'Brain pacemaker' used to treat Alzheimer's
Alzheimer’s disease could be eased by “the return of electric shock therapy”, the Daily Mail reported.
This story is based on a small safety trial that tested a technique called “deep brain stimulation” (DBS) in six patients with Alzheimer’s disease. The technique involves surgically implanting electrodes into the brain and delivering a series of mild electric pulses to the targeted brain region. However, although some patients showed slight improvements, the researchers’ objective was to test the safety of the technique, not whether it offered an effective treatment for Alzheimer’s. Therefore, they cannot confirm how DBS interacts with this complex disease or whether it does produce improvements.
The mild stimulation used in DBS is not to be confused with electroconvulsive therapy (ECT), or “shock therapy”, which is itself a valuable technique for helping some patients with severe depression. To explore their DBS technique further, the researchers are now conducting larger human trials and animal research, the results of which will show more clearly whether DBS could be used as a treatment.
Where did the story come from?
The study was carried out by researchers from the University of Toronto, the University of Zurich and Johns Hopkins University, Maryland. The research was supported by the Neurological Research and Education Foundation, the Dana Foundation and the Krembil Neuroscience Discovery Fund.
The original human trial was published in the peer-reviewed journal Annals of Neurology . The follow-up mouse study was published in the Journal of Neuroscience.
This study was reported accurately by the media. The Daily Mail appropriately outlined the limitations of the study, including the preliminary and small-scale nature of the research. However, the technique used in this study was not “electric shock therapy”; it was the use of an electrical device implanted directly into the brain to stimulate certain regions mildly.
What kind of research was this?
This clinical study examined the effect of deep brain stimulation (DBS) on the size and functioning of an area of the brain called the hypothalamus, which is involved in memory. The researchers thought that stimulating this area of the brain with electric pulses could alter the activity of the memory circuits in patients with early Alzheimer’s disease (AD).
This was a phase one clinical study, designed to test the safety of a new therapy. These trials are generally small, as the goal is to make sure that the method is acceptable to use in larger trials, and not to precisely define its effectiveness. Only once phase one trials have determined that a technique is safe can larger studies be conducted to determine how effective the technique is in a broader patient population.
What did the research involve?
The researchers recruited six patients who had been diagnosed with Alzheimer’s within the previous two years. All were receiving medication for the disease. The researchers surgically placed electrodes in the patients’ brains. The electrodes delivered a small electric pulse to the hypothalamus, and the therapy was used alongside the patients’ existing medication for one year. The researchers measured changes in the activity of various brain structures, the brain’s use of sugar (which has previously been shown to be reduced in patients with AD), and cognitive function at 1, 6 and 12 months after surgery.
To measure changes in the brain’s mental and physical functioning, the researchers used the following techniques:
- standardised low-resolution electromagnetic tomography (sLORETA), to map the brain and determine which regions were activated by the therapy
- an imaging technique called positron emission tomography (PET), to measure use of glucose in these specific brain regions
- the mini-mental state examination (MMSE) and the Alzheimer’s disease assessment scale (ADAS), to measure functional changes and the severity and progress of the disease – these accepted clinical assessments measure things such as memory and language function
The researchers took all three measurements at the start of the study (the “baseline”) and after 1, 6 and 12 months of deep brain stimulation treatment. They compared the post-surgery measures to the baseline measures to assess the effect of the therapy on structural, functional and clinical outcomes.
What were the basic results?
When assessing changes in patient functioning, as measured by the MMSE and ADAS, the researchers found that, compared to baseline measures:
- After one month of DBS, three patients showed slight improvement in functioning and three patients showed a slight worsening of functioning.
- After six months of DBS, four patients showed improvement in functioning and two showed either no change or worsening of functioning.
- After 12 months of DBS, one patient showed an improvement, and five showed a worsening of functioning.
When these results were compared to the expected change in functioning over one year of a typical patient with Alzheimer’s disease, it was found that two of the participants had a less severe decline in functioning than expected, one had a more severe decline than expected, and three had a similar change in functioning as expected.
The researchers mapped the areas of the brain that were affected by the DBS treatment. In addition to the areas being directly stimulated by DBS, regions involved with the brain’s memory circuit were consistently activated in all six patients. The researchers say this demonstrates that stimulation of the hypothalamus drives the activity of the brain’s memory circuit.
When the researchers measured brain activity (in terms of the brain’s use of sugar), they found that after both 1 and 12 months of DBS, all patients demonstrated increased activity in the brain areas affected by Alzheimer’s disease, compared to before treatment. In patients with Alzheimer’s disease, sugar use would be expected to decrease as brain activity declined.
How did the researchers interpret the results?
The researchers concluded that deep brain stimulation (DBS) produces “striking and sustained changes” in the activity of brain regions that are typically dysfunctional in patients with Alzheimer’s disease. They said that the technique was also shown to be safe.
Conclusion
This was a small, early-stage clinical study that tested the safety of using deep brain stimulation to treat Alzheimer’s disease. Due to the preliminary nature of this research and the fact it did not compare DBS patients against a control group, the results can’t be universally applied to all patients with Alzheimer’s disease. The researchers have since started a larger-scale study (involving 50 people) to assess the benefits and effectiveness of the treatment.
Potential issues with this sort of study are:
- Without a control group it isn’t possible to say that any slowing of the deterioration expected in people with Alzheimer’s was due to the treatment. It isn’t valid to compare the results from so few people with an “expected” rate of decline.
- The patients involved in this study were all in the early stages of the disease. The researchers said that having a particular memory circuit still functioning appears to be associated with how well people respond to DBS. As such, use of this therapy in patients with more advanced disease may not be possible. Undergoing this type of surgery may also be distressing or confusing for people who have lost some mental function.
- The process involves invasive brain surgery, and factors such as age-related illnesses may make the technique unsuitable for some people even if they are in the early stage of the disease.
- This study demonstrated the potential therapeutic benefit of this technique in patients in the early stages of the disease, but was unable to define the mechanism through which DBS may generate the changes seen. A follow-up study in mice showed that DBS resulted in the generation of new cells in another part of the brain involved in memory: the hippocampus.
Alzheimer’s is a complicated disease, and we don’t yet fully understand its underlying cause or precisely how all the observed dysfunctions fit together. The researchers acknowledged that they do not know how this treatment works, if it does at all. This research may prove to be a springboard for identifying new treatment options of this disease or, as with many exploratory ventures, it could prove to be ineffective.
