A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease.
OBJECTIVE
Alzheimer disease (AD) is characterized by functional impairment in the neural elements and circuits underlying cognitive and memory functions. We hypothesized that fornix/hypothalamus deep brain stimulation (DBS) could modulate neurophysiological activity in these pathological circuits and possibly produce clinical benefits.


METHODS
We conducted a phase I trial in 6 patients with mild AD receiving ongoing medication treatment. Patients received continuous stimulation for 12 months. Three main lines of investigation were pursued including: (1) mapping the brain areas whose physiological function was modulated by stimulation using standardized low-resolution electromagnetic tomography, (2) assessing whether DBS could correct the regional alterations in cerebral glucose metabolism in AD using positron emission tomography (PET), and 3) measuring the effects of DBS on cognitive function over time using clinical scales and instruments.


RESULTS
DBS drove neural activity in the memory circuit, including the entorhinal, and hippocampal areas and activated the brain's default mode network. PET scans showed an early and striking reversal of the impaired glucose utilization in the temporal and parietal lobes that was maintained after 12 months of continuous stimulation. Evaluation of the Alzheimer's Disease Assessment Scale cognitive subscale and the Mini Mental State Examination suggested possible improvements and/or slowing in the rate of cognitive decline at 6 and 12 months in some patients. There were no serious adverse events.


CONCLUSIONS
There is an urgent need for novel therapeutic approaches for AD. Modulating pathological brain activity in this illness with DBS merits further investigation.
Laxton
Adrian W
AW
Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.
Tang-Wai
David F
DF
McAndrews
Mary Pat
MP
Zumsteg
Dominik
D
Wennberg
Richard
R
Keren
Ron
R
Wherrett
John
J
Naglie
Gary
G
Hamani
Clement
C
Smith
Gwenn S
GS
Lozano
Andres M
AM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications* / Q000000981:diagnostic imaging / Q000473:pathology; D001921:Brain / Q000473:pathology / Q000502:physiology*; D001931:Brain Mapping; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use; D046690:Deep Brain Stimulation / Q000379:methods*; D004569:Electroencephalography / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D005625:Frontal Lobe / Q000502:physiology; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D007031:Hypothalamus / Q000502:physiology; D008279:Magnetic Resonance Imaging; D008297:Male; D008569:Memory Disorders / Q000000981:diagnostic imaging / Q000209:etiology* / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009434:Neural Pathways / Q000502:physiology; D009483:Neuropsychological Tests; D049268:Positron-Emission Tomography / Q000379:methods; D011569:Psychiatric Status Rating Scales; D013997:Time Factors
D002800:Cholinesterase Inhibitors