A circuit view of deep brain stimulation in Alzheimer’s disease and the possible mechanisms

Abstract

Alzheimer’s disease (AD) is characterized by chronic progressive cognitive deterioration frequently accompanied by psychopathological symptoms, including changes in personality and social isolation, which severely reduce quality of life. Currently, no viable therapies or present-day drugs developed for the treatment of AD symptoms are able to slow or reverse AD progression or prevent the advance of neurodegeneration. As such, non-drug alternatives are currently being tested, including deep brain stimulation (DBS). DBS is an established therapy for several neurological and psychiatric indications, such as movement disorders. Studies assessing DBS for other disorders have also found improvements in cognitive function, providing the impetus for clinical trials on DBS for AD. Targets of DBS in AD clinical trials and animal model studies include the fornix, entorhinal cortex (EC), nucleus basalis of Meynert (NBM), and vertical limb of diagonal band (VDB). However, there is still no comprehensive theory explaining the effects of DBS on AD symptoms or a consensus on which targets provide optimal benefits. This article reviews the anatomy of memory circuits related to AD, as well as studies on DBS rescue of AD in these circuits and the possible therapeutic mechanisms.

Brain-Wide Mapping of Afferent Inputs to Accumbens Nucleus Core Subdomains and Accumbens Nucleus Subnuclei

“…The ENT is divided into the ENTm and ENTl based on their distinctive cytoarchitecture and connectivity patterns. The ENTm contains strongly position-related (spatial) neurons, whereas the ENTl contains neurons encoding object information, attention, and motivation (Yu et al, 2019). In this study, we found that the ENTl and ENTm demonstrated the opposite projecting patterns to the NAcLS, NAcMS, and NAcC.…”

TMEM59 Haploinsufficiency Ameliorates the Pathology and Cognitive Impairment in the 5xFAD Mouse Model of Alzheimer’s Disease

“…Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder characterized by abnormal accumulation and deposition of various amyloid-β (Aβ) peptides derived from amyloid-β precursor protein (APP), formation of neurofibrillary tangles containing hyperphosphorylated tau, synaptic dysfunction, neuroinflammation, neuronal death, and cognitive decline (Crews and Masliah, 2010;Huang and Mucke, 2012;Guerreiro and Bras, 2015;Kocahan and Dogan, 2017;DeTure and Dickson, 2019). So far no effective therapies are available to cure this devastating disease (Yu et al, 2019). Since social and financial burdens for AD have become enormous as our population ages, there is an urgent need to elucidate the detailed molecular mechanisms underlying AD pathogenesis, so that new targets may be identified for therapeutic development.…”

Deep Brain Stimulation for Alzheimer's Disease: Stimulation Parameters and Potential Mechanisms of Action

“…Seven patients had syncope and/or falls; two patients had altered mental status; two patients were involved in seizures or possible seizure; one patient was involved in agitation in a delayed; three patients were involved in a skin infection, suspected aortic valve endocarditis, and rigidity. and Drevets, 2010); ILN and MTN are important components forming cortico-thalamo-cortical pathways (Saalmann, 2014); NBM participates in the base forebrain cholinergic circuit; and the fornix, MT, ANT, EC, and CA1 (hippocampus) are nodes in the Papez circuit (Yu et al, 2019). Figure 2 shows a schematic representation of these targets in the brain.…”

“…At present, there is little direct research on the mechanism of action of DBS in AD, and various hypotheses (changing the electrical activity of neurons, promoting neurogenesis and neurotransmitter release, etc.) have been proposed to explain its potential mechanism of action (Hescham et al, 2013a ; Laxton and Lozano, 2013 ; Kuhn et al, 2015a ; Aldehri et al, 2018 ; Jakobs et al, 2019 ; Yu et al, 2019 ).…”