**4. Therapeutic interventions**

#### **4.1. Neuromodulatory techniques**

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 rTMS enhance excitability in the targeted cortical region.

The physiologic impact of both neuromodulatory techniques involves synaptic plasticity, specifically LTP and LTD.

#### **4.2. Repetitive transcranial magnetic stimulation**

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 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 absence of any effects on memory and executive functions.

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 maintained for 24 weeks.

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 24 weeks after stimulation began.

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].
