Welcome to Novela’s series on Neurostimulation. We will explore applications to pathologies like epilepsy, Parkinson’s disease and neuropsychiatric disorders. Our blog posts are educational, therefore we used simpler constructs when possible rather than the precise scientific terminology.
AUTHOR JOSE VELAZQUEZ IS A SENIOR SCIENTIFIC ADVISORY BOARD MEMBER TO NOVELA NEUROTECHNOLOGIES.
The story of electrical stimulation of the nervous system has a long history that goes back to the times of the emperors Tiberius, Caligula and Claudius. Around 46 CE, Roman physician Scribonius Largus apparently used stingrays for the treatment of headaches, by touching the affected area with the animal.
Later, in the 11th century, the Indian physician Ibn-Sidah is said to have used catfish applied on the forehead of epileptic patients to relieve their seizures.
Today these primitive interventions would be called non-invasive i.e. they are treatments that do not break the skin, as opposed to the invasive Deep Brain Stimulation (DBS), where electrodes have to be inserted into the tissue. Non-invasive methods have the obvious advantage that surgery is not needed. However, the technology is currently immature. We seek non-invasive brain stimulation that has similar beneficial effects to those of Deep Brain Stimulation (DBS).
The modern history of electrical brain stimulation is considered to have started in the second half of the 1880’s by the pioneers E. Sciamanna, G.B. Duchenne de Boulogne and a few others.
In brief, the main idea of brain cell networks is that cells in the nervous system activate one another in chains. In primitive nervous systems like those of insects, one neuron activates another cell, and the chain from cell to cell can be mapped.
However, in advanced nervous systems, like our brains, it is more like a mass action. Many neuronal action potentials converge simultaneously on one neuron and many of its neighbors. This set of neurons then becomes synchronously active, generating action potentials that activate another set of many neurons downstream.
The neuronal activity is, mainly due to electrical fields, ions moving in and out of the cell. This is what generates action potentials and synaptic transmission from one neuron to another. Information is then passed from one cell network to another.
Neurotransmitter information is carried any time one cell network is bombarding another network with neurotransmitters, propagating the activity to others. This spread of potential differences gives rise to patterns of organized activity. They are recorded as a variety of oscillations which represent the activity of very large numbers of brain cells.
The characteristic pattern of nervous systems is that highly synchronous cellular activity effectively drives downstream cells, coordinating the activity in large cell ensembles. Therefore, any direct electrical field applied to the brain tissue will affect the mutual activation of cells.
In some cases, the activity will be significantly perturbed. For example, events like epileptic seizures, that require large synchronization of cellular activity, can be averted.
From these basic neurophysiological considerations, one can foresee that direct electrical stimulation can be used to prevent pathological brain activity, to control the brain.
The placement of electrodes in very specific brain regions allows for a more localized stimuli to be delivered. The method is invasive, as surgery is needed to have electrodes inserted into the brain. Normally those wires will remain inside for the duration of the treatment, sometimes throughout the life of the patient.
Certainly, there are non-invasive methods to apply stimuli, such as transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS). The former uses a coil to deliver magnetic fields that generate electrical potentials in the brain tissue, and the latter uses constant low direct current delivered via electrodes on the head.
However, for the time being these operations lack enough specificity to be used in some pathologies. Additionally, the device that sends the magnetic fields cannot be carried easily on the head. On the other hand, the DBS devices (electrodes and accessories) are fully portable and can be inserted deep into the tissue.
A current area of great interest in neuroscience is the possibility that DBS offers to change those collective cellular activity patterns. That enables altering cellular behavior and stopping pathological manifestations of the brain activity in incidences like epileptic seizures or Parkinsonian tremors. Perhaps the greatest success of DBS has been at ameliorating Parkinsonian symptoms. Interested readers can review several videos available on the Internet the almost immediate reduction of tremor after the DBS device is turned on.
DBS has been applied to a variety of pathologies, even though some applications are still in their infancy. Examples include the treatment of psychiatric disorders like depression, addiction, obsessive-compulsive disorder, anorexia nervosa, and Tourette’s. To those interested in the non-invasive methods (TMS and tDCS) in the treatment of addiction, the review by Feil and Zangen (2010) is recommended.
While some reasonable progress has been made with DBS in epilepsy and Parkinson’s disease, it is the neurostimulation methods in psychiatry that will probably revolutionize the field.
The history of medical treatments imposed on neuropsychiatric patients starts with staggeringly cruel ― at least by our current standards― therapies, like castration, ablative neurosurgery and its old predecessor of trepanation (pictorially represented in the 16th century painting by H. Bosch “The cure of folly”), cerebral diathermia (electrically induced heat), and treatments using compounds like insulin or other hormones, and lobotomy.
There is still today some psychosurgery being performed, but the advances in neuromodulation is paving the way towards non-invasive, and thus gentler, treatments which are based on the general idea of changing the electrical activity in the nervous system.
Nevertheless, as aforementioned, we are still in a time where non-invasive neuromodulation is at its infancy. Today most of these therapies still rely on the implantation of electrodes in brain tissue. For a recent and short perspective on electrical stimulation of the psychopathic brain, one can read Canavero (2014).
However, most of the present perturbations of brain dynamics use a rather brute-force approach, as the current deep brain stimulation techniques are mostly blind to the intrinsic brain dynamics. Because we lack deep understanding of brain dynamics, it is relatively unknown what the effects may be after disrupting one neural activity pattern that becomes another.
We seek an alternative method to this trial-and-error approach. A manner that considers neuronal dynamics in order to obtain the DBS protocol for a specific pathological condition in a way that a more efficient treatment is achieved.
There are some problematic aspects of DBS such as a succession of on and off episodes which results in having the device stimulating the brain almost all the time. This reduces battery life and can cause side-effects of the stimuli, such as anxiety, mania or a decline in word fluency. It should be noted, however, that the DBS side effects are few and much more tolerable than those caused by medications.
To circumvent the DBS side effects, protocols that trigger the stimulation on-demand are being developed. The name On-Demand Stimulation refers to the general idea is that aberrant brain activity patterns can be perturbed ―abolished, or “normalized”― by the application of precisely timed intracerebral and localized current stimulation.
The stimulation on-demand, also known by other names like closed-loop, feed-back or responsive stimulation, has certain advantages over continuous stimulation of brain tissue. Among the benefits are longer battery life of the device (since it is used only when needed) and fewer side effects.
Great advances in detecting abnormal patterns of brain cellular collective activity associated with neurological and psychiatric disorders have been achieved. This encourages to use these discoveries to trigger the feedback stimulation.
Whether it is closed-loop or continuous/intermittent stimulation protocols, all DBS procedures seem to work to some extent. However, a complex system like the nervous system precludes the finding of one technique of wide, general application. This should not be a problem though. There is no reason why specific methods could not be tailored for each patient in the rapidly emerging field of personalized medicine. And indeed, there is a patient-individual approach using electrodes manufactured by Novela Neurotechnologies. The method has shown to be very efficient at arresting seizure generation in a rodent model of epilepsy. Several years of research was needed to unravel some features of the neural dynamics of epileptiform activity, before the DBS protocol was designed and applied to the rats experiencing seizures.
The use of this informed approach to stimulate the brain still needs some careful study of the neural dynamics, though. The combination of the DBS hardware and software with the deep knowledge of brain dynamics could allow very efficient treatment of neuropsychiatric syndromes. This field of Dynamiceuticals is an extension of the old field of Pharmaceuticals and the more modern field of Electroceuticals.
The name Dynamiceuticals indicates the importance of knowing the intrinsic dynamics of the organ and pathology in question. It does not need to be the brain, it can be applied to almost any other system.
The miniaturization trend of electronic materials has fostered a vast interest in DBS coupled with microdevices that are able to record and analyze on-line brain activity. The current developments are starting to sound fantastic – even beyond science-fiction!
Large-Area Electronics is an example of new ways of manufacturing electronics. Their flexible, printable and organic electronic materials could support distributed intelligence based on printable logic circuits.
Not too far in the future, these advances, added to the novel organic electronics that can almost “fuse” with cell membranes, herald what can be considered a revolution in the brain-computer interface.
The emerging field of neurostimulation is growing so rapidly that soon the fiction will become the science. We began with a broad overview of the field. Our next installments will present more specific applications to different syndromes and the approaches to design DBS protocols.BIBLIOGRAPHY