Combining exercise with cognitive training and vitamin D3 to improve functional brain connectivity (FBC) in older adults with mild cognitive impairment (MCI). Results from the SYNERGIC trial.

Changes in functional brain connectivity (FBC) may indicate how lifestyle modifications can prevent the progression to dementia; FBC identifies areas that are spatially separate but temporally synchronized in their activation and is altered in those with mild cognitive impairment (MCI), a prodromal state between healthy cognitive aging and dementia. Participants with MCI were randomly assigned to one of five study arms. Three times per week for 20-weeks, participants performed 30-min of (control) cognitive training, followed by 60-min of (control) physical exercise. Additionally, a vitamin D3 (10,000 IU/pill) or a placebo capsule was ingested three times per week for 20-weeks. Using the CONN toolbox, we measured FBC change (Post-Pre) across four statistical models that collapsed for and/or included some or all study arms. We conducted Pearson correlations between FBC change and changes in physical and cognitive functioning. Our sample included 120 participants (mean age: 73.89 ± 6.50). Compared to the pure control, physical exercise (model one; p-False Discovery Rate (FDR) < 0.01 & < 0.05) with cognitive training (model two; p-FDR = < 0.001), and all three interventions combined (model four; p-FDR = < 0.01) demonstrated an increase in FBC between regions of the Default-Mode Network (i.e., hippocampus and angular gyrus). After controlling for false discovery rate, there were no significant correlations between change in connectivity and change in cognitive or physical function. Physical exercise alone appears to be as efficacious as combined interventional strategies in altering FBC, but implications for behavioral outcomes remain unclear.

Frailty and functional brain connectivity (FBC) in older adults with mild cognitive impairment (MCI): baseline results from the SYNERGIC Trial.

Functional brain connectivity (FBC), or areas that are anatomically separate but temporally synchronized in their activation, represent a sensitive biomarker for monitoring dementia progression. It is unclear whether frailty is associated with FBC in those at higher risk of progression to dementia (e.g., mild cognitive impairment -MCI-) and if sex plays a role. We used baseline data from the SYNERGIC trial, including participants with MCI that received brain MRI. In this cross-sectional analyses (n = 100), we measured frailty using a deficit accumulation frailty index. Using the CONN toolbox, we assessed FBC of networks and regions of interest across the entire connectome. We used Pearson's correlation to investigate the relationship between FBC and frailty index in the full sample and by sex. We also divided the full sample and each sex into tertiles based upon their frailty index score and then assessed between-tertile differences in FBC. The full sample (cluster: size = 291 p-FDR < 0.05) and males (cluster: size = 993 and 451 p-FDR < 0.01) demonstrated that increasing (stronger) connectivity between the right hippocampus and clusters in the temporal gyrus was positively correlated with increasing (worse) frailty. Males also demonstrated between-tertile differences in right hippocampus connectivity to clusters in the lateral occipital cortex (cluster: size = 289 p-FDR < 0.05). Regardless of frailty status, females demonstrated stronger within-network connectivity of the Default-Mode (p = 0.024). Our results suggest that increasing (worse) frailty was associated with increasing (stronger) connectivity between regions not typically linked, which may reflect a compensation tactic by the plastic brain. Furthermore, the relationship between the two variables appears to differ by sex. Our results may help elucidate why specific individuals progress to a dementia syndrome. NCT02808676. https://www.clinicaltrials.gov/ct2/show/NCT02808676.

Local and systemic transcriptomic responses from acute exercise induced muscle damage of the human knee extensors.

Skeletal muscle is adaptable to a direct stimulus of exercise-induced muscle damage (EIMD). Local muscle gene networks and systemic circulatory factors respond to EIMD within days, mediating anti-inflammation and cellular proliferation. Here we show in humans that local EIMD of one muscle group is associated with a systemic response of gene networks that regulate muscle structure and cellular development in nonlocal homologous muscle not directly altered by EIMD. In the nondominant knee extensors of seven males, EIMD was induced through voluntary contractions against an electric motor that lengthened muscles. Neuromuscular assessments, vastus lateralis muscle biopsies, and blood draws occurred 2 days prior and 1 and 2 days after the EIMD intervention. From the muscle and blood plasma samples, RNA-Seq measured transcriptome changes of differential expression using bioinformatic analyses. Relative to the time of the EIMD intervention, local muscle that was mechanically damaged had 475 genes differentially expressed, as compared with 33 genes in the nonlocal homologous muscle. Gene and network analysis showed that activity of the local muscle was related to structural maintenance, repair, and energetic processes, whereas gene and network activities of the nonlocal muscle (that was not directly modified by the EIMD) were related to muscle cell development, stress response, and structural maintenance. Altered expression of two novel miRNAs related to the EIMD response supported that systemic factors were active. Together, these results indicate that the expression of genes and gene networks that control muscle contractile structure can be modified in response to nonlocal EIMD in humans.

Length-dependent changes of lower limb muscle morphology in Chronic Inflammatory Demyelinating Polyneuropathy assessed with magnetic resonance imaging.

The objective of the present study was to assess muscle quantity of the thigh and leg in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) compared to age and sex matched controls in exploring length-dependent changes of innervated muscles. In five people with CIDP and seven controls, magnetic resonance imaging was used to assess muscle morphology of the four parts of the quadriceps and medial hamstring muscles. Findings were compared to the triceps surae from a subset of participants. The CIDP group had less contractile tissue in the quadriceps (11.5%, P<0.05), hamstrings (15.6%, P<0.05) and triceps surae (35.9%, P<0.05) compared to controls. Additionally, CIDP had less contractile tissue (18.7%) in the triceps surae compared to the hamstrings (P<0.05). Muscle quantity in the quadriceps and hamstrings in CIDP was less than controls, but differences were greater for the distal triceps surae. These findings support a length-dependent affect of CIDP on limb musculature composition.

Neuroprotective effects of exercise on the aging human neuromuscular system.

Human biological aging from maturity to senescence is associated with a gradual loss of muscle mass and neuromuscular function. It is not until very old age (>80 years) however, that these changes often manifest into functional impairments. A driving factor underlying the age-related loss of muscle mass and function is the reduction in the number and quality of motor units (MUs). A MU consists of a single motoneuron, located either in the spinal cord or the brain stem, and all of the muscle fibres it innervates via its peripheral axon. Throughout the adult lifespan, MUs are slowly, but progressively lost. The compensatory process of collateral reinnervation attempts to recapture orphaned muscle fibres following the death of a motoneuron. Whereas this process helps mitigate loss of muscle mass during the latter decades of adult aging, the neuromuscular system has fewer and larger MUs, which have lower quality connections between the axon terminal and innervated muscle fibres. Whether this process of MU death and degradation can be attenuated with habitual physical activity has been a challenging question of great interest. This review focuses on age-related alterations of the human neuromuscular system, with an emphasis on the MU, and presents findings on the potential protective effects of lifelong physical activity. Although there is some discrepancy across studies of masters athletes, if one considers all experimental limitations as well as the available literature in animals, there is compelling evidence of a protective effect of chronic physical training on human MUs. Our tenet is that high-levels of physical activity can mitigate the natural trajectory of loss of quantity and quality of MUs in old age.

The effect of physical exercise on functional brain network connectivity in older adults with and without cognitive impairment. A systematic review.

INTRODUCTION: Neurodegeneration is a biproduct of aging that results in concomitant cognitive decline. Physical exercise is an emerging intervention to improve brain health. The underlying neural mechanisms linking exercise to neurodegeneration, however, are unclear. Functional brain network connectivity (FBNC) refers to neural regions that are anatomically separate but temporally synched in functional signalling. FBNC can be measured using functional Magnetic Resonance Imaging (fMRI) and is affected by neurodegeneration. METHODS: We conducted a systematic review using PubMed and EMBASE to assess the effect of physical exercise on FBNC in older adults with and without cognitive impairment. RESULTS: Our search yielded 1474 articles; after exclusion, 13 were included in the final review, 8 of which focused on cognitively healthy older adults. 10 studies demonstrated an increase in FBNC post-exercise intervention, while 11 studies showed improvements in secondary outcomes (cognitive and/or physical performance). One study showed significant correlations between FBNC and cognitive performance measures that significantly improved post-intervention. DISCUSSION: We found evidence that physical exercise increases FBNC. When assessing the association between FBNC with physical and cognitive functioning, careful consideration must be given to variability in exercise parameters, neural regions of interest and networks examined, and heterogeneity in methodological approaches.

Brain Metabolite Levels in Sedentary Women and Non-contact Athletes Differ From Contact Athletes.

White matter tracts are known to be susceptible to injury following concussion. The objective of this study was to determine whether contact play in sport could alter white matter metabolite levels in female varsity athletes independent of changes induced by long-term exercise. Metabolite levels were measured by single voxel proton magnetic resonance spectroscopy (MRS) in the prefrontal white matter at the beginning (In-Season) and end (Off-Season) of season in contact (N = 54, rugby players) and non-contact (N = 23, swimmers and rowers) varsity athletes. Sedentary women (N = 23) were scanned once, at a time equivalent to the Off-Season time point. Metabolite levels in non-contact athletes did not change over a season of play, or differ from age matched sedentary women except that non-contact athletes had a slightly lower myo-inositol level. The contact athletes had lower levels of myo-inositol and glutamate, and higher levels of glutamine compared to both sedentary women and non-contact athletes. Lower levels of myo-inositol in non-contact athletes compared to sedentary women indicates long-term exercise may alter glial cell profiles in these athletes. The metabolite differences observed between contact and non-contact athletes suggest that non-contact athletes should not be used as controls in studies of concussion in high-impact sports because repetitive impacts from physical contact can alter white matter metabolite level profiles. It is imperative to use athletes engaged in the same contact sport as controls to ensure a matched metabolite profile at baseline.

Assessment of age-related differences in decomposition-based quantitative EMG in the intrinsic hand muscles: A multivariate approach.

OBJECTIVE: Decomposition-based quantitative electromyography (DQEMG) is one method of measuring neuromuscular physiology in human muscles. The objective of the current study is to compare the neuromuscular physiology of a typical aging population in the intrinsic hand muscles. METHODS: Measurements of DQEMG were detected with a standard concentric needle and surface EMG from the intrinsic hand muscles. DQEMG was obtained from the first dorsal interosseous (FDI), the abductor digiti minimi (ADM) and fourth dorsal interosseous (4DI). Multivariate analysis of variance (MANOVA) were performed for the surface and intramuscular EMG measures to identify age differences in motor unit properties. RESULTS: Large differences were observed between the age groups for the canonical intramuscular and surface EMG variables. Older adults demonstrated a large decrease in motor unit number estimation in the ADM and FDI. Likewise, medium to large decreases in motor unit stability were observed in the FDI, ADM and 4DI. CONCLUSIONS: With aging, there are decreases in motor unit number estimation and stability in the intrinsic hand muscles. Using a multivariate approach allows for age-related differences and the relationship between the variables to be further elucidated. SIGNIFICANCE: Multivariate analysis of DQEMG may be useful for identifying patterns of change in neuromuscular physiology with age-related changes to hand musculature. This may potentially lead to future prognostic biomarkers of age-related changes to hand muscles.

Abnormal motor unit firing rates in chronic inflammatory demyelinating polyneuropathy.

OBJECTIVE: Patients with CIDP have impairments, including muscle weakness, that could be consequences of demyelination, conduction block, and eventually axonal loss and denervation, leading to muscle atrophy. Consequently, motor unit (MU) activation of the muscle may be impaired contributing to weakness; but this has not been explored in CIDP. METHODS: MU firing rates were recorded at four levels of voluntary isometric dorsiflexion contractions (25%, 50%, 75% and 100% of maximal voluntary contraction [MVC]) in 8 (6 male, 2 female) patients with CIDP and 7 (4 male, 3 female) controls. RESULTS: Patients with CIDP were 33% weaker. The mean MU firing rates of the CIDP group were ~ 19 Hz at 25%, ~16 Hz at 50% MVC, ~18 Hz at 75% MVC and ~ 17 Hz at 100% MVC. The controls had rates of ~13 Hz at 25%, ~18 Hz at 50% MVC, ~32 Hz at 75% MVC and ~ 40 Hz at 100% MVC. Surface root mean squared electromyography normalized to the MVC was less in patients with CIDP at 50 and 75% MVC. CONCLUSIONS: As a consequence secondary to MU loss, patients with CIDP demonstrate significantly lower mean firing rates at high contraction intensities, and higher mean firing rates at low contraction intensities.

Nerve dysfunction leads to muscle morphological abnormalities in chronic inflammatory demyelinating polyneuropathy assessed by MRI.

Neuropathic features of chronic inflammatory demyelinating polyneuropathy (CIDP) have been well documented, however very little is known about the implication of this neuropathy on skeletal muscle, and whether nerve lesions in CIDP lead to uniform disruptions in skeletal muscles. In this study, we assessed the triceps surae complex, using magnetic resonance imaging (MRI) in a group (n = 10) of CIDP patients compared with a healthy age-matched control group (n = 9). MRI (T1 and T2) of the leg musculature as well as plantar flexion strength measurements were obtained from both groups. CIDP patients compared with controls had ∼28% lower plantar flexion strength and ∼19% less total muscle volume (T1) of the triceps surae. When strength was normalized to fat corrected triceps surae volume CIDP patients were ∼30% weaker than controls. Relaxation times from the T2 scans were significantly longer in CIDP with the soleus, medial head of gastrocnemius and lateral head of gastrocnemius showing ∼37%, ∼38% and ∼26% longer relaxation times, respectively. CIDP patients were significantly weaker compared to controls and despite normalizing strength to total triceps surae contractile tissue volume this difference remained. CIDP patients had significantly longer T2 times, reflecting increased noncontractile tissue infiltration. These results indicate reduced muscle quantity and quality as a result of alterations in axonal function. Furthermore, when present study results are considered together with a prior report on the anterior compartment (Gilmore et al. 2016, Muscle Nerve 3:413-420), it is clear that both anterior and posterior leg compartments are affected similarly in CIDP despite different terminal nerve innervation and functional properties. Clin. Anat. 32:77-84, 2019. © 2019 Wiley Periodicals, Inc.

Test-retest reliability of near-fibre jiggle in the ulnar intrinsic hand muscles.

OBJECTIVE: Near-fibre (NF) jiggle is one method of measuring the shape variability of motor unit potentials (MUPs) from successive firings during voluntary contractions. MUP shape variability has been associated with neuromuscular stability and health. The purpose of this study was to analyze the test-retest reliability of NF jiggle in the ulnar nerve innervated intrinsic hand muscles of healthy subjects. METHODS: Twenty healthy adult were tested (Mean age = 23.2 ±â€¯1.9; 8 females). Measurements of NF jiggle were assessed with a standard concentric needle during mild-moderate contractions from the first dorsal interosseous (FDI), the abductor digiti minimi (ADM), and the forth dorsal interosseous (4DI) muscles. Test-retest reliability were evaluated using intraclass-correlation coefficient (ICC). RESULTS: NF jiggle showed good test-retest reliability in the FDI, ADM and 4DI muscles with ICC values of 0.86, 0.85, and 0.87, respectively. The SEM for the FDI, ADM, and 4DI were 1.9%, 2.1%, and 2.5%. Finally, the MDC of the FDI, ADM and 4DI were 4.4%, 5.0%, and 7.1%. CONCLUSION: To date, this is the first investigation to explore NF jiggle in the intrinsic hand muscles. NF Jiggle demonstrates good test-retest reliability coefficients and with low measurement error.

Human motor unit characteristics of the superior trapezius muscle with age-related comparisons.

Current understanding of human motor unit (MU) control and aging is mostly derived from hand and limb muscles that have spinal motor neuron innervations. The aim here was to characterize and test whether a muscle with a shared innervation supply from brainstem and spinal MU populations would demonstrate similar age-related adaptations as those reported for other muscles. In humans, the superior trapezius (ST) muscle acts to elevate and stabilize the scapula and has primary efferent supply from the spinal accessory nerve (cranial nerve XI) located in the brainstem. We compared electrophysiological properties obtained from intramuscular and surface recordings between 10 young (22-33 yr) and 10 old (77-88 yr) men at a range of voluntary isometric contraction intensities (from 15 to 100% of maximal efforts). The old group was 41% weaker with 43% lower MU discharge frequencies compared with the young (47.2 ± 9.6 Hz young and 26.7 ± 5.8 Hz old, P < 0.05) during maximal efforts. There was no difference in MU number estimation between age groups (228 ± 105 young and 209 ± 89 old, P = 0.33). Furthermore, there were no differences in needle detected near fiber (NF) stability parameters of jitter or jiggle. The old group had lower amplitude and smaller area of the stimulated compound muscle action potential and smaller NF MU potential area with higher NF counts. Thus, despite age-related ST weakness and lower MU discharge rates, there was minimal evidence of MU loss or compensatory reinnervation.NEW & NOTEWORTHY The human superior trapezius (ST) has shared spinal and brainstem motor neuron innervation providing a unique model to explore the impact of aging on motor unit (MU) properties. Although the ST showed higher MU discharge rates compared with most spinally innervated muscles, voluntary strength and mean MU rates were lower in old compared with young at all contraction intensities. There was no age-related difference in MU number estimates with minimal electrophysiological evidence of collateral reinnervation.

Linked MRI signatures of the brain's acute and persistent response to concussion in female varsity rugby players.

Acute brain changes are expected after concussion, yet there is growing evidence of persistent abnormalities well beyond clinical recovery and clearance to return to play. Multiparametric MRI is a powerful approach to non-invasively study structure-function relationships in the brain, however it remains challenging to interpret the complex and heterogeneous cascade of brain changes that manifest after concussion. Emerging conjunctive, data-driven analysis approaches like linked independent component analysis can integrate structural and functional imaging data to produce linked components that describe the shared inter-subject variance across images. These linked components not only offer the potential of a more comprehensive understanding of the underlying neurobiology of concussion, but can also provide reliable information at the level of an individual athlete. In this study, we analyzed resting-state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI) within a cohort of female varsity rugby players (n = 52) through the in- and off-season, including concussed athletes (n = 21) who were studied longitudinally at three days, three months and six months after a diagnosed concussion. Linked components representing co-varying white matter microstructure and functional network connectivity characterized (a) the brain's acute response to concussion and (b) persistent alterations beyond clinical recovery. Furthermore, we demonstrate that these long-term brain changes related to specific aspects of a concussion history and allowed us to monitor individual athletes before and longitudinally after a diagnosed concussion.

Reductions in muscle quality and quantity in chronic inflammatory demyelinating polyneuropathy patients assessed by magnetic resonance imaging.

INTRODUCTION: Weakness in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) may be caused by decreases in muscle quantity and quality, but this has not been explored. METHODS: Twelve patients with CIDP (mean age 61 years) and 10 age-matched (mean age 59 years) control subjects were assessed for ankle dorsiflexion strength, and two different MRI scans (T1 and T2) of leg musculature. RESULTS: Isometric strength was 36% lower in CIDP patients compared with controls. Tibialis anterior muscle volumes of CIDP patients were smaller by ∼17% compared with controls, and non-contractile tissue volume was ∼58% greater in CIDP patients. When normalized to total muscle or corrected contractile volume, strength was ∼29% and ∼18% lower, respectively, in CIDP patients. DISCUSSION: These results provide insight into the structural integrity of muscle contractile proteins and pathologic changes to whole-muscle tissue composition that contribute to impaired muscle function in CIDP. Muscle Nerve 58: 396-401, 2018.

Reduced brain glutamine in female varsity rugby athletes after concussion and in non-concussed athletes after a season of play.

The purpose of this study was to use non-invasive proton magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) to monitor changes in prefrontal white matter metabolite levels and tissue microstructure in female rugby players with and without concussion (ages 18-23, n = 64). Evaluations including clinical tests and 3 T MRI were performed at the beginning of a season (in-season) and followed up at the end of the season (off-season). Concussed athletes were additionally evaluated 24-72 hr (n = 14), three months (n = 11), and six months (n = 8) post-concussion. Reduced glutamine at 24-72 hr and three months post-concussion, and reduced glutamine/creatine at three months post-concussion were observed. In non-concussed athletes (n = 46) both glutamine and glutamine/creatine were lower in the off-season compared to in-season. Within the MRS voxel, an increase in fractional anisotropy (FA) and decrease in radial diffusivity (RD) were also observed in the non-concussed athletes, and correlated with changes in glutamine and glutamine/creatine. Decreases in glutamine and glutamine/creatine suggest reduced oxidative metabolism. Changes in FA and RD may indicate neuroinflammation or re-myelination. The observed changes did not correlate with clinical test scores suggesting these imaging metrics may be more sensitive to brain injury and could aid in assessing recovery of brain injury from concussion.

Effect of very old age on anconeus motor unit loss and compensatory remodelling.

INTRODUCTION: It is not known how the process of compensatory remodeling through collateral reinnervation continues into very old age (>80 years) or whether there is a limit to effective motor unit (MU) reinnervation. Therefore, we explore electrophysiological properties related to motor unit number estimates (MUNEs) in very old participants (79-90 years of age) compared with young controls (25-29 years of age). METHODS: Decomposition-enhanced spike-triggered averaging was used to collect surface and intramuscular electromyography information from the anconeus to derive a MUNE. RESULTS: Young participants had a MUNE of ∼38 and ∼25 at 30% and 50% root mean squared maximum voluntary contraction (RMSMVC ) with surface motor unit potentials (S-MUPs) of ∼145 µV and 236 µV, respectively. Older participants had a MUNE of ∼23 and ∼16 at 30% and 50% RMSMVC with S-MUPs of 168 µV and 232 µV, respectively. DISCUSSION: In this muscle, an age limit to successful remodeling through collateral reinnervation, to compensate for the presumed ongoing losses of MUs, may have been surpassed. Muscle Nerve 57: 659-663, 2018.

Multiparametric MRI changes persist beyond recovery in concussed adolescent hockey players.

OBJECTIVE: To determine whether multiparametric MRI data can provide insight into the acute and long-lasting neuronal sequelae after a concussion in adolescent athletes. METHODS: Players were recruited from Bantam hockey leagues in which body checking is first introduced (male, age 11-14 years). Clinical measures, diffusion metrics, resting-state network and region-to-region functional connectivity patterns, and magnetic resonance spectroscopy absolute metabolite concentrations were analyzed from an independent, age-matched control group of hockey players (n = 26) and longitudinally in concussed athletes within 24 to 72 hours (n = 17) and 3 months (n = 14) after a diagnosed concussion. RESULTS: There were diffusion abnormalities within multiple white matter tracts, functional hyperconnectivity, and decreases in choline 3 months after concussion. Tract-specific spatial statistics revealed a large region along the superior longitudinal fasciculus with the largest decreases in diffusivity measures, which significantly correlated with clinical deficits. This region also spatially intersected with probabilistic tracts connecting cortical regions where we found acute functional connectivity changes. Hyperconnectivity patterns at 3 months after concussion were present only in players with relatively less severe clinical outcomes, higher choline concentrations, and diffusivity indicative of relatively less axonal disruption. CONCLUSIONS: Changes persisted well after players' clinical scores had returned to normal and they had been cleared to return to play. Ongoing white matter maturation may make adolescent athletes particularly vulnerable to brain injury, and they may require extended recovery periods. The consequences of early brain injury for ongoing brain development and risk of more serious conditions such as second impact syndrome or neural degenerative processes need to be elucidated.

Maintaining Motor Units into Old Age: Running the Final Common Pathway.

Invited Letter to the Editor. This article is a commentary on the recently published manuscript "Use it or lose it: tonic activity of slow motoneurons promotes their survival and preferentially increases slow fiber-type groupings in muscles of old lifelong recreational sportsmen". Mosole S, Carraro U, Kern H, Loefler S, Zampieri S. Use it or lose it: tonic activity of slow motoneurons promotes their survival and preferentially increases slow fiber-type groupings in muscles of old lifelong recreational sportsmen. Eur J Transl Myol 2016;26:5972. doi: 10.4081/ejtm.2016.5972. We offer some unique perspectives on masters athletes and the role of physical activity in maintaining the number and function of motor units into old age.