Publications by authors named "Aaron J Stegner"

25 Publications

  • Page 1 of 1

Safety and efficacy of short-term structured resistance exercise in Gulf War Veterans with chronic unexplained muscle pain: A randomized controlled trial.

Life Sci 2021 Oct 10;282:119810. Epub 2021 Jul 10.

William S. Middleton Memorial Veterans Hospital, Madison, WI, United States of America; University of Wisconsin-Madison, Madison, WI, United States of America.

Aims: Chronic widespread musculoskeletal pain (CMP) is a primary condition of Veterans suffering from Gulf War illness. This study evaluated the influence of resistance exercise training (RET) on symptoms, mood, perception of improvement, fitness, and total physical activity in Gulf War Veterans (GWV) with CMP.

Main Methods: Fifty-four GWV with CMP were randomly assigned to 16 weeks of RET (n = 28) or wait-list control (n = 26). Supervised exercise was performed twice weekly starting at a low intensity. Outcomes, assessed at baseline, 6, 11 and 17 weeks and 6- and 12-months post-intervention, were: pain, fatigue, mood, sleep quality, perception of improvement, and physical activity via self-report and accelerometry. Muscular strength was assessed at baseline, 8 and 16 weeks. Accelerometer data yielded estimates of time spent in sedentary, light, and moderate-to-vigorous physical activities. Analyses used separate linear mixed models with group and time point as fixed effects. All models, except for perceived improvement, included baseline values as a covariate.

Key Findings: Participants assigned to RET completed 87% of training sessions and exhibited strength increases between 16 and 34% for eight lifts tested (Hedges' g range: 0.47-0.78). The treatment by time interaction for perceived improvement (F = 16.94, p < 0.001) was characterized by greater perceived improvement since baseline for RET at each time point, until the 12-month follow-up. Effects were not significant for other outcomes (p > 0.05). RET caused no adverse events.

Significance: After 16 weeks of RET, GWV with CMP reported improvements in their condition and exhibited increases in muscular strength, without symptom exacerbation or reductions in total physical activity.
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http://dx.doi.org/10.1016/j.lfs.2021.119810DOI Listing
October 2021

Vagal nerve stimulation as a possible non-invasive treatment for chronic widespread pain in Gulf Veterans with Gulf War Illness.

Life Sci 2021 Oct 5;282:119805. Epub 2021 Jul 5.

Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey VA Medical Center, Houston TX, USA.

Aims: Widespread pain and headache are common in Gulf War Illness with suboptimal treatments available. We tested the efficacy of non-invasive, transcutaneous vagal nerve stimulation (nVNS) for relief of widespread pain and migraine in Gulf War Veterans with GWI.

Main Methods: A 10-week double-blind, randomized controlled trial of nVNS used the gammaCore (ElectroCore, Inc.) compared to sham stimulation with the same device followed by a 10-week open-label follow up with active nVNS. The primary outcome was a numerical pain rating at the end of the blinded period. Secondary outcomes included physical function, migraine frequency and severity, and impression of change during the blinded and open-label periods. Two-factor MANOVA models tested for significant differences between groups from baseline to end of the blinded period and during the open-label period.

Key Findings: Among 27 participants enrolled and issued a nVNS device, there was a slight improvement in pain ratings from baseline to the end of the blinded phase [6.18 (±0.82) vs. 5.05 (±2.3); p = 0.040] which did not differ between active and sham nVNS. Physical function was also slightly improved overall without group differences. There were no significant changes in migraine frequency or severity during the blinded period. Twenty participants started in the open-label phase; no statistically significant changes in pain, physical function, migraine measures, or impression of change were noted during this phase.

Significance: Veterans with GWI actively treated with nVNS reported no improvement in either widespread pain or migraine frequency or severity relative to Veterans with GWI who received sham nVNS.
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http://dx.doi.org/10.1016/j.lfs.2021.119805DOI Listing
October 2021

Predicting post-exertional malaise in Gulf War Illness based on acute exercise responses.

Life Sci 2021 Sep 10;280:119701. Epub 2021 Jun 10.

William S. Middleton Memorial Veterans Hospital, Madison, WI, United States of America; Department of Kinesiology, University of Wisconsin-Madison, Madison, WI, United States of America. Electronic address:

Aims: Post-exertional malaise (PEM) is poorly understood in Gulf War Illness (GWI). Exercise challenges have emerged as stimuli to study PEM; however, little attention has been paid to unique cardiorespiratory and perceptual responses during exercise. This study tested whether select exercise parameters explained variability in PEM responses.

Main Methods: Visual analog scale (0-100) versions of the Kansas questionnaire were used for daily symptom measurements one week before and one week after 30-min of cycling at 70% heart rate reserve in 43 Veterans with GWI and 31 Veteran controls (CON). Cardiopulmonary exercise testing (CPET) methods were used to measure oxygen (VO), carbon dioxide (VCO), ventilation (VE), heart rate, work rate, and leg muscle pain. Symptom changes and CPET parameters were compared between groups with independent samples t-tests. Linear regression (GLM) with VE/VCO, cumulative work, leg muscle pain, and self-reported physical function treated as independent variables and peak symptom response as the dependent variable tested whether exercise responses predicted PEM.

Key Findings: Compared to CON, Veterans with GWI had greater ventilatory equivalent for oxygen (VE/VO), peak leg muscle pain, fatigue, and lower VCO, VO, power, and cumulative work during exercise (p < 0.05), and greater peak symptom responses (GWI = 38.90 ± 29.06, CON = 17.84 ± 28.26, g = 0.70, p < 0.01). The final GLM did not explain significant variance in PEM (Pooled R = 0.15, Adjusted R = 0.03, p = 0.34).

Significance: The PEM response was not related to the selected combination of cardiorespiratory and perceptual responses to exercise.
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http://dx.doi.org/10.1016/j.lfs.2021.119701DOI Listing
September 2021

Nociceptive stress interferes with neural processing of cognitive stimuli in Gulf War Veterans with chronic musculoskeletal pain.

Life Sci 2021 Aug 26;279:119653. Epub 2021 May 26.

William S. Middleton Memorial Veterans Hospital, Madison, WI, USA; Department of Kinesiology, University of Wisconsin-Madison, Madison, WI, USA.

Aims: Disrupted cognition and chronic musculoskeletal pain (CMP) are prevalent experiences among Gulf War Veterans (GWV). A negative association between CMP and cognition (i.e., chronic pain-related cognitive interference) has been observed in some chronic pain populations but has not been evaluated in GWV. Additional research suggests that disrupted cognition in GWV with CMP may be exacerbated by stressing the nociceptive system. Therefore, we compared cognitive performance and related neural activity between CMP and healthy control (CO) GWV in the absence and presence of experimental pain.

Main Methods: During functional magnetic resonance imaging (fMRI), Veterans (CMP = 29; CO = 27) completed cognitive testing via congruent and incongruent conditions of a modified Stroop task (Stroop-only). A random subset (CMP = 13; CO = 13) also completed cognitive testing with experimental pain (Pain+Stroop). Yuen's modified t-test and robust mixed-model analysis of variance (ANOVA) models were used for analyzing cognitive performance data. Independent t-tests and repeated-measures ANOVA models were employed for fMRI data with thresholding for multiple-comparisons (p < 0.005) and cluster size (> 320 mm).

Key Findings: Functional MRI analysis revealed significant between-group differences for the incongruent but not congruent-Stroop run. Neither correct responses nor reaction time differed between groups in either Stroop condition (all p ≥ 0.21). Significant group (CMP, CO) by run (Stroop-only, Pain+Stroop) interactions revealed greater neural responses in CMP Veterans during Pain+Stroop runs. No significant interactions were observed for correct responses or reaction time (p ≥ 0.31).

Significance: GWV with CMP require a greater amount of neural resources to sustain cognitive performance during nociceptive stress.
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http://dx.doi.org/10.1016/j.lfs.2021.119653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243383PMC
August 2021

Post-exertional malaise in veterans with gulf war illness.

Int J Psychophysiol 2020 01 28;147:202-212. Epub 2019 Nov 28.

William S. Middleton Memorial Veterans Hospital, 2500 Overlook Terrace, Madison, WI 53705, United States of America; Department of Kinesiology, University of Wisconsin-Madison, 2000 Observatory Dr, Madison, WI 53706, United States of America. Electronic address:

Post-exertional malaise (PEM) is a potentially debilitating aspect of Gulf War Illness (GWI) that has received limited research attention. The purpose of the present investigation was to determine symptom severity changes following exercise in Veterans with GWI compared to control Veterans without GWI (CO). Sixty-seven Veterans (n = 39 GWI; n = 28 CO) underwent a 30-minute submaximal exercise challenge at 70% of heart rate reserve. Symptom measurements (e.g. fatigue, pain) occurred pre-, immediately post-, and 24-hour post-exercise. Self-reported physical and mental health, and physiological and perceptual responses to exercise were compared between groups using descriptive statistics, independent samples t-tests and repeated measures Analysis of Variance (RM-ANOVA). Post-exertional malaise was modeled using Group by Time (2 × 3) doubly-multivariate, RM-MANOVAs for (1) mood, (2) pain and (3) GWI-related symptoms, respectively (α = 0.05). Data were analyzed for the full sample of Veterans with GWI (n = 39) compared to CO (n = 28) and a subsample of Veterans (n = 18) who endorsed "feeling unwell after physical exercise or exertion" ("PEM endorsers") during screening. Veterans with GWI reported significantly lower physical and mental health. Groups exercised at similar relative exercise intensities, but GWI perceived exercise as more painful and fatiguing. Group-by-Time interactions were not significant for the entire sample for the three PEM models, however limiting the GWI sample to "PEM endorsers" resulted in significant interactions for Pain- and GWI-related PEM models. These results indicate that not all GVs with GWI experience PEM 24 h after exercise, and that more research is needed to determine the extent that exercise worsens symptoms in GWI.
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http://dx.doi.org/10.1016/j.ijpsycho.2019.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957714PMC
January 2020

Influence of pain anticipation on brain activity and pain perception in Gulf War Veterans with chronic musculoskeletal pain.

Psychophysiology 2019 12 20;56(12):e13452. Epub 2019 Aug 20.

William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.

Anticipation of a painful experience can influence brain activity and increase sensitivity to experimental somatosensory stimuli in healthy adults, but this response is poorly understood among individuals with chronic musculoskeletal pain (CMP). Studies of brain and perceptual responses to somatosensory stimuli are used to make inferences about central nervous system dysfunction as a potential mechanism of symptoms. As such, we sought to (a) determine the influence of pain anticipation on pain-relevant brain regions and pain perception, and (b) characterize potential differences in these responses between Gulf War Veterans with CMP and matched healthy control (CO) Veterans. CMP (N = 30) and CO Veterans (N = 31) were randomized to conditions designed to generate expectations that either painful (pain) or nonpainful (no pain) stimuli would be administered. Brain responses to five nonpainful thermal stimuli were measured during fMRI, and each stimulus was rated for pain intensity and unpleasantness. In the pain condition, an incremental linear decrease in activity across stimuli was observed in the posterior cingulate cortex, cingulate cortex, and middle temporal gyrus. Further, in the pain condition, differential responses were observed between CMP and CO Veterans in the middle temporal gyrus. These findings indicate that brain responses to nonpainful thermal stimuli in Veterans with CMP are sensitive to pain anticipation, and we recommend accounting for the influence of pain anticipation in future investigations of central nervous system dysfunction in CMP.
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http://dx.doi.org/10.1111/psyp.13452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803046PMC
December 2019

Fitness, independent of physical activity is associated with cerebral blood flow in adults at risk for Alzheimer's disease.

Brain Imaging Behav 2020 Aug;14(4):1154-1163

William S. Middleton Memorial Veterans Hospital, Madison, WI, 53705, USA.

Patterns of decreased resting cerebral blood flow (CBF) within the inferior temporal gyri, angular gyri, and posterior cingulate are a feature of aging and Alzheimer's disease (AD) and have shown to be predictive of cognitive decline among older adults. Fitness and physical activity are both associated with many indices of brain health and may positively influence CBF, however, the majority of research to date has examined these measures in isolation, leaving the potential independent associations unknown. The purpose of this study was to determine the unique contributions of fitness and physical activity when predicting CBF in cognitively healthy adults at risk for AD. One hundred participants (63% female) from the Wisconsin Registry for Alzheimer's Prevention underwent a maximal exercise test, physical activity monitoring, and a 3-D arterial spin labeling magnetic resonance imaging scan. For the entire sample, fitness was significantly associated with CBF while accounting for physical activity, age, gender, APOE ε4, family history of AD, education, and handedness (p = .026). Further, fitness explained significantly more variance than the combined effect of the covariates on CBF (R change = .059; p = .047). These results appear to be gender dependent, our data suggest fitness level, independent of physical activity, is associated with greater CBF in regions that are known to decline with age and AD for female (p = .011), but not male participants.
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http://dx.doi.org/10.1007/s11682-019-00068-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733668PMC
August 2020

Catastrophizing Interferes with Cognitive Modulation of Pain in Women with Fibromyalgia.

Pain Med 2018 12;19(12):2408-2422

William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.

Background: Pain modulation is a critical function of the nociceptive system that includes the ability to engage descending pain control systems to maintain a functional balance between facilitation and inhibition of incoming sensory stimuli. Dysfunctional pain modulation is associated with increased risk for chronic pain and is characteristic of fibromyalgia (FM). Catastrophizing is also common in FM. However, its influence on pain modulation is poorly understood.

Objective: To determine the role of catastrophizing on central nervous system processing during pain modulation in FM via examining brain responses and pain sensitivity during an attention-distraction paradigm.

Methods: Twenty FM patients and 18 healthy controls (CO) underwent functional magnetic resonance imaging while receiving pain stimuli, administered alone and during distracting cognitive tasks. Pain ratings were assessed after each stimulus. Catastrophizing was assessed with the Pain Catastrophizing Scale (PCS).

Results: The ability to modulate pain during distraction varied among FM patients and was associated with catastrophizing. This was demonstrated by significant positive relationships between PCS scores and pain ratings (P < 0.05) and brain responses in the dorsolateral prefrontal cortex (P < 0.01). Relationships between catastrophizing and pain modulation did not differ between FM and CO (P > 0.05).

Conclusions: FM patients with higher levels of catastrophizing were less able to distract themselves from pain, indicative of catastrophizing-related impairments in pain modulation. These results suggest that the tendency to catastrophize interacts with attention-resource allocation and may represent a mechanism of chronic pain exacerbation and/or maintenance. Reducing catastrophizing may improve FM symptoms via improving central nervous system regulation of pain.
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http://dx.doi.org/10.1093/pm/pny008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659027PMC
December 2018

An Objective Method to Accurately Measure Cardiorespiratory Fitness in Older Adults Who Cannot Satisfy Widely Used Oxygen Consumption Criteria.

J Alzheimers Dis 2018 ;61(2):601-611

William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.

Cardiorespiratory fitness (CRF) is routinely investigated in older adults; however, the most appropriate CRF measure to use for this population has received inadequate attention. This study aimed to 1) evaluate the reliability and validity of the oxygen uptake efficiency slope (OUES) as a sub-maximal measurement of CRF; 2) examine demographic, risk-factor, and exercise testing differences in older adults who satisfied standardized criteria for a peak oxygen consumption (V̇O2peak) test compared to those who did not; and 3) determine the difference between directly measured V̇O2peak values and OUES-predicted V̇O2peak values. One hundred ten enrollees from the Wisconsin Registry for Alzheimer's Prevention participated in this study. Participants performed a graded maximal exercise test and wore an accelerometer for 7 days. For each participant, the OUES was calculated at 75%, 90%, and 100% of exercise duration. V̇O2peak was recorded at peak effort, and one week of physical activity behavior was measured. OUES values calculated at separate relative exercise durations displayed excellent reliability (ICC = 0.995; p < 0.001), and were strongly correlated with V̇O2peak (rrange = 0.801-0.909; p < 0.001). As hypothesized, participants who did not satisfy V̇O2peak criteria were significantly older than those who satisfied criteria (p = 0.049) and attained a directly measured V̇O2peak that was 2.31 mL·kg·min-1 less than the value that was predicted by OUES V̇O2peak (p = 0.003). Older adults are less likely to satisfy V̇O2peak criteria, which results in an underestimation of their CRF. Without adhering to standardized criteria, V̇O2peak measurement error may lead to misinterpretation of CRF and age-related associations. Here, we conclude that OUES is a reliable, valid measurement of CRF which does not require achievement of standardized criteria.
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http://dx.doi.org/10.3233/JAD-170576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745283PMC
January 2019

Cerebral white matter structure is disrupted in Gulf War Veterans with chronic musculoskeletal pain.

Pain 2017 Dec;158(12):2364-2375

Department of Veterans Affairs, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.

Chronic musculoskeletal pain (CMP) affects ∼25% of the 700,000 Veterans deployed during the Persian Gulf War (1990-1991). The cause of their pain is unknown, and there are no efficacious treatments. A small body of literature suggests that brain abnormalities exist in Gulf War Veterans (GVs), yet relationships between brain abnormalities and disease symptoms remain largely unexplored. Our purpose was to compare white matter (WM) integrity between GVCMP and matched, healthy Veteran controls (GVCO) and investigate relationships between cerebral WM integrity and symptoms. Thirty GVCMP and 31 controls completed magnetic resonance imaging with diffusion tensor imaging. Tract-based spatial statistics estimated WM fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity over the whole brain (P < 0.05) and were corrected using threshold-free cluster enhancement. GVCMP had greater pain symptoms and mood disturbance and lower quality of life and physical function compared with GVCO (P < 0.05). GVCMP had lower WM integrity across several brain regions implicated in chronic pain (P < 0.05) including the middle and inferior frontal gyrus, corpus callosum, corona radiata, precentral gyrus, external capsule, and posterior thalamic radiation. For GVCMP, WM integrity was associated with pain and mood symptoms in widespread brain areas that were found to be different between groups (P < 0.05). Results indicate widespread WM microstructure disruption across brain regions implicated in pain processing and modulation in chronic pain. The observed relationships between WM microstructure and symptoms encourage the testing of treatments designed to improve the brain health of affected Veterans.
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http://dx.doi.org/10.1097/j.pain.0000000000001038DOI Listing
December 2017

Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity.

J Neurol Sci 2017 Apr 22;375:411-416. Epub 2017 Feb 22.

Department of Radiology, Weill Cornell Medicine, New York, NY, United States.

The purpose of this study was to investigate whether CFS patients without comorbid psychiatric diagnoses differ from CFS patients with comorbid psychiatric diagnoses and healthy control subjects in neuropsychological performance, the proportion with elevated spinal fluid protein or white cell counts, cerebral blood flow (CBF), brain ventricular lactate and cortical glutathione (GSH). The results of the study did not show any differences in any of the outcome measures between CFS patients with and without psychiatric comorbidity, thus indicating that psychiatric status may not be an exacerbating factor in CFS. Importantly, significant differences were found between the pooled samples of CFS compared to controls. These included lower GSH and CBF and higher ventricular lactate and rates of spinal fluid abnormalities in CFS patients compared to healthy controls. Thirteen of 26 patients had abnormal values on two or more of these 4 brain-related variables. These findings, which replicate the results of several of our prior studies, support the presence of a number of neurobiological and spinal fluid abnormalities in CFS. These results will lead to further investigation into objective biomarkers of the disorder to advance the understanding of CFS.
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http://dx.doi.org/10.1016/j.jns.2017.02.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393352PMC
April 2017

Relationships between cardiorespiratory fitness, hippocampal volume, and episodic memory in a population at risk for Alzheimer's disease.

Brain Behav 2017 03 17;7(3):e00625. Epub 2017 Feb 17.

William S. Middleton Memorial Veterans Hospital Madison WI USA; Geriatric Research Education and Clinical Center William S. Middleton Memorial Veterans Hospital Madison WI USA.

Introduction: Cardiorespiratory fitness (CRF) has been shown to be related to brain health in older adults. In individuals at risk for developing Alzheimer's disease (AD), CRF may be a modifiable risk factor that could attenuate anticipated declines in brain volume and episodic memory. The objective of this study was to determine the association between CRF and both hippocampal volume and episodic memory in a cohort of cognitively healthy older adults with familial and/or genetic risk for Alzheimer's disease (AD).

Methods: Eighty-six enrollees from the Wisconsin Registry for Alzheimer's Prevention participated in this study. Participants performed a graded maximal exercise test, underwent a T-1 anatomical magnetic resonance imaging scan, and completed the Rey Auditory Verbal Learning Test (RAVLT).

Results: There were no significant relationships between CRF and HV or RAVLT memory scores for the entire sample. When the sample was explored on the basis of gender, CRF was significantly associated with hippocampal volume for women. For men, significant positive associations were observed between CRF and RAVLT memory scores.

Summary: These results suggest that CRF may be protective against both hippocampal volume and episodic memory decline in older adults at risk for AD, but that the relationships may be gender specific.
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http://dx.doi.org/10.1002/brb3.625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346514PMC
March 2017

Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Brain Behav Immun 2017 May 17;62:87-99. Epub 2017 Feb 17.

Bateman Horne Center, Salt Lake City, UT, United States.

Post exertion malaise is one of the most debilitating aspects of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, yet the neurobiological consequences are largely unexplored. The objective of the study was to determine the neural consequences of acute exercise using functional brain imaging. Fifteen female Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients and 15 healthy female controls completed 30min of submaximal exercise (70% of peak heart rate) on a cycle ergometer. Symptom assessments (e.g. fatigue, pain, mood) and brain imaging data were collected one week prior to and 24h following exercise. Functional brain images were obtained during performance of: 1) a fatiguing cognitive task - the Paced Auditory Serial Addition Task, 2) a non-fatiguing cognitive task - simple number recognition, and 3) a non-fatiguing motor task - finger tapping. Symptom and exercise data were analyzed using independent samples t-tests. Cognitive performance data were analyzed using mixed-model analysis of variance with repeated measures. Brain responses to fatiguing and non-fatiguing tasks were analyzed using linear mixed effects with cluster-wise (101-voxels) alpha of 0.05. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients reported large symptom changes compared to controls (effect size ≥0.8, p<0.05). Patients and controls had similar physiological responses to exercise (p>0.05). However, patients exercised at significantly lower Watts and reported greater exertion and leg muscle pain (p<0.05). For cognitive performance, a significant Group by Time interaction (p<0.05), demonstrated pre- to post-exercise improvements for controls and worsening for patients. Brain responses to finger tapping did not differ between groups at either time point. During number recognition, controls exhibited greater brain activity (p<0.05) in the posterior cingulate cortex, but only for the pre-exercise scan. For the Paced Serial Auditory Addition Task, there was a significant Group by Time interaction (p<0.05) with patients exhibiting increased brain activity from pre- to post-exercise compared to controls bilaterally for inferior and superior parietal and cingulate cortices. Changes in brain activity were significantly related to symptoms for patients (p<0.05). Acute exercise exacerbated symptoms, impaired cognitive performance and affected brain function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients. These converging results, linking symptom exacerbation with brain function, provide objective evidence of the detrimental neurophysiological effects of post-exertion malaise.
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http://dx.doi.org/10.1016/j.bbi.2017.02.009DOI Listing
May 2017

Psychobiological Responses to Preferred and Prescribed Intensity Exercise in Major Depressive Disorder.

Med Sci Sports Exerc 2016 11;48(11):2207-2215

1Department of Family Medicine and Community Health, University of Wisconsin-Madison, Madison, WI; 2Department of Kinesiology, University of Wisconsin-Madison, Madison, WI; 3Department of Kinesiology, Iowa State University, Ames, IA; 4William S. Middleton Memorial Veterans Hospital, Madison, WI; and 5Department of Educational Psychology, University of Wisconsin-Madison, Madison, WI.

Exercise acutely improves mood in major depressive disorder (MDD). However, it is unknown whether benefits differ depending on whether exercise intensity is self-selected or prescribed.

Purpose: This study aimed to compare psychological and biological responses to preferred and prescribed steady-state exercise intensities to a patient-selected preferred intensity.

Method: Female adults (N = 24, age = 38.6 ± 14.0 yr) diagnosed with MDD completed four 30-min sessions of cycling exercise at three prescribed intensities (RPE of 11, 13, and 15) and one session with a self-selected intensity (preferred). Order was randomized and counterbalanced. Depressed mood (DM) was evaluated before, 10 min, and 30 min postexercise using the Profile of Mood States. Serum brain-derived neurotrophic factor (BDNF) was measured before and within 10 min postexercise. Changes in BDNF and DM for the preferred session were compared with the following prescribed sessions: 1) performed at the most similar intensity (matched on RPE; closest) and 2) with the greatest improvement in DM (greatest).

Results: Compared with the preferred session, improvement in DM was significantly larger after the greatest session (30 min postexercise: -11.8 ± 7.4 vs -3.4 ± 4.8), and the BDNF response was significantly greater after the closest session (5.4 ± 6.9 vs -1.4 ± 9.8 ng·mL).

Conclusions: Permitting patients to select their own exercise intensity did not maximize improvements in mood. Further, preferred intensity exercise was also associated with a smaller BDNF response. Overall, the results suggest that exercise undertaken to improve mood should be prescribed on an individual basis in MDD and not necessarily based on the patient's preferred intensity. Clinicians, psychologists, and other practitioners should consider providing clear exercise intensity recommendations for symptom management in depression rather than allowing patients to self-select their intensity.
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http://dx.doi.org/10.1249/MSS.0000000000001022DOI Listing
November 2016

Relationships between serum BDNF and the antidepressant effect of acute exercise in depressed women.

Psychoneuroendocrinology 2016 12 28;74:286-294. Epub 2016 Sep 28.

William S. Middleton Memorial Veterans Hospital, 2500 Overlook Terrace, Madison, WI 53705, USA; Department of Kinesiology, University of Wisconsin-Madison, 2000 Observatory Drive, Madison, WI 53706, USA.

Objective: Brain-derived neurotrophic factor (BDNF) has recently emerged as one potential mechanism with which exercise improves mood in major depressive disorder (MDD). This study examined the relationship between changes in serum total BDNF and mood following acute exercise in MDD. It was hypothesized that acute exercise would increase BDNF in an intensity-dependent manner and that changes in BDNF would be significantly related to improvement in depressed mood post-exercise.

Methods: Twenty-four women (age: 38.6±14.0years) with MDD exercised for 30min on a stationary bicycle at light, moderate and hard exercise intensities and performed a quiet rest session using a within-subjects, randomized and counter-balanced design. Before, 10 and 30min after each session, participants completed the profile of mood states (POMS). Blood was drawn before and within 10min after completion of each session and serum total BDNF (sBDNF) was measured by enzyme-linked immunosorbent assay. Acute exercise-induced changes in POMS Depression and sBDNF were analyzed via 4 session (quiet rest, light, moderate, hard) by 2 measurement (pre, post) ANOVA. Secondary analyses examined the effects of baseline mood and antidepressant usage on sBDNF.

Results: Exercise resulted in an acute improvement in depressed mood that was not intensity dependent (p>0.05), resulting in significant acute increases in sBDNF (p=0.006) that were also not intensity-dependent (p>0.05). Acute changes in sBDNF were not significantly correlated to changes in POMS depression at 10m (r=-0.171, p=0.161) or 30m (r=-0.151, p=0.215) post-exercise. The fourteen participants taking antidepressant medications exhibited lower post-exercise sBDNF (p=0.015) than the participants not currently taking antidepressants, although mood responses were similar.

Conclusion: Acute exercise is an effective mood-enhancing stimulus, although sBDNF does not appear to play a role in this short-term response. Patients who are not currently taking antidepressant medications and those who have greater pre-exercise depression may experience a greater sBDNF response to exercise, but the clinical significance of this is currently unclear. Circulating BDNF levels are unlikely to be altered by steady-state acute exercise in a linear dose-dependent manner. This does not eliminate its potential relevance in the antidepressant response to chronic exercise training, but suggests that other mechanisms are involved in the acute affective response to exercise in depression.
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http://dx.doi.org/10.1016/j.psyneuen.2016.09.022DOI Listing
December 2016

Meeting physical activity recommendations may be protective against temporal lobe atrophy in older adults at risk for Alzheimer's disease.

Alzheimers Dement (Amst) 2016 9;4:14-7. Epub 2016 Apr 9.

William S. Middleton Memorial Veterans Hospital, Madison, WI, USA; Department of Kinesiology, University of Wisconsin School of Education, Madison, WI, USA.

Introduction: Physical activity (PA) is associated with brain health in older adults. However, it is unknown whether the current physical activity recommendations (PAR) impart substantive benefit. The objective of this study was to compare temporal lobe volumes between older adults who met PAR and those who did not.

Methods: Ninety-one enrollees from the Wisconsin Registry for Alzheimer's Prevention wore an accelerometer for seven consecutive days to quantify their PA behaviors and underwent a T-1 anatomic magnetic resonance imaging scan. Participants were categorized as either having met PAR or not based on the US Department of Health and Human Services recommendations of 150 minutes of moderate-to-vigorous physical activity per week.

Results: Participants who met PAR possessed significantly greater inferior (η(2) P  = .050) and anterior (η(2) P  = .055) temporal lobe volumes compared with those who did not (P < .05).

Discussion: Individuals at-risk for AD experience accelerated rates of brain atrophy. These results suggest that regular engagement in PA at or above PAR could attenuate this decline.
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http://dx.doi.org/10.1016/j.dadm.2016.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4950614PMC
August 2016

Influence of Exercise Intensity for Improving Depressed Mood in Depression: A Dose-Response Study.

Behav Ther 2016 07 27;47(4):527-37. Epub 2016 Apr 27.

William S. Middleton Memorial Veterans Hospital, Madison, WI; University of Wisconsin-Madison.

Introduction: Exercise effectively improves mood in major depressive disorder (MDD), but the optimal exercise stimulus to improve depressed mood is unknown.

Purpose: To determine the dose-response relationship of acute exercise intensity with depressed mood responses to exercise in MDD. We hypothesized that the acute response to exercise would differ between light, moderate, and hard intensity exercise with higher intensities yielding more beneficial responses.

Methods: Once weekly, 24 women (age: 38.6±14.0) diagnosed with MDD underwent a 30-minute session at one of three steady-state exercise intensities (light, moderate, hard; rating of perceived exertion 11, 13 or 15) or quiet rest on a stationary bicycle. Depressed mood was evaluated with the Profile of Mood States before, 10 and 30 minutes post-exercise.

Results: Exercise reduced depressed mood 10 and 30 minutes following exercise, but this effect was not influenced by exercise intensity. Participants not currently taking antidepressants (n=10) had higher baseline depression scores, but did not demonstrate a different antidepressant response to exercise compared to those taking antidepressants.

Conclusions: To acutely improve depressed mood, exercise of any intensity significantly improved feelings of depression with no differential effect following light, moderate, or hard exercise. Pharmacological antidepressant usage did not limit the mood-enhancing effect of acute exercise. Acute exercise should be used as a symptom management tool to improve mood in depression, with even light exercise an effective recommendation. These results need to be replicated and extended to other components of exercise prescription (e.g., duration, frequency, mode) to optimize exercise guidelines for improving depression.
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http://dx.doi.org/10.1016/j.beth.2016.04.003DOI Listing
July 2016

Exercise Strengthens Central Nervous System Modulation of Pain in Fibromyalgia.

Brain Sci 2016 Feb 26;6(1). Epub 2016 Feb 26.

William S. Middleton Memorial Veterans Hospital, Madison, WI 53706, USA.

To begin to elucidate the mechanisms underlying the benefits of exercise for chronic pain, we assessed the influence of exercise on brain responses to pain in fibromyalgia (FM). Complete data were collected for nine female FM patients and nine pain-free controls (CO) who underwent two functional neuroimaging scans, following exercise (EX) and following quiet rest (QR). Brain responses and pain ratings to noxious heat stimuli were compared within and between groups. For pain ratings, there was a significant (p < 0.05) Condition by Run interaction characterized by moderately lower pain ratings post EX compared to QR (d = 0.39-0.41) for FM but similar to ratings in CO (d = 0.10-0.26), thereby demonstrating that exercise decreased pain sensitivity in FM patients to a level that was analogous to pain-free controls. Brain responses demonstrated a significant within-group difference in FM patients, characterized by less brain activity bilaterally in the anterior insula following QR as compared to EX. There was also a significant Group by Condition interaction with FM patients showing less activity in the left dorsolateral prefrontal cortex following QR as compared to post-EX and CO following both conditions. These results suggest that exercise appeared to stimulate brain regions involved in descending pain inhibition in FM patients, decreasing their sensitivity to pain. Thus, exercise may benefit patients with FM via improving the functional capacity of the pain modulatory system.
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http://dx.doi.org/10.3390/brainsci6010008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4810178PMC
February 2016

Physical activity, sustained sedentary behavior, and pain modulation in women with fibromyalgia.

J Pain 2012 Feb 13;13(2):195-206. Epub 2012 Jan 13.

Department of Kinesiology, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.

Unlabelled: Fibromyalgia (FM) has been conceptualized as a disorder of the central nervous system, characterized by augmented sensory processing and an inability to effectively modulate pain. We previously reported that physical activity is related to brain processing of pain, providing evidence for a potential mechanism of pain management. The purpose of this study was to extend our work by manipulating pain modulation and determining relationships to both physical activity and sustained sedentary behavior. Eleven women with FM completed accelerometer measures of physical activity and underwent functional magnetic resonance imaging of painful heat, administered alone and during distracting cognitive tasks. Results showed that physical activity was significantly (P < .005) and positively related to brain responses during distraction from pain in regions implicated in pain modulation including the dorsolateral prefrontal cortex (DLPFC), the dorsal posterior cingulate, and the periaqueductal grey. A significant negative relationship occurred in the left anterior insula. For sedentary time, significant negative relationships were observed in areas involved in both pain modulation and the sensory-discriminative aspects of pain including the DLPFC, thalamus, and superior frontal and pre- and post-central gyri. These results suggest that physical activity and sedentary behaviors are related to central nervous system regulation of pain in FM.

Perspective: Our results support a promising benefit of physical activity and highlight the potentially deleterious effects of sustained sedentary behavior for pain regulation in FM. Studies aimed at increasing physical activity or reducing sedentary behavior and determining the impact of these on pain regulation are warranted.
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http://dx.doi.org/10.1016/j.jpain.2011.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272134PMC
February 2012

Responses to exercise differ for chronic fatigue syndrome patients with fibromyalgia.

Med Sci Sports Exerc 2012 Jun;44(6):1186-93

Department of Kinesiology, University of Wisconsin - Madison, Madison, WI 53706, USA.

Unlabelled: Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are chronic multisymptom illnesses with substantial clinical and diagnostic overlap. We have previously shown that, when controlling for aerobic fitness and accounting for comorbid FM, CFS patients do not exhibit abnormal cardiorespiratory responses during maximal aerobic exercise compared with healthy controls, despite differences in pain and exertion.

Purpose: The purpose of the present study was to examine cardiac and perceptual responses to steady-state submaximal exercise in CFS patients and healthy controls.

Methods: Twenty-one CFS patients (13 CFS with comorbid FM (CFS + FM)) and 14 controls completed 20 min of submaximal cycling exercise. Impedance cardiography was used to determine cardiac responses during exercise. Systolic blood pressure (SBP), RPE, and leg muscle pain were also measured. Data were analyzed using a doubly multivariate, repeated-measures MANOVA to model the exercise response.

Results: There was a significant multivariate time-by-group interaction (P < 0.05). The CFS + FM group exhibited an exercise response characterized by higher stroke index, ventilatory equivalents for oxygen and carbon dioxide and RPE, lower SBP, and similar HR responses compared to controls.

Conclusions: The present results extend on our previous work with maximal exercise and show that CFS and CFS + FM differ in their responses to steady-state exercise. These results highlight the importance of accounting for comorbid conditions when conducting CFS research, particularly when examining psychophysiological responses to exercise.
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http://dx.doi.org/10.1249/MSS.0b013e3182417b9aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319493PMC
June 2012

The relationship between physical activity and brain responses to pain in fibromyalgia.

J Pain 2011 Jun 18;12(6):640-51. Epub 2011 Feb 18.

Department of Kinesiology, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.

Unlabelled: The relationship between physical activity and central nervous system mechanisms of pain in fibromyalgia (FM) is unknown. This study determined whether physical activity was predictive of brain responses to experimental pain in FM using functional magnetic resonance imaging (fMRI). Thirty-four participants (n = 16 FM; n = 18 Control) completed self-report and accelerometer measures of physical activity and underwent fMRI of painful heat stimuli. In FM patients, positive relationships (P < .005) between physical activity and brain responses to pain were observed in the dorsolateral prefrontal cortex, posterior cingulate cortex, and the posterior insula, regions implicated in pain regulation. Negative relationships (P < .005) were found for the primary sensory and superior parietal cortices, regions implicated in the sensory aspects of pain. Greater physical activity was significantly (P < .05) associated with decreased pain ratings to repeated heat stimuli for FM patients. A similar nonsignificant trend was observed in controls. In addition, brain responses to pain were significantly (P < .005) different between FM patients categorized as low active and those categorized as high active. In controls, positive relationships (P < .005) were observed in the lateral prefrontal, anterior cingulate, and superior temporal cortices and the posterior insula. Our results suggest an association between measures of physical activity and central nervous system processing of pain.

Perspective: Our data suggest that brain responses to pain represent a dynamic process where perception and modulation co-occur and that physical activity plays a role in balancing these processes. Physically active FM patients appear to maintain their ability to modulate pain while those who are less active do not.
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http://dx.doi.org/10.1016/j.jpain.2010.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3111901PMC
June 2011

Are women with fibromyalgia less physically active than healthy women?

Med Sci Sports Exerc 2011 May;43(5):905-12

Department of Kinesiology, University of Wisconsin-Madison, Madison, WI 53706, USA.

Purpose: The primary purpose was to quantify and compare physical activity in fibromyalgia (FM) patients to age-matched healthy controls using both objective and self-report measures. Secondary purposes were to compare self-reported and objective measurement of physical activity and to evaluate the relationship between physical activity and pain and mood.

Method: Patients with FM (n=39) and healthy controls (n=40) completed the International Physical Activity Questionnaire and wore an accelerometer at the hip for 7 d. Pain and mood were measured using the McGill Pain Questionnaire, Pain Catastrophizing Scale, Beck Depression Inventory, State-Trait Anxiety Inventory, Profile of Mood States, and Fibromyalgia Impact Questionnaire.

Results: FM patients had significantly lower physical activity than controls measured by both the International Physical Activity Questionnaire and accelerometer (P<0.05). Both groups self-reported significantly greater moderate and vigorous physical activities than were measured by the accelerometer (P < 0.05). Self-reported and objective measures of time spent in different intensities of activity showed significant correlations in healthy controls (r=0.41-0.51, ρ=0.41, P<0.05). No significant correlations between measures were found in FM patients (P>0.05). Finally, physical activity levels were negatively related (r=-0.37, P<0.05) to depressed mood for FM patients and positively related (r=-0.41, P<0.05) to self-reported vigor for healthy controls.

Conclusions: This controlled study objectively demonstrates that FM patients are less physically active than healthy controls, thus extending on two earlier investigations that did not show differences in total physical activity levels using wrist-mounted actigraphy methods. Physical activity levels were not predictive of pain in FM but were significantly related to depressed mood. FM patients may also have a greater variability in their manner of self-report than healthy controls. Therefore, physical activity measurement in FM patients should not be limited solely to self-report measures.
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http://dx.doi.org/10.1249/MSS.0b013e3181fca1eaDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4598051PMC
May 2011

Exercise alters pain sensitivity in Gulf War veterans with chronic musculoskeletal pain.

J Pain 2010 Aug 24;11(8):764-72. Epub 2010 Mar 24.

New Jersey War Related Injury and Illness Study Center, Veterans Affairs Medical Center, East Orange, New Jersey, USA.

Unlabelled: Since returning from the Persian Gulf, nearly 100,000 veterans of the first Gulf War (GVs) have reported numerous symptoms with no apparent medical explanation. A primary complaint of these individuals is chronic musculoskeletal pain (CMP). CMP symptoms in GVs are similar to those reported by patients with fibromyalgia (FM), but have not received equivalent scientific attention. Exercise research in CMP patients suggests that acute exercise may exacerbate pain while chronic exercise can reduce pain and improve other symptoms. However, the influence of exercise on GVs with CMP is largely unexplored. This study examined the impact of an acute bout of exercise on pain sensitivity in GVs with CMP. Thirty-two GVs (CMP, n = 15; Control, n = 17) were recruited to complete a series of psychophysical assessments to determine pain sensitivity to heat and pressure stimuli before and after exercise. In response to heat-pain stimuli, GVs with CMP reported higher pain intensity and affect ratings than healthy GVs and exhibited a significant increase in ratings following exercise. GVs with CMP rated exercise as more painful and effortful and were generally more sensitive to heat-pain stimuli than healthy GVs. These results are similar to what has been reported for acute exercise in patients with FM.

Perspective: Gulf War veterans with CMP perceive exercise as more painful and effortful than healthy GVs and experience increased pain sensitivity following exercise. These results suggest that similar abnormalities in central nervous system processing of nociceptive information documented in FM may also be occurring in GVs with CMP.
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http://dx.doi.org/10.1016/j.jpain.2009.11.010DOI Listing
August 2010

Imaging pain of fibromyalgia.

Curr Pain Headache Rep 2007 Jun;11(3):190-200

William S. Middleton Memorial Veterans Hospital, Madison, WI 53706, USA.

Brain imaging studies have provided objective evidence of abnormal central regulation of pain in fibromyalgia (FM). Resting brain blood flow studies have reported mixed findings for several brain regions, whereas decreased thalamic blood flow has been noted by several investigators. Studies examining the function of the nociceptive system in FM have reported augmented brain responses to both painful and non-painful stimuli that may be influenced by psychologic dispositions such as depressed mood and catastrophizing. Treatment approaches are beginning to demonstrate the potential for brain imaging to improve our understanding of pain-alleviating mechanisms. Data from other chronic conditions suggest that idiopathic pain may be maintained by similar central abnormalities as in FM, whereas chronic pain conditions with a known nociceptive source may not be. Future neuroimaging research in FM is clearly warranted and should continue to improve our understanding of factors involved in pain maintenance and symptom exacerbation.
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http://dx.doi.org/10.1007/s11916-007-0190-8DOI Listing
June 2007
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