Long-term olfactory enrichment promotes non-olfactory cognition, noradrenergic plasticity and remodeling of brain functional connectivity in older mice.

Brain functional and structural changes lead to cognitive decline during aging, but a high level of cognitive stimulation during life can improve cognitive performances in the older adults, forming the cognitive reserve. Noradrenaline has been proposed as a molecular link between environmental stimulation and constitution of the cognitive reserve. Taking advantage of the ability of olfactory stimulation to activate noradrenergic neurons of the locus coeruleus, we used repeated olfactory enrichment sessions over the mouse lifespan to enable the cognitive reserve buildup. Mice submitted to olfactory enrichment, whether started in early or late adulthood, displayed improved olfactory discrimination at late ages and interestingly, improved spatial memory and cognitive flexibility. Moreover, olfactory and non-olfactory cognitive performances correlated with increased noradrenergic innervation in the olfactory bulb and dorsal hippocampus. Finally, c-Fos mapping and connectivity analysis revealed task-specific remodeling of functional neural networks in enriched older mice. Long-term olfactory enrichment thus triggers structural noradrenergic plasticity and network remodeling associated with better cognitive aging and thereby forms a promising mouse model of the cognitive reserve buildup.

Sensory stimulations potentializing digital therapeutics pain control.

For the past two decades, using Digital Therapeutics (DTx) to counter painful symptoms has emerged as a novel pain relief strategy. Several studies report that DTx significantly diminish pain while compensating for the limitations of pharmacological analgesics (e.g., addiction, side effects). Virtual reality (VR) is a major component of the most effective DTx for pain reduction. Notably, various stimuli (e.g., auditory, visual) appear to be frequently associated with VR in DTx. This review aims to compare the hypoalgesic power of specific stimuli with or without a VR environment. First, this review will briefly describe VR technology and known elements related to its hypoalgesic effect. Second, it will non-exhaustively list various stimuli known to have a hypoalgesic effect on pain independent of the immersive environment. Finally, this review will focus on studies that investigate a possible potentialized effect on pain reduction of these stimuli in a VR environment.

Pain Reduction With an Immersive Digital Therapeutic Tool in Women Living With Endometriosis-Related Pelvic Pain: Randomized Controlled Trial.

BACKGROUND: Chronic pelvic pain is a common and disabling condition in women living with endometriosis. Pharmacological and surgical treatments are not always effective at controlling pain and present important restrictions. Digital therapeutics (DTx) are emerging as major nonpharmacological alternatives that aim to extend the analgesic therapeutic arsenal of patients. OBJECTIVE: In this randomized controlled trial (RCT), we aimed to measure the immediate and 4-hour persisting effects of a single use 20-minute DTx (Endocare) on pain in women experiencing pelvic pain due to endometriosis. METHODS: A total of 45 women with endometriosis participated in a randomized controlled study comparing the analgesic effect of a single use of a virtual reality digital treatment named Endocare (n=23, 51%) to a 2D digital control (n=22, 49%). Perceived pain and pain relief were measured before the treatment and 15, 30, 45, 60, and 240 minutes after the end of the treatment. RESULTS: The clustered posttreatment pain was significantly reduced compared to the pretreatment for both Endocare and the control group (all P<.01). Endocare was significantly more effective than the control group (all P<.01). Endocare decreased the mean pain intensity from 6.0 (SD 1.31) before the treatment to 4.5 (SD 1.71) posttreatment, while the control only decreased it from 5.7 (SD 1.36) to 5.0 (SD 1.43). When comparing each posttreatment measures to the pretest, Endocare significantly reduced pain perception for all points in time up to 4 hours posttreatment. The differences did not reached significance for the control group. Moreover, Endocare was significantly superior to the control group 15, 30, and 45 minutes after the treatment (all P<.001). The mean perceived pain relief was significantly higher for Endocare at 28% (SD 2%) compared to the control, which was 15% (SD 1%) for all the posttreatment measurements (all P>.05). CONCLUSIONS: Our study aimed to test the effects of a single use of a DTx treatment on reported pain at different time points in women diagnosed with endometriosis experiencing moderate-to-severe pelvic pain. Importantly, our results support that Endocare, a virtual reality immersive treatment, significantly reduce pain perception compared to a digital control in women living with endometriosis. Interestingly, we are the first to notice that the effect persisted up to 4 hours posttreatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT04650516; https://tinyurl.com/2a2eu9wv.

12 months is a pivotal age for olfactory perceptual learning and its underlying neuronal plasticity in aging mice.

Normal brain aging is associated with deficits in cognitive and sensory processes, due to subtle impairment of synaptic contacts and plasticity. Impairment may be discrete in basal conditions but is revealed when cerebral plasticity is involved, such as in learning contexts. We used olfactory perceptual learning, a non-associative form of learning in which discrimination between perceptually similar odorants is improved following exposure to these odorants, to better understand the cellular bases of olfactory aging in mice. We first evaluated learning ability and memory retention in 2-, 6-, 12-, and 18-month-old mice, and identified 12 months as a pivotal age when memory retention subtly declines before learning becomes totally impaired at later ages. We then showed that learning-induced structural plasticity of adult-born granule cells is specific to cells responding to the learned odorants in the olfactory bulb of young adult mice and loses its specificity in 12-month-old mice, in parallel to memory impairment. Taken together, our data refine our understanding of aging-related impairment of plasticity mechanisms in the olfactory bulb and consequent induction of olfactory learning and memory deficits.