Crossmodal Phase Reset and Evoked Responses Provide Complementary Mechanisms for the Influence of Visual Speech in Auditory Cortex.

Natural conversation is multisensory: when we can see the speaker's face, visual speech cues improve our comprehension. The neuronal mechanisms underlying this phenomenon remain unclear. The two main alternatives are visually mediated phase modulation of neuronal oscillations (excitability fluctuations) in auditory neurons and visual input-evoked responses in auditory neurons. Investigating this question using naturalistic audiovisual speech with intracranial recordings in humans of both sexes, we find evidence for both mechanisms. Remarkably, auditory cortical neurons track the temporal dynamics of purely visual speech using the phase of their slow oscillations and phase-related modulations in broadband high-frequency activity. Consistent with known perceptual enhancement effects, the visual phase reset amplifies the cortical representation of concomitant auditory speech. In contrast to this, and in line with earlier reports, visual input reduces the amplitude of evoked responses to concomitant auditory input. We interpret the combination of improved phase tracking and reduced response amplitude as evidence for more efficient and reliable stimulus processing in the presence of congruent auditory and visual speech inputs.SIGNIFICANCE STATEMENT Watching the speaker can facilitate our understanding of what is being said. The mechanisms responsible for this influence of visual cues on the processing of speech remain incompletely understood. We studied these mechanisms by recording the electrical activity of the human brain through electrodes implanted surgically inside the brain. We found that visual inputs can operate by directly activating auditory cortical areas, and also indirectly by modulating the strength of cortical responses to auditory input. Our results help to understand the mechanisms by which the brain merges auditory and visual speech into a unitary perception.

Daily listening to Mozart reduces seizures in individuals with epilepsy: A randomized control study.

OBJECTIVE: Epilepsy is one of the most common neurological disorders . Many individuals continue to have seizures despite medical and surgical treatments, suggesting adjunctive management strategies are required. Promising effects of daily listening to Mozart on reducing seizure frequency in individuals with epilepsy have been demonstrated over the last 20 years, but not in a rigorously controlled manner. In this study, we compared the effect on seizure frequency of daily listening to either Mozart K.448 or a spectrally similar, yet non-rhythmic control piece. We hypothesized that there would be no difference in seizure counts when participants listened to Mozart K.448 vs when they listened to the control piece. METHODS: We employed a randomized crossover design, in which each participant was exposed to both three months of daily listening to the first six minutes of Sonata for two pianos in D major by Mozart (Mozart K.448; treatment period) and three months of daily listening to phase-scrambled version (control period). There was a three-month baseline and a three-month follow-up period before and after the six-month listening period, respectively. Change in seizure counts obtained from the seizure diaries was considered as the main study outcome. RESULTS: Using three methodologies to investigate the existence of the treatment effect (paired t test, estimation statistics and plots, and Cohen's d), our results revealed a reduction in seizure counts during the treatment period, which was not observed for the control period (P-value < .001). SIGNIFICANCE: Using a spectrally similar control piece, our study advances previous reports that were limited by a "no music" control condition. Daily listening to Mozart K.448 was associated with reducing seizure frequency in adult individuals with epilepsy. These results suggest that daily Mozart listening may be considered as an adjunctive therapeutic option to reduce seizure burden in individuals with epilepsy.

Differential Generation of Saccade, Fixation, and Image-Onset Event-Related Potentials in the Human Mesial Temporal Lobe.

Event-related potentials (ERPs) are a commonly used electrophysiological signature for studying mesial temporal lobe (MTL) function during visual memory tasks. The ERPs associated with the onset of visual stimuli (image-onset) and eye movements (saccades and fixations) provide insights into the mechanisms of their generation. We hypothesized that since eye movements and image-onset provide MTL structures with salient visual information, perhaps they both engage similar neural mechanisms. To explore this question, we used intracranial electroencephalographic data from the MTLs of 11 patients with medically refractory epilepsy who participated in a visual search task. We characterized the electrophysiological responses of MTL structures to saccades, fixations, and image-onset. We demonstrated that the image-onset response is an evoked/additive response with a low-frequency power increase. In contrast, ERPs following eye movements appeared to arise from phase resetting of higher frequencies than the image-onset ERP. Intriguingly, this reset was associated with saccade onset and not termination (fixation), suggesting it is likely the MTL response to a corollary discharge, rather than a response to visual stimulation. We discuss the distinct mechanistic underpinnings of these responses which shed light on the underlying neural circuitry involved in visual memory processing.

The Noisy Brain: Power of Resting-State Fluctuations Predicts Individual Recognition Performance.

The unique profile of strong and weak cognitive traits characterizing each individual is of a fundamental significance, yet their neurophysiological underpinnings remain elusive. Here, we present intracranial electroencephalogram (iEEG) measurements in humans pointing to resting-state cortical "noise" as a possible neurophysiological trait that limits visual recognition capacity. We show that amplitudes of slow (<1 Hz) spontaneous fluctuations in high-frequency power measured during rest were predictive of the patients' performance in a visual recognition 1-back task (26 patients, total of 1,389 bipolar contacts pairs). Importantly, the effect was selective only to task-related cortical sites. The prediction was significant even across long (mean distance 4.6 ± 2.8 days) lags. These findings highlight the level of the individuals' internal "noise" as a trait that limits performance in externally oriented demanding tasks.

Convergent evolution of face spaces across human face-selective neuronal groups and deep convolutional networks.

The discovery that deep convolutional neural networks (DCNNs) achieve human performance in realistic tasks offers fresh opportunities for linking neuronal tuning properties to such tasks. Here we show that the face-space geometry, revealed through pair-wise activation similarities of face-selective neuronal groups recorded intracranially in 33 patients, significantly matches that of a DCNN having human-level face recognition capabilities. This convergent evolution of pattern similarities across biological and artificial networks highlights the significance of face-space geometry in face perception. Furthermore, the nature of the neuronal to DCNN match suggests a role of human face areas in pictorial aspects of face perception. First, the match was confined to intermediate DCNN layers. Second, presenting identity-preserving image manipulations to the DCNN abolished its correlation to neuronal responses. Finally, DCNN units matching human neuronal group tuning displayed view-point selective receptive fields. Our results demonstrate the importance of face-space geometry in the pictorial aspects of human face perception.

Medial prefrontal cortex supports perceptual memory.

Our visual environment constantly changes, yet we experience the world as a stable, unified whole. How is this stability achieved? It has been proposed that the brain preserves an implicit perceptual memory in sensory cortices [1] which stabilizes perception towards previously experienced states [2,3]. The role of higher-order areas, especially prefrontal cortex (PFC), in perceptual memory is less explored. Because PFC exhibits long neural time constants, invariance properties, and large receptive fields which may stabilize perception against time-varying inputs, it seems particularly suited to implement perceptual memory [4]. Support for this idea comes from a neuroimaging study reporting that dorsomedial PFC (dmPFC) correlates with perceptual memory [5]. But dmPFC also participates in decision making [6], so its contribution to perceptual memory could arise on a post-perceptual, decisional level [7]. To determine which role, if any, PFC plays in perceptual memory, we obtained direct intracranial recordings in six epilepsy patients while they performed sequential orientation judgements on ambiguous stimuli known to elicit perceptual memory [8]. We found that dmPFC activity in the high gamma frequency band (HGB, 70-150 Hz) correlates with perceptual memory. This effect is anatomically specific to dmPFC and functionally specific for memories of preceding percepts. Further, dmPFC appears to play a causal role, as a patient with a lesion in this area showed impaired perceptual memory. Thus, dmPFC integrates current sensory information with prior percepts, stabilizing visual experience against the perpetual variability of our surroundings.

Spatial variation in high-frequency oscillation rates and amplitudes in intracranial EEG.

OBJECTIVE: To assess the variation in baseline and seizure onset zone interictal high-frequency oscillation (HFO) rates and amplitudes across different anatomic brain regions in a large cohort of patients. METHODS: Seventy patients who had wide-bandwidth (5 kHz) intracranial EEG (iEEG) recordings during surgical evaluation for drug-resistant epilepsy between 2005 and 2014 who had high-resolution MRI and CT imaging were identified. Discrete HFOs were identified in 2-hour segments of high-quality interictal iEEG data with an automated detector. Electrode locations were determined by coregistering the patient's preoperative MRI with an X-ray CT scan acquired immediately after electrode implantation and correcting electrode locations for postimplant brain shift. The anatomic locations of electrodes were determined using the Desikan-Killiany brain atlas via FreeSurfer. HFO rates and mean amplitudes were measured in seizure onset zone (SOZ) and non-SOZ electrodes, as determined by the clinical iEEG seizure recordings. To promote reproducible research, imaging and iEEG data are made freely available (msel.mayo.edu). RESULTS: Baseline (non-SOZ) HFO rates and amplitudes vary significantly in different brain structures, and between homologous structures in left and right hemispheres. While HFO rates and amplitudes were significantly higher in SOZ than non-SOZ electrodes when analyzed regardless of contact location, SOZ and non-SOZ HFO rates and amplitudes were not separable in some lobes and structures (e.g., frontal and temporal neocortex). CONCLUSIONS: The anatomic variation in SOZ and non-SOZ HFO rates and amplitudes suggests the need to assess interictal HFO activity relative to anatomically accurate normative standards when using HFOs for presurgical planning.

The Hippocampus and Amygdala Are Integrators of Neocortical Influence: A CorticoCortical Evoked Potential Study.

Brain stimulation is increasingly viewed as an effective approach to treat neuropsychiatric disease. The brain's organization in distributed networks suggests that the activity of a remote brain structure could be modulated by stimulating cortical areas that strongly connect to the target. Most connections between cerebral areas are asymmetric, and a better understanding of the relative direction of information flow along connections could improve the targeting of stimulation to influence deep brain structures. The hippocampus and amygdala, two deep-situated structures that are crucial to memory and emotions, respectively, have been implicated in multiple neurological and psychiatric disorders. We explored the directed connectivity between the hippocampus and amygdala and the cerebral cortex in patients implanted with intracranial electrodes using corticocortical evoked potentials (CCEPs) evoked by single-pulse electrical stimulation. The hippocampus and amygdala were connected with most of the cortical mantle, either directly or indirectly, with the inferior temporal cortex being most directly connected. Because CCEPs assess the directionality of connections, we could determine that incoming connections from cortex to hippocampus were more direct than outgoing connections from hippocampus to cortex. We found a similar, although smaller, tendency for connections between the amygdala and cortex. Our results support the roles of the hippocampus and amygdala to be integrators of widespread cortical influence. These results can inform the targeting of noninvasive neurostimulation to influence hippocampus and amygdala function.

Increasing suppression of saccade-related transients along the human visual hierarchy.

A key hallmark of visual perceptual awareness is robustness to instabilities arising from unnoticeable eye and eyelid movements. In previous human intracranial (iEEG) work (Golan et al., 2016) we found that excitatory broadband high-frequency activity transients, driven by eye blinks, are suppressed in higher-level but not early visual cortex. Here, we utilized the broad anatomical coverage of iEEG recordings in 12 eye-tracked neurosurgical patients to test whether a similar stabilizing mechanism operates following small saccades. We compared saccades (1.3°-3.7°) initiated during inspection of large individual visual objects with similarly-sized external stimulus displacements. Early visual cortex sites responded with positive transients to both conditions. In contrast, in both dorsal and ventral higher-level sites the response to saccades (but not to external displacements) was suppressed. These findings indicate that early visual cortex is highly unstable compared to higher-level visual regions which apparently constitute the main target of stabilizing extra-retinal oculomotor influences.

Low-Frequency Cortical Oscillations Entrain to Subthreshold Rhythmic Auditory Stimuli.

Many environmental stimuli contain temporal regularities, a feature that can help predict forthcoming input. Phase locking (entrainment) of ongoing low-frequency neuronal oscillations to rhythmic stimuli is proposed as a potential mechanism for enhancing neuronal responses and perceptual sensitivity, by aligning high-excitability phases to events within a stimulus stream. Previous experiments show that rhythmic structure has a behavioral benefit even when the rhythm itself is below perceptual detection thresholds (ten Oever et al., 2014). It is not known whether this "inaudible" rhythmic sound stream also induces entrainment. Here we tested this hypothesis using magnetoencephalography and electrocorticography in humans to record changes in neuronal activity as subthreshold rhythmic stimuli gradually became audible. We found that significant phase locking to the rhythmic sounds preceded participants' detection of them. Moreover, no significant auditory-evoked responses accompanied this prethreshold entrainment. These auditory-evoked responses, distinguished by robust, broad-band increases in intertrial coherence, only appeared after sounds were reported as audible. Taken together with the reduced perceptual thresholds observed for rhythmic sequences, these findings support the proposition that entrainment of low-frequency oscillations serves a mechanistic role in enhancing perceptual sensitivity for temporally predictive sounds. This framework has broad implications for understanding the neural mechanisms involved in generating temporal predictions and their relevance for perception, attention, and awareness.SIGNIFICANCE STATEMENT The environment is full of rhythmically structured signals that the nervous system can exploit for information processing. Thus, it is important to understand how the brain processes such temporally structured, regular features of external stimuli. Here we report the alignment of slowly fluctuating oscillatory brain activity to external rhythmic structure before its behavioral detection. These results indicate that phase alignment is a general mechanism of the brain to process rhythmic structure and can occur without the perceptual detection of this temporal structure.

iELVis: An open source MATLAB toolbox for localizing and visualizing human intracranial electrode data.

BACKGROUND: Intracranial electrical recordings (iEEG) and brain stimulation (iEBS) are invaluable human neuroscience methodologies. However, the value of such data is often unrealized as many laboratories lack tools for localizing electrodes relative to anatomy. To remedy this, we have developed a MATLAB toolbox for intracranial electrode localization and visualization, iELVis. NEW METHOD: iELVis uses existing tools (BioImage Suite, FSL, and FreeSurfer) for preimplant magnetic resonance imaging (MRI) segmentation, neuroimaging coregistration, and manual identification of electrodes in postimplant neuroimaging. Subsequently, iELVis implements methods for correcting electrode locations for postimplant brain shift with millimeter-scale accuracy and provides interactive visualization on 3D surfaces or in 2D slices with optional functional neuroimaging overlays. iELVis also localizes electrodes relative to FreeSurfer-based atlases and can combine data across subjects via the FreeSurfer average brain. RESULTS: It takes 30-60min of user time and 12-24h of computer time to localize and visualize electrodes from one brain. We demonstrate iELVis's functionality by showing that three methods for mapping primary hand somatosensory cortex (iEEG, iEBS, and functional MRI) provide highly concordant results. COMPARISON WITH EXISTING METHODS: iELVis is the first public software for electrode localization that corrects for brain shift, maps electrodes to an average brain, and supports neuroimaging overlays. Moreover, its interactive visualizations are powerful and its tutorial material is extensive. CONCLUSIONS: iELVis promises to speed the progress and enhance the robustness of intracranial electrode research. The software and extensive tutorial materials are freely available as part of the EpiSurg software project: https://github.com/episurg/episurg.

Evaluation of cortical local field potential diffusion in stereotactic electro-encephalography recordings: A glimpse on white matter signal.

While there is a strong interest in meso-scale field potential recording using intracranial electroencephalography with penetrating depth electrodes (i.e. stereotactic EEG or S-EEG) in humans, the signal recorded in the white matter remains ignored. White matter is generally considered electrically neutral and often included in the reference montage. Moreover, re-referencing electrophysiological data is a critical preprocessing choice that could drastically impact signal content and consequently the results of any given analysis. In the present stereotactic electroencephalography study, we first illustrate empirically the consequences of commonly used references (subdermal, white matter, global average, local montage) on inter-electrode signal correlation. Since most of these reference montages incorporate white matter signal, we next consider the difference between signals recorded in cortical gray matter and white matter. Our results reveal that electrode contacts located in the white matter record a mixture of activity, with part arising from the volume conduction (zero time delay) of activity from nearby gray matter. Furthermore, our analysis shows that white matter signal may be correlated with distant gray matter signal. While residual passive electrical spread from nearby matter may account for this relationship, our results suggest the possibility that this long distance correlation arises from the white matter fiber tracts themselves (i.e. activity from distant gray matter traveling along axonal fibers with time lag larger than zero); yet definitive conclusions about the origin of the white matter signal would require further experimental substantiation. By characterizing the properties of signals recorded in white matter and in gray matter, this study illustrates the importance of including anatomical prior knowledge when analyzing S-EEG data.

Combating the scientific decline effect with confidence (intervals).

A symptom of the need for greater reproducibility in scientific practice is the decline effect-the fact that the size of many experimental effects decline with subsequent study or fail to replicate entirely. A simple way to combat this problem is for scientists to more routinely use confidence intervals (CIs) in their work. CIs provide frequentist bounds on the true size of an effect and can reveal when a statistically significant effect is possibly too small to be reliable or when a large effect might have been missed due to insufficient statistical power. CIs are often lacking in psychophysiological reports, likely due to the large number of dependent variables, which complicates deriving and visualizing CIs. In this article, I explain the value of CIs and show how to compute them for analyses involving multiple variables in various ways that adjust the intervals for the greater uncertainty induced by multiple statistical comparisons. The methods are illustrated using a basic visual oddball ERP dataset and freely available MATLAB software.

Human intracranial recordings link suppressed transients rather than 'filling-in' to perceptual continuity across blinks.

We hardly notice our eye blinks, yet an externally generated retinal interruption of a similar duration is perceptually salient. We examined the neural correlates of this perceptual distinction using intracranially measured ECoG signals from the human visual cortex in 14 patients. In early visual areas (V1 and V2), the disappearance of the stimulus due to either invisible blinks or salient blank video frames ('gaps') led to a similar drop in activity level, followed by a positive overshoot beyond baseline, triggered by stimulus reappearance. Ascending the visual hierarchy, the reappearance-related overshoot gradually subsided for blinks but not for gaps. By contrast, the disappearance-related drop did not follow the perceptual distinction - it was actually slightly more pronounced for blinks than for gaps. These findings suggest that blinks' limited visibility compared with gaps is correlated with suppression of blink-related visual activity transients, rather than with "filling-in" of the occluded content during blinks.

Combining task-evoked and spontaneous activity to improve pre-operative brain mapping with fMRI.

Noninvasive localization of brain function is used to understand and treat neurological disease, exemplified by pre-operative fMRI mapping prior to neurosurgical intervention. The principal approach for generating these maps relies on brain responses evoked by a task and, despite known limitations, has dominated clinical practice for over 20years. Recently, pre-operative fMRI mapping based on correlations in spontaneous brain activity has been demonstrated, however this approach has its own limitations and has not seen widespread clinical use. Here we show that spontaneous and task-based mapping can be performed together using the same pre-operative fMRI data, provide complimentary information relevant for functional localization, and can be combined to improve identification of eloquent motor cortex. Accuracy, sensitivity, and specificity of our approach are quantified through comparison with electrical cortical stimulation mapping in eight patients with intractable epilepsy. Broad applicability and reproducibility of our approach are demonstrated through prospective replication in an independent dataset of six patients from a different center. In both cohorts and every individual patient, we see a significant improvement in signal to noise and mapping accuracy independent of threshold, quantified using receiver operating characteristic curves. Collectively, our results suggest that modifying the processing of fMRI data to incorporate both task-based and spontaneous activity significantly improves functional localization in pre-operative patients. Because this method requires no additional scan time or modification to conventional pre-operative data acquisition protocols it could have widespread utility.

Physiology of functional and effective networks in epilepsy.

Epilepsy is a network phenomenon characterized by atypical activity during seizure both at the level of single neurons and neural populations. The etiology of epilepsy is not completely understood but a common theme among proposed mechanisms is abnormal synchronization between neuronal populations. Recent advances in novel imaging and recording technologies have enabled the inference of comprehensive maps of both the anatomical and physiological inter-relationships between brain regions. Clinical protocols established for diagnosis and treatment of epilepsy utilize both advanced neuroimaging techniques and neurophysiological data. These growing clinical datasets can be further exploited to better understand the complex connectivity patterns in the epileptic brain. In this article, we review results and insights gained from the growing body of research focused on epilepsy from a network perspective. In particular, we put an emphasis on two different notions of network connectivity: functional and effective; and studies investigating these notions in epilepsy are highlighted. We also discuss limitations and opportunities in data collection and analyses that will further our understanding of epileptic networks and the mechanisms of seizures.

Corticocortical evoked potentials reveal projectors and integrators in human brain networks.

The cerebral cortex is composed of subregions whose functional specialization is largely determined by their incoming and outgoing connections with each other. In the present study, we asked which cortical regions can exert the greatest influence over other regions and the cortical network as a whole. Previous research on this question has relied on coarse anatomy (mapping large fiber pathways) or functional connectivity (mapping inter-regional statistical dependencies in ongoing activity). Here we combined direct electrical stimulation with recordings from the cortical surface to provide a novel insight into directed, inter-regional influence within the cerebral cortex of awake humans. These networks of directed interaction were reproducible across strength thresholds and across subjects. Directed network properties included (1) a decrease in the reciprocity of connections with distance; (2) major projector nodes (sources of influence) were found in peri-Rolandic cortex and posterior, basal and polar regions of the temporal lobe; and (3) major receiver nodes (receivers of influence) were found in anterolateral frontal, superior parietal, and superior temporal regions. Connectivity maps derived from electrical stimulation and from resting electrocorticography (ECoG) correlations showed similar spatial distributions for the same source node. However, higher-level network topology analysis revealed differences between electrical stimulation and ECoG that were partially related to the reciprocity of connections. Together, these findings inform our understanding of large-scale corticocortical influence as well as the interpretation of functional connectivity networks.

Evoked effective connectivity of the human neocortex.

The role of cortical connectivity in brain function and pathology is increasingly being recognized. While in vivo magnetic resonance imaging studies have provided important insights into anatomical and functional connectivity, these methodologies are limited in their ability to detect electrophysiological activity and the causal relationships that underlie effective connectivity. Here, we describe results of cortico-cortical evoked potential (CCEP) mapping using single pulse electrical stimulation in 25 patients undergoing seizure monitoring with subdural electrode arrays. Mapping was performed by stimulating adjacent electrode pairs and recording CCEPs from the remainder of the electrode array. CCEPs reliably revealed functional networks and showed an inverse relationship to distance between sites. Coregistration to Brodmann areas (BA) permitted group analysis. Connections were frequently directional with 43% of early responses and 50% of late responses of connections reflecting relative dominance of incoming or outgoing connections. The most consistent connections were seen as outgoing from motor cortex, BA6-BA9, somatosensory (SS) cortex, anterior cingulate cortex, and Broca's area. Network topology revealed motor, SS, and premotor cortices along with BA9 and BA10 and language areas to serve as hubs for cortical connections. BA20 and BA39 demonstrated the most consistent dominance of outdegree connections, while BA5, BA7, auditory cortex, and anterior cingulum demonstrated relatively greater indegree. This multicenter, large-scale, directional study of local and long-range cortical connectivity using direct recordings from awake, humans will aid the interpretation of noninvasive functional connectome studies.

Seeing scenes: topographic visual hallucinations evoked by direct electrical stimulation of the parahippocampal place area.

In recent years, functional neuroimaging has disclosed a network of cortical areas in the basal temporal lobe that selectively respond to visual scenes, including the parahippocampal place area (PPA). Beyond the observation that lesions involving the PPA cause topographic disorientation, there is little causal evidence linking neural activity in that area to the perception of places. Here, we combined functional magnetic resonance imaging (fMRI) and intracranial EEG (iEEG) recordings to delineate place-selective cortex in a patient implanted with stereo-EEG electrodes for presurgical evaluation of drug-resistant epilepsy. Bipolar direct electrical stimulation of a cortical area in the collateral sulcus and medial fusiform gyrus, which was place-selective according to both fMRI and iEEG, induced a topographic visual hallucination: the patient described seeing indoor and outdoor scenes that included views of the neighborhood he lives in. By contrast, stimulating the more lateral aspect of the basal temporal lobe caused distortion of the patient's perception of faces, as recently reported (Parvizi et al., 2012). Our results support the causal role of the PPA in the perception of visual scenes, demonstrate that electrical stimulation of higher order visual areas can induce complex hallucinations, and also reaffirm direct electrical brain stimulation as a tool to assess the function of the human cerebral cortex.