Brain Networks are Independently Modulated by Donepezil, Sleep, and Sleep Deprivation

Abstract

Resting-state connectivity has been widely studied in the healthy and pathological brain. Less well-characterized are the brain networks altered during pharmacological interventions and their possible interaction with vigilance. In the hopes of finding new biomarkers which can be used to identify cortical activity and cognitive processes linked to the effects of drugs to treat neurodegenerative diseases such as Alzheimer's disease, the analysis of networks altered by medication would be particularly interesting. Eleven healthy subjects were recruited in the context of the European Innovative Medicines Initiative 'PharmaCog'. Each underwent five sessions of simultaneous EEG-fMRI in order to investigate the effects of donepezil and memantine before and after sleep deprivation (SD). The SD approach has been previously proposed as a model for cognitive impairment in healthy subjects. By applying network based statistics (NBS), we observed altered brain networks significantly linked to donepezil intake and sleep deprivation. Taking into account the sleep stages extracted from the EEG data we revealed that a network linked to sleep is interacting with sleep deprivation but not with medication intake. We successfully extracted the functional resting-state networks modified by donepezil intake, sleep and SD. We observed donepezil induced whole brain connectivity alterations forming a network separated from the changes induced by sleep and SD, a result which shows the utility of this approach to check for the validity of pharmacological resting-state analysis of the tested medications without the need of taking into account the subject specific vigilance.

Modular slowing of resting-state dynamic Functional Connectivity as a marker of cognitive dysfunction induced by sleep deprivation

“…We re-analyze here neuropsychological and fMRI data previously reported by Wirsich et al (2018). Within the framework of a work-package of the EU PharmaCog Innovative Medicine Initiative (https://www.imi.europa.eu/projects-results/project-factsheets/pharma-cog), fifteen healthy subjects were recruited (all male, 25-40 years old, Body Mass Index, BMI ≤ 27, right-handed) to participate in an experiment distributed over ten different days in blocks of 2 days each.…”

“…In the original experiment, some of the subjects were administered doses of various neuroenhancer drugs prior to the fMRI scan and the cognitive testing. For more details, see Wirsich et al (2018). Here, however, we prefer to focus uniquely on the placebo sessions, being more interested in statistical comparisons between dFC speed in different modules, than comparisons between dFC speed in different medication conditions.…”

“…For a detailed description on fMRI data acquisition, see Wirsich et al (2018). All images were acquired on a Siemens Magnetom Verio 3T MRI-Scanner (Siemens, Erlangen, Germany) with structural T1-weighted images acquired using a MPRAGE-sequence (TR = 2300 ms, TE = 2.98 ms, 1.0 × 1.0 × 1.0 mm, 176 slices), and 200 BOLD-sensitized EPI T2*-weighted MRI images acquired using a TR of 2.7 s (3.0 × 3.0 × 3.0 mm, TE = 30 ms, 40 slices, acquisition time of 9 min 5 s).…”

“…Previous studies have shown that SD affects time-averaged FC at the whole-brain level (Yeo, Tandi & Chee, 2015;Kaufmann et al, 2016;Wirsich et al, 2018). However, it is not very clear how such changes of static network topology relate to cognitive effects of sleep deprivation.…”

“…Finally, investigating dFC in SD may lead to the development of novel predictive markers of early network dysfunction in disease. Indeed, SD has also been proposed as a cognitive challenge model of cognitive impairment arising in Alzheimer's Disease, because of both the partially overlapping spectrum of induced cognitive deficits and their response to pharmacological treatment (Cheeh & Chuah, 2008;Repantis et al, 2010;Wirsich et al, 2018). For this reason, cognitive tests chosen with a sensitivity to both SD and cognitive dysfunction in Alzheimer's disease were chosen for the present study (Cummings et al 2012, Randall et al 2005, Dodds et al 2011, Kirova et al 2015.…”