High and low frequency anterior nucleus of thalamus deep brain stimulation: Impact on memory and mood in five patients with treatment resistant temporal lobe epilepsy.

High frequency anterior nucleus of the thalamus deep brain stimulation (ANT DBS) is an established therapy for treatment resistant focal epilepsies. Although high frequency-ANT DBS is well tolerated, patients are rarely seizure free and the efficacy of other DBS parameters and their impact on comorbidities of epilepsy such as depression and memory dysfunction remain unclear. The purpose of this study was to assess the impact of low vs high frequency ANT DBS on verbal memory and self-reported anxiety and depression symptoms. Five patients with treatment resistant temporal lobe epilepsy were implanted with an investigational brain stimulation and sensing device capable of ANT DBS and ambulatory intracranial electroencephalographic (iEEG) monitoring, enabling long-term detection of electrographic seizures. While patients received therapeutic high frequency (100 and 145 Hz continuous and cycling) and low frequency (2 and 7 Hz continuous) stimulation, they completed weekly free recall verbal memory tasks and thrice weekly self-reports of anxiety and depression symptom severity. Mixed effects models were then used to evaluate associations between memory scores, anxiety and depression self-reports, seizure counts, and stimulation frequency. Memory score was significantly associated with stimulation frequency, with higher free recall verbal memory scores during low frequency ANT DBS. Self-reported anxiety and depression symptom severity was not significantly associated with stimulation frequency. These findings suggest the choice of ANT DBS stimulation parameter may impact patients' cognitive function, independently of its impact on seizure rates.

Hotspot of human verbal memory encoding in the left anterior prefrontal cortex.

BACKGROUND: Treating memory and cognitive deficits requires knowledge about anatomical sites and neural activities to be targeted with particular therapies. Emerging technologies for local brain stimulation offer attractive therapeutic options but need to be applied to target specific neural activities, at distinct times, and in specific brain regions that are critical for memory formation. METHODS: The areas that are critical for successful encoding of verbal memory as well as the underlying neural activities were determined directly in the human brain with intracranial electrophysiological recordings in epilepsy patients. We recorded a broad range of spectral activities across the cortex of 135 patients as they memorised word lists for subsequent free recall. FINDINGS: The greatest differences in the spectral power between encoding subsequently recalled and forgotten words were found in low theta frequency (3-5 Hz) activities of the left anterior prefrontal cortex. This subsequent memory effect was proportionally greater in the lower frequency bands and in the more anterior cortical regions. We found the peak of this memory signal in a distinct part of the prefrontal cortex at the junction between the Broca's area and the frontal pole. The memory effect in this confined area was significantly higher (Tukey-Kramer test, p<0.05) than in other anatomically distinct areas. INTERPRETATION: Our results suggest a focal hotspot of human verbal memory encoding located in the higher-order processing region of the prefrontal cortex, which presents a prospective target for modulating cognitive functions in the human patients. The memory effect provides an electrophysiological biomarker of low frequency neural activities, at distinct times of memory encoding, and in one hotspot location in the human brain. FUNDING: Open-access datasets were originally collected as part of a BRAIN Initiative project called Restoring Active Memory (RAM) funded by the Defence Advanced Research Project Agency (DARPA). CT, ML, MTK and this research were supported from the First Team grant of the Foundation for Polish Science co-financed by the European Union under the European Regional Development Fund.

Distributed brain co-processor for tracking spikes, seizures and behaviour during electrical brain stimulation.

Early implantable epilepsy therapy devices provided open-loop electrical stimulation without brain sensing, computing, or an interface for synchronized behavioural inputs from patients. Recent epilepsy stimulation devices provide brain sensing but have not yet developed analytics for accurately tracking and quantifying behaviour and seizures. Here we describe a distributed brain co-processor providing an intuitive bi-directional interface between patient, implanted neural stimulation and sensing device, and local and distributed computing resources. Automated analysis of continuous streaming electrophysiology is synchronized with patient reports using a handheld device and integrated with distributed cloud computing resources for quantifying seizures, interictal epileptiform spikes and patient symptoms during therapeutic electrical brain stimulation. The classification algorithms for interictal epileptiform spikes and seizures were developed and parameterized using long-term ambulatory data from nine humans and eight canines with epilepsy, and then implemented prospectively in out-of-sample testing in two pet canines and four humans with drug-resistant epilepsy living in their natural environments. Accurate seizure diaries are needed as the primary clinical outcome measure of epilepsy therapy and to guide brain-stimulation optimization. The brain co-processor system described here enables tracking interictal epileptiform spikes, seizures and correlation with patient behavioural reports. In the future, correlation of spikes and seizures with behaviour will allow more detailed investigation of the clinical impact of spikes and seizures on patients.

Intracranial electrophysiological recordings from the human brain during memory tasks with pupillometry.

Data comprise intracranial EEG (iEEG) brain activity represented by stereo EEG (sEEG) signals, recorded from over 100 electrode channels implanted in any one patient across various brain regions. The iEEG signals were recorded in epilepsy patients (N = 10) undergoing invasive monitoring and localization of seizures when they were performing a battery of four memory tasks lasting approx. 1 hour in total. Gaze tracking on the task computer screen with estimating the pupil size was also recorded together with behavioral performance. Each dataset comes from one patient with anatomical localization of each electrode contact. Metadata contains labels for the recording channels with behavioral events marked from all tasks, including timing of correct and incorrect vocalization of the remembered stimuli. The iEEG and the pupillometric signals are saved in BIDS data structure to facilitate efficient data sharing and analysis.

Independent dynamics of low, intermediate, and high frequency spectral intracranial EEG activities during human memory formation.

A wide spectrum of brain rhythms are engaged throughout the human cortex in cognitive functions. How the rhythms of various frequency ranges are coordinated across the space of the human cortex and time of memory processing is inconclusive. They can either be coordinated together across the frequency spectrum at the same cortical site and time or induced independently in particular bands. We used a large dataset of human intracranial electroencephalography (iEEG) to parse the spatiotemporal dynamics of spectral activities induced during formation of verbal memories. Encoding of words for subsequent free recall activated low frequency theta, intermediate frequency alpha and beta, and high frequency gamma power in a mosaic pattern of discrete cortical sites. A majority of the cortical sites recorded activity in only one of these frequencies, except for the visual cortex where spectral power was induced across multiple bands. Each frequency band showed characteristic dynamics of the induced power specific to cortical area and hemisphere. The power of the low, intermediate, and high frequency activities propagated in independent sequences across the visual, temporal and prefrontal cortical areas throughout subsequent phases of memory encoding. Our results provide a holistic, simplified model of the spectral activities engaged in the formation of human memory, suggesting an anatomically and temporally distributed mosaic of coordinated brain rhythms.

Anterior nucleus of the thalamus seizure detection in ambulatory humans.

There is a paucity of data to guide anterior nucleus of the thalamus (ANT) deep brain stimulation (DBS) with brain sensing. The clinical Medtronic Percept DBS device provides constrained brain sensing power within a frequency band (power-in-band [PIB]), recorded in 10-min averaged increments. Here, four patients with temporal lobe epilepsy were implanted with an investigational device providing full bandwidth chronic intracranial electroencephalogram (cEEG) from bilateral ANT and hippocampus (Hc). ANT PIB-based seizure detection was assessed. Detection parameters were cEEG PIB center frequency, bandwidth, and epoch duration. Performance was evaluated against epileptologist-confirmed Hc seizures, and assessed by area under the precision-recall curve (PR-AUC). Data included 99 days of cEEG, and 20, 278, 3, and 18 Hc seizures for Subjects 1-4. The best detector had 7-Hz center frequency, 5-Hz band width, and 10-s epoch duration (group PR-AUC = .90), with 75% sensitivity and .38 false alarms per day for Subject 1, and 100% and .0 for Subjects 3 and 4. Hc seizures in Subject 2 did not propagate to ANT. The relative change of ANT PIB was maximal ipsilateral to seizure onset for all detected seizures. Chronic ANT and Hc recordings provide direct guidance for ANT DBS with brain sensing.

Invasive Electrophysiology for Circuit Discovery and Study of Comorbid Psychiatric Disorders in Patients With Epilepsy: Challenges, Opportunities, and Novel Technologies.

Intracranial electroencephalographic (iEEG) recordings from patients with epilepsy provide distinct opportunities and novel data for the study of co-occurring psychiatric disorders. Comorbid psychiatric disorders are very common in drug-resistant epilepsy and their added complexity warrants careful consideration. In this review, we first discuss psychiatric comorbidities and symptoms in patients with epilepsy. We describe how epilepsy can potentially impact patient presentation and how these factors can be addressed in the experimental designs of studies focused on the electrophysiologic correlates of mood. Second, we review emerging technologies to integrate long-term iEEG recording with dense behavioral tracking in naturalistic environments. Third, we explore questions on how best to address the intersection between epilepsy and psychiatric comorbidities. Advances in ambulatory iEEG and long-term behavioral monitoring technologies will be instrumental in studying the intersection of seizures, epilepsy, psychiatric comorbidities, and their underlying circuitry.

A Low-Cost Humidity Control System to Protect Microscopes in a Tropical Climate.

Introduction: A clean and functional microscope is necessary for accurate diagnosis of infectious diseases. In tropical climates, high humidity levels and improper storage conditions allow for the accumulation of debris and fungus on the optical components of diagnostic equipment, such as microscopes. Objective: Our objective was to develop and implement a low-cost, sustainable, easy to manage, low-maintenance, passive humidity control chamber to both reduce debris accumulation and microbial growth onto the optical components of microscopes. Methods: Constructed from easily-sourced and locally available materials, the cost of each humidity control chamber is approximately $2.35 USD. Relative humidity levels were recorded every 30 minutes over a period of 10 weeks from two chambers deployed at the Belize Vector and Ecology Center and the University of Belize. Results: The humidity control chamber deployed at the University of Belize maintained internal relative humidity at an average of 35.3% (SD = 4.2%) over 10 weeks, while the average external relative humidity was 86.4% (SD = 12.4%). The humidity control chamber deployed at the Belize Vector and Ecology Center effectively maintained internal relative humidity to an average of 54.5% (SD = 9.4%) over 10 weeks, while the average external relative humidity was 86.9% (SD = 12.9%). Conclusions: Control of relative humidity is paramount for the sustainability of medical equipment in tropical climates. The humidity control chambers reduced relative humidity to levels that were not conducive for fungal growth while reducing microscope contamination from external sources. This will likely extend the service life of the microscopes while taking advantage of low-cost, locally sourced components.