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

2. Materials and Methods 

We conducted this review following the Scale for the Assessment of Narrative Review Articles items [45]. We included clinical studies regarding: (1) the use of TMS parameters as dementia biomarkers and (2) the use of repetitive TMS in the treatment of dementia. We searched the electronic databases of MEDLINE through PubMed (United States National Library of Medicine, Bethesda, MD, USA), Scopus (Elsevier, Amsterdam, Netherlands), and Google Scholar (Google, Mountain View, CA, USA).for relevant research articles published up to March 2021. 

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The search strategy consisted of the following terms used in combination: “transcranial magnetic stimulation”, “TMS”, “dementia”, “cognitive impairment”, “Alzheimer’s disease”, “dementia with Lewy bodies”, “frontotemporal dementia”, “vascular dementia”, “Parkinson’s disease”, “mild cognitive impairment”, “diagnostics”, “diagnosis”, “therapy”, “treatment”, “biomarker”. We modified the search strategy for other methods (MeSH or free text terms), as appropriate. We conducted additional manual searches of the references of the related articles to gather information about the relevant supporting literature. In the following sections, we present the diagnostic and therapeutic utility of TMS in particular types of dementia.

3. Alzheimer’s Disease 

Alzheimer’s disease (AD) is the most common type of dementia, affecting about 3.9% of people over 60 years of age [46]. Distinctive clinical features of AD include short-term memory loss, speech deficits, lack of motivation and self-care, and prominent changes in behavior and mood. In the late stages, patients reveal motor disturbances such as rigidity and hypokinesia. Extracellular amyloid beta-protein deposition with intracellular clusters of hyperphosphorylated tau protein are the neuropathological hallmarks of AD. These changes primarily affect cholinergic transmission [47].

3.1. Increased Cortical Excitability in AD 

The first data, which were obtained with single-pulse TMS, revealed a decrease of MT [48,49] as a marker of hyperexcitability in AD patients, which was confirmed in further research [50]. It is observed even in the early stages of AD, long before the onset of the motor symptoms [51], and probably reflects the presence of AD-specific pathologic changes in the primary motor cortex [52]. In advanced stages of AD, MT increases due to marked cortical atrophy and the decrease in the density of cortico-spinal tract fibers [53,54].

3.2. Impaired Cortical Plasticity 

An increase in the amplitude of MEP after sessions of rTMS, which occurs in healthy subjects, does not occur in AD or is significantly limited [55,56]. Interestingly, the other direction of cortical plasticity, i.e., LTD after low-frequency rTMS, is probably significantly better preserved [57].

3.3. Impaired Cortical Inhibition 

Studies have consistently revealed the impairment of SAI in AD [58–65]. Reduction of SICI and LICI was reported less consistently [49,58,66–70]. However, together with MT, all three parameters showed significant differences in comparison to healthy controls in a recent meta-analysis [71]. ICF, on the other hand, was not altered [71]. Acetylcholinesterase inhibitors used to delay AD progression enhance cortical inhibition, expressed by SAI and SICI [60,72,73], with no impact on excitability (MT) [72,73].

3.4. Diagnostic Sensitivity and Specificity 

According to a meta-analysis by Mimura et al. [71], the effect size of MT and SAI decrease in AD is large, and it is medium for the decrease of SICI. Recently, Benussi et al. [65] conducted a multicenter study to examine the classification performance of TMS outcome measures in the differential diagnosis of three neurodegenerative dementias.

They included 273 patients diagnosed with AD, 67 with DLB, and 207 with FTD. Measurements included MT, SICI, LICI, ICF, and SAI. The machine learning model was employed to make a diagnosis based on the derived parameters. The classification accuracy yielded was very high (ranging from 0.89 to 0.92) as were the precision (0.86–0.92) and other parameters of overall diagnostic accuracy. Another study investigated TMS as an adjuvant diagnostic tool for routine clinical assessment [63]. TMS increased diagnostic accuracy from 82% (clinical work-up alone) to 98%, while PET and cerebrospinal fluid-based markers of amyloidosis increased the accuracy to 99%.

3.5. Therapy with rTMS 

Among dementia types, the therapeutic potential of rTMS has been investigated extensively in AD. In most reports, the DLPFC, uni- or bilaterally, or the precuneus was selected as the target for high-frequency (between 10 and 20 Hz) stimulation [74–76]. In the majority of studies, a beneficial effect was documented in various neurocognitive testing such as the AD Assessment Scale-cognitive subscale (ADAS-cog), the Mini-Mental State Examination (MMSE), and the Montreal Cognitive Assessment (MoCA). The studies were, however, small and, in many cases, uncontrolled. Among trials with rTMS, the study of Lee et al. [77] gained special attention, as the therapeutic effect exceeded that of acetylcholinesterase inhibitors. The study was among the few that used a multi-site rTMS approach. 

Stimulation of both dorsolateral prefrontal and parietal somatosensory-associated cortices as well as Broca’s and Wernicke’s areas were interleaved with specifically sequenced cognitive training. A similar approach was investigated in a recent multicenter study, which recruited over 130 patients with mild to moderate AD [78]. Thirty daily sessions of 10 Hz rTMS over six areas (targeted with help of the neuronavigation system) were combined with cognitive training, building up the therapeutic system known as neuroAD™ (Neuronix Ltd., Israel). The results showed improvement in ADAS-cog that lasted over a month after the therapy and which was not present in the sham group. Another study using the neuroAD™ Therapy System confirmed the beneficial effect on cognition and also noted the correlation of the therapeutic effect with the preservation of cortical plasticity in the course of AD [79]. The multisite approach is, to date, the only rTMS procedure for dementias that has obtained a therapeutic recommendation of IFCN [19]. 

One has to bear in mind that the patients recruited to studies with TMS were diagnosed in vivo and therefore, some heterogeneity within the treated groups cannot be excluded. Moreover, while the majority of the studies involved subjects diagnosed with possible/probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) [48–51,54,56–58,60–62,67–70,72,79], only a few used its revised version and recommendations the from National Institute on Aging-Alzheimer’s Association (NIA-AA) incorporating biomarkers (including [63,65,75,79]) [80–82]. These factors may potentially compromise diagnostic reliability and the therapeutic efficacy of rTMS in AD, and the need for long-term, longitudinal studies including autopsy reports is emerging as the use of TMS in patients with dementia increases. The incorporation of TMS into diagnostic and therapeutic workups, although warranted by published results, must be done with caution and in the proper context of clinical data and other diagnostic and therapeutic options.

4. Vascular Dementia 

Vascular dementia is the second most common type of dementia and is defined as cognitive dysfunction where a cerebrovascular or cardiovascular disease is a causative or contributing factor. Vascular cognitive impairment is a broad term encompassing all sorts of cognitive disorders caused by vascular brain injury or dysfunction leading to cerebral blood flow impairment [83]. Similarly to AD patients, those with VAD show reduced RMT across studies [70,84–86]. Only a few studies have reported the impairment of SAI [70,87], and another study has shown that SAI may be normal [88]. Such a discrepancy seems to represent the frequent overlap between those two entities [15,84]. SAI is more consistently impaired in a specific, genetic form of VAD called cerebral, autosomal-dominant arteriopathy with subcortical infarcts (CADASIL) [89], often with a decrease in ICF [90–92]. 

Interestingly, impairment of SAI cannot be reversed by dopamine in CADASIL, while it can in AD [92]. This finding reflects the differences in the mechanisms of impairment of cholinergic transmission which in CADASIL, may not be the result of neurodegenerative processes but of the specific locations of the infarcts, which interfere with the cholinergic pathways [92]. In most studies, other parameters obtained with TMS seem not to be consistently changed in VAD [13]. Therapeutic studies in humans are limited to one pilot trial by Rektorova et al. [93], where one session of high-frequency rTMS over the left DLPFC improved executive functions. In contrast, a large number of studies have investigated magnetic stimulation in animal models of VAD, mainly with promising results [94–100].

5. Dementia with Lewy Bodies 

DLB is a synucleinopathy affecting the subcortical structures and is regarded as the third most common type of dementia. Typical clinical features include cognitive fluctuations, a decline of executive functions, parkinsonian syndrome without tremors, visual hallucinations, and oversensitivity to neuroleptics. It is classified as one of the types of atypical parkinsonism along with progressive supranuclear palsy, corticobasal syndrome, and others. Despite all of them having their distinctive clinical features, the differential diagnosis is still challenging. Moreover, the clinical picture of DLB at an early stage might overlap with AD. Cognitive decline in both AD and DLB may be associated with the disconnection of cortical areas from their source of cholinergic innervations of the basal forebrain (nucleus basalis of Meynert and the medial septum nuclei) and nuclei of the brainstem (pedunculopontine nucleus) [101]. Diagnostic accuracy may be improved in DLB using presynaptic dopaminergic imaging, but the method still lacks sufficient validation on neuropathological diagnosis [102]. 

Similarly to AD, several studies with TMS have reflected the impairment of cholinergic transmission by showing a decrease in SAI [62,103]. Interestingly, while a decrease in SAI was comparable between AD and DLB patients, it showed a correlation with the severity of different symptoms, i.e., with visual hallucinations in DLB and a manic state in AD [62]. A study of [104], which preceded both mentioned studies, showed contradictive results, with SAI being significantly decreased only in AD, but not in DLB patients. The authors supposed that the cortical–cortical disconnection in DLB patients was less pronounced than in AD. This notion may be supported by the fact that in studies conducted on bigger samples, the difference in SAI between DLB and healthy controls has reached statistical significance [62,104,105]. Furthermore, in contrast to AD, no significant changes in MT are observed in DLB, which corresponds with the clinical lack of pyramidal signs [103,106]. 

A study using ppTMS revealed reduced SICI and ICF in DLB, cortico-basal syndrome (CBS), and PSP, but not in AD [105]. On the other hand, SAI was decreased in both AD and DLB, but not in PSP and CBS. These results characterize the pathology of DLB, which involves not only the disruption of cortical inhibition and facilitation mediated by GABAB and glutaminergic circuits but also the impairment of cholinergic transmission. In addition, the study documented the diagnostic potential of multimodal TMS measurements: The authors used neurophysiological outcome measures to construct a diagnostic decision tree model to correctly allocate patients with studied types of atypical parkinsonism and healthy controls. The results yielded a diagnostic accuracy of 85.2% for DLB subjects. 

A unique finding among dementias was the correlation between the phosphene threshold and the severity of visual hallucinations [107]. Phosphenes are the visual hallucinations that are experienced after TMS over the occipital area. The study, however, did not find differences in the phosphene threshold between patients and healthy controls, and the relevance of the documented correlation has not been investigated in further studies. Only one study used rTMS in DLB. In the six subjects, an improvement in depression was seen [108]. The influence of rTMS on other symptoms was not investigated.

6. Frontotemporal Lobar Degeneration 

Frontotemporal lobar degeneration (FLTD) is a group of degenerative disorders affecting the temporal and/or frontal lobes, consisting of a primary progressive aphasia (PPA) and frontotemporal lobar dementia (FTD) with its subtypes of behavioral variant (bv-FTD), progressive non-fluent aphasia (PNFA) and semantic dementia [109]. The leading symptoms may be social behavior or personality disturbances and/or disordered speech. In a proportion of patients, signs of motor neuron impairment or extrapyramidal symptoms coexist. The accumulations of cortical tau or TDP-43 inclusions are the pathological hallmarks of FTLD [110]. Single-pulse TMS studies in FTD revealed impairment of the corticospinal tract such as reduced or absent MEP or prolonged central motor conduction time in a significantly larger proportion of patients than those presenting clinical signs from upper motor neurons [72,111]. This finding seemed to be especially robust among patients with PNFA [111]. 

ppTMS studies have shown impaired glutamatergic and GABAergic neurotransmission. The aforementioned, multicenter study and other studies have documented the reduction of ICF, SICI, and LICI with the preservation of SAI [72,112,113]. Recently, a group of patients with FTD underwent iTBS and cTBS of primary motor areas to explore cortical plasticity. Interestingly, the response to both stimulations (increase and decrease of MEP amplitude, respectively) was decreased only among patients presenting extrapyramidal symptoms [114]. In another recent study, TMS was successfully used to monitor a therapeutic trial for FTD with palmitoylethanolamide combined with luteolin. Beneficial cognitive effects, mediated probably by anti-inflammatory and neuroprotective mechanisms, were seen in the Neuropsychiatric Inventory (NPI) and Frontal Assessment Battery (FAB). Concurrently, the restoration of LICI and the enhancement of TMS-induced, high-frequency oscillations were registered [115]. Finally, some improvement in the results of the Montreal cognitive assessment and other cognitive tests was seen in FTD after high-frequency rTMS over bilateral prefrontal areas in a small, open study [116].

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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