Cholinergic Deep Brain Stimulation for Memory and Cognitive Disorders

Abstract

Memory and cognitive impairment as sequelae of neurodegeneration in Alzheimer’s disease and age-related dementia are major health issues with increasing social and economic burden. Deep brain stimulation (DBS) has emerged as a potential treatment to slow or halt progression of the disease state. The selection of stimulation target is critical, and structures that have been targeted for memory and cognitive enhancement include the Papez circuit, structures projecting to the frontal lobe such as the ventral internal capsule, and the cholinergic forebrain. Recent human clinical and animal model results imply that DBS of the nucleus basalis of Meynert can induce a therapeutic modulation of neuronal activity. Benefits include enhanced activity across the cortical mantle, and potential for amelioration of neuropathological mechanisms associated with Alzheimer’s disease. The choice of stimulation parameters is also critical. High-frequency, continuous stimulation is used for movement disorders as a way of inhibiting their output; however, no overexcitation has been hypothesized in Alzheimer’s disease and lower stimulation frequency or intermittent patterns of stimulation (periods of stimulation interleaved with periods of no stimulation) are likely to be more effective for stimulation of the cholinergic forebrain. Efficacy and long-term tolerance in human patients remain open questions, though the cumulative experience gained by DBS for movement disorders provides assurance for the safety of the procedure.

Deep brain stimulation of the nucleus basalis of Meynert modulates hippocampal–frontoparietal networks in patients with advanced Alzheimer’s disease

“…These findings suggested that although NBM-DBS is a potential treatment for dementia, the commonly used stimulation parameters may not be optimal. In future DBS studies in AD, individualized intermittent stimulation and closed-loop stimulation could help to improve the long-term efficacy [ 36 ].…”

Rhythmicity of Prefrontal Local Field Potentials after Nucleus Basalis Stimulation

“…NB stimulation has been shown to be effective in improving performance in working memory as well as other cognitive tasks ( Blake et al, 2017 ; Liu et al, 2017 , 2018 ; Qi et al, 2021 ). As such, it holds promise for the treatment of cognitive decline in conditions such as age-related dementia and Alzheimer’s disease ( Subramaniam et al, 2021 ). However, substantial barriers remain before an effective translation of such an intervention to the clinic ( Nazmuddin et al, 2021 ).…”

“…Our results provide insights with direct relevance to optimizing the intervention, as they document signatures of rhythmic activity in cases where successful behavioral effects were documented. If similar changes in activity were to be observed in human patients, e.g., through frontal EEG readings, for stimulation sites that provided effective intervention, they could provide an independent means of verifying the effectiveness of the electrode placement, which is a non-trivial problem in clinical targeting ( Subramaniam et al, 2021 ).…”

“…Investigating the effects of NB stimulation on neuronal activity is essential for understanding its mechanism of action and optimizing its effectiveness ( Subramaniam et al, 2021 ). NB stimulation affects neuronal activity in the prefrontal cortex during performance of working memory tasks ( Qi et al, 2021 ).…”

Brain-wide human oscillatory LFP activity during visual working memory

“…Working memory, the ability to hold and manipulate information in the mind for a short period of time, is central for many cognitive processes, including planning, problem-solving and decision-making (Baddeley, 2012; Constantinidis and Klingberg, 2016). Pathological conditions such as stroke, schizophrenia, and Alzheimer’s disease are associated with working memory impairments (Westerberg et al, 2007; Subramaniam et al, 2012; Subramaniam et al, 2021). For this reason, understanding the neural basis of working memory has been a long-standing question in cognitive neuroscience research (Buschman and Miller, 2022).…”