Individualizing therapies with responsive epilepsy neurostimulation — A mirtazapine case study of hippocampal excitability

AbstractObjectivesThis study aimed to investigate mirtazapine-induced changes in responsive neurostimulator (RNS) recordings in a patient with epilepsy.Materials and methodsCortical detection/stimulation counts from an RNS implanted in a patient with bitemporal epilepsy were matched to mirtazapine use to see if that drug altered hippocampal excitability.ResultsMirtazapine decreased hippocampal stability; when mirtazapine was held after a washout period, DSC counts declined, but when it was retrialed, DSC counts increased. Responsive epilepsy neurostimulator system data helped design an optimal and individualized medication regimen for our patient with drug-resistant focal epilepsy.ConclusionsResponsive neurostimulator systems in epilepsy may assess a medication's effect on hippocampal excitability. Mirtazapine worsened hippocampal excitability in a patient with bitemporal epilepsy

Target cell-specific synaptic dynamics of excitatory to inhibitory neuron connections in supragranular layers of human neocortex.

Rodent studies have demonstrated that synaptic dynamics from excitatory to inhibitory neuron types are often dependent on the target cell type. However, these target cell-specific properties have not been well investigated in human cortex, where there are major technical challenges in reliably obtaining healthy tissue, conducting multiple patch-clamp recordings on inhibitory cell types, and identifying those cell types. Here, we take advantage of newly developed methods for human neurosurgical tissue analysis with multiple patch-clamp recordings, post-hoc fluorescent in situ hybridization (FISH), machine learning-based cell type classification and prospective GABAergic AAV-based labeling to investigate synaptic properties between pyramidal neurons and PVALB- vs. SST-positive interneurons. We find that there are robust molecular differences in synapse-associated genes between these neuron types, and that individual presynaptic pyramidal neurons evoke postsynaptic responses with heterogeneous synaptic dynamics in different postsynaptic cell types. Using molecular identification with FISH and classifiers based on transcriptomically identified PVALB neurons analyzed by Patch-seq, we find that PVALB neurons typically show depressing synaptic characteristics, whereas other interneuron types including SST-positive neurons show facilitating characteristics. Together, these data support the existence of target cell-specific synaptic properties in human cortex that are similar to rodent, thereby indicating evolutionary conservation of local circuit connectivity motifs from excitatory to inhibitory neurons and their synaptic dynamics

Lateralization of mesial temporal lobe epilepsy with chronic ambulatory electrocorticography

OBJECTIVE: Patients with suspected mesial temporal lobe (MTL) epilepsy typically undergo inpatient video-electroencephalography (EEG) monitoring with scalp and/or intracranial electrodes for 1 to 2 weeks to localize and lateralize the seizure focus or foci. Chronic ambulatory electrocorticography (ECoG) in patients with MTL epilepsy may provide additional information about seizure lateralization. This analysis describes data obtained from chronic ambulatory ECoG in patients with suspected bilateral MTL epilepsy in order to assess the time required to determine the seizure lateralization and whether this information could influence treatment decisions. METHODS: Ambulatory ECoG was reviewed in patients with suspected bilateral MTL epilepsy who were among a larger cohort with intractable epilepsy participating in a randomized controlled trial of responsive neurostimulation. Subjects were implanted with bilateral MTL leads and a cranially implanted neurostimulator programmed to detect abnormal interictal and ictal ECoG activity. ECoG data stored by the neurostimulator were reviewed to determine the lateralization of electrographic seizures and the interval of time until independent bilateral MTL electrographic seizures were recorded. RESULTS: Eighty-two subjects were implanted with bilateral MTL leads and followed for 4.7 years on average (median 4.9 years). Independent bilateral MTL electrographic seizures were recorded in 84%. The average time to record bilateral electrographic seizures in the ambulatory setting was 41.6 days (median 13 days, range 0-376 days). Sixteen percent had only unilateral electrographic seizures after an average of 4.6 years of recording. SIGNIFICANCE: About one third of the subjects implanted with bilateral MTL electrodes required >1 month of chronic ambulatory ECoG before the first contralateral MTL electrographic seizure was recorded. Some patients with suspected bilateral MTL seizures had only unilateral electrographic seizures. Chronic ambulatory ECoG in patients with suspected bilateral MTL seizures provides data in a naturalistic setting, may complement data from inpatient video-EEG monitoring, and can contribute to treatment decisions

Functional enhancer elements drive subclass-selective expression from mouse to primate neocortex

Viral genetic tools to target specific brain cell types in humans and non-genetic model organisms will transform basic neuroscience and targeted gene therapy. Here we used comparative epigenetics to identify thousands of human neuronal subclass-specific putative enhancers to regulate viral tools, and 34% of these were conserved in mouse. We established an AAV platform to evaluate cellular specificity of functional enhancers by multiplexed fluorescent in situ hybridization (FISH) and single cell RNA sequencing. Initial testing in mouse neocortex yields a functional enhancer discovery success rate of over 30%. We identify enhancers with specificity for excitatory and inhibitory classes and subclasses including PVALB, LAMP5, and VIP/LAMP5 cells, some of which maintain specificity in vivo or ex vivo in monkey and human neocortex. Finally, functional enhancers can be proximal or distal to cellular marker genes, conserved or divergent across species, and could yield brain-wide specificity greater than the most selective marker genes

Deep Brain Stimulation Surgery Using a Mobile Intraoperative CT Scanner.

Introduction Deep brain stimulation (DBS) is widely used for the treatment of movement disorders. Precise placement of electrodes is critical for treatment success. The aim of this study was to analyze the accuracy of the intraoperative computer tomography (CT) images compared to that of a traditional fixed CT for patients undergoing DBS procedures. Methods We retrospectively analyzed the charts from 30 patients who underwent DBS. In group 1, 10 patients underwent electrode implantation surgery using a fixed CT scanner for pre- and post-operative (OP) images. In group 2, 20 patients underwent surgery using an intraoperative CT scanner for pre- and post-operative images, as well as a fixed CT scanner for post-operative images. We compared the average pre-operative localizer box registration error acquired in these two groups. We also analyzed, in group 2, the final electrode position given on each post-operative CT images. We compared the average Euclidean distances between each set of cartesian coordinates to assess target accuracy between both scanning methodologies. Results Thirty patients had ages ranging from 40 to 88 years, with a median of 69 years old. In the 20 patients who utilized an intraoperative CT scanner pre-operatively in group 2, the mean error, given by the Medtronic software (Medtronic Minimally Invasive Therapies, Minneapolis, MN) with the Leksell frame on, was 0.37. For the 10 pre-operative scans with the stealth fixed CT scanner in group 1, the mean error was 0.44 (p = 0.13). In group 2, the average of the 20 Euclidean distances for each target, in those 20 patients who had post-operative images with both scanners, was 0.36. Conclusion We concluded that the accuracy of the intraoperative CT scanner is comparable to the gold standard fixed CT scanner for DBS electrode planning and placement, as well as for positioning confirmation after the electrodes are in place

Mitigating bit flips or single event upsets in epilepsy neurostimulators

Objectives: The objective of this study was to review software errors known as single event upsets (SEUs) or bit flips due to cosmic rays in epilepsy neurostimulators. Materials and methods: A case report of a single event upset or bit flip is discussed; device manufacturers and publicly available data were queried for both incidence and types of error as well as strategies of software error mitigation. Results: Neurostimulators, like other implanted devices such as pacemakers, are prone to single event upsets. Strategies for SEU mitigation are reviewed. Conclusions: Cosmic radiation can threaten RAM and settings of neurostimulators; neuromodulation teams and device designers need to take this threat into account when designing multifunctional neuromodulation systems