Increase in Seizure Susceptibility After Repetitive Concussion Results from Oxidative Stress, Parvalbumin-Positive Interneuron Dysfunction and Biphasic Increases in Glutamate/GABA Ratio.

Chronic symptoms indicating excess cortical excitability follow mild traumatic brain injury, particularly repetitive mild traumatic brain injury (rmTBI). Yet mechanisms underlying post-traumatic excitation/inhibition (E/I) ratio abnormalities may differ between the early and late post-traumatic phases. We therefore measured seizure threshold and cortical gamma-aminobutyric acid (GABA) and glutamate (Glu) concentrations, 1 and 6 weeks after rmTBI in mice. We also analyzed the structure of parvalbumin-positive interneurons (PVIs), their perineuronal nets (PNNs), and their electroencephalography (EEG) signature (gamma frequency band power). For mechanistic insight, we measured cortical oxidative stress, reflected in the reduced/oxidized glutathione (GSH/GSSG) ratio. We found that seizure susceptibility increased both early and late after rmTBI. However, whereas increased Glu dominated the E/I 1 week after rmTBI, Glu concentration normalized and the E/I was instead characterized by depressed GABA, reduced per-PVI parvalbumin expression, and reduced gamma EEG power at the 6-week post-rmTBI time point. Oxidative stress was increased early after rmTBI, where transient PNN degradation was noted, and progressed throughout the monitoring period. We conclude that GSH depletion, perhaps triggered by early Glu-mediated excitotoxicity, leads to late post-rmTBI loss of PVI-dependent cortical inhibitory tone. We thus propose dampening of Glu signaling, maintenance of redox state, and preservation of PVI inhibitory capacity as therapeutic targets for post-rmTBI treatment.

Ceftriaxone Treatment Preserves Cortical Inhibitory Interneuron Function via Transient Salvage of GLT-1 in a Rat Traumatic Brain Injury Model.

Traumatic brain injury (TBI) results in a decrease in glutamate transporter-1 (GLT-1) expression, the major mechanism for glutamate removal from synapses. Coupled with an increase in glutamate release from dead and dying neurons, this causes an increase in extracellular glutamate. The ensuing glutamate excitotoxicity disproportionately damages vulnerable GABAergic parvalbumin-positive inhibitory interneurons, resulting in a progressively worsening cortical excitatory:inhibitory imbalance due to a loss of GABAergic inhibitory tone, as evidenced by chronic post-traumatic symptoms such as epilepsy, and supported by neuropathologic findings. This loss of intracortical inhibition can be measured and followed noninvasively using long-interval paired-pulse transcranial magnetic stimulation with mechanomyography (LI-ppTMS-MMG). Ceftriaxone, a ß-lactam antibiotic, is a potent stimulator of the expression of rodent GLT-1 and would presumably decrease excitotoxic damage to GABAergic interneurons. It may thus be a viable antiepileptogenic intervention. Using a rat fluid percussion injury TBI model, we utilized LI-ppTMS-MMG, quantitative PCR, and immunohistochemistry to test whether ceftriaxone treatment preserves intracortical inhibition and cortical parvalbumin-positive inhibitory interneuron function after TBI in rat motor cortex. We show that neocortical GLT-1 gene and protein expression are significantly reduced 1 week after TBI, and this transient loss is mitigated by ceftriaxone. Importantly, whereas intracortical inhibition declines progressively after TBI, 1 week of post-TBI ceftriaxone treatment attenuates the loss of inhibition compared to saline-treated controls. This finding is accompanied by significantly higher parvalbumin gene and protein expression in ceftriaxone-treated injured rats. Our results highlight prospects for ceftriaxone as an intervention after TBI to prevent cortical inhibitory interneuron dysfunction, partly by preserving GLT-1 expression.

Personalized, Multisession, Multichannel Transcranial Direct Current Stimulation in Medication-Refractory Focal Epilepsy: An Open-Label Study.

PURPOSE: Animal and proof-of-principle human studies suggest that cathodal transcranial direct current stimulation may suppress seizures in drug-resistant focal epilepsy. The present study tests the safety, tolerability, and effect size of repeated daily cathodal transcranial direct current stimulation in epilepsy have not been established, limiting development of clinically meaningful interventions. METHODS: We conducted a 2-center, open-label study on 20 participants with medically refractory, focal epilepsy, aged 9 to 56 years (11 women and 9 children younger than18 years). Each participant underwent 10 sessions of 20 minutes of cathodal transcranial direct current stimulation over 2 weeks. Multielectrode montages were designed using a realistic head model-driven approach to conduct an inhibitory electric field to the target cortical seizure foci and surrounding cortex to suppress excitability and reduce seizure rates. Patients recorded daily seizures using a seizure diary 8 weeks prior, 2 weeks during, and 8 to 12 weeks after the stimulation period. RESULTS: The median seizure reduction was 44% relative to baseline and did not differ between adult and pediatric patients. Three patients experienced an increase in seizure frequency of >50% during the stimulation period; in one, a 36% increase in seizure frequency persisted through 12 weeks of follow-up. Otherwise, participants experienced only minor adverse events-the most common being scalp discomfort during transcranial direct current stimulation. CONCLUSIONS: This pilot study supports the safety and efficacy of multifocal, personalized, multichannel, cathodal transcranial direct current stimulation for adult and pediatric patients with medication-refractory focal epilepsy, although identifies a possibility of seizure exacerbation in some. The data also provide insight into the effect size to inform the design of a randomized, sham-stimulation controlled trial.

Discrepant expressive language lateralization in children and adolescents with epilepsy.

Neuronavigated transcranial magnetic stimulation (nTMS) has emerged as a presurgical language mapping tool distinct from the widely used functional magnetic resonance imaging (fMRI). We report fMRI and nTMS language-mapping results in 19 pediatric-epilepsy patients and compare those to definitive testing by electrical cortical stimulation, Wada test, and/or neuropsychological testing. Most discordant results occurred when fMRI found right-hemispheric language. In those cases, when nTMS showed left-hemispheric or bilateral language representation, left-hemispheric language was confirmed by definitive testing. Therefore, we propose nTMS should be considered for pediatric presurgical language-mapping when fMRI shows right-hemispheric language, with nTMS results superseding fMRI results in those scenarios.

Transcranial magnetic stimulation as a translational biomarker for AMPA receptor modulation.

TAK-653 is a novel α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-positive allosteric modulator being developed as a potential therapeutic for major depressive disorder (MDD). Currently, there are no translational biomarkers that evaluate physiological responses to the activation of glutamatergic brain circuits available. Here, we tested whether noninvasive neurostimulation, specifically single-pulse or paired-pulse motor cortex transcranial magnetic stimulation (spTMS and ppTMS, respectively), coupled with measures of evoked motor response captures the pharmacodynamic effects of TAK-653 in rats and healthy humans. In the rat study, five escalating TAK-653 doses (0.1-50 mg/kg) or vehicle were administered to 31 adult male rats, while measures of cortical excitability were obtained by spTMS coupled with mechanomyography. Twenty additional rats were used to measure brain and plasma TAK-653 concentrations. The human study was conducted in 24 healthy volunteers (23 males, 1 female) to assess the impact on cortical excitability of 0.5 and 6 mg TAK-653 compared with placebo, measured by spTMS and ppTMS coupled with electromyography in a double-blind crossover design. Plasma TAK-653 levels were also measured. TAK-653 increased both the mechanomyographic response to spTMS in rats and the amplitude of motor-evoked potentials in humans at doses yielding similar plasma concentrations. TAK-653 did not affect resting motor threshold or paired-pulse responses in humans. This is the first report of a translational functional biomarker for AMPA receptor potentiation and indicates that TMS may be a useful translational platform to assess the pharmacodynamic profile of glutamate receptor modulators.

Safety and Tolerability of Repetitive Transcranial Magnetic Stimulation During Pregnancy: A Case Report and Literature Review.

Patients with neuropsychiatric disease may benefit from repetitive transcranial magnetic stimulation as a nonpharmacologic alternative to relieve symptoms of major depression, obsessive compulsive disorder, and perhaps other syndromes such as epilepsy. We present a case of repetitive transcranial magnetic stimulation treatment as an adjunct therapy for a patient experiencing refractory epileptic seizures during the third trimester of pregnancy. Notably, the patient tolerated repetitive transcranial magnetic stimulation well, without adverse events, and delivered a healthy child. We also summarize the current literature pertaining to therapeutic repetitive transcranial magnetic stimulation use during pregnancy.

Alterations in the Timing of Huperzine A Cerebral Pharmacodynamics in the Acute Traumatic Brain Injury Setting.

Traumatic brain injury (TBI) may affect the pharmacodynamics of centrally acting drugs. Paired-pulse transcranial magnetic stimulation (ppTMS) is a safe and noninvasive measure of cortical gamma-aminobutyric acid (GABA)-mediated cortical inhibition. Huperzine A (HupA) is a naturally occurring acetylcholinesterase inhibitor with newly discovered potent GABA-mediated antiepileptic capacity, which is reliably detected by ppTMS. To test whether TBI alters cerebral HupA pharmacodynamics, we exposed rats to fluid percussion injury (FPI) and tested whether ppTMS metrics of cortical inhibition differ in magnitude and temporal pattern in injured rats. Anesthetized adult rats were exposed to FPI or sham injury. Ninety minutes post-TBI, rats were injected with HupA or saline (0.6 mg/kg, intraperitoneally). TBI resulted in reduced cortical inhibition 90 min after the injury (N = 18) compared to sham (N = 13) controls (p = 0.03). HupA enhanced cortical inhibition after both sham injury (N = 6; p = 0.002) and TBI (N = 6; p = 0.02). The median time to maximum HupA inhibition in sham and TBI groups were 46.4 and 76.5 min, respectively (p = 0.03). This was consistent with a quadratic trend comparison that projects HupA-mediated cortical inhibition to last longer in injured rats (p = 0.007). We show that 1) cortical GABA-mediated inhibition, as measured by ppTMS, decreases acutely post-TBI, 2) HupA restores lost post-TBI GABA-mediated inhibition, and 3) HupA-mediated enhancement of cortical inhibition is delayed post-TBI. The plausible reasons of the latter include 1) low HupA volume of distribution rendering HupA confined in the intravascular compartment, therefore vulnerable to reduced post-TBI cerebral perfusion, and 2) GABAR dysfunction and increased AChE activity post-TBI.

Huperzine A: A promising anticonvulsant, disease modifying, and memory enhancing treatment option in Alzheimer's disease.

Alzheimer's disease (AD) is the most frequent cause of dementia. Besides cognitive deterioration, patients with AD are prone to seizures - more than 20% of patients diagnosed with AD experience at least one unprovoked seizure and up to 7% have recurrent seizures. Although available antiepileptic drugs (AEDs) may suppress seizures in patients with AD, they may also worsen cognitive dysfunction and increase the risk of falls. On the basis of preclinical studies, we hypothesize that Huperzine A (HupA), a safe and potent acetylcholinesterase (AChE) inhibitor with potentially disease-modifying qualities in AD, may have a realistic role as an anticonvulsant in AD.