Transcranial magnetic stimulation (TMS)

Basic principles
TMS is an instrument that can be used to investigate the behavior-brain relationship and to explore the excitability of different regions of the brain. Since the discovery of TMS, this technique has been used to investigate the state of cortical excitability, excitability of the cortico-cortical and corticospinal pathways (Rothwell et al., 1987), the role of a given brain region in a particular cognitive function and the timing of its activity (Harris e Miniussi, 2003; Harris, Miniussi, Harris and Diamond, 2002; Marzi, Miniussi, Maravita, Bertolasi, Zanette, Rothwell and Sanes, 1998; Cotelli et al., 2012; Manenti et al., 2011; Rossi et al., 2001; Ruzzoli et al., 2010; Ruzzoli et al., 2011; Sandrini et al., 2008), the induced effects (Miniussi, Walsh and Ruzzoli 2010) as well as the pathophysiology of various disorders (e.g., Fregni and Pascual-Leone, 2006; Kobayashi and Pascual-Leone, 2003; Rossini and Rossi, 2007). Moreover it allows to interact with and to investigate the cortical oscillatory activity (Miniussi and Thut, 2010; Thut and Miniussi, 2009; Veniero et al., 2012; Brignani et al., 2008; Miniussi, Brignani and Pellicciari, 2012).
TMS involves the delivery of a brief (~200 µs) and powerful (0.2 to 4.0 T) magnetic pulse to the scalp through a coil. The magnetic pulse induces a transitory electric current in the cortical surface under the coil, which causes the depolarization of cell membranes (Barker et al., 1987; Barker et al., 1985) and transynaptic depolarization of a population of cortical neurons.
TMS was originally introduced in clinical neurophysiology for evaluation of the functional state of the corticospinal pathway (Pellicciari et al., 2009; Barker et al., 1987; Barker et al., 1985). It initially involved the delivery of single magnetic pulses. In the mid-1990s, technological advances allowed for the delivery of rhythmic trains of magnetic pulses in a rapid sequence with a repetition rate of up to 100 Hz. This has been referred to as repetitive TMS (rTMS). Studies have shown that rTMS interacts with cortical activity more effectively than TMS. Moreover, low- and high-frequency rTMS could have distinct effects on brain activity. The cut-off between high and low frequency is empirically based. Converging evidence has indicated that rTMS below 1 Hz reduces cortical excitability both locally and in functionally related regions, whereas rTMS trains above 5 Hz seem to have the opposite effect (Veniero et al., 2011; Chen et al., 1997; Maeda et al., 2000; Pascual-Leone et al., 1994). Therefore, rTMS allows for the transient modulation of neural excitability and the effect is dependent on the stimulation frequency.

Mechanisms of action at the synaptic level
NIBS techniques exert their effects on neuronal excitation through different mechanisms. TMS induces a current that can elicit action potentials in neurons. Changes induced by a single application of rTMS are reversible, last from a few minutes to more than an hour, and are dependent upon N-methyl D-aspartate (NMDA) (Ridding and Ziemann, 2010). Cortical inhibitory effects of 1 Hz rTMS depend on both γ-Aminobutyric acid (GABA) and NMDA receptor system activity (Fitzgerald et al., 2005). High-frequency stimulation might rely on the same systems but have opposite effects. These effects can be altered by administration of drugs that specifically interact with neurotransmission in the GABA and NMDA receptor systems (Ziemann et al., 1998a; Ziemann et al., 1998b). Candidate mechanisms to support stimulation-induced cerebral plasticity at the cellular level have been proposed. LTP, as the best investigated neural mechanism of behavioral plasticity (Bliss and Lomo, 1973), is known to depend on NMDA receptor activation (Collingridge et al., 1983). Both LTP and its opposite, LTD, have also been postulated to explain the persistent effects of NIBS on cortical activity (Cooke and Bliss, 2006; Thickbroom, 2007; Ziemann and Siebner, 2008). In addition to these notions, extensive information is available on the molecular and genetic aspects of NIBS-induced plasticity.
In sum, NIBS have been shown to be able to induce modifications of the cortical plasticity which may outlast the stimulation period itself. Given this potential, there is currently a growing interest in applying these methodologies therapeutically, to reduce cognitive deficits in patients with stroke and with chronic neurodegenerative diseases.

Treatment of cognitive deficits
The use of brain stimulation to study functions and dysfunctions in stroke and neurodegenerative patients has recently been the focus of much attention within the scientific community (e.g., Cotelli et al., 2006; Miniussi et al., 2008; Miniussi and Rossini, 2011; Miniussi and Vallar, 2011; Hummel and Cohen, 2006; Ridding and Rothwell, 2007).
Some preliminary data showed improved picture naming performance in vascular aphasia (Martin et al., 2004; Naeser et al., 2005; 2005b; Cotelli et al., 2011), in Primary Progressive Aphasia (Cotelli et al., 2012; Finocchiaro et al., 2006) and in Alzheimer’s disease (Cotelli et al., 2006; 2008). It has also been suggested that rTMS can be used to improve performance in sensory extinction (Oliveri et al., 1999; 2000) and unilateral neglect (Brighina et al., 2003; Oliveri et al., 2003; Shindo et al., 2006) associated with stroke.
The neural mechanisms responsible for the kinds of cognitive improvements that can be induced by brain stimulation techniques are mostly unknown, and research is urgently required in this field.

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