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.

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.

Phase I clinical trial of a recombinant canarypoxvirus (ALVAC) vaccine expressing human carcinoembryonic antigen and the B7.1 co-stimulatory molecule.

The generation of cytotoxic effector T cells requires delivery of two signals, one derived from a specific antigenic epitope and one from a costimulatory molecule. A phase I clinical trial was conducted with a non-replicating canarypoxvirus (ALVAC) constructed to express both human carcinoembryonic antigen (CEA) and the B7.1 costimulatory molecule. This was the first study in cancer patients to determine if the delivery of costimulation with a tumor vaccine was feasible and improved immune responses. Three cohorts of six patients, each with advanced CEA-expressing adenocarcinomas, were treated with increasing doses of an ALVAC-CEA-B7.1 vaccine (4.5 x 10(6), 4.5 x 10(7), and 4.5 x 10(8) plaque-forming units, PFU). Patients were vaccinated by intramuscular injection every 4 weeks for 3 months and monitored for side-effects, tumor growth and anti-CEA immune responses. ALVAC-CEA-B7.1 at doses up to 4.5 x 10(8) PFU was given without evidence of significant toxicity or autoimmune reactions. Three patients experienced clinically stable disease that correlated with increasing CEA-specific precursor T cells, as shown by in vitro interferon-gamma enzyme-linked immunoassay spot tests (ELISPOT). These three patients underwent repeated vaccination resulting in augmented CEA-specific T cell responses. This study represents the first use of costimulation to enhance antitumor vaccines in cancer patients. This approach resulted in CEA-specific immunity associated with stable diseases in three patients. This study also demonstrated that CEA-specific T cell responses could be sustained by repeated vaccinations. Although the number of patients was small, the addition of B7.1 to virus-based vaccines may improve immunological and stable diseases to vaccination against tumor-associated antigens with tolerable toxicity.

Strategies for cancer therapy using carcinoembryonic antigen vaccines.

Advances in molecular biology and immunology have renewed interest in the development of vaccines for the treatment or prevention of cancer. Research over the past 10 years has focused on the identification of suitable tumour antigens to use as targets for a variety of vaccine strategies. Carcinoembryonic antigen (CEA) was one of the first tumour antigens described, and is commonly expressed by a wide range of adenocarcinomas. Recent studies have identified several human-leukocyte-antigen-restricted epitopes (short peptides) within the CEA protein that can be recognised by human T lymphocytes (T cells). Although CEA-expressing tumour cells are generally weakly recognised by the immune system, several new strategies have been used to enhance immune responses against CEA. This includes using antibodies directed against CEA; inserting the CEA gene into recombinant viruses and bacteria as viral and bacterial vaccines; pulsing the CEA protein, peptides, DNA or RNA onto dendritic cells (specialised antigen-presenting cells); and combining CEA vaccines with cytokines or co-stimulatory molecules to increase vaccine effectiveness. Other factors that might be important in establishing systemic immunity against CEA are the dose, route, timing, and choice of vector and adjuvants for vaccine administration. Further research in understanding the fundamental processes involved in tumour-cell recognition by the immune system, better animal models, and improved clinical trial designs will help to define the full potential of CEA as a target for cancer vaccine development.