As of the end of 2020, the coronavirus (COVID-19) pandemic had resulted in over 88
million confirmed cases and nearly 2 million deaths worldwide. Recurring waves of
infection are forcing to impose continuing social restrictions and confinement measures
all around the world.

From a public health perspective, these measures could potentially have an important
negative impact on society and has led to the call for development of preventive and
interventional strategies.

However despite the generalized negative effects of infection some individuals seem
relatively protected from negative sequelae. Therefore, some people appear to be
particularly resilient and the characterization and better understanding of
characteristics that explain why some remain resilient has been highlighted as a critical
focus of needed research, as it allows the potential to identify factors that can be
targets for designing interventional strategies.

Resilience, the concept that describes the capacity of certain individuals to resist the
impact of illness and distress, is a broad term. In clinical psychology and mental
health, the concept of resilience has been historically been linked to the study of
individual differences (e.g., self-esteem, sense of control, perception of social
support, etc.) that determine the capacity to cope with the impact of life traumas in
order to maintain normal psychological and physical functioning and avoid serious mental
illness.

Beyond the psychological aspects, the determinants and factors that confer individual
differences in resilience require integrated assessment of specific person's social
context, engagement in positive lifestyles, and their interplay with its brain biological
substrates and mechanisms. Neuroimaging investigations have identified brain regions that
show specific activity and connectivity patterns during exposure to stressful or violent
stimuli and that may be correlated with scores in psychosocial scales of resilience or
predict subsequent coping abilities. Within the field of ageing and dementia some studies
have suggested the role of the frontal cortex, specifically the functional connectivity
of the dorsolateral prefrontal cortex to the rest of the brain or to particular networks
(DMN, SN), as a neural substrate of higher resilience, both in normal aging.

A critical aspect to consider is that, while it is tempting to leverage such neuroimaging
studies to try to identify a "human brain network of resilience", animal work on the
neural substrate of resilience illustrates the importance of interventional experimental
designs that employ stimuli that can be precisely quantified and controlled. Novel
neuroscience approaches allow to undertake substantial translational work to enable the
study of the neural substrates of resilience in humans, probing in a more direct causal
association between brain circuit function and metrics of cognitive function or
behavioral assessment - or subjective, i.e., related to wellbeing. As an example, the
stress-response paradigm, offers a useful framework for the definition and study of
resilience. It consists of three principal elements 1) a stressor; 2) an organism
response; and 3) a given outcome.

Importantly, the experimental approach can also be applied to directly modulate the
activity of brain networks subtending resilience processes.

Methods:

Can be actively modulate resilience? The main objective of subproject is to test the
possibility to modulate the activity of the neural network underlying resilience and
investigate the effects at the level of observable behavioral and neurophysiological
changes.

Researchers propose a double-blind brain stimulation study.

Participants Participants will be pseudo-randomly selected, stratifying where possible
for socio-demographical variables, amongst those individuals previously defined as
"vulnerable".

Sample size was calculated considering the effect size of the few previous studies
investigating the modulatory effect of non-invasive brain stimulation on functional and
behavioral outcomes of resilience to stress previous studies of our group that showed how
different non-invasive brain stimulation technique could differently modulate functional
magnetic resonance (fMRI) derived brain networks dynamics or studies that employed
stressor paradigms tasks to explore brain networks organization.

Non-invasive brain stimulation researchers will use transcranial alternating current
stimulation (tACS), combined with neuroimaging data and high density EEG (hdEEG).

tACS utilizes low-amplitude alternating currents to modulate brain activity and entrain
specific brain oscillations depending on the applied stimulation frequency. Researchers
previously developed a method for optimizing the configuration of multifocal tACS for
stimulation of specific brain networks (which effect can outlast the duration of
stimulation and the use of a novel (sham) control stimulation paradigm will ensure the
proper blinding of all participants.

tACS study protocol: general montage and configuration procedures tACS montages will be
designed with the Stimweaver montage optimization algorithm to determine the positions
and currents of the electrodes over the scalp that induce an electric field in the brain
that better approximates a weighted target electric field map. Stimulation will be
delivered using 8 circular electrodes with an area of 8 cm2. For safety issues, the
maximum current delivered by any electrode will be 2 milliampere (mA), while the maximum
current injected through all the electrodes will be 4 mA. In the real intervention
conditions, the current will be supplied during the whole experimental session. In all
groups, the current will be initially increased and finally decreased in a 30 s ramp-up
and ramp-down fashion. For the sham condition, the current dosage will be composed of an
initial ramp-up of 30 s immediately followed by a 1 min ramp- down, and a final ramp-down
of 30 s immediately preceded by a ramp-up of 1 min. All stimulation parameters will
adhere to general transcranial electrical stimulation current safety criteria guidelines.

Pre-post experimental stress coping paradigm To induce stress, researchers will use the
moving-circles paradigm. In this task there are two circles moving sometimes closer and
at times moving away from each other. When the circles touch, participants are delivered
a mild electric stressor. Circle movement has a high degree of unpredictability and the
circles might approach each other such that the stressor is more imminent, and then
retreat from each other for a period.

Study design:

Double-blind controlled tACS study In order to evaluate the effect of stimulation on the
modulation of the resilience networks, the researchers will implement a double-blind
controlled trial using tACS.

Participants will receive tACS stimulation in two conditions which will be administered
in a counterbalanced manner. In the first condition the researchers will target nodes of
the resilience network identified by subproject#1, and in the second condition
participants will receive sham stimulation. The study will be conducted in a double-blind
manner.