**1. Introduction**

Physiological aging is a finely controlled process which entails biological alterations at different dimensional scales, from molecules, to cells and integrated systems [1,2]. Some of these changes likely represent the undesirable outcome of exposure to stressors [3], whereas others are physiological and might subtend the attempt of the organism to maintain its function. The latter is particularly true for the central nervous system, whose functional remodeling during aging supports the preservation of activity performance in daily tasks [4]. Identifying specific patterns of neuronal activity linked to aging is a major challenge in neuroscience. In the motor system, for instance, neuromuscular degeneration, alterations in motoneuronal properties, changes in the activity and connectivity of multiple cortical circuits and modifications in the efficiency of synaptic plasticity mechanisms can be observed in older people [5–9]. Some of these abnormalities overlap those occurring in the early stages of patients with neurodegenerative diseases, including movement disorders or dementia [10–20]. Thus, understanding the various changes underlying physiological aging may help in discriminating between normal and pathological conditions. Neurophysiological techniques, in particular transcranial magnetic stimulation (TMS) and

**Citation:** Guerra, A.; Rocchi, L.; Grego, A.; Berardi, F.; Luisi, C.; Ferreri, F. Contribution of TMS and TMS-EEG to the Understanding of Mechanisms Underlying Physiological Brain Aging. *Brain Sci.* **2021**, *11*, 405. https://doi.org/ 10.3390/brainsci11030405

Academic Editors: Nico Sollmann and Petro Julkunen

Received: 10 February 2021 Accepted: 19 March 2021 Published: 22 March 2021

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TMS-electroencephalography (EEG) coregistration, are very useful to this aim. Indeed, they are able to assess the activity of several brain circuits with a very high-temporal resolution, thus allowing to identify even subtle changes in the functionality of mechanisms controlling movement, learning and cognitive performances [21,22].

In this review, we will describe changes in cortical excitability, connectivity and plasticity occurring during physiological aging in humans, as assessed by TMS and TMS-EEG studies. Since TMS allows to explore mainly neurophysiological functions of the primary motor cortex (M1), the majority of studies discussed in this article will focus on the motor system. In the first section of the review we report research providing evidence for spatially-restricted (i.e., limited to M1) neurophysiological changes during aging. Indeed, over the last decade, a large number of studies found that aging is associated with changes in global corticospinal excitability and function of different neurotransmitter systems within M1, including GABA-A-ergic, GABA-B-ergic, cholinergic and glutamatergic. In the second section we discuss age-related modifications occurring in large-scale sensorimotor networks, as investigated by TMS and TMS-EEG connectivity measures. Lastly, in the third section of the article, we review non-invasive brain stimulation (NIBS) studies which assessed possible alterations in synaptic plasticity and metaplasticity during aging. Indeed, cortical plastic changes occur throughout the normal lifespan in response to the numerous events that represent everyday experiences, and synaptic plasticity mechanisms, such as long-term potentiation (LTP) and long-term depression (LTD), must be tightly regulated to prevent saturation, which would impair learning and memory [23–28].
