Deep Brain Stimulation and Alzheimer’s Disease: A Look at the Research Studies

Deep brain stimulation, or DBS, is a neurosurgical technique that aims to regulate neuron activity via internal pulse generators to electrodes in specific target areas within the brain. The development of deep brain stimulation is largely attributed to Alim Benabid, who was utilizing surgical approaches to treat cases of Parkinson’s disease, dystonia, and several psychiatric conditions that had historically failed to respond to drug-based therapies.

Deep brain stimulation has since shown great promise for treating movement disorders associated with neurological diseases, such as Parkinson’s disease and essential tremor, and consequently is widely used in the field of neurological diseases.

More recently, researchers have begun investigating deep brain stimulation and Alzheimer’s disease. Below, we take a closer look at deep brain stimulation and Alzheimer’s disease, address the limitations of existing research, and propose a new gold standard for measuring therapeutic response.

How Is Deep Brain Stimulation Performed?

In general, deep brain stimulations systems have three main components:

• A neurostimulator: A programmable battery-powered, pacemaker-like device that creates electric pulses and is surgically implanted under the skin of the chest
• A lead: A coated wire with electrodes at the tip to deliver the electric pulses to brain tissue that is strategically and precisely placed inside the brain
• An extension: An insulated wire connecting the lead to the neurostimulator device that is placed under the skin, running from the scalp, behind the ear, down the neck, and into the chest

Whether performed using traditional approaches or robotically, deep brain stimulation is typically performed in three distinct stages:

1. Imaging and placement of bone markers/screws 
2. Placement of electrodes
3. Placement of the battery and lead extender

Deep Brain Stimulation and Alzheimer’s Disease: Animal Studies

Over the past decade, deep brain stimulation has shown several positive effects in animal models, demonstrating benefits such as enhanced short- and long-term memory, restoration of spatial memory-related functions, decreased amyloidosis, and decreased neuronal loss in the cortex and hippocampus. Animal studies have incorporated multiple stimulation targets, such as the midline thalamic nuclei (MTN), the intralaminar thalamic nucleus (ILN), the anterior nucleus of thalamus (ANT), the hippocampal CA1 subfield, and the entorhinal cortex (EC).

Deep Brain Stimulation and Alzheimer’s Disease: Human Studies

During this same time, deep brain stimulation has been investigated in several human clinical studies. Here is a look at some of the findings:

• A 2010 phase I trial demonstrated that after deep brain stimulation surgery, Alzheimer’s patients had improved memory, decreased rates of cognitive decline, and increased cerebral glucose metabolism.
• A 2015 phase I trial showed that after one year of deep brain stimulation, Alzheimer’s patients showed decreased rates of hippocampal atrophy as well as stabilization of nutritional status.
• A 2018 phase II trial found that participants under 65 showed similar rates of decline to controls (those without the neurostimulator device turned on), meaning there was no decrease in the rate of cognitive decline. However, participants over 65 showed decreased rates of cognitive decline compared to controls. This suggests that deep brain stimulation may not benefit individuals with early-onset Alzheimer’s disease (diagnosed under age 65) but may benefit those over 65. 

Stimulation targets in human studies involved the fornix, the nucleus basalis of Meynert (NBM), and the ventral capsule/ventral striatum (VC/VS).

The mechanism of action currently remains unclear; however, several potential mechanisms have been proposed, such as those listed below:

• Regulation of neural networks
• Reduction in beta-amyloid levels
• Reduction in tau levels
• Promotion of nerve oscillation
• Reduction of neuroinflammation
• Induction of nerve growth factor (NGF) synthesis
• Regulation of the cholinergic system

Limitations of Research Surrounding Deep Brain Stimulation and Alzheimer’s Disease

Currently, to assess and measure therapeutic response to deep brain stimulation in clinical trials, studies rely on narrow-natured, simple cognitive assessments, such the Mini-Mental State Exam (MMSE) and the Clinical Dementia Rating (CDR).

Many of these traditional assessments are purely cognitive batteries that only assess a small subset of neurocognitive domains. Assessment of Activities of Daily Living (ADLs) is arguably the most relevant and robust measure of neurocognitive function. However, traditional cognitive function assessment tools are not ecologically valid, meaning the design of the evaluation does not match and align with neurocognitive states representative of Activities of Daily Living (ADLs). Because of these limitations, these assessments frequently produce noisy, highly variable results that lack the specificity and granularity to confidently draw conclusions about the efficacy of deep brain stimulation.

To improve our understanding of therapeutic response to deep brain stimulation, it is important to assess a breadth of both cognitive and functional domains at a highly granular level.