Functional organization and neuromodulation of entorhinal cortex layer II neurons

Morphological and electrophysical properties of layer II neurons from the medial entorhinal cortex were investigated in a rat brain slice preparation to enhance our understanding of the role the entorhinal cortex plays in the gating of afferent stimuli to the hippocampal formation.Morphological characterization revealed that layer II projection neurons fell into two distinct categories. 65% of neurons were identified as the stellate cells described previously. The remaining 35% had, for the most, a pyramidal-like morphology, and were referred to as non-stellates.Electrophysiological characterization revealed that stellates and non-stellates had distinct electroresponsive properties. Notably, stellates, upon d.c. depolarization, generated subthreshold, sinusoidal-like, membrane potential oscillations at a mean frequency of 8.6 Hz and a 1-3 Hz repetitive bursting pattern, referred to as clustering. Non-stellates, when d.c. depolarized, never generated subthreshold oscillations nor spike clusters; instead they readily went into tonic firing.Investigation of the main ionic mechanisms endowing stellates and non-stellates with their differential electroresponsiveness revealed that stellates exclusively possessed a fast, low threshold, Ba$sp{2+}$-sensitive outward rectifier, which, in interplay with the persistent Na$sp+$ conductance, generated the membrane potential oscillations.The cholinergic agonist carbachol caused a depolarization in both stellates and non-stellates, associated with no change or a slight increase in apparent input resistance. In stellates, carbachol caused a decrease in the dominant frequency of the subthreshold membrane potential oscillations from 9.2 to 6.3 Hz. In non-stellates, carbachol transformed tonic firing into a slow voltage-dependent bursting discharge.Investigation of the ionic mechanisms of the carbachol-induced depolarization in stellates and non-stellates revealed that it resulted mainly from activation of a Ca$sp{2+}$ dependent cationic conductance largely carried by Na$sp+$, mediated predominantly through m1 muscarinic receptor subtype activation.Serotonin, in stellates, caused a variable response consisting of a hyperpolarization and/or depolarization, associated with a decrease in apparent input resistance, while in non-stellates, only the hyperpolarizing response was observed. In stellates, serotonin increased the frequency of subthreshold oscillations from 8.5 to 14.0 Hz. In non-stellates, serotonin did not affect spike-train adaptation nor the slow afterhyperpolarization following the train of spikes while it reduced both in stellates.These results attest to the presence, in layer II of the medial entorhinal cortex, of two parallel information processing channels, both projecting to the hippocampal formation, and differentially modulated by the cholinergic and serotoninergic systems. One of these, the stellate channel, is endowed with robust rhythmic properties whose fundamental frequency can vary widely, depending on the relative tone of these two major neurotransmitter systems

The Treatment of Brain AVMs Study (TOBAS): an all-inclusive framework to integrate clinical care and research

International audienc

Surgical treatment of brain arteriovenous malformations: clinical outcomes of patients included in the registry of a pragmatic randomized trial

International audienceOBJECTIVE The Treatment of Brain Arteriovenous Malformations Study (TOBAS) is a pragmatic study that includes 2 randomized trials and registries of treated or conservatively managed patients. The authors report the results of the surgical registry. METHODS TOBAS patients are managed according to an algorithm that combines clinical judgment and randomized allocation. For patients considered for curative treatment, clinicians selected from surgery, endovascular therapy, or radiation therapy as the primary curative method, and whether observation was a reasonable alternative. When surgery was selected and observation was deemed unreasonable, the patient was not included in the randomized controlled trial but placed in the surgical registry. The primary outcome of the trial was mRS score > 2 at 10 years (at last follow-up for the current report). Secondary outcomes include angiographic results, perioperative serious adverse events, and permanent treatment-related complications leading to mRS score > 2. RESULTS From June 2014 to May 2021, 1010 patients were recruited at 30 TOBAS centers. Surgery was selected for 229/512 patients (44%) considered for curative treatment; 77 (34%) were included in the surgery versus observation randomized trial and 152 (66%) were placed in the surgical registry. Surgical registry patients had 124/152 (82%) ruptured and 28/152 (18%) unruptured arteriovenous malformations (AVMs), with the majority categorized as low-grade Spetzler-Martin grade I–II AVM (118/152 [78%]). Thirteen patients were excluded, leaving 139 patients for analysis. Embolization was performed prior to surgery in 78/139 (56%) patients. Surgical angiographic cure was obtained in 123/139 all-grade (89%, 95% CI 82%–93%) and 105/110 low-grade (95%, 95% CI 90%–98%) AVM patients. At the mean follow-up of 18.1 months, 16 patients (12%, 95% CI 7%–18%) had reached the primary safety outcome of mRS score > 2, including 11/16 who had a baseline mRS score ≥ 3 due to previous AVM rupture. Serious adverse events occurred in 29 patients (21%, 95% CI 15%–28%). Permanent treatment-related complications leading to mRS score > 2 occurred in 6/139 patients (4%, 95% CI 2%–9%), 5 (83%) of whom had complications due to preoperative embolization. CONCLUSIONS The surgical treatment of brain AVMs in the TOBAS registry was curative in 88% of patients. The participation of more patients, surgeons, and centers in randomized trials is needed to definitively establish the role of surgery in the treatment of unruptured brain AVMs. Clinical trial registration no.: NCT02098252 ( ClinicalTrials.gov

Patient Selection in a Pragmatic Study on the Management of Patients with Brain Arteriovenous Malformations

The Treatment of Brain Arteriovenous Malformations Study (TOBAS) is an all-inclusive pragmatic study comprising 2 randomized clinical trials (RCTs). Patients excluded from the RCTs are followed in parallel treatment and observation registries, allowing a comparison between RCT and registry patients