**5. Discussion**

Julkunen and co-workers [33] have investigated functional connectivity between the motor cortex and other cortical regions. Fifty single TMS pulses 3 s apart were delivered to the motor cortex to evaluate spreading of navigated TMS-evoked EEG responses throughout the brain. Significant motor cortical differences from averaged left and right hemispheres in AD patients were observed. Using real-time integration of TMS and EEG, the authors also demonstrated prominent changes in cortical connectivity. The TMS-evoked response at 30–50 ms decreased significantly over multiple brain regions in patients with AD compared to both healthy elders and subjects with MCI. In particular, a significant reduction has been seen in the ipsilateral parietal cortex and contralateral fronto-central areas. In addition, a significant decrease in the N100 amplitude in the MCI subjects when compared with the control subjects has been found. In a subsequent study, Julkunen et al. [78] found that the TMS-EEG response P30 amplitude correlated with cognitive dysfunction and showed high specificity and sensitivity

RTMS is capable of modulating cortical excitability and inducing lasting effects [79, 80]; both have been shown to have potential therapeutic efficacy in cognitive neuroscience [81]. RTMS has been proven to influence cortical excitability and the metabolic activity of neurons. TDCS is another simple and powerful tool to modulate brain activity, which delivers constant low-intensity current (below the perceptual threshold, 1–2 mA) over the scalp via two large electrodes. The resulting constant electrical field penetrates the skull and influences neuronal function.

rTMS can be applied as continuous trains of low-frequency (1 Hz) or bursts of higher frequency (≥ 5 Hz) rTMS [81]. In general, low-frequency rTMS reduces, and high-frequency

The physiologic impact of both neuromodulatory techniques involves synaptic plasticity,

Three studies have dealt with rTMS effects on naming and language performance in AD patients. In two crossover, sham-controlled, single-session studies [82, 83], rTMS was applied to the dorsolateral prefrontal cortex (DLPFC) during the execution of naming tasks. In the first study, a significantly improved accuracy in action naming, but not in object naming, was observed after high-frequency rTMS of both the left or right DLPFC [82]. In the second study [83], the results of the previous study were obtained only in patients with mild AD (Mini-Mental-State-Examination (MMSE) ≥ 17/30), while in patients with moderate to severe AD (MMSE <17/30) both action and object naming were facilitated after rTMS over both left and right DLPFC. In a later study, Cotelli et al. [84] investigated whether the application of high-frequency rTMS to the left DLPFC may lead to a facilitation of language production and/ or comprehension in patients with moderate AD. Ten patients were assigned to one of two

in identifying healthy individuals from MCI or AD patients.

rTMS enhance excitability in the targeted cortical region.

**4.2. Repetitive transcranial magnetic stimulation**

**4. Therapeutic interventions**

12 Transcranial Magnetic Stimulation in Neuropsychiatry

**4.1. Neuromodulatory techniques**

specifically LTP and LTD.

This chapter intended to review the most relevant studies using non-invasive brain stimulation in dementias. A number of studies showed that several TMS techniques might represent a useful additional tool for the functional evaluation of patients with dementia. Among the studies focusing on motor cortical excitability measures, a particularly consistent and important finding is the significant reduction of SAI in AD patients. Abnormal SAI has also been reported in DLB [29] a form of dementia that responds to cholinergic medications [90]. In contrast, SAI was found to be normal in FTD [30], a non-cholinergic form of dementia. Therefore, SAI testing can be used as a non-invasive test for the assessment of cholinergic pathways in patients with dementia and may represent a useful additional tool in the differential diagnosis between the cholinergic and the non-cholinergic forms of dementia. Furthermore, TMS can thus be used to monitor AD progression and response to treatment [64]. It remains relatively unclear, how early in the course of the disease neurochemical and neuropathological alterations occur. However, neurobiological changes should be examined earlier in the disease process, when presumably they are more relevant for the pathogenesis of AD. Therefore, the findings that SAI abnormalities can be observed in patients with early diagnosis of AD [41] and even in patients with amnestic MCI-multiple domain may have potential diagnostic and therapeutic implications. Identification of SAI abnormalities that occur early in the course of the disease will allow earlier treatment with cholinergic drugs, and may be useful in identifying MCI individuals at increased risk of conversion to AD.

studies suggest that non-motor cortical regions, for example, temporo-parietal and frontal

Transcranial Magnetic Stimulation and Cognitive Impairment

http://dx.doi.org/10.5772/intechopen.75841

15

It should be noted that most of the TMS findings show considerable variability between studies. In addition to TMS methodological issues, age at disease onset and duration of disease, genetic factors may also represent a possible cause for such variability. It has been demonstrated that the Val66Met nucleotide polymorphism of the brain derivate neurotrophic factor (BDNF) gene differentially modulates brain plasticity and the response to transcranial stimulation [93]. In addition, the presence of Apolipoprotein E (*APOE*) and its ε4 allele is known to distinctively modulate the clinical phenotype of AD, as revealed by functional neuroimaging [94]. Therefore, the presence of BDNF-Val66Met polymorphism and of the *APOE-*ε4 may influence cortical excitability and plasticity as assessed by TMS. Moreover, it has been reported [95] that levels of total tau (t-Tau) detected in CSF of AD patients mediates abnormal excitatory activity, as measured with 1 Hz rTMS; CSF t-Tau may thus impact mechanisms of cortical plasticity.

The novel techniques of non-invasive neurostimulation have begun to be used to improve cognitive performances in AD. rTMS appears to be safe in patients with AD, even if long-term risks have not always been thoroughly evaluated. For all future studies a careful experimental design is needed and patient selection aspects, stimulation parameters, as well as clinical, cognitive and behavioral assessment tools should be considered. In fact, cognitive decline is not homogeneous across patients with AD and pathological features might affect neural networks differently. Of great importance would also be a careful choice of uniform and validate outcome measures, also to enable comparison across studies. Therefore, appropriately powered studies with more comprehensive outcome measures and sound blinding procedures are needed to confirm the effectiveness of rTMS in patients with dementia. On the other hand, the assumption that cortical plasticity enhancement is needed for the improvement of the cognitive status of patients with AD may be incorrect [96]. Even if TMS studies point to cortical hyperexcitability in AD, the employed techniques aimed at increasing cortical excitability. For this reason, the cortical physiology should be appropriately tested before and after therapeutic brain stimulation. In addition, high-frequency rTMS may not lead to an enhanced cortical excitability in AD. Indeed, rTMS effects are dependent on the baseline cortical activation

Finally, multiple-target stimulation protocols are necessary in order to overcome the widespread cognitive impairment in AD, especially in the more advanced stages of the disease [96].

1 Department of Neurology and Neuroscience Institute, Paracelsus Medical University

3 Karl Landsteiner Institute of Neurorehabilitation and Space Neurology, Salzburg, Austria

association cortices, are profoundly and early affected in AD.

state at the time of stimulation [97].

Stefan Martin Golaszewski1,3\* and Raffaele Nardone1,2 \*Address all correspondence to: s.golaszewski@salk.at

2 Department of Neurology, "F. Tappeiner" Hospital, Merano, Italy

**Author details**

Salzburg, Austria

The second most frequent cause of dementia following AD is VD. It was suggested that cholinergic mechanisms play a role also in the pathogenesis of VD; however, the role of the cholinergic system in the development of cognitive impairment is still under discussion in VD, also because previous studies failed to found significant SAI abnormalities in most VD patients.

Interestingly, the cumulative effect of micro bleeds (MBs) on cognition appears to be independent of coexisting ischemic cerebrovascular disease, in particular of the severity of ischemic subcortical VD as assessed by magnetic resonance imaging (MRI) white matter changes [68]. T2\* -weighted gradient echo-MRI may thus be a helpful adjunct to standard MRI in clarifying the mechanism of cognitive impairment in patients with cerebrovascular risk factors. Anyway, TMS studies in patients with VD and other dementias have some limitations. First, only post-mortem histology allows confirmation of the precise nature of dementia. Moreover, a simple visual evaluation of MRI was employed and not more advanced neuroimaging techniques, such as voxel-based morphometry, that could contribute to the identification of different forms of dementia.

The combination of TMS and EEG also enables the exploration of neural plasticity and connectivity across different neural networks. Encouraging findings, showing impaired cortical plasticity and functional connectivity between motor and non-motor brain regions in AD, have been obtained. This method may provide a novel tool for examining the degree and progression of dementia.

Overall, several issues should be more carefully addressed in future studies. The impact of TMS depends on the distance between targeted cortex and scalp, as the magnetic field decreases with distance [91]. Since regional cortical thinning has been observed in AD [92], brain atrophy can substantially alter the effect of TMS [81]. Volumetric studies of white matter volume and cortical thinning should thus be included in future studies in order to ameliorate the interpretation of TMS results in patients with cerebral atrophy and dementing illnesses.

On the other hand, the motor cortex does not seem the best cortical area to assess in AD patients, especially in the earlier stages of the disease. In fact, neuropathologic and neuroimaging

studies suggest that non-motor cortical regions, for example, temporo-parietal and frontal association cortices, are profoundly and early affected in AD.

It should be noted that most of the TMS findings show considerable variability between studies. In addition to TMS methodological issues, age at disease onset and duration of disease, genetic factors may also represent a possible cause for such variability. It has been demonstrated that the Val66Met nucleotide polymorphism of the brain derivate neurotrophic factor (BDNF) gene differentially modulates brain plasticity and the response to transcranial stimulation [93]. In addition, the presence of Apolipoprotein E (*APOE*) and its ε4 allele is known to distinctively modulate the clinical phenotype of AD, as revealed by functional neuroimaging [94]. Therefore, the presence of BDNF-Val66Met polymorphism and of the *APOE-*ε4 may influence cortical excitability and plasticity as assessed by TMS. Moreover, it has been reported [95] that levels of total tau (t-Tau) detected in CSF of AD patients mediates abnormal excitatory activity, as measured with 1 Hz rTMS; CSF t-Tau may thus impact mechanisms of cortical plasticity.

The novel techniques of non-invasive neurostimulation have begun to be used to improve cognitive performances in AD. rTMS appears to be safe in patients with AD, even if long-term risks have not always been thoroughly evaluated. For all future studies a careful experimental design is needed and patient selection aspects, stimulation parameters, as well as clinical, cognitive and behavioral assessment tools should be considered. In fact, cognitive decline is not homogeneous across patients with AD and pathological features might affect neural networks differently. Of great importance would also be a careful choice of uniform and validate outcome measures, also to enable comparison across studies. Therefore, appropriately powered studies with more comprehensive outcome measures and sound blinding procedures are needed to confirm the effectiveness of rTMS in patients with dementia. On the other hand, the assumption that cortical plasticity enhancement is needed for the improvement of the cognitive status of patients with AD may be incorrect [96]. Even if TMS studies point to cortical hyperexcitability in AD, the employed techniques aimed at increasing cortical excitability. For this reason, the cortical physiology should be appropriately tested before and after therapeutic brain stimulation. In addition, high-frequency rTMS may not lead to an enhanced cortical excitability in AD. Indeed, rTMS effects are dependent on the baseline cortical activation state at the time of stimulation [97].

Finally, multiple-target stimulation protocols are necessary in order to overcome the widespread cognitive impairment in AD, especially in the more advanced stages of the disease [96].
