Understanding cortical processing of spectrally degraded speech in normal-hearing subjects may provide insights into how sound information is processed by cochlear implant (CI) users. This study investigated electrocorticographic (ECoG) responses to noise-vocoded speech and related these responses to behavioral performance in a phonemic identification task. Subjects were neurosurgical patients undergoing chronic invasive monitoring for medically refractory epilepsy. Stimuli were utterances /aba/ and /ada/, spectrally degraded using a noise vocoder (1-4 bands). ECoG responses were obtained from Heschl's gyrus (HG) and superior temporal gyrus (STG), and were examined within the high gamma frequency range (70-150 Hz). All subjects performed at chance accuracy with speech degraded to 1 and 2 spectral bands, and at or near ceiling for clear speech. Inter-subject variability was observed in the 3- and 4-band conditions. High gamma responses in posteromedial HG (auditory core cortex) were similar for all vocoded conditions and clear speech. A progressive preference for clear speech emerged in anterolateral segments of HG, regardless of behavioral performance. On the lateral STG, responses to all vocoded stimuli were larger in subjects with better task performance. In contrast, both behavioral and neural responses to clear speech were comparable across subjects regardless of their ability to identify degraded stimuli. Findings highlight differences in representation of spectrally degraded speech across cortical areas and their relationship to perception. The results are in agreement with prior non-invasive results. The data provide insight into the neural mechanisms associated with variability in perception of degraded speech and potentially into sources of such variability in CI users.

While research on the cerebellar cortex is crystallizing our understanding of its function in learning behavior, many questions surrounding its downstream targets remain. Here, we evaluate the dynamics of cerebellar interpositus nucleus (IpN) neurons over the course of Pavlovian eyeblink conditioning. A diverse range of learning-induced neuronal responses was observed, including increases and decreases in activity during the generation of conditioned blinks. Trial-by-trial correlational analysis and optogenetic manipulation demonstrate that facilitation in the IpN drives the eyelid movements. Adaptive facilitatory responses are often preceded by acquired transient inhibition of IpN activity that, based on latency and effect, appear to be driven by complex spikes in cerebellar cortical Purkinje cells. Likewise, during reflexive blinks to periocular stimulation, IpN cells show excitation-suppression patterns that suggest a contribution of climbing fibers and their collaterals. These findings highlight the integrative properties of subcortical neurons at the cerebellar output stage mediating conditioned behavior.

The role of the cerebellum in predictive motor control and coordination has been thoroughly studied during movements of a single body part. In the real world, however, actions are often more complex. Here, we show that a small area in the rostral anterior interpositus nucleus (rAIN) of the mouse cerebellum is responsible for generating a predictive motor synergy that serves to protect the eye by precisely coordinating muscles of the eyelid, neck, and forelimb. Within the rAIN region, we discovered a new functional category of neurons with unique properties specialized for control of motor synergies. These neurons integrated inhibitory cutaneous inputs from multiple parts of the body, and their activity was correlated with the vigor of the defensive motor synergy on a trial-by-trial basis. We propose that some regions of the cerebellum are organized in poly-somatotopic "action maps" to reduce dimensionality and simplify motor control during ethologically relevant behaviors.

How we attend to and search for objects in the real world is influenced by a host of low-level and higher-level factors whose interactions are poorly understood. The vast majority of studies approach this issue by experimentally controlling one or two factors in isolation, often under conditions with limited ecological validity. We present a comprehensive regression framework, together with a matlab-implemented toolbox, which allows concurrent factors influencing saccade targeting to be more clearly distinguished. Based on the idea of gaze selection as a point process, the framework allows each putative factor to be modeled as a covariate in a generalized linear model, and its significance to be evaluated with model-based hypothesis testing. We apply this framework to visual search for faces as an example and demonstrate its power in detecting effects of eccentricity, inversion, task congruency, emotional expression, and serial fixation order on the targeting of gaze. Among other things, we find evidence for multiple goal-related and goal-independent processes that operate with distinct visuotopy and time course.

As we learn new information about the social and moral behaviors of other people, we form and update character judgments of them, and this can profoundly influence how we regard and act towards others. In the study reported here, we capitalized on two interesting neurological patient populations where this process of complex "moral updating" may go awry: patients with bilateral damage to ventromedial prefrontal cortex (vmPFC) and patients with bilateral damage to hippocampus (HC). We predicted that vmPFC patients, who have impaired emotion processing, would exhibit reduced moral updating, and we also investigated how moral updating might be affected by severe declarative memory impairment in HC patients. The vmPFC, HC, and brain-damaged comparison (BDC) participants made moral judgments about unfamiliar persons before and after exposure to social scenarios depicting the persons engaged in morally good, bad, or neutral behaviors. In line with our prediction, the vmPFC group showed the least amount of change in moral judgments, and interestingly, the HC group showed the most amount of change. These results suggest that the vmPFC and hippocampus play critical but complementary roles in updating moral character judgments about others: the vmPFC may attribute emotional salience to moral information, whereas the hippocampus may provide necessary contextual information from which to make appropriate character judgments.

The human brain extracts meaning using an extensive neural system for semantic knowledge. Whether broadly distributed systems depend on or can compensate after losing a highly interconnected hub is controversial. We report intracranial recordings from two patients during a speech prediction task, obtained minutes before and after neurosurgical treatment requiring disconnection of the left anterior temporal lobe (ATL), a candidate semantic knowledge hub. Informed by modern diaschisis and predictive coding frameworks, we tested hypotheses ranging from solely neural network disruption to complete compensation by the indirectly affected language-related and speech-processing sites. Immediately after ATL disconnection, we observed neurophysiological alterations in the recorded frontal and auditory sites, providing direct evidence for the importance of the ATL as a semantic hub. We also obtained evidence for rapid, albeit incomplete, attempts at neural network compensation, with neural impact largely in the forms stipulated by the predictive coding framework, in specificity, and the modern diaschisis framework, more generally. The overall results validate these frameworks and reveal an immediate impact and capability of the human brain to adjust after losing a brain hub.

The model for functional organization of human auditory cortex is in part based on findings in non-human primates, where the auditory cortex is hierarchically delineated into core, belt and parabelt fields. This model envisions that core cortex directly projects to belt, but not to parabelt, whereas belt regions are a major source of direct input for auditory parabelt. In humans, the posteromedial portion of Heschl's gyrus (HG) represents core auditory cortex, whereas the anterolateral portion of HG and the posterolateral superior temporal gyrus (PLST) are generally interpreted as belt and parabelt, respectively. In this scheme, response latencies can be hypothesized to progress in serial fashion from posteromedial to anterolateral HG to PLST. We examined this hypothesis by comparing response latencies to multiple stimuli, measured across these regions using simultaneous intracranial recordings in neurosurgical patients. Stimuli were 100 Hz click trains and the speech syllable /da/. Response latencies were determined by examining event-related band power in the high gamma frequency range. The earliest responses in auditory cortex occurred in posteromedial HG. Responses elicited from sites in anterolateral HG were neither earlier in latency from sites on PLST, nor more robust. Anterolateral HG and PLST exhibited some preference for speech syllable stimuli compared to click trains. These findings are not supportive of a strict serial model envisioning principal flow of information along HG to PLST. In contrast, data suggest that a portion of PLST may represent a relatively early stage in the auditory cortical hierarchy.

It is widely assumed that intracranial recordings from the brain are only minimally affected by contamination due to ocular-muscle electromyogram (oEMG). Here we show that this is not always the case. In intracranial recordings from five surgical epilepsy patients we observed that eye movements caused a transient biphasic potential at the onset of a saccade, resembling the saccadic spike potential commonly seen in scalp EEG, accompanied by an increase in broadband power between 20 and 200 Hz. Using concurrently recorded eye movements and high-density intracranial EEG (iEEG) we developed a detailed overview of the spatial distribution and temporal characteristics of the saccade-related oculomotor signal within recordings from ventral, medial and lateral temporal cortex. The occurrence of the saccadic spike was not explained solely by reference contact location, and was observed near the temporal pole for small (<2 deg) amplitude saccades and over a broad area for larger saccades. We further examined the influence of saccade-related oEMG contamination on measurements of spectral power and interchannel coherence. Contamination manifested in both spectral power and coherence measurements, in particular, over the anterior half of the ventral and medial temporal lobe. Next, we compared methods for removing the contaminating signal and found that nearest-neighbor bipolar re-referencing and ICA filtering were effective for suppressing oEMG at locations far from the orbits, but tended to leave some residual contamination at the temporal pole. Finally, we show that genuine cortical broadband gamma responses observed in averaged data from ventral temporal cortex can bear a striking similarity in time course and band-width to oEMG contamination recorded at more anterior locations. We conclude that eye movement-related contamination should be ruled out when reporting high gamma responses in human intracranial recordings, especially those obtained near anterior and medial temporal lobe.

A significant problem in neuroscience concerns the distinction between neural processing that is correlated with conscious percepts from processing that is not. Here, we tested if a hierarchical structure of causal interactions between neuronal populations correlates with conscious perception. We derived the hierarchical causal structure as a pattern of integrated information, inspired by the integrated information theory (IIT) of consciousness. We computed integrated information patterns from intracranial electrocorticography (ECoG) from six human neurosurgical patients with electrodes implanted over lateral and ventral cortices. During recording, subjects viewed continuous flash suppression (CFS) and backward masking (BM) stimuli intended to dissociate conscious percept from stimulus, and unmasked suprathreshold stimuli. Object-sensitive areas revealed correspondence between conscious percepts and integrated information patterns. We quantified this correspondence using unsupervised classification methods that revealed clustering of visual experiences with integrated information, but not with broader information measures including mutual information and entropy. Our findings point to a significant role of locally integrated information for understanding the neural substrate of conscious object perception.

Investigations of the neural basis of consciousness have greatly benefited from protocols that involve the presentation of stimuli at perceptual threshold, enabling the assessment of the patterns of brain activity that correlate with conscious perception, independently of any changes in sensory input. However, the comparison between perceived and unperceived trials would be expected to reveal not only the core neural substrate of a particular conscious perception, but also aspects of brain activity that facilitate, hinder or tend to follow conscious perception. We take a step towards the resolution of these confounds by combining an analysis of neural responses observed during the presentation of faces partially masked by Continuous Flash Suppression, and those responses observed during the unmasked presentation of faces and other images in the same subjects. We employed multidimensional classifiers to decode physical properties of stimuli or perceptual states from spectrotemporal representations of electrocorticographic signals (1071 channels in 5 subjects). Neural activity in certain face responsive areas located in both the fusiform gyrus and in the lateral-temporal/inferior-parietal cortex discriminated seen vs. unseen faces in the masked paradigm and upright faces vs. other categories in the unmasked paradigm. However, only the former discriminated upright vs. inverted faces in the unmasked paradigm. Our results suggest a prominent role for the fusiform gyrus in the configural perception of faces, and possibly other objects that are holistically processed. More generally, we advocate comparative analysis of neural recordings obtained during different, but related, experimental protocols as a promising direction towards elucidating the functional specificities of the patterns of neural activation that accompany our conscious experiences.

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.

This work sought correlates of pitch perception, defined by neural activity above the lower limit of pitch (LLP), in auditory cortical neural ensembles, and examined their topographical distribution. Local field potentials (LFPs) were recorded in eight patients undergoing invasive recordings for pharmaco-resistant epilepsy. Stimuli consisted of bursts of broadband noise followed by regular interval noise (RIN). RIN was presented at rates below and above the LLP to distinguish responses related to the regularity of the stimulus and the presence of pitch itself. LFPs were recorded from human cortical homologues of auditory core, belt, and parabelt regions using multicontact depth electrodes implanted in Heschl's gyrus (HG) and Planum Temporale (PT), and subdural grid electrodes implanted over lateral superior temporal gyrus (STG). Evoked responses corresponding to the temporal regularity of the stimulus were assessed using autocorrelation of the evoked responses, and occurred for stimuli below and above the LLP. Induced responses throughout the high gamma range (60-200 Hz) were present for pitch values above the LLP, with onset latencies of approximately 70 ms. Mapping of the induced responses onto a common brain space demonstrated variability in the topographical distribution of high gamma responses across subjects. Induced responses were present throughout the length of HG and on PT, which is consistent with previous functional neuroimaging studies. Moreover, in each subject, a region within lateral STG showed robust induced responses at pitch-evoking stimulus rates. This work suggests a distributed representation of pitch processing in neural ensembles in human homologues of core and non-core auditory cortex.

Human brain pathways supporting language and declarative memory are thought to have differentiated substantially during evolution. However, cross-species comparisons are missing on site-specific effective connectivity between regions important for cognition. We harnessed functional imaging to visualize the effects of direct electrical brain stimulation in macaque monkeys and human neurosurgery patients. We discovered comparable effective connectivity between caudal auditory cortex and both ventro-lateral prefrontal cortex (VLPFC, including area 44) and parahippocampal cortex in both species. Human-specific differences were clearest in the form of stronger hemispheric lateralization effects. In humans, electrical tractography revealed remarkably rapid evoked potentials in VLPFC following auditory cortex stimulation and speech sounds drove VLPFC, consistent with prior evidence in monkeys of direct auditory cortex projections to homologous vocalization-responsive regions. The results identify a common effective connectivity signature in human and nonhuman primates, which from auditory cortex appears equally direct to VLPFC and indirect to the hippocampus. VIDEO ABSTRACT.

Cerebellar inhibitory interneurons are important regulators of neural circuit activity for diverse motor and nonmotor functions. The molecular layer interneurons (MLIs), consisting of basket cells (BCs) and stellate cells (SCs), provide dendritic and somatic inhibitory synapses onto Purkinje cells, respectively. They are sequentially generated in an inside-out pattern from Pax2+ immature interneurons, which migrate from the prospective white matter to the ML of the cortex. However, little is known about how MLI subtype identities and pool sizes are determined, nor are their contributions to motor learning well understood. Here, we show that GABAergic progenitors fated to generate both BCs and SCs respond to the Sonic hedgehog (Shh) signal. Conditional abrogation of Shh signaling of either sex inhibited proliferation of GABAergic progenitors and reduced the number of Pax2+ cells, whereas persistent Shh pathway activation increased their numbers. These changes, however, did not affect early born BC numbers but selectively altered the SC pool size. Moreover, genetic depletion of GABAergic progenitors when BCs are actively generated also resulted in a specific reduction of SCs, suggesting that the specification of MLI subtypes is independent of Shh signaling and their birth order and likely occurs after Pax2+ cells settle into their laminar positions in an inside-out sequence. Mutant mice with reduced SC numbers displayed decreased dendritic inhibitory synapses and neurotransmission onto Purkinje cells, resulting in an impaired acquisition of eyeblink conditioning. These findings also reveal an essential role of Shh signaling-dependent SCs in regulating inhibitory dendritic synapses and motor learning.SIGNIFICANCE STATEMENT The cerebellar circuit that enables fine motor learning involves MLIs of BCs and SCs, which provide dendritic and somatic inhibitory synapses onto Purkinje cells. Little is known about how their identities and numbers are determined, nor are their specific contributions to motor learning well understood. We show that MLI subtypes are specified independent of Shh signaling and their birth orders but appear to occur in their terminal laminar positions according to the inside-out sequence. This finding challenges the current view that MLI subtypes are specified sequentially at the progenitor level. We also demonstrate that dendritic inhibition by Shh signaling-dependent SC pool is necessary for motor learning.

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.

Activity-induced gene expression underlies synaptic plasticity and brain function. Here, using molecular sequencing techniques, we define activity-dependent transcriptomic and epigenomic changes at the tissue and single-cell level in the human brain following direct electrical stimulation of the anterior temporal lobe in patients undergoing neurosurgery. Genes related to transcriptional regulation and microglia-specific cytokine activity displayed the greatest induction pattern, revealing a precise molecular signature of neuronal activation in the human brain.

Postictal apnea is thought to be a major cause of sudden unexpected death in epilepsy (SUDEP). However, the mechanisms underlying postictal apnea are unknown. To understand causes of postictal apnea, we used a multimodal approach to study brain mechanisms of breathing control in 20 patients (ranging from pediatric to adult) undergoing intracranial electroencephalography for intractable epilepsy. Our results indicate that amygdala seizures can cause postictal apnea. Moreover, we identified a distinct region within the amygdala where electrical stimulation was sufficient to reproduce prolonged breathing loss persisting well beyond the end of stimulation. The persistent apnea was resistant to rising CO2 levels, and air hunger failed to occur, suggesting impaired CO2 chemosensitivity. Using es-fMRI, a potentially novel approach combining electrical stimulation with functional MRI, we found that amygdala stimulation altered blood oxygen level-dependent (BOLD) activity in the pons/medulla and ventral insula. Together, these findings suggest that seizure activity in a focal subregion of the amygdala is sufficient to suppress breathing and air hunger for prolonged periods of time in the postictal period, likely via brainstem and insula sites involved in chemosensation and interoception. They further provide insights into SUDEP, may help identify those at greatest risk, and may lead to treatments to prevent SUDEP.