Transcranial magnetic stimulation to understand pathophysiology and as potential treatment for neurodegenerative diseases
© Ni and Chen. 2015
Received: 16 September 2015
Accepted: 10 November 2015
Published: 16 November 2015
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.
KeywordsAlzheimer’s disease Amyotrophic lateral sclerosis Huntington’s disease Parkinson’s disease Transcranial magnetic stimulation
Neurodegeneration involves progressive structural and functional loss of specific groups of neurons. The risk of being affected by a neurodegenerative disease increases dramatically with age. With increasing lifespan due to the population-wide health improvements, more individuals will be affected by neurodegenerative diseases in the coming decades. Common neurodegenerative diseases include Parkinson’s disease (PD) , Alzheimer’s disease (AD) , amyotrophic lateral sclerosis (ALS)  and Huntington’s disease (HD) . The mechanisms underlying neurodegenerative diseases are multifactorial and include genetic and environmental factors. Current treatments for neurodegenerative diseases are symptomatic and there is no accepted disease modifying therapy to slow disease progression [1–4].
Abnormalities in TMS measurements in neurodegenerative diseasesa
Single-pulse TMS measurements for Parkinson’s disease
Motor threshold is an important parameter of motor cortical excitability. Rest and active motor thresholds are defined as the minimum TMS intensities that elicit small but reproducible MEPs at rest and during voluntary muscle contraction, respectively . The motor threshold reflects the excitability of the most sensitive group of neurons in the stimulated area in M1. Most studies have reported that rest motor threshold is normal in PD [11–13]. Involuntary contraction caused by tremor and rigidity may affect the measurement in PD. Active motor threshold in PD appears to be normal although a correlation between the degree of bradykinesia and active threshold has been reported . In addition, MEP threshold does not change with medication status [11–13] or deep brain stimulation of the internal globus pallidus  or the subthalamic nucleus .
MEP amplitude (Fig. 1b) reflects the global excitability of cortical interneurons, corticospinal neurons and spinal motoneurons . Increased MEP amplitude at rest in PD patients has been reported [17, 18]. Increased MEP amplitude in PD may be related to an imbalance towards disinhibition in the motor pathway. Studies that showed decreased cortical inhibition, increased cortical facilitation and changes in cortical plasticity in PD are discussed below. Patients with internal globus pallidus deep brain stimulation also showed larger MEP amplitude than controls regardless of whether the stimulation was turned on or off .
When TMS is applied during voluntary contraction, a disruption of the ongoing muscle activity known as the silent period can be recorded following the MEP (Fig. 1b). The first part of the silent period is partly due to decreased spinal excitability. The latter part of the silent period mainly involves inhibitory effects at the cortical level, mediated by gamma-aminobutyric acid type B (GABAB) receptors [6, 19]. Shortening of the silent period in PD has been reported in many studies . However, such abnormality may not be pronounced at low stimulus intensities . Dopaminergic medication normalizes the shortened silent period in PD . High doses of levodopa may even lengthen the duration beyond the normal range .
An asymmetric 4-6 Hz resting tremor is a cardinal symptom of PD. Many PD patients also have postural tremor . When stimulation is applied to the motor pathway, the tremor may be transiently disrupted. The reoccurrence of the tremor is then time-locked to the stimulation and this phenomenon is referred to as tremor reset. Mechanical perturbation which modulates spinal reflex pathways has very little effect on postural tremor in PD, suggesting that spinal circuits may not be involved in generating PD postural tremor . TMS applied to M1 completely resets postural tremor in PD . PD rest tremor can also be reset by M1 TMS, suggesting that the M1 is involved in both resting and postural tremor in PD. In addition, cerebellar TMS is effective in resetting the PD postural tremor but not rest tremor, suggesting that the cerebellum is involved in the generation or transmission of postural tremor but not rest tremor in PD .
Intracortical circuits in Parkinson’s disease
The excitability of intracortical circuits in M1 can be investigated by a paired-pulse TMS paradigm. The effect of the first conditioning stimulus on the MEP elicited by the second test stimulus depends on the stimulus intensities, the interstimulus interval and the location of conditioning stimulus.
Short and long interval intracortical inhibitions
Long interval intracortical inhibition is elicited when a suprathreshold conditioning stimulus is applied 50-200 ms prior to the test stimulus and is likely mediated by GABAB receptors . Long interval intracortical inhibition is reported to be decreased in PD . This is consistent with shortened silent period (related to GABAB receptors) in PD. Using a triple-pulse TMS paradigm, it has been found that SICI is suppressed in the presence of long interval intracortical inhibition in a manner consistent with reduction in GABA release caused by presynaptic GABAB inhibition. The suppressive effect of long interval intracortical inhibition on SICI seen in healthy controls is absent in PD patients. Dopaminergic medications do not normalize this deficit, suggesting that presynpatic inhibition is impaired in PD and the impairment may be a non-dopaminergic feature of PD .
Interhemispheric inhibition can be measured by two TMS coils placed on bilateral M1s. Both conditioning and test stimuli are suprathreshold. Short and long latency interhemispheric inhibitions peak at interstimulu intervals of ~10 and ~50 ms. Inhibition is likely produced by interhemispheric inputs largely mediated through the corpus callosum . There is less long latency interhemispheric inhibition in PD patients with mirror movement than those without mirror movement, suggesting that deficits in transcallosal function may contribute to mirror activity in PD. Such abnormality is found for long latency interhemispheric inhibition from both the less affected to more affected side and from the more affected to less affected side. There is no significant abnormality in short latency interhemispheric inhibition in PD .
Cerebellar inhibition refers to the phenomenon that stimulation over the cerebellum suppresses the MEP produced by contralateral M1 TMS delivered 5 to 7 ms later. Cerebellar inhibition is mediated by the cerebellothalamocortical pathway. Cerebellar TMS activates cerebellar Purkinje’s cells that inhibit the deep cerebellar nuclei, which has an excitatory projection to the motor cortex via the ventral thalamus . Cerebellar inhibition is decreased in PD. Decreased inhibition correlated with the degree of reset of postural tremor caused by cerebellar stimulation, suggesting that the deficits on the cerebellothalamocortical pathway may be related to the tremor generation in PD .
Connectivity between the basal ganglia and M1
Inputs from the basal ganglia modulate M1 excitability. In PD patients with subthalamic nucleus deep brain stimulation, subthalamic stimulation leads to cortical evoked potential on the scalp with peak latencies of ~3 and ~20 ms . Moreover, single pulse subthalamic stimulation produced two phases of MEP facilitation at 2-4 ms and 21-24 ms after the stimulation. The time course of MEP facilitation coincides with that of the evoked potentials recorded at the scalp. Antidromic conduction along the corticosubthalamic pathway likely mediates the early phase of facilitation while the late phase is likely mediated by synaptic transmission through the basal ganglia-thalamo-cortical circuit .
Cortical plasticity in Parkinson’s disease
Therapeutic rTMS in Parkinson’s disease
rTMS involves trains of TMS pulses delivered with durations ranging from several seconds to several minutes at various frequencies and intensities. The effects of these pulses temporally summate to cause greater and longer duration of changes in neural activity than those from single-pulse TMS. Generally, high-frequency rTMS potentiates MEP and low-frequency rTMS suppresses MEP when delivered to the M1 [6, 7]. Since the effects of a single session of rTMS can last for several hours and repeated sessions may last for months, rTMS is a potential treatment for neurological disorders.
Therapeutic repetitive TMS protocols for neurodegenerative diseases
Potential beneficial effects
M1, SMA, PMd
Improve motor symptomsb, moodc
Improve levodopa induced dyskinesia
Improve memory, cognition
Amyotrophic lateral sclerosis
Improve motor symptoms
Stimulation of other areas outside the M1 may also be effective. In particular, a sham-controlled study with a relatively large sample size reported that 5 Hz rTMS applied to the supplementary motor area significantly improved the clinic rating scores and bradykinesia in PD patients . Continuous theta burst stimulation, a type of inhibitory rTMS, delivered to the cerebellum improved levodopa induced dyskinesia in PD . In addition, 5 Hz rTMS over dorsal premotor cortex facilitated MEP in healthy controls but not in PD patients off medications. After levodopa administration, the facilitatory effect of premotor cortical stimulation on the motor cortex was restored .
AD is the most common form of dementia and is characterized by progressive neuronal degeneration. The degenerative process leads to atrophy initially in the hippocampus and entorhinal cortex, then progressively expanding into wide areas including the cerebral cortex and subcortical regions [2, 53]. Mild cognitive impairment (MCI) is considered a transitional stage between normal aging and clinically probable AD. The functional impairments in AD measured with TMS paradigms are summarized in Table 1.
Single-pulse TMS measurements for Alzheimer’s disease
Rest motor threshold is decreased in AD . However, the threshold is preserved in patients with early disease  and in patients with MCI , suggesting that reduction in rest threshold may be a compensatory mechanism for the neuronal loss in motor cortical areas and may reflect a functional change in these areas with disease progression. Reduction in active motor threshold in AD has also been reported .
MEP amplitude and silent period
MEP amplitude may be normal at early stage of AD  but is increased in patients at advanced stages . Interestingly, a TMS mapping study showed that the hotspot did not change while the center of gravity for MEP amplitude shifted in a fronto-medial direction in patients with mild to moderate AD, suggesting an early cortical reorganization in AD . Silent period is shortened in moderate to severe AD, suggesting that AD may impair the function of GABAB receptor mediated inhibitory circuits in M1 at late disease stages .
Intracortical circuits in Alzheimer’s disease
Short latency afferent inhibition
Reduction in SAI is significant at many disease stages in AD [54, 56, 60–64] and this is consistent with postmortem studies showing central cholinergic impairment in AD . Decreased SAI correlated with the degree of memory loss  and the degree of euphoric manic state in AD . These correlations may be explained by the cholinergic dysfunction in temporo-limbic areas such as hippocampus, entorhinal cortex and amygdala. Administration of a single dose of rivastigmine (an acetylcholinesterase inhibitor) restored the decreased SAI in AD . Since decreased SAI was found in early AD  and even in amnesic MCI patients [63, 64], it is a potential biomarker for the diagnosis of AD.
Other intracortical circuits
Reduction in SICI has been reported . The degree of disinhibition correlated with the severity of AD . However, other studies reported no difference in SICI between patients and controls [54, 57]. Although AD may be related to changes in cortical glutamatergic transmission [53, 58], intracortical facilitation in AD and MCI patients were normal [54, 57, 64]. Interhemispheric inhibition is decreased in amnesic MCI patients . However, decreased inhibition does not correlate with the scores of mini-mental status examination or reduced SAI, suggesting that structural or functional impairment in transcallosal connection may occur earlier than the cognitive impairments in MCI .
Cortical plasticity in Alzheimer’s disease
Long term potentiation-like cortical plasticity is impaired in AD. Five Hz rTMS which produced MEP increase in healthy controls decreased MEP in AD patients . Similarly, paired associative stimulation  and intermittent theta burst stimulation , which induce MEP facilitation in normal subjects, also led to reduced cortical excitability in AD patients. Whether long term depression-like effect is altered in AD is controversial. One Hz rTMS, which produced MEP inhibition in healthy controls , had no effect in AD patients . However, MEP inhibition with continuous theta burst stimulation in AD was normal .
Therapeutic rTMS for Alzheimer’s disease
The assumption in AD that memory deficit is related to functional impairment in dorsolateral prefrontal cortex  makes this cortical area a common target of therapeutic intervention (Table 2). It was reported that application of 20 Hz rTMS to both the left and right dorsolateral prefrontal cortex improved the accuracy of an action naming task in both mild and moderate to severe AD patients . A subsequent study with daily 20 Hz rTMS with 2000 pulses applied to the left dorsolateral prefrontal cortex for 2 or 4 weeks showed long-lasting improvement (8 weeks) in language comprehension in moderate AD patients . Another study reported that 20 Hz right side followed by left side dorsal lateral prefrontal cortical stimulation applied for 5 days improved the score of mini-mental status examination in AD patients. On the other hand, 1 Hz stimulation applied in the same order (right followed by left side stimulation) had no effect, suggesting that facilitatory but not inhibitory stimulation has therapeutic effects in AD . However, another study reported that a single session of inhibitory 1 Hz rTMS over right dorsolateral prefrontal cortex increased the recognition memory performance in both healthy controls and MCI patients .
Amyotrophic lateral sclerosis
ALS is a rapidly progressive neurodegenerative disorder of the motoneurons in the M1, brainstem and spinal cord. A combination of upper and lower motoneuron dysfunction comprises the clinical ALS phenotypes .
Single-pulse TMS measurements in amyotrophic lateral sclerosis
MEP threshold is increased in ALS [75, 76] (Table 1). However, a longitudinal study reported reduced MEP threshold at early stage of the disease, which may explain muscle fasciculation with motor neuronal changes at this stage . Central motor conduction time is prolonged in ALS, reflecting axonal degeneration of the fast conducting fibers of corticospinal neurons . MEP amplitude increases in sporadic  and familial forms of ALS , prominently in the early stage of the disease. In addition, MEP amplitude correlates with traditional measurement of peripheral nerve functions (compound muscle action potential) and with measurement for axonal excitability in ALS, suggesting an association between cortical hyperexcitability and motoneuron degeneration . Reduction in duration of silent period is also prominent at early stage of ALS, indicating degeneration or dysfunction of inhibitory interneurons with reduced GABAB receptor functions in ALS [77, 78].
Intracortical circuits in amyotrophic lateral sclerosis
SICI is reduced or absent in ALS [77–79] (Table 1). This is consistent with the pathological finding of degeneration of inhibitory cortical interneurons in ALS . In addition, reduction in SICI precedes the clinical development of familial ALS, which may help in establishing the diagnosis . Intracortical facilitation is increased in ALS [77, 78], suggesting that glutamate mediated excitotoxicity may be involved in motoneuron hyperexcitability. Involvement of glutamate circuit in ALS pathophysiology is supported by the interesting finding that glutamate antagonist riluzole restored the decreased SICI in ALS patients . Interhemispheric inhibition is also decreased in ALS . Taken together, the reduction in cortical inhibition and increase in cortical facilitation may be related to hyperexcitability of cortical motoneurons in ALS patients.
Cortical plasticity and therapeutic rTMS for amyotrophic lateral sclerosis
Two weeks of daily sessions of 5 Hz rTMS only had transit benefit on motor performance and the quality of life in ALS patients . Twenty Hz rTMS even showed a tendency to accelerate disease progression . These studies suggest that facilitatory rTMS may have minor beneficial effects or may be harmful in some circumstances in ALS. Inhibitory 1 Hz rTMS showed slight benefits in two ALS patients , supporting the idea that down regulation of hyperexcited motoneurons may improve symptoms (Table 2). Subsequent studies by the same group tested the effect of inhibitory rTMS with a design delivering 5 consecutive daily sessions of continuous theta burst stimulation per month. Long term benefit was observed in studies with different durations (0.5-2 years) and different sample sizes. A 26-month trial in a single case reported a slower rate of deterioration with stimulation compared to baseline. The strongest beneficial effect was found in the first 12 months with stimulation . A six-month study reported a slight but significantly slower disease progression in 7 patients with real stimulation compared to 8 patients with sham stimulation . Unfortunately, a one-year follow up double blinded placebo-controlled study with more patients failed to confirm the positive effects of the previous studies .
HD is a genetic neurodegenerative disease due to pathological expansion of the triplet cytosine-adenine-guanine (CAG) repeat in the Huntingtin gene in chromosome 4, which results in an excessively long polyglutamine stretch in protein Huntingtin and eventually causes loss of GABAergic neurons in striatum . HD is characterized by a triad of symptoms with motor, cognitive and psychiatric disturbances.
Single- and paired-pulse TMS measurements in Huntington’s disease
Higher rest and active motor thresholds and smaller rest MEP size compared to healthy controls were found in both very early symptomatic HD patients and HD gene carriers . However, probably due to the small sample size and phenotypic heterogeneity, other studies found no difference in MEP threshold [88, 89] or amplitude  between HD patients and controls (Table 1). Although silent period may be normal at the early or preclinical stage of HD , progressive shortening in silent period with functional decline was found in symptomatic patients at two-year follow up . The finding is consistent with HD pathology with GABAergic neuronal loss in the brain and suggests that the silent period may be a potential biomarker of the disease progression. Several studies reported normal SICI in symptomatic HD patients [89, 91]. However, the results may be confounded by inclusion of patients with chorea due to various etiologies. The conditioning stimulus intensity for producing same degree of SICI was found to be increased in early and even in the preclinical stage of the disease . SAI was decreased in the same group of patients . These studies with single- and paired-pulse measurements support the view that cortical functional impairments occur early in HD.
Cortical plasticity and therapeutic rTMS in Huntington’s disease
Cortical plasticity is impaired in HD. MEP facilitation produced both by 5 Hz rTMS  and by paired associative stimulation  were reduced in HD patients. MEP inhibition produced by continuous theta burst stimulation was decreased in early symptomatic HD patients and HD gene carriers . The use of rTMS as a treatment for HD has been studied (Table 2). One Hz but not 5 Hz rTMS applied to the supplementary motor area reduced chorea scores in HD patients, suggesting that suppression of supplementary motor cortical excitability may lead to improvement in HD symptoms . Interestingly, dramatic improvement in dyskinesia lasting for 24 h after a single session of continuous theta burst stimulation to M1 was reported in a case of hemichorea secondary to midbrain and caudate hemorrhage .
Conclusions and final remarks
Although aging is the greatest risk factor for neurodegenerative diseases, many neurodegenerative diseases can be caused by genetic mutations and are associated with protein misfolding and degradation. The effects of neurodegeneration can be found in many different levels of neuronal circuitry ranging from the molecular level to the systems level. Studies using animal models and neuroimaging techniques are searching for the biomarkers for neurodegenerative diseases. Development of disease modifying therapies such as gene therapy, stem cell transplant and neuroprotective agent are actively being pursued .
TMS provides a non-invasive and powerful process to investigate the synaptic activity and to manipulate the synaptic plasticity in human cortex at the systems level. Studies with single- and paired-pulse TMS showed abnormal cortical excitability in patients with neurodegenerative diseases. rTMS within established guidelines is safe for the patients with neurodegenerative diseases and showed symptomatic benefit in some studies. Several major issues should be considered for future studies that focus on better understanding of the pathophysiology and novel therapeutics for neurodegenerative diseases. First, the protocols with diagnostic or therapeutic potentials should be translated into clinically practical applications. Currently, this is largely limited by the fact that many TMS measurements have large within-subject and between-subject variations [6, 7]. Second, there is no current biomarker which can confirm the diagnosis of neurodegenerative disease at early stage and monitor the disease progression. Recently, genetic (such as genome sequencing, proteomics) and neuroimaging (such as positron emission tomography, functional magnetic resonance imaging) approaches are being undertaken to identify potential biomarkers for neurodegenerative diseases. Future studies combining TMS with these techniques may provide new opportunity to find clinically useful biomarkers for neurodegenerative diseases. Third, the current evidence showed that the beneficial effects of rTMS for neurodegenerative diseases are mild to moderate and short-lasting. While multiple sessions of rTMS may extend the clinical benefit, development of rTMS into a practical treatment requires large, sham-controlled studies and may need to introduce new stimulation parameters. In addition, the combination of rTMS with other traditional therapeutic methods such as medications and deep brain stimulation may lead to new treatment strategies for neurodegenerative diseases.
amyotrophic lateral sclerosis
primary motor cortex
mild cognitive impairment
motor evoked potential
repetitive transcranial magnetic stimulation
short latency afferent inhibition
short interval intracortical inhibition
transcranial magnetic stimulation
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