Transcranial magnetic stimulation to understand pathophysiology and as potential treatment for neurodegenerative diseases

Abstract

Common neurodegenerative diseases include Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). Transcranial magnetic stimulation (TMS) is a noninvasive and painless method to stimulate the human brain. Single- and paired-pulse TMS paradigms are powerful ways to study the pathophysiological mechanisms of neurodegenerative diseases. Motor evoked potential studied with single-pulse TMS is increased in PD, AD and ALS, but is decreased in HD. Changes in motor cortical excitability in neurodegenerative diseases may be related to functional deficits in cortical circuits or to compensatory mechanisms. Reduction or even absence of short interval intracortical inhibition induced by paired-pulse TMS is common in neurodegenerative diseases, suggesting that there are functional impairments of inhibitory cortical circuits. Decreased short latency afferent inhibition in AD, PD and HD may be related to the cortical cholinergic deficits in these conditions. Cortical plasticity tested by paired associative stimulation or theta burst stimulation is impaired in PD, AD and HD. Repetitive TMS (rTMS) refers to the application of trains of regularly repeating TMS pulses. High-frequency facilitatory rTMS may improve motor symptoms in PD patients whereas low-frequency inhibitory stimulation is a potential treatment for levodopa induced dyskinesia. rTMS delivered both to the left and right dorsolateral prefrontal cortex improves memory in AD patients. Supplementary motor cortical stimulation in low frequency may be useful for HD patients. However, the effects of treatment with multiple sessions of rTMS for neurodegenerative diseases need to be tested in large, sham-controlled studies in the future before they can be adopted for routine clinical practice.

Keywords: Alzheimer’s disease; Amyotrophic lateral sclerosis; Huntington’s disease; Parkinson’s disease; Transcranial magnetic stimulation.

Fig. 1

Transcranial magnetic stimulation and its measurements. a When TMS is applied to the primary motor cortex, it produces descending volleys in the spinal cord. This in turn activates the spinal motoneurons and a motor-evoked potential (MEP) can be recorded in the target muscle (e.g. FDI muscle) with surface EMG. b MEP measurements. When TMS is delivered during voluntary muscle contraction, an MEP is followed by a silent period with no background EMG activity. MEP latency is defined as the time from TMS delivery to the onset of MEP. MEP amplitude is usually measured as the peak-to-peak value. Silent period can be measured from the onset or the end of MEP to the first recovery of background EMG activity. EMG = electromyogram, FDI = first dorsal interosseous, MEP = motor evoked potential, TMS = transcranial magnetic stimulation. Modified from Ni et al., Transcranial magnetic stimulation in different current directions activates separate cortical circuits, Journal of Neurophysiology 2011, 105:749-756 [8]

Fig. 2

Abnormal SICI in PD patients. Example of recordings from representative subjects are shown in a. The top row represents the recordings with test stimulus alone and other five rows are recordings for paired-pulse stimulation at different interstimulus intervals. SICI was tested at the interstimulus intervals where short interval intracortical facilitation was at its peaks and troughs. An additional interval of 1 ms was also tested. Note that SICI was decreased at facilitatory peaks and troughs in the PD OFF medication state, and this was normalized in the PD ON state. The group data analysis is shown in b. The abscissa indicates the interstimulus interval. The ordinate indicates the degree of SICI. It represents the amplitude of paired-pulse induced MEP expressed as a percentage of the MEP amplitude induced by test stimulus alone. Values more than 100 % indicate facilitation and those less than 100 % indicate inhibition. Filled circles indicate MEP in PD patients OFF medication. Triangles indicate MEP in PD patients ON medication. Open circles indicate MEP in healthy controls. * p < 0.05, ** p < 0.01, comparing PD OFF to control. # p < 0.05, comparing PD OFF to PD ON. “S” p < 0.05, comparing PD ON to control. SICI was reduced in PD OFF compared to controls at an ISI of 1 ms, at short interval intracortical facilitation peak 1, trough 1, peak 2 and peak 3. Reduced SICI in PD OFF compared to PD ON group was only found at facilitatory peaks. SICI for PD ON was still decreased compared to controls at ISI of 1 ms and at facilitatory trough 1. MEP = motor evoked potential, PD = Parkinson’s disease, SICI = short interval intracortical inhibition. Modified from Ni et al., Increased motor cortical facilitation and decreased inhibition in Parkinson disease, Neurology 2013, 80:1746-1753 [11]. Promotional and commercial use of the material in print, digital or mobile device format is prohibited without the permission from the publisher Wolters Kluwer Health. Please contact healthpermissions@wolterskluwer.com for further information

Fig. 3

Short latency afferent inhibition in Parkinson’s diseasepatients with subthalamic nucleus deep brain stimulation. The abscissa indicates the different experimental conditions. The ordinate indicates the degree of short latency afferent inhibition. It represents the amplitude of paired-pulse induced MEP expressed as a ratio of the MEP amplitude induced by test alone. Values more than 1 indicate facilitation and those less than 1 indicate inhibition. * p < 0.05, comparing patients at ON medication OFF stimulation state to healthy controls and patients at ON medication ON stimulation state. The ring asterisks above the columns represent significant inhibition compared to test alone. Note that short latency afferent inhibition was normal in Parkinson’s disease patients at OFF medication state while it was reduced at ON medication state. Reduced inhibition at the ON medication state was normalized by the deep brain stimulation. MEP = motor evoked potential. Modified from Sailer et al., Subthalamic nucleus stimulation modulates afferent inhibition in Parkinson disease, Neurology 2007, 68:356-363 [34]. Promotional and commercial use of the material in print, digital or mobile device format is prohibited without the permission from the publisher Wolters Kluwer Health. Please contact healthpermissions@wolterskluwer.com for further information

Fig. 4

Motor cortical plasticity induced by paired associative stimulation in Parkinson’s disease with subthalamic nucleus deep brain stimulation. The abscissa indicates the time points (0, 30 and 60 min) after the intervention of paired associative stimulation. The ordinate indicates the MEP amplitude after the intervention. The values are expressed as a ratio to the MEP amplitude at baseline (before intervention). Values more than 1 indicate facilitation and those less than 1 indicate inhibition. White columns represent healthy controls. Columns with dots represent patients at medication OFF and deep brain stimulation OFF state. Hatched columns represent patients at medication OFF and stimulation ON state. Grey columns represent patients at medication ON and stimulation OFF state. Black columns represent patients at both medication and stimulation ON state. Note that cortical plasticity was impaired in the patients compared to healthy controls. Impaired cortical plasticity was only restored at the medication ON and deep brain stimulation ON state. * p < 0.05, comparing MEP at different time points to that at baseline (before intervention). MEP = motor evoked potential. Modified from Kim et al., Effects of subthalamic nucleus stimulation on motor cortex plasticity in Parkinson disease, Neurology 2015, 85:425-32 [39]. Promotional and commercial use of the material in print, digital or mobile device format is prohibited without the permission from the publisher Wolters Kluwer Health. Please contact healthpermissions@wolterskluwer.com for further information