Final Report Summary - OSCILLINTERFERENCE (Therapeutic Mechanisms and Long Term Effects of Directed Transcranial Alternating Current Stimulation in Epileptic Seizures)
The main goal of the current research project is to investigate the neuronal network level mechanisms of epileptic seizures in order to reveal those cell-types and brain regions, which are responsible for the initiation and generalization of the seizures. Moreover we aim to develop new approaches to terminate the seizures by applying electrical pulses preferably by using non-invasive methods. One of the most epileptogenic parts of the brain is the hippocampus, which region is normally responsible for memory consolidation and spatial navigation. Even during healthy conditions, this structure usually develops highly synchronous oscillatory events (called sharp-wave ripples, SPW-R), which are very vulnerable to transform into pathologic patterns such as epileptic spikes. We assume that understanding and successfully interacting with these patterns is the key to build an efficient seizure control paradigm, thus we set out to electrophysiologically ‘dissect’ the activity of the hippocampus during physiological and epileptic conditions, and determine the role of the different subregions and neuron types in the early seizure initiation.
One of the bottlenecks while trying to draw conclusions about the working principles of the brain is the serious undersampling of the activity. Optimally, the information of a large number of neurons should be recorded simultaneously by placing microelectrodes in the close vicinity of all of them; however the amplification and transmission of such a large number of signals is making the implanted device bulky, and seriously constrains the free behavior of the experimental animals. To overcome this issue, we developed a signal compression approach that allows us to record approx. 100-1000 neurons at the same time, while using only a millimeter thick cable between the animal and the recording apparatus. This large-scale, dense sampling of the hippocampal activity led us to make several profound observations: We found that the information coded not only by the individual activity pattern of the neurons, but their coordinated (‘orchestrated’) temporal interplay has at least the same importance. We developed a method which can decode the content of this interplay by only observing the integral activity of thousands of neurons, while having no information about the individual components. Moreover we could also brake down this compound signal into its main anatomical sources, and found that the sources arriving from different brain regions are following a well-defined temporal order. These findings helped us to understand the input-output relationship of the hippocampal subregions, and thus reveal the level of information-conversion that takes place at these regions. Using these newly developed analytical tools, we identified that the above mentioned highly synchronous SPW-R events may originate from the long-neglected CA2 transitional zone of the hippocampus, and proved that the acetylcholine neuromodulator can decrease the occurrence of these vulnerable patterns. Based on these we showed that seizures can be terminated by targeted stimulation of neuromodulatiory regions.
It is a consensus that any approach to prevent or terminate seizures can only be successful if it is properly timed, and spatially focused to affect only the desired brain areas. Deep brain stimulation can meet these criteria, but is requires a complicated and invasive surgery to implant the stimulating electrodes at the correct spots in the brain. We developed and patented a method to spatially and temporally focus the effect of transcutaneous simulation as well (ISP – Intersectional Short Pulse stimulation), where the electrodes are placed either on the skin of the head or under the skin if esthetically desired, thus no major invasiveness is required.
These novel technologies will be suitable to implement an implantable transcranial seizure-suppression device for patients suffering from drug-resistant epilepsies, as well as for targeting the treatment of specific neuropsychiatric disorders using electrical interventions.
One of the bottlenecks while trying to draw conclusions about the working principles of the brain is the serious undersampling of the activity. Optimally, the information of a large number of neurons should be recorded simultaneously by placing microelectrodes in the close vicinity of all of them; however the amplification and transmission of such a large number of signals is making the implanted device bulky, and seriously constrains the free behavior of the experimental animals. To overcome this issue, we developed a signal compression approach that allows us to record approx. 100-1000 neurons at the same time, while using only a millimeter thick cable between the animal and the recording apparatus. This large-scale, dense sampling of the hippocampal activity led us to make several profound observations: We found that the information coded not only by the individual activity pattern of the neurons, but their coordinated (‘orchestrated’) temporal interplay has at least the same importance. We developed a method which can decode the content of this interplay by only observing the integral activity of thousands of neurons, while having no information about the individual components. Moreover we could also brake down this compound signal into its main anatomical sources, and found that the sources arriving from different brain regions are following a well-defined temporal order. These findings helped us to understand the input-output relationship of the hippocampal subregions, and thus reveal the level of information-conversion that takes place at these regions. Using these newly developed analytical tools, we identified that the above mentioned highly synchronous SPW-R events may originate from the long-neglected CA2 transitional zone of the hippocampus, and proved that the acetylcholine neuromodulator can decrease the occurrence of these vulnerable patterns. Based on these we showed that seizures can be terminated by targeted stimulation of neuromodulatiory regions.
It is a consensus that any approach to prevent or terminate seizures can only be successful if it is properly timed, and spatially focused to affect only the desired brain areas. Deep brain stimulation can meet these criteria, but is requires a complicated and invasive surgery to implant the stimulating electrodes at the correct spots in the brain. We developed and patented a method to spatially and temporally focus the effect of transcutaneous simulation as well (ISP – Intersectional Short Pulse stimulation), where the electrodes are placed either on the skin of the head or under the skin if esthetically desired, thus no major invasiveness is required.
These novel technologies will be suitable to implement an implantable transcranial seizure-suppression device for patients suffering from drug-resistant epilepsies, as well as for targeting the treatment of specific neuropsychiatric disorders using electrical interventions.