Mark A. Granner

Single-neuron responses to emotional visual stimuli recorded in human ventral prefrontal cortex

Both lesion and functional imaging studies in humans, as well as neurophysiological studies in nonhuman primates, demonstrate the importance of the prefrontal cortex in representing the emotional value of sensory stimuli. Here we investigated single-neuron responses to emotional stimuli in an awake person with normal intellect. Recording from neurons within healthy tissue in ventral sites of the right prefrontal cortex, we found short-latency (120–160 ms) responses selective for aversive visual stimuli.

Auditory cortex on the human posterior superior temporal gyrus

The human superior temporal cortex plays a critical role in hearing, speech, and language, yet its functional organization is poorly understood. Evoked potentials (EPs) to auditory click‐train stimulation presented binaurally were recorded chronically from penetrating electrodes implanted in Heschls gyrus (HG), from pial‐surface electrodes placed on the lateral superior temporal gyrus (STG), or from both simultaneously, in awake humans undergoing surgery for medically intractable epilepsy. The distribution of averaged EPs was restricted to a relatively small area on the lateral surface of the posterior STG. In several cases, there were multiple foci of high amplitude EPs lying along this acoustically active portion of STG. EPs recorded simultaneously from HG and STG differed in their sensitivities to general anesthesia and to changes in rate of stimulus presentation. Results indicate that the acoustically active region on the STG is a separate auditory area, functionally distinct from the HG auditory field(s). We refer to this acoustically sensitive area of the STG as the posterior lateral superior temporal area (PLST). Electrical stimulation of HG resulted in short‐latency EPs in an area that overlaps PLST, indicating that PLST receives a corticocortical input, either directly or indirectly, from HG. These physiological findings are in accord with anatomic evidence in humans and in nonhuman primates that the superior temporal cortex contains multiple interconnected auditory areas. J. Comp. Neurol. 416:79–92, 2000.

A chronic microelectrode investigation of the tonotopic organization of human auditory cortex

We investigated the functional organization of human auditory cortex using a new chronic microelectrode technique. Tonotopic mapping data was obtained at the single unit level for the first time in humans. All sound-driven units were noted to have frequency-dependent response patterns. The majority of units (73%) demonstrated sharply tuned excitatory best-frequency responses. Twenty seven percent of units showed wide receptive fields, representing excitatory responses to almost the entire range of frequencies presented. A tonotopic pattern was observed with best frequencies systematically increasing as more medial-caudal recording sites were sampled.

Nonconvulsive status epilepticus: EEG analysis in a large series.

Summary: We analyzed EEG characteristics comprehensively in a large series of nonconvulsive status epilepticus (NCSE) cases. Eighty‐five ictal episodes in 78 patients were analyzed. The ictal discharges were generalized (group G) in 59 episodes (69%), diffuse with focal predominance (group GF) in 15 (18%), and focal (group F) in 11 (13%). The morphologies and patterns of persistence varied greatly. Frequency of ictal discharge was also variable and was almost always <3 Hz. Demonstration of focal epileptic features in response to intravenous (i.v.) diazepam (DZP) and the presence of interictal focal epileptiform discharges in some cases in groups G and GF suggested possible focal onset secondarily generalized in these cases. This study suggests that electrographically NCSE is a highly heterogeneous epileptic state, and i.v. DZP may serve as a valuable diagnostic tool in differentiating generalized from focal onset NCSE.

A systematic review of validated methods for identifying seizures, convulsions, or epilepsy using administrative and claims data.

To systematically review algorithms to identify seizure, convulsion, or epilepsy cases in administrative and claims data, with a focus on studies that have examined the validity of the algorithms.

Sudden unexpected death in epilepsy: Fatal post-ictal respiratory and arousal mechanisms ☆

Sudden unexplained death in epilepsy (SUDEP) is the cause of premature death of up to 17% of all patients with epilepsy and as many as 50% with chronic refractory epilepsy. However, SUDEP is not widely recognized to exist. The etiology of SUDEP remains unclear, but growing evidence points to peri-ictal respiratory, cardiac, or autonomic nervous system dysfunction. How seizures affect these systems remains uncertain. Here we focus on respiratory mechanisms believed to underlie SUDEP. We highlight clinical evidence that indicates peri-ictal hypoxemia occurs in a large percentage of patients due to central apnea, and identify the proposed anatomical regions of the brain governing these responses. In addition, we discuss animal models used to study peri-ictal respiratory depression. We highlight the role 5-HT neurons play in respiratory control, chemoreception, and arousal. Finally, we discuss the evidence that 5-HT deficits contribute to SUDEP and sudden infant death syndrome and the striking similarities between the two.

Breathing Inhibited When Seizures Spread to the Amygdala and upon Amygdala Stimulation

Sudden unexpected death in epilepsy (SUDEP) is increasingly recognized as a common and devastating problem. Because impaired breathing is thought to play a critical role in these deaths, we sought to identify forebrain sites underlying seizure-evoked hypoventilation in humans. We took advantage of an extraordinary clinical opportunity to study a research participant with medically intractable epilepsy who had extensive bilateral frontotemporal electrode coverage while breathing was monitored during seizures recorded by intracranial electrodes and mapped by high-resolution brain imaging. We found that central apnea and O2 desaturation occurred when seizures spread to the amygdala. In the same patient, localized electrical stimulation of the amygdala reproduced the apnea and O2 desaturation. Similar effects of amygdala stimulation were observed in two additional subjects, including one without a seizure disorder. The participants were completely unaware of the apnea evoked by stimulation and expressed no dyspnea, despite being awake and vigilant. In contrast, voluntary breath holding of similar duration caused severe dyspnea. These findings suggest a functional connection between the amygdala and medullary respiratory network in humans. Moreover, they suggest that seizure spread to the amygdala may cause loss of spontaneous breathing of which patients are unaware, and thus has potential to contribute to SUDEP. SIGNIFICANCE STATEMENT Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with chronic refractory epilepsy. Impaired breathing during and after seizures is common and suspected to play a role in SUDEP. Understanding the cause of this peri-ictal hypoventilation may lead to preventative strategies. In epilepsy patients, we found that seizure invasion of the amygdala co-occurred with apnea and oxygen desaturation, and electrical stimulation of the amygdala reproduced these respiratory findings. Strikingly, the subjects were unaware of the apnea. These findings indicate a functional connection between the amygdala and brainstem respiratory network in humans and suggest that amygdala seizures may cause loss of spontaneous breathing of which patients are unaware—a combination that could be deadly.

The effects of vagus nerve stimulation on decision-making.

Subcortical and brainstem structures are increasingly becoming recognized as important contributors to higher cognitive functioning. Decision-making is one such function, particularly as viewed within the framework of the somatic marker hypothesis (SMH). The SMH views the participation in decision-making by the body proper as integral to emotional biasing and hence key to choosing in an advantageous manner. This study focuses on the vagus nerves as a possible conduit for somatic afferent signals pertinent to decision-making. We tested eight epileptic patients with implanted left vagus nerve stimulators. To assess decision-making we used the gambling task, which is sensitive to real-life decision-making deficits. Using a counterbalanced design, each participant performed the gambling task under a condition in which low-level vagus nerve stimulation (VNS) was covertly delivered, and another condition in which no VNS was delivered. Participants showed improved performance, that is, made more advantageous choices, in the stimulated relative to the unstimulated condition. Although these results should be viewed as preliminary, they suggest that the vagus nerve is a conduit for afferent somatic signals that can influence decision-making.

The Differences in Electroencephalographic Changes in Patients Undergoing Carotid Endarterectomies while under Local versus General Anesthesia

OBJECTIVE This study compared the electroencephalographic (EEG) changes occurring during carotid occlusion in 225 consecutive patients undergoing carotid endarterectomies performed by two surgeons, one using local and the other using general anesthesia. METHODS A retrospective review of patients undergoing carotid endarterectomies for carotid occlusive disease was conducted. EEG changes associated with intraoperative ischemia (decreased amplitude, generalized slowing, and loss of fast activity) resulting in the need for an indwelling arterial shunt were recorded for the two anesthesia groups. To determine the similarities or differences between the two groups, the groups were compared regarding age, risk factors, and indications for surgery. RESULTS Significant EEG changes were noted in 6 of 96 patients (6.3%) in the local anesthesia group versus 19 of 121 patients (15.7%) in the general anesthesia group. EEG changes consisted solely of generalized slowing in the local anesthesia group, whereas a more varied spectrum was observed in the general anesthesia group. The two groups were similar regarding age and risk factors. Although the local anesthesia group had more asymptomatic patients, symptomatic patients did not have a greater incidence of EEG changes. CONCLUSION There is a large difference in EEG changes potentially requiring shunt placement in patients undergoing surgery while under local (6.3%) versus general (15.7%) anesthesia. This could not be explained based on age, risk factors, interpretation of EEG findings, or indications between the two groups. We conclude that EEG monitoring may be insensitive and may fail to detect ischemia in patients who are under regional anesthesia. Alternately, the presence of general anesthetics may alter the character of the EEG findings and increase the sensitivity of EEG monitoring to ischemic events.

Bimodal ultradian seizure periodicity in human mesial temporal lobe epilepsy

BACKGROUND Mesial temporal lobe epilepsy (mTLE) has been suggested to follow a circadian rhythm. Previous research found an afternoon peak in mTLE seizure occurrence. We evaluated the pattern of seizure occurrence in patients with well-localized mTLE and hypothesized that peak seizure frequency would occur in the afternoon, and that this pattern would not be altered by age, gender, or seizure focus. METHODS We retrospectively identified consecutive mTLE patients with a seizure-free outcome following anterior temporal lobectomy from 1993 to 2004 with video-EEG captured seizures. We recorded and plotted the 24-h clock time for each seizure and performed cosinor analysis. SAS Proc GLIMMIX was used to fit the linearized transform of the cosinor model. Negative binomial regression fitted by the generalized estimating equations (GEE) method was also performed to estimate and compare the mean seizure rates over a 24-h day. RESULTS Sixty mTLE patients monitored between 2 and 16 days were analyzed. Mean (standard deviation), median number of seizures per subject were 10.47(7.86), 9.00. Cosinor plots indicated that the function had two modes: 7-8 a.m. and 4-5 p.m. GEE analysis was consistent with peak seizure frequency occurrence at 6-8 a.m. (p<0.0001) and 3-5 p.m. (p<0.01). CONCLUSIONS We found a bimodal pattern of seizure occurrence in human mTLE, with peak seizure frequencies occurring between 6-8 a.m. and 3-5 p.m. confirming an afternoon peak, as well as a previously unsuspected morning peak in seizure occurrence that provides rationale for future investigations of antiepileptic drug chronopharmacology and informs patient counseling regarding patterns of seizure occurrence.