Periodic Reporting for period 1 - MemoMCI (Targeting reconsolidation to strengthen memories in individuals with Mild Cognitive Impairment) Reporting period: 2016-09-01 to 2018-08-31 Summary of the context and overall objectives of the project Episodic memory displays the largest degree of age-related decline. This condition is accelerated in amnestic mild cognitive impairment (aMCI), which is often the precursor for emerging Alzheimer’s disease (AD). Since AD produces tremendous chronic burdens on individuals, families and health care systems around the world, the development of effective interventions to prevent or delay AD is an urgent priority. Noninvasive brain stimulation with transcranial direct current (tDCS) has demonstrated efficacy in enhancing long-term memory in healthy human subjects. In addition, reactivation of consolidated memories triggers reconsolidation, a time-limited period during which consolidated memories can be modified (e.g. strengthened). Recent reconsolidation studies in older adults have shown that tDCS over the prefrontal cortex (PFC) significantly strengthened consolidated verbal episodic memories. The aim of this study was twofold: 1) To determine whether active relative to sham/placebo tDCS applied over the PFC after a memory reactivation would enhance episodic memory performance in older adults with aMCI; 2) To identify aMCI individuals who can benefit the most from this tDCS intervention based on gray matter and white matter integrity assessed using magnetic resonance imaging (MRI), or presence of specific genetic polymorphisms (BDNF, SNAP-25) associated to memory. To accomplish his career goal of becoming an independent researcher, the fellow's training objectives were: 1) To develop a strong knowledge in neuropsychological evaluations, mechanisms of rehabilitation and recovery, and cognitive rehabilitation interventions tailored to meet individuals' specific needs using an interdisciplinary approach; 2) To develop additional technical skills in MRI; 3) To familiarize himself with molecular genotyping; 4) To enhance his teaching experience. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far Blood sample and MRI measures were collected on different days before the memory task. MRI and genetic analyses were performed at during the secondment periods. The entire research was hosted and supervised by Casa di Cura del Policlinco (CCP, Milan, Italy). During the memory task, older adults with aMCI (n=15) learned 20 words. 24h later, participants received PFC-tDCS (active or sham). Memory recognition was tested 48h and one month after the learning session. The behavioural results did not show a positive effect of active tDCS on memory recognition performance relative to sham tDCS. The genetic analyses showed that most of the aMCI patients were carriers of specific polymorphisms that have been associated to pathological conditions characterized by episodic memory decline. Regarding the correlations between memory performance and gray/white matter measures, there was a statistically significant correlation between memory recognition performance at Day 3 and white matter microstructure of the left Uncinate Fasciculus (UF), a large white matter bundle linking functionally regions of the temporal lobe to regions of the frontal lobe.Although a larger sample size is needed in order to make reliable conclusions, the lack of a behavioural effect might be due to the fact that MCI is a heterogeneous population. In addition, patients with aMCI were diagnosed on the basis of clinical criteria without assessing the accumulation of amyloid plaques in the brain, one of the hallmarks of AD. Therefore, it was not possible to determine if the patients enrolled were MCI due to AD. To achieve his training objectives the fellow performed neuropsychological assessments, observed clinical activities and cognitive interventions in patients with neurological disorders. He attended clinical rounds, journal clubs and seminars about neurological cases, novel interventions and their mechanism of action. He acquired skills in MRI analysis to map the structural changes associated with neurological disorders in order to better understand the pathological processes and to monitor the effects of treatment interventions on brain structure. He also observed the basic procedures to perform analysis of specific genetic polymorphisms. Finally, he gave lectures at high schools and universities using a research-based teaching approach. He presented his research on human memory and the MemoMCI project at different universities and research institutions in Italy (n=2: Padova, Milan), UK (n=4, London) and US (n=1). He also participated as a speaker in workshops and conferences regarding neurorehabilitation (n=5). Furthermore, he presented preliminary data of the MemoMCI project at an event about memory and dementia organized by the host institution exclusively dedicated to general practitioners. In collaboration with the Scientific Director, Dr. Massimo Corbo, the fellow wrote an opinion article about the possibility to modulate reconsolidation with non-invasive brain stimulation, and organized a workshop at CCP about the use of tDCS as an adjuvant strategy for rehabilitation of motor and cognitive deficits. From this workshop emerged that further investigations on extensive case studies, through neuroimaging and neurophysiological techniques, are indispensable to better clarify the complex mechanisms of basic action and determine the duration of the tDCS-induced effects. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) The knowledge gained during the fellowship will be critical for the fellow’s future research career. The clinical training and the expertise gained during the secondment periods will be important for future work in physiological and pathological aging. Specifically, the training in MRI will be critical to conduct studies using structural and functional MRI alone or in combination with tDCS. This multimodal, innovative approach will be useful to determine the brain mechanisms of action of this promising technique in humans. In addition, after the teaching experience, the fellow believes that taking a scholarly approach to education will benefit the students and teachers. The findings of this project suggest that the white matter microstructure of the left UF might be an important factor in predicting episodic memory performance, confirming as in previous’ studies the presence of early and significant structural changes in prodromal AD. In addition, neuroimaging and genetic analysis at baseline could become a valuable tool to predict which patients will respond positively to memory-targeted tDCS interventions. Therefore, patient’s precise characterization is necessary to individualize the appropriate treatment. It will then be possible to propose useful guidelines on the parameters to be applied also in interaction with classical rehabilitation techniques and to validate protocols aimed at the individualized treatment for patients with memory impairment. Thus, the PI and the host institution will collaborate and continue to recruit aMCI patients, because a larger sample size is critical to better understand the effects of tDCS on this population at risk of developing AD, an issue of potential clinical impact. The fellow’s future plan is to present the research findings of MemoMCI at neuroscience conferences and to write a manuscript for a high-impact journal.