[NEWS] Novel discoveries in preventing epileptic seizures – ScienceDaily

Date:October 13, 2020

Source:Florida State University

Summary:Researchers have found that an amino acid produced by the brain could play a crucial role in preventing a type of epileptic seizure.

FULL STORY

A team of researchers from the Florida State University College of Medicine has found that an amino acid produced by the brain could play a crucial role in preventing a type of epileptic seizure.

Temporal lobe epileptic seizures are debilitating and can cause lasting damage in patients, including neuronal death and loss of neuron function.

Sanjay Kumar, an associate professor in the College of Medicine’s Department of Biomedical Sciences, and his team are paving the way toward finding effective therapies for this disease.

The research team found a mechanism in the brain responsible for triggering epileptic seizures. Their research indicates that an amino acid known as D-serine could work with the mechanism to help prevent epileptic seizures, thereby also preventing the death of neural cells that accompanies them.

The team’s findings were published in the journal Nature Communications.

The temporal lobe processes sensory information and creates memories, comprehends language and controls emotions. Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults and is not improved with current anti-epileptic medications.

“A hallmark of TLE is the loss of a vulnerable population of neurons in a particular brain region called the entorhinal area,” Kumar said. “We’re trying to understand why neurons die in this brain region in the first place. From there, is there anything that we can do to stop these neurons from dying? It’s a very fundamental question.”

To help further understand TLE pathophysiology, the Kumar lab studies underlying receptors in the brain. Receptors are proteins located in the gaps, or junctions, between two or more communicating neurons. They convert signals between the neurons, aiding in their communication.

Kumar and his team discovered a new type of receptor that they informally named the “FSU receptor” in the entorhinal cortex of the brain. The FSU receptor is a potential target for TLE therapy.

“What’s striking about this receptor is that it is highly calcium-permeable, which is what we believe underlies the hyperexcitability and the damage to neurons in this region,” Kumar said.

When FSU receptors allow too much calcium to enter neurons, TLE patients experience epileptic seizures as neurons become overstimulated from the influx. The overstimulation, or hyperexcitability, is what causes neurons to die, a process known as excitotoxicity.

The research team also found that the amino acid D-serine blocks these receptors to prevent excess levels of calcium from reaching neurons, thereby preventing seizure activity and neuronal death.

“What’s unique about D-serine, unlike any other drugs that are out there, is that D-serine is made in the brain itself, so it’s well-tolerated by the brain,” Kumar said. “Many medications that deal with treating TLE are not well-tolerated, but given that this is made in the brain, it works very well.”

With assistance from Michael Roper’s lab in the FSU Department of Chemistry and Biochemistry, the research team found that D-serine levels were depleted in epileptic animals, indicating that TLE patients may not produce D-serine like they should.

“The loss of D-serine essentially removes the brakes on these neurons, making them hyperexcitable,” Kumar said. “Then, the calcium comes in and causes excitotoxicity, which is the reason why neurons die. So, if we provide the brakes — if we provide D-serine — then you don’t get that loss of neurons.”

Kumar’s research points to neuroinflammation as the cause for diminished D-serine levels in the entorhinal cortex of the brain. D-serine is typically produced by glial cells, but neuroinflammation experienced as part of TLE causes cellular and molecular changes in the brain that can prevent it from being produced.

The next step in exploring D-serine as a viable therapy is investigating potential administration techniques.

“We have to find creative ways to administer D-serine to that particular region of the human brain,” Kumar said. “Getting it to that right place is the challenge. We have to look at what effect it has when administered locally to that region of the brain compared to systemically through an IV, for example.”

TLE often results from an injury such as a concussion or other traumatic brain injury. When administered to the appropriate region, D-serine has been shown to work in preventing the secondary effects of such an injury.

“A pie-in-the-sky type idea is a hypothetical scenario where you were to have a nebulizer, or have people inhale D-serine, go play football, and if they experience a concussion, no neurons would be lost because the D-serine would provide a sort of cushion just in case there is a traumatic brain injury that can lead to loss of neurons in the temporal lobe,” Kumar said.

“There are some very interesting questions to ask and solve,” he added. “The important thing is that we’ve outlined the basic bread-and-butter mechanisms of why D-serine works. What we’ve established is the discovery of the receptors, discovery of the antagonist for these receptors (D-serine), how it works and how to prevent the emergence of TLE. The mechanisms and pathophysiology are as relevant to the animal model as they are to human beings, and that’s where the excitement lies.”

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Story Source: Materials provided by Florida State University. Original written by Melissa Powell. Note: Content may be edited for style and length.

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Journal Reference: 1.Stephen Beesley, Thomas Sullenberger, Kathryn Crotty, Roshan Ailani, Cameron D’Orio, Kimberly Evans, Emmanuel O. Ogunkunle, Michael G. Roper, Sanjay S. Kumar. D-serine mitigates cell loss associated with temporal lobe epilepsy. Nature Communications, 2020; 11 (1) DOI: 10.1038/s41467-020-18757-2

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Florida State University. “Novel discoveries in preventing epileptic seizures.” ScienceDaily. ScienceDaily, 13 October 2020. <www.sciencedaily.com/releases/2020/10/201013164414.htm>.

[WEB SITE] Towards enhanced regenerative medicine to cure epilepsy – CORDIS

August 21, 2018, CORDIS

Credit: Gabriella Panuccio

At the border between regenerative medicine and neural engineering lies enhanced regenerative medicine. Using brain tissue modulated by electronic components, EU research has tackled the most common form of epilepsy.

Temporal lobe epilepsy (TLE) is the most common form of epilepsy and yet, the most unresponsive to treatment. Patients have a typical pattern of progressive brain damage that affects cognitive and emotional processes.

The H2020 EU project Re.B.Us worked to lay the foundation of biohybrid approaches to induce self-healing of the dysfunctional brain. As the fellow, Dr. Gabriella Panuccio, explains, “Our goal was to achieve the proof-of-concept that the diseased brain can be healed by means of a biohybrid approach, which merges tools from biology and engineering.”

Patterns of electrical activity in TLE

Researchers used an in vitro model of TLE – rodent brain slices including key-player brain areas in TLE, treated pharmacologically to induce the typical electrical activity patterns seen in TLE patients.

Microelectrode array electrophysiology and engineering tools were combined to modulate these patterns. A physiological dialogue between affected brain regions was re-established via electronic bridges. “At the core of the experimental design was the signal generated by the hippocampus, which can prevent seizures initiated by the cortex but is compromised in TLE,” Dr. Panuccio points out.

Dialogue restoration between cortex and hippocampus

The researchers were able to rectify cortical seizure-propensity by first replacing the missing hippocampal brain signal with a surrogate electrical stimulation pattern that mimics the temporal dynamics of hippocampal activity.

Subsequently, they used a unidirectional electronic bridge to re-establish the functional dialogue between hippocampus and cortex. Ultimately, a hippocampal slice was used as ‘graft’ tissue to replace the hippocampus of the ‘host’ cortex slice to control seizure activity in the latter. “This represents the ultimate goal of Re.B.Us and these pioneering experiments herald the feasibility of the biohybrid approach proposed by Re.B.Us,” stresses Dr. Panuccio.

Ingenious electrical modulation

In its ultimate piece of work, Re.B.Us researchers established a bidirectional electronic bridge between two distinct brain slices, one acting as the ‘healthy’ graft hippocampus and the other acting as the ‘diseased’ host cortex. Pathological events detected in the cortex triggered electrical stimulation of the hippocampus; which in turn, caused detection of activity in the hippocampus and electrical stimulation onto the cortex. The developed control software was carefully refined to achieve the optimal stimulation policy to reciprocally engage the graft and host tissues to significantly decrease seizure activity.

Into the realms of the unknown – neuromorphic engineering and AI

Following the simplified in vitro paradigm of Re.B.Us, the next logical step is using hippocampal organoids as graft tissue in epileptic rodents in vivo. Dr. Panuccio explains, “Hippocampal organoids are bioengineered replicas of hippocampal tissue that can be generated in vitro starting from stem cells. Very little is known about their electrical activity, since they have only recently been obtained with tissue engineering techniques, but they appear to be intrinsically endowed with the ability to generate the pattern that can suppress seizures.”

Future strategies to cure epilepsy could rely on the joint exploitation of neural transplants with neuromorphic engineering and artificial intelligence (AI). Neuromorphic engineering could be an unprecedented solution for the design of biomimetic brain prostheses, which behave similarly to the brain and learn how to operate to promote healthy graft-host integration. AI would optimise in real-time the function of neuromorphic electronics to prevent the graft entrainment and damage from pathological activity of the host brain. “The leading view is that neuromorphic electronics and AI algorithms would eventually deactivate upon successful recovery of brain function, when their intervention would no longer be necessary,” Dr. Panuccio points out.

Summing up Re.B.Us’ achievements, Dr. Panuccio states, “I think that Re.B.Us represents the starting point of a novel approach to brain repair, based on the joint exploitation of regenerative medicine and neural engineering; a biohybrid exploitation strategy that will possibly overturn the way we approach brain disorders, shifting the current paradigm from treating the diseased brain to healing it.”

 Explore further: Automated detection of focal epileptic seizures in a sentinel area of the human brain

Provided by: CORDIS

 

via Towards enhanced regenerative medicine to cure epilepsy

[ARTICLE] Cathodal transcranial direct-current stimulation for treatment of drug-resistant temporal lobe epilepsy: A pilot randomized controlled trial – Full Text HTML

Summary

Objective

To investigate the effect of cathodal transcranial direct-current stimulation (c-tDCS) on seizure frequency in patients with drug-resistant temporal lobe epilepsy (TLE).

Method

Twenty-nine patients with drug-resistant TLE participated in this study. They were randomized to experimental or sham group. Twenty participants (experimental group) received within-session repeated c-tDCS intervention over the affected temporal lobe, and nine (sham group) received sham tDCS. Paired-pulse transcranial magnetic stimulation was used to assess short interval intracortical inhibition (SICI) in primary motor cortex ipsilateral to the affected temporal lobe. SICI was measured from motor evoked potentials recorded from the contralateral first dorsal interosseous muscle. Adverse effects were monitored during and after each intervention in both groups. A seizure diary was given to each participant to complete for 4 weeks following the tDCS intervention. The mean response ratio was calculated from their seizure rates before and after the tDCS intervention.

Results

The experimental group showed a significant increase in SICI compared to the sham group (F = 10.3, p = 0.005). None of the participants reported side effects of moderate or severe degree. The mean response ratio in seizure frequency was −42.14% (standard deviation [SD] 35.93) for the experimental group and −16.98% (SD 52.41) for the sham group.

Significance

Results from this pilot study suggest that tDCS may be a safe and efficacious nonpharmacologic intervention for patients with drug-resistant TLE. Further evaluation in larger double-blind randomized controlled trials is warranted.

Key Points

• Within-session repeated (9-20-9 protocol) c-tDCS has shown no or minimal side effects in patients with drug-resistant temporal lobe epilepsy
• Cortical excitability was reduced, as measured by SICI, after one application of c-tDCS using the 9-20-9 protocol in patients with drug-resistant temporal lobe epilepsy
• Seizure rates reduced by 42% after one application of c-tDCS using the 9-20-9 protocol in patients with drug-resistant temporal lobe epilepsy

Epilepsy impacts 50 million people (1% of the population) worldwide.[1] Management for patients with epilepsy includes antiepileptic drugs (AEDs), and for some patients with drug-resistant seizures, surgery. Temporal lobe epilepsy (TLE) is often resistant to AEDs,[2] and >40% of patients with epilepsy have adverse reactions to AEDs. Removing the epileptogenic regions surgically is not always feasible for patients, and the outcome is not ideal in 30–50% of cases.[3] Consequently, alternative methods of seizure control warrant more investigation.

The excitability of the γ-aminobutyric acid (GABA)ergic intracortical inhibitory circuits in primary motor cortex (M1) can be assessed noninvasively in humans by paired-pulse transcranial magnetic stimulation (TMS). In this technique, two stimuli are delivered 1–5 msec apart through the same coil. The first stimulus is subthreshold for a motor response; however, it activates intracortical inhibition (ICI) circuits and reduces the size of the motor evoked potentials (MEPs) elicited by the second stimulus, which is supra-threshold for a motor response.[4] It has been shown that ICI measured using this method reflects the cortical activity of GABAergic interneurons in the M1 area.[5] This inhibition is termed short-interval intracortical inhibition or SICI.

ICI circuits have been assessed extensively with a paired-pulse paradigm in patients with epilepsy.[6-8] Several studies on drug-naive patients with focal epilepsy showed a decrease in SICI in the ipsilateral hemisphere.[9-15] Badawy et al. showed increased M1 excitability and decreased SICI in 35 patients with focal epilepsy 24 h before and after a seizure.

Transcranial direct current stimulation (tDCS) is a well-established cortical stimulation method that can be used noninvasively to modulate neuronal excitability in humans.[16] In this technique, a low intensity current (1–2 mA) is used that can affect the membrane potentials in two ways. Cathodal tDCS (c-tDCS) hyperpolarizes the resting membrane potentials, whereas anodal tDCS acts toward depolarization.[16] Modification of seizure network excitability by tDCS is a potentially valuable noninvasive alternative for reducing the excitability of this abnormal network in patients with epilepsy and thereby reducing the seizure rates in this population.

The aim of this study was to examine the effects of this noninvasive therapeutic approach on seizure frequency in this group of patients. We hypothesized that compared to sham tDCS, application of c-tDCS over the temporal lobe in patients with drug-resistant TLE, decreases seizure frequency and increases intracortical inhibition in the ipsilateral M1 area.

Continue —> Cathodal transcranial direct-current stimulation for treatment of drug-resistant temporal lobe epilepsy: A pilot randomized controlled trial – Zoghi – 2016 – Epilepsia Open – Wiley Online Library

Experimental set-up. All participants received one session of c-tDCS or sham tDCS paradigm (9-20-9 protocol). The active surface electrode (cathode) was placed over the temporal lobe in the affected hemisphere. The return (anode) electrode was placed over the supraorbital area contralateral to the stimulated hemisphere. SICI was assessed before and after tDCS intervention. Seizure rates were recorded for 4 weeks after tDCS intervention.