Transcranial magnetic stimulation parameters as neurophysiological biomarkers in Alzheimer’s disease

Action mechanism of TMS

TMS is based on Faraday’s law of electromagnetic induction.4 Rapidly changing pulses of current passing through a coil positioned above the head generate magnetic fields that penetrate the scalp and skull to reach the brain and induce secondary electric currents in the cortex.5,6 These electric currents depolarize the neuron membranes either directly or indirectly. They can markedly influence changes in excitability from the regional cortex to the subcortex and distant areas that are connected to the stimulated area via neural pathways,7-10 with these changes ultimately affecting human cognition and behavior.11

rTMS can be used to modulate synaptic plasticity, especially long-term potentiation (LTP)12 and long-term depression (LTD).13 LTP is a phenomenon in which synapses are persistently strengthened, and it is an important mechanism of memory and learning at the neuron level. High-frequency rTMS and theta-burst stimulation (TBS) affect the expression levels of various receptors, including N-methyl-D-aspartate (NMDA) receptors,14 and neurotransmitters.15 High-frequency rTMS reduces the synaptic conduction threshold, leading to enhanced synaptic connections and synaptic plasticity.16 These structural and functional changes in synapses lead to the induction of LTP, which affects cognitive function.

TMS devices and stimulation paradigms

A TMS device consists of a coil and a stimulator. There are several types of coil: circular or round, figure-of-eight, double-cone, and H-coil. The amplitude of currents flowing in the coil controls the intensity of the induced magnetic field, and the type of coil determines where that field is focused. A figure-of-eight coil is the most widely used and provides more focal stimulation compared with a circular coil, for which the electric field is more widely distributed and provides bihemispheric stimulation.17 An H-coil stimulates a wide and deep area of the brain,18 while a double-cone coil stimulates deep and focal areas such as deep parts of the cerebellum19 or the leg motor area.20

The stimulator generates pulse waves of appropriate frequency, intensity, and number of pulses to influence the effects of TMS.21 Generally, high-frequency stimulation (5-25 Hz) induces cortical excitability while low-frequency stimulation (≤ 1 Hz) inhibits cortical activities.22 However, high-frequency stimulation at low intensities decreases cortical activity, while high-frequency stimulation at high intensities increases cortical excitability.23 TBS is a variant of rTMS that increases cortical excitability when applied intermittently and decreases cortical excitability when applied continuously.24

Single-pulse TMS

Single-pulse TMS is generally used to estimate the motor threshold (MT) or cortical excitability when recording motor evoked potentials (MEPs). When single-pulse TMS is applied to the primary motor cortex, series of recordable corticospinal volleys are generated that reflect the trans-synaptic activation of cortical neurons.

Paired-pulse TMS

The paired-pulse TMS protocol involves the application of two different sequential stimuli with various interstimulus intervals (ISIs). This can provide information about the integrity of corticocortical connections. There are two inhibitory circuits and two facilitatory circuits determined by the intensity and ISI of this protocol: short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI), intracortical facilitation (ICF), and short-interval intracortical facilitation. Paired-pulse TMS, like short-latency afferent inhibition (SAI), is used to investigate sensory-motor interactions in the cerebral cortex.

Repetitive TMS

rTMS involves applying a train of single TMS pulses with a constant frequency and intensity for a given time to the brain target area. It can modulate cortical excitability, with low-frequency rTMS (≤ 1 Hz) suppressing cortical excitability40 and high-frequency rTMS (≥ 5 Hz) increasing cortical excitability.41 rTMS can also be used to noninvasively induce long-lasting modulation of the cortical excitability. The mechanism underlying how rTMS modulates cortical excitability beyond the duration of stimulation is unclear, but LTP and LTD of the cortical synapses are a possible mechanism. Such lasting modulation of cortical activity by rTMS can also be induced in areas outside the motor cortex, and these findings raise the possibility of therapeutic applications of rTMS.

Diagnostic and prognostic applications of TMS in dementia

Recent studies have suggested that TMS could be a novel tool for investigating the early features of synaptic dysfunction in AD patients and the identification of biomarkers.3,29,42 The initial AD pathological changes were considered to be the aggregation and accumulation of amyloid-beta and tau proteins that damaged neuron synapses long before the presentation of clinical dementia. These toxic oligomeric species impair synaptic transmission, which could be more precisely correlated with the severity of the disease and an additional cognitive decline related to AD.3 AD patients show different MTs and SAIs at different stages of the disease. A lower RMT, which reflects hyperexcitability of the motor cortex, presents in MCI and the early stage of AD. The RMT decreases with disease progression, and at an advanced stage, it reduces further with global cortical atrophy of the brain.26 Thus, TMS parameters well reflect the functional changes in synapses according to the state in AD patients.

The characteristics of TMS parameters differ among several types of dementia.43 In FTD, TMS has revealed central motor circuit abnormalities through reduced-amplitude or absent MEPs, and increased latency of MEPs and the central motor conduction time, even in the absence of clinical pyramidal involvement.31 Changes in cortical excitability (RMT), central cholinergic activity (SAI), or intracortical inhibition/facilitation were not observed in FTD.43,44 Pierantozzi et al.45 reported that early-onset AD patients showed significant low SICI (ISI = 2-3 ms), whereas FTD patients did not.

Based on the above observations, some studies have investigated using TMS to differentiate AD patients from healthy controls and those with other types of dementia. One study used TMS-based assessment of GABAergic and cholinergic neurotransmission to distinguish patients with AD from FTD patients and healthy controls.42 AD showed significant impairment of SAI, and FTD showed dysfunction of SICI-ICF. These findings had high sensitivity and specificity in differentiating patients with each disease from healthy controls. Another multicenter study found that AD and DLB patients showed low SAI, representation of cholinergic deficits, and that FTD and DLB had an abnormality of SICI-ICF associated with GABAergic and glutamatergic circuits.46 Moreover, LICI was most impaired in FTD. These results are related to the biological pathology of neurotransmitters in each neurodegenerative disease, and demonstrate the ability to use TMS parameters to differentiate the diseases with high sensitivity and specificity (Table 1).

Table 1.

Summary of abnormalities of TMS outcome parameters in dementia

It has been suggested that the SAI measure could be used as a tool to identify MCI patients with an increased risk of converting to dementia.47 In studies of MCI patients and healthy controls, SAI was reduced in multiple-domains amnestic MCI, which has the highest risk of converting to dementia, while it did not differ in single-domain amnestic and non-amnestic MCI patients compared with normal cognition.47,48

One study investigated the benefit of acetylcholinesterase inhibitor (AChEi) treatment in changing plasticity within cortical glutamatergic circuits.49 MEP amplitudes were measured during 5-Hz rTMS (which reflects short-term synaptic plasticity) before and after AChEi administration. The application of AChEi for 2 months did not influence the alteration in cortical excitability or short-term synaptic plasticity. Other studies have estimated SAI, which represents central cholinergic activity, and found that the low SAI in AD could be restored by the administration of a single dose of AChEi.37,50 Furthermore, AD patients who showed a large increase in SAI after a single dose of AChEi respond well to long-term treatment.

It appears conclusive that the clinical benefit of AChEi treatment is related more closely to factors including cholinergic activity than to the activity of glutamatergic NMDA receptors. Therefore, evaluating SAI could be useful for predicting the response to AChEi.

Therapeutic interventions

Multiple sessions of rTMS have recently been proposed as a promising treatment for improving cognitive performance in AD (Table 2). rTMS can result in temporal changes in focal cortical excitability producing prolonged changes in neuron integrity. LTP-like cortical plasticity is disrupted in the early stage of AD, whereas high-frequency rTMS can enhance LTP-like cortical plasticity at both the local and network levels.51 Multiple sessions of rTMS induced synaptic plasticity and especially LTP, which was the most important mechanism in learning and memory. rTMS was helpful in restoring brain functions and could reflect the potential of rTMS to recruit compensatory networks that underlie memory-encoding and other cognitive processes.52

Table 2.

Summary of recent rTMS studies of cognitive effects in Alzheimer’s disease and mild cognitive impairment

High-frequency rTMS over the dorsolateral prefrontal cortex (dlPFC) can improve global cognition, action naming, object naming, episodic memory, and information processing speed in patients with AD, MCI, and cognitively normal controls.53-55 Most rTMS studies have focused on the dlPFC, and this area is affected in both the early and late stages of dementia. Researchers have recently applied rTMS to the posterior parietal cortex and precuneus, which were affected in the early stage and had prominent neuropathological abnormalities. The effects of rTMS in various types of dementia are summarized in Fig. 1.

Fig. 1.

Effects of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) in Alzheimer’s disease (AD) according to cortical areas. dlPFC, dorsolateral prefrontal cortex; MCI, mild cognitive impairment; CGIC, clinical global impressions of change.

We have reported on the effect of rTMS with cognitive training (rTMS-CT) in patients with mild-to-moderate AD.56 The participants in that study received rTMS in 6 cortical areas and showed cognitive improvement after 30 sessions. The effect was maintained at 6 weeks after the end of the treatment, and was more prominent in the mild-AD group. Similar to our study, other studies have found better cognitive effects of rTMS in the early stage of AD.57 These results might be due to the degree of gray-matter atrophy in AD-related brain regions contributing to the variability of rTMS-induced cognitive aftereffects.58 Patients with AD who received rTMS-CT showed slower cognitive decline than did those who only took AChEis over 3 years.59 That study revealed for how long rTMS-CT could affect the disease course.

rTMS can improve neuropsychiatric symptoms in AD as well as enhance cognitive function. A meta-analysis of the efficacy of rTMS on the neuropsychiatric symptoms of AD found that rTMS could persistently improve the neuropsychiatric symptoms at an early stage after treatment.60 However, following the evidence-based guidelines on the therapeutic use of rTMS,61 further evidence is needed for the use of rTMS as a therapeutic tool in AD and MCI.

TBS is emerging as a more efficient treatment paradigm in terms of time and energy than rTMS.62 TBS involves applying a 50-Hz triplet pulse burst with a 200-ms interburst interval, typically at 80% of the active MT. Continuous TBS (cTBS) delivers 600 pulses for 40 seconds without interruption, while intermittent TBS (iTBS) involves 2-s-long TBS trains repeated every 10 seconds for a total of 20 cycles. cTBS generally decreases cortical excitability for up to 1 hour, while iTBS increases cortical excitability more rapidly than conventional rTMS.24 Several studies have applied iTBS for treating dementia. In an open-label study, 13 patients with AD received 14 sessions of iTBS daily over a 2-week period.63 After treatment, they showed cognitive improvement in memory, attention executive, and language functions, and their behavioral and psychiatric symptoms were also ameliorated.