Periodic Reporting for period 1 - NIBSAD (Electrophysiological markers of cognitive processes and neuroplasticity in healthy ageing and Alzheimer`s disease)
Reporting period: 2015-11-01 to 2017-10-31
The ageing of the European population is increasing the prevalence of age-related diseases such as Alzheimer’s disease (AD). AD is considered a public health priority due to the high socio-economic costs that it involves and the limited efficacy of the current pharmacological treatments. Non-invasive brain stimulation techniques (NIBS) such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) represent promising tools for improve cognitive functioning and prevent and/or delay the cognitive deficits related to AD. However, the optimal NIBS parameters (for example, type of tDCS current, intensity, frequency of the applied TMS pulses, targeted brain area, state of the participants during the application of NIBS protocols -for instance, resting state vs. performing a cognitive task) that would lead to maximize the cognitive improvement as well as the neurophysiological mechanisms underlying the cognitive changes are poorly understood. The main objective of this project was contributing to identify the optimal TMS and tDCS parameters that are able to improve cognitive functioning and investigating the underlying neural modulations in healthy elderly and AD patients. This objective is of vital importance because it will allow improving the efficacy of the current cognitive rehabilitation programmes.
During the lifetime of the project, a theoretical review and two sets of experiments were performed, as explained in the next paragraphs. The theoretical review focused on studies that used non-pharmacological interventions to improve the cognitive functioning in elderly subjects. The review provides a theoretical rationale to combine cognitive training, physical exercise and non-invasive brain stimulation (transcranial direct current stimulation -tDCS- and transcranial magnetic stimulation -TMS) to maximize the efficacy of cognitive rehabilitation programmes (Cespón et al., under review, Ageing Research Reviews).
The main set of experiments involved the use of tDCS to improve the working memory ability in samples of healthy young and elderly participants as well as in Alzheimer’s disease patients (AD). Eighteen healthy young, eighteen healthy elderly and twelve AD patients performed a working memory task before and after applying three sessions of tDCS (anodal, which increases brain excitability; cathodal, which decreases brain excitability; sham, which was used to control placebo and learning related effects) over the left dorsolateral prefrontal cortex (DLPFC, a brain area that is involved in working memory processes). These tDCS experiments demonstrated that application of anodal tDCS over the left DLPFC improved the performance in the working memory task in healthy elderly subjects. This working memory improvement correlated with increased frontal activity related to attentional processes during the task performance. Thus, anodal tDCS was useful to ameliorate the reported age-related decline in attentional capacity and thus, increase the working memory abilities. On the other hand, tDCS was not useful to improve the performance in the sample of young participants, which was attributed to a ceiling effect in the performance of young subjects. These results were presented in the Learning and Plasticity Congress (April 2017, Akaslompolo, Finland) and recently published (Cespón et al., 2017, Frontiers in Aging Neuroscience). AD patients did not improve their working memory performance after applying the tDCS. This result is consistent with recent meta-analytical studies demonstrating that offline protocols -i.e. protocols that involve the application of tDCS during resting state- are not usually successful to induce a cognitive improvement in AD patients, which was related with damaged neuroplasticity mechanisms. These results were presented in ICON 2017 congress (August 2017, Amsterdam, Holland). Importantly, even if a net improvement was not observed in AD patients at group level, the cathodal tDCS was able to increase frontal activity related to memory retrieval processes during the working memory task. Moreover, we observed that increased frontal activity after cathodal tDCS in AD patients correlated with the magnitude of the improvement in the working memory task. These results will be submitted for publication in the upcoming weeks (Cespón et al., in preparation, Clinical Neurophysiology).
Another set of experiments involved the use of TMS in samples of healthy young and elderly participants. Twenty one healthy young and twenty healthy elderly subjects took part in an experiment that involved the performance of an inhibitory control task before and after applying repetitive TMS (rTMS) over the left parietal region in two different experimental sessions (real rTMS, which consisted in the application 1200 TMS pulses; and sham rTMS). In addition, the brain excitability of the left parietal region was assessed by applying 80 single TMS pulses before and after applying the rTMS. The results from TMS experiments showed that application of rTMS over the left parietal region did not alter the performance during the cognitive control task in young but disrupted the normal functioning in healthy elderly, leading to impaired cognitive control (i.e. greater difficulty to ignore the spatial position of a visual stimulus even if that position was irrelevant to perform the task). Currently, electrophysiological results from this experiment are being analysed to study the relationships between altered brain excitability and altered brain activity during the task performance.
In addition to the scientific dissemination, a set of public engagement activities were performed:
Presentation in an association of retired persons (Centro Diurno Franchi, Brescia):
Fertonani, A., Cespón J. L’invecchiamento e la memoria (Ageing and memory).
Publication in divulgation magazines:
Cespón, J., Miniussi, C. (2017). Centre for neuromodulation and neurorehabilitation: integrating non-invasive brain stimulation within multimodal cognitive rehabilitation programmes. IPA Bulletin, Volume 34, 3.
Cespón, J. (submitted to publication). Stimolazione cerebrale non-invasiva. Un approccio terapeutico per la malattia di Alzheimer. Rivista Fatebenefratelli.
The main set of experiments involved the use of tDCS to improve the working memory ability in samples of healthy young and elderly participants as well as in Alzheimer’s disease patients (AD). Eighteen healthy young, eighteen healthy elderly and twelve AD patients performed a working memory task before and after applying three sessions of tDCS (anodal, which increases brain excitability; cathodal, which decreases brain excitability; sham, which was used to control placebo and learning related effects) over the left dorsolateral prefrontal cortex (DLPFC, a brain area that is involved in working memory processes). These tDCS experiments demonstrated that application of anodal tDCS over the left DLPFC improved the performance in the working memory task in healthy elderly subjects. This working memory improvement correlated with increased frontal activity related to attentional processes during the task performance. Thus, anodal tDCS was useful to ameliorate the reported age-related decline in attentional capacity and thus, increase the working memory abilities. On the other hand, tDCS was not useful to improve the performance in the sample of young participants, which was attributed to a ceiling effect in the performance of young subjects. These results were presented in the Learning and Plasticity Congress (April 2017, Akaslompolo, Finland) and recently published (Cespón et al., 2017, Frontiers in Aging Neuroscience). AD patients did not improve their working memory performance after applying the tDCS. This result is consistent with recent meta-analytical studies demonstrating that offline protocols -i.e. protocols that involve the application of tDCS during resting state- are not usually successful to induce a cognitive improvement in AD patients, which was related with damaged neuroplasticity mechanisms. These results were presented in ICON 2017 congress (August 2017, Amsterdam, Holland). Importantly, even if a net improvement was not observed in AD patients at group level, the cathodal tDCS was able to increase frontal activity related to memory retrieval processes during the working memory task. Moreover, we observed that increased frontal activity after cathodal tDCS in AD patients correlated with the magnitude of the improvement in the working memory task. These results will be submitted for publication in the upcoming weeks (Cespón et al., in preparation, Clinical Neurophysiology).
Another set of experiments involved the use of TMS in samples of healthy young and elderly participants. Twenty one healthy young and twenty healthy elderly subjects took part in an experiment that involved the performance of an inhibitory control task before and after applying repetitive TMS (rTMS) over the left parietal region in two different experimental sessions (real rTMS, which consisted in the application 1200 TMS pulses; and sham rTMS). In addition, the brain excitability of the left parietal region was assessed by applying 80 single TMS pulses before and after applying the rTMS. The results from TMS experiments showed that application of rTMS over the left parietal region did not alter the performance during the cognitive control task in young but disrupted the normal functioning in healthy elderly, leading to impaired cognitive control (i.e. greater difficulty to ignore the spatial position of a visual stimulus even if that position was irrelevant to perform the task). Currently, electrophysiological results from this experiment are being analysed to study the relationships between altered brain excitability and altered brain activity during the task performance.
In addition to the scientific dissemination, a set of public engagement activities were performed:
Presentation in an association of retired persons (Centro Diurno Franchi, Brescia):
Fertonani, A., Cespón J. L’invecchiamento e la memoria (Ageing and memory).
Publication in divulgation magazines:
Cespón, J., Miniussi, C. (2017). Centre for neuromodulation and neurorehabilitation: integrating non-invasive brain stimulation within multimodal cognitive rehabilitation programmes. IPA Bulletin, Volume 34, 3.
Cespón, J. (submitted to publication). Stimolazione cerebrale non-invasiva. Un approccio terapeutico per la malattia di Alzheimer. Rivista Fatebenefratelli.
Results from this project demonstrated that, in healthy elderly, improved working memory after anodal tDCS applied over the left dorsolateral prefrontal cortex can be related to the promotion of frontal compensatory mechanisms associated to attentional processes. Also, the frontal activity related to memory retrieval in AD patients was modulated by cathodal tDCS. These results indicate that optimal parameters to improve cognition differ in healthy elderly and AD patients. The advances in the knowledge about the tDCS parameters that can improve cognition in healthy elderly and AD patients and the investigation about the more appropriate way to combine non-pharmacological interventions (cognitive training, physical exercise, tDCS and TMS) will be able to maximize the efficacy of cognitive rehabilitation programmes and delay the onset of the AD symptoms. Achieving these aims will substantially contribute to increase the quality of life at advanced stages of the lifespan and save a lot of economic resources from the public health systems.