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Transcranial Magnetic Stimulation (TMS) in Alzheimer's Disease (AD)

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Transcranial Magnetic Stimulation (TMS) in Alzheimer's Disease (AD)

Transcranial Magnetic Stimulation (TMS) is a non invasive and non lesion brain stimulation technique also used in research on neurodegenerative diseases including dementia due to Alzheimer’s Disease (AD).[1] Using TMS has contributed to better understanding of cortical neurophysiology of the ageing and degenerating brain and to identifying early AD.[2] Implementing TMS also resulted in mitigated cognitive dysfunction associated with AD such as action and object naming, verbal comprehension or enhanced episodic memory and associative memory, indicating the potential of TMS for therapeutic use of neurodegenerative diseases.[1][2][3]

Transcranial magnetic stimulation.jpg
Alzheimer dementia (3) presenile onset.jpg

TMS as indicator of AD pathophysiology[edit]

TMS was first used for stimulating the motor cortex resulting in muscle activity referred to as motor evoked potentials (MEPs). MEPs are altered in dementia and in AD due to degeneration of the primary motor cortex which is underpinned by the formation of neurofibrillary tangles and beta amyloid plaques.[4][3] Using TMS allows monitoring the changes in motor cortex excitability due to AD.[5]

Early evidence on altered motor cortex excitability[edit]

Early studies used TMS while recording MEPs from the target muscles of the limbs and it was found that motor cortex excitability was decreased in AD. This resulted in significantly higher MEP thresholds in elderly and AD participants, with missing MEPs in severely affected participants what indicates loss and/or dysfunction of motor cortex neurons in AD patients.[6][7] On contrary, other studies reported no difference in MEP thresholds after stimulating the motor cortex by TMS and neither was there a difference across the left hemisphere and right hemisphere.[5]

Recent evidence on altered motor cortex excitability[edit]

More recently, it was hypothesised that motor activity in AD is preserved and motor cortex hyper excitability in in AD patients was reported following TMS.[4]This was explained by possible neuronal reorganisation including the dysregulation of inhibitory gamma-amino butyric acid (GABA) neural circuits and their integration to excitatory neural networks demonstrating as decreased intra cortical inhibition (ICI) and lower MEP thresholds.[4] Decreased MEP thresholds and hyper excitability were also significantly correlated with the stage of cognitive impairment severity.[8] Further findings indicated that decreased ICI was abolished by acetyl cholinesterase inhibitors (AchI) and this finding pinpointed the possible link of acetylcholine (Ach) pathways to GABA pathways.[9] These results suggest that TMS has the potential to monitor the progress of the disease and assess the effect of pharmacological therapies for AD.[10] Conversely a group of mild to moderate AD patients was compared to healthy controls after administering repetitive TMS (rTMS) resulting in AD patients lacking MEP facilitation. This suggests an altered cortical plasticity in excitatory glutamaergic circuits within the motor cortex of AD patients.[11]

Summary of TMS and AD pathophysiology[edit]

Literature reviews concluded that TMS can indicate changes in neurophysiology in AD by detecting alterations in motor cortex excitability demonstrating as decreased ICI and cortical reorganisation of motor output.[12][13] Motor cortex hyper excitability and sub clinical motor reorganisation were detected in early AD. These findings are dominant across studies in contrast to findings reporting hypo excitability. Hyper excitability is thought to be a compensatory mechanism, but it remains unclear if it is down to over involvement of glutamaergic circuits or impairment of GABA ergic activity.[12][13] Furthermore different research studies explain reorganisation as a shifting and integration of frontal inhibitory centres to the motor excitatory networks.[12][14]

TMS and AD assessment[edit]

The idea of diagnosing AD by TMS is inspired by the findings about the changes in motor cortex excitability in AD detectable by TMS earlier than the actual symptoms.[9] One study found different patterns of cortical excitability in early possible AD patients compared to fronto-teporal dementia (FTD) patients by using TMS.[9] This suggests that TMS is useful for distinguishing AD form other types of dementia. Importantly, reduced short latency afferent inhibition (SAI) demonstrating as suppressed MEPs after stimulating the afferent nerves of the hand was present in AD but not in FD.[15][9] Vascular dementia and AD can be also differentiated based on differences in SAI, however SAI was almost equally impaired in dementia with Lewy bodies. Based on this, investigating changes in SAI by TMS can be used for assessing and differentiating cholinergic and non cholinergic types of dementia and for estimating the degree of impairment of cholinergic pathways.[14] Furthermore using TMS combined with electroencephalography (EEG) indicated strong TMS-EEG response of the P30 amplitude which was significantly reduced and correlated with cognitive decline in AD compared to mild cognitive impairment (MCI). This technique showed good specificity and sensitivity to identifying healthy controls form participants with MCI or AD suggesting that this method could be useful for assessing MCI and AD.[16]

TMS as potential treatment of AD symptoms[edit]

Administering TMS resulted in improved cognitive abilities of AD patients such as for instance general mental state,[17] attention and psychomotor speed[18], language abilities,[17][19][20][21][22][23] memory performance[24] and also apathy and dependence on caregivers[25].

TMS and cognitive symptoms in AD[edit]

Numerous randomised control trials (RCT) showed effectiveness in treating cognitive symptoms associated with AD.[26][27] A pilot study reported significant improvement of attention and psychomotor speed after rTMS to the right inferior frontal gyrus.[18] Improvement of cognitive symptoms in AD was even more salient and maintained over three months after using high frequency rTMS (> 5 Hz) administered once a day across five days bilaterally to dorso lateral prefrontal cortex (dlPFC).[17] Furthermore, results were even better when combined with cognitive training.[22][23]

TMS and language dysfunction in AD[edit]

Evidence indicated that TMS could possibly tackle different aspects of language impairment in AD such as action naming[19] or difficulty to find words called anomia.[20] Administering rTMS to the dlPFC also improved auditory sentence comprehension with a lasting effect for up until eight weeks.[21] In addition, improved language abilities were reported after rTMS by functional magnetic resonance imaging (fMRI) showing higher activation in the rTMS stimulated areas.[28]

TMS and associative memory in AD[edit]

TMS was also tested for treating memory problems in older people with dysfunctional memory. One RCT reported significant immediate improvement of associative memory after administering rTMS to the prefrontal cortex of twenty older participants with subjective memory problems and low memory performance[24].

Summary of TMS as potential treatment for AD[edit]

The above findings are supported by systematic literature reviews summarising that almost all studies on MCI and AD used high frequency rTMS and the most commonly stimulated site was the dlPFC. There was a high variation on the number of pulses administered per day and the frequency range was also high (5-25HZ). Some studies mentioned headaches and tiredness as side effects.[29] Furthermore, accounting for rTMS as well as transcranial direct current stimulation (tDS) in both healthy older adults as well as adults with AD a meta analysis reported significant effect size of 1.35 for cognitive outcomes for AD after non invasive brain stimulation.[30] This was more prominent for ‘online’ stimulation when participants were engaged in a cognitive task during the stimulation. Based on these reports, brain stimulation seems to be a promising method to ease the consequences of cognitive decline in older adults and patients with AD .[30][12][31]

Criticism, future directions and ethical considerations[edit]

In general TMS in AD research is criticised for methodological issues such as too small sample sizes, high between subjects variability and methodological heterogeneity leading to discrepancies in evidence. Furthermore the age, onset of the disease, levels of atrophy[32][33] and genetic factors may also be potential cofounds in studies.[29][33][13] Also, the underlying neuronal mechanisms are not well understood[30]and there is a lack of understanding of the long lasting effects of rTMS as a possible therapy for AD[29]. In terms of using TMS for researching the neuropathology in AD, the motor cortex is not the best cortical target to study as there are other affected brain areas negatively impacting on cognitive and overall functioning.[33] Limitations of using rTMS as AD treatment are based on the reasoning that rTMS is exciting the cortex which is already hyper excitable, thus it is not known if these areas will benefit from being further exited. Also, cognitive function is more complex than just performing on different tasks and more comprehensive tasks applicable to every day performance are needed for assessing AD by TMS.[33][14] Moreover, there is a need to standardise the TMS procedure and optimise the stimulation parameters, length and frequency of treatment and agree on specific cortical areas to be consistently stimulated.[28] Future directions of using TMS in AD are proposed in terms of the use of TMS with other imaging methods and progressing form TMS to deep brain stimulation.[29][12][34] However, these stimulation technologies have a potential to impact on personal identity and the ethical consequences of this are not to be overseen while conducting research by these means.[35]

See Also[edit]

Transcranial Direct Current Stimulation

Deep Brain Stimulation

Brain Stimulation


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