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Transcranial magnetic stimulation (TMS) is a non-invasive technique for focal brain stimulation based on electromagnetic induction where a fluctuating magnetic field induces a small intracranial electric current in the brain. For more than 35 years, TMS has shown promise in the diagnosis and treatment of neurological and psychiatric disorders in adults. In this review, we provide a brief introduction to the TMS technique with a focus on repetitive TMS (rTMS) protocols, particularly theta-burst stimulation (TBS), and relevant rTMS-derived metrics of brain plasticity. We then discuss the TMS-EEG technique, the use of neuronavigation in TMS, the neural substrate of TBS measures of plasticity, the inter- and intraindividual variability of those measures, effects of age and genetic factors on TBS aftereffects, and then summarize alterations of TMS-TBS measures of plasticity in major neurological and psychiatric disorders including autism spectrum disorder, schizophrenia, depression, traumatic brain injury, Alzheimer’s disease, and diabetes. Finally, we discuss the translational studies of TMS-TBS measures of plasticity and their therapeutic implications.

Despite the availability of numerous pharmacologic and nonpharmacologic antiseizure therapies, a fraction of patients with epilepsy remain refractory to current treatment options, underscoring the need for novel drugs and neuromodulatory therapies. Transcranial magnetic stimulation (TMS), coupled with either electromyography or electroencephalography, enables rapid measurement of the cortical excitation/inhibition ratio, which is pathologically shifted toward excess excitability in patients with epilepsy. In this review, we summarize: (1) TMS protocols that have been deployed to identify promising compounds in the antiepilepsy drug (AED)-development pipeline, and (2) the therapeutic potential of TMS in the treatment of drug-resistant seizures. A focused literature review of the use of TMS in epilepsy, using a PubMed search, was performed. Over 70 articles were included that pertained to: (1) the use of TMS-EMG and TMS-EEG in elucidating the mechanisms of action of AEDs and in discovering potential new AEDs; and (2) the use of repetitive TMS in the treatment of seizures. Studies from the literature have reported that AEDs alter TMS-derived metrics, typically by leading to a net increase in cortical inhibition with successful therapy. Preclinical TMS work in rodent models of epilepsy has led to the development of novel antiseizure drug compounds. Clinical translational studies of TMS have been used to determine guidelines on the dosages of other agents in the AED pipeline in preparation for clinical trials. Several studies have described the use of therapeutic repetitive TMS in both the ictal and interictal states of epilepsy, with inconsistent results. TMS has diagnostic and therapeutic potential in epilepsy. TMS-derived markers can enable early-stage measures of AED target engagement, and can facilitate studies of the pharmacokinetic and pharmacodynamic properties of AEDs. TMS may also be used in the early prediction of the efficacy of different AEDs in treating patients, and in direct neuromodulation of epileptic networks. From the therapeutics perspective, despite favorable results in some trials, the optimization of treatment paradigms and the determination of ideal candidates for TMS are still needed. Finally, preclinical experiments of TMS have provided mechanistic insight into its effects on the excitation/inhibition ratio, and may facilitate rational drug–device coupling paradigms. Overall, the capacity of TMS in both the modulation and measurement of changes in cortical excitability highlights its unique role in advancing antiepilepsy therapeutics

The mechanisms that extend lifespan in humans are poorly understood. Here we show that extended longevity in humans is associated with a distinct transcriptome signature in the cerebral cortex that is characterized by downregulation of genes related to neural excitation and synaptic function. In Caenorhabditis elegans , neural excitation increases with age and inhibition of excitation globally, or in glutamatergic or cholinergic neurons, increases longevity. Furthermore, longevity is dynamically regulated by the excitatory–inhibitory balance of neural circuits. The transcription factor REST is upregulated in humans with extended longevity and represses excitation-related genes. Notably, REST-deficient mice exhibit increased cortical activity and neuronal excitability during ageing. Similarly, loss-of-function mutations in the C. elegans REST orthologue genes spr-3 and spr-4 elevate neural excitation and reduce the lifespan of long-lived daf-2 mutants. In wild-type worms, overexpression of spr-4 suppresses excitation and extends lifespan. REST, SPR-3, SPR-4 and reduced excitation activate the longevity-associated transcription factors FOXO1 and DAF-16 in mammals and worms, respectively. These findings reveal a conserved mechanism of ageing that is mediated by neural circuit activity and regulated by REST. Studies of humans, mice and nematodes reveal a conserved role of neural activity and the transcription factor REST in extended longevity.

People with diabetes can wear a device that measures blood glucose and delivers just the amount of insulin needed to return the glucose level to within bounds. Currently, people with epilepsy do not have access to an equivalent wearable device that measures a systemic indicator of an impending seizure and delivers a rapidly acting medication or other intervention (e.g., an electrical stimulus) to terminate or prevent a seizure. Given that seizure susceptibility is reliably increased in systemic inflammatory states, we propose a novel closed‐loop device where release of a fast‐acting therapy is governed by sensors that quantify the magnitude of systemic inflammation. Here, we review the evidence that patients with epilepsy have raised levels of systemic indicators of inflammation than controls, and that some anti‐inflammatory drugs have reduced seizure occurrence in animals and humans. We then consider the options of what might be incorporated into a responsive anti‐seizure system.

Excessive extracellular glutamate after traumatic brain injury (TBI) contributes to excitotoxic cell death and likely to post-traumatic epilepsy. Glutamate transport is the only known mechanism of extracellular glutamate clearance, and glutamate transporter 1 (GLT-1) is the major glutamate transporter of the mammalian brain. We tested, by immunoblot, in the rat lateral fluid percussion injury TBI model whether GLT-1 expression is depressed in the cortex after TBI, and whether GLT-1 expression after TBI is restored after treatment with ceftriaxone, a well-tolerated β-lactam antibiotic previously shown to enhance GLT-1 expression in noninjured animals. We then tested whether treatment with ceftriaxone mitigates the associated regional astrogliosis, as reflected by glial fibrillary acid protein (GFAP) expression, and also whether ceftriaxone treatment mitigates the severity of post-traumatic epilepsy. We found that 7 days after TBI, GLT-1 expression in the ipsilesional cortex was reduced by 29% (n=7/group; p<0.01), relative to the contralesional cortex. However, the loss of GLT-1 expression was reversed by treatment with ceftriaxone (200 mg/kg, daily, intraperitoneally). We found that ceftriaxone treatment also decreased the level of regional GFAP expression by 43% in the lesioned cortex, relative to control treatment with saline (n=7 per group; p<0.05), and, 12 weeks after injury, reduced cumulative post-traumatic seizure duration (n=6 rats in the ceftriaxone treatment group and n=5 rats in the saline control group; p<0.001). We cautiously conclude that our data suggest a potential role for ceftriaxone in treatment of epileptogenic TBI.

The concurrent combination of transcranial magnetic stimulation (TMS) with electroencephalography (TMS-EEG) is a powerful technology for characterizing and modulating brain networks across developmental, behavioral, and disease states. Given the global initiatives in mapping the human brain, recognition of the utility of this technique is growing across neuroscience disciplines. Importantly, TMS-EEG offers translational biomarkers that can be applied in health and disease, across the lifespan, and in humans and animals, bridging the gap between animal models and human studies. However, to utilize the full potential of TMS-EEG methodology, standardization of TMS-EEG study protocols is needed. In this article, we review the principles of TMS-EEG methodology, factors impacting TMS-EEG outcome measures, and the techniques for preventing and correcting artifacts in TMS-EEG data. To promote the standardization of this technique, we provide comprehensive guides for designing TMS-EEG studies and conducting TMS-EEG experiments. We conclude by reviewing the application of TMS-EEG in basic, cognitive and clinical neurosciences, and evaluate the potential of this emerging technology in brain research.

Epilepsy is associated with numerous neurodevelopmental disorders. Transcranial magnetic stimulation (TMS) of the motor cortex coupled with electromyography (EMG) enables biomarkers that provide measures of cortical excitation and inhibition that are particularly relevant to epilepsy and related disorders. The motor threshold (MT), cortical silent period (CSP), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), and long interval intracortical inhibition (LICI) are among TMS-derived metrics that are modulated by antiepileptic drugs. TMS may have a practical role in optimization of antiepileptic medication regimens, as studies demonstrate dose-dependent relationships between TMS metrics and acute medication administration. A close association between seizure freedom and normalization of cortical excitability with long-term antiepileptic drug use highlights a plausible utility of TMS in measures of anti-epileptic drug efficacy. Finally, TMS-derived biomarkers distinguish patients with various epilepsies from healthy controls, and thus may enable development of disorder-specific biomarkers and therapies both within and outside of the epilepsy realm.

The utility of continuous theta-burst stimulation (cTBS) as index of cortical plasticity is limited by inadequate characterization of its test-retest reliability. We thus evaluated the reliability of cTBS aftereffects, and explored the roles of age and common single-nucleotide polymorphisms in the brain-derived neurotrophic factor ( ) and apolipoprotein E ( ) genes. Twenty-eight healthy adults (age range 21-65) underwent two identical cTBS sessions (median interval = 9.5 days) targeting the motor cortex. Intraclass correlation coefficients (ICCs) of the log-transformed, baseline-corrected amplitude of motor evoked potentials (ΔMEP) at 5-60 min post-cTBS (T5-T60) were calculated. Adjusted effect sizes for cTBS aftereffects were then calculated by taking into account the reliability of each cTBS measure. ΔMEP at T50 was the most-reliable cTBS measure in the whole sample (ICC = 0.53). Area under-the-curve (AUC) of ΔMEPs was most reliable when calculated over the full 60 min post-cTBS (ICC = 0.40). cTBS measures were substantially more reliable in younger participants (< 35 years) and in those with Val66Val and ε4- genotypes. cTBS aftereffects are most reliable when assessed 50 min post-cTBS, or when cumulative ΔMEP measures are calculated over 30-60 min post-cTBS. Reliability of cTBS aftereffects is influenced by age, and and polymorphisms. Reliability coefficients are used to adjust effect-size calculations for interpretation and planning of cTBS studies.

: To assess changes in the developmental trajectory of corticospinal tracts (CST) maturation in children with hemiplegic cerebral palsy (HCP). : Neuroimaging data were obtained from 36 children with HCP for both the more affected (MA) and less affected (LA) hemispheres, and, for purposes of direct comparison, between groups, 15 typically developing (TD) children. With diffusion tensor imaging (DTI), we estimated the mean fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) of the corticospinal tract, parameters indicative of factors including myelination and axon density. Transcranial magnetic stimulation (TMS) was performed as a neurophysiologic measure of corticospinal tract integrity and organization. Resting motor threshold (rMT) was obtained per hemisphere, per patient. : We observed a significant AD and MD developmental trajectory, both of which were inversely related to age (decrease in AD and diffusivity corresponding to increased age) in both hemispheres of TD children ( < 0.001). This maturation process was absent in both MA and LA hemispheres of children with HCP. Additionally, the TMS-derived previously established rMT developmental trajectory was preserved in the LA hemisphere of children with HCP ( = 26; < 0.0001) but this trajectory was absent in the MA hemisphere. : Corticospinal tract maturation arrests in both hemispheres of children with HCP, possibly reflecting perinatal disruption of corticospinal tract myelination and axonal integrity.