Modulation of Cortical Inhibition by Lovastatin in Neurofibromatosis Type 1: A Randomized, Triple-Blind, Placebo-Controlled Clinical Trial

Neurofibromatosis type 1 (NF1) is associated with GABAergic dysfunction which has been suggested as the underlying cause of cognitive impairments. Previous intervention trials investigated the statins’ effects using cognitive outcome measures. However, available outcome measures have led to inconclusive results and there is a need to identify other options. Here, we aimed at investigating alternative outcome measures in a feasibility trial targeting cortical inhibition mechanisms known to be altered in NF1. We explored the neurochemical and physiological changes elicited by lovastatin, with magnetic resonance spectroscopy and transcranial magnetic stimulation (TMS). Fifteen NF1 adults participated in this randomized, triple-blind, placebo-controlled crossover trial (Clinicaltrials.gov NCT03826940) composed by one baseline and two reassessment visits after lovastatin/placebo intake (60mg/day, 3-days). Motor cortex GABA+ and Glx concentrations were measured using HERMES and PRESS sequences, respectively. Cortical inhibition was investigated by paired-pulse, input-output curve and cortical silent period (CSP) TMS protocols. CSP ratios were significantly increased by lovastatin (relative: p=0.027; absolute: p=0.034) but not by placebo. CSP durations showed a negative correlation with LICI 50ms amplitude ratio. Lovastatin was able to modulate cortical inhibition in NF1, as assessed by TMS CSP ratios, highlighting the potential of this outcome measure to be considered in future large-scale studies.

Competition, Conflict and Change of Mind: A Role of GABAergic Inhibition in the Primary Motor Cortex

Deciding between different voluntary movements implies a continuous control of the competition between potential actions. Many theories postulate a leading role of prefrontal cortices in this executive function, but strong evidence exists that a motor region like the primary motor cortex (M1) is also involved, possibly via inhibitory mechanisms. This was already shown during the pre-movement decision period, but not after movement onset. For this pilot experiment we designed a new task compatible with the dynamics of post-onset control to study the silent period (SP) duration, a pause in electromyographic activity after single-pulse transcranial magnetic stimulation that reflects inhibitory mechanisms. A careful analysis of the SP during the ongoing movement indicates a gradual increase in inhibitory mechanisms with the level of competition, consistent with an increase in mutual inhibition between alternative movement options. However, we also observed a decreased SP duration for high-competition trials associated with change-of-mind inflections in their trajectories. Our results suggest a new post-onset adaptive process that consists in a transient reduction of GABAergic inhibition within M1 for highly conflicting situations. We propose that this reduced inhibition softens the competition between concurrent motor options, thereby favoring response vacillation, an adaptive strategy that proved successful at improving behavioral performance.

Electrophysiological assessment of the cranial reflexes

Electrophysiological assessment methods play a key role in the diagnosis of various neurological disorders. Electrophysiological evaluation of cranial reflexes is particularly valuable for neurologists. This article provides an overview of electrophysiological evaluation methods for cranial reflexes, which are most commonly used in clinical practice. They provide objective assessment of the functional integrity of nervous system structures that make up the cranial reflex arc, identify the level and, in some cases, the nature of disease, as well as pathophysiological mechanisms of central and peripheral nervous system disorders. We describe the instruments and main approaches to analysing the results for the standard blink reflex, blink reflex with prepulse inhibition, blink reflex with paired stimuli and recovery curve evaluation, reflex inhibition of the levator palpebrae superioris, jaw jerk reflex, and reflex inhibition (cutaneous silent period) of the masseter muscle.

A Methodological Framework to Capture Neuromuscular Fatigue Mechanisms Under Stress

Neuromuscular fatigue is exacerbated under stress and is characterized by shorter endurance time, greater perceived effort, lower force steadiness, and higher electromyographic activity. However, the underlying mechanisms of fatigue under stress are not well-understood. This review investigated existing methods of identifying central mechanisms of neuromuscular fatigue and the potential mechanisms of the influence of stress on neuromuscular fatigue. We found that the influence of stress on the activity of the prefrontal cortex, which are also involved in exercise regulation, may contribute to exacerbated fatigue under stress. We also found that the traditional methods involve the synchronized use of transcranial magnetic stimulation, peripheral nerve stimulation, and electromyography to identify the contribution of supraspinal fatigue, through measures such as voluntary activation, motor evoked potential, and silent period. However, these popular techniques are unable to provide information about neural alterations upstream of the descending drive that may contribute to supraspinal fatigue development. To address this gap, we propose that functional brain imaging techniques, which provide insights on activation and information flow between brain regions, need to be combined with the traditional measures of measuring central fatigue to fully understand the mechanisms behind the influence of stress on fatigue.

Longer Neurophysiological vs. Clinical Recovery Following Sport Concussion

Objectives: The objective of this study was to assess if injury-related alterations in the Sport Concussion Assessment Tool-5 (SCAT5) are matched by changes in transcranial magnetic stimulation-derived intracortical inhibition. We hypothesised that neurophysiological measures would take longer to return to normal than recovery assessed by the SCAT5 following sport related concussion (SRC).Methods: Thirteen male contact sport athletes (20.5 ± 4.5 years), who reported a concussion were recruited from local Rugby and American football clubs. Participants were tested at 4 timepoints throughout the concussion recovery period: within 24 h of concussion (day 0), and at 7, 9, and 11 days after concussion. All participants completed the SCAT5 and underwent TMS to assess cortical silent period duration (CSp), a measure of intracortical inhibition.Results: After concussion CSp significantly declined from day 0 (122 ± 28 ms) to day 11 (106 ± 15 ms) [F(3, 33) = 7.80, p < 0.001]. SCAT5 measures of symptom number and severity were significantly decreased [symptom number: χ(3)2 = 30.44, p < 0.01; symptom severity: χ(3)2 = 25.75, p < 0.001] between the day 0 timepoint and each of the other timepoints. SCAT5 balance errors (mBESS) decreased significantly [F(3, 33) = 19.55, p < 0.001] between the day 0 timepoint and each of the other timepoints. CSp and SCAT5 recovery patterns were different. SCAT5 domains recovered faster showing no further significant changes after day 7, whilst CSp was still decreasing between days 7 and 9. Due to the small sample size we also used a Bayesian linear model to investigate the recovery of CSp and mBESS. The posterior distribution of our Bayesian model provided evidence that CSp decreased at day 7 and it continued to decrease at day 9, unlike mBESS which decreased at day 7 and then reached a plateau.Conclusion: There are clinically important discrepancies between clinical and neurophysiological measures of concussion recovery. This finding has important implications for return to play (RTP) protocols and the prevention of complications after sport concussion.

Submaximal isometric fatiguing exercise of the elbow flexors has no age-related effect on GABAB mediated inhibition

Age-related changes in the neuromuscular system can result in differences in fatigability between young and older adults. Previous research has shown that single joint isometric fatiguing exercise of small muscle results in an age-related compensatory decrease in GABAB mediated inhibition. However, this has yet to be established in a larger muscle group. In 15 young (22 ± 4 years) and 15 older (65 ± 5 years) adults, long interval cortical inhibition (LICI; 100 ms ISI) and corticospinal silent period (SP) were measured in the biceps brachii during a 5% EMG contraction using transcranial magnetic stimulation (TMS) before, during and after a submaximal contraction (30% MVC force) held intermittently to task failure. Both age groups developed similar magnitude of fatigue (~24% decline in MVC; P = 0.001) and ~28% decline in LICI (P = 0.001) post fatiguing exercise. No change in SP duration was observed during and immediately following fatigue (P = 0.909) but ~ 6% decrease was seen at recovery in both age groups (P<0.001)." Contrary to previous work in a small muscle, these findings suggest no age-related differences in GABAB mediated inhibition following single joint isometric fatiguing exercise of the elbow flexors, indicating that GABAB modulation with ageing may be muscle group dependent. Furthermore, variations in SP duration and LICI modulation during and post fatigue in both groups suggest that these measures are likely mediated by divergent mechanisms.

Increased motor cortex inhibition as a marker of compensation to chronic pain in knee osteoarthritis

This study aims to investigate the associative and multivariate relationship between different sociodemographic and clinical variables with cortical excitability as indexed by transcranial magnetic stimulation (TMS) markers in subjects with chronic pain caused by knee osteoarthritis (OA). This was a cross-sectional study. Sociodemographic and clinical data were extracted from 107 knee OA subjects. To identify associated factors, we performed independent univariate and multivariate regression models per TMS markers: motor threshold (MT), motor evoked potential (MEP), short intracortical inhibition (SICI), intracortical facilitation (ICF), and cortical silent period (CSP). In our multivariate models, the two markers of intracortical inhibition, SICI and CSP, had a similar signature. SICI was associated with age (β: 0.01), WOMAC pain (β: 0.023), OA severity (as indexed by Kellgren–Lawrence Classification) (β: − 0.07), and anxiety (β: − 0.015). Similarly, CSP was associated with age (β: − 0.929), OA severity (β: 6.755), and cognition (as indexed by the Montreal Cognitive Assessment) (β: − 2.106). ICF and MT showed distinct signatures from SICI and CSP. ICF was associated with pain measured through the Visual Analogue Scale (β: − 0.094) and WOMAC (β: 0.062), and anxiety (β: − 0.039). Likewise, MT was associated with WOMAC (β: 1.029) and VAS (β: − 2.003) pain scales, anxiety (β: − 0.813), and age (β: − 0.306). These associations showed the fundamental role of intracortical inhibition as a marker of adaptation to chronic pain. Subjects with higher intracortical inhibition (likely subjects with more compensation) are younger, have greater cartilage degeneration (as seen by radiographic severity), and have less pain in WOMAC scale. While it does seem that ICF and MT may indicate a more acute marker of adaptation, such as that higher ICF and MT in the motor cortex is associated with lesser pain and anxiety.