**3. Cortical excitability, connectivity and plasticity**

#### **3.1. Motor threshold**

Most of the studies found significantly reduced RMT in neuropsychiatric disorders as compared with healthy subjects [24–36], while other reports have found a tendency toward a reduced RMT without statistical significance [37–44]. One study noted no difference in RMT between patients with Alzheimer disease (AD) and controls [45], while [46] found increased RMT in AD patients. It can be hypothesized that, in the early stages, mechanisms related to RMT are preserved [45], or that RMT changes reflect functional damage of cortical motor neurons. As the disease progresses, the decrease in RMT might be compensatory to the loss of motor cortex neurons [36, 39]. In a combined TMS-MRI study [47], it was reported recently that motor cortex excitability did not correlate with the cortical thickness in AD subjects. It can be hypothesized that a protective mechanism of hyperexcitability on the sensorimotor cortex may counteract the loss of cortical volume. This protective mechanism was not found in the patients with mild cognitive impairment (MCI). Lahr et al. [48] could show in MCI patients with the TMS technique of paired-associative stimulation (PAS) that there is no difference in synaptic long-term potentiation (LTP)-like plasticity between MCI patients and healthy controls [48]. Another study with transcranial magnetic stimulation addressed mild cognitive impairment in the elderly [49]. About 10 Hz rTMS everyday enhanced memory in the elderly MCI patients after 10 sessions. Thus, rTMS might be effective in cognitive therapy for MCI patients. In a recent study, Nardone et al. [50] found a normal short-latency afferent inhibition (SAI) in 20 subjects with subjective memory impairment [50]. An abnormal SAI was reported in amnestic multiple domain mild cognitive impairment patients. Therefore, SAI holds promise to be a useful biomarker for differentiating individuals with subjective memory complaints those in whom cholinergic degeneration has occurred.

subcortical ischemic disease without dementia [54]. In a study of Guerra et al. [55], there is evidence for common compensatory mechanisms in subcortical ischemic vascular dementia as it is known from Alzheimer's disease [55] supporting the idea that cortical hyperexcitability can promote cortical plasticity. These results indicate that motor cortex hyperexcitability is

Transcranial Magnetic Stimulation and Cognitive Impairment

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

9

Most studies found no significant differences in MEP amplitude between patients with AD and healthy subjects [25, 27, 31–33, 38, 45, 46], while significant increases in MEP amplitude in AD patients were detected in fewer studies [24, 26, 36]. Interestingly, the center of gravity of motor cortical output shows a frontal and medial shift in patients with AD, without changes in the hot-spot location [39]. This finding may indicate functional reorganization,

MEP amplitude was found to be larger in patients with subcortical ischemic VD with demen-

None of the studies that examined CMCT in AD [24, 26, 27, 40–42, 46] found statistically significant differences between patients and healthy age-matched subjects. These results confirm that the integrity of the corticospinal tract is not compromised at least in mild to moderate

In contrast, Di Lazzaro et al. [30] found that cortical excitability to single-pulse TMS was impaired in 5 out 20 patients with frontotemporal dementia (FTD). In three patients, MEPs were absent, and a very small MEP was obtained only at maximum stimulator output in two patients. In agreement with these results, patients with FDT are more likely than patients with AD to have motor abnormalities. This finding suggests that TMS may reveal subclinical central motor pathways involvement in patients with FTD. Paired pulse TMS applying the parameters SICI, ICF and SAI can also distinguish AD from FTD with a sensitivity of 91.8% and specificity of 88.6% [56]. AD patients show an impairment of SAI, while FTD shows a

A significant reduction of SICI was found by some authors [35, 40, 42, 45], but most studies did not find differences in SICI between AD patients and control subjects [27–29, 31, 36, 37, 41]. In a study, the amount of disinhibition was found to correlate with the severity of AD [40]. Most studies by [25, 27, 32, 40], but not all [24, 46] studies failed to find any significant differences in the cSP duration between AD patients and healthy controls. Taken together, these findings do not support impairments in GABAergic inhibitory circuits in AD. On the other hand, dysfunction of GABAergic circuits has not been demonstrated, and the GABA system

Di Lazzaro et al. found an impairment of SICI in 16% of patients with VD [29]. One study showed a decrease in cortical benzodiazepine receptors in patients with VD due to leukoaraiosis [58],

a common finding in different dementing illnesses, subcortical or cortical in origin.

**3.2. Motor evoked potential amplitude and central motor conduction time**

likely including the dysregulation of the inhibitory frontal centers [39].

remarkable dysfunction of SICI and ICF parameter.

seems to be relatively spared in AD [57].

**3.3. Cortical silent period, intracortical inhibition and facilitation**

stages of AD.

tia than in patients with subcortical ischemic disease without dementia [54].

There are a few studies that have assessed AMT in AD patients; only two found significant decreases in AMT when compared with healthy subjects [31, 36]. Therefore, the excitability of spinal projections seems to be relatively preserved during early course AD.

The increased excitability to TMS in AD patients may be the functional correlate of an abnormal glutamatergic system. This hypothesis has been supported by a study demonstrating an altered response to rTMS in AD patients [32].

In contrast with AD patients, patients with dementia with Lewy bodies (DLB) present a normal excitability to single-pulse TMS [29, 51]. This finding suggests that the glutamatergic system is not involved in DLB patients. However, cortical excitability to visual stimuli of lower visual areas (V1–3) as measured by TMS appears to be normal in DLB. TMS-determined phosphene threshold and fMRI-related visual activation shows a positive relationship in controls but a negative one in DLB that suggests a loss of inhibition in the visual system in DLB, which may predispose individuals to visual dysfunction and visual hallucinations [52].

Patients with vascular dementia (VD) have decreased RMT [29, 53]. This increased excitability could represent a functional consequence of the vascular lesions. RMT was recently found to be significantly lower in patients with subcortical ischemic VD, but not in patients with subcortical ischemic disease without dementia [54]. In a study of Guerra et al. [55], there is evidence for common compensatory mechanisms in subcortical ischemic vascular dementia as it is known from Alzheimer's disease [55] supporting the idea that cortical hyperexcitability can promote cortical plasticity. These results indicate that motor cortex hyperexcitability is a common finding in different dementing illnesses, subcortical or cortical in origin.

#### **3.2. Motor evoked potential amplitude and central motor conduction time**

**3. Cortical excitability, connectivity and plasticity**

memory complaints those in whom cholinergic degeneration has occurred.

spinal projections seems to be relatively preserved during early course AD.

may predispose individuals to visual dysfunction and visual hallucinations [52].

altered response to rTMS in AD patients [32].

There are a few studies that have assessed AMT in AD patients; only two found significant decreases in AMT when compared with healthy subjects [31, 36]. Therefore, the excitability of

The increased excitability to TMS in AD patients may be the functional correlate of an abnormal glutamatergic system. This hypothesis has been supported by a study demonstrating an

In contrast with AD patients, patients with dementia with Lewy bodies (DLB) present a normal excitability to single-pulse TMS [29, 51]. This finding suggests that the glutamatergic system is not involved in DLB patients. However, cortical excitability to visual stimuli of lower visual areas (V1–3) as measured by TMS appears to be normal in DLB. TMS-determined phosphene threshold and fMRI-related visual activation shows a positive relationship in controls but a negative one in DLB that suggests a loss of inhibition in the visual system in DLB, which

Patients with vascular dementia (VD) have decreased RMT [29, 53]. This increased excitability could represent a functional consequence of the vascular lesions. RMT was recently found to be significantly lower in patients with subcortical ischemic VD, but not in patients with

Most of the studies found significantly reduced RMT in neuropsychiatric disorders as compared with healthy subjects [24–36], while other reports have found a tendency toward a reduced RMT without statistical significance [37–44]. One study noted no difference in RMT between patients with Alzheimer disease (AD) and controls [45], while [46] found increased RMT in AD patients. It can be hypothesized that, in the early stages, mechanisms related to RMT are preserved [45], or that RMT changes reflect functional damage of cortical motor neurons. As the disease progresses, the decrease in RMT might be compensatory to the loss of motor cortex neurons [36, 39]. In a combined TMS-MRI study [47], it was reported recently that motor cortex excitability did not correlate with the cortical thickness in AD subjects. It can be hypothesized that a protective mechanism of hyperexcitability on the sensorimotor cortex may counteract the loss of cortical volume. This protective mechanism was not found in the patients with mild cognitive impairment (MCI). Lahr et al. [48] could show in MCI patients with the TMS technique of paired-associative stimulation (PAS) that there is no difference in synaptic long-term potentiation (LTP)-like plasticity between MCI patients and healthy controls [48]. Another study with transcranial magnetic stimulation addressed mild cognitive impairment in the elderly [49]. About 10 Hz rTMS everyday enhanced memory in the elderly MCI patients after 10 sessions. Thus, rTMS might be effective in cognitive therapy for MCI patients. In a recent study, Nardone et al. [50] found a normal short-latency afferent inhibition (SAI) in 20 subjects with subjective memory impairment [50]. An abnormal SAI was reported in amnestic multiple domain mild cognitive impairment patients. Therefore, SAI holds promise to be a useful biomarker for differentiating individuals with subjective

**3.1. Motor threshold**

8 Transcranial Magnetic Stimulation in Neuropsychiatry

Most studies found no significant differences in MEP amplitude between patients with AD and healthy subjects [25, 27, 31–33, 38, 45, 46], while significant increases in MEP amplitude in AD patients were detected in fewer studies [24, 26, 36]. Interestingly, the center of gravity of motor cortical output shows a frontal and medial shift in patients with AD, without changes in the hot-spot location [39]. This finding may indicate functional reorganization, likely including the dysregulation of the inhibitory frontal centers [39].

MEP amplitude was found to be larger in patients with subcortical ischemic VD with dementia than in patients with subcortical ischemic disease without dementia [54].

None of the studies that examined CMCT in AD [24, 26, 27, 40–42, 46] found statistically significant differences between patients and healthy age-matched subjects. These results confirm that the integrity of the corticospinal tract is not compromised at least in mild to moderate stages of AD.

In contrast, Di Lazzaro et al. [30] found that cortical excitability to single-pulse TMS was impaired in 5 out 20 patients with frontotemporal dementia (FTD). In three patients, MEPs were absent, and a very small MEP was obtained only at maximum stimulator output in two patients. In agreement with these results, patients with FDT are more likely than patients with AD to have motor abnormalities. This finding suggests that TMS may reveal subclinical central motor pathways involvement in patients with FTD. Paired pulse TMS applying the parameters SICI, ICF and SAI can also distinguish AD from FTD with a sensitivity of 91.8% and specificity of 88.6% [56]. AD patients show an impairment of SAI, while FTD shows a remarkable dysfunction of SICI and ICF parameter.

#### **3.3. Cortical silent period, intracortical inhibition and facilitation**

A significant reduction of SICI was found by some authors [35, 40, 42, 45], but most studies did not find differences in SICI between AD patients and control subjects [27–29, 31, 36, 37, 41]. In a study, the amount of disinhibition was found to correlate with the severity of AD [40]. Most studies by [25, 27, 32, 40], but not all [24, 46] studies failed to find any significant differences in the cSP duration between AD patients and healthy controls. Taken together, these findings do not support impairments in GABAergic inhibitory circuits in AD. On the other hand, dysfunction of GABAergic circuits has not been demonstrated, and the GABA system seems to be relatively spared in AD [57].

Di Lazzaro et al. found an impairment of SICI in 16% of patients with VD [29]. One study showed a decrease in cortical benzodiazepine receptors in patients with VD due to leukoaraiosis [58], thus the abnormality of SICI in some VD patients might be related to the disruption of inhibitory GABAergic circuits. However, a study provides evidence of functional changes also in excitatory cortical circuits in patients with subcortical ischemic vascular disease and cognitive impairment (but no dementia) [59].

SAI was evaluated in 20 patients with FTD and compared data with those from 20 patients with AD and 20 control subjects [30]. SAI was normal in FTD, whereas it has been reduced in AD. SAI may thus represent an additional tool to discriminate FTD from AD. These findings are consistent with post-mortem studies showing central cholinergic deficits in AD [72–74]

Transcranial Magnetic Stimulation and Cognitive Impairment

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

11

A reduced SAI has been found in patients with VD, but not to the same extent as AD. Nardone et al. [66] reported that SAI responses in patients with subcortical ischemic VD varied widely, ranging from normal to markedly reduced values. In another TMS study, significant SAI abnormalities were disclosed in 3 out of 12 patients with VD [29]; SAI was strongly correlated with neuropsychological measures of long-term memory and other cognitive functions. In patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the amount of SAI was found to be significantly smaller than in normal subjects [76]. This finding supports the hypothesis of a central cholinergic system impairment in CADASIL. Interestingly, Mesulam [77] demonstrated that pure white matter infarcts, similar to those seen in subcortical VD, can cause cortical cholinergic denervation.

It should be considered that AD and VD are not mutually exclusive conditions; VD patients with SAI abnormalities could have concomitant neuropathological changes of AD and thus

In contrast to AD where the major features of the cholinergic neuropathology show few interindividual variations, VD may show considerable interindividual variation in the location of subcortical infarcts and, therefore, in the distribution and magnitude of the resultant cortical cholinergic deficits. In contrast to AD, where there are a few interindividual variations in the pattern and extent of the cholinergic neuropathology, VD may show considerable interindividual variation in the location of subcortical infarcts and, therefore, in the distribution and

Some studies have examined non-invasively motor cortical plasticity and functional connectivity in AD. Inghilleri et al. [32] investigated the effects of modulation of cortical motor areas induced by suprathreshold high-frequency (5 Hz) rTMS. Whereas in control subjects 5 Hz-rTMS elicited normal MEPs that progressively increased in size, in AD patients the amplitude of MEPs progressively decreased during the training. These results suggest an altered cortical plasticity in excitatory motor cortical circuits in AD. Conversely, 5 Hz rTMS induced an increase in cSP in both groups, thus indicating a normal plasticity of the cortical inhibitory circuits. Battaglia et al. [38] studied LTP-like plasticity of the motor cortex in AD patients and healthy subjects by employing PAS with interval between peripheral nerve stimulation and TMS set at 25 ms (PAS25); they also performed biochemical analyses in brain slices of amyloid precursor protein (APP)/presenilin-1 (PS1) mice, an AD animal model. PAS-induced plasticity has been significantly reduced in AD patients; moreover, 4–4.5-month-old APP/PS1 mice exhibited deficits of NMDA receptor-dependent neocortical and hippocampal long-term potentiation (LTP), and a marked alteration of NMDA

represent the percentage of patients with a mixed form of dementia.

magnitude of the resultant cortical cholinergic deficit.

**3.5. Cortical plasticity and functional connectivity**

but not in FTD [75].

receptor activity.

Alberici et al. [37] found that patients with FTD were comparable with healthy subjects and AD patients for SICI and ICF. In contrast, patients with corticobasal degeneration (CBD) presented significantly reduced SICI at ISI 3 ms, the selective impairment of intracortical inhibition in CBD may help in distinguishing among the FTD clinical spectrum.

None of the previous studies has found significant changes in ICF in patients with AD as compared to healthy controls [27, 35–37, 40–42, 45]. These findings seem to point to a normal NMDA receptor-dependent glutamate excitatory activity in AD, as tested by this cortical excitability measure. However, other studies suggest that abnormalities of glutamatergic neurotransmission might play an important role in AD. The glutamatergic hypothesis of AD has been proposed as an auxiliary mechanism to the cholinergic hypothesis [39] and this may be due to an imbalance between the non-NMDA and NMDA neurotransmission [39, 60–63].

### **3.4. Short-latency afferent inhibition**

The most consistent finding of abnormal cortical excitability in AD patients regards SAI. In fact, all studies reported significant reductions of SAI in patients with AD as compared to healthy individuals [27, 29–31, 34, 41, 42, 44, 60, 64, 65]. SAI was also found to be negatively correlated with performance in abstract thinking [29, 31] and long-term memory [29]. SAI testing may be a useful marker of central cholinergic dysfunction even in early stages of AD [66], while it was found to be not significantly reduced in subjects with MCI [44]. However, in this study the diagnosis of MCI was based on criteria proposed by Petersen in 1999 instead of the revised ones [67] and the relationships to the different MCI subtypes was not defined. In a more recent study, a reduced SAI was found in amnestic MCI-multiple domain patients, while SAI was not significantly different in amnestic MCI-single domain patients and in nonamnestic MCI patients [68].

SAI is significantly reduced also in adults with Down Syndrome (DS) and Alzheimer-type dementia [51] the values correlated with the patient's age and the score on Dementia Scale for DS. This technique may thus represent an additional tool for the diagnosis of Alzheimer-type dementia in subjects with DS.

Nardone et al. [51] described this putative marker of cholinergic activity in patients with DLB and showed a clear tendency toward a reduced SAI. These authors performed SAI testing without randomization of different conditions and the diagnosis of DLB was based on criteria proposed in 1996 instead of the revised ones [69]. Di Lazzaro et al. [29] examined 10 patients with a clinical diagnosis of DLB according to the NINCDS-ADRDA criteria [69] and found a significantly reduced SAI in these patients. Interestingly, SAI correlates with hallucinations in DLB patients and with euphoric manic state and disinhibition in AD patients [70]. SAI investigation may also be useful in the distinction between DLB and Parkinson's disease (PD), because SAI is normal or even enhanced in PD [12, 71].

SAI was evaluated in 20 patients with FTD and compared data with those from 20 patients with AD and 20 control subjects [30]. SAI was normal in FTD, whereas it has been reduced in AD. SAI may thus represent an additional tool to discriminate FTD from AD. These findings are consistent with post-mortem studies showing central cholinergic deficits in AD [72–74] but not in FTD [75].

A reduced SAI has been found in patients with VD, but not to the same extent as AD. Nardone et al. [66] reported that SAI responses in patients with subcortical ischemic VD varied widely, ranging from normal to markedly reduced values. In another TMS study, significant SAI abnormalities were disclosed in 3 out of 12 patients with VD [29]; SAI was strongly correlated with neuropsychological measures of long-term memory and other cognitive functions. In patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the amount of SAI was found to be significantly smaller than in normal subjects [76]. This finding supports the hypothesis of a central cholinergic system impairment in CADASIL. Interestingly, Mesulam [77] demonstrated that pure white matter infarcts, similar to those seen in subcortical VD, can cause cortical cholinergic denervation.

It should be considered that AD and VD are not mutually exclusive conditions; VD patients with SAI abnormalities could have concomitant neuropathological changes of AD and thus represent the percentage of patients with a mixed form of dementia.

In contrast to AD where the major features of the cholinergic neuropathology show few interindividual variations, VD may show considerable interindividual variation in the location of subcortical infarcts and, therefore, in the distribution and magnitude of the resultant cortical cholinergic deficits. In contrast to AD, where there are a few interindividual variations in the pattern and extent of the cholinergic neuropathology, VD may show considerable interindividual variation in the location of subcortical infarcts and, therefore, in the distribution and magnitude of the resultant cortical cholinergic deficit.

#### **3.5. Cortical plasticity and functional connectivity**

thus the abnormality of SICI in some VD patients might be related to the disruption of inhibitory GABAergic circuits. However, a study provides evidence of functional changes also in excitatory cortical circuits in patients with subcortical ischemic vascular disease and cognitive

Alberici et al. [37] found that patients with FTD were comparable with healthy subjects and AD patients for SICI and ICF. In contrast, patients with corticobasal degeneration (CBD) presented significantly reduced SICI at ISI 3 ms, the selective impairment of intracortical inhibi-

None of the previous studies has found significant changes in ICF in patients with AD as compared to healthy controls [27, 35–37, 40–42, 45]. These findings seem to point to a normal NMDA receptor-dependent glutamate excitatory activity in AD, as tested by this cortical excitability measure. However, other studies suggest that abnormalities of glutamatergic neurotransmission might play an important role in AD. The glutamatergic hypothesis of AD has been proposed as an auxiliary mechanism to the cholinergic hypothesis [39] and this may be due to an imbalance between the non-NMDA and NMDA neurotransmission [39, 60–63].

The most consistent finding of abnormal cortical excitability in AD patients regards SAI. In fact, all studies reported significant reductions of SAI in patients with AD as compared to healthy individuals [27, 29–31, 34, 41, 42, 44, 60, 64, 65]. SAI was also found to be negatively correlated with performance in abstract thinking [29, 31] and long-term memory [29]. SAI testing may be a useful marker of central cholinergic dysfunction even in early stages of AD [66], while it was found to be not significantly reduced in subjects with MCI [44]. However, in this study the diagnosis of MCI was based on criteria proposed by Petersen in 1999 instead of the revised ones [67] and the relationships to the different MCI subtypes was not defined. In a more recent study, a reduced SAI was found in amnestic MCI-multiple domain patients, while SAI was not significantly different in amnestic MCI-single domain patients and in non-

SAI is significantly reduced also in adults with Down Syndrome (DS) and Alzheimer-type dementia [51] the values correlated with the patient's age and the score on Dementia Scale for DS. This technique may thus represent an additional tool for the diagnosis of Alzheimer-type

Nardone et al. [51] described this putative marker of cholinergic activity in patients with DLB and showed a clear tendency toward a reduced SAI. These authors performed SAI testing without randomization of different conditions and the diagnosis of DLB was based on criteria proposed in 1996 instead of the revised ones [69]. Di Lazzaro et al. [29] examined 10 patients with a clinical diagnosis of DLB according to the NINCDS-ADRDA criteria [69] and found a significantly reduced SAI in these patients. Interestingly, SAI correlates with hallucinations in DLB patients and with euphoric manic state and disinhibition in AD patients [70]. SAI investigation may also be useful in the distinction between DLB and Parkinson's disease (PD),

tion in CBD may help in distinguishing among the FTD clinical spectrum.

impairment (but no dementia) [59].

10 Transcranial Magnetic Stimulation in Neuropsychiatry

**3.4. Short-latency afferent inhibition**

amnestic MCI patients [68].

dementia in subjects with DS.

because SAI is normal or even enhanced in PD [12, 71].

Some studies have examined non-invasively motor cortical plasticity and functional connectivity in AD. Inghilleri et al. [32] investigated the effects of modulation of cortical motor areas induced by suprathreshold high-frequency (5 Hz) rTMS. Whereas in control subjects 5 Hz-rTMS elicited normal MEPs that progressively increased in size, in AD patients the amplitude of MEPs progressively decreased during the training. These results suggest an altered cortical plasticity in excitatory motor cortical circuits in AD. Conversely, 5 Hz rTMS induced an increase in cSP in both groups, thus indicating a normal plasticity of the cortical inhibitory circuits. Battaglia et al. [38] studied LTP-like plasticity of the motor cortex in AD patients and healthy subjects by employing PAS with interval between peripheral nerve stimulation and TMS set at 25 ms (PAS25); they also performed biochemical analyses in brain slices of amyloid precursor protein (APP)/presenilin-1 (PS1) mice, an AD animal model. PAS-induced plasticity has been significantly reduced in AD patients; moreover, 4–4.5-month-old APP/PS1 mice exhibited deficits of NMDA receptor-dependent neocortical and hippocampal long-term potentiation (LTP), and a marked alteration of NMDA receptor activity.

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 in identifying healthy individuals from MCI or AD patients.

groups in which they received either 4-week real rTMS or 2 weeks of sham rTMS followed by 2 weeks of real rTMS stimulation. No significant effects were found on naming performance, while a significant effect was detected on auditory sentence comprehension after 2 weeks of real rTMS sessions. Two additional weeks of daily rTMS sessions resulted in no further improvements, while a significant beneficial effect on auditory sentence comprehension was still observed 8 weeks after the end of the rTMS intervention. An important finding was the

Transcranial Magnetic Stimulation and Cognitive Impairment

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

13

Rektorova et al. [85] examined whether one session of high-frequency rTMS applied over the left DLPFC or over the left motor cortex (MC) would induce any evaluable cognitive changes in seven patients with cerebrovascular disease and MCI. Patients improved in the Stroop interference results after stimulation of the DLPFC but not MC, and in the digit symbols subtest of the Wechsler adult intelligence scale-revised regardless of the stimulation site. Recently, Cotelli et al. [84] found that rTMS of the left parietal cortex increased accuracy in an association memory task in a patient with amnestic MCI, and the improvement was main-

In another study, Ahmed et al. [86] aimed to compare the long-term effects of high- versus low-frequency rTMS, applied over the DLPFC of both hemispheres, on cortical excitability and cognitive function of AD patients. All patients received one session daily for five consecutive days. The high-frequency rTMS group improved significantly more than the lowfrequency and sham groups in all assessed rating scales (MMSE, Instrumental Daily Living Activity Scale and the Geriatric Depression Scale). The improvement was still significant

Since cognitive training (COG) is known to improve cognitive functions in AD, Bentwich et al. [87] aimed to obtain a synergistic effect of rTMS interlaced with COG (rTMS-COG). Eight patients with mild or moderate probable AD were subjected to daily rTMS-COG sessions (5/week) for 6 weeks, followed by a maintenance phase (2/week) for additional 3 months. Broca's and Wernicke's areas, right and left DLPFC, right and left parietal somatosensory association cortex were stimulated, and COG tasks were developed to fit these brain regions. Alzheimer Disease Assessment Scale (ADAS)-Cognitive and Clinical Global Impression of Change improved significantly after both 6 weeks and 4.5 months of treatment. MMSE, the ADAS-Activities of Daily Living, and the Hamilton Depression Scale improved, but without statistically significant differences. In a recent single case study [88], a patient with initial AD was treated by rTMS over the left DLPFC for 10 stimulation sessions over 2 weeks. Cognitive improvements occurred especially in tests of episodic memory and speed processing, and were still evident 1 month after the last stimulation. In a recent study, Rabey and Dobronevsky could prove that rTMS combined with cognitive training is a safe and effective modality for the treatment of Alzheimer's disease [89].

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

absence of any effects on memory and executive functions.

tained for 24 weeks.

**5. Discussion**

24 weeks after stimulation began.
