BACKGROUND. Seizure-induced inhibition of respiration plays a critical role in sudden unexpected death in epilepsy (SUDEP). However, the mechanisms underlying seizure-induced central apnea in pediatric epilepsy are unknown. METHODS. We studied 8 pediatric patients with intractable epilepsy undergoing intracranial electroencephalography. We recorded respiration during seizures and during electrical stimulation mapping of 174 forebrain sites. A machine-learning algorithm was used to delineate brain regions that inhibit respiration. RESULTS. In 2 patients, apnea coincided with seizure spread to the amygdala. Supporting a role for the amygdala in breathing inhibition in children, electrically stimulating the amygdala produced apnea in all 8 subjects (3-17 years old). These effects did not depend on epilepsy type and were relatively specific to the amygdala, as no other site affected breathing. Remarkably, patients were unaware that they had stopped breathing, and none reported dyspnea or arousal, findings critical for SUDEP. Finally, a machine-learning algorithm based on 45 stimulation sites and 210 stimulation trials identified a focal subregion in the human amygdala that consistently produced apnea. This site, which we refer to as the amygdala inhibition of respiration (AIR) site includes the medial subregion of the basal nuclei, cortical and medial nuclei, amygdala transition areas, and intercalated neurons. CONCLUSIONS. A focal site in the amygdala inhibits respiration and induces apnea (AIR site) when electrically stimulated and during seizures in children with epilepsy. This site may prove valuable for determining those at greatest risk for SUDEP and as a therapeutic target.

Learning complex ordering relationships between sensory events in a sequence is fundamental for animal perception and human communication. While it is known that rhythmic sensory events can entrain brain oscillations at different frequencies, how learning and prior experience with sequencing relationships affect neocortical oscillations and neuronal responses is poorly understood. We used an implicit sequence learning paradigm (an “artificial grammar”) in which humans and monkeys were exposed to sequences of nonsense words with regularities in the ordering relationships between the words. We then recorded neural responses directly from the auditory cortex in both species in response to novel legal sequences or ones violating specific ordering relationships. Neural oscillations in both monkeys and humans in response to the nonsense word sequences show strikingly similar hierarchically nested low-frequency phase and high-gamma amplitude coupling, establishing this form of oscillatory coupling—previously associated with speech processing in the human auditory cortex—as an evolutionarily conserved biological process. Moreover, learned ordering relationships modulate the observed form of neural oscillatory coupling in both species, with temporally distinct neural oscillatory effects that appear to coordinate neuronal responses in the monkeys. This study identifies the conserved auditory cortical neural signatures involved in monitoring learned sequencing operations, evident as modulations of transient coupling and neuronal responses to temporally structured sensory input.

Retrieving the names of friends, loved ones, and famous people is a fundamental human ability. This ability depends on the left anterior temporal lobe (ATL), where lesions can be associated with impaired naming of people regardless of modality (e.g., picture or voice). This finding has led to the idea that the left ATL is a modality-independent convergence region for proper naming. Hypotheses for how proper-name dispositions are organized within the left ATL include both a single modality-independent (heteromodal) convergence region and spatially discrete modality-dependent (unimodal) regions. Here we show direct electrophysiologic evidence that the left ATL is heteromodal for proper-name retrieval. Using intracranial recordings placed directly on the surface of the left ATL in human subjects, we demonstrate nearly identical responses to picture and voice stimuli of famous U.S. politicians during a naming task. Our results demonstrate convergent and robust large-scale neurophysiologic responses to picture and voice naming in the human left ATL. This finding supports the idea of heteromodal (i.e., transmodal) dispositions for proper naming in the left ATL.

The systems-level mechanisms underlying loss of consciousness (LOC) under anesthesia remain unclear. General anesthetics suppress sensory responses within higher-order cortex and feedback connections, both critical elements of predictive coding hypotheses of conscious perception. Responses to auditory novelty may offer promise as biomarkers for consciousness. This study examined anesthesia-induced changes in auditory novelty responses over short (local deviant [LD]) and long (global deviant [GD]) time scales, envisioned to engage preattentive and conscious levels of processing, respectively. Electrocorticographic recordings were obtained in human neurosurgical patients (3 male, 3 female) from four hierarchical processing levels: core auditory cortex, non-core auditory cortex, auditory-related, and PFC. Stimuli were vowel patterns incorporating deviants within and across stimuli (LD and GD). Subjects were presented with stimuli while awake, and during sedation (responsive) and following LOC (unresponsive) under propofol anesthesia. LD and GD effects were assayed as the averaged evoked potential and high gamma (70-150 Hz) activity. In the awake state, LD and GD effects were present in all recorded regions, with averaged evoked potential effects more broadly distributed than high gamma activity. Under sedation, LD effects were preserved in all regions, except PFC. LOC was accompanied by loss of LD effects outside of auditory cortex. By contrast, GD effects were markedly suppressed under sedation in all regions and were absent following LOC. Thus, although the presence of GD effects is indicative of being awake, its absence is not indicative of LOC. Loss of LD effects in higher-order cortical areas may constitute an alternative biomarker of LOC. Development of a biomarker that indexes changes in the brain upon loss of consciousness (LOC) under general anesthesia has broad implications for elucidating the neural basis of awareness and clinical relevance to mechanisms of sleep, coma, and disorders of consciousness. Using intracranial recordings from neurosurgery patients, we investigated changes in the activation of cortical networks involved in auditory novelty detection over short (local deviance) and long (global deviance) time scales associated with sedation and LOC under propofol anesthesia. Our results indicate that, whereas the presence of global deviance effects can index awareness, their loss cannot serve as a biomarker for LOC. The dramatic reduction of local deviance effects in areas beyond auditory cortex may constitute an alternative biomarker of LOC.

The functional organization of human auditory cortex can be probed by characterizing responses to various classes of sound at different anatomical locations. Along with histological studies this approach has revealed a primary field in posteromedial Heschl's gyrus (HG) with pronounced induced high-frequency (70–150 Hz) activity and short-latency responses that phase-lock to rapid transient sounds. Low-frequency neural oscillations are also relevant to stimulus processing and information flow, however, their distribution within auditory cortex has not been established. Alpha activity (7–14 Hz) in particular has been associated with processes that may differentially engage earlier versus later levels of the cortical hierarchy, including functional inhibition and the communication of sensory predictions. These theories derive largely from the study of occipitoparietal sources readily detectable in scalp electroencephalography. To characterize the anatomical basis and functional significance of less accessible temporal-lobe alpha activity we analyzed responses to sentences in seven human adults (4 female) with epilepsy who had been implanted with electrodes in superior temporal cortex. In contrast to primary cortex in posteromedial HG, a non-primary field in anterolateral HG was characterized by high spontaneous alpha activity that was strongly suppressed during auditory stimulation. Alpha-power suppression decreased with distance from anterolateral HG throughout superior temporal cortex, and was more pronounced for clear compared to degraded speech. This suppression could not be accounted for solely by a change in the slope of the power spectrum. The differential manifestation and stimulus-sensitivity of alpha oscillations across auditory fields should be accounted for in theories of their generation and function.SIGNIFICANCE STATEMENT To understand how auditory cortex is organized in support of perception, we recorded from patients implanted with electrodes for clinical reasons. This allowed measurement of activity in brain regions at different levels of sensory processing. Oscillations in the alpha range (7–14 Hz) have been associated with functions including sensory prediction and inhibition of regions handling irrelevant information, but their distribution within auditory cortex is not known. A key finding was that these oscillations dominated in one particular non-primary field, anterolateral Heschl's gyrus, and were suppressed when subjects listened to sentences. These results build on our knowledge of the functional organization of auditory cortex and provide anatomical constraints on theories of the generation and function of alpha oscillations.