Connectomics in Epilepsy

Gustavo Gavrel Pacheco

Sebastian Seung’s book, “Connectome: How the Brain’s Wiring Makes Us Who We Are”, presents the idea that the signaling and intercommunication between brain cells dictates our behavior, and that it is possible to identify cell-to-cell interactions using imaging techniques. I became interested in the mental disorder of epilepsy which affects millions of people. I found this topic to be of interest because it has implications in neurosurgery. My career aspiration is to become a neurosurgeon, and neurosurgical techniques are used to treat epilepsy.While this disorder could be involved in multiple syndromes, it is characterized by involuntary seizures which can be in some cases associated within families. According to Dr. Seung, “epilepsy is defined by repeated spontaneous ‘seizures’ or episodes of excessive neural activity”. This page discusses causes of and treatments for, epilepsy, as well as their link to connectomics.

There are structural and genetic causes for epilepsy including Lissencephaly epilepsy, a structural cause, as well as in some cases of mental retardation, a genetic cause. Lissencephalyis a mental disorder in which the cortex lacks the folds that normally give it a wrinkled look and the brain contains other structural abnormalities that are visible under the microscope. Lissencephaly can be caused by mutations in genes that control neuronal migration during gestation. Defective genes of ion channels can also cause epilepsy leading to channelopathy. Channelopathies can lead to uncontrolled spiking of neurons, also known as epileptic seizures.

The techniques discussed are rooted in the theory of connectomics. The techniques discussed attempt to prevent the excitation of neurons to spread throughout a region and cause a seizure because of over stimulation. Essentially, the connections between neurons are being cut off. With the increasing advances in the field of connectomics hopefully the prevention of epilepsy will be as simple as the inactivation of a synapse.

Epilepsy can be treated with drugs, surgery and stimulation. Surgery and stimulation are desired in cases of drug-resistance since they are more invasive than drug treatments and are used as a second resort. One neurosurgical technique that is able to treat epilepsy in progressive cases is hemispherectomy, a procedure in which the one hemisphere of the cerebrum responsible for seizures is removed. Vining and collaborators (Vining, 2011) reported the outcomes of the fifty-eight hemispherectomies conducted at Johns Hopkins Medical Center on children. Approximately seven percent of the fifty-eight cases suffered perioperative death, in which patients died within two weeks of the surgery. Of the surviving children, fifty-four percent were free of seizures, twenty-four percent had non-handicapping seizures, and twenty-three percent had residual seizures that somewhat interfered with function. Hemispherectomies have statistically shown to decrease the burden of epilepsy by decreasing the number of seizures and allowing the patient to have a more normal life.

Hemispherectomies have been used to show that functions of a specified cortical region on the removed hemisphere migrate to the remaining hemisphere. For example, linguistic functions (usually found in regions in the left hemisphere) migrate to the right hemisphere following a hemispherectomy (Seung, 2012). This treatment for epilepsy has identified areas of the cortex with specific movable functions. This has been mainly observed in cases of brain injury. In light of connectomics, all epileptic surgeries essentially remove neurons from a connectome.

Another interventional technique for epilepsy is optogenetics which is a promising new technique to treat seizures. Optogenetics refers to the control of brain cell activity with visible light (Fisher, 2012). Light sensitivity is conferred to a specific subpopulation of cells using a method that introduces new light-sensitive proteins using viral vectors., which are injected into a structure of interest. The proteins introduced vary on the wavelength of light they respond to (red versus yellow) and whether they excite or inhibit neuronal activity. The proteins vary on their response to light (For example, red versus yellow) and whether they excite or inhibit neuronal activity.

Lentivirus, a genus of viruses that deliver a significant amount of genetic material to the host cells has been used as a vector to treat epilepsy. This vector genus was chosen because it is known to have a long incubation period which allows for the treatment to be effective for more than one epileptic attack. Excitatory and inhibitory opsin proteins sensitive to light are introduced by the vectors. Delivery of inhibitory halorhodopsin eNpHR3 to the hippocampus in rat pups was tested (Fisher, 2012). Through the use of a calmodulin kinase promoter (CaMKIIa), selective light sensitivity of pyramidal neurons and dendrites were targeted. Hippocampal slices evidenced pyramidal cell hyperpolarizations to orange light. Hyperpolarization is a change in potential that increases the polarized state of a membrane. Orange light interrupted epileptiform stimulus train induced bursting. As shown in the figure below a yellow-orange light activates channel rhodopsin. Whereas chloride channels open, the hyperpolarization of transfected neurons inhibits firing of action potentials of neurons. Another point provided by Figure 1 is that stimulus train-induced bursting in hippocampal culture slices is inhibited by halorhodopsin response to orange light.



Figure 1

A.	Hippocampal culture. A yellow-orange light (indicated by bar).

B.	Stimulus train-induced bursting in hippocampal cultured slices. (Taken from Fisher, 2011).

Whereas the previous two techniques are used to prevent epilepsy, the following method is used to treat the patient during the epileptic seizures. A clinical seizure focus can be inactivated by cooling down the region of focus below twenty-seven degrees celsius. Lower temperatures block synaptic transmission and epileptiform bursting. In Figure 2 a Peltier cooling device is placed over a seizure focus in an anesthetized rat. In Peltier cooling device 2, adjacent metal plates of different conductivity produce heat on one side and cold on the other. The device on the figure has the cold side in contact with the seizure focus. The figure also shows the readings of epileptiform spikes during an induced seizure after cooling of the focus, and during the rewarming of the brain. The results indicate a possibility for seizures to be treated through cooling of the brain. This techique has many limitations for practical implementation which include the dissipation of heat and difficulty in obtaining an adequate portable power supply.



Figure 2

A. Peltier cooling device.

B. The upper shows spikes at 37oC. Middle panel attenuation at lower temperatures and the lower panel shows reversibility of process (Taken from Fisher, 2011)

After considering the problems this technique faces and its application in humans, I have some suggestions. First, to remedy the problem of a portable power supply, I suggest that a rechargable battery be implanted in the person. A possible way to recharge the battery is to use solar cells placed on the scalp of the patient. Second, to deal with the dissipation of heat a ventilation and cooling system could be implanted to allow the heat to simply flow out of the head through openings. A better understanding of the connectome could lead to exciting new developments for treating epilepsy.

Works Cited

Fisher, Robert S. Therapeutic Devices for Epilepsy. Pub. N.p.: Annals of Neurology, 2011. Print.

Seung, Sebastian. Connectome: how the brain’s wiring makes us who we are. New York: Houghton Mifflin Harcourt Publishing Company, 2012. Print.

Vining, Eileen P.G., et al., Why Would You Remove Half a Brain? The Outcome of 58 Children After Hemispherectomy- The Johns Hopkins Experience. Pub. Elk Grove Village: Pediatrics, 1997. Print.