Deep Brain Stimulation: Diving Deeper into Possible Treatments for Alzheimer’s Disease

Alzheimer’s Disease is the leading cause of dementia worldwide. Dementia is a debilitating disorder marked by memory problems, personality changes, and impaired reasoning. A person suffering from dementia may become violent, even towards their loved ones, and experience potent delusions. The early stages of this disease, when the patient is still cognizant enough to understand what is happening, are marked by terror, confusion, and depression. Alzheimer’s Disease is the leading cause of suicide in people over 65 years of age. Dementia is the only leading cause of suicide not related to mental health issues, substance use disorder, or family history. A 2002 study conducted by the NIH found that 7.4% of AD patients admitted in one year to an urban medical center for treatment, had been admitted immediately following a suicide attempt (Aizenberg, Barak, 2002). Suicide attempts were the highest in people still in early stages of the disease, with high functioning ability. A 2019 study found that the most common blog themes for unpaid caregivers of AD were “end of life care,” “thoughts of death and euthanasia by the person with Alzheimer’s Disease Related Dementia (ADRD),” “surrogate decision making,” “thoughts of suicide by the caregiver,” and “thoughts of suicide and euthanasia by the caregiver (Anderson, Eppes, O’Dwyer, 2019).”

There are currently 5.7 million Americans living with AD, and this number is expected to grow. As the average life-expectancy continues to increase, so will the amount of people suffering from neurodegenerative diseases. In 2018, AD cost the US government 227 billion dollars. This number is expected to reach 1.1 trillion by 2050 unless viable treatments options and early detection methods are discovered (Alzheimer’s Association, 2018). Additionally, there are approximately 16.1 million unpaid caregivers providing support to fellow community members, friends, and family suffering from AD. Those afflicted with Alzheimer’s require constant care, oftentimes their unpaid caregivers have to leave their jobs and abandon their old ways of life to support someone who can’t even recognize them, or understand what is happening. Not enough of the $1.9 billion in research funds for AD is going to develop effective treatment methods. 

An exciting new possibility for the treatment of AD may lie in Deep Brain Stimulation (DBS). Deep Brain Stimulation became FDA approved for treating Parkinson’s Disease in 2002 (Gardner, 2013). It has also been FDA approved to treat epilepsy, essential tremor, dystonia, chronic pain, OCD, and Tourette’s (Mayo Clinic, 2018). However, DBS is only a treatment option, not a cure, and the procedure is clinically invasive offering a range of possible side effects. The implantation of the DBS device, which can be compared to the surgical implantation of a cardiac pacemaker (American Association of Neurological Surgeons, 2018), is divided into two parts. The first part of this procedure is brain surgery. The surgical team uses MRI to determine where electrodes should be implanted. The electrode is the conductor of the electricity used to stimulate the brain. Next, the patient is given a local anesthetic to numb the scalp. A small hole is drilled into the skull, and a thin wire lead with electrodes at its tips is run through the hole and placed into the pre-determined target areas of the brain. The patient remains awake for this part of surgery so that the attending surgeons can be sure they are implanting the electrodes into the correct locations. The patient does experience pain during this part of the procedure due to the administration of local anesthetic to the scalp and the lack of pain receptors in the brain. During the second part of the surgery, the patient is placed under general anesthesia. This is chest surgery. The pulse generator portion of the DBS device is placed under the skin of the patient’s chest near his or her collarbone and wires from the electrodes are placed under the skin and guided down to the pulse generator. The patient has the ability to control this generator with a special remote control. The device is not activated right away. The patient is monitored for adverse reactions from surgical complications before activation. The doctor will activate the device several weeks post-op and provide the patient with specific instructions on how to operate the remote control and determine the correct amount of stimulation necessary to alleviate symptoms.

Because DBS has been so successful in the treatment of disorders involving neural circuitry (most notably motor circuits and pain circuits), it makes sense that this treatment option may be effective for the memory circuits involved with AD. AD can be considered a neural circuitry disorder because “it effects several integrated pathways linking specific cortical and subcortical sites, especially those serving aspects of memory and cognition” (Mirzadeh, Bari, Lozano, 2015). In 2010, a research team composed of doctors from the University of Toronto’s Geriatric Medicine and Functional Neurosurgery departments and lead by Dr. Laxton, a neurosurgeon, investigated the use of DBS to treat AD in a Phase I Clinical Trial. Their targets were the fornix/hypothalamus. The fornix is an arched bundle of nerve fibers in the brain which receives output from the hippocampus, the memory center in the brain. The hypothalamus is a small part of the brain which regulates hormones and body temperature. The Laxton team wanted to determine if DBS in these areas could slow the rate of cognitive decline in AD patients. Their results showed that it did work in some patients. This seems promising, however, there are some limitations to consider when reading this study. Because it was a Phase I trial, the subject pool was small. The research team only used six patients and each of the six patients expressed only mild forms of AD. In the results section of the initial paper, Laxton et. al acknowledges these limitations and discusses the need for further investigation into the use of DBS, as well as the need for more insight into the pathological brain activity of AD (Laxton, et al., 2010).

Laxton’s team decided to target the hypothalamus because of a 2008 study published by Hamani et al. in the Annals of Neurology. Hamani was using DBS to treat a patient struggling with obesity. The hypothalamus influences feeding behavior in humans and animals and modulates memory (Hamani, et al., 2008). While undergoing treatment for obesity, the patient unexpectedly demonstrated an evocation of detailed, autobiographical memories. When the first electrode contact was activated at 3.0 volts, the patient expressed experiencing “déjà vu,” and he described a scene from his past where he was in the park with his old friends and a past girlfriend in vivid detail. Hamani’s group fact checked the accuracy of these memories and found them to be reliable. When the voltage increased from 3.0 to 5.0, the patient’s recollection of the scene became even clearer. The effects of these electric contacts were reproducible in a blind study with the same patient, and the positions of the electrodes were confirmed with computed tomography imaging. The patient also underwent a neuropsychological/memory evaluation for baseline data, and finished the same evaluation three weeks after the completion of hypothalamic deep brain stimulation.  The patient showed improvement in almost every memory test except for the two involving facial recognition. However, facial recognition is a task which is more associated with the fusiform face area, located in the fusiform gyrus than the hypothalamus. (Smithsonian Magazine, 2017).

The patient also underwent two additional recognition tests to determine if hypothalamic stimulation increased recognition. The first test involved 80 pairs of words. The patient was given each pair of words and then asked to identify which word in the pairing was more pleasant. After ten minutes, the patient was shown different pairings of the same words and asked to determine if these pairings were intact, recombined, or new. If he identified a word pairing as being intact or recombined, he had to state whether he “remembered” or “knew” that to be the case. In the study remembering something was defined as the ability to “recall elements of the study episode” where know was defined as “the ability to recognize that a pair of words went together but to be “unable to recall the original context of the association between words.” The patient underwent this recognition test with and without the activation of the DBS device. The second recognition test was preformed one year after the initial activation of stimulation. For this test, the patient studied 120 pairs of words. He was asked to create meaningful sentences out of each word pairing. Then he was tested on word recognition. The original word pairings were scrambled and the patient was asked to identify the pairs which contained two of the studied words. Both the identified recombined pairs and the intact pairs comprised positive responses. In the second part of this task, the patient was asked to identify only the intact pairs of words. The proportion of identified recombined pairs in this part of the task and the first part of the task was used to estimate recollection and familiarity. This test was repeated with DBS activated and deactivated. The recollection index and the familiarity index both increased when the hypothalamus was being stimulated. This suggests a definite link between hypothalamic stimulation and an increase in memory function (Hamani, et al., 2008). This study marks the serendipitous beginning of using DBS to treat AD.  

When Laxton and his team at the University of Toronto began their 2010 study, their ideas on where to place the DBS targets stemmed primarily from the 2008 paper published by Hamani et al. In addition to electrode placements in the hypothalamus Laxton’s team decided to place target DBS electrons in the fornix. Lesions in the fornix produce memory deficits in both experimental animals and humans. They were hoping to find that stimulation in the fornix would make it possible to activate and modulate memory mediating circuits (Laxton, et al., 2010). The researchers chose to select patients with mild forms of AD because they assumed that the structural integrity of the examined circuits would be more intact than those in patients with more progressed forms of the disease. Each of the six patients underwent DBS implantation surgery. The DBS target and contacts were applied to the same points in the brain for each patient. The electrodes were implanted while the patient was awake and stimulation was turned on to monitor for adverse reactions. Two weeks after the surgery, the patients returned to the hospital for a clinical evaluation and follow-up. Their DBS devices were activated during this appointment. The neuropsychological and neurophysiological measures involved in evaluating each patient before and after surgery and after DBS activation consisted of PET, to measure cerebral glucose metabolism, sLORETA (standardized Low Resolution Brain Electromagnetic Tomography), to identify and map the brain areas effected by DBS, ADAS-cog (Alzheimer’s Disease Assessment Scale-Cognitive Subscale), and the MMSE (Mini Mental State Examination). After 6 months of stimulation, 4 of the 6 patients showed improvement according to these measures. However, after 12 months, the results were more mixed and are described in the paper as being “variable, nonlinear, and controversial (Laxton, et al., 2010).” One patient continued to score approximately 4 points lower on the ADAS-cog than on baseline, two patients showed a two point increase, one patient showed a five point increase, and one patient showed an increase greater than five points. The higher the patient’s score on the ADAS-cog, the more progressed AD is. The MMSE scores for each patient showed similar variances, ranging from an improvement of two points to a declination of eight. Researchers observed that the improvement in ADAS-cog was mostly driven by improvement in the recall and recognition components of this metric evaluation. This suggests that despite mixed results from the study, DBS might work to drive memory function (Laxton, et al., 2010). Laxton and his team explained that the discrepancies in the results may be due to differences in the structural integrity of the hypothalamus/fornix pathway. Furthermore, the PET scans of each patient showed a “large and sustained change in glucose metabolism in brain regions that were dysfunctional.” In conclusion, DBS may be a viable treatment option for younger patients with mild forms of AD, but no positive results can be guaranteed. Even though the PET scans showed an improvement of pathological symptoms of AD, there was no significant clinical improvement. The best treatment plan would include ways to treat both the pathological and clinical symptoms of the disease, resulting in a higher quality of life for both the patient and their caregiver.

In 2015, a team of researchers from the Department of Psychiatry and Psychotherapy from the University of Cologne, Germany preformed DBS on the NBM (Nucleus Basalis of Meynert) for treatment of AD. Kuhn and his team decided to target the NBM because severe atrophy and the reduction of cholinergic innervation in this area are part of the pathological cascade in AD. They had also observed that stimulation of the cholinergic pathways impacted neuro-plasticity during and after stimulation in the brains of rats They concluded that “DBS of the NBM is both technically feasible and well tolerated” (Kuhn, et al., 2015). However, their study only used 6 people. This was a clinical double-blind sham-controlled Phase I investigation. Similar to the Laxton study, these patients demonstrated mild to moderate forms of AD. The method of electrode implantation was also the same as was demonstrated in previous studies. It is interesting to note that the electrodes used in each of these studies are from the same company, Medtronic.

The primary measure of the surgical outcome in this study was performance on the ADS-cog after one year. Secondary assessments included the MMSE, the trail making task, the Stroop task, the verbal fluency test, subtests of the Wechsler Memory Scale, subtests of Wechsler Adult Intelligence Scale, and two psychopathological tests to indicate levels of depression in the subjects. PET and EEG were also used to measure the effects of DBS on the pathological neurodegenerative cascade. The results of the study were mixed, similar to what was seen with the Laxton study. Overall, the ADAS-cog scores worsened by three points after one year of DBS. The MMSE scores decreased on average by 0.3 which is a significant improvement over the 4-point worsening usually seen in AD patients only being treated pharmacologically. On the individual scale, however, the results were very different. One of the patients deteriorated slightly, one of the patients “deteriorated markedly” (exact measurements were not given), one of the patients “improved significantly which would be exceptional in AD” (again no figures were given), and two of the patients remained stable. The improvements demonstrated by the PET and EEG imaging tests seemed to correlate with improved clinical symptoms. There was a “global increase” of 2-5% in cortical glucose metabolism. A decrease in cortical glucose metabolism results in cell death in the hippocampus, which speeds neurodegeneration. However, we again see differences on the individual level (Kuhn, et al., 2015). The inconsistencies in, and discrepancies between the positive results among individuals undergoing DBS surgery raise questions about the ethics involved in this procedure. There were two patients who experienced serious adverse effects as a result of the DBS because of technical complications with the device. In one patient, the implanted device was incorrectly assembled and in another patient the “plug-in connection of the lead as well as the stimulation generator were incorrectly assembled” (Kuhn, et al., 2015).

In 2015, the Lozano group, based at the University of Pennsylvania, led a Phase II Clinical Study investigating fornix deep drain stimulation in mild Alzheimer’s Disease. Their sample size included 42 patients from the United States and Canada. This study reported that the “surgery and electrical stimulation were safe and well tolerated (Lozano, et al., 2015)” but that there were “no significant differences in primary cognitive outcomes” and no significant increase was seen in glucose metabolism one year after stimulation. The Lozano group used essentially the same methods to implant the electrodes and measure the cognitive outcomes post-op as both the Laxton group and the Kuhn group. Notably, Lozano is listed as a contributing author on both the 2008 Hamani et al. paper and the 2010 Laxton et al. paper. The 2008 paper received mostly negative reviews from Lozano’s peers who declared that his results “were not conclusive for clinical outcome (Bittlinger, Muller, 2018).” However, these reviews did not deter Lozano and his research team from lauding their work as a success, and suggesting that DBS would be a viable option for the treatment of AD. In 2018 the team of Bittlinger and Muller, doctors from the University of Berlin Department for Psychiatry and Psychotherapy and the Division of Mind and Body surveyed 113 deep brain experts across twelve different countries and found that “the prospects of success with regard to DBS for AD has been evaluated with skepticism from the outset (Bittlinger, Muller, 2018). Andres Lozano is the founder of the company Functional Neuromodulation Ltd. and the co-inventor of a US patent on fornix DBS for AD. It is possible that both his involvement with a neuromodulation company and the US patent influence his research. The role of patents for neuro-technological research is still being debated (Bittlinger, Muller, 2018).

A review published in 2018 entitled “Opening the Debate on Deep Brain Stimulation for Alzheimer disease- A Critical Evaluation of Rationale, Shortcomings, and Ethical Justification” written by Merlin Bittlinger and Sabine Muller, examines the literature written on DBS for AD and cites the 2010 study by Laxton et al., the 2015 study published by Kuhn et al., and the 2015 by Lozano et al. The review ultimately comes to the conclusion that using DBS to treat AD and dementia is unethical because of shortcomings that are both “scientific and ethical in nature” (Bittlinger, Muller, 2018) and because its “efficacy and safety are not yet empirically established to be likely.” None of the clinical trials have shown “statistically significant and clinically meaningful effects of DBS for patients with AD for primary outcomes (Bittlinger, Muller, 2018).” Most of the “positive” outcomes of these trials are seen in the measurements of glucose metabolism as determined by neuro-imaging studies done by PET and EEGs, which are secondary or tertiary measures of DBS success. Yet the studies continue. Clinicaltrials.gov currently lists three actively recruiting studies for DBS treatment in AD, four studies with “unknown” statuses, and six studies with “completed” statues (clinicaltrials.gov, 2018).  The FDA and the European Medicines Agency (EMA) place DBS into their class Three Implants, which denotes the implants with the highest risk. Some of the risks associated with DBS implantation include hemorrahage, wound infection, hardware failure, suicide, inner restlessness, autonomic and cardiovascular effects, lead repositioning, and chronic subdural hematoma. While the percentage likelihoods of these side effects are not necessarily significant, the amount of people undergoing DBS implantation for AD treatment is also very low, and two of patients in the Kuhn 2015 study did experience hardware malfunctioning which required surgical intervention to rectify (Kuhn, et al. 2015). 

The risk of implanting DBS into patients suffering from AD is much higher than the possible payoff. It does not seem necessary to continue further investigations of this treatment method for AD as many of the published results demonstrate similar findings, but it may be beneficial to continue research into AD as a neural circuitry disease, affecting memory circuits, rather than just as a neurodegenerative disease. It would also be interesting and perhaps beneficial for the scientific community to examine the role of DBS in activating vivid, autobiographical memories like those initially seen in the 2008 Hamani et al. paper. The research studies stemming from this initial work used only patients suffering from mild to moderate forms of AD and the DBS targeted only the areas of the brain known to be implicated in AD. It would be unethical to preform DBS on patients who did not need it, and it would also be unethical to target brain areas that are not directly implicated with the disease the patient is suffering from. It is therefore interesting that so many studies have been done on DBS as a treatment for AD, when the results from the original study which sparked interest in this idea cannot be replicated.

Citations

Alzheimer’s Association. (2018). Facts and Figures. Retrieved December 9, 2018, from https://www.alz.org/alzheimers-dementia/facts-figures 

American Association of Neurosurgeons. (2018). Deep Brain Stimulation. Retrieved December 9, 2018, from https://www.aans.org/Patients/Neurosurgical-Conditions-and-Treatments/Deep-Brain-Stimulation

Anderson, J. G., Eppes, A., & O’Dwyer, S. T. (2019, March 03). “Like Death is Near”: Expressions of Suicidal and Homicidal Ideation in the Blog Posts of Family Caregivers of People with Dementia. Retrieved March 9, 2019, from    https://www.ncbi.nlm.nih.gov/pubmed/30832390

Barak, Y., & Aizenberg, D. (2002). Suicide amongst Alzheimer’s disease patients: A 10-year survey. Retrieved March 9, 2019, from             https://www.ncbi.nlm.nih.gov/pubmed/12145457?dopt=Abstract

Bittlinger, M., & Müller, S. (2018). Opening the debate on deep brain stimulation for Alzheimer disease – a critical evaluation of rationale, shortcomings, and ethical justification. BMC medical ethics19(1), 41. doi:10.1186/s12910-018-0275-4 Retrieved December 10, 2018 from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994654/ 

Gardner J. (2013). A history of deep brain stimulation: Technological innovation and the role of clinical assessment tools. Social Studies of Science43(5), 707–728. Retrieved December 9, 2018, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3785222/

Hamani, C., McAndrews, M. P., Cohn, M., Michael, Zumsteg, D., Shapiro, C. M., . . . Lozano, A. M. (2008, January 29). Memory enhancement induced by hypothalamic/fornix deep brain stimulation. Retrieved December 9, 2018, from https://onlinelibrary.wiley.com/doi/full/10.1002/ana.21295

Laxton, A. W., Tang‐Wai, D. F., McAndrews, M. P., Zumsteg, D., Wennberg, R., Keren, R., . . . Lozano, A. M. (2010, August 04). A phase I trial of deep brain stimulation of memory   circuits in Alzheimer’s disease. Retrieved December 9, 2018, from             https://onlinelibrary.wiley.com/doi/full/10.1002/ana.22089

Lewis, D. (2017, January 10). The Part of Your Brain That Recognizes Faces Continues Growing Later in Life. Retrieved December 9, 2018, from             https://www.smithsonianmag.com/smart-news/part-brain-used-recognize-faces-continues-grow-throughout-life-180961723/

Kuhn, J., Hardenacke, K., Lenartz, D., Gruendler, T., Ullsperger, M., Mai, J. K., Bartsch, C., … Sturm, V. (2016, May 6) Deep Brain Stimulation of the Nucleus Basalis of Meynert in Alzheimer’s Dementia. Molecular Psychiatry, 20, 353-360. Retrieved December 9, 2018 from https://www.nature.com/articles/mp201432

Mayo Clinic. (2018, June 23). Deep brain stimulation. Retrieved December 9, 2018, from  https://www.mayoclinic.org/tests-procedures/deep-brain-stimulation/about/pac-20384562

Mirzadeh, Z., Bari, A., & Lozano, A. M. (2016, July). The rationale for deep brain stimulation in Alzheimer’s disease. Retrieved December 9, 2018, from    https://www.ncbi.nlm.nih.gov/pubmed/26443701

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