Moderated Mediation for Exercise Maintenance in Pain and PTSD: A Randomized Trial

Abstract

This study utilizes the Science of Behavior Change (SOBC) experimental medicine approach to evaluate the effects of a 3-month, individually prescribed progressive exercise training program on neurobiological, cognitive and motivational mechanisms by which our exercise-training paradigm may foster exercise maintenance. We will investigate hypothesized relationships between exercise-training associated augmentation of neuropeptide Y (NPY) system function and improvements in self-regulation and reward sensitivity—cognitive control and motivational processes posited to promote self-efficacy and intrinsic motivation, which have been shown to predict exercise maintenance. This study will recruit Veterans with chronic low back pain and PTSD. Procedures include a baseline, acute cardiopulmonary exercise challenge assessment that will inform the exercise prescription for a 12-week progressive exercise training program comprised of three 45-minute aerobic exercise sessions per week—all of which will be supervised by an exercise physiologist. Additionally, a week-7 and week-14 exercise challenge assessment will track changes in NPY system function and the variables of interest. We hypothesize that increases in the capacity to release NPY in response to acute exercise testing will be associated with improvements in self-regulation and reward sensitivity, which will in turn be associated with self-efficacy and intrinsic motivation to maintain regular exercise. Ninety participants will be randomized either to the “active exercise training condition” or to the “wait list symptom monitoring condition”. The study aims to demonstrate the feasibility of procedures and elucidate mechanisms relevant to developing individually prescribed, motivationally based exercise regimens to reduce negative consequences of PTSD and low back pain over the long-term.

Introduction

Background and Rationale

Need for Non-Pharmacological Approaches to Treating CP/PTSD

The National Institute of Health (NIH) and the Veterans Health Administration (VHA) have emphasized the importance of developing novel, non-pharmacological approaches to chronic pain management. In addition, there is substantial evidence that the co-prevalence of chronic pain and posttraumatic stress disorder (PTSD) negatively impacts the course of both disorders, such that individuals suffering from chronic pain/PTSD experience greater levels of pain severity, affective distress and disability, compared to individuals who suffer from either chronic pain or PTSD alone (Asmundson, Coons, Taylor, & Katz, 2002; Geisser, Roth, Bachman, & Eckert, 1996; Scioli, Otis, & Keane, 2010; Otis, Keane, & Kerns, 2003). Thus, there is a clear and critical need for researchers to respond to the NIH and VHA calls for novel, non-pharmacological approaches, including health behavior change, to treat and manage comorbid chronic pain/PTSD.

Endogenous Neuropeptide-Y in Response to Stress and Pain

Research in rodents and humans shows that severe chronic or life-threatening stress reduces resting plasma and central nervous system neuropeptide-Y (NPY) levels (Scioli-Salter, et al., 2015). At adequate levels, NPY has anti-stress, pro-reward, and anti-nociceptive properties (Scioli-Salter et al., 2015). For example, NPY is negatively associated with PTSD symptoms (Pitman et al., 2012), enhances dopamine-mediated reward in the nucleus accumbens (Josselyn & Beninger, 1993; Brown, Coscina, & Fletcher, 2000), and prevents progression from acute to chronic pain, as well as opiate tolerance and withdrawal (Solway, Bose, Corder, Donahue, & Taylor, 2011).

Exercise-Training Induced Augmentation of NPY System Function Can Mediate Benefits in CP/PTSD

Research from several laboratories indicates that acute exercise at a vigorous intensity (average ~70% VO₂ maximum) induces NPY release in medically healthy men and women without psychiatric illness (Lundberg, Saria, Franco-Cereceda, & Theodorsson-Norheim, 1985; Pernow et al., 1986; Rasmusson, 2007; Rämson, Jürimäe, Jürimäe, & Mäestu, 2012; Scioli-Salter et al., 2016). Preliminary work by Rasmusson (2007) (Figure 1) showed that NPY is released during maximum load exercise testing at the anaerobic/lactate threshold. It is otherwise well-known that the lactate threshold varies markedly among individuals relative to VO₂ max (Fig. 1), but increases along with increases in the peak VO₂ in response to exercise training (Bassett & Howley, 2000). In turn, Scioli-Salter et al. (2016) showed that resting baseline NPY levels and NPY responses to maximum load exercise testing in trauma-exposed individuals with and without chronic pain/PTSD were positively associated with peak VO₂, an index of fitness (r = 0.66, p < 0.05 and r = 0.69, p < 0.05, respectively). These data thus suggested that improving fitness might increase: a) resting NPY levels at baseline, and/or b) NPY responses to intense sympathetic system activation (i.e., acute exercise stress, pain, psychological stress). This possibility is supported by the work of Levenson et al. (1998) showing that 18 weeks of voluntary wheel running in rodents increased the capacity for acute exercise-induced NPY release. In addition, a human study by Rämson et al. (2012) found that 2-weeks of vigorous intensity exercise training (rowing) in healthy trained male rowers increased the capacity for NPY release in response to acute exercise testing. To our knowledge, however, Dr. Scioli’s current Veterans Affairs (VA) Rehabilitation Research and Development (RR&D) Career Development Award (IK2-RX000704) is the only study testing the ability of exercise training to upregulate NPY system function in a human population with pathology. That study in a trauma-exposed population with chronic pain/PTSD further tests whether changes in NPY system function in response to an individually tailored long-term (progressive) exercise training program are associated with improvements in chronic pain and/or PTSD.

Figure 1. NPY Release as it Relates to %VO₂ and Lactate Threshold.

Note. %VO₂ Peak for NPY release and %VO₂ Peak for Anaerobic Threshold are Correlated (r=0.95, p< 0.001)

Such health behavior change paradigms are thought to be critical to improving chronic pain in medically and psychiatrically complex populations (Tkachuk & Martin, 1999; Biddle & Mutrie, 2008), as well as to reducing chronic pain-related disability (Chatzitheodorou, Kabitsis, Malliou, & Mougios, 2007) and dependence on medications with high potential for abuse and morbidity, such as opioids (Brown et al., 2010). However, although many researchers have helped patients initiate regular exercise, exercise maintenance has been difficult to achieve in both general (Marcus et al., 2000) and clinical (Stathopoulou, Powers, Berry, Smits, & Otto, 2006) populations. Preliminary data from the CDA-2 study showed that acutely increased plasma levels of NPY in participants with Chronic pain/PTSD during maximum load exercise testing correlated with exercise-based intrinsic motivation and self-efficacy, which have been previously shown to foster exercise maintenance (Ingledew, Markland & Medley, 1998;Ryan, Frederick, Lepes, Rubio & Sheldon, 1997; Prochaska and Marcus, 1994). The present R21 Science of Behavior Change (SOBC) study (described below) seeks to investigate the neurobiological and related cognitive and motivational mechanisms by which a similar individually tailored 3-month progressive exercise-training paradigm might foster exercise maintenance.

Cognitive and Motivational Factors Related to Exercise Maintenance

Complementary Theoretical Integration.

Since 2009, there have been calls for research to integrate complementary theories of exercise behavior change, with the objective of translating the most salient variables that help participants adopt and sustain exercise into individualized prescriptions for tailored exercise and behavior change (Hagger, 2009). According to Scioli-Salter (2014), an integration of the Transtheoretical Model of Exercise Behavior Change (TTM) and Self-Determination Theory (SDT) provides a unitary, theoretically driven approach to capturing participant transitions from pre-active to active stages of exercise adoption through sustained exercise adherence (exercise maintenance). Thus, the motivational aspect of our 3-month progressive exercise paradigm is based on a combination of TTM and SDT for exercise. While the TTM captures one’s external motivation to adopt and sustain exercise, SDT captures internal motivation (Scioli, Biller, Rossi, & Riebe, 2009). The TTM also measures exercise-based self-efficacy, which increases as one progresses through the TTM stages of change (Prochaska & Marcus, 1994), while the SDT captures changes in intrinsic motivation (necessary to sustain exercise long-term) as one transitions through the exercise stages. As stated above, in our exploratory work, we found the capacity for release of NPY in response to maximum load exercise testing to be correlated with both exercise-related self-efficacy and intrinsic motivation.

Since the SDT is based on theories of self-regulation and learning (Ryan & Deci, 2000), SDT supports our contention that capacities for self-regulation and reward-based learning could constitute cognitive and motivational manifestations of the effects of our 3-month training program on NPY system function and support motivation to sustain exercise. Our hypotheses are also supported by empirical evidence demonstrating that self-efficacy (McAuley, & Blissmer, 2000) and intrinsic motivational factors predict TTM-defined active stages of behavioral change, including exercise maintenance, in the general population (Ingledew, Markland & Medley, 1998; Buckworth et al., 2007). This accords with our recent findings in a /PTSD population (Scioli-Salter et al., 2017). Among trauma-exposed women with fibromyalgia (n=20, 73% with PTSD), there was a large effect size (Cohen’s d=.92) for an association between level of self-efficacy and attainment of the action and maintenance stages of exercise. These findings support our current proposal and suggest that patients with chronic pain/PTSD who have or achieve a high degree of exercise-based self-efficacy will have an increased likelihood of sustaining exercise long-term. Taken together, exercise based self-efficacy and intrinsic motivation may have NPY-mediated self-regulatory and reward-based motivational underpinnings worthy of investigation.

Self-Regulation and Reward Sensitivity

Self-Regulation.

According to Albert Bandura (1988), “Humans are able to control their behavior through a process known as self-regulation.” Self-regulation is a multidimensional concept that has gained attention in health behavior change research since the early 2000’s when the medical field shifted from a disease model to a prevention-based health model (Bandura, 2005). The premise of self-regulation acknowledges the individual as an active agent in their decision-making, such that they are in control of their thoughts, feelings/desires and actions in the service of attaining higher goals (Bandura, 1988). Thus, self-regulation is comprised of cognitive and motivational processes.

In this study, we focus on cognitive control defined as the capacity to override automatic or habitual behaviors, as well as to modify our perception, thoughts and actions in order to support goal directed behavior (Miller, 2000). Like motivation, cognitive control can be conceptualized as falling on a continuum where the individual engages in varying degrees of cognitive control needed to meet the demands of the task. Although there is individual variability in the capacity one has for cognitive control, just as we posit regular exercise can increase the capacity to release NPY through improvements in fitness capacity, we posit the capacity for cognitive control can be improved through improvements in motivation, particularly since cognitive control is impacted by motivation and effort (Shenhav et al, 2017). Therefore, we acknowledge both cognitive control and motivational aspects of self-regulation in order to capture and foster participant decision-making leading toward the higher goal of achieving exercise maintenance.

Reward Sensitivity.

Anhedonia, or loss of pleasure, is a salient factor in capturing and understanding reward sensitivity. It is also a transdiagnostic symptom of psychopathology observed in PTSD and depression- and is thus relevant to our current study (see below). Clinical neuroscience research into mechanisms underlying anhedonia has drawn on a rich animal literature on the neural systems that support reward or motivational processing (Berridge & Kringelbach, 2013; Berridge & Kringelbach, 2015). Studies have elucidated two psychologically and neurobiologically distinct systems that support reward processing: 1) reward anticipation, incentive motivation or interest in pursuing reward-relevant items or activities, which is mediated primarily by mesolimbic dopaminergic mechanisms (Berridge, Robinson, & Aldridge, 2009; Knutson, Adams, Fong, & Hommer, 2001), as well as tracking of anticipated reward values via the orbitofrontal cortex (OFC) (Kahnt et al., 2010; Howard et al., 2015); and 2) reward consumption, or the capacity for pleasure upon receiving a reward, which is supported by a neural network including prefrontal regions implicated in reward valuation, and ‘hedonic hotspots’ in the ventral striatum and brainstem. Clinical neuroscience research in humans suggests that both components are implicated in depression (Treadway, Bossaller, Shelton, & Zald, 2012) and PTSD (Nawjin et al., 2015). As such, the proposed project will examine exercise-training associated change in each of these components of motivationally-based reward sensitivity in relationship to changes in NPY system function (see Figure 2) as well as in relationship to changes in symptoms of anhedonia, depression and PTSD, exercise-based self-efficacy and intrinsic motivation as well as exercise maintenance (see Figure 3).

Figure 2. Moderated Mediation Approach to Exercise Maintenance.

Note: Time Point (TP), TP-1=Week-0 Baseline EX, CM, CPT; TP-2= Week-7 Midpoint EX, CM, CPT; TP-3= Week-14 Endpoint EX, CM, CPT; TP-6= 6-month follow-up assessment

Figure 3. Exercise Change in Depression, Pain and PTSD.

Note: Time Point (TP), TP-1=Week-0 Baseline EX, CM, CPT; TP-2= Week-7 Midpoint EX, CM, CPT; TP-3= Week-14 Endpoint EX, CM, CPT

Role of Major Depression

Epidemiological studies have consistently demonstrated that the increase in depression that occurs after trauma exposure is almost always comorbid with PTSD. Because several symptoms of major depressive disorder are also symptoms of PTSD, the two disorders are not independent. Rather, it has been suggested that comorbid depression/PTSD may essentially constitute more severe PTSD (e.g., Breslau, Davis, Peterson, & Schultz, 2000). Therefore, we will analyze potential effects of the exercise intervention and changes in NPY system function on depressive symptoms (using a depression symptom rating scale) as well as on PTSD symptoms (using the Clinician-Administered PTSD Scale-5 (CAPS-5). As with other measures of PTSD, the CAPS-5 PTSD symptoms include a depression factor that will be defined by factor analysis in larger samples of veterans at VABHS, as has been done previously for studies using the CAPS-IV (e.g., the dysphoria factor defined by Simms, Watson, & Doebbelling, 2002). Therefore, recruiting individuals with PTSD (as measured by the CAPS-5) and MDD as measured by the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders 5^th edition (SCID-5) during screening-see appendix) in addition to PTSD patients not meeting diagnostic criteria for depression will ensure that a full range of PTSD and depressive symptom severity is represented in the study sample (Figure 3).

Objectives

The present study (R21-AT010293) is designed to use an experimental medicine approach (Riddle & SOBC Working Group, 2015) to assess the effects of a rigorous, closely monitored, individually tailored, 3-month progressive aerobic exercise training program on NPY system function in patients with chronic low back pain/PTSD. Specifically, we will evaluate whether a) exercise training associated changes in resting NPY levels and NPY peak responses to a standardized cardiopulmonary exercise challenge test, are associated with b) changes in self-regulation and reward sensitivity (putative cognitive control and motivational capacities promoting exercise-based intrinsic motivation and self-efficacy and predict exercise maintenance (Figure 2). The proposed research also will assess exercise training associated changes in NPY system function in relation to changes in pain sensitivity, depression and PTSD (see Figure 3).

In this R21 experimental mechanisms study, our sample consists of previously deployed Veterans suffering from chronic low back pain and deployment-related PTSD. We have focused on chronic low back pain because it is the most prevalent chronic pain condition among Veterans and is highly comorbid with PTSD (Lew et al., 2009; Goulet et al., 2016). Also, the literature indicates that vigorous vs. low intensity exercise is important for managing chronic low back pain (Chatzitheodoreau et al., 2007; Gordon & Bloxham, 2016). Study participants will be randomly assigned to a 3-month wait-list (WL) symptom monitoring control condition vs. the 3-month active exercise training (AET) condition.

A WL condition has been included to ensure that changes in the variables of interest (i.e. improvements in NPY system function, self-regulation, reward sensitivity, exercise based self-efficacy and intrinsic motivation,) are due to the three-month progressive exercise training intervention rather than other effects of participating in a study (e.g. generic behavior activation, the passage of time, or extinction, habituation or even worsening of trauma symptoms due to participant exposure to trauma reminders during symptom assessments). WL participants will perform the same ratings, exercise assessments, and blood draws as participants assigned to the AET condition, but not receive the progressive exercise training intervention. To control for social support received by participants engaging in the AET as they engage in 3x/week exercise training sessions in clinic, participants in the WL condition will present 3x/week for a sham exercise session comprised of stretching exercises. At the conclusion of the waiting period (12 weeks), the WL participants will be offered the opportunity to participate in the AET condition in order to receive the actual 3x/week progressive exercise training intervention. The primary statistical comparison will be between the AET and WL. We will also perform within-subject comparisons for participants completing the AET after the WL condition. The overall aims of this study are as follows:

Aim 1. Evaluate whether neurobiological, cognitive control and motivational factors change differently across time in AET vs. WL participants. (Figure 2). Assessments will occur at baseline (week 0), midpoint (week 7) and endpoint of the exercise intervention (week 14). Hypothesis 1: Participants in the AET vs. WL condition will demonstrate greater increases, across the exercise intervention, in the release of NPY, during acute exercise challenge testing, and improvements in self-regulation, including reward sensitivity, and exercise-based motivational (self-efficacy, intrinsic motivation) outcomes.

Aim 2: Evaluate whether changes in NPY system function correlate with improvements in cognitive control, motivational and exercise-based motivational factors to predict exercise maintenance (Figure 2). Assessments will occur at baseline (week 0), midpoint (week 7) and endpoint of the exercise intervention (week 14), as well as 6 months post intervention phase. Hypothesis 2: AET associated increases in the capacity to release NPY will be associated with increases in self-regulation, including reward sensitivity, exercise-based self-efficacy and intrinsic motivation, as well as greater rates of exercise maintenance at the six-month post-intervention follow-up assessment.

Aim 3. Evaluate whether changes in NPY system function across the 3-month exercise intervention correlate with improvements in pain and psychological symptoms (Figure 3). Assessments will occur at baseline (week 0), midpoint (week 7) and endpoint of the intervention (week 14).

Hypothesis 3: Increases in baseline plasma NPY levels and NPY peak responses to exercise challenge testing across exercise training will correlate with reductions in pain-related interference and sensitivity, as well as depression and PTSD severity.

Method

Trial Design

This study is a short-term prospective randomized trial, with two arms; one is an active exercise training condition (AET) and the other is a wait list, symptom monitoring condition (WL). The study will last 16 weeks, including pre-screening and enrollment visit(s), a 12-week exercise intervention phase, and a delayed six-month follow-up assessment for exercise maintenance. After completing the WL condition, participants will be offered the opportunity to enroll in the active condition.

Participants will be recruited by trained research assistants, and those determined to be eligible will be randomized either to the AET or WL condition using a modified randomized block design (1:1 ratio). The groups will be stratified by sex, as NPY synthesis is facilitated by testosterone and reduced by estradiol (Zukowska-Grojec, 1995), and tobacco use, which impacts sympathetic nervous system and hypothalamic-pituitary-adrenal (HPA) system responses to stress, and thus may impact NPY responses to exercise (Rasmusson, Picciotto, & Krishnan-Sarin 2006; Familoni et al., 2016).

A randomization sequence will be created by Sealed Envelope Ltd. with random block sizes of 4 and 6. The file will be concealed by use of password protection and privacy covers. Group allocation will be implemented by a study research assistant within the lab who does not participate in assessment or training sessions. The group allocation will be revealed to relevant study staff only (e.g. exercise physiologists and research assistants who are running the study sessions) once participants complete baseline assessments and enter their respective groups (Kim & Shin, 2014). Group allocation will not be revealed to assessors. At the conclusion of the three-month WL condition, participants in this condition will have the option to engage in the active exercise training condition.

Participants, Interventions, and Outcomes

Study Setting.

All study visits will take place at the National Center for Posttraumatic Stress Disorder or the Clinical Studies Unit (CSU), both at the Jamaica Plain campus of the VA Boston Healthcare System (VABHS).

Recruitment and Screening.

We will recruit 90 Veterans (45 men and 45 women) to participate in the study, which has been approved by the Institutional Review Boards of both Boston University School of Medicine and the VA Boston Healthcare System. Participants will be recruited by posted advertisement (on bulletin boards, in print media, on the internet, on transportation routes and vehicles), by radio, and via pamphlets distributed in VA clinics or gathering places for Veterans. Potential participants will be asked to phone the study recruiter, who will administer a phone screen (approved by an IRB, with a HIPAA waiver). During this phone call, the study and its procedures will be described in brief and participants will be assessed for eligibility. If it appears that the study eligibility requirements may be met, participants will be scheduled for an in-person screening appointment, during which the informed consent process will precede performance of diagnostic assessments aimed to assess eligibility.

Eligibility Criteria.

Rigorous inclusion and exclusion criteria will be employed for safety reasons, as well as to allow valid and meaningful interpretation of study results in this mechanism-focused study.

Participants must have an ICD-9 or ICD-10 diagnosis of chronic low back pain, as confirmed by the consulting rehabilitation MD. Participants must meet criteria for current chronic PTSD (≥ 3 months duration) as assessed by the Clinician Administered PTSD Scale (CAPS)-5, 1-Month Diagnostic Version (Weathers et al., 2013a). Other anxiety or depressive disorders are permitted.

Participants entering the study will be insufficiently active, as defined by the American College of Sports Medicine (i.e., performing less than 30 minutes per day and less than 150 minutes per week of moderate intensity physical activity, and less than 75 minutes per week of vigorous intensity physical activity (Garber, et al., 2011). Individuals already engaged in resistance training (i.e., weight lifting or strength training) will be included in the study so long as the total of these and other physical activities do not exceed 150 minutes per week at a moderate intensity or 75 minutes per week at a vigorous intensity.

Participants will be included only if a medical history, physical examination, vital signs, resting electrocardiogram, and baseline laboratory studies including urine toxicology screens indicate that symptom-limited cardiopulmonary exercise stress (exercise challenge) testing and exercise training will be safe. Women of child-bearing capacity must agree to use effective contraception while participating; a urine pregnancy test is performed on the morning prior to completing each exercise challenge test. Participant with a mild traumatic brain injury (TBI), grades I-III, or moderate TBI, determined by the VA Boston Assessment of Traumatic Brain Injury-Lifetime (Fortier et al., 2014) will be included.

Participants must be free for 2-6 weeks of psychotropic and other medications or substances (e.g., illicit drugs and alcohol) with effects that could hinder data interpretation (e.g., those that could directly impact NPY release based on the literature) before the cold pressor test (CPT) and exercise challenge testing (depending on the medication and frequency of use). Allowed medications must be taken at a stable dose for three months and remain stable throughout participation in the study. Those using tobacco or nicotine products will be included in the study and will not be required to lower or stop their dosage/intake; intensity of nicotine exposure will be monitored across the study via use of urine testing for cotinine (a long-lived metabolite of nicotine) at each test session. Regular morning nicotine users will be instructed to smoke/chew/vape to satisfaction just prior to arriving at the CSU for testing, which will be approximately 2-3 hours prior to performance of the cold pressor and exercise challenge assessments. Opiates will not be allowed, but if using other pain medications, participants must transiently discontinue them for 5 half-lives before the cold pressor and exercise challenge testing, generally about 24 hours. Participants may be involved in supportive psychotherapies as long as their participation has been stable for 3 months prior to study entry and remains stable throughout the course of the study.

Participants will be excluded from participation in the study if they have a life threatening or acute physical illness (e.g., cancer, cardiovascular disease) that would place them at risk, current schizophreniform illnesses (except for either schizophrenia spectrum disorder or other psychotic disorder due to PTSD related sensory hallucinations), bipolar I disorder, or active suicidal or homicidal ideation or other risk to self or others requiring clinical intervention. Individuals with current or past alcohol and/or substance dependence (less than three months from date of screening assessment) will be excluded. Women who are pregnant or planning to become pregnant within the next six months will be excluded. Individuals seeking significant new pain treatment, such as surgical interventions, or who have a neuropathic origin to their pain will be excluded. Participants who cannot tolerate exercising on a treadmill will be excluded. Those with a history of coronary artery disease or positive stress test, uncontrolled cardiac arrhythmia, a QTc greater than 500, moderate-to-severe aortic stenosis, greater than moderately severe arterial hypertension (systolic > 165 mmHg, diastolic >100 mm Hg), or more than first degree atrioventricular block will be excluded. Individuals with severe TBI, as evidenced on the Boston Assessment of Traumatic Brain Injury–Lifetime (BAT-L) (see appendix) will not be included in the study and will be referred for evaluation to the VA TBI Center of Excellence at the VA Boston Healthcare System, if interested, and for care to an appropriate VA clinic.

Assessments

Exercise Challenge Testing.

The symptom limited cardiopulmonary exercise challenge test session controls for confounders that potentially impact NPY levels or release. Participants will present to the CSU at 8:30 am after fasting (except for water intake) since midnight. Urine toxicology and pregnancy testing, vital signs, and an electrocardiogram will be obtained, after which a standardized 6 kcal/kg breakfast of carbohydrate/protein bars will be provided. The exercise challenge test is performed after two hours of rest and within thirty minutes of a baseline, resting blood draw. During the two-hour waiting period, rating scales (Table 1) will be administered.

Table 1.

Timeline of Assessments

Measures	Eligibility Screening Session	Baseline Resting CPT/CM	Baseline Ex/CM/CPT	Midpoint Ex/CM/CPT	Post-Train Resting CPT/CM	Post-Train Ex/CM/CPT
Diagnostic Status
SCID-5, LEC-5, BAT-L, CSSR	X
CAPS-5	X					X
Pain Ratings
*WHYMPI- Interference	X		X	X		X
BPI-NRS	X	X	X	X	X	X
Cold Pressor Test (CPT)		X	X	X	X	X
Psychiatric Symptoms
*BDI-II, *PCL-5	X		X	X		X
Exercise Behavior
*TTM Stage of Change	X		X	X		X
Self-Regulation Cognitive Control
Operation Span Task**		X	X	X	X	X
Change Detection Task**		X	X	X	X	X
gradCPT**		X	X	X	X	X
Dimensional Card Sort**		X	X	X	X	X
Difficulties in Emotion Regulation Scale-SF			X	X		X
Motivation
Exercise Self-Efficacy (TTM)	X		X	X		X
Exercise Motivation Scale (SDT)	X		X	X		X
General Self-Efficacy Scale	X		X	X		X
Reward Sensitivity Measures:
*TEPS			X	X		X
EEfRT**		X	X	X	X	X
Blood Biomarker: NPY		X	X	X	X	X

¹Note. Measures marked with * will be administered by phone at 1- month, 3- months, and 6- months after the end of intervention assessment session to determine if exercise maintenance has been achieved and to monitor any changes in primary variables of interest.

²Abbreviations. CM, Cognitive and Motivation (Self-Regulation) as measured with computerized tasks**. SCID, Structured Clinical Interview for DSM-V; LEC-5, Life Events Checklist for DMS-V; BAT-L, Boston Assessment of Traumatic Brain Injury Lifetime; CSSRS, Columbia Suicide Severity Rating Scale; CAPS-5, Clinician Administered PTSD Scale for DSM-V; WHYMPI, West Haven-Yale Multidimensional Pain Inventory; BPI, Brief Pain Inventory-Numerical Rating Scale; BDI-II, Beck Depression Inventory II; PCL-5, PTSD Checklist for DSM-V; DERS-SF, Difficulties in Emotion Regulation Scale – Short Form; TTM, Transtheoretical Model; SDT, Self Determination Theory; EMS, Exercise Motivation Scale; GSES, Generalized Self-Efficacy Scale;; TEPS, Temporal Experience of Pleasure Scale; EEfRT, Effort Expenditure for Rewards Task.

The exercise challenge test is performed by a trained exercise physiologist per guidelines of the American College of Cardiology (Gibbons et al., 1997). Participants will exercise using a modified Bruce protocol on a treadmill (McInnis & Balady,1994), which allows people with low exercise tolerance to attempt a test they would otherwise find too strenuous. Participants will exercise to their symptomatic limits, with encouragement, to achieve VO₂ peak, based on meeting 3 of 5 criteria: 1) respiratory exchange ratio >1.1; 2) plateau of VO₂ (i.e., < 150 ml/min change in VO₂ with increased load); 3) heart rate levels reach >85% of predicted maximum heart rate; 4) inability to maintain treadmill speed due to fatigue or safety; 5) a rating of perceived exercise >17 on the 6-20 Borg scale (Borg, 1982). The lactate threshold (i.e., the point where lactate concentrations increases to 1mM above resting levels) will be identified using blood lactate samples obtained via finger stick in the last 30 seconds of each 3-minute stage. In order to prescribe the participant’s 12-week program we will first calculate their Heart Rate Reserve (HRR). In order to calculate the HRR we will take the participant’s Heart Rate (HR) at their Lactate Threshold (HR_LT) and subtract their resting heart rate (HR_Rest). With HRR calculated, we will then multiply that by the prescribed range, depending on the week (i.e. Week 1 = 40-60% HRR), and add that value back to their resting heart rate [HRR% = [(HR_LT-HR_Rest) X (Prescribed Range %)] + HR_Rest]. If, at any time, participants wish to terminate or are unable to perform the exercise challenge, the session will be terminated after an appropriate and safe cool-down period. We will draw 20 cc of blood at 5-minutes and 30-minutes after the exercise challenge when NPY and other neurohormones of interest, respectively, are understood to peak (Scioli-Salter et al., 2016).

Cognitive Control Testing.

Participants will complete a battery of computer-based cognitive control tests measuring different aspects of attention, executive functioning, and cognitive effort/motivation to measure the cognitive component of self-regulation. These tasks will take approximately 1.5 hours with breaks. Working memory capacity will be assessed with the well-validated operation-word-span task (Turner & Engle, 1989; Unsworth, Heitz, Schrock, & Engle, 2005). Additionally, visual short-term memory capacity will be assessed with a well-validated change detection test (Xu, Adam, Fang, & Vogel, 2018). Sustained attention and inhibitory control will be assessed with the well-validated gradual onset continuous performance task (gradCPT; Esterman et al., 2013), shown to be sensitive to PTSD and other trauma-related comorbidities (Esterman et al., 2019), as well as the impact of reward and motivation (Esterman, Reagan, Liu, Turner, & DeGutis,2014; Esterman, Poole, Liu, & DeGutis, 2016; DeGutis et al., 2015). Attention switching will be assessed via the dimensional card sort task from the NIH toolbox (Zelazo et al., 2013).

Cold Pressor Test (CPT).

Trained research assistants will implement the CPT per standard procedures (McRae et al., 2006). All participants are instructed to 1 hold their right hand, up to the wrist, in a temperature-controlled ice water bath (4 degrees Celsius), while keeping the hand still. They are instructed to indicate when they first experience pain and to withdraw their hand when the pain becomes intolerable. Pain threshold is defined as the number of seconds between hand immersion and the first report of “pain.” Pain tolerance is defined as the number of seconds between hand immersion and hand withdrawal from the water. To prevent risk to participants, a 7-minute time limit for immersion, unknown to them, is imposed. The cold pressor test is performed after exercise challenge and cognitive control testing to assess effects of acute exercise on pain sensitivity. To assess effects of exercise training on resting pain sensitivity, the cognitive control tasks and cold pressor also will be performed one week before each exercise challenge and at the exercise-training midpoint. At these sessions, participants will engage in the same procedures (except the exercise challenge) at the same time of day as those performed at the exercise challenge sessions.

Scheduling of Women.

Each cold pressor and exercise assessment session in women will be scheduled 2-6 days after the start of menses during the early follicular phase (when estrogen and progesterone levels are low, stable and most comparable to levels in men) or after initiation of a new pill cycle in women on oral contraceptives. Women on other types of steroid contraception that suppress ovulation will be scheduled as convenient, as cycling between the follicular and luteal phases of the menstrual cycle is prevented and estradiol and progesterone levels approximate those in the follicular phase of the cycle (Scioli-Salter et al. 2016).

Blood Plasma Collection, Processing and Assay

Blood Drawing.

We will draw 10 cc of blood at the screening session. We will draw 20 cc of blood before the exercise challenge sessions. At the exercise challenge testing sessions only, we also will perform finger pricks to obtain blood for lactate measurements at each stage of the exercise test and draw 20 cc of blood at 5 and 30 minutes after exercise challenge. We will draw 10 cc of blood 45 minutes after the cold pressor test. Therefore, a total of ~250 cc of blood will be drawn during the study, which corresponds to half the amount of a standard blood donation. Previous experiences show that participants tolerate blood drawing at this level during exercise testing without difficulty.

Blood Processing.

Blood will be collected in EDTA tubes, placed immediately on wet ice, and spun within 20 min. of collection at 3000 rpm for 15 min. in a refrigerated centrifuge. Plasma will be aliquoted into tubes for storage at −80 degrees C until assays of the NPY or other neurohormones of interest are performed. Blood samples for potential future genomics analysis also will be collected and stored per standard procedures

Biological Assays.

Plasma NPY will be measured by a validated sensitive and specific immunoassay (e.g., as previously reported) (Scioli-Salter et al., 2016).

Assessment of Exercise Maintenance.

Exercise Maintenance will be measured using the exercise stage of change measure, based on the Transtheoretical Model of Health Behavior Change (TTM) (Prochaska & Velicer, 1997). According to the TTM, exercise maintenance is defined as performing regular exercise, in accordance with the American College of Sport Medicine guidelines, for a minimum of six months. Thus, participants will be expected to shift from the action stage of exercise, during the intervention phase of the study, to the maintenance stage of exercise by the three-month follow-up timepoint. In addition, we will assess whether participants were successful at remaining in the maintenance stage at the 6-month follow-up assessment.

Additional Assessments.

Please see the Appendix for the diagnostic and symptom rating scales to be implemented by trained research assistants. The rating scales will be completed at relevant study time points as indicated in Table 1. All self-report data will be checked by trained research assistants for completeness.

Intervention

Exercise Training Program.

To design an exercise program that is safe for patients with chronic low back pain and PTSD, we reviewed exercise studies in patients with heart failure and cardiovascular disease, which have pathophysiological characteristics similar to those in patients with chronic low back pain/PTSD (Tkachuk & Martin, 1999). We determined that a progressive training method is likely to provide the most clinical benefit, as well as reduce the risk of exercise related adverse events in this vulnerable population (Oka et al., 2000; Goodrich, Larkin, Lowery, Holleman, & Richardson, 2007; Smeets et al., 2006). Based on the “Active Physical Treatment Model”, individuals with chronic pain are primarily sedentary and physically deconditioned and need a progressive approach to work up to standard exercise prescriptions, as defined by the Garber and colleagues (2011). According to Goodrich and colleagues (2007), progressive exercise training can help to minimize the risk or occurrence of a range of exercise-related adverse medical events, particularly with a complex study population that will be starting at a relatively sedentary level and therefore may not be able to initially achieve the heart rate goals prescribed in standard exercise-training protocols. Thus, we plan to prescribe a 12-week, individually tailored and progressive aerobic exercise training regimen to ease sedentary chronic low back pain/PTSD participants into exercise. We believe that this design will both maximize the clinical benefits of the intervention for most patients, as well as allow us to investigate relationships between exercise-induced changes in chronic pain and PTSD symptoms and changes in NPY physiology, as well as cognitive and motivational factors.

Progressive Exercise Training.

Target heart rates for the exercise training sessions will be prescribed based on the heart rate at which participants hit their lactate threshold during the exercise challenge test. Importantly, the exercise intensity will be modified to match each participant’s individual capability/ability level. All participants will be instructed to wear a pedometer and heart rate monitor while progressively increasing their walking/running duration and intensity over each week. The devices will be programmed by the exercise physiologist and will allow the participant to walk at a frequency, intensity and duration in accordance with a target heart rate defined by their lactate threshold during the baseline exercise challenge test. The devices will record activity performed by the participant and allow the exercise physiologist to adjust instructions accordingly when the participant returns for each clinic visit. This will minimize improper performance of the exercise prescription, and along with close monitoring by study staff, (i.e. telephone calls and check-ins, as well as midpoint and endpoint in-person exercise challenge tests), will feasibly, safely and effectively promote realization of the exercise training goal.

Summary of Exercise Training Implementation.

Upon completion of the initial exercise challenge, neurocognitive and CPT session, each participant in the AET condition will be instructed to return to VABHS for all exercise training sessions with our experienced exercise physiologist who will teach them how to conduct their exercise regimens. Participants in the WL condition will return 3x per week for “sham” exercise training sessions that consist of stretching exercises. For the AET condition, after the first two sessions, the exercise physiologist will instruct the participants to gradually increase the frequency of their prescribed exercise sessions to meet the target heart rate. To enhance motivation and to promote retention, the principal investigator (PI) or other appointed and trained research staff will call the participant at weeks 4 and 10 to provide a brief check-in and discuss any barriers to exercise. The PI or other qualified staff, who are trained in the identification of barriers to maintaining exercise compliance, will use basic motivational interviewing techniques (i.e. reflective listening) and problem-solving strategies (the current standard of care in this area) to facilitate exercise compliance while maintaining participant safety. At weeks 7 and 14, participants will complete midpoint and final ratings, respectively. Participant compliance will be tracked for all training sessions and communicated by study research assistants to the PI during weekly team meetings.

Data Management.

All data will be double-entered by trained research assistants, and cross checked via data checking procedures in SPSS; discrepancies will be resolved by review of the study documents and team discussion.

Power and Sample Size Considerations.

Power calculations were carried out based on our prior study (Scioli-Salter et al., 2016) using the key constructs of interest, including TTM-based interventions, dependent neurobiological variables, and exercise outcomes. That study measured NPY at baseline and at 5-minutes after completion of a single exercise challenge test. In this prior study, VO₂ at peak exercise was strongly (r=.69) associated with peak levels of NPY, evidencing the capacity for acute maximum load exercise testing to trigger the release of NPY. In addition, we consulted studies that examined the impact of TTM-based exercise interventions on exercise maintenance (e.g., Fahrenwald et al., 2004). For the present study, attaining Cohen’s effect size of d ≥ 0.5 will suggest statistically and clinically significant effects of the treatment on the targeted mediating mechanisms (self-regulation and reward sensitivity), as well as post-treatment study outcomes (i.e., exercise maintenance); based on the literature (e.g., Marshall & Biddle, 2001), we anticipate effect sizes of 0.6 or larger. Thus, to obtain 75% power at an alpha level of .05, a sample size of 40 participants per group will be required. However, due to the expected dropout rate of 18-20% (Kerns, Turk, Holzman, & Rudy, 1985), the proposed recruitment is 45 participants per group (total of 90 participants). This will allow sufficient power to identify meaningful associations among these variables, as well as provide preliminary evidence of complex associations (e.g., moderated mediation in longitudinal models) to inform a larger, multi-site study of these and perhaps other mechanisms that have not yet been examined. Note, however, that the use of direct maximum likelihood estimation, the effective N will be the number of cases randomized to either the AET or WL condition, irrespective of attrition.

In addition to our adjustment for anticipated attrition, we will attend to and address any missing data using multiple imputation strategies. This process will involve first investigating the potential nature of missing data to determine the patterns of missingness. If we determine that there is non-trivial missingness associated with measured factors (e.g., age, gender), we will consider using multiple imputation to address the missingness for Aims 2 and 3. For the latent growth models specified for Aim 1, we will apply a full information maximum likelihood approach (FIML; Muthén & Muthén, 1998-2017), which makes use of all available data, including cases for whom data are not available at all time points. While we will examine and account for missing data in each of the above Aims, it is important to note that in our previous study (Scioli-Salter et al., 2016), which is similar in design and study population (i.e., included participants with all types of chronic musculoskeletal pain and PTSD), there were no dropouts once participants entered the active phase (n=20). Also, for the highly controlled nature of the assessment sessions, we observed missing data at a rate of less than 1%. Thus, we do not anticipate a greater than 5% missing data rate for this entire study.

Data Analyses.

Baseline demographics and descriptive variables (e.g., age, sex, pain duration) will be summarized. Descriptive summaries for continuous variables will be presented as means and standard deviations, while discrete variables will be summarized as relative frequencies and percentages. Covariates for hypotheses 1 and 2 will include: age, sex, smoking status and medication status (medical and psychotropic), as these variables can influence the levels of NPY and other variables of interest under investigation.

Aim 1: Hypothesis 1 will be evaluated by (1) examining the presence of group differences in NPY levels and responses to the exercise challenge sessions, repeated-measures analyses of variance (ANOVAs) will be conducted (2) examining conditional latent growth models via M-plus statistical software, which will model trajectories of change over time by group. For the LGMs, the Intercept of the model will be centered on the NPY levels and self-report data from the baseline exercise challenge assessment and NPY levels and self-report data (i.e., first Slope loading will be fixed to 0.0). The intermittent time point (midpoint exercise challenge assessment and NPY levels and self-report data) will be freely estimated and the final time point (i.e. the 14-week exercise challenge assessment and NPY levels and self-report data) will have a corresponding Slope factor loading fixed to 1.0. Accordingly, the mean and variance of the Slope factor will convey the fixed (average) and random effects (individual differences) of change for the time interval of interest. The two study groups will be dummy coded (using the “active exercise training condition” as the reference condition in the initial models) and included as predictors in the LGM to account for individual differences in continuous variable improvement (i.e. NPY, cognitive and motivational factors) due to treatment assignment. The Intercept will be regressed onto the treatment covariates to examine any pre-exercise training differences among treatment conditions. Moreover, individual differences in pre-treatment functioning will be held constant by regressing the Slope onto the Intercept. Hypotheses 1 will be supported in part by the statistical significance of the study group (dummy code) Slope paths. In fact, these paths reflect study group x Time interaction effects. The nature of these interaction effects in the LGMs will be characterized using the procedures described by Curran, Bauer, and Willoughby (2004). All outcome measures will be analyzed in this fashion.

Aim 2: Hypothesis 2 will be evaluated using a moderated mediation analysis to examine the indirect effects, with bootstrapping to estimate standard errors. To determine if changes in NPY system function bolster the overall and indirect effects of the AET intervention, indices of NPY release will be examined as potential moderators of the relationship between AET participation and the candidate self-regulation, reward sensitivity, and exercise-based motivational mediators. Indices of NPY release also will be examined as potential moderators of the association between the candidate mediators and exercise maintenance (+/−) at the 6-month follow-up time point, via logistic regression.

Aim 3: Hypothesis 3 will be evaluated at each of the three exercise challenge tests time points. The continuous neurobiological, cognitive, reward sensitivity, and exercise-based motivational factors under investigation will be cross-sectionally correlated with each other, as well as with pain, depression and PTSD symptoms, as assessed by Pearson or Spearman correlation, as appropriate.

Note, Secondary analyses for Aims 1 and 2 will be evaluated by comparing the WL symptom monitoring condition with the D-AET condition using the same analytic strategy described above.

Data Safety Monitoring Board (DSMB).

The DSMB is comprised of PhD and MD researchers not associated with the research project. No member of the Committee has collaborated or co-published with the PI within the past three years. The committee members are qualified to review the patient safety data generated by this study because of their unique expertise. Of note, there will be no interim analyses conducted during the data acquisition phase of the study. Any study modification and/or serious adverse events that are unanticipated or serious, and possibly related to the study intervention will be reported to the Independent Safety Monitor(s), IRB, and the National Center for Complementary and Integrative Health, in accordance with requirements. All regulatory audits will be conducted by the research compliance officers from VA Boston Healthcare System and Boston University. Auditors will be independent of the study investigators and sponsor.

Consent.

Informed consent will be obtained by either the study PI or other qualified study staff. All co-investigators obtaining consent will be trained by Dr. Scioli through mock informed consent role plays and direct observation. Potential participants will be told that they can ask any questions or obtain further information about the protocol or procedures from the PI either in person or by phone.

Confidentiality.

Only the research team will have access to the information collected from subjects in this study. The paper data collected from this study will be kept in a locked cabinet in a locked office, while the electronic data will be coded and stored without personal identifiers on secure VA computers. The audio recording from the screening evaluation will be identified only by a code number excluding any personal identifiers. Only members of the research team will have access to the recording, which will be used to monitor diagnostic accuracy and destroyed at the end of the study. All personally identifiable information (i.e., the signed Informed Consent Form) and the file that links a subject’s personal identifying information to the research code will be kept on a separate drive with password protection or in a locked cabinet in a different locked office from the other information collected in this study. Actigraph and heart rate data will be coded and stored using protections described above. Blood samples will be labeled with the research code (which lacks personal identifying information), and processed and stored using appropriate procedures to protect confidentiality in the Massachusetts Veterans Epidemiology Research and Information Center Biorepository located at VA Boston.

Declaration of Interests.

There are no financial or competing interests for the PI or co-investigators of this study.

Access to Data.

The study PI and co-investigators will be given access to the cleaned data sets. Project data sets will be housed on a VA secure drive and all data sets will be password protected. In order to ensure confidentiality, data dispersed to project team members will have research codes only and not contain any personal identifiers.

Ancillary and Post-Trial Care.

All participants will receive medical care, including emergency treatment, in the event he or she is injured as a result of participating in the study. This care or treatment is governed by federal law and VA policy. Participants will also have the right to file any legal action, as in any instance of alleged negligence.

Dissemination Policy.

In line with the NIH Science of Behavior Change initiative, this project is conducted with an emphasis on scientific transparency to enhance replicability of the findings and to exemplify rigorous, mechanistic science (Sumner et al., 2018). As such, this study is pre-registered through the Open Science framework (https://osf.io/epfmk). Therefore, final anonymized, data sets and associated syntax underlying all publications/conference presentations resulting from this research will be shared in electronic format through OSF. Also, as required by the Department of Health and Human Services, and in line with the current definition of clinical trials, this trial has been pre-registered at https://clinicaltrials.gov/ct2/show/NCT03644927. Authorship eligibility will be based on substantive contributions made by the PI, co-investigators and qualified research staff to the design, conduct, interpretation, and reporting of the clinical trial.

Discussion

This study has the potential to impact chronic low back pain and PTSD treatment research and development in several important ways. First, aerobic exercise has been shown to independently benefit both chronic pain and PTSD (Hegberg, Hayes, & Hayes, 2019). Our research is highly controlled and rigorous and examines several theoretically supported neurobiological, cognitive control and motivational mechanisms of action to explain these relationships. This is particularly important, as there has been little to no research examining mechanisms that drive the therapeutic effects of aerobic exercise on chronic pain/PTSD symptoms. As such, this research illustrates a translational experimental medicine approach and has the potential to inform the development of future exercise intervention research and exercise prescriptions for populations prone to comorbid chronic pain/PTSD (e.g., military veterans and/or civilians exposed to chronic, intense stress). If the study is successful in inducing longer-term exercise maintenance, implementation of such exercise training programs could potentially reduce long-term disability and premature mortality in chronic low back pain/PTSD.

Roles and responsibilities-committees.

Principal Investigator and Co-Investigators:	Research Assistant & Exercise Physiologist
-Design and conduct of the trial	-Maintenance of database and entry
-Preparation of protocol and revisions	-Implementation of all study sessions per protocol

Appendix. Descriptions of Assessments to be Administered

Structured Clinical Interview for DSM-5 (SCID)-5:

(First, Williams, Karg, & Spitzer, 2015) This current gold-standard clinician-administered interview will be used to diagnose psychiatric and substance abuse disorders except for PTSD (see below).

Life Events Checklist (LEC-5):

(Weathers et al., 2013b) The LEC-5 will be used to code exposure to potential traumatic experiences and serve as a reference for the CAPS-5 assessment.

Clinician-Administered PTSD Scale-5 (CAPS-5):

(Weathers et al., 2013a) This 30-item structured interview yields a dichotomous diagnosis of PTSD and a continuous score of severity for each symptom. The CAPS-5 is currently being validated, but the previous version CAPS-IV demonstrated excellent sensitivity (.81) and specificity (.95) (Weathers, Ruscio, & Keane, 1999).

VA Boston Assessment of Traumatic Brain Injury (BATL) Military and Civilian versions:

(Fortier et al., 2014) The BAT-L is the first validated semi-structured clinical interview to characterize head injuries due to blast or blunt neurotrauma and diagnose TBIs throughout the lifespan.

Beck Depression Inventory (BDI-II):

(Beck, Steer, & Brown, 1996) The BDI is a well-validated 21-item self-report measure of depressive symptom severity. It yields a total score and subscale scores for depressive cognitive and somatic symptoms.

PTSD Checklist (PCL-5):

(Weathers et al., 2013c) The PCL is a 20-item self-report that assesses the extent to which an individual is bothered by each PTSD symptom during the past month using a 5-point Likert-type scale. The PCL-5 is undergoing validation, but the previous PCL based on DSM-IV had good sensitivity (.82) and specificity (.83).

Columbia Suicide Severity Rating Scale (CSSRS):

(Posner et al., 2008) This validated scale is used routinely in clinical trials to assess historical and current risk for self/other harm.

Transtheoretical Model of Exercise Stage of Change:

(Prochaska & Velicer, 1997) This 23-item continuous measure categorizes stages of behavioral change (precontemplation, contemplation, preparation, action and maintenance).

Self-Efficacy for Exercise:

(Marcus, Selby, Niaura & Rossi, 1992) This 18-item scale is used to determine confidence in one’s ability to exercise.

Exercise Motivation Scale:

(Li, 1999) This 31-item scale is used to determine extrinsic and intrinsic variants of exercise motivation based on Self-Determination Theory. Results from various analyses showed adequate evidence for the a priori hypothesized EMS factorial structure, acceptable subscale reliability estimates, and nomological validity.

Temporal Experience of Pleasure Scale (TEPS):

(Gard, Gard, Kring, & John, 2006) This18-item self-report measure uses a Likert-like scale (1-6) to assess reward sensitivity. Two sub-scales with convergent and discriminant validity assess anticipatory and consummatory aspects of reward sensitivity.

Effort Expenditure for Rewards Task (EEfRT):

(Treadway, Buckholtz, Schwartzman, Lambert, & Zald, 2009; Treadway, Bossaller, Shelton, & Zald, 2012) This computerized (Matlab) task (for which scripts have been obtained from the developer for study use) captures willingness to expend effort for rewards. EEfRT scores have been inversely related to anhedonia. The task has been validated in healthy college students (Treadway, Buckholtz, Schwartzman, Lambert, & Zald, 2009) and adults with major depression and schizophrenia (Treadway, Bossaller, Shelton, & Zald, 2012)

The Generalized Self-Efficacy Scale (GSE):

(Schwarzer & Jerusalem, 1995) This 12-item taps into a global sense of self-efficacy, or belief by an individual in his or her ability (e.g., “I can always solve difficult problems if I try hard enough,” and “I can usually handle whatever comes”). Participants are asked to rate how true these statements are to them using a 7-point Likert scale from 1 (Never true) to 6 (Always true), with 7 indicating a middle position (Neutral). Higher scores reflect a greater sense of self-efficacy, and two items are reverse coded. The GSE has a Chronbach’s alpha ranging from .76 to .90 and has been positively correlated with positive emotions and negatively correlated with complaints about health.

The Difficulties in Emotion Regulation Scale – Short Form (DERS-SF):

(Kaufman, et al., 2015) This is a validated 18-item version of the full 36-item DERS to capture problems with regulating emotions in adults and adolescents. Items are clustered into 6 subscales (strategies, non-acceptance, impulse, goals, awareness, and clarity) related to cognitions and behaviors in response to being upset and an ability to gauge one’s own feelings (e.g., “When I’m upset, I have difficulty controlling my behaviors” and “I am confused about how I feel”). The items are rated on a 5-point Likert scale from 1 (Almost Never / 0 – 10%) to 5 (Almost Always / 91 – 100%). Higher scores represent greater emotional dysregulation and the awareness subscale is reverse coded. The Chronbach’s alpha for the DERS-SF subscales and total score ranges from .78 to .91 and has strong correlations with the DERS subscales and total, ranging from .90 to .97.