Effects of repetitive TMS of the motor cortex on disease progression and on glutamate and GABA levels in ALS: A proof of principle study

Lazzaro, Vincenzo Di; Pellegrino, Giovanni; Ranieri, Federico; Florio, Lucia; Musumeci, Gabriella; Caulo, Massimo; Ferretti, Andrea; Capone, Fioravante

doi:10.1016/j.brs.2017.05.003

Cited by 16 publications

(9 citation statements)

References 9 publications

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“…Changes in metabolites were accompanied and associated with therapeutic effects. In amyotrophic lateral sclerosis, a study found no significant changes in GABA after bilateral cTBS ( Di Lazzaro et al, 2017 ). However, the authors found a relationship between GABA concentration increase and milder disease progression.…”

Section: Magnetic Resonance Spectroscopy Evaluation Of Repetitive Tra...mentioning

confidence: 99%

Insight Into the Effects of Clinical Repetitive Transcranial Magnetic Stimulation on the Brain From Positron Emission Tomography and Magnetic Resonance Imaging Studies: A Narrative Review

2022

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Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a therapeutic tool to alleviate symptoms for neurological and psychiatric diseases such as chronic pain, stroke, Parkinson’s disease, major depressive disorder, and others. Although the therapeutic potential of rTMS has been widely explored, the neurological basis of its effects is still not fully understood. Fortunately, the continuous development of imaging techniques has advanced our understanding of rTMS neurobiological underpinnings on the healthy and diseased brain. The objective of the current work is to summarize relevant findings from positron emission tomography (PET) and magnetic resonance imaging (MRI) techniques evaluating rTMS effects. We included studies that investigated the modulation of neurotransmission (evaluated with PET and magnetic resonance spectroscopy), brain activity (evaluated with PET), resting-state connectivity (evaluated with resting-state functional MRI), and microstructure (diffusion tensor imaging). Overall, results from imaging studies suggest that the effects of rTMS are complex and involve multiple neurotransmission systems, regions, and networks. The effects of stimulation seem to not only be dependent in the frequency used, but also in the participants characteristics such as disease progression. In patient populations, pre-stimulation evaluation was reported to predict responsiveness to stimulation, while post-stimulation neuroimaging measurements showed to be correlated with symptomatic improvement. These studies demonstrate the complexity of rTMS effects and highlight the relevance of imaging techniques.

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Section: Magnetic Resonance Spectroscopy Evaluation Of Repetitive Tra...mentioning

confidence: 99%

Insight Into the Effects of Clinical Repetitive Transcranial Magnetic Stimulation on the Brain From Positron Emission Tomography and Magnetic Resonance Imaging Studies: A Narrative Review

2022

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“…This finding was not replicated in a following trial in which the duration of cTBS treatment was extended to 12 months (90). Of note, in a further small study by the same group (93) in which the dosage of cTBS was doubled to 10 days/month, a tendency to a slower progression over 6 months was observed when comparing with pooled data of patients treated for 5 days/month and of "sham"-treated patients from the previous studies (88,90), even if it was not possible to demonstrate a reduction from baseline progression in this new patients' group (93). The other two studies with cTBS are small case series in which stimulation was delivered for a prolonged period of >2 years in one subject (91) or for a period of 1 year as an "open-label" extension study of previous trial in three subjects who had been observed for 1 year under placebo stimulation (92): in both cases, a reduction of ALSFRS-R score was observed in comparison with baseline observation.…”

Section: Repetitive Transcranial Magnetic Stimulationmentioning

confidence: 89%

Brain Stimulation as a Therapeutic Tool in Amyotrophic Lateral Sclerosis: Current Status and Interaction With Mechanisms of Altered Cortical Excitability

et al. 2021

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In the last 20 years, several modalities of neuromodulation, mainly based on non-invasive brain stimulation (NIBS) techniques, have been tested as a non-pharmacological therapeutic approach to slow disease progression in amyotrophic lateral sclerosis (ALS). In both sporadic and familial ALS cases, neurophysiological studies point to motor cortical hyperexcitability as a possible priming factor in neurodegeneration, likely related to dysfunction of both excitatory and inhibitory mechanisms. A trans-synaptic anterograde mechanism of excitotoxicity is thus postulated, causing upper and lower motor neuron degeneration. Specifically, motor neuron hyperexcitability and hyperactivity are attributed to intrinsic cell abnormalities related to altered ion homeostasis and to impaired glutamate and gamma aminobutyric acid gamma-aminobutyric acid (GABA) signaling. Several neuropathological mechanisms support excitatory and synaptic dysfunction in ALS; additionally, hyperexcitability seems to drive DNA-binding protein 43-kDA (TDP-43) pathology, through the upregulation of unusual isoforms directly contributing to ASL pathophysiology. Corticospinal excitability can be suppressed or enhanced using NIBS techniques, namely, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), as well as invasive brain and spinal stimulation. Experimental evidence supports the hypothesis that the after-effects of NIBS are mediated by long-term potentiation (LTP)-/long-term depression (LTD)-like mechanisms of modulation of synaptic activity, with different biological and physiological mechanisms underlying the effects of tDCS and rTMS and, possibly, of different rTMS protocols. This potential has led to several small trials testing different stimulation interventions to antagonize excitotoxicity in ALS. Overall, these studies suggest a possible efficacy of neuromodulation in determining a slight reduction of disease progression, related to the type, duration, and frequency of treatment, but current evidence remains preliminary. Main limitations are the small number and heterogeneity of recruited patients, the limited “dosage” of brain stimulation that can be delivered in the hospital setting, the lack of a sufficient knowledge on the excitatory and inhibitory mechanisms targeted by specific stimulation interventions, and the persistent uncertainty on the key pathophysiological processes leading to motor neuron loss. The present review article provides an update on the state of the art of neuromodulation in ALS and a critical appraisal of the rationale for the application/optimization of brain stimulation interventions, in the light of their interaction with ALS pathophysiological mechanisms.

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“…As an example Di Lazzaro et al . recently published data suggesting that the clinical effect of repetitive TMS in ALS is associated strongly with the modulation of GABA 20 .…”

Section: Discussionmentioning

confidence: 99%

Short echo-time Magnetic Resonance Spectroscopy in ALS, simultaneous quantification of glutamate and GABA at 3 T

Blicher

Eskildsen

Stærmose

et al. 2019

Sci Rep

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Cortical hyperexcitability has been found in early Amyotrophic Lateral Sclerosis (ALS) and is hypothesized to be a key factor in pathogenesis. The current pilot study aimed to investigate cortical inhibitory/excitatory balance in ALS using short-echo Magnetic Resonance Spectroscopy (MRS). Patients suffering from ALS were scanned on a 3 T Trio Siemens MR scanner using Spin Echo Full Intensity Acquired Localized (SPECIAL) Magnetic Resonance Spectroscopy in primary motor cortex and the occipital lobe. Data was compared to a group of healthy subjects. Nine patients completed the scan. MRS data was of an excellent quality allowing for quantification of a range of metabolites of interest in ALS. In motor cortex, patients had Glutamate/GABA and GABA/Cr- ratios comparable to healthy subjects. However, Glutamate/Cr (p = 0.002) and the neuronal marker N-acetyl-aspartate (NAA/Cr) (p = 0.034) were low, possibly due to grey-matter atrophy, whereas Glutathione/Cr (p = 0.04) was elevated. In patients, NAA levels correlated significantly with both hand strength (p = 0.027) and disease severity (p = 0.016). In summary SPECIAL MRS at 3 T allows of reliable quantification of a range of metabolites of interest in ALS, including both excitatory and inhibitory neurotransmitters. The method is a promising new technique as a biomarker for future studies on ALS pathophysiology and monitoring of disease progression.

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Effects of repetitive TMS of the motor cortex on disease progression and on glutamate and GABA levels in ALS: A proof of principle study

Cited by 16 publications

References 9 publications

Insight Into the Effects of Clinical Repetitive Transcranial Magnetic Stimulation on the Brain From Positron Emission Tomography and Magnetic Resonance Imaging Studies: A Narrative Review

Insight Into the Effects of Clinical Repetitive Transcranial Magnetic Stimulation on the Brain From Positron Emission Tomography and Magnetic Resonance Imaging Studies: A Narrative Review

Brain Stimulation as a Therapeutic Tool in Amyotrophic Lateral Sclerosis: Current Status and Interaction With Mechanisms of Altered Cortical Excitability

Short echo-time Magnetic Resonance Spectroscopy in ALS, simultaneous quantification of glutamate and GABA at 3 T

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