Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of the motor neurons in the motor cortex, brainstem and spinal cord. A combination of upper and lower motor neuron dysfunction comprises the clinical ALS phenotype. Although the ALS phenotype was first observed by Charcot over 100 years ago, the site of ALS onset and the pathophysiological mechanisms underlying the development of motor neuron degeneration remain to be elucidated. Transcranial magnetic stimulation (TMS) enables non-invasive assessment of the functional integrity of the motor cortex and its corticomotoneuronal projections. To date, TMS studies have established motor cortical and corticospinal dysfunction in ALS, with cortical hyperexcitability being an early feature in sporadic forms of ALS and preceding the clinical onset of familial ALS. Taken together, a central origin of ALS is supported by TMS studies, with an anterograde transsynaptic mechanism implicated in ALS pathogenesis. Of further relevance, TMS techniques reliably distinguish ALS from mimic disorders, despite a compatible peripheral disease burden, thereby suggesting a potential diagnostic utility of TMS in ALS. This review will focus on the mechanisms underlying the generation of TMS measures used in assessment of cortical excitability, the contribution of TMS in enhancing the understanding of ALS pathophysiology and the potential diagnostic utility of TMS techniques in ALS.

Altered cortical beta‐band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis

“…Direct evidence of cortical hyperexcitability in ALS was provided by TMS [Vucic et al, 2013b]. Conditioning pulse protocols have reliably demonstrated reduced intracortical inhibition as a characteristic feature of ALS [Menon et al, 2015; Yokota et al, 1996; Ziemann et al, 1997], which may be partly ameliorated by reducing glutamatergic influence through administration of Riluzole—the only licensed disease‐modifying therapy in ALS [Stefan et al, 2001; Vucic et al, 2013a].…”

“…Abnormal increased functional connectivity has been demonstrated within specific cortical subregions [Agosta et al, 2013; Douaud et al, 2011; Zhou et al, 2014], perhaps underpinned by cortical hyperexcitability. This potentially pathogenic mechanism is also implicated by abnormal responses to transcranial magnetic stimulation (TMS) [Vucic et al, 2013b], which may reflect loss of cortical inhibitory interneuronal influences [Turner and Kiernan, 2012; Turner et al, 2005a, 2005b]. …”

Transcranial Magnetic Stimulation for the Assessment of Neurodegenerative Disease

“…Although the precise identity of neural circuits activated by TMS remains to be elucidated [10], it has been determined that TMS stimulates the motor cortex at a depth of 1.5 to 2.1 cm [11]. Animal studies have suggested that cortical stimulation results in generation of a complex corticomotoneuronal volley composed of direct (D) waves and multiple indirect (I) waves ( Fig.…”

Clinical Measures of Disease Progression in Amyotrophic Lateral Sclerosis

“…However, in the early 1990s, several studies showed that cortical excitability was altered in ALS by the use of transcranial magnetic stimulation (TMS) [69][70][71]. Many studies since then have been pursued, and a number of measures appear to be altered in ALS, including motor threshold (generally reduced early in the disease, supporting the presence of increased excitability), motor-evoked potential (generally also increased early in the disease), central motor conduction time (generally prolonged in the disease), and cortical silent period (reduced in the disease) [72]. While such differences in ALS are identifiable, how well each tracks disease progression is less well studied.…”