Evidence for an excitatory GABAA response in human motor cortex in idiopathic generalised epilepsy

Silbert, Benjamin I.; Heaton, A; Cash, Robin; James, Ian; Dunne, John W.; Lawn, Nicholas; Silbert, Peter L.; Mastaglia, Frank; Thickbroom, Gary

doi:10.1016/j.seizure.2015.01.014

Cited by 16 publications

(39 citation statements)

References 72 publications

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“…Impairment of SICI has been reported across a wide range of neurological disorders [ [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] ], but due to its large variability between patients and overlap with normal subjects, conventional SICI has limited clinical diagnostic use [ 19 , 20 ]. However, T-SICI is emerging as a potentially useful diagnostic test [ [21] , [22] , [23] , [24] ].…”

Section: Introductionmentioning

confidence: 99%

Short-interval intracortical inhibition: Comparison between conventional and threshold-tracking techniques

et al. 2018

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BackgroundShort-interval intracortical inhibition (SICI) is conventionally measured as the relative amplitude reduction of motor evoked potentials (MEPs) by subthreshold conditioning stimuli. In threshold-tracking SICI (T-SICI), stimulus intensity is instead adjusted repeatedly to maintain a constant MEP and inhibition is measured as the relative threshold increase. T-SICI is emerging as a useful diagnostic test, but its relationship to conventional amplitude SICI (A-SICI) is unclear.ObjectiveTo compare T-SICI and its reliability with conventional A-SICI measurements.MethodsIn twelve healthy volunteers (6 men, median age 30 years), conventional and T-SICI were recorded at conditioning stimuli (CS) of 50–80% resting motor threshold (RMT) and interstimulus interval of 2.5 ms. Measurements were repeated on the same day and at least a week later by a single operator.ResultsAcross the CS range, mean group T-SICI showed a strong linear relationship to the mean group values measured by conventional technique (y = 29.7–0.3x, R2 = 0.99), but there was considerable interindividual variability. At CS 60–80% RMT, T-SICI had excellent intraday (intraclass correlation coefficient, ICC, 0.81–0.92) and adequate-to-excellent interday (ICC 0.61–0.88) reproducibility. Conventional SICI took longer to complete (median of 5.8 vs 3.8 min, p < 0.001) and tended to have poorer reproducibility (ICC 0.17–0.42 intraday, 0.37–0.51 interday). With T-SICI, smaller sample sizes were calculated for equally powered interventional studies.ConclusionThe close relationship between conventional and T-SICI suggests that both techniques reflect similar cortical inhibitory mechanisms. Threshold-tracking measurements of SICI may be able to improve reproducibility, to shorten acquisition time and to reduce sample sizes for interventional studies compared with the conventional technique.

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Section: Introductionmentioning

confidence: 99%

Short-interval intracortical inhibition: Comparison between conventional and threshold-tracking techniques

et al. 2018

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“…A potentially relevant finding has been described in the context of emergence of psychosis following the establishment of seizure control in uncontrolled epilepsy patients . A recent study of interictal cortical inhibition using transcranial magnetic stimulation in patients with idiopathic generalized epilepsy did find in vivo evidence for excitatory GABA transmission . This might be due to absence of normal developmental maturation of GABA A receptor subunits and altered chloride transporter expressions patterns .…”

Section: Discussionmentioning

confidence: 98%

“…34 A recent study of interictal cortical inhibition using transcranial magnetic stimulation in patients with idiopathic generalized epilepsy did find in vivo evidence for excitatory GABA transmission. 35 This might be due to absence of normal developmental maturation of GABA A receptor subunits and altered chloride transporter expressions patterns. 36 In keeping with this, the Na-K-Cl cotransporter (NKCC1) antagonist bumetanide can augment phenobarbital (GABA enforcing) anticonvulsive action in different rodent models, including a hypoxic rat model.…”

Section: Discussionmentioning

confidence: 99%

Behavioral disinhibition and antiepileptic treatment in childhood epilepsy: A retrospective cohort study

et al. 2017

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SummaryObjectiveTo test whether specific classes of antiepileptic drugs increase the risk for behavioral disinhibition, a frequent complication of treatment of childhood epilepsy.MethodsIn a sample of children with active epilepsy and antiepileptic drug (AED) treatment (n = 146, age 4–17 years), we performed a retrospective chart analysis of the occurrence of symptoms indicating reduced behavioral disinhibition following AED treatment. We used a risk‐set approach to analyze whether the presence or recent addition of AED categories defined by their mechanism of action were associated with enhanced risk for behavioral disinhibition symptoms.ResultsMean duration of follow‐up was 2,343 days (range 218–6,292, standard deviation [SD] 1,437). Episodes of behavioral disinhibition were reported in 51 (34.9%) children, with variable latencies between latest change and occurrence of behavioral disinhibition symptoms (mean 67 days, range 2–367). Current use of AEDs targeting gamma‐aminobutyric acid (GABA) (odds ratio [OR] 1.8, 95% confidence interval [CI] 1.02–3.29, p = 0.04) and SV2A‐mediated neurotransmitter release (SV2A)‐mediated (2.0, 1.13–3.60, p = 0.02) neurotransmitter release was associated with increased risk for behavioral disinhibition. Restricting the analysis to the 90 days before behavioral disinhibition episode occurrence revealed that only addition of GABAergic AEDs (OR = 26.88, 95% CI = 6.71–107.76, p < 0.001) was associated with behavioral disinhibition. In contrast to our expectations, seizure control was reported to have improved parallel to most behavioral disinhibition episodes.SignificanceThis exploration of behavioral disinhibition in relation to antiepileptic drug treatment indicates that GABA potentiating drugs are specifically associated with behavioral problems during treatment of childhood epilepsy. Behavioral disinhibition episodes often occurred while seizure control improved, which may have reduced alertness for the consequences of AEDs on interictal symptoms. Our findings may be related to the increasing evidence for a role for excitatory actions of GABA in childhood epilepsy.

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“…When the interval between the paired pulses is only a few milliseconds, the ratio reflects the activation of GABA A receptors. When this interval is up to hundreds of milliseconds, the ratio reflects the activation of GABA B receptors (21).…”

Section: The Neural Basis Of Inhibition In Cortical Activitiesmentioning

confidence: 99%

A facilitation tool: transcranial magnetic stimulation in epilepsy research

Zhou

2016

Eur J Bio Med Res

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Transcranial magnetic stimulation (TMS) is a noninvasive and relatively safe method to modulate the cortical activities and thus becomes popular in clinical research such as epilepsy studies. These studies mainly focus on the use of paired-pulse TMS as biomarkers and the effects of repetitive TMS (rTMS) in epilepsy treatment. Paired-pulse TMS measures the cortical excitability under different pathological circumstances by deriving and analyzing paired-pulse recovery curve, which has been proved reliable and widely used to study the physiological and pharmacological mechanisms in epilepsy. rTMS is able to modulate the brain functions and has been considered as a potential treatment for epilepsy, yet the evidence is insufficient and further exploration is required. This review intends to examine the methodologies and outcomes presented by relevant studies and to discuss the pros and cons of current TMS research. This review gives a brief introduction to background and principle of TMS. It reviews the methods measuring cortical excitability and the key findings in accordance with the mechanisms of epilepsy. It also reviews the existing controlled studies in therapeutic effectiveness of rTMS and analyzes the advantages of different designs and parameter choices.In the end, this review suggests directions for future research.

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Evidence for an excitatory GABAA response in human motor cortex in idiopathic generalised epilepsy

Abstract: Pre- and post-synaptic GABA-mediated inhibitory mechanisms are altered in IGE. The findings lend in vivo support to evidence from experimental models and in vitro studies of human epileptic brain tissue that GABA may have a paradoxical excitatory role in ictogenesis.

Cited by 16 publications

References 72 publications

Short-interval intracortical inhibition: Comparison between conventional and threshold-tracking techniques

Short-interval intracortical inhibition: Comparison between conventional and threshold-tracking techniques

Behavioral disinhibition and antiepileptic treatment in childhood epilepsy: A retrospective cohort study

A facilitation tool: transcranial magnetic stimulation in epilepsy research

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