The Impact of Inflammation on Thermal Hyperpnea: Relevance for Heat Stress and Febrile Seizures.

Extreme heat caused by climate change is increasing the transmission of infectious diseases, resulting in a sharp rise in heat-related illness and mortality. Understanding the mechanistic link between heat, inflammation, and disease is thus important for public health. Thermal hyperpnea, and consequent respiratory alkalosis, is crucial in febrile seizures and convulsions induced by heat stress in humans. Here, we address what causes thermal hyperpnea in neonates and how it is affected by inflammation. Transient receptor potential cation channel subfamily V member 1 (TRPV1), a heat-activated channel, is sensitized by inflammation and modulates breathing and thus may play a key role. To investigate whether inflammatory sensitization of TRPV1 modifies neonatal ventilatory responses to heat stress, leading to respiratory alkalosis and an increased susceptibility to hyperthermic seizures, we treated neonatal rats with bacterial LPS, and breathing, arterial pH, in vitro vagus nerve activity, and seizure susceptibility were assessed during heat stress in the presence or absence of a TRPV1 antagonist (AMG-9810) or shRNA-mediated TRPV1 suppression. LPS-induced inflammatory preconditioning lowered the threshold temperature and latency of hyperthermic seizures. This was accompanied by increased tidal volume, minute ventilation, expired CO2, and arterial pH (alkalosis). LPS exposure also elevated vagal spiking and intracellular calcium concentrations in response to hyperthermia. TRPV1 inhibition with AMG-9810 or shRNA reduced the LPS-induced susceptibility to hyperthermic seizures and altered the breathing pattern to fast shallow breaths (tachypnea), making each breath less efficient and restoring arterial pH. These results indicate that inflammation exacerbates thermal hyperpnea-induced respiratory alkalosis associated with increased susceptibility to hyperthermic seizures, primarily mediated by TRPV1 localized to vagus neurons.

Mechanisms of infantile epileptic spasms syndrome: What have we learned from animal models?

The devastating developmental and epileptic encephalopathy of infantile epileptic spasms syndrome (IESS) has numerous causes, including, but not limited to, brain injury, metabolic, and genetic conditions. Given the stereotyped electrophysiologic, age-dependent, and clinical findings, there likely exists one or more final common pathways in the development of IESS. The identity of this final common pathway is unknown, but it may represent a novel therapeutic target for infantile spasms. Previous research on IESS has focused largely on identifying the neuroanatomic substrate using specialized neuroimaging techniques and cerebrospinal fluid analysis in human patients. Over the past three decades, several animal models of IESS were created with an aim to interrogate the underlying pathogenesis of IESS, to identify novel therapeutic targets, and to test various treatments. Each of these models have been successful at recapitulating multiple aspects of the human IESS condition. These animal models have implicated several different molecular pathways in the development of infantile spasms. In this review we outline the progress that has been made thus far using these animal models and discuss future directions to help researchers identify novel treatments for drug-resistant IESS.

KCTD7-related progressive myoclonic epilepsy: Report of 42 cases and review of literature.

OBJECTIVE: KCTD7-related progressive myoclonic epilepsy (PME) is a rare autosomal-recessive disorder. This study aimed to describe the clinical details and genetic variants in a large international cohort. METHODS: Families with molecularly confirmed diagnoses of KCTD7-related PME were identified through international collaboration. Furthermore, a systematic review was done to identify previously reported cases. Salient demographic, epilepsy, treatment, genetic testing, electroencephalographic (EEG), and imaging-related variables were collected and summarized. RESULTS: Forty-two patients (36 families) were included. The median age at first seizure was 14 months (interquartile range = 11.75-22.5). Myoclonic seizures were frequently the first seizure type noted (n = 18, 43.9%). EEG and brain magnetic resonance imaging findings were variable. Many patients exhibited delayed development with subsequent progressive regression (n = 16, 38.1%). Twenty-one cases with genetic testing available (55%) had previously reported variants in KCTD7, and 17 cases (45%) had novel variants in KCTD7 gene. Six patients died in the cohort (age range = 1.5-21 years). The systematic review identified 23 eligible studies and further identified 59 previously reported cases of KCTD7-related disorders from the literature. The phenotype for the majority of the reported cases was consistent with a PME (n = 52, 88%). Other reported phenotypes in the literature included opsoclonus myoclonus ataxia syndrome (n = 2), myoclonus dystonia (n = 2), and neuronal ceroid lipofuscinosis (n = 3). Eight published cases died over time (14%, age range = 3-18 years). SIGNIFICANCE: This study cohort and systematic review consolidated the phenotypic spectrum and natural history of KCTD7-related disorders. Early onset drug-resistant epilepsy, relentless neuroregression, and severe neurological sequalae were common. Better understanding of the natural history may help future clinical trials.

Intermittent vs continuous ketogenic diet: Impact on seizures, gut microbiota, and mitochondrial metabolism.

We have shown previously that the ketogenic diet (KD) is effective in reducing seizures associated with infantile spasms syndrome (ISS) and that this benefit is related to alterations in the gut microbiota. However, it remains unclear whether the efficacy of the KD persists after switching to a normal diet. Employing a neonatal rat model of ISS, we tested the hypothesis that the impact of the KD would diminish when switched to a normal diet. Following epilepsy induction, neonatal rats were divided into two groups: continuous KD for 6 days; and a group fed with KD for 3 days and then a normal diet for 3 days. Spasms frequency, mitochondrial bioenergetics in the hippocampus, and fecal microbiota were evaluated as major readouts. We found that the anti-epileptic effect of the KD was reversible, as evidenced by the increased spasms frequency in rats that were switched from the KD to a normal diet. The spasms frequency was correlated inversely with mitochondrial bioenergetic function and a set of gut microbes, including Streptococcus thermophilus and Streptococcus azizii. These findings suggest that the anti-epileptic and metabolic benefits of the KD decline rapidly in concert with gut microbial alterations in the ISS model.

Febrile seizures lead to prolonged epileptiform activity and hyperoxia that when blocked prevents learning deficits.

OBJECTIVE: In adult brain tissue, oxygen levels typically remain in the normoxic zone, but status epilepticus results in hyperoxia, whereas brief self-terminating seizures lead to postictal hypoxia. The dynamic changes in oxygen levels and the underlying mechanisms are unknown in juveniles with febrile seizures. METHODS: Eight-day-old female and male rat pups were implanted with an electrode and oxygen-sensing optode in the hippocampus and then received once daily injections of lipopolysaccharide for 4 days to induce an immune response. Local partial pressure of oxygen (pO2 ) and local field potentials were recorded before, during, and after a heat-induced febrile seizure. Separate groups of pups received injections of vehicle or drugs targeting cyclooxygenase (COX)-1, COX-2, L-type calcium channels (LTCCs), and cannabinoid receptor type 1 (CB1) and transient receptor potential vanilloid-1 (TRPV1) receptors prior to febrile seizure induction to determine pO2 mechanisms. Following febrile seizures, a subset of pups were raised to young adulthood and then tested for learning impairments using the novel object recognition task. RESULTS: Febrile seizures resulted in predictable oxygen dynamics that were related to behavioral seizures and epileptiform activity. During a behavioral seizure, pO2 rapidly increased, rapidly decreased, and then returned to near baseline. When the behavioral seizure terminated, oxygen levels climbed into the hyperoxic zone during a time of prolonged epileptiform activity. When epileptiform activity terminated, oxygen levels slowly returned to baseline. A COX-1 antagonist prevented hyperoxia, whereas a COX-2 antagonist did not. An LTCC antagonist exacerbated hyperoxia. Boosting levels of an endocannabinoid also exacerbated hyperoxia, whereas blocking CB1 receptors and TRPV1 receptors reduced hyperoxia. Inhibiting TRPV1 receptors during a febrile seizure prevented learning deficits in young adult female rats. SIGNIFICANCE: Brain oxygenation during and following a febrile seizure has a distinct pattern and multiple mechanisms. Brain oxygen dynamics may be an important consideration in the development of treatments for febrile seizures.

Impaired cardiorespiratory responses to hypercapnia in neonatal mice lacking PAC1 but not VPAC2 receptors.

The evidence is mounting for a role for abnormal signaling of the stress peptide pituitary adenylate cyclase activating polypeptide (PACAP) and its canonical receptor PAC1 in the pathogenesis of sudden infant death syndrome. In this study, we investigated whether the PACAP receptors PAC1 or VPAC2 are involved in the neonatal cardiorespiratory response to hypercapnic stress. We used head-out plethysmography and surface ECG electrodes to assess cardiorespiratory responses to an 8% hypercapnic challenge in unanesthetized and spontaneously breathing 4-day-old PAC1 or VPAC2 knockout (KO) and wild-type mouse pups. We demonstrate that compared with WTs, breathing frequency (RR) and minute ventilation ([Formula: see text]) in PAC1 KO pups were significantly blunted in response to hypercapnia. Although heart rate was unaltered in PAC1 KO pups during hypercapnia, heart rate recovery posthypercapnia was impaired. In contrast, cardiorespiratory impairments in VPAC2 KO pups were limited to only an overall higher tidal volume (VT), independent of treatment. These findings suggest that PACAP signaling through the PAC1 receptor plays a more important role than signaling through the VPAC2 receptor in neonatal respiratory responses to hypercapnia. Thus deficits in PACAP signaling primarily via PAC1 may contribute to the inability of infants to mount an appropriate protective response to homeostatic stressors in childhood disorders such as SIDS.

Reelin Improves Cognition and Extends the Lifespan of Mutant Ndel1 Mice with Postnatal CA1 Hippocampus Deterioration.

The glycoprotein Reelin maintains neuronal positioning and regulates neuronal plasticity in the adult brain. Reelin deficiency has been associated with neurological diseases. We recently showed that Reelin is depleted in mice with a targeted disruption of the Ndel1 gene in forebrain postnatal excitatory neurons (Ndel1 conditional knockout (CKO)). Ndel1 CKO mice exhibit fragmented microtubules in CA1 pyramidal neurons, profound deterioration of the CA1 hippocampus and a shortened lifespan (~10 weeks). Here we report that Ndel1 CKO mice (of both sexes) experience spatial learning and memory deficits that are associated with deregulation of neuronal cell adhesion, plasticity and neurotransmission genes, as assessed by genome-wide transcriptome analysis of the hippocampus. Importantly, a single injection of Reelin protein in the hippocampus of Ndel1 CKO mice improves spatial learning and memory function and this is correlated with reduced intrinsic hyperexcitability of CA1 pyramidal neurons, and normalized gene deregulation in the hippocampus. Strikingly, when treated with Reelin, Ndel1 CKO animals that die from an epileptic phenotype, live twice as long as nontreated, or vehicle-treated CKO animals. Thus, Reelin confers striking beneficial effects in the CA1 hippocampus, and at both behavioral and organismal levels.

Dynamic oxygen changes during status epilepticus and subsequent endogenous kindling.

OBJECTIVE: Brain tissue oxygen (partial oxygen pressure [pO2 ]) levels are tightly regulated to stay within the normoxic zone, with deviations on either side resulting in impaired brain function. Whereas pathological events such as ischemic attacks and brief seizures have previously been shown to result in pO2 levels well below the normoxic zone, oxygen levels during prolonged status epilepticus (SE) and the subsequent endogenous kindling period are unknown. METHODS: We utilized two models of acquired temporal lobe epilepsy in rats: intrahippocampal kainic acid infusion and prolonged perforant pathway stimulation. Local tissue oxygen was measured in the dorsal hippocampus using an optode during and for several weeks following SE. RESULTS: We observed hyperoxia in the hippocampus during induced SE in both models. Following termination of SE, 88% of rats initiated focal self-generated spiking activity in the hippocampus within the first 7 days, which was associated with dynamic oxygen changes. Self-generated and recurring epileptiform activity subsequently organized into higher-frequency bursts that became progressively longer and were ultimately associated with behavioral seizures that became more severe with time and led to postictal hypoxia. SIGNIFICANCE: Induced SE and self-generated recurrent epileptiform activity can have profound and opposing effects on brain tissue oxygenation that may serve as a biomarker for ongoing pathological activity in the brain.

Bridging the healthcare gap: Building the case for epilepsy virtual clinics in the current healthcare environment.

Access to quality healthcare remains a challenge that is complicated by mounting pressures to control costs, and now, as we witness, the unprecedented strain placed on our healthcare delivery systems due to the COVID-19 pandemic. Challenges in healthcare access have driven a need for innovative approaches ensuring connectivity to health providers. Telehealth services and virtual clinics offer accessible disease management pathways for patients living in health resource limited areas or, as in the case of the COVID-19 pandemic, where there may be potential barriers to existing healthcare resources. Those suffering with serious chronic disorders often cannot be seen by a healthcare specialist due to their limited availability, or the lack of a specialist within a reasonable proximity. Epilepsy represents such a disorder where most of the world's population lacks the availability of necessary specialists. Virtual clinics allow for specialist care and an ability to perform necessary ambulatory electroencephalogram (EEG) monitoring by placing the technologies directly in patients' homes or at local clinics near the patients' homes. By moving the diagnostic process out of the hospital or epilepsy center, it becomes possible to overcome growing gaps in neurology services. Virtual clinics have the potential to expand access to high-quality, cost-effective care for the patient. The virtual clinic remotely connects those in need of medical support with specialists anywhere in the world, at any time of the day.

Impaired neonatal cardiorespiratory responses to hypoxia in mice lacking PAC1 or VPAC2 receptors.

The stress peptide pituitary adenylate cyclase activating polypeptide (PACAP) and its specific receptor PACAP type 1 receptor (PAC1) have been implicated in sudden infant death syndrome (SIDS). PACAP is also critical to the neonatal cardiorespiratory response to homeostatic stressors identified in SIDS, including hypoxia. However, which of PACAP's three receptors, PAC1, vasoactive intestinal peptide receptor type 1 (VPAC1), and/or vasoactive intestinal peptide receptor type 2 (VPAC2), are involved is unknown. In this study, we hypothesized that PAC1, but not VPAC2, is involved in mediating the cardiorespiratory response to hypoxia during neonatal development. To test this hypothesis, head-out plethysmography and surface ECG electrodes were used to assess the cardiorespiratory variables of unanesthetized postnatal day 4 PAC1 and VPAC2-knockout (KO) and wild-type (WT) mice in response to a 10% hypoxic challenge. Our results demonstrate that compared with WT pups, the early and late hypoxic rate of expired CO2 (V̇co2), V̇co2 and ventilatory responses were blunted in PAC1-KO neonates, and during the posthypoxic period, minute ventilation (V̇e), V̇co2 and heart rate were increased, while the increase in apneas normally associated with the posthypoxic period was reduced. Consistent with impaired cardiorespiratory control in these animals, the V̇e/V̇co2 slope was reduced in PAC1-KO pups, suggesting that breathing was inappropriately matched to metabolism. In contrast, VPAC2-KO pups exhibited elevated heart rate variability during hypoxia compared with WT littermates, but the effects of the VPAC2-KO genotype on breathing were minimal. These findings suggest that PAC1 plays the principal role in mediating the cardiorespiratory effects of PACAP in response to hypoxic stress during neonatal development and that defective PACAP signaling via PAC1 may contribute to the pathogenesis of SIDS.

Vagal TRPV1 activation exacerbates thermal hyperpnea and increases susceptibility to experimental febrile seizures in immature rats.

Thermal hyperpnea, a pattern of breathing during hyperthermia that is characterized by an increase in tidal volume as well as breathing frequency, is known to lead to respiratory alkalosis. Thermal hyperpnea-induced respiratory alkalosis is linked to febrile seizures (FS). The heat-sensitive transient receptor potential vanilloid-1 (TRPV1) receptors are localized in, and implicated in the heat sensitivity of peripheral and central structures involved in the respiratory response to hyperthermia. We, therefore, hypothesize that TRPV1 activation increases susceptibility to experimental FS (EFS) in immature rats due to an exacerbated thermal hyperpnea. We found that peripheral, but not central TRPV1 activation had pro-convulsant effects. These pro-convulsant effects were associated with an increased rate of expired CO2 due to an exaggerated ventilatory response to hyperthermia. The TRPV1 antagonist, AMG-9810, and TRPV1 deletion abolished the pro-convulsant effects, while exposure to 5% CO2, bilateral vagotomy and DREADD (designer receptor exclusively activated by designer drugs)-mediated inhibition of TRPV1-containing cells in the vagal nodose ganglia significantly attenuated these effects. These findings suggest that vagal TRPV1-driven thermal hyperpnea likely increases susceptibility to FS in immature rodents. This identifies a novel peripheral anatomical and molecular target that should be considered when developing therapeutics for FS.

Successful treatment of epileptic encephalopathy with spike wave activation in sleep with anakinra.

Patients with epileptic encephalopathy with spike wave activation in sleep (EE-SWAS) often display drug-resistant epilepsy. The activation of epileptic activity during sleep is associated temporally with neurocognitive impairment and causes a spectrum of disorders within the epilepsy-aphasia syndrome. The prognosis is dependent on promptness of treatment and etiology. However, there is no clear consensus with regards to the optimal management for patients with EE-SWAS. We queried our Pediatric Epilepsy Outcome-Informatics Project (PEOIP) database for all patients treated with anakinra in our centre. We herein report a case of a female with EE-SWAS, who demonstrated remarkable neurocognitive improvement with anakinra. We suggest that a trial of anakinra may be an option for patients with EE-SWAS due to non-structural and possibly inflammatory etiology.

Channelopathies in epilepsy: an overview of clinical presentations, pathogenic mechanisms, and therapeutic insights.

Pathogenic variants in genes encoding ion channels are causal for various pediatric and adult neurological conditions. In particular, several epilepsy syndromes have been identified to be caused by specific channelopathies. These encompass a spectrum from self-limited epilepsies to developmental and epileptic encephalopathies spanning genetic and acquired causes. Several of these channelopathies have exquisite responses to specific antiseizure medications (ASMs), while others ASMs may prove ineffective or even worsen seizures. Some channelopathies demonstrate phenotypic pleiotropy and can cause other neurological conditions outside of epilepsy. This review aims to provide a comprehensive exploration of the pathophysiology of seizure generation, ion channels implicated in epilepsy, and several genetic epilepsies due to ion channel dysfunction. We outline the clinical presentation, pathogenesis, and the current state of basic science and clinical research for these channelopathies. In addition, we briefly look at potential precision therapy approaches emerging for these disorders.

Protocol for continuous video-EEG/EMG recording to study brain function in neonatal rats.

The electroencephalogram (EEG) is crucial for real-time brain physiology research in epilepsy. However, maternal care reliance limits its use in immature rodents. Our "pup-in-cup" setup overcomes this, enabling continuous, uninterrupted video-EEG/electromyogram (EMG) recordings in neonatal rats. This protocol details the steps for video-EEG/EMG system setup, EEG headmount implantation, and recording continuous video-EEG/EMG traces from postnatal days 4-12. For complete details on the use and execution of this protocol, please refer to Choudhary et al.1.

Protocol for nutritional intervention in neonatal rats using the "pup-in-a-cup" artificial rearing system.

Early-life nutrition fundamentally influences newborn development and health. Here, we present a protocol for nutritional intervention in neonatal rats using the "pup-in-a-cup" artificial rearing system. We describe steps for rat milk substitute preparation, cheek cannulation and maintenance, and nutritional manipulation during the suckling period. This protocol enables investigation into the role of nutritional factors in newborns by artificially rearing rats away from the mother with experimental diets starting at postnatal day 4 for up to 18 days. For complete details on the use and execution of this protocol, please refer to Wang et al.,1 Choudhary et al.,2 and Mu et al.3,4.

Proposed Pathway for the Utilization of Pediatric Ambulatory EEG.

PURPOSE: The clinical utility of pediatric ambulatory-EEG (A-EEG) has been studied for decades, but limited information exists regarding which variables influence its utility. The authors aimed to evaluate clinical/EEG variables that may influence A-EEG yields and to develop a pathway for A-EEG utilization in children. METHODS: Single-center retrospective review of A-EEGs performed from July 2019 to January 2021 in a tertiary referral center. The primary outcome was whether the A-EEG test successfully answered the referring physician's clinical question or influenced therapy. When it did, the A-EEG test was deemed useful. Clinical and EEG variables were assessed for their ability to predict utility. Further, the literature review generated 10 relevant prior studies whose details were used to generate a pathway for A-EEG utilization in children. RESULTS: One hundred forty-two A-EEG studies were included (mean age 8.8 years, 48% male patients, mean A-EEG duration 33.5 hours). Overall, A-EEG was considered useful in 106 children (75%) but heavily influenced by A-EEG indication. Specifically, it was deemed useful for 94% of patients evaluated for electrical status epilepticus in slow-wave sleep, 92% of those evaluated for interictal/ictal burden, and 63% of those undergoing spell classification. The test indication (P < 0.001), a diagnosis of epilepsy (P = 0.02), and an abnormal routine EEG (P = 0.04) were associated with A-EEG test utility, although the multivariate analysis confirmed the test indication as the only independent outcome predictor of A-EEG. CONCLUSIONS: Pediatric A-EEG is extremely useful for evaluating electrical status epilepticus in slow-wave sleep and interictal/ictal burden and is often helpful for spell classification. Among all clinical and EEG variables analyzed, the test indication was the only independent outcome predictor of obtaining a helpful A-EEG.

Lunapark deficiency leads to an autosomal recessive neurodevelopmental phenotype with a degenerative course, epilepsy and distinct brain anomalies.

LNPK encodes a conserved membrane protein that stabilizes the junctions of the tubular endoplasmic reticulum network playing crucial roles in diverse biological functions. Recently, homozygous variants in LNPK were shown to cause a neurodevelopmental disorder (OMIM#618090) in four patients displaying developmental delay, epilepsy and nonspecific brain malformations including corpus callosum hypoplasia and variable impairment of cerebellum. We sought to delineate the molecular and phenotypic spectrum of LNPK-related disorder. Exome or genome sequencing was carried out in 11 families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals, including review of previously reported patients. We identified 12 distinct homozygous loss-of-function variants in 16 individuals presenting with moderate to profound developmental delay, cognitive impairment, regression, refractory epilepsy and a recognizable neuroimaging pattern consisting of corpus callosum hypoplasia and signal alterations of the forceps minor ('ear-of-the-lynx' sign), variably associated with substantia nigra signal alterations, mild brain atrophy, short midbrain and cerebellar hypoplasia/atrophy. In summary, we define the core phenotype of LNPK-related disorder and expand the list of neurological disorders presenting with the 'ear-of-the-lynx' sign suggesting a possible common underlying mechanism related to endoplasmic reticulum-phagy dysfunction.

Flashing lights and epileptic spasms: should we be routinely performing intermittent photic stimulation in infants?

Abnormal cortical excitation in response to photic stimulation (photosensitivity) has historically been associated with generalized epilepsies, in patients outside of infancy. At our tertiary centre, we encountered a patient with infantile spasms secondary to a mutation in ALG13 (c320A>G) who had photic stimulation-induced epileptic spasms over a broad range of frequencies on multiple EEGs, which were worse without treatment and decreased as treatment was escalated. This is the first reported case of epileptic spasms triggered by photic stimulation and it is unclear whether the phenomenon is unique to this patient, to those with this mutation or whether it is present in a broader group of patients with infantile spasms.

Animal Models in Epileptic Spasms and the Development of Novel Treatment Options.

SUMMARY: The infantile spasms (IS) syndrome is a catastrophic developmental epileptic encephalopathy syndrome characterized by an age-specific expression of epileptic spasms that are associated with extremely abnormal, oftentimes described as chaotic, interictal EEG pattern known as hypsarrhythmia. Patients with IS generally have poor neurodevelopmental outcomes, in large part because of the frequent epileptic spasms and interictal EEG abnormalities. Current first-line treatments such as adrenocorticotropic hormone or vigabatrin are often ineffective and are associated with major toxic side effects. There is therefore a need for better and safer treatments for patients with IS, especially for the intractable population. Hope is on the horizon as, over the past 10 years, there has been robust progress in the development of etiology-specific animal models of IS. These models have been used to identify potential new treatments for IS and are beginning to provide some important insights into the pathophysiological substrates for this disease. In this review, we will highlight strengths and weaknesses of the currently available animal models of IS in addition to new insights into the pathophysiology and treatment options derived from these models.

Gut-based manipulations spur hippocampal mitochondrial bioenergetics in a model of pediatric epilepsy.

A growing body of evidence supports a role of the gut microbiota in regulating diverse physiological processes, including neural function and metabolism via the gut-brain axis. Infantile spasms syndrome is an early-onset epileptic encephalopathy associated with perturbed brain mitochondrial bioenergetics. Employing a neonatal rat model of infantile spasms, mitochondria respirometry and biochemical analyses, the present study reveals that gut microbiota manipulation by diet, antibiotics and probiotics have the potential to enhance hippocampal mitochondrial bioenergetics. Although preliminary in nature, our data reveal that microbial manipulation that regulates brain mitochondrial function may be a novel strategy for the treatment of epileptic disorders.