Transcranial Magnetic Stimulation for the Assessment of Neurodegenerative Disease

Abstract

Transcranial magnetic stimulation (TMS) is a noninvasive technique that has provided important information about cortical function across an array of neurodegenerative disorders, including Alzheimer's disease, frontotemporal dementia, Parkinson's disease, and related extrapyramidal disorders. Application of TMS techniques in neurodegenerative diseases has provided important pathophysiological insights, leading to the development of pathogenic and diagnostic biomarkers that could be used in the clinical setting and therapeutic trials. Abnormalities of TMS outcome measures heralding cortical hyperexcitability, as evidenced by a reduction of short-interval intracortical inhibition and increased in motor-evoked potential amplitude, have been consistently identified as early and intrinsic features of amyotrophic lateral sclerosis (ALS), preceding and correlating with the ensuing neurodegeneration. Cortical hyperexcitability appears to form the pathogenic basis of ALS, mediated by trans-synaptic glutamate-mediated excitotoxic mechanisms. As a consequence of these research findings, TMS has been developed as a potential diagnostic biomarker, capable of identifying upper motor neuronal pathology, at earlier stages of the disease process, and thereby aiding in ALS diagnosis. Of further relevance, marked TMS abnormalities have been reported in other neurodegenerative diseases, which have varied from findings in ALS. With time and greater utilization by clinicians, TMS outcome measures may prove to be of utility in future therapeutic trial settings across the neurodegenerative disease spectrum, including the monitoring of neuroprotective, stem-cell, and genetic-based strategies, thereby enabling assessment of biological effectiveness at early stages of drug development.

Keywords: Amyotrophic lateral sclerosis; frontotemporal dementia; neurodegeneration; short interval intracortical inhibition; transcranial magnetic stimulation.

Figures

Fig. 1

Transcranial magnetic stimulation evokes a descending corticospinal volley composed of direct (D) and multiple indirect (I) waves. The resultant motor evoked potential (green curve) is recorded from a target muscle and is a biomarker of upper motor neuron function

Fig. 2

Threshold-tracking transcranial magnetic stimulation (TMS) technique (A) tracks a magnetic evoked potential (MEP) response of 0.2 mV (tracking target), which lies in the steepest portion of the stimulus response curve. (B) When the MEP amplitude is larger than the tracking target (a) the stimulus intensity is reduced, and conversely when the MEP amplitude is lower than the target (b) the stimulus is reduced. Consequently, inhibition is heralded by higher magnetic stimuli, while facilitation by lower stimuli. By setting the tracking target in the steepest portion of the stimulus–response curve, much larger variations in MEP amplitude translate to smaller variations in the stimulus intensity (the outcome variable). (C) Short-interval intracortical inhibition (SICI) is represented by the stimulus intensity (threshold) being above the zero line (dotted line) and has 2 distinct peaks at interstimulus interval 1 and 3 ms. Intracortical facilitation is heralded by the curve below zero (dotted line). RMT = resting motor threshold

Fig. 3

Short-interval intracortical inhibition is reduced in (A) sporadic amyotrophic lateral sclerosis (ALS) and (B) in familial ALS secondary to mutations in SOD1 and c9orf72

Fig. 4

Receiver–operator characteristic curve disclosed that averaged short-interval intracortical inhibition (SICI; between interstimulus interval 1–7 ms) is the most robust of the transcranial magnetic stimulation (TMS) outcome parameters in differentiating amyotrophic lateral sclerosis from mimicking diseases. Reduction in cortical silent period (CSP) duration is the second most robust biomarker followed by intracortical facilitation (ICF), motor-evoked potential (MEP) amplitude, and resting motor threshold (RMT). Central motor conduction time is least sensitive (not shown). The figure is adapted from [5]