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.

Keywords: Acetylcholine; basal forebrain; prefrontal cortex; working memory.

Fig. 1

A) Schematic illustration of monopolar (left) and bipolar stimulation (right). Arrows represent current flow from the stimulating electrode. B) Schematic illustration of monophasic and biphasic stimulation. Current amplitude is represented as a function of time.

Fig. 2

A) Location of the nucleus basalis of Meynert (dotted ellipse) in the human brain. B) Targeted DBS for memory and cognitive enhancement. Schematic representation of bilateral deep brain stimulation of the nucleus basalis of Meynert. C) Target areas likely to undergo enhancement of activity after nucleus basalis stimulation include the prefrontal, parietal, and temporal association cortexes (shaded ellipses).

Fig. 3

Schematic illustration of simultaneous recording and stimulation in a nonhuman primate performing a behavioral task.