Jeffrey M. Chung

Representation of retrieval confidence by single neurons in the human medial temporal lobe

Memory-based decisions are often accompanied by an assessment of choice certainty, but the mechanisms of such confidence judgments remain unknown. We studied the response of 1,065 individual neurons in the human hippocampus and amygdala while neurosurgical patients made memory retrieval decisions together with a confidence judgment. Combining behavioral, neuronal and computational analysis, we identified a population of memory-selective (MS) neurons whose activity signaled stimulus familiarity and confidence, as assessed by subjective report. In contrast, the activity of visually selective (VS) neurons was not sensitive to memory strength. The groups further differed in response latency, tuning and extracellular waveforms. The information provided by MS neurons was sufficient for a race model to decide stimulus familiarity and retrieval confidence. Together, our results indicate a trial-by-trial relationship between a specific group of neurons and declared memory strength in humans. We suggest that VS and MS neurons are a substrate for declarative memories.

Persistently active neurons in human medial frontal and medial temporal lobe support working memory

Persistent neural activity is a putative mechanism for the maintenance of working memories. Persistent activity relies on the activity of a distributed network of areas, but the differential contribution of each area remains unclear. We recorded single neurons in the human medial frontal cortex and medial temporal lobe while subjects held up to three items in memory. We found persistently active neurons in both areas. Persistent activity of hippocampal and amygdala neurons was stimulus-specific, formed stable attractors and was predictive of memory content. Medial frontal cortex persistent activity, on the other hand, was modulated by memory load and task set but was not stimulus-specific. Trial-by-trial variability in persistent activity in both areas was related to memory strength, because it predicted the speed and accuracy by which stimuli were remembered. This work reveals, in humans, direct evidence for a distributed network of persistently active neurons supporting working memory maintenance.

Intravenous Lacosamide in refractory nonconvulsive status epilepticus

BACKGROUND Many patients present with refractory Status epilepticus (SE) despite multiple anti-epileptic drugs (AEDs). Lacosamide (LCM) was recently approved as an adjunct AED for partial-onset seizures. It has unique mechanism of modulating voltage-gated sodium channels by enhancing their slow inactivation. LCM has demonstrated efficacy in animal models of pharmacoresistant seizures. To date, there are isolated anecdotal reports of LCM use in SE. OBJECTIVE To report a single center experience with IV Lacosamide in patients with NCSE. METHODS Pharmacy records were reviewed to identify patients with SE who received IV LCM in our institution. Data on demographics, response to therapy and adverse effects/outcomes were analyzed. All patients had continuous EEG monitoring. RESULTS 10 patients (4 men, 6 women), age 16-90 years with refractory SE were given LCM. Eight patients were in focal non-convulsive SE (NCSE), 2 were in generalized non-convulsive SE. The etiologies included anoxic brain injury, idiopathic, encephalitis, tumor, posterior reversible encephalopathy syndrome (PRES), stroke, and AVM. IV LCM was added after traditional AEDs, including drug-induced coma in some, failed to control the SE. NCSE resolved in 7/10 patients whereas 1/10 patient showed partial response with cessation of NCSE but still frequent electrographic seizures and 2/10 patients were resistant to therapy. CONCLUSIONS LCM is a useful adjunct in refractory NCSE. The IV formulation allows prompt administration in the intensive care unit setting. Response was seen especially in focal SE. Similar to other AEDs, response was poor in patients with postanoxic injury. Our data is limited by the small number of patients. Larger controlled studies are necessary to assess accurately the efficacy of IV LCM as an early treatment of SE.

Acid ceramidase deficiency associated with spinal muscular atrophy with progressive myoclonic epilepsy

Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is an extremely rare disorder related to the lysosomal storage disease, Farber lipogranulomatosis. Both disorders are autosomal recessive conditions caused by mutations in the ASAH1 gene encoding acid ceramidase. Farber disease is associated with joint deformities, lipomatous skin nodules, and often is fatal by 2-3 years of age; while SMA-PME is characterized by childhood-onset motor neuron disease and progressive myoclonic epilepsy. We report a case of SMA-PME with a novel mutation in the ASAH1 gene encoding acid ceramidase. The proband presented with childhood-onset of diffuse muscle atrophy and hypotonia. He also had diffuse weakness with greater proximal than distal involvement. Tongue fasciculations were present and his reflexes were either diminished or absent. He ambulated with an unsteady and hesitant gait. He subsequently developed myoclonic epilepsy along with other associated features including tremor, polymyoclonus, and sensorineural hearing loss. Neurophysiological studies revealed a motor neuron disorder and generalized epilepsy. Exome sequencing analysis identified compound heterozygous variants and biochemical analysis indicated acid ceramidase activity was approximately 12 percent of normal controls. Our proband was phenotypically similar to other cases of SMA-PME, albeit with somewhat lesser severity, slower progression, and greater longevity. As lysosomal disorders are sometimes amendable to early interventions, it is important to make early diagnoses in these cases. The combination of motor neuron disease and progressive myoclonic epilepsy should prompt genetic evaluation of ASAH1.

Seizures in the acute stroke setting

Abstract Stroke is one of the leading causes of long-term disability. One in six people in the world will suffer a stroke in their lifetime, with the annual incidence about 117 per 100 000 person-years in developing countries. It has also been shown to be the cause of 10–15% of epilepsies, more prevalent in patients above 60 years of age. The incidence of early seizures in acute stroke ranges 3–33%, with 50–78% of the seizures occurring within the first 24 hours. Occurrence of seizures within 24 hours of stroke is associated with higher 30-day mortality, which may be a reflection of severe neuronal damage. Alteration in intracellular ion concentrations and hyper-excitability are thought to be etiologies for early seizures in acute stroke, and the increased stress on already vulnerable tissues may result in worsening of stroke symptoms. Early detection of seizures and subsequent effective treatment can prevent additional metabolic burden and damage to the blood–brain barrier, which may improve recovery and overall outcome. Clinical seizures can be recognized readily at bedside and lead to prompt medical intervention. In contrast, electrographic seizures with subtle or no clinical sign and non-convulsive status epilepticus (NCSE) may escape clinical observation and be left untreated. With the use of continuous electroencephalogram monitoring (cEEG), patients with electrographic seizures can be better identified and medically treated more quickly. In addition to electrographic seizures, the presence of isolated and periodic epileptiform patterns on electroencephalogram (EEG) suggests the need for medical treatment since up to 75% of these patients have been found to develop early post-stroke seizures. Newer anti-epileptic medications with intravenous formulation, together with traditional regimen and barbiturate, have shown promise in controlling early post-stroke seizures and possibly improving outcome.

The human amygdala parametrically encodes the intensity of specific facial emotions and their categorical ambiguity

The human amygdala is a key structure for processing emotional facial expressions, but it remains unclear what aspects of emotion are processed. We investigated this question with three different approaches: behavioural analysis of 3 amygdala lesion patients, neuroimaging of 19 healthy adults, and single-neuron recordings in 9 neurosurgical patients. The lesion patients showed a shift in behavioural sensitivity to fear, and amygdala BOLD responses were modulated by both fear and emotion ambiguity (the uncertainty that a facial expression is categorized as fearful or happy). We found two populations of neurons, one whose response correlated with increasing degree of fear, or happiness, and a second whose response primarily decreased as a linear function of emotion ambiguity. Together, our results indicate that the human amygdala processes both the degree of emotion in facial expressions and the categorical ambiguity of the emotion shown and that these two aspects of amygdala processing can be most clearly distinguished at the level of single neurons.

Rethinking clinical language mapping approaches: discordant receptive and expressive hemispheric language dominance in epilepsy surgery candidates.

Summary: Neuroimaging studies have shed light on cortical language organization, with findings implicating the left and right temporal lobes in speech processing converging to a left-dominant pattern. Findings highlight the fact that the state of theoretical language knowledge is ahead of current clinical language mapping methods, motivating a rethinking of these approaches. The authors used magnetoencephalography and multiple tasks in seven candidates for resective epilepsy surgery to investigate language organization. The authors scanned 12 control subjects to investigate the time course of bilateral receptive speech processes. Laterality indices were calculated for left and right hemisphere late fields ∼150 to 400 milliseconds. The authors report that (1) in healthy adults, speech processes activated superior temporal regions bilaterally converging to a left-dominant pattern, (2) in four of six patients, this was reversed, with bilateral processing converging to a right-dominant pattern, and (3) in three of four of these patients, receptive and expressive language processes were laterally discordant. Results provide evidence that receptive and expressive language may have divergent hemispheric dominance. Right-sided receptive language dominance in epilepsy patients emphasizes the need to assess both receptive and expressive language. Findings indicate that it is critical to use multiple tasks tapping separable aspects of language function to provide sensitive and specific estimates of language localization in surgical patients.

Continuous electroencephalogram patterns are suggestive of eventual neurologic outcomes in post-cardiac arrest patients treated with therapeutic hypothermia.

INTRODUCTION Therapeutic hypothermia (TH) after cardiac arrest (CA) resuscitation is the first therapy proven to increase survival to discharge and neurologic recovery. Methods for neurologic and mortality prognostication after CA resuscitation have been called into question because they were developed based on evidence that was developed prior to the advent of TH. This study examines the relationship between electroencephalogram (EEG) patterns and mortality and neurologic outcomes in post-CA patients undergoing TH. METHODS Eighty-three of 732 patients who had continuous EEG (cEEG) monitoring during TH were included. Continuous EEG tracings were classified as isoelectric, low voltage, burst suppression, epileptic form, and diffuse slowing. Primary outcomes are survival to discharge and Cerebral Performance Categories (CPCs) at hospital discharge. RESULTS Among patients with favorable neurologic outcomes (CPC1 and CPC2), the duration cardiopulmonary resuscitation and time until return of spontaneous circulation were shorter than observed in patients with poorer neurologic outcomes (CPC3, CPC4, and CPC5). The time to target temperature was equivalent among neurologic outcome groups (499.5 minutes vs 431.0 minutes, P = .09). Favorable neurologic outcome was associated with initial presentation with ventricular tachycardia or ventricular fibrillation and had cEEG patterns suggestive of diffuse slowing and epileptiform waves. DISCUSSION The use of cEEG can provide prognostication information otherwise not obtainable by clinical examination. Specific cEEG patterns predicted probability of mortality for patients according to their initial rhythm of CA as a function of cardiopulmonary resuscitation time.

Atypical cortical language organization in epilepsy patients: evidence for divergent hemispheric dominance for receptive and expressive language function.

Summary: The central goal of presurgical language mapping is to identify brain regions that subserve cortical language function to minimize postsurgical language deficits. Presurgical language mapping in patients with epilepsy presents a key challenge because of the atypical pattern of hemispheric language dominance found in this population, with higher incidences of bilateral and right-biased language dominance than typical. In this prospective study, we combine magnetoencephalography with a panel of tasks designed to separately assess receptive and expressive function to provide a sensitive measure of language function in 15 candidates for resective surgery. We report the following: 4 of 15 patients (27%) showed left hemisphere dominance across all tasks, 4 of 15 patients (27%) showed right hemisphere dominance across all tasks, and 7 of 15 (46%) showed discordant language dominance, with right-dominant receptive and left-dominant expressive language. All patients with discordant language dominance showed this right-receptive and left-expressive pattern. Results provide further evidence supporting the importance of using a panel of tasks to assess separable aspects of language function. The clinical relevance of the findings is discussed, especially about current clinical operative measures for assessing language dominance, which use single hemisphere procedure (intracarotid amobarbital procedure and awake intraoperative stimulation) for determining language laterality.

Dataset of human medial temporal lobe single neuron activity during declarative memory encoding and recognition

We present a dataset of 1,576 single neurons recorded from the human amygdala and hippocampus in 65 sessions from 42 patients undergoing intracranial monitoring for localization of epileptic seizures. Subjects performed a recognition memory task with pictures as stimuli. Subjects were asked to identify whether they had seen a particular image the first time (‘new’) or second time (‘old’) on a 1–6 confidence scale. This comprehensive dataset includes the spike times of all neurons and their extracellular waveforms, behavior, electrode locations determined from post-operative MRI scans, demographics, and the stimuli shown. As technical validation, we provide spike sorting quality metrics and assessment of tuning of cells to verify the presence of visually-and memory selective cells. We also provide analysis code that reproduces key scientific findings published previously on a smaller version of this dataset. Together, this large dataset will facilitate the investigation of the neural mechanism of declarative memory by providing a substantial number of hard to obtain human single-neuron recordings during a well characterized behavioral task.