A Stimulating Dementia Treatment Option

by Women's Brain Health Initiative:Driven by the urgent need for effective new treatments for dementia, deep brain stimulation (DBS) is being studied as a potential therapy to improve cognition and memory, or delay decline – and it is showing some initial promise. DBS is a neurosurgical procedure that involves the implantation of a neurotransmitter (a medical device sometimes referred to as a brain pacemaker), which sends electrical impulses to specific targets in the brain to alter mental and emotional processes.DBS has been used with success to help treat movement disorders such as Parkinson’s disease, as well as psychiatric disorders such as major depression, so scientists wondered whether similar stimulation techniques (on different parts of the brain) could be used to halt or slow the progression of dementia.To date, a limited amount of research has been conducted and the results have been diverse, with some researchers showing support for DBS to recover memories lost due to dementia and other researchers remaining skeptical.Some of the studies have examined the use of direct stimulation (which requires surgery), while others have investigated indirect, non-invasive stimulation methods. Different areas of the brain have been targeted, with either continuous or intermittent stimulation, and experiments have been conducted on both animal and human subjects. This article highlights some of the most recent research on this topic.Direct Deep Brain StimulationDirect deep brain stimulation requires participants to undergo surgery to implant minute electrodes in the brain to deliver electrical impulses through a pacemaker-like device placed under the skin of the chest. The electrical impulses target particular parts of the brain, depending on the placement of the electrodes.A series of studies with human subjects is currently underway, looking at the effects of DBS that targets the fornix – an area of white matter in the brain between the hippocampus and hypothalamus that serves as the “main highway” to and from the brain’s memory circuit.

• The series began with an accidental discovery. Researchers were using DBS to treat a morbidly obese patient by targeting the hypothalamus, a part of the brain that helps regulate appetite. They discovered that as a result of the procedure, which activated the fornix, the patient experienced improvement in certain memory functions. This research was conducted by Hamani et al. and was published in the Annals of Neurology in January 2008.
• Some of the researchers involved in this experiment, together with new members to the research team, decided to perform the same procedure on six individuals with mild Alzheimer’s disease in a phase I trial. The participants received continuous stimulation for a 12-month period, during which time there was evidence that some of their brains were physically changing in positive ways. For instance, examination of positron emission tomography (PET) scans revealed that participants experienced an “early and striking reversal” of impaired glucose utilization (the brains of Alzheimer’s patients use much less glucose than do the brains of healthy patients).

Additionally, magnetic resonance imaging (MRI) scans showed that two of the participants experienced growth in hippocampus volume – one grew by 8%, and another by 5% (as Alzheimer’s disease progresses, the memory areas of the brain typically shrink). The researchers also assessed changes in participants’ cognitive performance, using the Alzheimer’s Disease Assessment Scale—cognitive subscale and the Mini Mental State Examination. The results of these tests were mixed, with two participants demonstrating improvement and two others remaining the same. The results from this phase I trial, conducted by Laxton et al., were published in the Annals of Neurology in October 2010.

• The researchers decided to expand the study with a phase II trial – this time, 42 patients with mild Alzheimer’s disease participated. To better measure the impact of electric stimulation in the brain, the patients were randomly assigned to either the “on” stimulation group (meaning that they received the treatment stimulation) or the “off” stimulation group (meaning that the electrodes were implanted, but were not activated during the study) and were monitored for a 12-month period following their procedure.

Notably, glucose metabolism increased in the brains of those in the “on” group, indicating that there had been improvement in the dysfunctional brain circuits affected by Alzheimer’s disease. However, no difference in cognitive function was found between the two groups overall. When the researchers examined the data in greater detail, though, they discovered an interesting trend: participants aged 65 years and older who received deep brain stimulation seemed to experience slower cognitive decline, while participants under the age of 65 tended to get worse if they were in the “on” group rather than the “off” group. “These results gave us a better idea of which patients may benefit the most from deep brain stimulation of the fornix and provided evidence that DBS for treating Alzheimer’s disease is safe,” explained lead researcher, Dr. Andres Lozano from the Krembil Neuroscience Centre of Toronto Western Hospital. “We will begin a phase III trial in 2018 that will take between two and three years to complete. Patients who might be interested in participating in that trial can contact our clinic for more information.” This research was published in the Journal of Alzheimer’s Disease in June 2016.Recent research on animals has also provided some preliminary evidence in support of DBS as a potential treatment for dementia.

• For instance, researchers in Singapore (Liu et al.) implanted electrodes in middle-aged rats to provide DBS of the ventromedial prefrontal cortex – the part of the brain that is important for the formation and recall of memories. The researchers found that brief stimulation improved short-term memory, but not long-term memory. However, more sustained stimulation improved both short-and long-term memory. In addition, they discovered that DBS led to the growth of new brain cells in a different region of the brain, the hippocampus, which is also involved in memory. These findings were published in 2015 in eLIFE.
• In another study involving rats – conducted by Hescham et al. and published in Brain Structure and Function online in February 2016 – the researchers assessed the long-term effects of direct brain stimulation of the fornix. The researchers found that the treatment improved the rats’ long-term spatial memory, and that this result occurred without any DBS-induced growth of new brain cells.
• Another group of researchers has studied the effects of DBS of the nucleus basalis of Meynert, a small area in the front of the brain that degenerates in both Alzheimer’s disease and Parkinson’s disease. Working with adult monkeys, the researchers began using continuous stimulation and soon discovered that this approach actually impaired memory. Conversely, when the monkeys received intermittent stimulation of the same area in the brain, they were able to remember tasks up to five times longer in a standard test of working memory.
• Intermittent stimulation also resulted in increased levels of available acetylcholine in the targeted region of the brain. Acetylcholine is a neurotransmitter (chemical messenger in the brain) that is important for memory, thinking and judgement. Alzheimer’s disease is associated with inadequate levels of acetylcholine. These findings were shared in the September 2017 issue of Current Biology.

Non-invasive Brain StimulationOther researchers have explored alternative ways of providing deep brain stimulation without the patient having to undergo surgery. A number of different types of indirect, non-invasive methods have been studied, including transcranial magnetic stimulation and transcranial direct current stimulation.Transcranial magnetic stimulation (TMS) uses electromagnetic induction to induce electrical current in specific brain regions. The pulses of electrical current are discharged through a wound copper coil encased in plastic that can be placed against the scalp in different shapes to alter the characteristics of the magnetic field (for instance, to make it more focused or able to reach greater depths). Typically, continuous low frequency stimulation decreases cortical excitability and metabolism, while high frequency stimulation increases activity in the targeted brain area.When stimulation is intermittent, it seems to enhance excitability. A review of research involving non-invasive brain stimulation for patients with Alzheimer’s disease – prepared by Gonsalvez et al. and published in 2017 in Current Alzheimer Research – found that the results of using TMS in Alzheimer’s patients varied across studies, with different protocols for applying TMS resulting in varied outcomes. TMS has been used successfully to enhance cognitive abilities, depending on the specific area of the brain targeted, but the reviewers encourage caution when interpreting those positive results, pointing out that the studies to date have had small sample sizes and the designs have had serious limitations.Transcranial direct current stimulation (tDCS) regulates brain excitability through the application of low-amplitude direct current applied with electrodes attached to the scalp. In the aforementioned review prepared by Gonsalvez et al., the reviewers found that some studies of tDCS demonstrated enhanced cognitive function in healthy participants. However, the researchers also noted that the studies to date have been small and limited, and therefore these positive results must be interpreted with caution.Ethical ConsiderationsEarly studies of deep brain stimulation for the treatment of dementia (both direct and indirect) have paved a path for future clinical trials, but there are unique ethical challenges with this vulnerable population regarding decision-making abilities and access to post-study treatment that researchers need to address, according to Penn Medicine researchers, Siegel et al. The researchers outlined the ethical challenges and their proposed guidelines for studying DBS in individuals with Alzheimer’s disease in the Journal of Alzheimer’s Disease in 2017.They encouraged researchers to take active steps to ensure (1) that the patient has the cognitive capacity to make an informed decision about participating; and (2) that the patient understands that the primary goal of the study is scientific, not therapeutic, and he or she may or may not experience improvements by participating.Researchers are also encouraged to consider how those participants who benefit from deep brain stimulation during a clinical trial will continue to receive treatment, and who will pay the associated ongoing costs. The Penn Medicine researchers suggested that “denying a patient access to the only intervention known to alleviate their suffering is tantamount to violating the sacrosanct principle of ‘do no harm.’”For more information about the upcoming phase III trial being conducted by Dr. Andres Lozano and his colleagues, please contact their clinic at Toronto Western Hospital at 416-603-5800, ext. 3712.Source: MIND OVER MATTER V6