Overlapping and distinct phenotypic profiles in Alzheimer's disease and late onset epilepsy: a biologically-based approach.

Due to shared hippocampal dysfunction, patients with Alzheimer's dementia and late-onset epilepsy (LOE) report memory decline. Multiple studies have described the epidemiological, pathological, neurophysiological, and behavioral overlap between Alzheimer's Disease and LOE, implying a bi-directional relationship. We describe the neurobiological decline occurring at different spatial in AD and LOE patients, which may explain why their phenotypes overlap and differ. We provide suggestions for clinical recognition of dual presentation and novel approaches for behavioral testing that reflect an "inside-out," or biologically-based approach to testing memory. New memory and language assessments could detect-and treat-memory impairment in AD and LOE at an earlier, actionable stage.

A consensus statement on detection of hippocampal sharp wave ripples and differentiation from other fast oscillations.

Decades of rodent research have established the role of hippocampal sharp wave ripples (SPW-Rs) in consolidating and guiding experience. More recently, intracranial recordings in humans have suggested their role in episodic and semantic memory. Yet, common standards for recording, detection, and reporting do not exist. Here, we outline the methodological challenges involved in detecting ripple events and offer practical recommendations to improve separation from other high-frequency oscillations. We argue that shared experimental, detection, and reporting standards will provide a solid foundation for future translational discovery.

Time-dependent transformations of memory representations differ along the long axis of the hippocampus.

Research has shown that sleep is beneficial for the long-term retention of memories. According to theories of memory consolidation, memories are gradually reorganized, becoming supported by widespread, distributed cortical networks, particularly during postencoding periods of sleep. However, the effects of sleep on the organization of memories in the hippocampus itself remains less clear. In a 3-d study, participants encoded separate lists of word-image pairs differing in their opportunity for sleep-dependent consolidation. Pairs were initially studied either before or after an overnight sleep period, and were then restudied in a functional magnetic resonance imaging (fMRI) scan session. We used multivariate pattern similarity analyses to examine fine-grained effects of consolidation on memory representations in the hippocampus. We provide evidence for a dissociation along the long axis of the hippocampus that emerges with consolidation, such that representational patterns for object-word memories initially formed prior to sleep become differentiated in anterior hippocampus and more similar, or overlapping, in posterior hippocampus. Differentiation in anterior hippocampal representations correlated with subsequent behavioral performance. Furthermore, representational overlap in posterior hippocampus correlated with the duration of intervening slow wave sleep. Together, these results demonstrate that sleep-dependent consolidation promotes the reorganization of memory traces along the long axis of the hippocampus.

Sounds of seizures.

PURPOSE: A phase I feasibility study to determine the accuracy of identifying seizures based on audio recordings. METHODS: We systematically generated 166 audio clips of 30 s duration from 83 patients admitted to an epilepsy monitoring unit between 1/2015 and 12/2016, with one clip during a seizure period and one clip during a non-seizure control period for each patient. Five epileptologists performed a blinded review of the audio clips and rated whether a seizure occurred or not, and indicated the confidence level (low or high) of their rating. The accuracy of individual and consensus ratings were calculated. RESULTS: The overall performance of the consensus rating between the five epileptologists showed a positive predictive value (PPV) of 0.91 and a negative predictive value (NPV) of 0.66. The performance improved when confidence was high (PPV of 0.96, NPV of 0.70). The agreement between the epileptologists was moderate with a kappa of 0.584. Hyperkinetic (PPV 0.92, NPV 0.86) and tonic-clonic (PPV and NPV 1.00) seizures were most accurately identified. Seizures with automatisms only and non-motor seizures could not be accurately identified. Specific seizure-related sounds associated with accurate identification included disordered breathing (PPV and NPV 1.00), rhythmic sounds (PPV 0.93, NPV 0.80), and ictal vocalizations (PPV 1.00, NPV 0.97). CONCLUSION: This phase I feasibility study shows that epileptologists are able to accurately identify certain seizure types from audio recordings when the seizures produce sounds. This provides guidance for the development of audio-based seizure detection devices and demonstrate which seizure types could potentially be detected.

Mesial temporal resection following long-term ambulatory intracranial EEG monitoring with a direct brain-responsive neurostimulation system.

OBJECTIVE: To describe seizure outcomes in patients with medically refractory epilepsy who had evidence of bilateral mesial temporal lobe (MTL) seizure onsets and underwent MTL resection based on chronic ambulatory intracranial EEG (ICEEG) data from a direct brain-responsive neurostimulator (RNS) system. METHODS: We retrospectively identified all patients at 17 epilepsy centers with MTL epilepsy who were treated with the RNS System using bilateral MTL leads, and in whom an MTL resection was subsequently performed. Presumed lateralization based on routine presurgical approaches was compared to lateralization determined by RNS System chronic ambulatory ICEEG recordings. The primary outcome was frequency of disabling seizures at last 3-month follow-up after MTL resection compared to seizure frequency 3 months before MTL resection. RESULTS: We identified 157 patients treated with the RNS System with bilateral MTL leads due to presumed bitemporal epilepsy. Twenty-five patients (16%) subsequently had an MTL resection informed by chronic ambulatory ICEEG (mean = 42 months ICEEG); follow-up was available for 24 patients. After MTL resection, the median reduction in disabling seizures at last follow-up was 100% (mean: 94%; range: 50%-100%). Nine patients (38%) had exclusively unilateral electrographic seizures recorded by chronic ambulatory ICEEG and all were seizure-free at last follow-up after MTL resection; eight of nine continued RNS System treatment. Fifteen patients (62%) had bilateral MTL electrographic seizures, had an MTL resection on the more active side, continued RNS System treatment, and achieved a median clinical seizure reduction of 100% (mean: 90%; range: 50%-100%) at last follow-up, with eight of fifteen seizure-free. For those with more than 1 year of follow-up (N = 21), 15 patients (71%) were seizure-free during the most recent year, including all eight patients with unilateral onsets and 7 of 13 patients (54%) with bilateral onsets. SIGNIFICANCE: Chronic ambulatory ICEEG data provide information about lateralization of MTL seizures and can identify additional patients who may benefit from MTL resection.

Temporal lobe surgery and memory: Lessons, risks, and opportunities.

Careful study of the clinical outcomes of temporal lobe epilepsy (TLE) surgery has greatly advanced our knowledge of the neuroanatomy of human memory. After early cases resulted in profound amnesia, the critical role of the hippocampus and associated medial temporal lobe (MTL) structures to declarative memory became evident. Surgical approaches quickly changed to become unilateral and later, to be more precise, potentially reducing cognitive morbidity. Neuropsychological studies following unilateral temporal lobe resection (TLR) have challenged early models, which simplified the lateralization of verbal and visual memory function. Diagnostic tests, including intracarotid sodium amobarbital procedure (WADA), structural magnetic resonance imaging (MRI), and functional neuroimaging (functional MRI (fMRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT)), can more accurately lateralize and localize epileptogenic cortex and predict memory outcomes from surgery. Longitudinal studies have shown that memory may even improve in seizure-free patients. From 70 years of experience with epilepsy surgery, we now have a richer understanding of the clinical, neuroimaging, and surgical predictors of memory decline-and improvement-after TLR. "Special Issue: Epilepsy & Behavior's 20th Anniversary".

Cortical gray-white matter blurring and declarative memory impairment in MRI-negative temporal lobe epilepsy.

Magnetic resonance imaging (MRI)-negative temporal lobe epilepsy (TLE) may be a distinct syndrome from TLE with mesial temporal sclerosis (TLE-MTS). Imaging and neuropsychological features of TLE-MTS are well-known; yet, these features are only beginning to be described in MRI-negative TLE. This study examined whether a quantitative measure of cortical gray and white matter blurring (GWB) was elevated in the temporal lobes ipsilateral to the seizure onset zone of individuals with MRI-negative TLE relative to TLE-MTS and healthy controls (HCs) and whether GWB elevations were associated with neuropsychological comorbidity. Gray-white matter blurring from 34 cortical regions and hippocampal volumes were quantified and compared across 28 people with MRI-negative TLE, 15 people with TLE-MTS, and 51 HCs. Declarative memory was assessed with standard neuropsychological tests and the intracarotid amobarbital procedure (IAP). In the group with MRI-negative TLE (left and right onsets combined), hippocampal volumes were within normal range but GWB was elevated, relative to HCs, across several mesial and lateral temporal lobe regions ipsilateral to the seizure onset zone. Gray-white matter blurring did not differ between the groups with TLE-MTS and HC or between the groups with TLE-MTS and MRI-negative TLE. The group with MRI-negative TLE could not be distinguished from the group with TLE-MTS on any of the standard neuropsychological tests; however, ipsilateral hippocampal volumes and IAP memory scores were lower in the group with TLE-MTS than in the group with MRI-negative TLE. The group with left MRI-negative TLE had lower general cognitive abilities and verbal fluency relative to the HC group, which adds to the characterization of neuropsychological comorbidities in left MRI-negative TLE. In addition, ipsilateral IAP memory performance was reduced relative to contralateral memory performance in MRI-negative TLE, indicating some degree of ipsilateral memory dysfunction. There was no relationship between hippocampal volume and IAP memory scores in MRI-negative TLE; however, decreased ipsilateral IAP memory scores were correlated with elevated GWB in the ipsilateral superior temporal sulcus of people with left MRI-negative TLE. In sum, GWB elevations in the ipsilateral temporal lobe of people with MRI-negative TLE suggest that GWB may serve as a marker for reduced structural integrity in regions in or near the seizure onset zone. Although mesial temporal abnormalities might be the major driver of memory dysfunction in TLE-MTS, a loss of structural integrity in lateral temporal lobe regions may contribute to IAP memory dysfunction in MRI-negative TLE.

A deep learning approach for real-time detection of sleep spindles.

OBJECTIVE: Sleep spindles have been implicated in memory consolidation and synaptic plasticity during NREM sleep. Detection accuracy and latency in automatic spindle detection are critical for real-time applications. APPROACH: Here we propose a novel deep learning strategy (SpindleNet) to detect sleep spindles based on a single EEG channel. While the majority of spindle detection methods are used for off-line applications, our method is well suited for online applications. MAIN RESULTS: Compared with other spindle detection methods, SpindleNet achieves superior detection accuracy and speed, as demonstrated in two publicly available expert-validated EEG sleep spindle datasets. Our real-time detection of spindle onset achieves detection latencies of 150-350 ms (~two-three spindle cycles) and retains excellent performance under low EEG sampling frequencies and low signal-to-noise ratios. SpindleNet has good generalization across different sleep datasets from various subject groups of different ages and species. SIGNIFICANCE: SpindleNet is ultra-fast and scalable to multichannel EEG recordings, with an accuracy level comparable to human experts, making it appealing for long-term sleep monitoring and closed-loop neuroscience experiments.

Measurements and models of electric fields in the in vivo human brain during transcranial electric stimulation.

Transcranial electric stimulation aims to stimulate the brain by applying weak electrical currents at the scalp. However, the magnitude and spatial distribution of electric fields in the human brain are unknown. We measured electric potentials intracranially in ten epilepsy patients and estimated electric fields across the entire brain by leveraging calibrated current-flow models. When stimulating at 2 mA, cortical electric fields reach 0.8 V/m, the lower limit of effectiveness in animal studies. When individual whole-head anatomy is considered, the predicted electric field magnitudes correlate with the recorded values in cortical (r = 0.86) and depth (r = 0.88) electrodes. Accurate models require adjustment of tissue conductivity values reported in the literature, but accuracy is not improved when incorporating white matter anisotropy or different skull compartments. This is the first study to validate and calibrate current-flow models with in vivo intracranial recordings in humans, providing a solid foundation to target stimulation and interpret clinical trials.

Clinical predictors of frequent patient telephone calls in Parkinson's disease.

BACKGROUND: Patient telephone calls are a major form of unreimbursed healthcare utilization in Parkinson's disease (PD), yet little is known about potential risk factors for frequent calling behavior. METHODS: Prospective cohort study of 175 non-demented outpatients with PD. Our primary outcome measure was the frequency of patient telephone calls over a three-month period relative to baseline demographics, State-Trait Anxiety Index (STAI) and Beck Anxiety Inventory (BAI) scores, Unified Parkinson's Disease Rating Scale (UPDRS) motor scores, and medication use. Based on the median call rate (1 call/3 months), subjects were dichotomized into frequent (≥2 calls) and infrequent (≤1 call) caller groups. RESULTS: A total of 297 calls were received, of which 264 (89%) were from the frequent caller group (n = 63 subjects), and only 33 (11%) were from the infrequent caller group (n = 112 subjects). Compared with calls from infrequent callers, those from frequent callers more commonly related to somatic symptoms of PD (46.8% vs. 19.4%, p = 0.007). In multivariate logistic regression analysis, independent predictors of frequent calling were: anxiety (STAI ≥55; adjusted OR = 2.62, p = 0.02), sleep disorders (adjusted OR = 2.36, p = 0.02), dyskinesias (adjusted OR = 3.07, p = 0.03), and dopamine agonist use (adjusted OR = 2.27, p = 0.03). Baseline demographics, UPDRS motor scores, and levodopa use were similar in both groups. CONCLUSIONS: Frequent patient telephone calls in PD are independently associated with anxiety, sleep disorders, dyskinesias, and dopamine agonist use, with a minority of patients accounting for the majority of calls. Aggressive treatment of these non-motor symptoms and motor complications might potentially reduce the burden of patient telephone calls in PD.

A case-controlled study of altered visual art production in Alzheimer's and FTLD.

OBJECTIVE: To characterize dementia-induced changes in visual art production. BACKGROUND: Although case studies show altered visual artistic production in some patients with neurodegenerative disease, no case-controlled studies have quantified this phenomenon across groups of patients. METHOD: Forty-nine subjects [18 Alzheimer disease, 9 frontotemporal dementia (FTD), 9 semantic dementia (SD), 15 healthy older controls (NC)] underwent formal neuropsychologic testing of visuospatial, perceptual, and creative functioning, and produced 4 drawings. Subjective elements of drawings were rated by an expert panel that was blind to diagnosis. RESULTS: Despite equal performance on standard visuospatial tests, dementia groups produced distinct patterns of artistic features that were significantly different from NCs. FTDs used more disordered composition and less active mark-making (P<0.05). Both FTDs and SDs drawings were rated as more bizarre and demonstrated more facial distortion than NCs (P<0.05). Also, SDs drastically failed a standardized test of divergent creativity. Alzheimer disease artwork was more similar to controls than to FTDs or SDs, but showed a more muted color palette (P<0.05) and trends toward including fewer details, less ordered compositions, and occasional facial distortion. CONCLUSIONS: These group differences in artistic style likely resulted from disease-specific focal neurodegeneration, and elucidate the contributions of particular brain regions to the production of visual art.