Long-Term Neuromodulatory Effects of Repetitive Transcranial Magnetic Stimulation (rTMS) on Plasmatic Matrix Metalloproteinases (MMPs) Levels and Visuospatial Abilities in Mild Cognitive Impairment (MCI).

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that is used against cognitive impairment in mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, the neurobiological mechanisms underlying the rTMS therapeutic effects are still only partially investigated. Maladaptive plasticity, glial activation, and neuroinflammation, including metalloproteases (MMPs) activation, might represent new potential targets of the neurodegenerative process and progression from MCI to AD. In this study, we aimed to evaluate the effects of bilateral rTMS over the dorsolateral prefrontal cortex (DLPFC) on plasmatic levels of MMP1, -2, -9, and -10; MMPs-related tissue inhibitors TIMP1 and TIMP2; and cognitive performances in MCI patients. Patients received high-frequency (10 Hz) rTMS (MCI-TMS, n = 9) or sham stimulation (MCI-C, n = 9) daily for four weeks, and they were monitored for six months after TMS. The plasmatic levels of MMPs and TIMPs and the cognitive and behavioral scores, based on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Beck Depression Inventory II, Beck Anxiety Inventory, and Apathy Evaluation Scale, were assessed at baseline (T0) and after 1 month (T1) and 6 months (T2) since rTMS. In the MCI-TMS group, at T2, plasmatic levels of MMP1, -9, and -10 were reduced and paralleled by increased plasmatic levels of TIMP1 and TIMP2 and improvement of visuospatial performances. In conclusion, our findings suggest that targeting DLPFC by rTMS might result in the long-term modulation of the MMPs/TIMPs system in MCI patients and the neurobiological mechanisms associated with MCI progression to dementia.

Repetitive Transcranial Magnetic Stimulation (rTMS) of Dorsolateral Prefrontal Cortex May Influence Semantic Fluency and Functional Connectivity in Fronto-Parietal Network in Mild Cognitive Impairment (MCI).

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that is increasingly used as a nonpharmacological intervention against cognitive impairment in Alzheimer's disease (AD) and other dementias. Although rTMS has been shown to modify cognitive performances and brain functional connectivity (FC) in many neurological and psychiatric diseases, there is still no evidence about the possible relationship between executive performances and resting-state brain FC following rTMS in patients with mild cognitive impairment (MCI). In this preliminary study, we aimed to evaluate the possible effects of rTMS of the bilateral dorsolateral prefrontal cortex (DLPFC) in 27 MCI patients randomly assigned to two groups: one group received high-frequency (10 Hz) rTMS (HF-rTMS) for four weeks (n = 11), and the other received sham stimulation (n = 16). Cognitive and psycho-behavior scores, based on the Repeatable Battery for the Assessment of Neuropsychological Status, Beck Depression Inventory-II, Beck Anxiety Inventory, Apathy Evaluation Scale, and brain FC, evaluated by independent component analysis of resting state functional MRI (RS-fMRI) networks, together with the assessment of regional atrophy measures, evaluated by whole-brain voxel-based morphometry (VBM), were measured at baseline, after five weeks, and six months after rTMS stimulation. Our results showed significantly increased semantic fluency (p = 0.026) and visuo-spatial (p = 0.014) performances and increased FC within the salience network (p ≤ 0.05, cluster-level corrected) at the short-term timepoint, and increased FC within the left fronto-parietal network (p ≤ 0.05, cluster-level corrected) at the long-term timepoint, in the treated group but not in the sham group. Conversely, regional atrophy measures did not show significant longitudinal changes between the two groups across six months. Our preliminary findings suggest that targeting DLPFC by rTMS application may lead to a significant long-term increase in FC in MCI patients in a RS network associated with executive functions, and this process might counteract the progressive cortical dysfunction affecting this domain.