information 
will likely be distressing to the participant. 
8. In rare cases, MRI can result in burning or tingling sensation, skin irritation, or swelling at the 
tattooed areas without lasting effects or complications (MRI safety.com, 2016; FDA, 2015). One 
study retrospectively examining reports from 108 individuals with tattoos who have undergone 
an MRI scan found no complications (Nouredinne, et al., 2015). In another study, only two out 
of 135 participants (1.5%) reported slight tingling or burning sensation (Toppe, et al., 2002). The 
authors also reported that an estimate of less than 10% of individuals who have undergone an 
MRI scan have reported transient symptoms (swelling, heating or burning sensation, or skin 
irritation). In one case study that reported an athlete experiencing skin reddening and mild 
swelling at the tattooed areas after an MRI reported that the symptoms were resolved within 12 
hours with no permanent effects (Ross & Matava, 2011). These risks may higher if the tattoo is 
directly in the exposure volume of the transmit coil; therefore, we will exclude participants who 
have face or neck tattoos.  
 
Risks Associated with the treadmill/elliptical tests:  During treadmill/elliptical tests, the 
American College of Cardiology/American Heart Association (2002) note that about 4 in 10,000 
people will experience chest pains or a heart attack during the maximal exercise test and about 1 
in 10,000 people may actually die from cardiovascular related problems during a maximal 
exercise test. Experiencing syncope during a maximal exercise test is more common, occurring 
in about 1 in 100 people. In addition, the treadmill test can cause dry mouth, fatigue and minor 
muscle and joint discomfort, as well as possible soreness or injury.   
 
Risks associated with the aerobic exercise and/or stretching and toning interventions. Participants 
will be informed that any time they are physically active (in this case, during the supervised 
physical activity sessions) there is always a risk for muscle soreness and discomfort both during 
and after exercise activities. 
 

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Risk associated with blood draws: pain, a bruise at the point where blood is taken, redness and 
swelling of the vein and infection, and a rare risk of fainting.  
 
Since we will be evaluating and monitoring subjects for the presence and the development of a 
psychiatric disorder, we have instituted procedures for the management of anticipated clinical 
issues. 
 
Management of Risks: 
Limits to confidentiality will be detailed on the consent/assent forms and will be discussed 
explicitly in the initial interview.  Specifically, subjects will be informed that they will not be 
asked specifically about any illegal activities, but if they should discuss such activities, the 
information could be requested by authorities such as the police or court system. In addition, 
they will be told that there are limits to confidentiality, including our requirement to report 
information about: child abuse or neglect, a crime that the subject plans to commit, or harm that 
may come to the subject or others. With respect to child abuse or neglect, research staff will 
comply with state laws and complete a child abuse report with the state Department of Child 
Protective Services. If there is risk of harming self or others, research staff will take necessary 
actions, including notifying significant others who may assist in the protection of the subject’s 
safety or notifying others who might be affected, such as intended victims, or notifying the 
police. 
 
Risks of stigma and undue anxiety from identification as “at risk” of a serious mental disorder 
will be minimized in the following ways: 
a. Information regarding possible outcomes and causes will be routinely provided. Subjects will 
be informed about possible outcomes, including remission, persistent symptoms, or worsening of 
symptoms. They will be informed that causes of symptoms include a normal adolescent or early 
adult maturation, a reaction to a life stressor, a symptom of drug use, symptoms of a metabolic 
disorder, the symptoms of a mood disorder or anxiety disorder, or the early warning signs of 
affective disorder or schizophrenia.  
b. Study participants who are judged to be in need of psychiatric or psychological 
evaluation/treatment, and are not currently receiving treatment, will be referred as clinically 
indicated.  
c. In addition, to minimize risk of undue anxiety related to uncertainty of diagnosis at screening 
we will also conduct a careful systematic diagnostic interview (the Structured Clinical Interview 
for DSM IV, SCID) and cognitive evaluation to determine whether there is an active diagnosable 
condition.  
 
The risk that the subjects may find the study questions and procedures tedious, or that they may 
be distressed by the discussion of personal issues will be minimized by having a study staff 
person monitor the subject’s experiences during the study procedures, and by having a study 
clinician familiar with the participant available to assist the subject if she or he becomes 
distressed by study procedures. In addition, participants will be told that they may decline to 
answer any questions or discuss any issue if they do not want to or if they find it distressing. 
Efforts will be made to make the study assessment procedures and exercise intervention as 
pleasant as possible for the subject, and to detect and address any problems with evaluation 
procedures.  

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This protocol will be performed using an MR scanner employing pulse sequences and hardware 
that have been approved by the FDA for human clinical use. There is no known radiological risk 
of MRI scanning. Participants will be carefully screened to exclude those who may have metal in 
or on their bodies that cannot be removed (e g., bullets, metal filings, body piercings, etc.). MR 
Facility rules strictly forbid staff from entering the magnet room carrying metal objects. The risk 
of claustrophobia is minimized by screening subjects for self-reported claustrophobia and 
making sure the subject is lying comfortably with head and neck supported and providing ear 
protection with headphones, a mirror to see out, a button to signal distress, and an intercom.  
Scan time will be kept to a minimum. Although there are no know risks to unborn fetuses, 
pregnant individuals are not permitted in the scanner. We will follow CTI’s protocol for ruling 
out pregnancy: safety screening (please see supporting documents) is administered right before 
the scan even if the participants filled the form out beforehand. The form includes “are you 
pregnant?” question, and the scanning technician will not scan anyone who know or think they 
may be pregnant. Participants will also be reminded that they can discontinue participation in the 
study at any time and need not divulge to the researchers the reason for their discontinuation 
(i.e., if they determine they are pregnant, they need not disclose that information). Scan time will 
be kept to a minimum and will not exceed the noted time allotment. All participants will be 
screened for tattoos. Participants will be made aware of minimal risks associated with tattoos in 
MRI scanners and asked to inform the MR technician if they start feeling any sensation at the 
tattooed area. If they report any sensation, the tech will stop the scan immediately to avoid 
potential skin irritation and burning and tingling sensation at the tattooed site. With regard to 
PNS, participants are given a squeeze ball to use in case of an emergency. They are informed 
that if they experience PNS related sensations or are otherwise uncomfortable, they can alert the 
MRI technologist via the squeeze ball and the technologist will stop the scan immediately.  
 
These risks associated with blood draws are minimal, and are reduced in this study because 
trained personnel who have extensive venipuncture experience, and are trained in aseptic 
technique, will implement the blood drawing procedures in a clean room.  
 
Steps to ensure safety with regard to the potential risk from study participation have been noted 
below. The sample size does not allow for adequate power to make specific estimates with 
regard to how the frequency of any adverse events from the exercise trial would carry over into a 
larger trial (Leon et al., 2010). In addition it should be noted that previous studies of aerobic 
exercise interventions including Dr. Mittal’s have shown minimal adverse events.  
 
A number of steps have been taken to safeguard privacy and confidentiality across the study. All 
study staff will be required to sign statements indicating that they understand confidentiality and 
agree to protect against risk of confidentiality. During phone screening, participants will be 
asked at the start of the phone call if they are able to speak privately, and if not, will be offered 
an opportunity to reschedule the phone call. Project staff will use private offices and a private 
voicemail has been established specifically for screening (and recruitment) of clinical studies 
such as this one. Only project staff will have access to the voicemail code to access messages. In 
the Zoom version of the 12 month follow up interview, IRB approved study staff conducting the 
assessment will store the video locally on encrypted, locked hard drive. For Zoom follow ups, 

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staff will ask the participant ahead of time to secure a private, quiet place where they can talk 
about their thoughts, feelings, and experiences without violating privacy. 
 
With regard to the minimization of risks specific to exercise training, all participants will be 
phone screened for contraindications related to physical activity generally and to the maximal 
exercise test in particular.  In terms of the risks related to the maximal exercise treadmill test, the 
primary protective measure taken to assure the physical safety of participants is the test location.  
The American College of Sports Medicine certified exercise physiologist, Elizabeth Skender will 
be present for all of the maximal exercise tests. Elizabeth Skender’s ACMSM certification 
number is 1043289. In addition, she is and Advanced Cardiovascular Life Support (ACLS) 
provider (please see her certifications under supporting documents). If any exercise physiology 
or research personnel have any concerns about the participant’s health or safety during the 
maximal exercise treadmill test, the session will be terminated immediately.  The following 
specific protective measures will be taken for all participants: (1) Participants will be asked 
during the initial phone screen if they have any history of cardiovascular or respiratory disease so 
as to decrease the risk of a participant experiencing cardiac problems during physical activity.  
(2) During the phone screen, participants will be asked prior to the maximal exercise test to 
assure that they have no undiagnosed medical contraindications that would make it dangerous for 
them to participate in either the maximal exercise treadmill test or the aerobic activity 
interventions.  (3) During the maximal exercise test, the participant’s heart rate and EKG will be 
monitored to assure that they are not experiencing an adverse cardiac event and to assure that 
they are healthy enough to safely participate in a moderate to vigorous intensity aerobic exercise 
program after the test. (4) Automated external defibrillator (AED) is available on site, and the 
exercise psychologist is trained on ACLS. No medical personnel presence is necessary during the 
VO2max test. 
 
With regard to risks related to exercise during the supervised exercise sessions, all participants 
participating in the exercise interventions will receive individual instruction regarding safe 
exercise practices by our exercise physiologist.  The structure of the aerobic exercise 
intervention, which is quite standard in exercise training interventions to improve cardiovascular 
fitness, is designed so that participants gradually work up to their training level of intensity.  
Further, exercise prescriptions are tailored to each participant’s current level of cardiovascular 
fitness.  Because participants begin slowly and move gradually up to the recommended level of 
exercise, and exercise takes place under close supervision of trained exercise physiology and 
exercise research personnel, the potential for injury during exercise should be minimized for this 
study.  
 
Only low risk participants will complete the exercise study. The young adult and adolescent 
populations are at low risk for heart attack or exercise related injuries, and as noted throughout 
the protocol, the pre-screening questionnaire includes questions which exclude individuals who 
may be at a higher risk from the study. Participants will receive instructions that they should: 1) 
wear appropriate exercise clothes and shoes for testing; 2) be well nourished and hydrated prior 
to testing; 3) avoid alcohol, caffeine and tobacco within 3 hours of testing; 4) be rested and avoid 
significant exertion or exercise the day of testing; and 5) report any medication use to the testing 
staff prior to testing. Participants will warm up prior to testing and cool down after testing. 
Standard emergency procedures will be followed in the event of an emergency. Masks and 

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mouthpieces are disinfected between participants. Participants will be monitored at all times 
during the VO2max test by at least one technician or team member who is knowledgeable and 
trained in two specific areas: 1) administration of graded exercise tests, including ability to 
conduct pre-test health screenings, and knowledge and recognition of signs and symptoms of 
cardiovascular disease; 2) procedures for conducting metabolic measures. In addition, the 
exercise physiologist will monitor all exercise visits, and as noted, she has all the necessary 
training to provide life support in a case of an emergency. Moreover, the automated external 
defibrillator (AED) is available on site, and campus police, who are located two floors below are 
lab, can be reached in a case of an emergency. Test termination criteria include any of the 
following: subject requests to stop, physical or verbal manifestations of fatigue, failure of test 
equipment. 
 
Procedures for the management of anticipated clinical issues include the following: 
 a. As noted a legal guardian of the participant (for minors) or the participant (for adults cases), 
will be screened over the telephone.  Individuals will also be notified in advance beginning 
screening of the limits to confidentiality. During the phone screening process, a number of steps 
will be put into place to protect against clinical risk.  If a caller expresses non-emergent mental 
health needs, research staff will provide this person with the phone number of the behavioral 
health clinic and instruct her to call to set up an appointment.  If over the course of the phone 
interview the caller becomes emotionally distressed, is not making clear sense, sounds 
intoxicated or impaired, or expresses thoughts of suicide or homicide, the interviewer will use a 
second phone line to have the study investigator join them, without losing verbal contact with the 
participant.  At that point the study investigator will guide the interview to ascertain the acuity 
and/or potential for harm. The study investigator will first determine if the caller is alone or has 
access to another person capable of transportation.  If the study investigator determines that the 
individual is in need of emergent care, the options for such care will be discussed with the caller 
and may include – referral to the closest emergency room, notification of emergency services for 
transportation to ER, emergent appointment (that day).  If the subject declines such a referral, the 
emergency services will be notified of the clinical concern for safety.  b. If at the initial in-person 
screening visit the subject that is found to have a medical condition that may have caused the 
prodromal symptoms, they will be excluded from further participation. If either an exclusionary 
medical condition or an incidental medical condition is suspected, the participant will be advised 
to consult with their physician or referred. If a psychiatric disorder is found to be present at 
baseline, or is found to develop during the course of the study participants will be advised to 
consult with their mental health care provider or referred. These participants will continue to be 
followed in the study, with information on treatment recorded in the database. Minor subjects 
and their parents or guardians will be informed that we will be doing urine drug screens as part 
of the routine study evaluations. We will explicitly inform parents and potential minor subjects, 
in the written informed consent document and orally, that we will not inform the parent of the 
results of the drug test, because revealing this information could affect the willingness of the 
minor subject to participate in the study or answer truthfully. We will tell both the minor subject 
and the parent or guardian our clinical policy regarding confidentiality, as follows: If a minor 
subject is found to have a positive drug screen, the PI will discuss the risks of drug use with the 
subject, and encourage the minor subject to discuss their use of drugs with their parent or 
guardian. If the subject is found to have a substance use disorder, we will discuss the need for 
treatment with the subject, and encourage the subject to allow us to speak with their parent or 

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guardian about our concerns.  The University’s IRB has approved this procedure and it has been 
affective in our ongoing studies of UHR individuals. Participating minors will be informed that 
their parents will be notified in the event that they are engaging in or plan to engage in behavior 
(i.e., suicidal attempt) that is dangerous to themselves or others. e. To summarize, our procedures 
will follow routine clinical research procedures to reduce risk to participants, and follow all State 
regulations regarding treatment of minors and informing parents and guardians.  A single 
clinician attempts to engage the minor in a therapeutic relationship, and maintains confidentiality 
unless there is a specific, immediate safety risk (e.g., suicidal ideation).   
 
Drug testing  
Participants will be informed “You will be asked questions about illegal activities that 
he/she/you may have been involved in. Although it is not likely, it is possible that their/your 
answers could be requested by the police or the courts and used against them.” Otherwise, results 
of drug tests will remain confidential. 
 
Thoughts of Suicide 
We will carefully monitor suicidality throughout the study, and the investigators and the clinical 
services are well equipped to handle psychiatric emergencies.  Specifically, all research 
assistants are provided ongoing education and supervision with respect to the identification of 
potential clinical problems.  In addition, all are educated to have a very low threshold for 
obtaining consultation. In addition, Dr. Mittal will carry a mobile phone listed with all study staff 
to be available 24/7.  We will have available 24/7 on call and emergency services. Additionally, 
Dr. Molly Lubin will be available for clinical guidance and consultation. Potential suicidality 
will be queried for all subjects within the context of the noted clinical interviews and patients 
will be carefully observed when participating in the exercise trial. If suicidality is present, gold 
standard procedures will be implemented (i.e., determining if a plan or means are available, 
contracting for safety, informing parent/guardian of risk (in the case of minors), ensuring 
removal of any potential means or in severe cases encouraging self-hospitalization/requiring 
involuntary hospitalization. In the case of minors for voluntary or involuntary hospitalization, 
participants will be escorted to the Evanston Hospital. For Zoom follow up, the assessor will 
collect current location and phone number to protect against risk during remote assessment. The 
current location and phone number information will be discarded as soon as the interview is 
completed. This information will be necessary in the situation that gold standard procedures need 
to be implemented remotely. 
 
 
Training of Staff  
All research staff will be trained in the regulations governing the conduct of human subjects 
research, as well as HIPAA regulations. All investigators and consultants have passed the IRB 
examination, which requires knowledge of basic ethical principles and federal regulations 
concerning human subjects research. Investigators will assure that all research assistants 
complete the same training.   
 
All clinical evaluators will receive intensive training prior to conducting phone screens or 
assessments with study participants. In addition to training on the specific measures, training will 
include education about orientation to the assessment process, possible risks to participants, and 

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an extensive 2-month training period for phone screens and assessments (observing live 
interviews with trained raters) observed by investigators. As reviewed above, we plan to hold 
weekly meetings involving related project faculty and staff to review assessments and cases and 
discuss any clinical issues (note: the exercise physiologist, who will be aware of which 
participants are in the treatment groups, will not participate in these meetings to maintain 
blindness). Separate weekly meetings will be held with the exercise physiologist to track 
progress, discuss motivation and attenuation or participants, and address any clinical/safety 
issues.  
 
Protection against Risk associated with the Ultra High-Risk Waitlisted-Control Group 
Assignment 
We have taken careful steps to minimize potential risks associated with assignment to the control 
group. Because of the critical period associated with the prodrome, all UHR participants will be 
encouraged to maintain any concomitant treatments already in place or referred to appropriate 
treatment providers in the community if they are not already receiving any treatment (Note: this 
is standard procedure in all current treatment and naturalistic investigations of UHR youth). As 
noted, individuals with a history or current treatment with antipsychotics will not participate in 
the study and those naturalistically treated with psychotherapy will be balanced between the two 
groups. Concerns regarding the withholding of an active intervention are mitigated by the 
treatment development nature of this project and our lack of knowledge at this point regarding 
the efficacy of the exercise-intervention approach. However, while the proposed exercise trial 
has not been proved to be efficacious, participants and parents will likely wish to participate in 
anything that is potentially helpful during this critical risk period. To address this concern, we 
will offer the UHR waitlisted-controls the option to also receive 12-weeks of exercise 
immediately following the waitlist period (that is immediately following the post interviews. 
Participants are also invited to engage in the exercise portion at any point after these post 
interviews even before or after the 12 and 24 month visits). Although there will be no research 
questions tied to this option (there will be no additional assessments or time-compensation given 
post-waitlist period) the participants will have the chance to participate in supervised aerobic 
exercise. This will allow for the UHR controls to benefit from any potential positive effects 
associated with an aerobic intervention. As noted, should any individuals elect to take this 
option, they will be excluded from longitudinal follow- up analyses examining the effects or 
exercise/waitlist on clinical course/conversion outcome. 
 
Potential Benefits to Subjects 
Anticipated benefit to subjects and/or society is a greater understanding of the factors that 
influence risk of development of a psychotic illness. In addition, participants may benefit directly 
from the exercise intervention.  
 
Consistent with the ethical obligation to the participants, we will provide information about 
community treatment resources for those who are deemed in need, but are not currently receiving 
clinical care.  At the initial assessment and post-intervention assessment the participant will be 
asked to provide information on treatment history. For minors, parents will also be asked to 
provide this information. The following data will be collected; previous and current treatment 
counselors or mental health providers, psychotropic medications prescribed, current medication, 
and diagnoses.  

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Assessment results from each participant will be discussed in a weekly research meeting with 
Graduate Research Assistants and Drs. Mittal and Lubin.  In cases where the results suggest the 
need for further treatment and the participant is not currently under the care of a mental health 
professional, the participant (parent for minors) will be provided with a list of mental health care 
professionals in the area who have the necessary expertise. Any participant found to be suffering 
from an Axis I psychotic disorder at the initial assessment will not be included in the study and 
as noted, referred to appropriate treatment in the community. It should be noted that prospective 
participants and parents who contact our center usually have serious concerns about their or their 
child’s adjustment. The findings from previous research in this population suggest that these 
concerns are often warranted.  Specifically, research has shown that treatment for psychosis 
generally leads to a good outcome when the treatment is initiated “at onset” – meaning as soon 
as frankly psychotic symptoms are detected in the context of regular monitoring visits.  
Generally it is possible to treat such patients as outpatients without loss of days of work or 
school, without disruption of ongoing social networks, and without the development of 
potentially stigmatizing events such as frankly abnormal behavior or hospitalization (Haroun et 
al., 2006; Corcoran et al., 2010). In line with the proposed protocol, treatment guidelines for the 
prodrome are just beginning to emerge and currently recommend that the patient be carefully 
monitored, but that antipsychotic or other medication treatment not be initiated, as there are no 
data regarding the risk-benefit ratio, and the risks of antipsychotic treatment in particular may be 
substantial in this population (McGlashan et al., 2007).  Thus this proposal is consistent with 
current clinical practice guidelines. While data from ongoing prodromal studies are now 
emerging to address this issue, further research is needed before practice guidelines for treatment 
of the prodrome will be established.  It is unlikely that empirical data will be available for expert 
consensus panels to address the issue of treatment of the prodrome before this project is 
completed.  Furthermore, we anticipate that the results of this study would contribute to such 
guidelines by informing the discussion of characterizing high-risk individuals where a targeted 
intervention would be of highest value. 
 
Importance of the Knowledge To Be Gained 
The results of this study will increase ability to understand etiological factors in high-risk 
individuals prior to the onset of schizophrenia or other psychotic disorders. In addition, we will 
be testing the feasibility of a potentially helpful exercise intervention.  Improved comprehension 
of this group will facilitate future preventative research. Intervention in early psychosis is of 
tremendous potential public health importance and thus the risk involved in this observational 
study are relatively small in proportion to potential impact on treatment of psychosis.   
 
Additionally, all participants will have the opportunity to examine their own exercise behavior in 
the context of completing the measures. Further, participants will learn about their maximal 
oxygen consumption, a measure of their aerobic exercise capacity and current level of aerobic 
fitness. Participants will have their cognitive functioning assessed by experts both in terms of 
brain physiology and cognitive tests. For the older adults in this study, both interventions 
(aerobic and strengthening and toning) are designed to increase health. Thus, regardless of which 
condition participants are randomized to be in, participants will gain information about their 
health and engage in healthy behaviors by completing the requirements of the study. The 
minimal costs associated with participation in this research seem reasonable in relation to both 

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individual benefits to the participants as well as the anticipated potential of the findings to 
increase the body of knowledge about the mediators and moderators of exercise behavior change. 
 
Vulnerable Populations 
This research program will be treating and studying persons who are at risk for developing 
schizophrenia or a related psychiatric disorder. However, it is not possible to study psychiatric 
disorders without studying individuals who have the psychiatric disorder being investigated.  
Additionally, based on our aim to study the prodromal period of psychotic illness, we will focus 
on adolescent and young adult subjects.  Given that the risks involved in the measures of this 
program are minimal, and that the data derived are anticipated to be extremely useful for 
improving our understanding of the disorder and develop a potentially important treatment, we 
believe that the involvement of these UHR patients is justifiable. 
 
Sources of Materials 
Sources of material will come primarily from the participant, in the form of the results of 
questionnaires, clinical interviews, neurocognitive battery, and neuroimaging.  For minors, a 
parent/legal guardian will provide information. Biological specimens will be collected at 
screening (urine) to help determine recent substance use. Written and oral consent will be 
obtained from participants, or their legal guardian for minor participants. Assent will be obtained 
from minors.  These measures are described in greater detail in the body of the proposal. All 
materials are obtained for research purposes.  Procedures for maintaining confidentiality, 
including linkage to participants and access to identifiers are described below under “Minimizing 
Risks to Confidentiality.” 
 
Provisions for Data and Safety Monitoring of Participants 
As noted, there will be weekly meetings with the clinical and exercise staff (separately) to 
discuss case progress and any potential clinical issues, or complications relating to exercise (e.g., 
sore muscles, aching joints, trouble breathing, dizziness). The PI-s will be responsible for 
monitoring and reporting any clinical or exercise related adverse events. 
 
Data Safety Monitoring Plans  
Symptoms and diagnosis will be evaluated as part of the study during the visit (and throughout 
the visit this information will be collected), and in the event of any concerning symptoms or 
diagnostic status, an ADAPT assessor will contact the family (if the patient is younger than 18), 
the patient (if the patient is older than 18), and the outside treatment team for the respective 
individual. The trained assessor will carefully review each case and discuss details with the PI. 
Data will be reviewed after each visit. If a patient reports suicidal ideation at any time during a 
research assessment, referrals, and if needed, appropriate recommendations of inpatient care to 
insure the safety of the subject will be made. If the subject is a minor, the participant’s legal 
guardians will be informed, and a safety plan will be established. If inpatient care is needed 
immediately, 911 will be called, and the assessor will wait with the participant until someone 
takes them to the Northwestern Hospital. All ADAPT personnel are trained in assessing for 
suicidality and are required to consult with a licensed treatment provider on staff to ensure 
adequate assessment. Additionally, if inpatient care is not warranted, ADAPT staff are trained to 
make “contract agreements” with participants for their safety and follow-up with the participant 
to continue to assess for safety. 

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Suicidal Thoughts 
We will carefully monitor suicidality throughout the study, and the investigators and the clinical 
services are well equipped to handle psychiatric emergencies. Specifically, all research team 
provides ongoing education and supervision with respect to the identification of potential clinical 
problems. In addition, all are educated to have a very low threshold for obtaining consultation. In 
addition, Dr. Mittal will carry a cell phone listed with all study staff to be available 24/7. We will 
have available 24/7 on call and emergency services. Potential suicidality will be queried for all 
subjects within the context of the noted clinical interviews. Specifically, the BDI-II will be 
scored before the participant leaves the laboratory. If participants endorse current suicidal 
ideation on item 9 of the BDI-II, a clinical psychology graduate student will complete a suicide 
assessment.  The BDI will be scored directly after the assessment, while the participant is in the 
room. Scoring item 9 on the BDI takes no time at all – about 30 seconds in which the assessor 
looks at what number was circled (2=”I would like to kill myself” in which case the assessor will 
know to move forward accordingly). The assessor will let the participant know they are just 
reviewing everything briefly while they look over the BDI and other notes if needed (just in case 
the assessor needs additional information). Upon completion of this assessment, student 
clinicians will collaborate with the PI Mittal (a licensed clinical psychologist) to decide on a plan 
of action before allowing the participant to leave the laboratory.  If suicidality is present, gold 
standard procedures will be implemented (i.e., determining if a plan or means are available, 
contracting for safety, informing /guardian of risk (in the case of minors), ensuring removal of 
any potential means or in severe cases encouraging self-hospitalization/requiring involuntary 
hospitalization. The student co-investigator (Tina Gupta) has been trained on conducting suicide 
assessments. If the student judges a participant’s suicidality to be mild or moderate, and 
determines that the participant is not in imminent danger, then the student clinician will provide 
the participant with information to local low-cost/sliding scale treatment providers. In cases of 
high-risk (i.e., a specific plan, a means to achieve the plan, no-one else in the residence to 
monitor the individual or provide a safety network) voluntary or involuntary hospitalization will 
be directed to the Northwestern Hospital, which has a world-class adult psychiatric unit. Acute 
suicidality has been rare in our ongoing studies with this population (although SPD and FEP 
individual commonly show depressive symptomatology including symptoms of suicidality), but 
these noted procedures and precautions have proved effective in our ongoing work with 
psychosis samples.  This plan can also be done remotely during the Zoom follow up assessment 
as referrals will be available electronically for those who are not in imminent danger. For high-
risk cases, the participant’s current location is collected immediately before the remote interview 
by the interviewer, and the nearest appropriate medical center will be substituted for 
Northwestern Hospital. 
 
Confidentiality and Data Management 
Strict standards of confidentiality are maintained. All paper records (consent forms and SIPS) 
containing identifying information (including the subject contact list) and all subject videotapes 
will be stored in a locked file in a locked office in ADAPT program at Northwestern. All data is 
given a deidentified ID code. All electronic databases will have deidentifying information and be 
password protected/encrypted.  Deidentified data may be shared with other researchers to 
advance science, as specified by the updated Northwestern IRB consent form template. Subjects 
will remain anonymous in all datasets and subsequent publications. Unless Northwestern IRB 

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approval is sought and obtained to extend the period of data storage, data will be stored for 30 
years after study completion and then destroyed. Videotapes will be stored for 30 years after 
which point they will be destroyed unless individual approval is sought to continue their storage 
and use for teaching and research purposes.  
 
Confidentiality will be maintained by assigning each patient a study number, and coding all 
data collected with that number. Identifying information will not be stored on computer 
databases, and will not be stored with the study subject number. All computer databases 
are password protected, and hard copies of all data and records will be stored in locked 
filing cabinets. All study personnel will be certified to conduct research with human 
subjects, and will be aware of the importance of maintaining strict confidentiality.   
 
Cortisol samples will be labeled marked by the appropriate subject ID number and 1, 2, 3, 4 
(e.g. 5555-1, 5555-2, 5555-3, 5555-4). The take home samples will be labeled with the 
subject ID number followed by a 01, 02, 03, 04, 05, 06 (e.g. 5555-01, 02, 03, 04, 05, 06).  
II. 
 
Strict standards of confidentiality are maintained.  MRI data will be electronically stored 
and analyzed using ID codes. If the data are published subjects will remain anonymous in 
all publications.  Data will be stored indefinitely and will not be shared with other 
investigators without explicit permission from the Northwestern IRB. All imaging data and 
behavioral data will be uploaded to the Northwestern University Research Image 
Processing System (NURIPS), an online collaborative research environment for securely 
storing, managing, analyzing and sharing de-identified medical imaging, associated data 
(e.g. behavioral), and results from advanced customizable processing pipelines. NURIPS is 
supported by both NUIT and FSM-IT and takes advantage of the NU high performance 
computing cluster, Quest. NURIPS is a secure environment that supports the latest NU 
policy and procedures for encryption of data during transit and rest, provides granular 
project level access controls with varying permissions based on user groups, and allows 
non-NU collaborators access once they obtain an affiliate NetId. All data are backed up and 
have restore points that go back for 30 days. Users have access to common data analysis 
pipelines and the opportunity to create and share their own pipelines. 
 
 
All instances of shared data within this protocol will be specifically approved by the IRB, 
and will be noted in the consent/assent forms, including how and what information will be 
shared. Subjects decide if they would like to share their data with other investigators. Every 
consent form has check boxes included to allow for this.  
 
Basic identifying information (name, address, phone number/email address) is collected 
from every research participant for the purpose of research logistics (schedule visits, etc.) 
and mailing of the radiological review letter, as appropriate.  
 
Provisions to Protect the Privacy Interests of Subjects 
Prescreens: In accordance with Northwestern IRB’s guidelines for pre-screening potential 
participants only first names or initials will be collected to identify the potential participant 
during this phone screen (prescreen). In order to protect participant confidentiality, the 

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first five pages of the phone screen form will be shredded immediately after the phone 
screen (pre-screen) is complete. Only the information relevant to contacting the participant 
on the last page of the phone screen will remain. This contact information will be important 
for the study team to retain so that we will be able to contact participants concerning their 
study appointments. Participant contact information will be stored in a separate research 
folder, apart from all other study documents. This folder will be stored in a locked filing 
cabinet in the ADAPT lab. Upon study closure, all contact information sheets will be 
shredded. At the end of the phone screen session, eligible individuals will be provided with 
a detailed description of the study. These eligible individuals will be made aware of the 
required laboratory sessions, supervised exercise sessions, physiological measures, 
psychological measures, and potential risks involved with participation. Eligible individuals 
who verbally indicate their willingness to participate in the research will be scheduled for a 
baseline appointment. Upon scheduling a baseline appointment, potential participants will 
be provided, via e-mail attachment or hard copy mail (depending upon their preference), a 
letter that will include the time and date of their appointment, as well as information 
detailing the American College of Sports Medicine (ACSM) 9th edition guidelines for 
participating in a maximal exercise test. Once potential participants arrive for their 
baseline appointment, they will hear a presentation about the research program and will 
have the opportunity to ask any questions they have about participating. Once all of their 
questions have been answered, potential participants will be asked to carefully read an 
informed consent document. The informed consent form will reiterate the experimental 
procedures, monetary compensation, risks and benefits, of all data obtained, and the 
voluntary nature of all components of the study. If participants agree with all of the 
information in the consent form, they will be instructed to sign their name on the space 
provided indicating they consent to participate in the research. 
 
For 12 and/or 24 month follow-up clinical assessments that take place over the phone, the 
assessor doing the assessment will talk to the participant in a private room at the 1801 Maple 
Avenue ADAPT lab location to ensure privacy during the phone call.  
 
Setting 
As noted above, participants will call in for a phone screening. If they are found to be a good fit 
for the study, the will be asked to come into the lab located at 1801 Maple Avenue, suite 3120 
Evanston, IL 60201. The VO2max test will be taken place Northwestern University, Department 
of Physical Therapy and Human Movement Science, 645 N. Michigan Ave. 10th Floor, Chicago 
IL 60611. The MRI scan will be taken place at CTI located at 737 N. Michigan Ave, Suite 1600 
Chicago IL 60611.  
 
Resources Available 
All individuals that will have direct contact with participants that are minors are trained and 
skilled in administering the primary interview named the SIPS. PI’s and Co-PI’s have had 
several years of experience working with UHR youth and dealing with various situations. After 
each case, the assessor will discuss the details of the case with the PI of the study, an expert in 
working with UHR participants. Reliability checks of the SIPS interview will occur often in 
order to make sure assessors are adhering to interview standards.  
 

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Our research lab is completely private. Food, snacks, water, and magazines are available to 
participants in order to create a comfortable environment. If participants would like further 
resources, they will be referred to other health care providers that may be a good fit for them. 
 
All new assessors upon the approval of the study will be given a copy of the protocol to review 
and study. They will have a meeting with the PI to discuss details such as study procedures, and 
confidentiality to ensure they understand their role and the study protocol. Additionally, they will 
have CITI training complete in order to begin working with participants.  
 
Recruitment Methods 
We will be using ads on Craigslist and job search engines, flyers, and brochures for recruitment. 
We will utilize flyers in Spanish for referrals but are recruiting only English speakers (e.g., a 
Spanish speaking individual who may want to refer an English speaking family member or 
friend). If a participant who is not a minor with a Spanish speaking family member or a friend 
wishes for that individual to accompany them, we have a fluent Spanish speaker (Teresa Vargas 
who is native Spanish speaker) on the research team who can translate pertinent aspects of the 
study (e.g., time commitment, type of tasks administered) and answer questions. If the 
participant agrees, she can also inform them about participant’s progress and referral sources. 
We also aim to recruit via social media networks (e.g., Facebook) by posting ads in social media 
groups (please see a script in supporting documents), electronic dissemination of ads via email, 
Pandora Radio ads, Psychology Department’s paid research registry, and ADAPT’s website (the 
website will include the note we are recruiting for the study and a webpage where participants 
can express interest in participating by responding to a Qualtircs survey asking them to respond 
if they are 16-24 and to provide contact information for a study team member to contact them).  
 
Phone Screening: 
A legal guardian of the participant (for minors) or the participant (for adults cases), will be 
screened over the telephone by an experienced staff member about, 1) the presence of prodromal 
symptoms in the past month; 2) past treatment for a psychiatric disorder; 3) presence of an 
exclusionary neurological medical condition; and 4) age. Patients who are likely to meet study 
inclusion criteria based on the results of the screen will be invited to the research center for 
consent procedures and the screening evaluation. Those persons who do not meet criteria for a 
prodromal syndrome (e.g., having minor symptoms, or meeting criteria for a psychotic disorder) 
will be referred to appropriate treatment sources in the community. Minor subjects that self refer 
or are referred from a health-care provider will be required to bring a parent or guardian with 
them to the initial consenting visit. On initial in person screening the purpose of the study will be 
explained. Individuals who are interested in participating in the study will receive more detailed 
information, both orally and with a written informed consent. Children under the age of 18 will 
provide written assent, and written parental consent will be obtained for their participation. 
 
Consent Process 
A legal guardian of the participant (for participants under age 18) or the participating probands 
will be screened over the telephone for, 1) the presence of prodromal symptoms in the past month; 
2) past treatment for a psychiatric disorder; 3) presence of an exclusionary neurological medical 
condition; and 4) age. Patients who are likely to meet study inclusion criteria based on the results 

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of the screen will be invited to the ADAPT lab for consent the study. Minor subjects that self refer 
will be required to bring a parent or guardian with them to the visit.  
During the consent process, the purpose of the study will be explained. Individuals who are 
interested in participating in the study will receive more detailed information, both orally and with 
a written informed consent. Children under the age of 18 will provide written assent, and one 
parent that is competent, reasonably available, and shares legal responsibility for the care and 
custody of the child will provide written permission for their child to participate. If the potential 
participant is an adult, they will read over the consent form and sign when they are ready. Consent 
procedures will not be rushed. We expect participant to complete consent after about 30 minutes, 
however we will let participants know that they are welcome to take their time. Additionally, 
participants will be reminded that the study is completely voluntary, and they are welcome to 
withdraw from the study at any point. Participants will also be informed that being videotaped is 
completely voluntary as well. 
 
Online Consent/Assent. For the optional online 12 month follow up offered to CHR participants, 
we will use Qualtrics to obtain the electronic signature of the adult (for those 18 years of age or 
older) or the electronic signature of the parent/legal guardian and of the minor (for those less 
than 18 years of age). An IRB approved study staff member will assess for attention and 
comprehension of the document over the phone or on Zoom, based on participant preference. We 
will coordinate the online consent/assent over email by scheduling a time to talk and by sending 
a Qualtrics link with a password to their consent/assent form. For minors, we will require the 
parent/legal guardian be present for the whole meeting to assess both people’s comprehension of 
the document before the e-signature is acquired by both minor and parent/legal guardian. 
 
 
Consent forms will be written in language that is comprehensible to individuals that have at 
minimum an eighth grade education. The consent form will contain information about the nature 
of the study. In providing participants with information about the research, there are two chief 
considerations; 1) to minimize psychological discomfort and potentially damaging negative 
expectations, and 2) to provide information that is based on the best currently available scientific 
data. The PI of this project, and Co-I’s have considerable experience with strategies for informing 
potential participants about the purpose of the research and for minimizing distress and anxiety. 
We explain that some individuals experience changes in their perceptions, thinking, emotions, or 
behavior. While some are not bothered by these changes, others may find them distressing because 
they interfere with their ability to function. We then explain the possible reasons for such changes, 
including that they may be part of normal adolescent/young adult development, a reaction to a life 
stressor, symptoms of drug use, symptoms of a metabolic disorder, symptoms of a mood disorder 
or anxiety disorder, or the early warning signs of bipolar disorder or schizophrenia. We then 
discuss the possible course of the “changes”, including that symptoms/signs often go away, remain 
stable, or worsen, particularly if they are the early signs of a disorder.  
 
In order to minimize subject discomfort and attrition, it will be important to reduce the burden of 
participation in the study. As described in the protocol, the full assessment will take about 2 hours. 
Within the constraints of the research design, efforts will be made to accommodate participants’ 
schedules and, when indicated, to avoid fatigue (e.g. breaks). 

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It is relevant to note that potential prodromal participants are usually experiencing subjective 
distress and are therefore motivated to take part in the clinical research assessment. Similarly, their 
family members typically encourage them to participate and are readily engaged in the assessment 
process. 
 
Additionally, in the consent forms, we have used the term “thought disorder” to minimize 
stigmas that may be associated with using the phrase “at risk for psychosis,” and to avoid distress 
that can accompany the phrase as well. “Thought disorder” and “prodromal symptoms” are 
interchangeable 
 
In order to minimize subject discomfort and attrition, it will be important to reduce the burden of 
participation in the study. As described in the proposal, the full initial assessment will take about 
6.5 hours total: 3 hours for screening visit/clinical interview, 2 hours for the cognitive 
assessment, 30 minutes for imaging and 30 minutes for the aerobic fitness evaluation.  The post 
exercise trial will take 5 hours (the 1.5 hour baseline screening which involves providing study 
information, signing consents, getting background information, and diagnosing a prodromal 
syndrome will not be included, but participants will be administered the entire SIPS and SCID 
post intervention to track changes in symptoms and clinical status).  Based on our experience in 
working with UHR adolescents and young adults, this time-requirement will be entirely feasible. 
Within the constraints of the research design, efforts will be made to accommodate participants’ 
schedules and, when indicated, to avoid fatigue. As noted, our group has significant experience 
in working with this population, and has perfected a number of effective strategies to ease burden 
and strain on participants and their families (e.g., schedule breaks, snacks, reimbursement of 
travel/lunch/parking costs).  The exercise trial will require 30 minutes of cardiovascular exercise. 
The exercise prescription will be tailored to the current fitness level of the participant, and the 
same research personnel will supervise the participants at each session to increase comfort. 
Finally, upon scheduling their fitness assessment, participants will be provided a letter that will 
include the time and date of their appointment, as well as information detailing the American 
College of Sports Medicine (ACSM) 9th edition guidelines for participating in a maximal 
exercise test. Once potential participants arrive for their appointment, they will hear a description 
of the fitness assessment, and will have the opportunity to ask any questions they have about 
participating their participation.  
 
It is relevant to note that UHR participants are usually experiencing subjective distress and are 
therefore motivated to take part in the clinical research assessment. Similarly, their family 
members typically encourage them to participate and are readily engaged in the assessment 
process. 
 
Process to Document Consent 
 
For all subjects, written informed consent will be obtained using consent forms that are approved 
by the Northwestern University Institutional Review Board (IRB) after the procedures are fully 
explained. For the Zoom follow up, if the participant chooses to complete the follow up 
interview online, the consent form will be e-signed on Qualtrics during a phone call or Zoom call 
with an IRB approved staff member. The vast majority of the patients potentially eligible for this 
program will have the capacity to consent, as this program involves outpatients who are active 

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participants in their own health care decisions. We will use the following procedures with 
potential participants to ensure comprehension of the information provided in the informed 
consent forms. A staff member will help each subject read the consent form and discuss the 
content point-by-point. Potential participants will be asked to paraphrase each section to insure 
comprehension of the content.  Indicators that a participant cannot currently comprehend 
meaningfully the content of the consent form will include: (1) the potential participant has severe 
formal thought disorder that does not allow him or her to ask understandable questions about the 
program or to paraphrase the basic points in the consent form; (2) the potential participant is 
unable to maintain attention to the description of the consent form long enough to perceive the 
individual basic points in the consent from; (3) the potential participant cannot ask questions or 
respond sufficiently to indicate agreement due to symptoms like catatonia; and (4) the potential 
participant expresses delusions related to the program that distort significantly his or her basic 
understanding of the nature of the research. On the other hand, some of the indicators that the 
potential participant can, at the time of approach, provide meaningful consent to participate will 
include: (1) ability to pay attention well enough to read the form or have it read and described to 
them; (2) ability to paraphrase the basic points in the consent form; and (3) ability to ask 
reasonable questions about the research and associated treatment conditions. For patient 
participants, comprehension of the informed consent form will be evaluated by administering an 
IRB-approved questionnaire about the content of the consent forms. Participants who are unable 
to demonstrate comprehension of the informed consent on the basis of this evaluation will not be 
enrolled.  All participants are informed that they can request breaks as needed, or withdraw from 
the study at any time. 
 
Signed consent forms will be stored in a locked filing cabinet in the PI’s laboratory, (the ADAPT 
Lab). Zoom online consent forms will be stored on Qualtrics, only available to IRB approved 
study staff. All data from questionnaires will be stored on password protected computers and on 
the PI’s password protected server, both of which are only accessible to research staff.  To 
further ensure participants’ confidentiality, all participant data (non-contact information) will be 
identified with a unique research subject identifier. The study team will generate a single master 
list linking numbers to names and other contact information for the purpose of scheduling and 
completing follow-up assessments. Zoom interview video recordings will be saved locally on 
encrypted hard drives in lockboxes. Only ADAPT research assistants who have received IRB 
approval to work on this project will have access to this master link file and only for the purpose 
of scheduling follow-up appointments or assessments. This master list as well as all identifying 
contact information will be destroyed at the conclusion of the final round of data collection. At 
that point, all data files will be identifiable only by each participant’s unique number. After the 
destruction of identifying information, it will be virtually impossible to link a participant’s 
identity with any of the data she provided during her enrollment in the study. 
 
If the content of the consent forms change, currently enrolled participants will be informed with 
a document outlining the changes since they initially signed the consent form for the study. 
Participants will be taken through the changes in person with a lab manager at their next visit to 
the lab using the document outlining consent changes. 
 
 
VI.     References 

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ACSM American fitness index ranks 50 largest metro areas on health and community fitness (2011).  Last 
Accessed 5/20/2013 from, http://www.acsm.org/about-acsm/media-room/acsm-in-the-
news/2011/08/01/acsm-american-fitness-index-ranks-50-largest-metro-areas-on-health-and-
community-fitness  
Addington, D., Addington, J., Schissel, B. (1990). A depression rating scale for schizophrenics. 
Schizophrenia Research 3; 247-251.  
America’s 15 most active cities (2011).  Time Magazine.  Accessed 5/27/2013 from 
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cities/photo/denver/ 
Aimone JB, Wiles JGage FH (2006). Potential role for adult neurogenesis in the encoding of 
time in new memories. Nat Neurosci 9, 723-7. 
Allen P, Seal ML, Valli I, Fusar-Poli P, Perlini C, Day F, Wood SJ, Williams SCMcguire PK 
(2011). Altered prefrontal and hippocampal function during verbal encoding and 
recognition in people with prodromal symptoms of psychosis. Schizophrenia Bulletin 
37, 746-56. 
Amminger GP, Schafer MR, Papageorgiou K, Klier CM, Cotton SM, Harrigan SM, Mackinnon A, 
Mcgorry PDBerger GE (2010). Long-chain omega-3 fatty acids for indicated 
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Auther AM, Smith CWCornblatt B (2006). Global Functioning: Social Scale (GF: Social), New 
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Avula CP, Muthukumar AR, Zaman K, Mccarter RFernandes G (2001). Inhibitory effects of 
voluntary wheel exercise on apoptosis in splenic lymphocyte subsets of C57BL/6 
mice. J Appl Physiol 91, 2546-52. 
Barlati S, De Peri L, Deste G, Fusar-Poli PVita A (2012). Cognitive remediation in the early 
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Beck, A. T., Epstein, N., Brown, G., & Steer, R. A. (1988). An inventory for measuring clinical 
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Becker S (2005). A computational principle for hippocampal learning and neurogenesis. 
Hippocampus 15, 722-38. 
Benoit A, Bodnar M, Malla AK, Joober RLepage M (2012). The structural neural substrates of 
persistent negative symptoms in first-episode of non-affective psychosis: a voxel-
based morphometry study. Front Psychiatry 3, 42. 
Berle JO, Hauge ER, Oedegaard KJ, Holsten FFasmer OB (2010). Actigraphic registration of 
motor activity reveals a more structured behavioural pattern in schizophrenia than in 
major depression. BMC Res Notes 3, 149. 
Borg, G. (1998). Borg’s perceived exertion and pain scales. Champaign, IL: Human Kinetics. 
Brewer WJ, Francey SM, Wood SJ, Jackson HJ, Pantelis C, Phillips LJ, Yung AR, Anderson 
VAMcgorry PD 2005. Memory impairments identified in people at ultra-high risk for 
psychosis who later develop first-episode psychosis. American Journal of Psychiatry. 
Buchan DS, Young JD, Simpson AD (2012). The effects of a novel high intensity exercise 
intervention on established markers of cardiovascular disease and health in Scottish 
adolescent youth. J Public Health Res. 

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