Our results suggest that seizure generation and spread during spontaneous mesial-temporal LVF onset events in humans may result from increased inhibitory neuron firing that spawns a subsequent increase in excitatory neuron firing and seizure evolution. Ann Neurol 2018;84:588-600.

Animal studies have shown that substantia nigra (SN) dopaminergic (DA) neurons strengthen action-reward associations during reinforcement learning, but their role in human learning is not known. Here, we applied microstimulation in the SN of 11 patients undergoing deep brain stimulation surgery for the treatment of Parkinson's disease as they performed a two-alternative probability learning task in which rewards were contingent on stimuli, rather than actions. Subjects demonstrated decreased learning from reward trials that were accompanied by phasic SN microstimulation compared with reward trials without stimulation. Subjects who showed large decreases in learning also showed an increased bias toward repeating actions after stimulation trials; therefore, stimulation may have decreased learning by strengthening action-reward associations rather than stimulus-reward associations. Our findings build on previous studies implicating SN DA neurons in preferentially strengthening action-reward associations during reinforcement learning.

Objective The authors report methods developed for the implantation of micro-wire bundles into mesial temporal lobe structures and subsequent single neuron recording in epileptic patients undergoing in-patient diagnostic monitoring. This is done with the intention of lowering the perceived barriers to routine single neuron recording from deep brain structures in the clinical setting. Approach Over a 15 month period, 11 patients were implanted with platinum micro-wire bundles into mesial temporal structures. Protocols were developed for A) monitoring electrode integrity through impedance testing, B) ensuring continuous 24-7 recording, C) localizing micro-wire position and “splay” pattern and D) monitoring grounding and referencing to maintain the quality of recordings. Main Result Five common modes of failure were identified: 1) broken micro-wires from acute tensile force, 2) broken micro-wires from cyclic fatigue at stress points, 3) poor in-vivo micro-electrode separation, 4) motion artifact and 5) deteriorating ground connection and subsequent drop in common mode noise rejection. Single neurons have been observed up to 14 days post implantation and on 40% of micro-wires. Significance Long-term success requires detailed review of each implant by both the clinical and research teams to identify failure modes, and appropriate refinement of techniques while moving forward. This approach leads to reliable unit recordings without prolonging operative times, which will help increase the availability and clinical viability of human single neuron data.

Spreading depression (SD) is an intense and prolonged depolarization in the central nervous systems from insect to man. It is implicated in neurological disorders such as migraine and brain injury. Here, using an in vivo mouse model of focal neocortical seizures, we show that SD may be a fundamental defense against seizures. Seizures induced by topical 4-aminopyridine, penicillin or bicuculline, or systemic kainic acid, culminated in SDs at a variable rate. Greater seizure power and area of recruitment predicted SD. Once triggered, SD immediately suppressed the seizure. Optogenetic or KCl-induced SDs had similar antiseizure effect sustained for more than 30 min. Conversely, pharmacologically inhibiting SD occurrence during a focal seizure facilitated seizure generalization. Altogether, our data indicate that seizures trigger SD, which then terminates the seizure and prevents its generalization.

Summary Objective To gain understanding of the neuronal mechanisms underlying regional seizure spread, the impact of regional synchrony between seizure focus and downstream networks on neuronal activity during the transition to seizure in those downstream networks was assessed. Methods Seven patients undergoing diagnostic intracranial electroencephalographic studies for surgical resection of epileptogenic regions were implanted with subdural clinical electrodes into the cortex (site of seizure initiation) and mesial temporal lobe (MTL) structures (downstream) as well as microwires into MTL. Neural activity was recorded (24/7) in parallel with the clinical intracranial electroencephalogram recordings for the duration of the patient's diagnostic stay. Changes in (1) regional synchrony (ie, coherence) between the presumptive neocortical seizure focus and MTL, (2) local synchrony between MTL neurons and their local field potential, and (3) neuronal firing rates within MTL in the time leading up to seizure were examined to study the mechanisms underlying seizure spread. Results In seizures of neocortical origin, an increase in regional synchrony preceded the spread of seizures into MTL (predominantly hippocampal). Within frequencies similar to those of regional synchrony, MTL networks showed an increase in unit‐field coherence and a decrease in neuronal firing rate, specifically for inhibitory interneuron populations but not pyramidal cell populations. Significance These results suggest a mechanism of spreading seizures whereby the seizure focus first synchronizes local field potentials in downstream networks to the seizure activity. This change in local field coherence modifies the activity of interneuron populations in these downstream networks, which leads to the attenuation of interneuronal firing rate, effectively shutting down local interneuron populations prior to the spread of seizure. Therefore, regional synchrony may influence the failure of downstream interneurons to prevent the spread of the seizures during generalization.

Objective Test the efficacy of Poloxamer P188 to reduce cell death & immune response associated with mechanical trauma to cells during implantation of a chronic recording electrode. Approach Ceramic multi-site recording electrodes were implanted bilaterally into 15 adult male Long Evans rats. One of each pair was randomly assigned to receive a coating of Poloxamer while the other was treated with saline. The extent of neuron loss, and glial cell recruitment was characterized at 2, 4 and 6 weeks post implantation by stereologic analysis. Main Result At 2 and 4 weeks post implantation, Poloxamer coated implants showed significantly fewer glial cells and more neurons in the peri-electrode space than controls; however this significance was lost by 6 weeks. Significance These findings are the first tosuggest that Poloxamer has neuroprotective effects in-vivo, however at a fixed loading dose, these effects are limited to approximately 1 month post implantation.

BackgroundElectrode contact locations are important when planning tailored brain surgeries to identify pathological tissue targeted for resection and conversely avoid eloquent tissue. Current methods employ trained experts to use neuroimaging scans that are manually co-registered and localize contacts within ~2 mm. Yet, the state of the art is limited by either the expertise needed for each type of intracranial electrode or the inter-modality co-registration which increases error, reducing accuracy. Patients often have a variety of strips, grids and depths implanted; therefore, it is cumbersome and time-consuming to apply separate localization methods for each type of electrode, requiring expertise across different approaches.New methodTo overcome these limitations, a computational method was developed by separately registering an implant magnetic resonance image (MRI) and implant computed tomography image (CT) to the pre-implant MRI, then calculating an iterative closest point transformation using the contact locations extracted from the signal voids as ground truth.ResultsThe implant MRI is robustly co-registered to the pre-implant MRI with a boundary-based registration algorithm. By extracting and utilizing ‘signal voids’ (the metal induced artifacts from the implant MRI) as electrode fiducials, the novel method is an all-in-one approach for all types of intracranial electrodes while eliminating inter-modality co-registration errors.Comparison with existing methodsThe distance between each electrode centroid and the brain's surface was measured, for the proposed method as well as the state of the art method using two available software packages, SPM 12 and FSL 4.1. The method presented here achieves the smallest distances to the brain's surface for all strip and grid type electrodes, i.e. contacts designed to rest directly on the brain surface.ConclusionWe use one of the largest reported sample sizes in localization studies to validate this novel method for localizing different kinds of intracranial electrodes including grids, strips and depth electrodes.

Purpose of reviewCardiovascular disease (CVD) is the leading cause of death in women. Women with history of adverse pregnancy outcomes (APOs) have approximately two-fold risk of future CVD, but until recently the association with future heart failure (HF) was unclear. Here, we summarize evidence for associations of APOs with HF, potential underlying mechanisms, and future directions for clinical translation.Recent findingsWomen with history of hypertensive disorders of pregnancy (HDPs) have roughly two-fold risk of future HF compared with other parous women even after accounting for interval development of coronary artery disease. The HDPs portend heightened risk of HF with both reduced and preserved ejection fraction. Gestational diabetes mellitus (GDM) and other APOs such as preterm delivery, small-for-gestational-age delivery, and placental abruption may also confer additional risk for HF development. Possible underlying mechanisms linking APOs to HF include shared upstream risk factors and genetics, accelerated development of cardiometabolic risk factors postpartum, persistent endothelial and microvascular dysfunction, and impaired natriuretic peptide signaling.SummaryHistory of APOs, including HDPs and GDM, confer increased risk for development of HF years after delivery. Further research is needed to define strategies to optimize prepregnancy and postpartum cardiovascular health toward HF prevention.