Efficacy of Repetitive Transcranial Magnetic Stimulation (r-TMS) Combined With Conventional Cognitive Treatment on Cognitive-behavioral Symptoms of Left Hemispatial Neglect in Right-stroke Patients Within Three Months Post-onset Compared to Conventional Cognitive Treatment Only: a Randomized Controlled Trial

BACKGROUND: A frequent and disabling impairment in persons who suffered acquired brain injury after stroke is left hemispatial neglect (LHSN). LHSN is a spatial attentive syndrome characterized by a reduced ability to attend, perceive and consciously represent the left contralesional space, in the absence of a primary sensory deficit. Commonly, the LHSN is due to a lesion on the right inferior parietal cortex and/or on the right fronto-parietal areas. Furthermore in stroke, LHSN is often associated with a mixture of attention and motor deficits leading to complex cognitive and behavioral pictures, which may even interfere with the administration of standard cognitive treatments for LHSN. However, several studies already demonstrated the efficacy of rehabilitation treatments on patients with LHSN, in terms of reducing disability, using various rehabilitative techniques and assessment tests. The rehabilitation techniques can be distinguished, accordingly to the used tools in: cognitive treatments (i.e. visual scanning training) and non-invasive brain stimulation methods (i.e. r-TMS). Conventional cognitive treatments (CCT) for LHSN involve different types of exercises aimed at reducing attentive bias for the ipsilesional space and/or promoting awareness of contralesional space by a continuous training of the patient's spatial exploration abilities. Instead, the TMS is a non-invasive method to modulate excitability of the cerebral cortex. The frequency of TMS pulse determines the type of modulation on the cerebral cortex (i.e. inhibitory <1 Hz; excitatory> 5 Hz). The most used TMS paradigm for the rehabilitation of LHSN is the r-TMS (repetitive transcranial magnetic stimulation) and it is based on the model of the inter-hemispheric competition. According to the model, the cerebral areas responsible for spatial orientation are contralateral to the attended hemifield (i.e. the left cerebral areas are responsible for the spatial orientation towards the right hemifield) and exert a reciprocal inter-hemispheric inhibition. The left and right fronto-parietal cortices are part of a intra-hemispheric network, which together with a parietal inter-hemispheric pathway, control the spatial orientation. In particular, a lesion on the right parietal cortex causes disinhibiting of the left parietal cortex and therefore a pathological over-activation of the latter.

According to the model, this left over-activation inhibits the right contralateral neural activity, as an increase of the healthy hemisphere inhibition activity on the damaged hemisphere. For these reasons, in the LHSN, a pathological orientation or pathological attention bias is determined towards the right hemifield after right stroke. Often, the r-TMS treatments aimed at rebalancing the inter-hemispheric competition through a stimulation of the parietal-parietal pathway, in particular inhibiting the intact areas of the left parietal cortex. The results showed significant post-treatment improvements in several neuropsychological and behavioral tests. In particular, a recent study showed how low- frequency r-TMS on the intact contralesional parietal areas reduced the clinical symptoms of LHSN after 10 treatment sessions. Improvements were stable 15 days after the treatment.

Despite evidence of efficacy of single treatment on cognitive symptoms of LHSN, many authors agree that the use of different rehabilitative techniques on the same patient are useful for generalizing clinical improvement and have a greater potential in reducing long-term global disability. However, in the literature, only few study tested effects of combined interventions on LHSN. Here, we aim at assessing the efficacy of a novel rehabilitation protocol, based on r-TMS in combination with a CCT, based on visual scanning training AIMS

To compare the efficacy of a combined r-TMS and CCT intervention aiming at reducing cognitive symptoms of LHSN, in a sample of right Stroke patients with LHSN, within the context of an RCT.

To evaluate the long- term impact of the intervention To evaluate the effect of the intervention on other clinical measures (activity of daily living, attentive and motor functions) and on psychophysiological indices.