Customized Application of tDCS for Clinical Rehabilitation in Alzheimer's Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive-behavior deficits, which strongly impact daily-life activities (Weintraub et al., 2012). Currently, the limited efficacy of pharmacological treatments has encouraged researchers to develop nonpharmacological interventions, such as cognitive training and non-invasive brain stimulation (NIBS) treatments, designed to prevent or delay cognitive impairment (Cass, 2017; Cespón et al., 2018). In recent years, there has been growing interest in evaluating the use of NIBS to improve cognitive functioning in healthy and pathological aging (Hsu et al., 2015; Cappon et al., 2016), and to integrate this modality in dementia rehabilitation programs (Prehn and Flöel, 2015). In particular, some experimental (Ferrucci et al., 2008; Boggio et al., 2012; Marceglia et al., 2016) and meta-analytical (Hill et al., 2016; Indahlastari et al., 2021) studies have supported the clinical utility of transcranial direct current stimulation (tDCS). The potential of tDCS lies on its mechanisms of action. Specifically, tDCS has local impacts on the GABA/glutamate balance (Stagg et al., 2009), which has been found to be altered in AD patients (Guerra et al., 2011). It also influences functional connectivity, synchronization, and oscillatory activities in prefrontal cortex (Keeser et al., 2011), a region substantially affected by AD. In addition, tDCS may have non-neuronal effects, as almost all tissues and cells are sensitive to electric fields (Ruohonen and Karhu, 2012). For instance, tDCS could potentially modulate the inflammatory response and the conformation of beta-amyloid and other pathological proteins (Toschi et al., 2009), involved in the progression of AD. Nevertheless, several studies have found very little or null effects (e.g., Horvath et al., 2015) of tDCS on various cognitive domains. These results have been attributed to high inter-study (Pellicciari andMiniussi, 2018) and inter-individual variability in response to tDCS (Li et al., 2015), even though the sources of inter-individual variability were not clearly identified. Importantly, although the sheer number of parameters (e.g., polarity, intensity, location, electrodes size) that can be varied could represent a weakness of these protocols, they also mean the application of tDCS is highly customizable. Consequently, exploring inter-individual differences and how these might influence the effects of tDCS has become crucial. In the following section, we point to Brain Reserve (and the related grade of brain atrophy), Cognitive Reserve and baseline performance measures as potential sources for the inter-individual variability reflected in results obtained after applying tES protocols.