Conference Agenda

Since the very beginning, the application of transcranial electrical stimulation was aimed at treating the region beneath to the stimulation site, as first described by the Roman physician Scribonius Largus in his masterpiece the «Compositiones» in 47 A.D., where he stated «A live black torpedo is applied to the aching part, until the pain stops and the aching part starts becoming numb». However, with the reappraisal of this technique, now called tDCS, it immediately become clear that tDCS, similarly to other NIBS techniques such as rTMS, in addition to influencing the regional neural activity underlying the stimulation location was also able to modulate distant interconnected network activity throughout the brain. This aspect is key for its application in different neurological and neuropsychiatric disorders, since successful behavior requires the concerted action of multiple brain regions. These findings generated a great deal of interest in adopting NIBS approaches after stroke, based on the concept of interhemispheric rivalry, as also the application of tDCS in the treatment of depression by stimulating the L-DLPFC.

To better understand the physiology of the indirect effects of tDCS, we investigated the raphe activity in response to acute and chronic prefrontal-tDCS, in particular by analysing serotonin (5-HT) neural activity by single-unit in-vivo electrophysiology and HPLC. Indeed, one of the main neurotransmitters involved in the pathophysiology and psychopharmacology of depression is 5-HT, released by neurons of the dorsal raphe nuclei. We observed different spontaneous firing outcomes after acute and chronic tDCS, with some effects lasting up to one month. Additionally, in the motor cortex, we observed that the combination of tDCS and physical activity results in a boosting effect of neural plasticity in both hemispheres.

Altogether, these data indicate a strong functional influence of tDCS on cortical connectivity, and not only in the directly stimulated region.

Motor recovery after brain damage induced by an ischemic event is always challenging and often unsuccessful. Despite several innovative approaches have emerged to treat ischemic patients acutely, for most of them the treatment can be applied only in the subacute phase after injury. This time window is extremely precious for its plastic potential and offers the possibility to recover motor function by guiding peri-lesional areas to vicariate what was lost. Unfortunately, this plastic potential, if not properly guided, could led to maladaptive rearrangements and unwanted movement patterns.

Here we use a mouse model of stroke in forelimb motor cortex to test novel and highly translational neurorehabilitative approaches in subacute phase by combining robotic rehabilitation with plasticizing treatments. Recently, we tested the efficacy of non-invasive neurostimulation approaches and investigated the role of Gamma band and Parvalbumin Interneurons (PV-IN) in post-stroke recovery. We assessed the consequences of the ischemic lesion onto PV-IN activity by electrophysiological recordings in perilesional healthy tissue during active movement and Wide Field Imaging of PV-IN in awake head restrained mice before and after stroke. Based on the results obtained we successfully tested non-invasive brain stimulation approaches, first selectively targeting PV-IN by Gamma band optogenetic stimulation and then using a more translational approach with Non-Invasive Transcranial Alternating Current Stimulation (tACS).

Both of the approaches led to a significant improvement of forelimb motor function and plastic changes in the perilesional tissue and pave the way for successful combined approaches in clinical practice.

Behavior and cognition are characterized by engagement of functional distributed networks within the brain. Such networks organization is especially significant in pathological condition modulating brain activity such as stroke, and requires a high degree of intra-modal and inter-modal integration of information flow arriving from several, different and often remote brain sources. These networks dynamically connect adjacent and/or remote cortical neuronal assemblies via cortico-cortical connections. These neural networks undergo relevant changes due to stroke insult. Currently, non-invasive brain stimulation (NIBS) techniques, such as transcranial electrical stimulation (tES), as already illustrated in the previous talks of this symposium, are adopted to modulate stroke effect on the brain, acting on networks proprieties and connectivity. Novel approach, also applying concepts from graph theory to neurophysiological data, is a promising new way to characterize brain activity, providing a method to evaluate whether functional connectivity patterns between brain areas resemble the organization of theoretically efficient, flexible or robust networks, based on strength of synchronization of different brain regions. Here we will summarize the possible aspect of analyzing connectivity changes due to NIBS in stroke mouse model, and how to apply EEG graph theory analyses on stroke patient in order to predict functional recovery basing of classification procedures. More specifically, in the mouse model, an increased total functional coupling following tDCS might correlate with the speed rather than the degree of recovery, while Small World index in the acute stroke patient, gives a significant weight of recovery prediction.

Transcranial direct current stimulation (tDCS) is a non-invasive technique that has been receiving increasing attention as an effective tool to modulate motor cortical excitability in physiological and pathological conditions. Although animal studies revealed that tDCS over the primary motor cortex (M1) affects the functional plasticity, its underlying mechanisms still need to be fully clarified. Indeed, recent growing evidence suggests that tDCS might also affect the structural plasticity by modulating dendritic spine density and morphology. However, the morphological plasticity is also positively affected by physical activity; vice versa, the aging process has been proved to negatively influence it. Both of these factors act on the dendritic spine density and morphology, as tDCS does. Thus, this study aims at investigating the effects of coupling anodal tDCS over the right M1 and weak physical activity on the morphological plasticity in M1 layer II/II and layer V in young (2-3 months) and middle-aged (14-16 months) healthy mice. At both ages the combination of stimulation and physical activity results in an increased number of activated cells and in a higher density of spines in basal and apical dendrites in both hemispheres, in parallel with an increase of the post-synaptic scaffolding protein PSD95, compared to single interventions only. Furthermore, by investigating the functional M1-M1 synchronization, coherence analysis revealed a significantly higher cross-talking within the theta frequency band when the tDCS-physical activity coupling occurs. Altogether, our data suggests that the combination of anodal tDCS with the physiological activation of the motor cortex induces a boosting effect of structural plasticity in both hemispheres and a modulation of the inter-hemispheric M1-M1 communication.