09. Neureka™

Epilepsy I

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.

In spite of the efforts of combinatorial chemistry and high throughput screening in the design of new antiepileptic drugs, about 30% of patients still have pharmaco-resistant seizures. These patients are candidates for Deep Brain Stimulation (DBS), or other alternative treatments like Electroconvulsive Therapy (ECT)―which, paradoxically, promoting hyperexcitability of the brain using ECT reduces seizure frequency. We will explain why in one of our following blogs―vagal nerve stimulation (VNS), ketogenic diet and others…

Therefore, the somewhat limited success in the pharmacological treatment of epileptic syndromes has aroused an increasing interest in the possibility of stopping seizures by brief direct electrical stimulation of specific brain areas using DBS.

The idea substantiating the possible success of electrical perturbations at preventing seizures—or, if not stopping them at least shortening the ictal events—is based on the assumption that if the dynamics of the presumed abnormal synchrony that characterizes these paroxysms is perturbed by stimulations, then the ictus may not occur at all, or is forced to stop if already initiated.

We should note that one thing is to stop seizures, another to cure epilepsy.

Reducing or halting seizures may not resolve the underlying neurophysiological abnormality that results in the syndrome of epilepsy, of which seizures represent just one manifestation. Having said this, however, stopping seizure occurrence will be undoubtedly beneficial because these events represent a most disabling manifestation of the epileptic condition. So, using electrical means to stop ictal events may not cure the syndrome but it will make the patient’s life easier.

Experimental efforts to alter epileptiform activity by direct electrical stimulation date back to the mid 1950s, when it was shown that cerebellum stimulation shortened electroshock-induced seizures. This led to the implantation of cerebellar stimulators in epilepsy patients, and some promising results were reported. (Readers are encouraged to consult chapter 3 of ‘The Brain-Behaviour Continuum’ / World Scientific.)

In the late 1960s, headsets with earphones were used to monitor electrical activity of the brain (EEG). These headsets, that triggered a loud noise in the contralateral ear, were tried on patients, reporting success in just a number of them. Thus, we can see that a variety of non-specific perturbations seem to halt, transiently, paroxysmal activity.

And perhaps at the summit of non-specificity, we find the report by Penfield and Jasper in 1954, where a spike-and-wave discharge (a type of seizure) was suppressed both by electrical stimulation of the neocortex and by a cognitive task. In the task the patient was forced to concentrate on a problem; resulting in the ictus stopping for a while until the patient found the solution to the problem (FIGURE 1, from Penfield and Jasper, 1954).

In the figure, a recording taken from the patient’s brain shows the effects of the intracerebral electrical stimulation (‘stim 18’), with similar effects as concentrating in solving the problem, to arrest the seizure.

Animal Models of Epilepsy

The fact that very non-specific stimuli can arrest seizures can be seen in animal models of epilepsy too. As a comparison to the above results in patients, the next figure shows the arrest of a seizure in two rats (rat 1 and rat 2), that occurs when the experimenter (yours truly) claps his hands. The recording of rat 3 does not show any seizure but is presented because the artefact associated with hand clasping is clearly visible. Notice too that the seizure resumes after ~1 second.

These figures demonstrate that one does not need much to stop seizures. Indeed, some patients know when they are about to have a seizure and have learned a response (like touching a part of their body) to stop it.

Some seizures are difficult or impossible to stop once they start. This is why it is important to stop the generation of the ictus. These methods that attempt to halt seizure generation by stimulating the brain just ahead of an impending ictus are known generally as closed-loop, or on-demand, DBS. They will be commented in a future blog, as these techniques are currently the main interest.

Vagus Nerve Stimulation (VNS)

A diversity of brain areas (or the nervous system) have been the targets for neurostimulation. The following list shows some of these brain (or others outside the brain) regions where electrodes have been placed.

  • Cerebellum
  • Hypothalamus (mamillary nuclei)
  • Vagus nerve
  • Trigeminal nerve
  • Caudate nucleus
  • Substantia nigra
  • Centromedian thalamus
  • Anterior thalamus
  • Subthalamic nucleus
  • Hippocampus
  • Amygdala

More than 18,000 patients have been treated worldwide with this method of Vagus Nerve Stimulation (VNS). Apparently, it all started based on the observations that vagal stimulation desynchronized the EEG of the cat. VNS cannot be called DBS because the electrodes are not implanted into the brain, rather it is the vagus nerve, outside the brain, that stimulated.

But the vagus nerve is connected to many brain areas. Hence the neuroanatomical bases for possible VNS effects have been proposed to be a direct effect via nucleus tractus solitarii projections to the medulla, cerebellum, locus coeruleus, hypothalamus, thalamus, amygdala, hippocampus, cingulate gyrus and somatosensory cortex.

As one can see, stimulating the vagus stimulates almost half of the brain! There could be other indirect effects acting via the reticular activating system… so now the brain stimulation would be almost complete!

It was also studied in dogs with refractory epilepsy, but the results were unclear, although some decrease in seizures experienced by the animals was found during the last 4 weeks of the treatment (Muñana et al., 2002).

No need to even turn the stimulator on

The observation that seems to be most interesting in this VNS field is that there is not even a need for stimulation, that is, no need to turn the stimulator on to reduce the number of seizures in patients. Seizure reduction was already observed in patients right after the surgery to implant the stimulator, before it was turned on (Hodaie et al., 2002; Parrent and Almeida, 2006).

Examination of a database of patients with implanted VNS devices revealed that the “benefits in seizure control with VNS in humans appear to have little specific to do with active stimulation of the vagus nerve” (Wennberg, 2004). In fact, after battery depletion (and thus the device would not operate), some patients continued to experience very few seizures.

Does this mean we are witnessing a placebo effect? The concept of neuroplasticity is globally accepted, and DBS, VNS, and neurostimulation in general act by changing this neuroplasticity. However, nobody said that the stimuli to cause this plasticity have to come from the outside. It could come from the inside, from the brain itself.

The celebrated placebo effect is a most interesting phenomenon. The internal brain dynamics may be at work here self-altering its activity. We have already seen above in the figure the result of the Penfield’s “cognitive-based” trick to stop seizures: the brain itself is perturbing its own dynamics, arresting the paroxysmal discharge while occupied in solving a problem. There are other psychological methods (Schmid-Schönbein, 1998) that can be considered as cognitive-based approaches.

As in the case of VNS, some controversies have appeared in the intracerebral stimulation using DBS. But the fact is that, one way or another, direct current stimulation of nervous tissue works at stopping seizures.

What can we learn from these results?

Considering the wide variety of neurostimulation targets and protocols for the electrical stimulation that have been used, and as well the efficacy of pharmacological medications with such a variety of actions, putting all together seems to suggest that being too specific may not be the best strategy to treat epilepsy.

It is conceivable that the aforementioned drugs or electrical therapies are efficacious due to their wide-spectrum actions (recall the aforementioned wide action brain arousal after the vagus nerve is stimulated), rather than operating via one specific action.

A possible answer to the question of why there is such a success in a majority of patients (~70%) with pharmacological therapy rests in the many actions of the drugs, which, as a result, alter significantly the brain state space dynamics.

The more parameters are perturbed, the more likely the neural dynamics is to change.

To understand the neurophysiological basis of DBS and related methods, we need some knowledge of how the nervous system functions. Our previous blog post already presented some basic notions. The next will present a few more ideas that will help understand the reasons for the possible success of DBS in epilepsy, Parkinson’s disease, and other neuropsychiatric syndromes.

Author Jose Velazquez is a senior scientific advisory board member to Novela Neurotechnologies.

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