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Tra le tecniche di stimolazione cerebrale non invasive (NIBS), la stimolazione transcranica a corrente continua (tDCS) e la stimolazione transcranica a corrente alternata (tACS) sono in grado di modulare l’eccitabilità e la plasticità corticale, inducendo una polarizzazione o depolarizzazione dei neuroni (Nitsche, Cohen, Wassermann, Priori, Lang, Antal, Paulus, Hummel, Boggio, Fregni, et al., 2008; Polanía et al., 2018) e la sincronizzazione delle oscillazioni cerebrali a diverse frequenze (Polanía et al., 2018; Vosskuhl et al., 2018). Ad oggi, nonostante la relativa facilità di applicazione e i risultati promettenti di tDCS e tACS in contesti sia sperimentali sia clinici, manca un consenso sui protocolli di stimolazione più efficaci. Pertanto, questa tesi ha l’intento di indagare le potenziali fonti di variabilità per consentire un perfezionamento dei protocolli di stimolazione al fine di ottenere effetti comportamentali più consistenti, sia a scopo clinico sia sperimentale. In particolare, gli studi presentati nella tesi hanno valutato sistematicamente gli effetti comportamentali dipendenti dalla polarità e dal momento di applicazione della tDCS, e gli effetti sia comportamentali sia neurofisiologici conseguenti all’applicazione di una stimolazione tACS bifocale cross-frequency. In particolare, il primo studio di questa tesi ha indagato l'effetto comportamentale dipendente dalla polarità della tDCS in partecipanti sani, conducendo due esperimenti randomizzati-controllati rispettivamente con tDCS anodica e catodica sulla corteccia parietale posteriore destra (rPPC) durante l'esecuzione di una versione modificata del Posner Cueing Task (Posner, 1980). I risultati hanno evidenziato che la comune assunzione dell’effetto polarità dipendente, anodica-eccitatoria e catodica-inibitoria (Nitsche & Paulus, 2000) non si traduce in modo semplicistico sul comportamento in effetti facilitatori della performance per l’anodica e peggiorativi per la catodica. Il secondo, Among the non-invasive brain stimulation techniques (NIBS), transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS) can modulate cortical excitability and plasticity, respectively with sub-threshold induced polarization or depolarization of neurons (Nitsche, Cohen, Wassermann, Priori, Lang, Antal, Paulus, Hummel, Boggio, Fregni, et al., 2008; Polanía et al., 2018) and entraining brain oscillation at different frequencies (Polanía et al., 2018; Vosskuhl et al., 2018). To date, despite their relative ease of application and the promising findings in the use of tDCS and tACS in both experimental and clinical settings, there is a lack of consensus on the most efficient protocols of stimulation. Thus, the present study aims to address the open issues on this topic to allow a better refinement of stimulation protocols to obtain more consistent behavioural effects, both for clinical and research purposes. In particular, the studies presented in the dissertation systematically assessed the polarity-dependent and timing-dependent behavioural effects of tDCS, and the behavioural and neurophysiological effects of a novel cross-frequency tACS. The first main study of this dissertation investigated the polarity-dependence of tDCS behavioural effects in healthy participants running two sham-controlled experiments with anodal and cathodal tDCS respectively on the right posterior parietal cortex (rPPC) during the execution of a modified version of the Posner Cueing Task (Posner, 1980). The results highlighted that the assumption of anodal-excitation and cathodal-inhibition (Nitsche & Paulus, 2000) does not consistently translate into anodal-facilitatory and cathodal-inhibitory effects on behaviour. The second main study explored how different coupling of the tDCS-induced stimulation with the endogenous stimulation induced by a concurrent task execution affect the behaviour, for both polarities, in healthy participants. Two sham-contr

Motor regions atrophy has been traditionally assumed to account for selective deficits of verb (V) vs. noun (N) processing in amyotrophic lateral sclerosis (ALS) patients via action semantic impairment (Embodied Cognition Theory, ECT). Nonetheless, accounts pertaining to both motor region sensitivity to the morpho-phonological structure of Vs and executive functioning (EF) contribution (task difficulty) have not been evenly endorsed. This study aimed at assessing neurocognitive underpinnings of N and V processing in ALS patients. ALS patients were compared to healthy participants (HPs) on tasks evaluating N and V semantic and post-semantic processing. Effects of semantic motor content (actionality) of Ns and Vs and of argument structure complexity of Vs were assessed. EF measures were put into relation to language tasks in patients. Both groups performed worse in V than in N lexical retrieval. Patients had difficulties in retrieving low-actionality Vs, being also sensitive to both transitive Vs and those with 2 and 3 arguments. Patients differed form HPs on both object- and action-semantic measures. EF measures were highly related to patients’ V-retrieval performance. ECT-framed explanations for N > V discrepancies in ALS patients are inconsistent with the present results. Indeed, ALS patients showed semantic deficits that are not limited to the action domain and retrieved more easily high-actionality Vs. N > V discrepancies in ALS patients would thus reflect a magnification of a differential processing demand for Vs and Ns, which is likely intrinsic to the neurocognitive system. Nonetheless, ALS patients being sensitive to argument structure complexity of Vs might imply motor regions involvement in V post-semantic processing, possibly at the lemma level.

Background: This study aims at reviewing, within the framework of motor neuron disease-frontotemporal degeneration (MND-FTD)-spectrum disorders, evidence on the co-occurrence between primary progressive aphasia (PPA) and MND in order to profile such a complex at pathological, genetic and clinical levels. Methods: This review was pre-registered (osf.io/ds8m4) and performed in accordance with the 2020 PRISMA guidelines. Case reports/series and group studies were included if addressing (1) progressive non-fluent aphasia (PNFA) or semantic dementia (SD) with MND or (2) MND patients with co-morbid PNFA/SD. Results: Out of 546 initial records, 56 studies were included. As to case reports/series (N = 35), which included 61 PPA-MND patients, the following findings yielded: (1) PNFA is more frequent than SD in PPA-MND; (2) in PPA-MND, the most prevalent motor phenotypes are amyotrophic lateral sclerosis and predominant-upper MND, with bulbar involvement being ubiquitous; (3) extrapyramidal features are moderately frequent in PPA-MND; (4) PPA-MND patients usually display frontotemporal, left-greater-than-right involvement; (5) TDP-43-B is the typical pathological substrate of PPA-MND; (6) TBK1 mutations represent the most frequent genetic risk factors for PPA-MND. As to group studies, including 121 patients, proportional meta-analytic procedures revealed that: (1) the lifetime prevalence of MND in PPA is 6%; (2) PPA occurs in 19% of patients with co-morbid MND and FTD; (3) MND is more frequent in PNFA (10%) than in SD patients (3%). Discussion: Insights herewith delivered into the clinical, neuropathological and genetic features of PPA-MND patients prompt further investigations aimed at improving clinical practice within the MND-FTD spectrum.

Background. Motor neuron disease (MND) patients can show oral language deficits mimicking those of frontotemporal degeneration (FTD). Although dysgraphic features have also been reported within the MND-FTD continuum, their characteristics and clinical relevance are still largely unexplored. Aims. Profiling writing disorders in MND patients can help further define their cognitive semiology and thus convey relevant clinical entailments. Therefore, this study aimed at reviewing evidence of writing impairment in MND patients. This review was implemented and reported by consulting Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Qualitative/quantitative measures of writing abilities in MND patients were the primary outcome. Both group studies and case reports/series were taken into consideration. Twenty contributions were included out of an initial N = 83. Potential biases in generalizing results were qualitatively controlled for by extracting background, disease-related, neuropsychological, and neuroanatomofunctional secondary outcomes. Main Contribution. Fifteen studies assessed writing abilities in Japanese patients, whereas the remaining eight in western patients. Central dysgraphic features were reported in both neuropsychologically impaired and unimpaired MND patients. Non-phonologically plausible and morpho-syntactic errors were frequently reported. Although FTD was frequently co-occurent, neither cognitive nor language impairment fully accounted for writing impairment in some patients. By contrast, evidence of peripheral dysgraphia was scarce. Patients displaying writing deficits often presented with bulbar signs and perisylvian cortex involvement (including Exner’s area and the left angular gyrus). Writing deficits proved to be associated with abnormalities in executive functioning and its neural substrates. Writing-to-dictation tasks as well as writing samples assessment proved to be useful to detect writing errors. Conclusion

The coupling of tDCS polarity-dependent opposite effect is well established in the sensorimotor domain but is still controversial when higher cognitive functions are targeted. Previous studies from our group showed that at resting state anodal tDCS (a-tDCS) over the right parietal cortex (rPPC) elicited a widespread increase of cortical excitability, whereas cathodal stimulation (c-TDCS) failed to modulate cortical excitability, being indistinguishable from sham stimulation. Here we assessed whether the active state of the targeted region might change the picture. We applied c-tDCS over the rPPC while our participants were performing a visuo-attentional task, namely Posner Cueing task (PCT). TDCS neurophysiological aftereffects were tracked performing TMS-EEG recordings pre- and post- either sham or real stimulation. In particular, single pulses TMS were delivered over the left PPC and TMS evoked potentials were recorded with a 64ch cap. Analyses were then performed both at the sensors and at the cortical source level. Behavioral results showed that c-tDCS significantly slowed down PCT performance in comparison to sham condition. Crucially, at a neurophysiological level, c-tDCS but not Sham significantly reduced cortical excitability in the brain areas involved in task execution, namely in a fronto-parietal network. Therefore, c-TDCS neurophysiological effects over rPPC resulted depending on the background activity. These results hold relevant implications for tDCS set up both in cognitive neuroscience experiments and rehabilitation protocols.

Introduction: Common assessment tools for aphasia evaluate single language impairments but not their functional impact on patient’s communication skills in daily life. The lack of tools focused on ecological aspects might affect the choice of rehabilitative trainings. The Communicative Effectiveness Index (CETI) represents an attempt to assess the communicative abilities in “ecologic” context. This study aimed to explore psychometrics properties of the Italian translation and adaptation of CETI (I-CETI). Methods: Sixty-eight patients with aphasia due to left hemispheric stroke admitted to post-acute rehabilitation units and their relatives were included in the study. Data were collected in three different sessions. At study entry, patients were assessed for language, depression, and functional abilities, while their caregivers and speech therapists independently completed the I-CETI to assess inter-rater agreement (baseline). One week later, caregivers and speech therapists completed again I-CETI, to assess test-retest reliability (T1). Last, at discharge, patients completed again the evaluation protocol, and caregivers and speech therapists completed I-CETI (T2). Results: I-CETI showed high internal validity, excellent reliability, and good correlation between scores obtained by speech therapists and caregivers. Moreover, scores of I-CETI had quite good correlations with a traditional tool to assess language, and with measures of functional independence both at study entry and at discharge. Discussion: I-CETI showed good psychometric proprieties. These results allowed considering I-CETI as a reliable tool to assess effects of speech treatments on the communicative abilities in patients with aphasia. Furthermore, I-CETI might help clinicians to develop treatments more tailored on the “ecologic” difficulties of patients.

Background: Oropharyngeal dysphagia (OD) is common in amyotrophic lateral sclerosis (ALS), leading to a reduction of swallowing safety and efficacy. The tongue has an important role in swallowing function for oral processing and bolus propulsion through the pharynx. The study aims to analyze the association between instrumental findings of OD and tongue pressure. Methods: Patients with ALS referred for fiberoptic endoscopic evaluation of swallowing (FEES) were recruited. FEES was conducted to test swallowing function with liquid (5, 10, and 20 ml), semisolid (5, 10, and 20 ml), and solid. FEES recordings were assessed for swallowing safety, using the penetration-aspiration scale (PAS), and for swallowing efficacy, using the Yale Pharyngeal Residue Severity Rating Scale (YPRSRS). PAS scores >2 were suggestive of penetration, PAS scores >5 of aspiration, and YPRSRS scores >2 of residue. Maximum tongue pressure (MTP) and tongue endurance were measured using the Iowa Oral Performance Instrument. Tongue pressure measurements were compared between patients with and without penetration, aspiration, or residue. Key results: Fifty-five patients with ALS were included. Mean MTP was 29.7 kPa, and median tongue endurance was 10 seconds. Patients with residue in the pyriform sinus had a significantly lower MTP than patients without residue in the pyriform sinus with semisolids 10 ml (P =.011) and 20 ml (P =.032). Patients with a tongue endurance <10 seconds exhibited higher frequency of penetration with liquids 5 ml (P =.046), liquids 10 ml (P =.015), and solids (P =.22). Conclusion and inferences: In patients with ALS, MTP is significantly associated with an impairment of swallowing efficacy and tongue endurance was significantly associated with an impairment of swallowing safety.

Background and purpose: Oropharyngeal dysphagia is generally recognized to increase the risk of malnutrition; however, its role in patients with neurodegenerative disease has yet to be determined. This cross-sectional study aimed to investigate the impact of swallowing function on malnutrition risk in patients with neurodegenerative diseases. Methods: Patients with oral nutrition and diagnosis of Huntington disease (HD), Parkinson disease (PD), or amyotrophic lateral sclerosis (ALS) were recruited. Demographic and clinical data were collected. The swallowing assessment included a fiberoptic endoscopic evaluation of swallowing, an oral phase assessment, and a meal observation scored with the Mealtime Assessment Scale (MAS). Malnutrition risk was assessed with the Mini Nutritional Assessment. Results: Overall, 148 patients were recruited (54 HD, 33 PD, and 61 ALS). One hundred (67.6%) patients were considered at risk of malnutrition. In the multivariate analysis, age ≥ 65 years (odds ratio [OR] = 3.16, p = 0.014), disease severity (moderate vs mild OR = 3.89, severe vs mild OR = 9.71, p = 0.003), number of masticatory cycles (OR = 1.03, p = 0.044), and MAS safety (OR = 1.44, p = 0.016) were significantly associated with malnutrition risk. Conclusions: Prolonged oral phase and signs of impaired swallowing safety during meals, together with older age and disease severity, are independent predictors of malnutrition risk in neurodegenerative diseases. This study broadens the focus on dysphagia, stressing the importance of early detection not only of pharyngeal signs, but also of oral phase impairment and meal difficulties through a multidimensional swallowing assessment.

Due to its safety, portability, and cheapness, transcranial direct current stimulation (tDCS) use largely increased in research and clinical settings. Despite tDCS’s wide application, previous works pointed out inconsistent and low replicable results, sometimes leading to extreme conclusions about tDCS’s ineffectiveness in modulating behavioral performance across cognitive domains. Traditionally, this variability has been linked to significant differences in the stimulation protocols across studies, including stimulation parameters, target regions, and electrodes montage. Here, we reviewed and discussed evidence of heterogeneity emerging at the intra-study level, namely inter-individual differences that may influence the response to tDCS within each study. This source of variability has been largely neglected by literature, being results mainly analyzed at the group level. Previous research, however, highlighted that only a half—or less—of studies’ participants could be classified as responders, being affected by tDCS in the expected direction. Stable and variable inter-individual differences, such as morphological and genetic features vs. hormonal/exogenous substance consumption, partially account for this heterogeneity. Moreover, variability comes from experiments’ contextual elements, such as participants’ engagement/baseline capacity and individual task difficulty. We concluded that increasing knowledge on inter-dividual differences rather than undermining tDCS effectiveness could enhance protocols’ efficiency and reproducibility.