Characterizing off-target corticospinal responses to double-cone transcranial magnetic stimulation.

INTRODUCTION: The double-cone coil (D-CONE) is frequently used in transcranial magnetic stimulation (TMS) experiments that target the motor cortex (M1) lower-limb representation. Anecdotal evidence and modeling studies have shed light on the off-target effects of D-CONE TMS but the physiological extent remains undetermined. PURPOSE: To characterize the off-target effects of D-CONE TMS based on bilateral corticospinal responses in the legs and hands. METHODS: Thirty (N = 30) participants (9 women, age: 26 ± 5yrs) completed a stimulus-response curve procedure with D-CONE TMS applied to the dominant vastus lateralis (cVL) and motor-evoked potentials (MEPs) recorded in each active VL and resting first dorsal interosseous (FDI). As a positive control (CON), the dominant FDI was directly targeted with a figure-of-eight coil and MEPs were similarly recorded in each active FDI and resting VL. MEPMAX, V50 and MEP latencies were compared with repeated-measures ANOVAs or mixed-effects analysis and Bonferroni-corrected pairwise comparisons. RESULTS: Off-target responses were evident in all muscles, with similar MEPMAX in the target (cVL) and off-target (iVL) leg (p = 0.99) and cFDI compared with CON (p = 0.99). cFDI and CON MEPMAX were greater than iFDI (p < 0.01). A main effect of target (p < 0.001) indicated that latencies were shorter with CON but similar in all muscles with D-CONE. DISCUSSION: Concurrent MEP recordings in bilateral upper- and lower-extremity muscles confirm that lower-limb D-CONE TMS produces substantial distance-dependent off-target effects. In addition to monitoring corticospinal responses in off-target muscles to improve targeting accuracy in real-time, future studies may incorporate off-target information into statistical models post-hoc.

Use-dependent corticospinal excitability is associated with resilience and physical performance during simulated military operational stress.

Simulated military operational stress (SMOS) provides a useful model to better understand resilience in humans as the stress associated with caloric restriction, sleep deficits, and fatiguing exertion degrades physical and cognitive performance. Habitual physical activity may confer resilience against these stressors by promoting favorable use-dependent neuroplasticity, but it is unclear how physical activity, resilience, and corticospinal excitability (CSE) relate during SMOS. To examine associations between corticospinal excitability, physical activity, and physical performance during SMOS. Fifty-three service members (age: 26 ± 5 yr, 13 women) completed a 5-day and -night intervention composed of familiarization, baseline, SMOS (2 nights/days), and recovery days. During SMOS, participants performed rigorous physical and cognitive activities while receiving half of normal sleep (two 2-h blocks) and caloric requirements. Lower and upper limb CSE were determined with transcranial magnetic stimulation (TMS) stimulus-response curves. Self-reported resilience, physical activity, military-specific physical performance (TMT), and endocrine factors were compared in individuals with high (HIGH) and low CSE based on a median split of lower limb CSE at baseline. HIGH had greater physical activity and better TMT performance throughout SMOS. Both groups maintained physical performance despite substantial psychophysiological stress. Physical activity, resilience, and TMT performance were directly associated with lower limb CSE. Individual differences in physical activity coincide with lower (but not upper) limb CSE. Such use-dependent corticospinal excitability directly relates to resilience and physical performance during SMOS. Future studies may use noninvasive neuromodulation to clarify the interplay among CSE, physical activity, and resilience and improve physical and cognitive performance.NEW & NOTEWORTHY We demonstrate that individual differences in physical activity levels coincide with lower limb corticospinal excitability. Such use-dependent corticospinal excitability directly relates to resilience and physical performance during a 5-day simulation of military operational stress with caloric restriction, sleep restriction and disruption, and heavy physical and cognitive exertion.

Reliability of corticospinal excitability estimates for the vastus lateralis: Practical considerations for lower limb TMS task selection.

Transcranial magnetic stimulation (TMS) is increasingly used to examine lower extremity corticospinal excitability (CSE) in clinical and sports research. Because CSE is task-specific, there is growing emphasis on the use of ecological tasks. Nevertheless, the comparative reliability of CSE measurements during established (e.g. knee extensions; KE) and more recent ecological (e.g. squats; SQT) lower extremity tasks has received less attention. The aim of this study was to compare the test-retest reliability of CSE, force, and muscle activity (EMG) during isometric SQT and KE. 19 right-footed men (age: 25 ± 5 yrs) with similar fitness and body composition performed SQT (N = 7) or KE (N = 12) on two consecutive days. Force and EMG were recorded during maximum voluntary isometric contractions (MVC). Corticospinal excitability was determined in the dominant leg during light (15% MVC) contractions based on motor evoked potential (MEP) stimulus-response-curves (SRC). Test-retest reliability, absolute agreement, and consistency were determined for force, EMG, and SRC MEP maximum (MEPMAX) and rising phase midpoint (V50). As a secondary analysis, all outcomes were compared between groups with mixed-methods ANCOVAs (Task × Time, covariate: body-fat-percentage). Compared with SQT, KE displayed better test-retest reliability and agreement for MEPMAX whereas V50, force, and EMG were similarly reliable. Force (p = 0.01) and MEPMAX (p = 0.02) were also greater during KE despite a similar V50 (p = 0.11). Differences in test-retest reliability, absolute agreement, and between-group comparisons highlight the need to carefully select lower limb TMS assessment tasks and encourage future efforts to balance ecological validity with statistical sensitivity.

Cognitive deficits in multiple sclerosis patients with cerebellar symptoms.

BACKGROUND: Cerebellar dysfunction is common in patients with multiple sclerosis (MS). However, neuropsychological studies of this clinical feature are lacking. OBJECTIVE: We investigate the neuropsychological features in relapsing-remitting MS (RR-MS) patients with and without cerebellar dysfunction. METHODS: Twenty-one RR-MS patients with cerebellar dysfunction (RR-MSc), characterized by prevalent ataxic gait and nystagmus, and 21 RR-MS patients without any cerebellar manifestation (RR-MSnc) pair-matched for demographical and clinical variables were studied. All patients from each group underwent an extensive battery of neuropsychological tests. Magnetic resonance imaging analysis included hyperintense fast fluid-attenuated inversion-recovery lesion load in the whole brain as well as in the four lobes separately. RESULTS: Any significant differences were detected in total and regional lesion load measurements between the two groups. RR-MSc group performed equally as well as the RR-MSnc group on many of the cognitive exploration measures. Nevertheless, the RR-MSc group performed more poorly than the RR-MSnc group on attention tests (Symbol Digit Modalities Test) and verbal fluency tests (Controlled Oral Word Association Test); neither of the test results proved to be affected by regional lesion loads. CONCLUSION: These results highlight the importance of considering cognitive deficits associated with the presence of cerebellar symptoms in RR-MS.

CASP-9: A susceptibility locus for multiple sclerosis in Italy.

Caspase-9 is a primary effector CASP that executes programmed cell death, which plays an important role in the development of multiple sclerosis (MS). Polymorphisms in the CASP-9 gene may influence its activity, thereby modulating the susceptibility to MS. To test this hypothesis, we evaluated a SNP in the CASP-9 gene in a set of Italian patients from Southern Italy and healthy control subjects. Our results suggest that the presence of the G/G genotype represents a higher risk factor in our MS population and a differential production of CASP-9 might be a contributory factor in determining the severity of MS.

Evidence for positive selection at the pantophysin (Pan I) locus in walleye pollock, Theragra chalcogramma.

Nucleotide polymorphism at the pantophysin (Pan I) locus in walleye pollock, Theragra chalcogramma, was examined using DNA sequence data. Two distinct allelic lineages were detected in pollock, resulting from three amino acid replacement mutations in the first intravesicular domain of the protein. The common Pan I allelic group, comprising 94% of the samples, was less polymorphic (pi = 0.005) than the uncommon group (pi = 0.008), and nucleotide diversity in both was higher than for two allelic lineages in the related Atlantic cod, Gadus morhua. Phylogenetic analyses of Pan I sequences from these two species did not clearly resolve orthology among allelic groups, in part because of recombination that has occurred between the two pollock lineages. Conventional tests of neutrality comparing polymorphisms within and between homologous regions of the Pan I locus in walleye pollock and Atlantic cod did not detect the effects of selection. This result is likely attributed to low levels of synonymous divergence among allelic lineages and a lack of mutation-drift equilibrium inferred from nucleotide mismatch frequency distributions. However, the ratio of nonsynonymous to synonymous substitutions per site (dN/dS) exceeded unity in two intravesicular domains of the protein and the influence of positive selection at multiple codon sites was strongly inferred through the use of maximum-likelihood analyses. In addition, the frequency spectrum of linked neutral variation showed indirect effects of adaptive hitchhiking in pollock resulting from a selective sweep of the common allelic lineage. Recombination between the two allelic classes may have prevented complete loss of the older, more polymorphic lineage. The results suggest that recurrent sweeps driven by positive selection is the principle mode of evolution at the Pan I locus in gadid fishes.

Inverse relationship between F and microsatellite polymorphism in the marine fish, walleye pollock (Theragra chalcogramma): implications for resolving weak population structure.

Microsatellites have proved to be useful for the detection of weak population structure in marine fishes and other species characterized by large populations and high gene flow. None the less, uncertainty remains about the net effects of the particular mutational properties of these markers, and the wide range of locus polymorphism they exhibit, on estimates of differentiation. We examined the effect of varying microsatellite polymorphism on the magnitude of observed differentiation in a population survey of walleye pollock, Theragra chalcogramma. Genetic differentiation at 14 microsatellite loci among six putative populations from across the North Pacific Ocean and Bering Sea was weak but significant on large geographical scales and conformed to an isolation-by-distance pattern. A negative relationship was found between locus variability and the magnitude of estimated population subdivision. Estimates of F(ST) declined with locus polymorphism, resulting in diminished power to discriminate among samples, and we attribute this loss to the effects of size homoplasy. This empirical result suggests that mutation rates of some microsatellite loci are sufficiently high to limit resolution of weak genetic structure typical of many marine fishes.