Electrical Brain Stimulation in Treatment of Neurodegenerative Diseases

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The early Egyptians and Romans recognized the numbing effect of the electric properties of catfish. In fact, Romans were the first to cultivate electric fishes for pain relieving effect. But since then, not much has changed in the development of electricity based medical treatments. Things only started to change two millennia later with the discovery of electricity and a better understanding of neurophysiology.

Electroconvulsive therapy was born in the middle of the 19th century. In the early days, it was primarily used to treat neuropsychiatric disorders. In the mid-19th century, direct electric current was used for electroconvulsive therapy. By the end of 19th-century, the alternate current was discovered, and its use along with the use of magnetic fields became the subject of experiments not only investigating neuropsychiatric conditions but also other diseases like epilepsy and chronic severe headaches.

Electroconvulsive therapy is still used in the treatment of severe neuropsychiatric conditions like schizophrenia or depression, where suicidal tendencies do not respond to pharmacological agents. Unlike in the old days, now this is a non-invasive treatment usually performed under general anesthesia. The therapy non-selectively resets various centers in the brain and thus has wide-ranging side effects like loss of memory, headaches, and muscle aches.

Considering the widespread side effects of electroconvulsive therapy, the need for more selective stimulation of particular brain centers specific for a particular disease was obvious. The improvements in understanding of brain physiology and surgical techniques gave rise to “deep brain stimulation” (DBS). This is an invasive method where electrodes are surgically placed inside the specific part of the brain that are connected to a small electrical device that generates the stimulation.

At present, DBS has been shown to be effective in the treatment of Parkinson’s disease, epilepsy, obsessive compulsive disorder, and dystonia. It is being studied for applications in treating depression, drug addiction, and other neurodegenerative disorders such as dementia. As the method is invasive and involves the surgical implantation of electrodes inside the brain, it is reserved for cases that fail to respond to pharmacological therapy.

Deep brain stimulation in Parkinson’s disease

Dopamine is a chemical messenger in the brain that plays an important role in physical movement. In Parkinson’s disease, there is a progressive loss of dopamine-producing neurons resulting in motor deficiencies. Thus, the first line therapy for this disease is to give dopamine replacement therapy by prescribing a drug called levodopa.

The problem is, one-third of cases of Parkinson’s disease progress quickly and stop responding to the therapy with levodopa or other pharmacological agents, thus necessitating a treatment like DBS.

For the best results, it is recommended to go for DBS well before the symptoms become debilitating. In the later stages, the effectiveness of DBM tends to be lower.

DBS in Parkinson’s disease involves the application of continuous high-frequency electrical pulses through electrodes implanted in the subthalamic nucleus (STN) in the brain (though sometimes other locations may also be chosen). The STN is demonstrated to be over-activated in Parkinson’s disease. These electrodes are connected to the compatible pulse generating device. The pulse generator uses various pulses to achieve the optimal effect, where the right kind of settings can be chosen for a person by assessing treatment effectiveness.

Continuous DBS was shown to improve motor symptoms in more than two-thirds of patients, as compared to no stimulation or intermitted stimulation.

In one of the clinical studies, bilateral STN DBS was performed on patients that were not responding to the maximum dose of levodopa or to a continuous infusion of apomorphine. DBS showed marked improvement in motor function in 61% of cases. After the procedure, there was a 37.1% decrease in the daily dosage of levodopa in the patients. There was an almost 70% decrease in the need for apomorphine, with some patients not requiring apomorphine at all. Thus, the effectiveness of bilateral STN DBS in advanced Parkinson’s disease is well established.

Although the exact mechanism whereby DBS is effective is still unknown, it is believed to involve overcoming abnormal electrical patterns generated in the basal ganglia.

With the devices and surgical technique being constantly refined,  the effectiveness of this treatment may improve sufficiently enough to be widely used during the early stages of the disease in the future.

Deep brain stimulation in Alzheimer’s disease

In Alzheimer’s disease, DBS is still an experimental treatment. Lots of research with the use of various techniques has been done on animals, some with positive results. In one such study in monkeys, intermittent DBS was used with 60 pulses for 20 seconds with an interval of 40 seconds in between. The experiment demonstrated improvements in the memory of the primates. The experiment also showed deterioration of memory following continuous stimulation. The differences with results in the treatment of Parkinsonism might be explained by the differing pathological mechanisms involved.

After months of intermittent stimulation, the monkeys demonstrated improvements in memory even on discontinuation of stimulation. This lasting effect has not yet been explained. It is quite possible that such intermittent stimulation results in an improved connection between neurons, or higher levels of release of the neurotransmitter acetylcholine.

DBS has certain benefits over drugs, as it stimulates specific areas of the brain, while anticholinergic drugs used to treat Alzheimer’s have widespread non-selective action. Thus, DBM may prove to be a safer treatment option in the future.

It has to be noted that apart from DBS, non-invasive neurostimulation using transcranial magnetic stimulation has also demonstrated promising effects in animal studies.

References

Dubljevi?, V., Saigle, V., Racine, E., 2014. The Rising Tide of tDCS in the Media and Academic Literature. Neuron 82, 731–736. doi:10.1016/j.neuron.2014.05.003.

Elder, G.J., Taylor, J.-P., 2014. Transcranial magnetic stimulation and transcranial direct current stimulation: treatments for cognitive and neuropsychiatric symptoms in the neurodegenerative dementias? Alzheimers Res. Ther. 6, 74. doi:10.1186/s13195-014-0074-1.

Green, A.L., Bittar, R.G., Bain, P., Scott, R.B., Joint, C., Gregory, R., Aziz, T.Z., 2006. STN vs. Pallidal Stimulation in Parkinson Disease: Improvement with Experience and Better Patient Selection: STN vs. Pallidal DBS. Neuromodulation Technol. Neural Interface 9, 21–27. doi:10.1111/j.1525-1403.2006.00038.x.

Hansen, N., 2014. Brain Stimulation for Combating Alzheimer’s Disease. Front. Neurol. 5. doi:10.3389/fneur.2014.00080.

Little, S., Pogosyan, A., Neal, S., Zavala, B., Zrinzo, L., Hariz, M., Foltynie, T., Limousin, P., Ashkan, K., FitzGerald, J., Green, A.L., Aziz, T.Z., Brown, P., 2013. Adaptive deep brain stimulation in advanced Parkinson disease. Ann. Neurol. 74, 449–457. doi:10.1002/ana.23951.

Mallet, L., 2010. Deep Brain Stimulation in Psychiatric Disorders, in: Koob, G.F., Moal, M.L., Thompson, R.F. (Eds.), Encyclopedia of Behavioral Neuroscience. Academic Press, Oxford, pp. 376–381. doi:10.1016/B978-0-08-045396-5.00249-9.

Sharifi, M.S., 2013. Treatment of Neurological and Psychiatric Disorders with Deep Brain Stimulation; Raising Hopes and Future Challenges. Basic Clin. Neurosci. 4, 266–270. PMCID: PMC4202568.

Varma, T.R.K., Fox, S.H., Eldridge, P.R., Littlechild, P., Byrne, P., Forster, A., Marshall, A., Cameron, H., McIver, K., Fletcher, N., Steiger, M., 2003. Deep brain stimulation of the subthalamic nucleus: effectiveness in advanced Parkinson’s disease patients previously reliant on apomorphine. J Neurol Neurosurg Psychiatry 74, 170–174. doi:10.1136/jnnp.74.2.170.

Image via PublicDomainPictures/Pixabay.

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