Author: Devon Sheppard Edited by: Inês Barreiros
Since the first applications of bioelectricity and the discovery of the electrical nature of the nervous system, communicating with it directly through an electric medium has been a possibility. While seamless integration of artificial components to augment nerve function has not been achieved yet, feeding electrical information directly into the central nervous system (CNS) is already happening and continues to make astonishing progress in a number of critical areas of human health. The use of small probes that interface directly with the nervous system allows passage of controlled electrical pulses directly to neurons. And, while we do not yet have the capability to pass specific information or knowledge to the CNS, the information we can currently use with electrical messaging has great therapeutic value.
There are a number of neurological conditions for which electrical interference or resetting of electrical networks and patterns can be therapeutic. For instance, neurostimulation devices can be used in conditions where pharmaceutical options are often accompanied by an extensive list of adverse effects. These devices follow a format first utilised in the pacemaker, where an implantable battery is connected to a probe that delivers a pattern of electrical bursts at a given frequency. Additionally, they are toxicity-free and allow for a localised action with simplified pharmacokinetics.
One example of where this type of application can be utilised is for treatment of neurodegenerative diseases. Take Parkinson’s disease. It is a debilitating neurological disorder in which progressive loss of dopamine-producing neurons results in a loss of control over general motor function. There are a number of pharmacological treatment options available to counteract and help deal with symptoms of this disease. Since the 1980’s another treatment option has been to use Deep Brain Stimulation (DBS) – an implant that uses electrical pulses to disrupt the neural signalling responsible for tremors. As Parkinson's progresses, neurons become depleted and inappropriate electrical patterning becomes locked, but high frequency disruption through DBS allows the neural network to reset.[i] This allows patients to regain control over their movement in situations where medication has failed.
DBS has been established as an effective and efficient treatment for not only Parkinson’s but also in severe movement disorders. Currently it is being used to successfully treat Tourette’s syndrome and Obsessive Compulsive Disorder (OCD), where locked patterns of behaviour or tics are disrupted and reset. The extension of this approach into neuropsychiatric disorders suggests that there is an underlying commonality of network disruption responsive to treatment.[ii] The use of DBS in refractory epilepsy, another condition in which sufferers cannot efficiently control symptoms through drug therapy, has provided the patients relief.[iii]
Still, neurostimulation is having its most significant impact in long-term neuropathic pain management. The use of drugs in pain treatment is one that requires constant maintenance and supervision. The adaptation of the nervous system reduces effectiveness of the treatments and there are many toxicity concerns, not to mention the potential for addiction and chemical dependence. The use of spinal cord stimulation for a number of pain disorders from peripheral ischemic limb pain to complex regional pain syndrome is becoming increasingly widespread thanks to its stable efficacy and cost-effectiveness over the long term.
With the establishment of safety and availability of risk assessments of CNS electrical implants, their therapeutic applications just become an issue of appropriate placement and suitable pulse selection. Alterations in intensity, frequency or burst sequence are all elements that can be optimised and tuned for the most effective treatment course for a given issue. Basic research allows us to expand of the use of neurostimulation to other disorders, and industry already established the production of these medical devices to bring new treatment options to patients. Clinical trials in the use of the DBS towards neurological damage and stroke recovery have been initiated at the Cleveland Clinic’s Department of Neuroscience with the aid of funding from the National Institute of Health Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative. [iv] Research on DBS use in the more widespread neurodegenerative disorder of Alzheimer’s disease has also started and the aim is to broaden the application to psychiatric disorders, including schizophrenia.[v][vi]
Recent work has made this technology even more exciting as a therapeutic tool beyond the CNS. The ‘inflammatory reflex’ is a signal via the vagus nerve that inhibits inflammatory cytokines, primary drivers of a number of autoimmune disorders. Since vagus nerve stimulation has been used successfully in the treatment of epilepsy, a clinical study of its use in autoimmunity does not require the same preliminary testing that would be needed with a novel pharmaceutical. A study from the University of Amsterdam recently found significant improvements in both early and later stage rheumatoid arthritis patients using vagus nerve stimulation.[vii] The underlying mechanism of this points towards choline acetyltransferase-positive T cells, however the precise mechanism is not well understood. What is known is that yet another disorder that relies heavily on long term pharmaceutical treatment may benefit from an additional approach that improves selectivity and toxicity.
As the research on neurostimulation allows novel applications, it is clear that the quick nature of patient treatment with this method has tremendous advantages over pharmacological options. While the assessment of the efficacy of these new applications is still in its infancy, their production and treatment methodology have already been well established as in the case of Parkinson’s and pain management among other disorders. There are a multitude of companies already producing devices for usage, including Medtronic and St Jude Medical, two of the largest producers of medical devices. The pipeline from basic neurological research to translational research to biomedical applications is one that is clear, unhindered, and it is only going to grow as novel applications of this technology continue to develop.
[i] Fang J, Tolleson C (2017) ‘The role of deep brain stimulation in Parkinson’s disease: an overview and update on new developments’ Neuropsychiatr Dis Treat 13:723-732
[ii] Frick L, Pittenger C (2016) ‘Microglial Dysregulation in OCD, Tourette Syndrome, and PANDAS’ J Immun Res 2016:1-8
[iii] Dalkilic E (2017) ‘Neurostimulation Devices Used in Treatment of Epilepsy’ Curr Treat Options Neurol 19:1-7
[v] Viaña J, Vickers J, Cook M, Gilbert F (2017) ‘Current of memory: recent progress, translational challenges, and ethical consideration in fornix deep brain stimulation trials for Alzheimer’s disease’ Neurobiol Aging pii: S0197-4580(17)30072-6. doi: 10.1016/j.neurobiolaging.2017.03.001. [Epub ahead of print]
[vi] Hadar R, Bikovski L, Soto-Montenegro ML, Schimke J, Maier P, Ewing S, Voget M, Wieske F, Götz T, Desco M, Hamani C, Pascau J, Weiner I, Winter C (2017) “Early neuromodulation prevents the development of brain and behavioural abnormalities in a rodent model of schizophrenia” Mol Psychiatry doi: 10.1038/mp.2017.52. [Epub ahead of print]
[vii] Koopman F, Chaven S, Miljko S, Grazio S, Sokolovic S, Schuurman PR, Mehta A, Levine Y, Faltys M, Zitnik R, Tracey K, Tak P (2017) Proc Natl Acad Sci “Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis”113: 8284-8289