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

Purpose Impaired GABAergic inhibition has been implicated in the pathophysiology of epilepsy. The possibility of a paradoxical excitatory effect of GABA in epilepsy has been suggested, but has not been investigated in vivo. We investigated pre- and post-synaptic GABAergic mechanisms in patients with idiopathic generalised epilepsy (IGE). Method In 10 patients and 12 control subjects we explored short- and long-interval intracortical inhibition (SICI, LICI; post-synaptic GABAA and GABAB-mediated respectively) and long-interval intracortical facilitation (LICF; pre-synaptic disinhibition) using transcranial magnetic stimulation. Results While post-synaptic GABAB-mediated inhibition was unchanged in IGE (p = 0.09), LICF was reduced compared to controls (controls: 141 ± 17% of baseline; untreated patients: 107 ± 12%, p = 0.2; treated patients: 79 ± 10%, p = 0.003). GABAA-mediated inhibition was reduced in untreated patients (response amplitude 56 ± 4% of baseline vs. 26 ± 6% in controls, p = 0.004) and normalised with treatment (37 ± 12%, p = 0.5 vs. controls). When measured during LICI, GABAA-mediated inhibition became excitatory in untreated IGE (response amplitude 120 ± 10% of baseline, p = 0.017), but not in treated patients. Conclusion 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

Central venous-to-arterial carbon dioxide gradient as a marker of occult tissue hypoperfusion after major surgery

The central venous-arterial carbon dioxide tension gradient ('CO₂gap') has been shown to correlate with cardiac output and tissue perfusion in septic shock. Compared to central venous oxygen saturation (SCVO2), the CO₂gap is less susceptible to the effect of hyperoxia and may be particularly useful as an adjunctive haemodynamic target in the perioperative period. This study investigated whether a high CO₂gap was associated with an increased systemic oxygen extraction (O2ER >0.3) or occult tissue hypoperfusion in 201 patients in the immediate postoperative period. The median CO₂gap of all patients was 8 mmHg (IQR 6 to 9), and a large CO₂gap was very common (> 6mmHg in 139 patients [69%], 95% CI 63 to 75; >5 mmHg in 170 patients [85%], 95% CI 79 to 89). A CO₂ gap >5 mmHg had a higher sensitivity (93%) and negative predictive value (74%) than a CO₂gap >6 mmHg in excluding occult tissue hypoperfusion. Of the four variables that were predictive of an increased O₂ER in the multivariate analysis-CO₂gap, arterial pH, haemoglobin and arterial lactate concentrations-the CO₂gap (odds ratio 4.41 per mmHg increment, 95% CI 1.7 to 11.2, P=0.002) was most important and explained about 34% of the variability in the risk of occult tissue hypoperfusion. In conclusion, a normal CO₂ gap (<5 mmHg) had a high sensitivity and negative predictive value in excluding inadequate systemic oxygen delivery and may be useful as an adjunct to other haemodynamic targets in avoiding occult tissue hypoperfusion in the perioperative setting when high inspired oxygen concentrations are used

Prognostic significance of blood-brain barrier disruption in patients with severe nonpenetrating traumatic brain injury requiring decompressive craniectomy

Object. The authors assessed the risk factors and outcomes associated with blood-brain barrier (BBB) disruption in patients with severe, nonpenetrating, traumatic brain injury (TBI) requiring decompressive craniectomy. Methods. At 2 major neurotrauma centers in Western Australia, a retrospective cohort study was conducted among 97 adult neurotrauma patients who required an external ventricular drain (EVD) and decompressive craniectomy during 2004-2012. Glasgow Outcome Scale scores were used to assess neurological outcomes. Logistic regression was used to identify factors associated with BBB disruption, defined by a ratio of total CSF protein concentrations to total plasma protein concentration > 0.007 in the earliest CSF specimen collected after TBI. Results. Of the 252 patients who required decompressive craniectomy, 97 (39%) required an EVD to control intracranial pressure, and biochemical evidence of BBB disruption was observed in 43 (44%). Presence of disruption was associated with more severe TBI (median predicted risk for unfavorable outcome 75% vs 63%, respectively; p = 0.001) and with worse outcomes at 6, 12, and 18 months than was absence of BBB disruption (72% vs 37% unfavorable outcomes, respectively; p = 0.015). The only risk factor significantly associated with increased risk for BBB disruption was presence of nonevacuated intracerebral hematoma (> 1 cm diameter) (OR 3.03, 95% CI 1.23-7.50; p = 0.016). Although BBB disruption was associated with more severe TBI and worse long-term outcomes, when combined with the prognostic information contained in the Corticosteroid Randomization after Significant Head Injury (CRASH) prognostic model, it did not seem to add significant prognostic value (area under the receiver operating characteristic curve 0.855 vs 0.864, respectively; p = 0.453). Conclusions. Biochemical evidence of BBB disruption after severe nonpenetrating TBI was common, especially among patients with large intracerebral hematomas. Disruption of the BBB was associated with more severe TBI and worse long-term outcomes, but when combined with the prognostic information contained in the CRASH prognostic model, this information did not add significant prognostic value

Modulation of corticomotor excitability by an I-wave intervention delivered during low-level voluntary contraction

Transcranial magnetic stimulation (TMS) interventions that modulate cortical plasticity may achieve a more functional benefit if combined with neuro-rehabilitation therapies. With a TMS protocol targeting I-wave dynamics, it is possible to deliver stimuli while a subject performs a motor task, and this may more effectively target functional networks related to the task. However, the efficacy of this intervention during a simple task such as a low-level voluntary contraction is not known. We delivered paired-pulse TMS at an inter-pulse interval (IPI) of 1.5 ms for 15 min while subjects performed a 10 ± 2.5% voluntary contraction of the first dorsal interosseous (FDI) muscle and made motor evoked potential (MEP) amplitude and short-interval intracortical facilitation (SICF) curve measurements. Pre-intervention SICF curves showed only a single peak at 1.3–1.5 ms IPI. During the intervention, MEP amplitude steadily increased (P < 0.001) to 137 ± 13% of its initial value. After the intervention, SICF curves were increased in amplitude (P < 0.001) and later peaks emerged at 2.8 and 4.3 ms IPIs. A control experiment, replacing paired-pulse stimulation with single-pulse stimulation showed no effect on MEP amplitude (P = 0.951). We conclude that the I-wave intervention can be administered concurrently with a simple motor task and that it acts by increasing trans-synaptic efficacy across a number of I-waves. The ability to perform a motor task simultaneously with a TMS intervention could confer a degree of specificity to the induced excitability changes and may be beneficial for functional neuro-rehabilitation programs built around motor learning and retraining