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 motorevoked 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.

Transcranial Magnetic and Direct Current Stimulation (TMS/tDCS) for the Treatment of Headache: A Systematic Review

“…4 For a comprehensive review of TMS technology, refer to Hallet et al 2 There are various protocols of TMS that can be used for different purposes, including single-pulse (sTMS), paired-pulse TMS, and repetitive (rTMS) stimulation. Of the repetitive stimulation modes, there is opportunity to stimulate at low frequency (1 Hz), high frequency (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) Hz), or extremely high frequency (50 Hz), defined as theta burst (TBS). TBS can be delivered in an intermittent (iTBS) or continuous (cTBS) manner.…”

An Appraisal of Novel Biomarkers for Evaluating and Monitoring Neurologic Diseases: Editorial Introduction

“…Given that abnormal excitability in axons and cell bodies has been suggested to be important in ALS, these techniques are currently being utilized in several clinical trials studying drugs expected to affect ion channels. Similar techniques are being used in motor cortex, where transcranial magnetic stimulation paradigms have been developed to evaluate corticomotor neuron excitability [12]. Finally, magnetoencephalography combined with complex imaging techniques is now assisting surgeons in efficiently planning epilepsy surgery [3].…”

Absence of subcerebral projection neurons delays disease onset and extends survival in a mouse model of ALS

“…While the origin of ALS remains a debated question [54], recent evidences from neurophysiological and pathological studies conducted on patients [6,67] are nourishing a revival of interest for Charcot's initial view of the disease as a primarily cortical impairment [11]. Indeed, whether disease propagation relies on altered neuronal excitability and subsequent excitotoxicity [67], or on prion-like propagation of misfolded proteins [5], both schools of thought converge to a common cortical origin of ALS and propagation along the corticofugal tracts [18,24]. While several clinical features support a cortical origin of the disease [19], and recent longitudinal imaging analyses suggest a propagation of impairments along the corticofugal tracts, [32,66], the hypothesis cannot be tested in patients.…”

“…Together, the two sets of data suggest that absence of diseased CSN or instead maintenance of genetically corrected CSN may be equally beneficial, and that Sod1/SOD1 mutant transgene-expressing CSN may be detrimental to their downstream targets. Yet, it is worth mentioning that AAV9 likely targeted all types cortical excitatory projection neurons and inhibitory interneurons, and could have contributed to correct more broadly the cortical circuit dysfunctions which have been reported in the Sod1 G93A and the TDP-43 A315T mouse models of ALS [33,73], and are reminiscent of the cortical hyperexcitability that characterizes ALS patients [67]. Future celltype specific genetic ablation experiments could further inform on the contribution of individual populations of neurons and glia to cortical circuit dysfunction and impairment on the downstream targets of the cerebral cortex.…”

“…Following Charcot's histological description of the disease, comprehensive clinical examination of ALS patients unravelled series of signs highly suggestive of a cortical origin of the disease, such as the split hand syndrome and typical gait abnormalities for instance [19]. Meanwhile, trans-cranial magnetic stimulation studies unravelled early hyperexcitability of the motor cortex that characterizes both sporadic and familial ALS patients, negatively correlates with survival, and manifests prior to disease onset, pointing to a potential role of the motor cortex in disease initiation [67]. Cortical hyperexcitability has been proposed to translate into glutamatergic excitotoxicity to the downstream targets of the corticospinal neurons, the alpha motoneurons of the brain stem and spinal cord, providing a first possible mechanism for corticospinal propagation [18].…”