The role of exercise in the treatment of depression: biological underpinnings and clinical outcomes.

Globally, depression is a leading cause of disability and has remained so for decades. Antidepressant medications have suboptimal outcomes and are too frequently associated with side effects, highlighting the need for alternative treatment options. Although primarily known for its robust physical health benefits, exercise is increasingly recognized for its mental health and antidepressant benefits. Empirical evidence indicates that exercise is effective in treating individuals with depression; however, the mechanisms by which exercise exerts anti-depressant effects are not fully understood. Acute bouts of exercise have been shown to transiently modulate circulating levels of serotonin and norepinephrine, brain-derived neurotrophic factor, and a variety of immuno-inflammatory mechanisms in clinical cohorts with depression. However, exercise training has not been demonstrated to consistently modulate such mechanisms, and evidence linking these putative mechanisms and reductions in depression is lacking. The complexity of the biological underpinnings of depression coupled with the intricate molecular cascade induced by exercise are significant obstacles in the attempt to disentangle exercise's effects on depression. Notwithstanding our limited understanding of these effects, clinical evidence uniformly argues for the use of exercise to treat depression. Regrettably, exercise remains underutilized despite being an accessible, low-cost alternative/adjunctive intervention that can simultaneously reduce depression and improve overall health. To address the gaps in our understanding of the clinical and molecular effects of exercise on depression, we propose a model that leverages systems biology and multidisciplinary team science with a large-scale public health investment. Until the science matches the scale of complexity and burden posed by depression, our ability to advance knowledge and treatment will continue to be plagued by fragmented, irreproducible mechanistic findings and no guidelines for standards of care.

Using Inferred Mobility Status to Estimate the Time to Major Depressive Disorder Diagnosis Post-Spinal Cord Injury.

OBJECTIVE: Estimate (1) prevalence of major depressive disorder (MDD) diagnosis; (2) risk factors associated with MDD diagnosis; (3) time at which MDD is diagnosed post-spinal cord injury (SCI); and (4) interaction of inferred mobility status (IMS) in a commercially insured population over 3 years. DESIGN: Retrospective longitudinal cohort design. SETTING: A commercial insurance claims database from January 1, 2010 to December 31, 2013. PARTICIPANTS: Individuals with an index cervical or thoracic SCI in 2011 or 2012, without history of MDD ≤30 days pre-SCI (N=1409). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Prevalence of, risk factors associated with, and time to MDD diagnosis post-SCI. A stratified survival analysis using IMS, based upon durable medical equipment (DME) claims, was also completed. RESULTS: Post-SCI, 294 out of 1409 (20.87%) were diagnosed with new-onset MDD. Significant (P<.05) risk factors included: employment, length of index hospitalization, discharge from index hospitalization with healthcare services, rehabilitation services post-SCI, and 2 of 5 IMS comparisons. Median time to MDD was 86 days. Survival analysis demonstrated a significant difference between 6 of 10 IMS comparisons. Regarding new-onset or recurring MDD, 432 out of 1409 (30.66%) were diagnosed post-SCI. Significant risk factors included: female, employment, length of index hospitalization, discharge from index hospitalization with healthcare services, rehabilitation services post-SCI, MDD>30 days pre-SCI, catheter claims, and 2 of 5 IMS comparisons. Median time to MDD was 74 days. Survival analysis demonstrated a significant difference between 4 of 10 IMS comparisons. CONCLUSIONS: Prevalence of MDD post-SCI is greater than the general population. Stratification by IMS illustrated that individuals with greater inferred reliance on DME are at a greater risk for MDD and have shorter time to MDD diagnosis post-SCI.

Feasibility of performing a multi-arm clinical trial examining the novel combination of repetitive transcranial magnetic stimulation and aerobic exercise for post-stroke depression.

BACKGROUND: Post-stroke depression (PSD) occurs in approximately one-third of chronic stroke survivors. Although pharmacotherapy reduces depressive symptoms, side effects are common and stroke survivors have increased likelihood of multimorbidity and subsequent polypharmacy. Thus, alternative non-pharmacological treatments are needed. Combining two non-pharmacological anti-depressant treatments, aerobic exercise (AEx) and repetitive transcranial magnetic stimulation (rTMS), has been demonstrated to be feasible and well-tolerated in chronic stroke survivors. OBJECTIVES: The purpose of this trial was to determine the feasibility of conducting a multi-arm combinatorial trial of rTMS and AEx and to provide an estimate of effect size of rTMS+AEx on PSD symptoms. METHODS: Twenty-four participants were allocated to one of four treatment arms AEx, rTMS, rTMS+AEx, or non-depressed Control receiving AEx. All participants received a total of 24 treatment sessions. Participant adherence was the primary outcome measure for feasibility and within group effect sizes in Patient Health Questionnaire-9 (PHQ-9) score was the primary outcome for preliminary efficacy. RESULTS: Mean adherence rates to the exercise intervention for AEx, rTMS+AEx, and Control subjects were 83%, 98%, and 95%, respectively. Mean adherence rates for rTMS and rTMS+AEx subjects were 97% and 99%, respectively. The rTMS and rTMS+AEx treatment groups demonstrated clinically significant reductions of 10.5 and 6.2 points in PHQ-9 scores, respectively. CONCLUSION: Performing a multi-arm combinatorial trial examining the effect of rTMS+AEx on PSD appears feasible. All treatment arms demonstrated strong adherence to their respective interventions and were well received. rTMS and the combination of AEx with rTMS may be alternative treatments for PSD.

Effect of power training on rate of torque development and spatiotemporal gait parameters post stroke.

BACKGROUND: Maximizing independence and function post-stroke are two common therapy goals. Rate of torque development in lower-extremity muscles was recently reported to be associated with walking speed; however, trainability and subsequent effect on gait is unknown. This study aimed to determine effect of power training on paretic and non-paretic limb torque parameters, spatiotemporal gait parameters, and walking speed in chronic stroke survivors. METHODS: Individuals with chronic stroke (n = 22; 7 females; 62.7 ± 8.8 yrs) completed 24 progressive power-training sessions over 8 weeks with pre and post assessments. Knee extensor strength was assessed via dynamometry with torque parameters measured from maximal voluntary isometric contractions. Gait speed and spatiotemporal gait parameters were assessed via an instrumented gait mat, and a 6-min walk test was performed. FINDINGS: Rate of torque development at 200 ms and peak torque improved 58.6% and 14.1%, respectively, in the quadricep of the paretic limb (p < 0.05); conversely the non-paretic limb was unchanged. On average, self-selected walking speed, fastest-comfortable walking speed, and 6-min walk test improved 21.7%, 21.1%, and 19.5%, respectively (all p < 0.05). Change in torque development at 100 ms in the quadricep of the non-paretic limb was positively associated with improvements in self-selected and fastest-comfortable walking speeds (both r = 0.70, p < 0.05) and 6-min walk (r = 0.78, p < 0.001). INTERPRETATIONS: These findings suggest power training may be an effective intervention for improving torque development in the quadricep of the paretic limb in individuals with chronic stroke. Further research to explore utility and mechanistic aspects of force development for gait function in chronic stroke survivors is warranted.

FES-assisted Cycling Improves Aerobic Capacity and Locomotor Function Postcerebrovascular Accident.

PURPOSE: After a cerebrovascular accident (CVA) aerobic deconditioning contributes to diminished physical function. Functional electrical stimulation (FES)-assisted cycling is a promising exercise paradigm designed to target both aerobic capacity and locomotor function. This pilot study aimed to evaluate the effects of an FES-assisted cycling intervention on aerobic capacity and locomotor function in individuals post-CVA. METHODS: Eleven individuals with chronic (>6 months) post-CVA hemiparesis completed an 8-wk (three times per week; 24 sessions) progressive FES-assisted cycling intervention. V˙O2peak, self-selected, and fastest comfortable walking speeds, gait, and pedaling symmetry, 6-min walk test (6MWT), balance, dynamic gait movements, and health status were measured at baseline and posttraining. RESULTS: Functional electrical stimulation-assisted cycling significantly improved V˙O2peak (12%, P = 0.006), self-selected walking speed (SSWS, 0.05 ± 0.1 m·s, P = 0.04), Activities-specific Balance Confidence scale score (12.75 ± 17.4, P = 0.04), Berg Balance Scale score (3.91 ± 4.2, P = 0.016), Dynamic Gait Index score (1.64 ± 1.4, P = 0.016), and Stroke Impact Scale participation/role domain score (12.74 ± 16.7, P = 0.027). Additionally, pedal symmetry, represented by the paretic limb contribution to pedaling (paretic pedaling ratio [PPR]) significantly improved (10.09% ± 9.0%, P = 0.016). Although step length symmetry (paretic step ratio [PSR]) did improve, these changes were not statistically significant (-0.05% ± 0.1%, P = 0.09). Exploratory correlations showed moderate association between change in SSWS and 6-min walk test (r = 0.74), and moderate/strong negative association between change in PPR and PSR. CONCLUSIONS: These results support FES-assisted cycling as a means to improve both aerobic capacity and locomotor function. Improvements in SSWS, balance, dynamic walking movements, and participation in familial and societal roles are important targets for rehabilitation of individuals after CVA. Interestingly, the correlation between PSR and PPR suggests that improvements in pedaling symmetry may translate to a more symmetric gait pattern.

Combining therapeutic approaches: rTMS and aerobic exercise in post-stroke depression: a case series.

Objective and importance Residual effects of stroke include well-documented functional limitations and high prevalence of depression. Repetitive transcranial magnetic stimulation (rTMS) and aerobic exercise (AEx) are established techniques that improve depressive symptoms, but a combination of the two has yet to be reported. The purpose of this case series is to examine the safety, feasibility, and impact of combined rTMS and AEx on post-stroke depression and functional mobility. Clinical presentation Three participants with a history of stroke and at least mild depressive symptoms (Patient Health Questionare-9 ≥5). Intervention Both rTMS and AEx were completed 3 times/week for 8-weeks. rTMS was applied to the left dorsolateral prefrontal cortex, 5000 pulses/session at 10 Hz, at an intensity of 120% of resting motor threshold. AEx consisted of 40 min of treadmill walking at 50-70% of heart rate reserve. Results Depressive symptoms improved in all three participants, with all demonstrating response (≥50% improvement in symptoms) and likely remission. All participants improved their Six Minute Walk Test distance and Participants 1 and 2 also improved Berg Balance Scale scores. Participants 1 and 3 improved overground walking speeds. No serious adverse events occurred with the application of rTMS or AEx and the participants' subjective reports indicated positive responses. Adherence rate for both rTMS and AEx was 98%. Conclusion Combined treatment of rTMS and AEx appears safe, feasible, and tolerable in individuals with a history of stroke and at least mild depressive symptoms. All participants had good compliance and demonstrated improvements in both depressive symptoms and walking capacity.