Deep brain stimulation in Alzheimer's disease

Benefits from symptomatic and etiologic treatments in Alzheimer's Disease (AD), the most frequent dementia, are still insufficient. During the last decade, several studies showed that electrical stimulation of memory circuits could enhance memory in humans without memory impairment. First, improvement of verbal recollection was reported after deep brain stimulation (DBS) of the fornix in the hypothalamus in a patient treated for morbid obesity. Several studies in epileptic patients explored by deep electrodes reported that visuo-spatial memorization was facilitated by electrical stimulation of the entorhinal cortex or theta burst stimulation of the fornix. Recent studies suggested that DBS could be useful to modulate memory circuits in patients with cognitive decline. Phase I and II studies (about 50 patients) showed that chronic fornix DBS was safe and could achieved to stabilize or slow the memory decline of some patients with mild to moderate AD, especially older ones with less severe and/or advanced disease. DBS of the cholinergic nucleus of Meynert also has been explored in phase I studies in AD and Parkinson-related dementia. Growing experimental data suggest several mechanisms of action: restoration of hippocampal theta rhythms, enhanced long term potentiation, increase of hippocampal neurogenesis, neuroprotection by release of neurotrophic factors, diffuse reactivation of hypoactive neocortical associative regions. However, DBS in AD is still investigational and numerous issues remain to be solved before envisaging its use in clinical practice, including optimal anatomical DBS target, stimulation modalities (continuous, intermittent, theta-bursts, closed loop stimulation), best candidate patients, relevant targeted symptoms, ethical considerations.