Processing of auditory novelty in human cortex during a semantic categorization task.

Auditory semantic novelty - a new meaningful sound in the context of a predictable acoustical environment - can probe neural circuits involved in language processing. Aberrant novelty detection is a feature of many neuropsychiatric disorders. This large-scale human intracranial electrophysiology study examined the spatial distribution of gamma and alpha power and auditory evoked potentials (AEP) associated with responses to unexpected words during performance of semantic categorization tasks. Participants were neurosurgical patients undergoing monitoring for medically intractable epilepsy. Each task included repeatedly presented monosyllabic words from different talkers ("common") and ten words presented only once ("novel"). Targets were words belonging to a specific semantic category. Novelty effects were defined as differences between neural responses to novel and common words. Novelty increased task difficulty and was associated with augmented gamma, suppressed alpha power, and AEP differences broadly distributed across the cortex. Gamma novelty effect had the highest prevalence in planum temporale, posterior superior temporal gyrus (STG) and pars triangularis of the inferior frontal gyrus; alpha in anterolateral Heschl's gyrus (HG), anterior STG and middle anterior cingulate cortex; AEP in posteromedial HG, lower bank of the superior temporal sulcus, and planum polare. Gamma novelty effect had a higher prevalence in dorsal than ventral auditory-related areas. Novelty effects were more pronounced in the left hemisphere. Better novel target detection was associated with reduced gamma novelty effect within auditory cortex and enhanced gamma effect within prefrontal and sensorimotor cortex. Alpha and AEP novelty effects were generally more prevalent in better performing participants. Multiple areas, including auditory cortex on the superior temporal plane, featured AEP novelty effect within the time frame of P3a and N400 scalp-recorded novelty-related potentials. This work provides a detailed account of auditory novelty in a paradigm that directly examined brain regions associated with semantic processing. Future studies may aid in the development of objective measures to assess the integrity of semantic novelty processing in clinical populations.

Magnetic Resonance Imaging of Iron Metabolism with T2* Mapping Predicts an Enhanced Clinical Response to Pharmacologic Ascorbate in Patients with GBM.

PURPOSE: Pharmacologic ascorbate (P-AscH-) is hypothesized to be an iron (Fe)-dependent tumor-specific adjuvant to chemoradiation in treating glioblastoma (GBM). This study determined the efficacy of combining P-AscH- with radiation and temozolomide in a phase II clinical trial while simultaneously investigating a mechanism-based, noninvasive biomarker in T2* mapping to predict GBM response to P-AscH- in humans. PATIENTS AND METHODS: The single-arm phase II clinical trial (NCT02344355) enrolled 55 subjects, with analysis performed 12 months following the completion of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method and compared across patient subgroups with log-rank tests. Forty-nine of 55 subjects were evaluated using T2*-based MRI to assess its utility as an Fe-dependent biomarker. RESULTS: Median OS was estimated to be 19.6 months [90% confidence interval (CI), 15.7-26.5 months], a statistically significant increase compared with historic control patients (14.6 months). Subjects with initial T2* relaxation < 50 ms were associated with a significant increase in PFS compared with T2*-high subjects (11.2 months vs. 5.7 months, P < 0.05) and a trend toward increased OS (26.5 months vs. 17.5 months). These results were validated in preclinical in vitro and in vivo model systems. CONCLUSIONS: P-AscH- combined with temozolomide and radiotherapy has the potential to significantly enhance GBM survival. T2*-based MRI assessment of tumor iron content is a prognostic biomarker for GBM clinical outcomes. See related commentary by Nabavizadeh and Bagley, p. 255.

Distribution of multiunit pitch responses recorded intracranially from human auditory cortex.

The perception of pitch is a fundamental percept, which is mediated by the auditory system, requiring the abstraction of stimulus properties related to the spectro-temporal structure of sound. Despite its importance, there is still debate as to the precise areas responsible for its encoding, which may be due to species differences or differences in the recording measures and choices of stimuli used in previous studies. Moreover, it was unknown whether the human brain contains pitch neurons and how distributed such neurons might be. Here, we present the first study to measure multiunit neural activity in response to pitch stimuli in the auditory cortex of intracranially implanted humans. The stimulus sets were regular-interval noise with a pitch strength that is related to the temporal regularity and a pitch value determined by the repetition rate and harmonic complexes. Specifically, we demonstrate reliable responses to these different pitch-inducing paradigms that are distributed throughout Heschl's gyrus, rather than being localized to a particular region, and this finding was evident regardless of the stimulus presented. These data provide a bridge across animal and human studies and aid our understanding of the processing of a critical percept associated with acoustic stimuli.

Gamma Activation and Alpha Suppression within Human Auditory Cortex during a Speech Classification Task.

The dynamics of information flow within the auditory cortical hierarchy associated with speech processing and the emergence of hemispheric specialization remain incompletely understood. To study these questions with high spatiotemporal resolution, intracranial recordings in 29 human neurosurgical patients of both sexes were obtained while subjects performed a semantic classification task. Neural activity was recorded from posteromedial portion of Heschl's gyrus (HGPM) and anterolateral portion of Heschl's gyrus (HGAL), planum temporale (PT), planum polare, insula, and superior temporal gyrus (STG). Responses to monosyllabic words exhibited early gamma power increases and a later suppression of alpha power, envisioned to represent feedforward activity and decreased feedback signaling, respectively. Gamma activation and alpha suppression had distinct magnitude and latency profiles. HGPM and PT had the strongest gamma responses with shortest onset latencies, indicating that they are the earliest auditory cortical processing stages. The origin of attenuated top-down influences in auditory cortex, as indexed by alpha suppression, was in STG and HGAL. Gamma responses and alpha suppression were typically larger to nontarget words than tones. Alpha suppression was uniformly greater to target versus nontarget stimuli. Hemispheric bias for words versus tones and for target versus nontarget words, when present, was left lateralized. Better task performance was associated with increased gamma activity in the left PT and greater alpha suppression in HGPM and HGAL bilaterally. The prominence of alpha suppression during semantic classification and its accessibility for noninvasive electrophysiologic studies suggests that this measure is a promising index of auditory cortical speech processing.SIGNIFICANCE STATEMENT Understanding the dynamics of cortical speech processing requires the use of active tasks. This is the first comprehensive intracranial electroencephalography study to examine cortical activity within the superior temporal plane, lateral superior temporal gyrus, and the insula during a semantic classification task. Distinct gamma activation and alpha suppression profiles clarify the functional organization of feedforward and feedback processing within the auditory cortical hierarchy. Asymmetries in cortical speech processing emerge at early processing stages. Relationships between cortical activity and task performance are interpreted in the context of current models of speech processing. Results lay the groundwork for iEEG studies using connectivity measures of the bidirectional information flow within the auditory processing hierarchy.

Learning nonnative speech sounds changes local encoding in the adult human cortex.

Adults can learn to identify nonnative speech sounds with training, albeit with substantial variability in learning behavior. Increases in behavioral accuracy are associated with increased separability for sound representations in cortical speech areas. However, it remains unclear whether individual auditory neural populations all show the same types of changes with learning, or whether there are heterogeneous encoding patterns. Here, we used high-resolution direct neural recordings to examine local population response patterns, while native English listeners learned to recognize unfamiliar vocal pitch patterns in Mandarin Chinese tones. We found a distributed set of neural populations in bilateral superior temporal gyrus and ventrolateral frontal cortex, where the encoding of Mandarin tones changed throughout training as a function of trial-by-trial accuracy ("learning effect"), including both increases and decreases in the separability of tones. These populations were distinct from populations that showed changes as a function of exposure to the stimuli regardless of trial-by-trial accuracy. These learning effects were driven in part by more variable neural responses to repeated presentations of acoustically identical stimuli. Finally, learning effects could be predicted from speech-evoked activity even before training, suggesting that intrinsic properties of these populations make them amenable to behavior-related changes. Together, these results demonstrate that nonnative speech sound learning involves a wide array of changes in neural representations across a distributed set of brain regions.

Electrophysiology of the Human Superior Temporal Sulcus during Speech Processing.

The superior temporal sulcus (STS) is a crucial hub for speech perception and can be studied with high spatiotemporal resolution using electrodes targeting mesial temporal structures in epilepsy patients. Goals of the current study were to clarify functional distinctions between the upper (STSU) and the lower (STSL) bank, hemispheric asymmetries, and activity during self-initiated speech. Electrophysiologic properties were characterized using semantic categorization and dialog-based tasks. Gamma-band activity and alpha-band suppression were used as complementary measures of STS activation. Gamma responses to auditory stimuli were weaker in STSL compared with STSU and had longer onset latencies. Activity in anterior STS was larger during speaking than listening; the opposite pattern was observed more posteriorly. Opposite hemispheric asymmetries were found for alpha suppression in STSU and STSL. Alpha suppression in the STS emerged earlier than in core auditory cortex, suggesting feedback signaling within the auditory cortical hierarchy. STSL was the only region where gamma responses to words presented in the semantic categorization tasks were larger in subjects with superior task performance. More pronounced alpha suppression was associated with better task performance in Heschl's gyrus, superior temporal gyrus, and STS. Functional differences between STSU and STSL warrant their separate assessment in future studies.

Oscillatory correlates of auditory working memory examined with human electrocorticography.

This work examines how sounds are held in auditory working memory (AWM) in humans by examining oscillatory local field potentials (LFPs) in candidate brain regions. Previous fMRI studies by our group demonstrated blood oxygenation level-dependent (BOLD) response increases during maintenance in auditory cortex, inferior frontal cortex and the hippocampus using a paradigm with a delay period greater than 10s. The relationship between such BOLD changes and ensemble activity in different frequency bands is complex, and the long delay period raised the possibility that long-term memory mechanisms were engaged. Here we assessed LFPs in different frequency bands in six subjects with recordings from all candidate brain regions using a paradigm with a short delay period of 3 s. Sustained delay activity was demonstrated in all areas, with different patterns in the different areas. Enhancement in low frequency (delta) power and suppression across higher frequencies (beta/gamma) were demonstrated in primary auditory cortex in medial Heschl's gyrus (HG) whilst non-primary cortex showed patterns of enhancement and suppression that altered at different levels of the auditory hierarchy from lateral HG to superior- and middle-temporal gyrus. Inferior frontal cortex showed increasing suppression with increasing frequency. The hippocampus and parahippocampal gyrus showed low frequency increases and high frequency decreases in oscillatory activity. This work demonstrates sustained activity patterns during AWM maintenance, with prominent low-frequency increases in medial temporal lobe regions.

In Vivo Testing of a Prototype Intradural Spinal Cord Stimulator in a Porcine Model.

BACKGROUND: Chronic midline low back pain is the number one reason for disability in the United States despite the prolific use of medical and surgical interventions. Notwithstanding the widespread use of epidural spinal cord stimulators (SCSs), there remains a large portion of the population with inadequate pain control thought to be because of the limited volume of stimulated neural tissue. Intradural SCSs represent an underexplored alternative strategy with the potential to improve selectivity, power efficiency, and efficacy. We studied and carried out development of an intradural form of an SCS. Herein we present the findings of in vivo testing of a prototype intradural SCS in a porcine model. METHODS: Six female juvenile pigs underwent surgical investigation. One control animal underwent a laminectomy only, whereas the 5 other animals had implantation of an intradural SCS prototype. One of the prototypes was fully wired to enable acute stimulation and concurrent electromyographic recordings. All animals underwent terminal surgery 3 months postimplantation, with harvesting of the spinal column. Imaging (microcomputed tomography scan) and histopathologic examinations were subsequently performed. RESULTS: All animals survived implantation without evidence of neurologic deficits or infection. Postmortem imaging and histopathologic examination of the spinal column revealed no evidence of spinal cord damage, cerebrospinal fluid fistula formation, abnormal bony overgrowth, or dural defect. Viable dura was present between the intra- and extradural plates of the device. Electromyographic recordings revealed evoked motor units from the stimulator. CONCLUSIONS: Chronically implanted intradural device in the porcine model demonstrated safety and feasibility for translation into humans.

A Sound-Sensitive Source of Alpha Oscillations in Human Non-Primary Auditory Cortex.

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.

Differential responses to spectrally degraded speech within human auditory cortex: An intracranial electrophysiology study.

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.

Auditory Predictive Coding across Awareness States under Anesthesia: An Intracranial Electrophysiology Study.

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.SIGNIFICANCE STATEMENT 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.

Electrocorticographic delineation of human auditory cortical fields based on effects of propofol anesthesia.

The functional organization of human auditory cortex remains incompletely characterized. While the posteromedial two thirds of Heschl's gyrus (HG) is generally considered to be part of core auditory cortex, additional subdivisions of HG remain speculative. To further delineate the hierarchical organization of human auditory cortex, we investigated regional heterogeneity in the modulation of auditory cortical responses under varying depths of anesthesia induced by propofol. Non-invasive studies have shown that propofol differentially affects auditory cortical activity, with a greater impact on non-core areas. Subjects were neurosurgical patients undergoing removal of intracranial electrodes placed to identify epileptic foci. Stimuli were 50Hz click trains, presented continuously during an awake baseline period, and subsequently, while propofol infusion was incrementally titrated to induce general anesthesia. Electrocorticographic recordings were made with depth electrodes implanted in HG and subdural grid electrodes implanted over superior temporal gyrus (STG). Depth of anesthesia was monitored using spectral entropy. Averaged evoked potentials (AEPs), frequency-following responses (FFRs) and high gamma (70-150Hz) event-related band power were used to characterize auditory cortical activity. Based on the changes in AEPs and FFRs during the induction of anesthesia, posteromedial HG could be divided into two subdivisions. In the most posteromedial aspect of the gyrus, the earliest AEP deflections were preserved and FFRs increased during induction. In contrast, the remainder of the posteromedial HG exhibited attenuation of both the AEP and the FFR. The anterolateral HG exhibited weaker activation characterized by broad, low-voltage AEPs and the absence of FFRs. Lateral STG exhibited limited activation by click trains, and FFRs there diminished during induction. Sustained high gamma activity was attenuated in the most posteromedial portion of HG, and was absent in all other regions. These differential patterns of auditory cortical activity during the induction of anesthesia may serve as useful physiological markers for field delineation. In this study, the posteromedial HG could be parcellated into at least two subdivisions. Preservation of the earliest AEP deflections and FFRs in the posteromedial HG likely reflects the persistence of feedforward synaptic activity generated by inputs from subcortical auditory pathways, including the medial geniculate nucleus.

An ovine model of spinal cord injury.

OBJECTIVE: To develop a large animal model of spinal cord injury (SCI), for use in translational studies of spinal cord stimulation (SCS) in the treatment of spasticity. We seek to establish thresholds for the SCS parameters associated with reduction of post-SCI spasticity in the pelvic limbs, with implications for patients. STUDY DESIGN: The weight-drop method was used to create a moderate SCI in adult sheep, leading to mild spasticity in the pelvic limbs. Electrodes for electromyography (EMG) and an epidural spinal cord stimulator were then implanted. Behavioral and electrophysiological data were taken during treadmill ambulation in six animals, and in one animal with and without SCS at 0.1, 0.3, 0.5, and 0.9 V. SETTING: All surgical procedures were carried out at the University of Iowa. The gait measurements were made at Iowa State University. MATERIAL AND METHODS: Nine adult female sheep were used in these institutionally approved protocols. Six of them were trained in treadmill ambulation prior to SCI surgeries, and underwent gait analysis pre- and post-SCI. Stretch reflex and H-reflex measurements were also made in conscious animals. RESULTS: Gait analysis revealed repeatable quantitative differences in 20% of the key kinematic parameters of the sheep, pre- and post-SCI. Hock joint angular velocity increased toward the normal pre-injury baseline in the animal with SCS at 0.9 V. CONCLUSION: The ovine model is workable as a large animal surrogate suitable for translational studies of novel SCS therapies aimed at relieving spasticity in patients with SCI.

Neural Correlates of Vocal Production and Motor Control in Human Heschl's Gyrus.

The present study investigated how pitch frequency, a perceptually relevant aspect of periodicity in natural human vocalizations, is encoded in Heschl's gyrus (HG), and how this information may be used to influence vocal pitch motor control. We recorded local field potentials from multicontact depth electrodes implanted in HG of 14 neurosurgical epilepsy patients as they vocalized vowel sounds and received brief (200 ms) pitch perturbations at 100 Cents in their auditory feedback. Event-related band power responses to vocalizations showed sustained frequency following responses that tracked voice fundamental frequency (F0) and were significantly enhanced in posteromedial HG during speaking compared with when subjects listened to the playback of their own voice. In addition to frequency following responses, a transient response component within the high gamma frequency band (75-150 Hz) was identified. When this response followed the onset of vocalization, the magnitude of the response was the same for the speaking and playback conditions. In contrast, when this response followed a pitch shift, its magnitude was significantly enhanced during speaking compared with playback. We also observed that, in anterolateral HG, the power of high gamma responses to pitch shifts correlated with the magnitude of compensatory vocal responses. These findings demonstrate a functional parcellation of HG with neural activity that encodes pitch in natural human voice, distinguishes between self-generated and passively heard vocalizations, detects discrepancies between the intended and heard vocalization, and contains information about the resulting behavioral vocal compensations in response to auditory feedback pitch perturbations. SIGNIFICANCE STATEMENT: The present study is a significant contribution to our understanding of sensor-motor mechanisms of vocal production and motor control. The findings demonstrate distinct functional parcellation of core and noncore areas within human auditory cortex on Heschl's gyrus that process natural human vocalizations and pitch perturbations in the auditory feedback. In addition, our data provide evidence for distinct roles of high gamma neural oscillations and frequency following responses for processing periodicity in human vocalizations during vocal production and motor control.

Cost-utility and biological underpinnings of Mindfulness-Based Stress Reduction (MBSR) versus a psychoeducational programme (FibroQoL) for fibromyalgia: a 12-month randomised controlled trial (EUDAIMON study).

BACKGROUND: The EUDAIMON study focuses on fibromyalgia syndrome (FMS), a prevalent chronic condition characterized by pain, fatigue, cognitive problems and distress. According to recent reviews and meta-analyses, Mindfulness-Based Stress Reduction (MBSR) is a promising therapeutic approach for patients with FMS. The measurement of biomarkers as part of the analysis of MBSR effects would help to identify the neurobiological underpinnings of MBSR and increase our knowledge of FMS pathophysiology. The main objectives of this 12-month RCT are: firstly, to examine the effectiveness and cost-utility for FMS patients of MBSR as an add-on to treatment as usual (TAU) versus TAU + the psychoeducational programme FibroQoL, and versus TAU only; secondly, to examine pre-post differences in brain structure and function, as well as levels of specific inflammatory markers in the three study arms and; thirdly, to analyse the role of some psychological variables as mediators of 12-month clinical outcomes. METHODS: Effectiveness, cost-utility, and neurobiological analyses performed alongside a 12-month RCT. The participants will be 180 adult patients with FMS recruited at the Sant Joan de Déu hospital (St. Boi de Llobregat, Spain), randomly allocated to one of the three study arms: TAU + MBSR vs. TAU + FibroQol vs. TAU. A comprehensive assessment to collect functional, quality of life, distress, costs, and psychological variables will be conducted pre-, post-intervention, and at 12-month post-intervention. Fifty per cent of study participants will be evaluated at pre- and post-treatment using Voxel-Based Morphometry, Diffusion Tensor Imaging, pseudo-continuous Arterial Spin Labeling, and resting state fMRI. A cytokine multiplex kit of high-sensitivity will be applied (cytokines IL-6, IL-8, IL-10 + high-sensitivity CRP test). DISCUSSION: The findings obtained from this RCT will indicate whether MBSR is potentially cost-effective for FMS and contribute to knowledge of any brain and inflammatory changes associated with MBSR in FMS patients. Specifically, we will determine whether there are morphometric and functional changes associated with participation in MBSR in brain regions related to meta-awareness, body awareness, memory consolidation-reconsolidation, emotion regulation and in networks postulated to underpin the sensory-discriminative, cognitive-evaluative and affective-motivational aspects of the pain experience. TRIAL REGISTRATION: NCT02561416 . Registered 23 September 2015.

Invasive recordings in the human auditory cortex.

This chapter provides an overview of current invasive recording methodology and experimental paradigms used in the studies of human auditory cortex. Invasive recordings can be obtained from neurosurgical patients undergoing clinical electrophysiologic evaluation for medically refractory epilepsy or brain tumors. This provides a unique research opportunity to study the human auditory cortex with high resolution both in time (milliseconds) and space (millimeters) and to generate valuable information about its organization and function. A historic overview presents the development of the experimental approaches from the pioneering works of Wilder Penfield to modern day. Practical issues regarding research subject population, stimulus presentation, data collection, and analysis are discussed for acute (intraoperative) and chronic experiments. Illustrative examples are provided from experimental paradigms, including studies of spectrotemporal processing, functional connectivity, and functional lesioning in human auditory cortex.

Sensory-motor networks involved in speech production and motor control: an fMRI study.

Speaking is one of the most complex motor behaviors developed to facilitate human communication. The underlying neural mechanisms of speech involve sensory-motor interactions that incorporate feedback information for online monitoring and control of produced speech sounds. In the present study, we adopted an auditory feedback pitch perturbation paradigm and combined it with functional magnetic resonance imaging (fMRI) recordings in order to identify brain areas involved in speech production and motor control. Subjects underwent fMRI scanning while they produced a steady vowel sound /a/ (speaking) or listened to the playback of their own vowel production (playback). During each condition, the auditory feedback from vowel production was either normal (no perturbation) or perturbed by an upward (+600 cents) pitch-shift stimulus randomly. Analysis of BOLD responses during speaking (with and without shift) vs. rest revealed activation of a complex network including bilateral superior temporal gyrus (STG), Heschl's gyrus, precentral gyrus, supplementary motor area (SMA), Rolandic operculum, postcentral gyrus and right inferior frontal gyrus (IFG). Performance correlation analysis showed that the subjects produced compensatory vocal responses that significantly correlated with BOLD response increases in bilateral STG and left precentral gyrus. However, during playback, the activation network was limited to cortical auditory areas including bilateral STG and Heschl's gyrus. Moreover, the contrast between speaking vs. playback highlighted a distinct functional network that included bilateral precentral gyrus, SMA, IFG, postcentral gyrus and insula. These findings suggest that speech motor control involves feedback error detection in sensory (e.g. auditory) cortices that subsequently activate motor-related areas for the adjustment of speech parameters during speaking.

Direct physiologic evidence of a heteromodal convergence region for proper naming in human left anterior temporal lobe.

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.

Modulation of response patterns in human auditory cortex during a target detection task: an intracranial electrophysiology study.

Selective attention enhances cortical activity representing an attended sound stream in human posterolateral superior temporal gyrus (PLST). It is unclear, however, what mechanisms are associated with a target detection task that necessitates sustained attention (vigilance) to a sound stream. We compared responses elicited by target and non-target sounds, and to sounds presented in a passive-listening paradigm. Subjects were neurosurgical patients undergoing invasive monitoring for medically refractory epilepsy. Stimuli were complex tones, band-limited noise bursts and speech syllables. High gamma cortical activity (70-150 Hz) was examined in all subjects using subdural grid electrodes implanted over PLST. Additionally, responses were measured from depth electrodes implanted within Heschl's gyrus (HG) in one subject. Responses to target sounds recorded from PLST were increased when compared to responses elicited by the same sounds when they were not-targets, and when they were presented during passive listening. Increases in high gamma activity to target sounds occurred during later portions (after 250 ms) of the response. These increases were related to the task and not to detailed stimulus characteristics. In contrast, earlier activity that did not vary across conditions did represent stimulus acoustic characteristics. Effects observed on PLST were not noted in HG. No consistent effects were noted in the averaged evoked potentials in either cortical region. We conclude that task dependence modulates later activity in PLST during vigilance. Later activity may represent feedback from higher cortical areas. Study of concurrently recorded activity from frontoparietal areas is necessary to further clarify task-related modulation of activity on PLST.

Postsurgical pathologies associated with intradural electrical stimulation in the central nervous system: design implications for a new clinical device.

Spinal cord stimulation has been utilized for decades in the treatment of numerous conditions such as failed back surgery and phantom limb syndromes, arachnoiditis, cancer pain, and others. The placement of the stimulating electrode array was originally subdural but, to minimize surgical complexity and reduce the risk of certain postsurgical complications, it became exclusively epidural eventually. Here we review the relevant clinical and experimental pathologic findings, including spinal cord compression, infection, hematoma formation, cerebrospinal fluid leakage, chronic fibrosis, and stimulation-induced neurotoxicity, associated with the early approaches to subdural electrical stimulation of the central nervous system, and the spinal cord in particular. These findings may help optimize the safety and efficacy of a new approach to subdural spinal cord stimulation now under development.