Summary: Centromedian thalamic nucleus is an intralaminar nucleus with vast connectivity to cerebral cortex and basal ganglia. It receives afferents from the brain stem through the central tegmental tract and is part of the diffuse thalamic projection system. Because the reticulothalamic system has been related to initiation and propagation of epileptic activity (centroencephalic theory of epilepsy), deep brain stimulation has been proposed to interfere with seizure genesis or propagation. Centromedian thalamic nucleus is a large nucleus laying nearby the anatomical references for stereotaxis and therefore a convenient surgical target to approach. Electrodes are implanted in the anterior ventral lateral part of the nucleus (parvocellular area), guided by intraoperative recruiting responses elicited by unilateral 6 to 8 Hz electrical stimulation delivered through the deep brain stimulation electrode. Therapeutic stimulation is delivered with the following parameters: 60 Hz, 450 μs, 3.0 V. Seizure control runs between 69% and 83% in different reports, decreasing mainly generalized seizures from the start, with significant improvement in neuropsychological performance. Significant decrease in seizure occurs from hours to days after the onset of deep brain stimulation. Some reports refer that seizure improvement may occur by the simple insertion of the deep brain stimulation electrodes, and therefore, it was used to treat refractory epileptic status.

Experimental evidence indicates that cannabidiol (CBD) induces anxiolytic and antiepileptic effects through the activation of 5-HT1A receptors. These receptors are coupled to Gi/o proteins and induce inhibitory effects. At present, the interaction of CBD with 5-HT1A receptors in the human brain is unknown. The aim of this study focused on evaluating the interaction between CBD and 5-HT1A receptors in cell membranes obtained from the hippocampus and temporal neocortex of autopsies and patients with drug-resistant mesial temporal lobe epilepsy (DR-MTLE). Cell membranes were isolated from the hippocampus and temporal neocortex of a group of patients with DR-MTLE who were submitted to epilepsy surgery (n = 11) and from a group of autopsies (n = 11). The [3H]-8-OH-DPAT binding assay was used to determine the pharmacological interaction of CBD with 5-HT1A receptors. The [35S]-GTPγS assay was used to investigate the CBD-induced activation of Gi/o proteins through its action on 5-HT1A receptors.The CBD affinity (pKi) for 5-HT1A receptors was similar for autopsies and patients with DR-MTLE (hippocampus: 4.29 and 4.47, respectively; temporal neocortex: 4.67 and 4.74, respectively). Concerning the [35S]-GTPγS assay, no statistically significant changes were observed for both hippocampal and neocortical tissue (p > 0.05) at low CBD concentrations (1 pM to 10 μM). In contrast, at high concentrations (100 μM), CBD reduced the constitutive activity of Gi/o proteins of autopsies and DR-MTLE patients (hippocampus: 39.2% and 39.6%, respectively; temporal neocortex: 35.2% and 24.4%, respectively). These changes were partially reversed in the presence of WAY-100635, an antagonist of 5-HT1A receptors, in the autopsy group (hippocampus, 59.8%, p < 0.0001; temporal neocortex, 71.5%, p < 0.0001) and the group of patients with DR-MTLE (hippocampus, 53.7%, p < 0.0001; temporal neocortex, 68.5%, p < 0.001). Our results show that CBD interacts with human 5-HT1A receptors of the hippocampus and temporal neocortex. At low concentrations, the effect of CBD upon Gi/o protein activation is limited. However, at high concentrations, CBD acts as an inverse agonist of 5-HT1A receptors. This effect could modify neuronal excitation and epileptic seizures in patients with DR-MTLE.

OBJECTIVE The authors sought to determine the antiseizure effects of deep brain stimulation (DBS) of the parahippocampal cortex (PHC) for treatment of drug-resistant mesial temporal lobe epilepsy (MTLE). METHODS After a 3-month baseline period, 6 adult patients with drug-resistant MTLE and hippocampal sclerosis (HS) had stereoelectroencephalography (SEEG)–DBS electrodes implanted at the PHC for identification of the seizure onset zone (SOZ). Patients entered an 8-month, randomized, double-blind protocol for DBS, followed by a 12-month open-phase study. Monthly reports of seizure frequency were collected, with separate counting of focal seizures with or without awareness impairment (focal impaired awareness seizures [FIAS] or focal aware seizures [FAS], respectively) and focal evolving to bilateral generalized tonic clonic seizures (GTCS). Stimulation parameters were 130 Hz, 450 μsec, 2.5–3 V, and cyclic stimulation 1 minute on/4 minutes off. RESULTS The total seizure rate decrement during follow-up was 41% (CI 25%–56%), with better seizure control for GTCS (IQR 19%–20%) and FIAS (IQR 0%–16%), with FAS being less responsive (IQR 67%–236%). No neuropsychological deterioration was observed. CONCLUSIONS PHC DBS induced important antiseizure effects in patients with incapacitating FIAS and GTCS, most likely through blocking the propagation of hippocampal-onset seizures. The PHC target can be easily and safely approached due to positioning away from vascular structures, and there was no evidence of DBS-induced cognitive deterioration.

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