Protocol for mapping of the supplementary motor area using repetitive navigated transcranial magnetic stimulation

BackgroundDamage to the supplementary motor area (SMA) can lead to impairments of motor and language function. A detailed preoperative mapping of functional boarders of the SMA could therefore aid preoperative diagnostics in these patients.ObjectiveThe aim of this study was the development of a repetitive nTMS protocol for non-invasive functional mapping of the SMA while assuring effects are caused by SMA rather than M1 activation.MethodsThe SMA in the dominant hemisphere of 12 healthy subjects (28.2 ± 7.7 years, 6 females) was mapped using repetitive nTMS at 20 Hz (120% RMT), while subjects performed a finger tapping task. Reductions in finger taps were classified in three error categories (≤15% = no errors, 15–30% = mild, >30% significant). The location and category of induced errors was marked in each subject’s individual MRI. Effects of SMA stimulation were then directly compared to effects of M1 stimulation in four different tasks (finger tapping, writing, line tracing, targeting circles).ResultsMapping of the SMA was possible for all subjects, yet effect sizes varied. Stimulation of the SMA led to a significant reduction of finger taps compared to baseline (BL: 45taps, SMA: 35.5taps; p < 0.01). Line tracing, writing and targeting of circles was less accurate during SMA compared to M1 stimulation.ConclusionMapping of the SMA using repetitive nTMS is feasible. While errors induced in the SMA are not entirely independent of M1, disruption of the SMA induces functionally distinct errors. These error maps can aid preoperative diagnostics in patients with SMA related lesions

Mapping of the supplementary motor area using repetitive navigated transcranial magnetic stimulation

Background: The supplementary motor area (SMA) is important for motor and language function. Damage to the SMA may harm these functions, yet tools for a preoperative assessment of the area are still sparse. Objective: The aim of this study was to validate a mapping protocol using repetitive navigated transcranial magnetic stimulation (rnTMS) and extend this protocol for both hemispheres and lower extremities. Methods: To this purpose, the SMA of both hemispheres were mapped based on a finger tapping task for 30 healthy subjects (35.97 ± 15.11, range 21–67 years; 14 females) using rnTMS at 20 Hz (120% resting motor threshold (RMT)) while controlling for primary motor cortex activation. Points with induced errors were marked on the corresponding MRI. Next, on the identified SMA hotspot a bimanual finger tapping task and the Nine-Hole Peg Test (NHPT) were performed. Further, the lower extremity was mapped at 20 Hz (140%RMT) using a toe tapping task. Results: Mean finger tapping scores decreased significantly during stimulation (25.70taps) compared to baseline (30.48; p < 0.01). Bimanual finger tapping led to a significant increase in taps during stimulation (28.43taps) compared to unimanual tapping (p < 0.01). Compared to baseline, completion time for the NHPT increased significantly during stimulation (baseline: 13.6 s, stimulation: 16.4 s; p < 0.01). No differences between hemispheres were observed. Conclusion: The current study validated and extended a rnTMS based protocol for the mapping of the SMA regarding motor function of upper and lower extremity. This protocol could be beneficial to better understand functional SMA organisation and improve preoperative planning in patients with SMA lesions

Protocol for mapping of the supplementary motor area using repetitive navigated transcranial magnetic stimulation

Background: Damage to the supplementary motor area (SMA) can lead to impairments of motor and language function. A detailed preoperative mapping of functional boarders of the SMA could therefore aid preoperative diagnostics in these patients. Objective: The aim of this study was the development of a repetitive nTMS protocol for non-invasive functional mapping of the SMA while assuring effects are caused by SMA rather than M1 activation. Methods: The SMA in the dominant hemisphere of 12 healthy subjects (28.2 +/- 7.7 years, 6 females) was mapped using repetitive nTMS at 20 Hz (120% RMT), while subjects performed a finger tapping task. Reductions in finger taps were classified in three error categories (30% significant). The location and category of induced errors was marked in each subject's individual MRI. Effects of SMA stimulation were then directly compared to effects of M1 stimulation in four different tasks (finger tapping, writing, line tracing, targeting circles). Results: Mapping of the SMA was possible for all subjects, yet effect sizes varied. Stimulation of the SMA led to a significant reduction of finger taps compared to baseline (BL: 45taps, SMA: 35.5taps; p < 0.01). Line tracing, writing and targeting of circles was less accurate during SMA compared to M1 stimulation. Conclusion: Mapping of the SMA using repetitive nTMS is feasible. While errors induced in the SMA are not entirely independent of M1, disruption of the SMA induces functionally distinct errors. These error maps can aid preoperative diagnostics in patients with SMA related lesions

Low-frequency repetitive transcranial magnetic stimulation in patients with motor deficits after brain tumor resection: a randomized, double-blind, sham-controlled trial

ObjectiveSurgical resection of motor eloquent tumors poses the risk of causing postoperative motor deficits which leads to reduced quality of life in these patients. Currently, rehabilitative procedures are limited with physical therapy being the main treatment option. This study investigated the efficacy of repetitive navigated transcranial magnetic stimulation (rTMS) for treatment of motor deficits after supratentorial tumor resection.MethodsThis randomized, double-blind, sham-controlled trial (DRKS00010043) recruited patients with a postoperatively worsened upper extremity motor function immediately postoperatively. They were randomly assigned to receive rTMS (1Hz, 110% RMT, 15 minutes, 7 days) or sham stimulation to the motor cortex contralateral to the injury followed by physical therapy. Motor and neurological function as well as quality of life were assessed directly after the intervention, one month and three months postoperatively.ResultsThirty patients were recruited for this study. There was no significant difference between both groups in the primary outcome, the Fugl Meyer score three months postoperatively [Group difference (95%-CI): 5.05 (-16.0; 26.1); p=0.631]. Patients in the rTMS group presented with better hand motor function one month postoperatively. Additionally, a subgroup of patients with motor eloquent ischemia showed lower NIHSS scores at all timepoints.ConclusionsLow-frequency rTMS facilitated the recovery process in stimulated hand muscles, but with limited generalization to other functional deficits. Long-term motor deficits were not impacted by rTMS. Given the reduced life expectancy in these patients a shortened recovery duration of deficits can still be of high significance.Clinical Trial Registrationhttps://drks.de/DRKS00010043

Safety and Tolerability of Accelerated Low-Frequency Repetitive Transcranial Magnetic Stimulation Over the Primary Motor Cortex–A Pilot Study

Low-frequency repetitive transcranial magnetic stimulation (rTMS) is capable of inducing changes in the functional organization of underlying brain regions, however, often at the cost of long stimulation protocols over several weeks. As these protocols can be difficult to implement in clinical settings, the aim of the present pilot study was to show the feasibility and safety of an accelerated low-frequency rTMS protocol applying multiple sessions daily. To this purpose, nine healthy subjects received 14 sessions of rTMS (1 Hz, 30 min, 110% RMT) to the hand motor hotspot. Subjects received stimulation for either 14 days once daily [classical rTMS (c-rTMS)], 7 days twice daily (accelerated rTMS; a-rTMS), or sham stimulation for 14 days once daily (s-rTMS). Daily stimulation sessions in the a-rTMS group were delivered with a 90-min break in between. In total, 74% of rTMS sessions in the c-rTMS group, 89% in the a-rTMS group, and 98% in the s-rTMS group were free of any side effects. Brief headaches and fatigue in stimulated muscle groups were the most frequent side effects. All side effects were reported to be at maximum mild and of short duration. Thus, accelerated low-frequency rTMS of the motor cortex seems to be a safe and feasible method, previously shown to induce a functional reorganization of the motor system. By shortening treatment duration in days, this approach can potentially make rTMS protocols more accessible to a wider range of patients.Peer Reviewe

No Impact of Functional Connectivity of the Motor System on the Resting Motor Threshold: A Replication Study

The physiological mechanisms of corticospinal excitability and factors influencing its measurement with transcranial magnetic stimulation are still poorly understood. A recent study reported an impact of functional connectivity (FC) between the primary motor cortex (M1) and the dorsal premotor cortex (PMd) on the resting motor threshold (RMT) of the dominant hemisphere. We aimed to replicate these findings in a larger sample of 38 healthy right-handed subjects with data from both hemispheres. Resting-state FC was assessed between the M1 and five a priori defined motor-relevant regions on each hemisphere as well as interhemispherically between both primary motor cortices. Following the procedure by the original authors, we included age, cortical gray matter volume, and coil-to-cortex distance (CCD) as further predictors in the analysis. We report replication models for the dominant hemisphere as well as an extension to data from both hemispheres and support the results with Bayes factors. FC between the M1 and the PMd did not explain the variability in the RMT, and we obtained moderate evidence for the absence of this effect. In contrast, CCD could be confirmed as an important predictor with strong evidence. These findings contradict the previously proposed effect, thus questioning the notion of the PMd playing a major role in modifying corticospinal excitability

Low-frequency repetitive transcranial magnetic stimulation in patients with motor deficits after brain tumor resection: a randomized, double-blind, sham-controlled trial

Objective: Surgical resection of motor eloquent tumors poses the risk of causing postoperative motor deficits which leads to reduced quality of life in these patients. Currently, rehabilitative procedures are limited with physical therapy being the main treatment option. This study investigated the efficacy of repetitive navigated transcranial magnetic stimulation (rTMS) for treatment of motor deficits after supratentorial tumor resection. Methods: This randomized, double-blind, sham-controlled trial (DRKS00010043) recruited patients with a postoperatively worsened upper extremity motor function immediately postoperatively. They were randomly assigned to receive rTMS (1Hz, 110% RMT, 15 minutes, 7 days) or sham stimulation to the motor cortex contralateral to the injury followed by physical therapy. Motor and neurological function as well as quality of life were assessed directly after the intervention, one month and three months postoperatively. Results: Thirty patients were recruited for this study. There was no significant difference between both groups in the primary outcome, the Fugl Meyer score three months postoperatively [Group difference (95%-CI): 5.05 (-16.0; 26.1); p=0.631]. Patients in the rTMS group presented with better hand motor function one month postoperatively. Additionally, a subgroup of patients with motor eloquent ischemia showed lower NIHSS scores at all timepoints. Conclusions: Low-frequency rTMS facilitated the recovery process in stimulated hand muscles, but with limited generalization to other functional deficits. Long-term motor deficits were not impacted by rTMS. Given the reduced life expectancy in these patients a shortened recovery duration of deficits can still be of high significance. Clinical Trial Registration: https://drks.de/DRKS00010043.Peer Reviewe

Factors of Cortical Plasticity in Brachial Plexus Injury

Cortical plasticity is the brain’s capability of decoding new information through growth and reorganization over our whole life spam. It is the basis for good outcomes after reinnervation and for rehabilitation of adult and obstetric brachial plexus injury. Knowledge about cortical reorganization is crucial to reconstructive surgeons and physiotherapists that aim to give their patients a reasonable prognosis. This chapter intends to present and summarize the current literature on how to detect and quantify cortical plasticity and how research on factors that influence cortical plasticity, mainly in relation to peripheral nerve and more precise brachial plexus injury progresses. Peculiarities of adult and obstetric brachial plexus injuries and their treatment are given. We present techniques that visualize and quantify cortical plasticity with focus on functional imaging like fMRI and nTMS as well as molecular aspects. Future research is needed to understand mechanisms of how molecular changes on a synaptic level of a neuron influence the macroscopic plasticity, to improve rehabilitative resources, to understand the exact prognostic value of nTMS in brachial plexus injury and to investigate the therapeutic capability of rTMS

Inflammatory Activity of Epithelial Stem Cell Variants from Cystic Fibrosis Lungs Is Not Resolved by CFTR Modulators

Rationale CFTR (cystic fibrosis transmembrane conductance regulator) modulator drugs restore function to mutant channels in patients with cystic fibrosis (CF) and lead to improvements in body mass index and lung function. Although it is anticipated that early childhood treatment with CFTR modulators will significantly delay or even prevent the onset of advanced lung disease, lung neutrophils and inflammatory cytokines remain high in patients with CF with established lung disease despite modulator therapy, underscoring the need to identify and ultimately target the sources of this inflammation in CF lungs. Objectives To determine whether CF lungs, like chronic obstructive pulmonary disease (COPD) lungs, harbor potentially pathogenic stem cell “variants” distinct from the normal p63/Krt5 lung stem cells devoted to alveolar fates, to identify specific variants that might contribute to the inflammatory state of CF lungs, and to assess the impact of CFTR genetic complementation or CFTR modulators on the inflammatory variants identified herein. Methods Stem cell cloning technology developed to resolve pathogenic stem cell heterogeneity in COPD and idiopathic pulmonary fibrosis lungs was applied to end-stage lungs of patients with CF (three homozygous CFTR:F508D, one CFTR F508D/L1254X; FEV1, 14–30%) undergoing therapeutic lung transplantation. Single-cell–derived clones corresponding to the six stem cell clusters resolved by single-cell RNA sequencing of these libraries were assessed by RNA sequencing and xenografting to monitor inflammation, fibrosis, and mucin secretion. The impact of CFTR activity on these variants after CFTR gene complementation or exposure to CFTR modulators was assessed by molecular and functional studies. Measurements and Main Results End-stage CF lungs display a stem cell heterogeneity marked by five predominant variants in addition to the normal lung stem cell, of which three are proinflammatory both at the level of gene expression and their ability to drive neutrophilic inflammation in xenografts in immunodeficient mice. The proinflammatory functions of these three variants were unallayed by genetic or pharmacological restoration of CFTR activity. Conclusions The emergence of three proinflammatory stem cell variants in CF lungs may contribute to the persistence of lung inflammation in patients with CF with advanced disease undergoing CFTR modulator therapy

Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of diseas