BDNF polymorphism and inter hemispheric balance of motor cortex excitability: a preliminary study

Preclinical studies have demonstrated that Brain-Derived Neurotrophic Factor (BDNF) plays a crucial role in the homeostatic regulation of cortical excitability and excitation/inhibition balance. Using transcranial magnetic stimulation (TMS) techniques we investigated whether BDNF polymorphism could influence cortical excitability of the left and right primary motor cortex in healthy humans. Twenty-nine participants were recruited and genotyped for the presence of the BDNF Val66Met polymorphism, namely homozygous for the valine allele (Val/Val), heterozygotes (Val/Met), and homozygous for the methionine allele (Met/Met). Blinded to the latter, we evaluated inhibitory and facilitatory circuits of the left (LH) and right motor cortex (RH) by measuring resting (RMT) and active motor threshold (AMT), short interval intracortical inhibition (SICI) and intracortical facilitation (ICF). For each neurophysiological metric we also considered the inter-hemispheric balance expressed by the Laterality Index (LI). Val/Val participants (n= 21) exhibited an overall higher excitability of the LH compared to the RH, as probed by lower motor thresholds, lower SICI and higher ICF. Val/Val participants displayed positive LI, especially for AMT and ICF (all p< 0.05), indicating higher LH excitability and more pronounced inter-hemispheric excitability imbalance as compared to Met carriers. Our preliminary results suggest that BDNF Val66Met polymorphism might influence interhemispheric balance of motor cortex excitability.

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 &lt; 0.001]. SCAT5 measures of symptom number and severity were significantly decreased [symptom number: χ(3)2 = 30.44, p &lt; 0.01; symptom severity: χ(3)2 = 25.75, p &lt; 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 &lt; 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.

Effects of low-frequency repetitive transcranial magnetic stimulation in adductor laryngeal dystonia: a safety, feasibility, and pilot study

Purpose The effects of neuromodulation are virtually unexplored in adductor laryngeal dystonia (AdLD), a disorder characterized by involuntary contraction of intrinsic laryngeal muscles. Recent findings indicated that intracortical inhibition is reduced in people with AdLD. Low-frequency repetitive transcranial magnetic stimulation (rTMS) induces prolonged intracortical inhibition, but the effects in AdLD are unexplored. This pilot and feasibility study aimed to examine the safety, feasibility, and effects of a single session 1 Hz rTMS over the laryngeal motor cortex (LMC) in people with AdLD and healthy individuals. Methods The stimulation location was individualized and determined through TMS-evoked responses in the thyroarytenoid muscles using fine-wire electrodes. 1200 pulses of 1 Hz rTMS were delivered to the left LMC in two groups: Control (n = 6) and AdLD (n = 7). Tolerance, adverse effects, intracortical inhibition, and voice recordings were collected immediately before and after rTMS. Voice quality was assessed with acoustic-based and auditory-perceptual measures. Results All participants tolerated the procedures, with no unexpected adverse events or worsening of symptoms. No significant effects on intracortical inhibition were observed. In the AdLD group, there was a large-effect size after rTMS in vocal perturbation measures and a small-effect size in decreased phonatory breaks. Conclusions One rTMS session over the LMC is safe and feasible, and demonstrated trends of beneficial effects on voice quality and phonatory function in AdLD. These preliminary findings support further investigation to assess clinical benefits in a future randomized sham-controlled trial. ClinicalTrials.gov NCT02957942, registered on November 8, 2016.

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.

Neurophysiological Predictors of Response to Medication in Parkinson's Disease

Background: Although dopaminergic medication has been the foundation of Parkinson's disease (PD) therapy for decades, sensitive and specific therapeutic response biomarkers that allow for better treatment optimization are lacking.Objective: We tested whether the features of Transcranial Magnetic Stimulation-based neurophysiological measures taken off-medication are associated with dopaminergic medication-induced clinical effects.Method: Motor cortex excitability [short-latency intracortical inhibition (SICI), intracortical facilitation (ICF), short-latency afferent inhibition (SAI), and input-output (IO) curve], and plasticity [paired associative stimulation (PAS) protocol] neurophysiological measures were examined in 23 PD patients off-medication. Clinical features were quantified by the motor section of the Unified Parkinson's Disease Scale (total score and lateralized total, bradykinesia, and rigidity sub-scores), and the differences between measures off-medication and on-medication (following the usual morning dose), were determined. Total daily dopaminergic medication dose (expressed as levodopa equivalent daily dose-LEDD), was also determined.Results: SICI significantly correlated with changes in lateralized UPDRS motor and bradykinesia sub-scores, suggesting that patients with stronger basal intracortical inhibition benefit more from dopaminergic treatment than patients with weaker intracortical inhibition. Also, ICF significantly negatively correlated with LEDD, suggesting that patients with stronger intracortical facilitation require less dopaminergic medication to achieve optimal therapeutic benefit. Both associations were independent of disease severity and duration.Conclusions: The results suggest variability of (patho) physiological phenotypes related to intracortical inhibitory and facilitatory mechanisms determining clinical response to dopaminergic medication in PD. Measures of intracortical excitability may help predict patients' response to dopaminergic therapy, thus potentially providing a background for developing personalized therapy in PD.

Short-interval intracortical inhibition and facilitation targeting upper and lower limb muscles

Transcranial magnetic stimulation (TMS) can be used to study excitability of corticospinal neurons in human motor cortex. It is currently not fully elucidated if corticospinal neurons in the hand vs. leg representation show the same or different regulation of their excitability by GABAAergic and glutamatergic interneuronal circuitry. Using a paired-pulse TMS protocol we tested short-interval intracortical inhibition (SICI) and short-interval intracortical facilitation (SICF) in 18 healthy participants. Motor evoked potentials were evoked in one hand (abductor digiti minimi) and one leg muscle (tibialis anterior), with systematic variation of the intensities of the first (S1) and second (S2) pulse between 60 and 140% resting motor threshold (RMT) in 10% steps, at two interstimulus intervals of 1.5 and 2.1 ms. For the hand and leg motor representations and for both interstimulus intervals, SICI occurred if the intensities of S1 < RMT and S2 > RMT, while SICF predominated if S1 = S2 ≤ RMT, or S1 > RMT and S2 < RMT. Findings confirm and extend previous evidence that the regulation of excitability of corticospinal neurons of the hand versus leg representation in human primary cortex through GABAAergic and glutamatergic interneuronal circuits is highly similar, and that corticospinal neurons of both representations are activated by TMS transsynaptically in largely identical ways.