Transcranial Magnetic Stimulation As A Diagnostic And Therapeutic Tool in Various Types Of DementiaⅠ

Abstract: 

Dementia is recognized as a healthcare and social burden and remains challenging in terms of proper diagnosis and treatment. Transcranial magnetic stimulation (TMS) is a diagnostic and therapeutic tool in various neurological diseases that noninvasively investigates cortical excitability and connectivity and can induce brain plasticity. This article reviews findings on TMS in common dementia types as well as therapeutic results. Alzheimer’s disease (AD) is characterized by increased cortical excitability and reduced cortical inhibition, especially as mediated by cholinergic neurons and as documented by impairment of short latency inhibition (SAI). 

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In vascular dementia, excitability is also increased. SAI may have various outcomes, which probably reflects its frequent overlap with AD. Dementia with Lewy bodies (DLB) is associated with SAI decrease. Motor cortical excitability is usually normal, reflecting the lack of corticospinal tract involvement. DLB and other dementia types are also characterized by impairment of short-interval intracortical inhibition. In frontotemporal dementia, cortical excitability is increased, but SAI is normal. Repetitive transcranial magnetic stimulation has the potential to improve cognitive function. It has been extensively studied in AD, showing promising results after multisite stimulation. TMS with electroencephalography recording opens new possibilities for improving diagnostic accuracy; however, more studies are needed to support the existing data. 

Keywords: dementia; Alzheimer’s disease; vascular dementia; dementia with Lewy bodies; frontotemporal dementia; Parkinson’s disease; mild cognitive impairment; transcranial magnetic stimulation; paired-pulse transcranial magnetic stimulation; biomarker

1 Introduction 

With life expectancy still increasing, dementia has become one of the main healthcare and social burdens in developed countries. In 2015, it affected nearly 50 million people, and it will affect over 130 million in 2050 [1]. Global costs of dementia are estimated at USD 1 trillion [2]. Dementia is the main cause of dependence and disability among older people and makes a profound impact on the life of their relatives [3]. Among about 50 identified types and etiologies of dementia, the most prevailing ones are Alzheimer’s disease (AD), vascular dementia (VAD), and dementia with Lewy bodies (DLB). Less frequent, but still with an impact on public health, are frontotemporal dementia (FTD) and Parkinson’s disease (PD) dementia (PDD) [4–7]. 

A significant population fulfills the criteria of mild cognitive impairment (MCI)—a condition characterized by the decline of cognitive performance not interfering with activities of daily living, but more advanced than in healthy peers and associated with the risk of developing dementia [8]. The definite diagnosis of dementia is based on histopathological changes seen in an autopsy [9–11]. In most cases, diagnosis is made upon initial and prevailing signs and symptoms, age of onset, family history, and other demographic and clinical data. Even though the clinical picture of various degenerative and other dementia types has been extensively described, it is still a challenge to detect the proper etiology in vivo and even to differentiate the pathological process from normal aging. 

The symptoms may be subtle and overlapping between different types, which often results in the diagnosis of mixed dementia [12]. As a result, several radiologic, laboratory, and neurophysiologic techniques have been involved to increase the reliability of in vivo diagnosis as well as to create screening tests. Since about twenty years ago, several studies have reported promising results regarding the use of transcranial magnetic stimulation (TMS) as an adjuvant diagnostic tool enabling assessment of the excitatory and inhibitory properties of the motor cortex as well as brain connectivity. Paired pulse TMS (ppTMS) is a TMS modality that may provide insight into the neurophysiological properties of particular dementia subtypes and MCI and enable the monitoring of disease progression [13–17]. 

Moreover, through its potential to induce brain plasticity, TMS is now also recognized as an alternative therapeutic option for various neuropsychiatric conditions including dementia. The therapeutic modality of TMS is termed repetitive TMS (rTMS). In this method, a series of magnetic stimuli produce long-lasting changes in local cortical excitability, which—depending on site, pattern, and intensity of stimulation—may be associated with cognitive enhancement, mood stabilization, and other beneficial, therapeutic effects [18–20].

1.1. TMS 

The method uses brief pulses of a time-varying magnetic field with intensity up to around 1.5 T, which is generated by the stimulator and attached coil held over the scalp area selected by the TMS operator. The magnetic field can penetrate the cortex and depolarize the neurons underneath the coil. Structures located deeper and beside the coil are not excited directly, as the magnetic field decreases exponentially with the distance from the coil. 

However, they can be influenced indirectly via neuronal networks [21]. At the beginning of TMS, which was in 1985, single pulses were used to excite the primary motor cortex (PMC) and, in turn, to induce descending volleys down the pyramidal tract and the peripheral motor pathways and finally, to induce the contraction of skeletal muscles, which was recorded electrophysiologically as the motor evoked potential (MEP). This basic technique was used and still is, primarily in neurology, to assess the conduction in central motor pathways [22]. In the case of diagnostics and research on dementia, stimulation with single pulses may contribute to the assessment of motor cortical excitability and inhibition by estimating the motor threshold (MT) and the cortical silent period (CSP). 

MT is defined as the minimal intensity of a magnetic field able to reliably evoke MEPs. Estimation of MT is operationalized in most studies, as the lowest intensity of the magnetic field—expressed as the percentage of the maximal stimulator output—evokes MEPs of amplitudes over 50 µV after at least five out of ten stimuli [23]. CSP is the period of involuntary relaxation of skeletal muscles, which follows the MEP when TMS is applied during the voluntary efforts of those muscles. When examined according to the guidelines published by the International Federation of Clinical Neurophysiology (IFCN) [23], CSP lasts between 100 and 200 milliseconds [ms] and represents cortical and spinal inhibition, partly generated by intracortical GABAB circuits and in part by spinal mechanisms [24].

1.2. Paired Pulse TMS 

ppTMS gives a more detailed and dimensional insight into excitability and inhibition of the motor cortex. In this method, the magnetic stimulus elicited to evoke motor response is preceded by a conditioning stimulus. This conditioning stimulus may be elicited by the same magnetic coil and in that case, its strength is usually below MT. In addition, it may be an electrical stimulus applied to excite the peripheral nerve. A test stimulus is second, and its strength is adjusted to evoke motor responses of a certain amplitude, e.g., 0.2 mV when applied without the conditioning stimulus. 

Depending on the length of the interval, the conditioning stimulus may have an inhibitory effect, i.e., it may decrease the amplitude of the MEP evoked by the test stimulus, or it may have the opposite effect [25]. In the method called the threshold tracking technique, which is gaining interest thanks to the reduced variability of its results, paired pulses are elicited repetitively, every few seconds.

The built-in algorithm automatically adjusts the strength of the test stimuli, keeping the amplitude of the MEP response unchanged concerning the responses after the test stimulus alone. Next, the cortical inhibition and facilitation by the conditioning stimulus are expressed in threshold tracking as the increase and decrease in the strength of the test stimulus, respectively [26]. The parameters obtained with ppTMS described below are, meanwhile, the main established measurements of cortical excitability.

1.4. Intracortical Facilitation 

For intracortical facilitation (ICF), the interstimulus interval (ISI) is between 7 and 20 ms, and the amplitude of MEP may even quadruple [28,29]. The mechanism of ICF is not elucidated. ICF is reduced by the administration of the NMDA receptor antagonist dextromethorphan [30]. Hence, it is likely to be mediated by glutamatergic transmission.

1.5. Long-Interval Intracortical Inhibition 

Long-interval intracortical inhibition (LICI) requires a suprathreshold conditioning stimulus and ISI between 50 and 300 ms [31–33]. It is mediated predominantly by GABAB receptors [34,35].

1.6. Short-Latency Afferent Inhibition 

In short-latency afferent inhibition (SAI), the test stimulus is preceded by the electric stimulus to the contralateral, peripheral nerve, usually the median nerve, at the wrist. ISI depends on the latency of the responses recorded over the primary sensory cortex as somatosensory-evoked potential after electric stimulation on the same site as the conditioning stimulus. Usually, the latency is around 20 ms, and the respective ISI is 22 ms. 

Two milliseconds are added, as that is the time duration needed for the transmission via sensorimotor projections. In normal subjects, the conditioning stimuli should inhibit the test responses [36].

1.7. Repetitive Transcranial Magnetic Stimulation 

In rTMS, a series of magnetic stimuli are applied to repetitively depolarize targeted neurons. Repetitive depolarization induces synaptic plasticity, which outlasts the stimulation. Depending on the stimulation pattern, induced plasticity may be directed toward long-term potentiation (LTP) with the enhancement of synaptic transmission and increased neuronal firing and metabolism or long-term depression (LTD) with opposite changes. rTMS with high frequencies, i.e., five or more stimuli per second, and a more complex pattern called intermittent theta burst stimulation (iTBS), as well as several other less frequently used patterns, induce predominantly LTP, whereas low-frequency stimulation (one stimulus or less per second), continuous theta burst stimulation (cTBS) and several other protocols result predominantly in LTD [37]. 

One of the well-known neurophysiologic manifestations of induced plasticity is the increase in the MEP amplitude after high-frequency stimulation [38]. A clinical correlate is an increase in muscle strength or dexterity and a reduction of spasticity in post-stroke patients and other neurologic conditions [39–44]. Stimulation over non-motor cortical areas will induce other effects, which may also bring a therapeutic benefit [19]. While the effects of one rTMS session, consisting typically of several hundred to several thousand stimuli, last for minutes, hours, or rarely, days, repeated sessions may induce long-lasting effects, bringing significant alterations to the severity of psychiatric or neurologic disease and improving quality of life [19].

to be continued......

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Jakub Antczak, Gabriela Rusin * and Agnieszka Słowik

Department of Neurology, Jagiellonian University Medical College, Jakubowskiego 2, 30-688 Krakow, Poland; jakub.antczak@uj.edu.pl (J.A.); slowik@neuro.cm-uj.krakow.pl (A.S.) * Correspondence: grusin@su.krakow.pl; Tel.: +48-12-400-2550