Search

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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.

Objective: A significant proportion of the more than 50 million people worldwide currently suffering with epilepsy are resistant to antiepileptic drugs (AEDs). As an alternative to AEDs, novel therapies based on cell transplantation offer an opportunity for long-lasting modification of epileptic circuits. To develop such a treatment requires careful preclinical studies in a chronic epilepsy model featuring unprovoked seizures, hippocampal histopathology, and behavioral comorbidities., Methods: Transplantation of progenitor cells from embryonic medial or caudal ganglionic eminence (MGE, CGE) were made in a well-characterized mouse model of status epilepticus-induced epilepsy (systemic pilocarpine). Behavioral testing (handling and open field), continuous video-electroencephalographic (vEEG) monitoring, and slice electrophysiology outcomes were obtained up to 270 days after transplantation (DAT). Post-hoc immunohistochemistry was used to confirm cell identity., Results: MGE progenitors transplanted into the hippocampus of epileptic mice rescued handling and open field deficits starting at 60 DAT. In these same mice, an 84% to 88% reduction in seizure activity was observed between 180 and 210 DAT. Inhibitory postsynaptic current frequency, measured on pyramidal neurons in acute hippocampal slices at 270 DAT, was reduced in epileptic mice but restored to naïve levels in epileptic mice receiving MGE transplants. No reduction in seizure activity was observed in epileptic mice receiving intrahippocampal CGE progenitors., Interpretation: Our findings demonstrate that transplanted MGE progenitors enhance functional GABA-mediated inhibition, reduce spontaneous seizure frequency, and rescue behavioral deficits in a chronic epileptic animal model more than 6 months after treatment. Ann Neurol 2017;82:530-542., (© 2017 American Neurological Association.)

Neurosurgery for the treatment of psychological disorders has a checkered history in the United States. Prior to the advent of antipsychotic medications, individuals with severe mental illness were institutionalized and subjected to extreme therapies in an attempt to palliate their symptoms. Psychiatrist Walter Freeman first introduced psychosurgery, in the form of frontal lobotomy, as an intervention that could offer some hope to those patients in whom all other treatments had failed. Since that time, however, the use of psychosurgery in the United States has waxed and waned significantly, though literature describing its use is relatively sparse. In an effort to contribute to a better understanding of the evolution of psychosurgery, the authors describe the history of psychosurgery in the state of Iowa and particularly at the University of Iowa Department of Neurosurgery. An interesting aspect of psychosurgery at the University of Iowa is that these procedures have been nearly continuously active since Freeman introduced the lobotomy in the 1930s. Frontal lobotomies and transorbital leukotomies were performed by physicians in the state mental health institutions as well as by neurosurgeons at the University of Iowa Hospitals and Clinics (formerly known as the State University of Iowa Hospital). Though the early technique of frontal lobotomy quickly fell out of favor, the use of neurosurgery to treat select cases of intractable mental illness persisted as a collaborative treatment effort between psychiatrists and neurosurgeons at Iowa. Frontal lobotomies gave way to more targeted lesions such as anterior cingulotomies and to neuromodulation through deep brain stimulation. As knowledge of brain circuits and the pathophysiology underlying mental illness continues to grow, surgical intervention for psychiatric pathologies is likely to persist as a viable treatment option for select patients at the University of Iowa and in the larger medical community.

The tragedy of epilepsy emerges from the combination of its high prevalence, impact upon sufferers and their families, and unpredictability. Childhood epilepsies are frequently severe, presenting in infancy with pharmaco-resistant seizures; are often accompanied by debilitating neuropsychiatric and systemic comorbidities; and carry a grave risk of mortality. Here, we review the most current basic science and translational research findings on several of the most catastrophic forms of pediatric epilepsy. We focus largely on genetic epilepsies and the research that is discovering the mechanisms linking disease genes to epilepsy syndromes. We also describe the strides made toward developing novel pharmacological and interventional treatment strategies to treat these disorders. The research reviewed provides hope for a complete understanding of, and eventual cure for, these childhood epilepsy syndromes.

Introduction: Millions of people worldwide suffer with spasticity related to irreversible damage to the brain or spinal cord. Typical antecedent events include stroke, traumatic brain injury, and spinal cord injury, although insidious onset is also common. Regardless of the cause, the resulting spasticity leads to years of disability and reduced quality of life. Many treatments are available to manage spasticity; yet each is fraught with drawbacks including incomplete response, high cost, limited duration, dose-limiting side effects, and periodic maintenance. Spinal cord stimulation (SCS), a once promising therapy for spasticity, has largely been relegated to permanent experimental status., Methods: In this review, our goal is to document and critique the history and assess the development of SCS as a treatment of lower limb spasticity. By incorporating recent discoveries with the insights gained from the early pioneers in this field, we intend to lay the groundwork needed to propose testable hypotheses for future studies., Results: SCS has been tested in over 25 different conditions since a potentially beneficial effect was first reported in 1973. However, the lack of a fully formed understanding of the pathophysiology of spasticity, archaic study methodology, and the early technological limitations of implantable hardware limit the validity of many studies. SCS offers a measure of control for spasticity that cannot be duplicated with other interventions., Conclusions: With improved energy-source miniaturization, tailored control algorithms, novel implant design, and a clearer picture of the pathophysiology of spasticity, we are poised to reintroduce and test SCS in this population., (© 2017 International Neuromodulation Society.)

Objective: Define the indications and outcomes for subjects undergoing treatment utilizing the extended middle cranial fossa approach (EMCF)., Study Design: Retrospective records review., Setting: University-based tertiary referral center., Patients: Subjects undergoing treatment of posterior cranial fossa (PCF) lesions., Intervention(s): EMCF exposure and treatment of the indicating PCF lesion., Main Outcome Measure(s): Demographic, audiometric, and cranial nerve functioning variables were assessed., Results: Thirty-five subjects who underwent an EMCF exposure were identified over a 12-year period. The most common indication was meningioma (18; 51%) followed by schwannomas (six, 17%), and vascular lesions (five, 14%). Preoperative cranial nerve complaints were common (32, 94%) as were objective cranial nerve abnormalities on physical examination (21; 60%). Preoperative audiometric data from subjects with hearing demonstrated good functioning including pure-tone average (PTA) (21.7 ± 15.6 dB HL) and word understanding scores (95.1 ± 7.4%). Most (34, 97%) subjects had intact facial nerve function. The average length of stay was 11.6 days (median = 9). Cranial neuropathies were common postoperatively with 27 (79%) subjects demonstrating some objective cranial nerve dysfunction, the most common of which was trigeminal nerve hypesthesia (21, 61.7%). Subjects with identifiable pre- and postoperative audiometric data and preoperative hearing demonstrated small declines in the four-tone average (16.2 dB) and word recognition scores (22.4%). Two subjects (6%) had new profound hearing loss postoperatively., Conclusions: The EMCF approach can provide safe and effective exposure of the anterior PCF.

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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.

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.

The production and perception of music is preferentially mediated by cortical areas within the right hemisphere, but little is known about how these brain regions individually contribute to this process. In an experienced singer undergoing awake craniotomy, we demonstrated that direct electrical stimulation to a portion of the right posterior superior temporal gyrus (pSTG) selectively interrupted singing but not speaking. We then focally cooled this region to modulate its activity during vocalization. In contrast to similar manipulations in left hemisphere speech production regions, pSTG cooling did not elicit any changes in vocal timing or quality. However, this manipulation led to an increase in the pitch of speaking with no such change in singing. Further analysis revealed that all vocalizations exhibited a cooling-induced increase in the frequency of the first formant, raising the possibility that potential pitch offsets may have been actively avoided during singing. Our results suggest that the right pSTG plays a key role in vocal sensorimotor processing whose impact is dependent on the type of vocalization produced., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: We review the types, indications, and common regimens of systemic forms of therapy offered in early-stage breast cancer. We further detail the mechanism of action, approved uses, major toxicities, and relevance to breast reconstruction of specific agents. Methods: A review of the literature on PubMed and Cochrane databases was undertaken to define the indications and common regimens of systemic therapy in early-stage breast cancer. In addition, literature describing relevant information regarding specific systemic agents was reviewed. Results: The main objectives of systemic therapy, when provided in the perioperative setting, are to reduce the risk for future recurrence and prolong overall survival. Systemic forms of therapy consist of chemotherapy, hormonal therapy, and targeted therapy and are increasingly being offered to women with early-stage breast cancer. Similarly, as more women are diagnosed with disease that is amenable to surgical extirpation, rates of breast reconstruction are on the rise. Many agents have effects that may impact patient safety with respect to breast reconstruction. Conclusions: Increasingly, women with breast cancer receive 1 or more forms of systemic therapy during the course of their treatment. It is therefore of significant importance that plastic surgeons have a clear understanding of the issues surrounding the use of systemic agents.

Background: Understanding brain function requires knowledge of how one brain region causally influences another. This information is difficult to obtain directly in the human brain, and is instead typically inferred from resting-state fMRI., New Method: Here, we demonstrate the safety and scientific promise of a novel and complementary approach: concurrent electrical stimulation and fMRI (es-fMRI) at 3T in awake neurosurgical patients with implanted depth electrodes., Results: We document the results of safety testing, actual experimental setup, and stimulation parameters, that safely and reliably evoke activation in distal structures through stimulation of amygdala, cingulate, or prefrontal cortex. We compare connectivity inferred from the evoked patterns of activation with that estimated from standard resting-state fMRI in the same patients: while connectivity patterns obtained with each approach are correlated, each method produces unique results. Response patterns were stable over the course of 11min of es-fMRI runs. COMPARISON WITH EXISTING METHOD: es-fMRI in awake humans yields unique information about effective connectivity, complementing resting-state fMRI. Although our stimulations were below the level of inducing any apparent behavioral or perceptual effects, a next step would be to use es-fMRI to modulate task performances. This would reveal the acute network-level changes induced by the stimulation that mediate the behavioral and cognitive effects seen with brain stimulation., Conclusions: es-fMRI provides a novel and safe approach for mapping effective connectivity in the human brain in a clinical setting, and will inform treatments for psychiatric and neurodegenerative disorders that use deep brain stimulation., (Copyright © 2016 Elsevier B.V. All rights reserved.)

After immigrating to the United States from Russia in the wake of the First World War, Anatole Kolodny became the first surgeon in Iowa to specialize in neurological surgery. Kolodny was vital to the initial practice of neurosurgery in the state of Iowa and to the specific development of academic neurosurgery at the University of Iowa. In an effort to improve his surgical outcomes, Kolodny invented a hemostat that bears his name and is still used for cranial hemostasis. He also provided early outcomes of myelomenigocele repair and wrote extensively on bone sarcoma. Kolodny's achievements brought favorable attention to the university and altered the course of neurosurgery at the University of Iowa. Of significant importance, Kolodny influenced and trained Iowa's second neurosurgeon, Olan Hyndman, and this action led the way to the eventual recruitment of the university's first division head of neurosurgery. The purpose of this manuscript is to shed light on Kolodny's important contributions to the development of neurosurgery not only at Iowa, but also in the profession as a whole., (Copyright © 2016 by the Congress of Neurological Surgeons.)

Advances in functional neurosurgery, including neuromodulation and more recently ultrasonic ablation of basal ganglia structures, have improved the quality of life for patients with debilitating movement disorders. What is little known, however, is that both of these neurosurgical advances, which remain on the cutting edge, have their origin in the pioneering work of Russell Meyers, whose contributions are documented in this paper. Meyers' published work and professional correspondence are reviewed, in addition to documents held by the Department of Neurosurgery at the University of Iowa. Meyers was born in Brooklyn, New York, and received his neurosurgical training at hospitals in New York City under Jefferson Browder. In 1939, a chance encounter with a young woman with damaged bilateral ventral striata convinced Meyers that the caudate could be resected to treat Parkinsonism without disrupting consciousness. Shortly thereafter, he performed the first caudate resection for postencephalitic Parkinsonism. In 1946, Meyers became the first chairman of neurosurgery at the State University of Iowa (now the University of Iowa), which led to the recruitment of 8 faculty members and the training of 18 residents during his tenure (1946-1963). Through collaboration with the Fry brothers at the University of Illinois, Meyers performed the first stereotactic ultrasonic ablations of deep brain structures to treat tremor, choreoathetosis, dystonia, intractable pain, and hypothalamic hamartoma. Meyers left academic neurosurgery in 1963 for reasons that are unclear, but he continued clinical neurosurgery work for several more years. Despite his early departure from academic medicine, Meyers' contributions to functional neurosurgery provided a lasting legacy that has improved the lives of many patients with movement disorders.

Background: Decompressive craniectomy procedures are performed in patients with malignant intracranial hypertension. A bone flap is removed to relieve pressure. Later, a second operation is performed to reconstruct the skull after brain swelling has resolved. This surgical treatment would be improved if it were possible to perform a single operation that decompressed the brain acutely and eliminated the need for a second operation. To design a device and procedure that achieve this objective, it is essential to understand how the brain swells after a craniectomy procedure., Methods: We identified 20 patients with ischemic stroke who underwent a decompressive hemicraniectomy operation. Skull defect morphology and postoperative brain swelling were measured using computed tomography scan data. Additional intracranial volume created by placing a hypothetical cranial plate implant offset from the skull surface by 5 mm was measured for each patient., Results: The average craniectomy area and brain herniation volume was 9999 ± 1283 mm 2 and 30.48 ± 23.56 mL, respectively. In all patients, the additional volume created by this hypothetical implant exceeded the volume of brain herniation observed., Conclusions: These findings show that a cranial plate with a 5-mm offset accommodates the brain swelling that occurs in this patient population., (Copyright © 2016. Published by Elsevier Inc.)

Background: Cervical spondylotic myelopathy (CSM) is a common disease of aging that leads to gait instability resulting from loss of leg sensory and motor functions. The results of surgical intervention have been studied using a variety of methods, but no test has been reported that objectively measures integrative leg motor sensory functions in CSM patients., Objective: To determine the feasibility of using a novel single leg squat (SLS) test to measure integrative motor sensory functions in patients with CSM before and after surgery., Methods: Fifteen patients with CSM were enrolled in this prospective study. Clinical data and scores from standard outcomes questionnaires were obtained before and after surgery. Patients also participated in experimental test protocols consisting of standard kinematic gait testing, the Purdue pegboard test, and the novel SLS test., Results: The SLS test protocol was well tolerated by CSM patients and generated objective performance data over short test periods. In patients who participated in postoperative testing, the group measures of mean SLS errors decreased following surgery. Gait velocity measures followed a similar pattern of group improvement postoperatively. Practical barriers to implementing this extensive battery of tests resulted in subject attrition over time. Compared with kinematic gait testing, the SLS protocol required less space and could be effectively implemented more efficiently., Conclusions: The SLS test provides a practical means of obtaining objective measures of leg motor sensory functions in patients with CSM. Additional testing with a larger cohort of patients is required to use SLS data to rigorously examine group treatment effects., Abbreviations: BW, body weightCSM, cervical spondylotic myelopathymJOA, modified Japanese Orthopedic AssociationSLS, single leg squat.

Inactivating mutations of the TSC1/TSC2 complex (TSC1/2) cause tuberous sclerosis (TSC), a hereditary syndrome with neurological symptoms and benign hamartoma tumours in the brain. Since TSC effectors are largely unknown in the human brain, TSC patient cortical tubers were used to uncover hyperphosphorylation unique to TSC primary astrocytes, the cell type affected in the brain. We found abnormal hyperphosphorylation of catenin delta-1 S268, which was reversible by mTOR-specific inhibitors. In contrast, in three metastatic astrocytoma cell lines, S268 was under phosphorylated, suggesting S268 phosphorylation controls metastasis. TSC astrocytes appeared epithelial (i.e. tightly adherent, less motile, and epithelial (E)-cadherin positive), whereas wild-type astrocytes were mesenchymal (i.e. E-cadherin negative and highly motile). Despite their epithelial phenotype, TSC astrocytes outgrew contact inhibition, and monolayers sporadically generated tuberous foci, a phenotype blocked by the mTOR inhibitor, Torin1. Also, mTOR-regulated phosphokinase C epsilon (PKCe) activity induced phosphorylation of catenin delta-1 S268, which in turn mediated cell-cell adhesion in astrocytes. The mTOR-dependent, epithelial phenotype of TSC astrocytes suggests TSC1/2 and mTOR tune the phosphorylation level of catenin delta-1 by controlling PKCe activity, thereby regulating the mesenchymal-epithelial-transition (MET). Thus, some forms of TSC could be treated with PKCe inhibitors, while metastasis of astrocytomas might be blocked by PKCe stimulators., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background and Objectives: The authors sought to study patient-reported outcomes following nipple-sparing mastectomy (NSM)., Methods: From 2008 to 2011, the BREAST-Q was administered to women undergoing NSM surgery for cancer treatment or risk-reduction prior to surgery and at 2 years after completion of reconstruction. The change in score over time and the impact of surgical indication, complication occurrence, and laterality on scores were analyzed., Results: The BREAST-Q was prospectively administered to 39 women undergoing NSM for cancer treatment (n = 17) or risk-reduction (RR) (n = 22). At 2 years after operation, median overall satisfaction with breasts was 75 (IQR = 67,100). There were significant postoperative increases in scores for overall satisfaction with breasts (+8, P = 0.021) and psychosocial well-being (+14, P = 0.003). Postoperatively, RR patients had significantly higher scores for psychosocial wellness, physical impact (chest), and overall satisfaction with outcome compared to cancer treatment patients (P < 0.05). Also, increase from preoperative to postoperative psychosocial wellness was higher in the RR compared to cancer treatment patients (+17 vs. +1, P = 0.043). Complication occurrence did not significantly impact postoperative scores., Conclusions: Following NSM for cancer treatment or RR, patients demonstrated high levels of satisfaction and quality of life as measured by BREAST-Q. Satisfaction level increased 2 years following operation. J. Surg. Oncol. 2016;114:416-422. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Interneuron-based cell transplantation is a powerful method to modify network function in a variety of neurological disorders, including epilepsy. Whether new interneurons integrate into native neural networks in a subtype-specific manner is not well understood, and the therapeutic mechanisms underlying interneuron-based cell therapy, including the role of synaptic inhibition, are debated. In this study, we tested subtype-specific integration of transplanted interneurons using acute cortical brain slices and visualized patch-clamp recordings to measure excitatory synaptic inputs, intrinsic properties, and inhibitory synaptic outputs. Fluorescently labeled progenitor cells from the embryonic medial ganglionic eminence (MGE) were used for transplantation. At 5 wk after transplantation, MGE-derived parvalbumin-positive (PV+) interneurons received excitatory synaptic inputs, exhibited mature interneuron firing properties, and made functional synaptic inhibitory connections to native pyramidal cells that were comparable to those of native PV+ interneurons. These findings demonstrate that MGE-derived PV+ interneurons functionally integrate into subtype-appropriate physiological niches within host networks following transplantation., (Copyright © 2016 the American Physiological Society.)

Naming people, places, and things is a fundamental human ability that is often impaired in patients with language-dominant anterior temporal lobe (ATL) dysfunction or ATL resection as part of epilepsy treatment. Convergent lines of evidence point to the importance of the ATL in name retrieval. The physiologic mechanisms that mediate name retrieval in the ATL, however, are not well understood. The purpose of this study was to characterize the electrophysiologic responses of the human ATL during overt cued naming of famous people and objects. Eight neurosurgical patients with suspected temporal lobe epilepsy who underwent implantation of intracranial electrodes for seizure focus localization were the subjects of this study. Specialized coverage of the ATL was achieved in each subject. The subjects named pictures of U.S. presidents and images of common hand-held tools. Event-related band power was measured for each ATL recording site. Both the left and right ATL demonstrated robust and focal increases in beta-band (14-30 Hz) power during person and tool naming. The onset of this response typically occurred at 400 ms but sometimes as early as 200 ms. Visual naming of famous people and tools is associated with robust and localized modulation of the beta band in both the left and right ATL. Measurement of visual naming responses may provide the groundwork for future mapping modalities to localize eloquent cortex in the ATL., (Copyright © 2016 the American Physiological Society.)

OBJECT Anterior skull base meningiomas are frequently associated with changes in personality and behavior. Although such meningiomas often damage the ventromedial prefrontal cortex (vmPFC), which is important for higher cognition, the cognitive and behavioral effects of these meningiomas remain poorly understood. Using detailed neuropsychological assessments in a large series of patients, this study examined the cognitive and behavioral effects of meningioma lesions involving the vmPFC. METHODS The authors reviewed neuropsychology and lesion mapping records of 70 patients who underwent resection of meningiomas. The patients were drawn from the Neurological Patient Registry at the University of Iowa. Patients were sorted into 2 groups: those with lesions involving the vmPFC and those with lesions that did not involve the vmPFC. Neuropsychological data pertaining to a comprehensive array of cognitive and behavioral domains were available preoperatively in 20 patients and postoperatively in all 70 patients. RESULTS No change occurred in basic cognitive functions (e.g., attention, perception, memory, construction and motor performance, language, or executive functions) from the preoperative to postoperative epochs for the vmPFC and non-vmPFC groups. There was a significant decline in the behavioral domain, specifically adaptive function, for both the vmPFC and non-vmPFC groups, and this decline was more pronounced for the vmPFC group. Additionally, postoperative data indicated that the vmPFC group had a specific deficit in value-based decision making, as evidenced by poor performance on the Iowa Gambling Task, compared with the non-vmPFC group. The vmPFC and non-vmPFC groups did not differ postoperatively on other cognitive measures, including intellect, memory, language, and perception. CONCLUSIONS Lesions of the vmPFC resulting from meningiomas are associated with specific deficits in adaptive function and value-based decision making. Meningioma patients showed a decline in adaptive function postoperatively, and this decline was especially notable in patients with vmPFC region meningiomas. Early detection and resection of meningiomas of the anterior skull base (involving the gyrus rectus) may prevent these deficits.

Background: Animal and human studies highlight the role of oxytocin in social cognition and behavior and the potential of intranasal oxytocin (IN-OT) to treat social impairment in individuals with neuropsychiatric disorders such as autism. However, extensive efforts to evaluate the central actions and therapeutic efficacy of IN-OT may be marred by the absence of data regarding its temporal dynamics and sites of action in the living human brain., Methods: In a placebo-controlled study, we used arterial spin labeling to measure IN-OT-induced changes in resting regional cerebral blood flow (rCBF) in 32 healthy men. Volunteers were blinded regarding the nature of the compound they received. The rCBF data were acquired 15 min before and up to 78 min after onset of treatment onset (40 IU of IN-OT or placebo). The data were analyzed using mass univariate and multivariate pattern recognition techniques., Results: We obtained robust evidence delineating an oxytocinergic network comprising regions expected to express oxytocin receptors, based on histologic evidence, and including core regions of the brain circuitry underpinning social cognition and emotion processing. Pattern recognition on rCBF maps indicated that IN-OT-induced changes were sustained over the entire posttreatment observation interval (25-78 min) and consistent with a pharmacodynamic profile showing a peak response at 39-51 min., Conclusions: Our study provides the first visualization and quantification of IN-OT-induced changes in rCBF in the living human brain unaffected by cognitive, affective, or social manipulations. Our findings can inform theoretical and mechanistic models regarding IN-OT effects on typical and atypical social behavior and guide future experiments (e.g., regarding the timing of experimental manipulations)., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Oxytocin is a neuropeptide regulating social-affiliative and reproductive behaviour in mammals. Despite robust preclinical evidence for the antinociceptive effects and mechanisms of action of exogenous oxytocin, human studies have produced mixed results regarding the analgesic role of oxytocin and are yet to show a specific modulation of neural processes involved in pain perception. In the present study, we investigated the analgesic effects of 40 IU of intranasal oxytocin in 13 healthy male volunteers using a double-blind, placebo-controlled, cross-over design and brief radiant heat pulses generated by an infrared laser that selectively activate Aδ- and C-fibre nerve endings in the epidermis, at the same time as recording the ensuing laser-evoked potentials (LEPs). We predicted that oxytocin would reduce subjective pain ratings and attenuate the amplitude of the N1, N2 and P2 components. We observed that oxytocin attenuated perceived pain intensity and the local peak amplitude of the N1 and N2 (but not of P2) LEPs, and increased the latency of the N2 component. Importantly, for the first time, the present study reports an association between the analgesic effect of oxytocin (reduction in subjective pain ratings) and the oxytocin-induced modulation of cortical activity after noxious stimulation (attenuation of the N2 LEP). These effects indicate that oxytocin modulates neural processes contributing to pain perception. The present study reports preliminary evidence that is consistent with electrophysiological studies in rodents showing that oxytocin specifically modulates Aδ/C-fibre nociceptive afferent signalling at the spinal level and provides further specificity to evidence obtained in humans indicating that oxytocin may be modulating pain experience by modulating activity in the cortical areas involved in pain processing., (© 2015 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Objective: Compare therapeutic response of patients to conventional versus high-frequency spinal cord stimulation (SCS)., Methods: Twelve patients with back and leg pain who met standard clinical criteria for a trial of conventional SCS (low-frequency stimulation [LFS]) participated in a half-day session of high-frequency stimulation (HFS) during their weeklong conventional trial. HFS consisted of frequencies ranging from 50 Hz to 4 kHz, or 100 Hz to10 kHz, at constant voltage settings increasing from 0.5 V to 10 V. Visual Analog Scale scores from 0 to10 were recorded, along with notes of any clinical discomfort and open patient comments., Results: Two of 12 patients had no benefit from either LFS or HFS. In the remaining 10 patients, paresthesias were significantly altered by HFS, and four experienced complete elimination of paresthesias. Five patients preferred HFS to LFS, with an additional three preferring both equally. Abrupt sensation to the onset of HFS was described in six patients, and in ten patients, HFS allowed maximum voltage stimulation of 10 V without discomfort. The four patients who did not have a successful trial of stimulation had significantly longer duration of pain compared to the eight patients who went on to permanent implant (11.2 vs. 4.3 years, P = 0.04)., Conclusions: HFS significantly altered the feeling of paresthesias in the majority of patients (ten of 12), was preferred to LFS in five of 12 patients, and non-inferior to LFS in eight of 12 patients. Both 4 kHz and 10 kHz stimulation allowed patients to benefit from HFS. HFS allowed maximum voltage stimulation without discomfort., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Spoken language is a central part of our everyday lives, but the precise roles that individual cortical regions play in the production of speech are often poorly understood. To address this issue, we focally lowered the temperature of distinct cortical regions in awake neurosurgical patients, and we relate this perturbation to changes in produced speech sequences. Using this method, we confirm that speech is highly lateralized, with the vast majority of behavioral effects seen on the left hemisphere. We then use this approach to demonstrate a clear functional dissociation between nearby cortical speech sites. Focal cooling of pars triangularis/pars opercularis (Broca's region) and the ventral portion of the precentral gyrus (speech motor cortex) resulted in the manipulation of speech timing and articulation, respectively. Our results support a class of models that have proposed distinct processing centers underlying motor sequencing and execution for speech., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Generative models, such as predictive coding, posit that perception results from a combination of sensory input and prior prediction, each weighted by its precision (inverse variance), with incongruence between these termed prediction error (deviation from prediction) or surprise (negative log probability of the sensory input). However, direct evidence for such a system, and the physiological basis of its computations, is lacking. Using an auditory stimulus whose pitch value changed according to specific rules, we controlled and separated the three key computational variables underlying perception, and discovered, using direct recordings from human auditory cortex, that surprise due to prediction violations is encoded by local field potential oscillations in the gamma band (>30 Hz), changes to predictions in the beta band (12-30 Hz), and that the precision of predictions appears to quantitatively relate to alpha band oscillations (8-12 Hz). These results confirm oscillatory codes for critical aspects of generative models of perception.

Ventriculoperitoneal (VP) shunt placement is used to treat hydrocephalus. Shunt migration following VP shunt placement has been reported. The risk factors related to this complication have not been previously evaluated to our knowledge. In this retrospective cohort study, we aimed to determine risk factors leading to distal catheter migration and review the literature on the current methods of management and prevention. Adult patients undergoing VP shunt placement from June 2011 to December 2013 at a single institution were identified using electronic health records. The records were reviewed for demographic and procedural information, and subsequent treatment characteristics. The parameters of patients with distal shunt migration were compared to those undergoing new VP shunt placement for the same time period. We identified 137 patients undergoing 157 new VP shunt procedures with an average age of 57.7 ± standard deviation of 18.4 years old. There were 16 distal shunt migrations. Body mass index >30 kg/m(2) and number of previous shunt procedures were found to be independent risk factors for distal catheter migration. Obesity and number of previous shunt procedures were factors for distal catheter migration. Providers and patients should be aware of these possible risk factors prior to VP shunt placement., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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.

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., (Copyright © 2016 the authors 0270-6474/16/362302-14$15.00/0.)

Cervical spondylotic myelopathy (CSM) is the leading cause of spinal cord related disability in the elderly. It results from degenerative narrowing of the spinal canal, which causes spinal cord compression. This leads to gait instability, loss of dexterity, weakness, numbness and urinary dysfunction. There has been indirect data that implicates a genetic component to CSM. Such a finding may contribute to the variety in presentation and outcome in this patient population. The Val66Met polymorphism, a mutation in the brain derived neurotrophic factor (BDNF) gene, has been implicated in a number of brain and psychological conditions, and here we investigate its role in CSM. Ten subjects diagnosed with CSM were enrolled in this prospective study. Baseline clinical evaluation using the modified Japanese Orthopaedic Association (mJOA) scale, Nurick and 36-Item Short Form Health Survey (SF-36) were collected. Each subject underwent objective testing with gait kinematics, as well as hand functioning using the Purdue Peg Board. Blood samples were analyzed for the BDNF Val66Met mutation. The prevalence of the Val66Met mutation in this study was 60% amongst CSM patients compared to 32% in the general population. Individuals with abnormal Met allele had worse baseline mJOA and Nurick scores. Moreover, baseline gait kinematics and hand functioning testing were worse compared to their wild type counterpart. BDNF Val66Met mutation has a higher prevalence in CSM compared to the general population. Those with BDNF mutation have a worse clinical presentation compared to the wild type counterpart. These findings suggest implication of the BDNF mutation in the development and severity of CSM., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In everyday conversation, viewing a talker's face can provide information about the timing and content of an upcoming speech signal, resulting in improved intelligibility. Using electrocorticography, we tested whether human auditory cortex in Heschl's gyrus (HG) and on superior temporal gyrus (STG) and motor cortex on precentral gyrus (PreC) were responsive to visual/gestural information prior to the onset of sound and whether early stages of auditory processing were sensitive to the visual content (speech syllable versus non-speech motion). Event-related band power (ERBP) in the high gamma band was content-specific prior to acoustic onset on STG and PreC, and ERBP in the beta band differed in all three areas. Following sound onset, we found with no evidence for content-specificity in HG, evidence for visual specificity in PreC, and specificity for both modalities in STG. These results support models of audio-visual processing in which sensory information is integrated in non-primary cortical areas.

Our laboratories are developing treadmill-based gait analysis employing sheep to investigate potential efficacy of intra-dural spinal cord stimulation in the treatment of spinal cord injury and neuropathic pain. As part of efforts to establish the performance characteristics of the experimental arrangement, this study measured the treadmill speed via a tachometer, video belt-marker timing and ambulation-rate observations of the sheep. The data reveal a 0.1-0.3% residual drift in the baseline (unloaded) treadmill speed which increases with loading, but all three approaches agree on final speed to within 1.7%, at belt speeds of ≈ 4 km/h. Using the tachometer as the standard, the estimated upper limit on uncertainty in the video belt-marker approach is ± 0.18 km h(-1) and the measured uncertainty is ± 0.15 km h(-1). Employment of the latter method in determining timing differences between contralateral hoof strikes by the sheep suggests its utility in assessing severity of SCI and responses to therapeutic interventions.

Patients with neuropathic pain commonly present with spontaneous pain, in addition to allodynia and hyperalgesia. Although evoked responses in neuropathic pain models are well characterized, determining the presence of spontaneous pain is more challenging. We determined whether the chronic constriction injury (CCI) model could be used to measure effects of treatment of spontaneous pain, by evaluating dorsal horn neuron (DHN) spontaneous activity and spontaneous pain-related behaviors. We measured conditioned place preference (CPP) to analgesia produced by sciatic nerve block with bupivacaine in rats with established CCI. We undertook another CPP experiment using hind paw incision. We also examined DHN spontaneous activity in CCI rats. Although CCI produced nocifensive responses to mechanical stimuli, CPP to analgesic nerve block was not evident 14 days after injury: Compared with baseline (314 ± 65 seconds), CCI rats did not show a preference for the bupivacaine-paired chamber after conditioning (330 ± 102 seconds). However, sciatic nerve block after hind paw incision produced CPP on postoperative day 1, serving as a positive control. The proportion of spontaneously active DHNs (33%) was not significantly increased in CCI rats compared with the sham (21%). The median rate of spontaneous activity in the CCI group (12.6 impulses per second) was not different from the sham group (9.2 impulses per second). Also, there was no change in DHN spontaneous activity after sciatic nerve block with bupivacaine. Our findings suggest that CCI as a neuropathic pain model should not be used to measure effects of treatment of spontaneous pain driven by the peripheral input.

We are developing a novel intradural spinal cord (SC) stimulator designed to improve the treatment of intractable pain and the sequelae of SC injury. In-vivo ovine models of neuropathic pain and moderate SC injury are being implemented for pre-clinical evaluations of this device, to be carried out via gait analysis before and after induction of the relevant condition. We extend previous studies on other quadrupeds to extract the three-dimensional kinematics of the limbs over the gait cycle of sheep walking on a treadmill. Quantitative measures of thoracic and pelvic limb movements were obtained from 17 animals. We calculated the total-error values to define the analytical performance of our motion capture system for these kinematic variables. The post- vs. pre-injury time delay between contralateral thoracic and pelvic-limb steps for normal and SC-injured sheep increased by ~24s over 100 steps. The pelvic limb hoof velocity during swing phase decreased, while range of pelvic hoof elevation and distance between lateral pelvic hoof placements increased after SC injury. The kinematics measures in a single SC-injured sheep can be objectively defined as changed from the corresponding pre-injury values, implying utility of this method to assess new neuromodulation strategies for specific deficits exhibited by an individual., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Spectro-Temporal Receptive Fields (STRFs) were estimated from both multi-unit sorted clusters and high-gamma power responses in human auditory cortex. Intracranial electrophysiological recordings were used to measure responses to a random chord sequence of Gammatone stimuli. Traditional methods for estimating STRFs from single-unit recordings, such as spike-triggered-averages, tend to be noisy and are less robust to other response signals such as local field potentials. We present an extension to recently advanced methods for estimating STRFs from generalized linear models (GLM). A new variant of regression using regularization that penalizes non-zero coefficients is described, which results in a sparse solution. The frequency-time structure of the STRF tends toward grouping in different areas of frequency-time and we demonstrate that group sparsity-inducing penalties applied to GLM estimates of STRFs reduces the background noise while preserving the complex internal structure. The contribution of local spiking activity to the high-gamma power signal was factored out of the STRF using the GLM method, and this contribution was significant in 85 percent of the cases. Although the GLM methods have been used to estimate STRFs in animals, this study examines the detailed structure directly from auditory cortex in the awake human brain. We used this approach to identify an abrupt change in the best frequency of estimated STRFs along posteromedial-to-anterolateral recording locations along the long axis of Heschl's gyrus. This change correlates well with a proposed transition from core to non-core auditory fields previously identified using the temporal response properties of Heschl's gyrus recordings elicited by click-train stimuli.

High gamma power has become the principal means of assessing auditory cortical activation in human intracranial studies, albeit at the expense of low frequency local field potentials (LFPs). It is unclear whether limiting analyses to high gamma impedes ability of clarifying auditory cortical organization. We compared the two measures obtained from posterolateral superior temporal gyrus (PLST) and evaluated their relative utility in sound categorization. Subjects were neurosurgical patients undergoing invasive monitoring for medically refractory epilepsy. Stimuli (consonant-vowel syllables varying in voicing and place of articulation and control tones) elicited robust evoked potentials and high gamma activity on PLST. LFPs had greater across-subject variability, yet yielded higher classification accuracy, relative to high gamma power. Classification was enhanced by including temporal detail of LFPs and combining LFP and high gamma. We conclude that future studies should consider utilizing both LFP and high gamma when investigating the functional organization of human auditory cortex., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Sudden unexpected death in epilepsy (SUDEP) is increasingly recognized as a common and devastating problem. Because impaired breathing is thought to play a critical role in these deaths, we sought to identify forebrain sites underlying seizure-evoked hypoventilation in humans. We took advantage of an extraordinary clinical opportunity to study a research participant with medically intractable epilepsy who had extensive bilateral frontotemporal electrode coverage while breathing was monitored during seizures recorded by intracranial electrodes and mapped by high-resolution brain imaging. We found that central apnea and O2 desaturation occurred when seizures spread to the amygdala. In the same patient, localized electrical stimulation of the amygdala reproduced the apnea and O2 desaturation. Similar effects of amygdala stimulation were observed in two additional subjects, including one without a seizure disorder. The participants were completely unaware of the apnea evoked by stimulation and expressed no dyspnea, despite being awake and vigilant. In contrast, voluntary breath holding of similar duration caused severe dyspnea. These findings suggest a functional connection between the amygdala and medullary respiratory network in humans. Moreover, they suggest that seizure spread to the amygdala may cause loss of spontaneous breathing of which patients are unaware, and thus has potential to contribute to SUDEP., Significance Statement: Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with chronic refractory epilepsy. Impaired breathing during and after seizures is common and suspected to play a role in SUDEP. Understanding the cause of this peri-ictal hypoventilation may lead to preventative strategies. In epilepsy patients, we found that seizure invasion of the amygdala co-occurred with apnea and oxygen desaturation, and electrical stimulation of the amygdala reproduced these respiratory findings. Strikingly, the subjects were unaware of the apnea. These findings indicate a functional connection between the amygdala and brainstem respiratory network in humans and suggest that amygdala seizures may cause loss of spontaneous breathing of which patients are unaware-a combination that could be deadly., (Copyright © 2015 the authors 0270-6474/15/3510281-09$15.00/0.)

Background: Patients undergoing mastectomy and prosthetic breast reconstruction have significant acute postsurgical pain, routinely mandating inpatient hospitalization. Liposomal bupivacaine (LB) (Exparel; Pacira Pharmaceuticals, Inc., Parsippany, N.J.) has been shown to be a safe and effective pain reliever in the immediate postoperative period and may be advantageous for use in mastectomy and breast reconstruction patients., Methods: Retrospective review of 90 immediate implant-based breast reconstruction patient charts was completed. Patients were separated into 3 groups of 30 consecutively treated patients who received 1 of 3 pain treatment modalities: intravenous/oral narcotic pain control (control), bupivacaine pain pump, or LB injection. Length of hospital stay, patient-reported Visual Analog Scale (VAS) pain scores, postoperative patient-controlled analgesia usage, and nausea-related medication use were abstracted and subjected to analysis of variance and multiple linear-regression analysis, as appropriate., Results: Subjects were well-matched for age (P = 0.24) regardless of pain-control modality. Roughly half (53%) of control and pain pump-treated subjects had bilateral procedures, as opposed to 80% of LB subjects. Mean length of stay for LB subjects was significantly less than control (1.5 days vs 2.00 days; P = 0.016). LB subjects reported significantly lower VAS pain scores at 4, 8, 12, 16, and 24 hours compared with pain pump and control (P < 0.01). There were no adverse events in the LB group., Conclusion: Use of LB in this group of immediate breast reconstruction patients was associated with decreased patient VAS pain scores in the immediate postoperative period compared with bupivacaine pain pump and intravenous/oral narcotic pain management and reduced inpatient length of stay.

Tinnitus can occur when damage to the peripheral auditory system leads to spontaneous brain activity that is interpreted as sound [1, 2]. Many abnormalities of brain activity are associated with tinnitus, but it is unclear how these relate to the phantom sound itself, as opposed to predisposing factors or secondary consequences [3]. Demonstrating "core" tinnitus correlates (processes that are both necessary and sufficient for tinnitus perception) requires high-precision recordings of neural activity combined with a behavioral paradigm in which the perception of tinnitus is manipulated and accurately reported by the subject. This has been previously impossible in animal and human research. Here we present extensive intracranial recordings from an awake, behaving tinnitus patient during short-term modifications in perceived tinnitus loudness after acoustic stimulation (residual inhibition) [4], permitting robust characterization of core tinnitus processes. As anticipated, we observed tinnitus-linked low-frequency (delta) oscillations [5-9], thought to be triggered by low-frequency bursting in the thalamus [10, 11]. Contrary to expectation, these delta changes extended far beyond circumscribed auditory cortical regions to encompass almost all of auditory cortex, plus large parts of temporal, parietal, sensorimotor, and limbic cortex. In discrete auditory, parahippocampal, and inferior parietal "hub" regions [12], these delta oscillations interacted with middle-frequency (alpha) and high-frequency (beta and gamma) activity, resulting in a coherent system of tightly coupled oscillations associated with high-level functions including memory and perception., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: In an attempt to shed light on management of chronic pain conditions, there has long been a desire to complement behavioral measures of pain perception with measures of underlying brain mechanisms. Using functional magnetic resonance imaging (fMRI), we undertook this study to investigate changes in brain activity following the administration of naproxen or placebo in patients with pain related to osteoarthritis (OA) of the carpometacarpal (CMC) joint., Methods: A placebo-controlled, double-blind, 2-period crossover study was performed in 19 individuals with painful OA of the CMC joint of the right hand. Following placebo or naproxen treatment periods, a functionally relevant task was performed, and behavioral measures of the pain experience were collected in identical fMRI examinations. Voxelwise and a priori region of interest analyses were performed to detect between-period differences in brain activity., Results: Significant reductions in brain activity following treatment with naproxen, compared to placebo, were observed in brain regions commonly associated with pain perception, including the bilateral primary somatosensory cortex, thalamus, and amygdala. Significant relationships between changes in perceived pain intensity and changes in brain activity were also observed in brain regions previously associated with pain intensity., Conclusion: This study demonstrates the sensitivity of fMRI to detect the mechanisms underlying treatments of known efficacy. The data illustrate the enticing potential of fMRI as an adjunct to self-report for detecting early signals of efficacy of novel therapies, both pharmacologic and nonpharmacologic, in small numbers of individuals with persistent pain., (© 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)