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Key points Heart Rate Variability (HRV) is associated with descending pain modulation as measured by the Conditioned Pain Modulation paradigm (CPM) There is an association between CPM scores and the functional connectivity between the periaqueductal grey (PAG) and ventro-medial prefrontal cortex (vmPFC) CPM scores are also associated with vmPFC grey matter (GM) The strength of functional connectivity between the PAG and vmPFC mediates the association between HRV and CPM Our data provide new evidence of interactions between ANS and descending pain mechanisms. Abstract There is a strict interaction between the autonomic nervous system (ANS) and pain, which might involve descending pain modulatory mechanisms. The periaqueductal grey (PAG) is involved both in descending pain modulation and ANS, but its role in mediating this relationship has not yet been explored. Here, we sought to determine brain regions mediating ANS and descending pain control associations. 30 participants underwent Conditioned Pain Modulation (CPM) assessments, in which they rated painful pressure stimuli applied to their thumbnail, either alone or with a painful cold contralateral stimulation. Differences in pain ratings between 'pressure-only' and 'pressure+cold' stimuli provided a measure of descending pain control. In 18 of the 30 participants, structural scans and two functional MRI assessments, one pain-free and one during cold-pain were acquired. Heart Rate Variability (HRV) was simultaneously recorded. Normalised low-frequency HRV (LF-HRVnu) and the CPM score were negatively correlated; individuals with higher LF-HRVnu during pain reported reductions in pain during CPM. PAG-ventro-medial prefrontal cortex (vmPFC) and PAG-rostral ventromedial medulla (RVM) functional connectivity correlated negatively with the CPM. Importantly, PAG-vmPFC functional connectivity mediated the strength of LF-HRVnu-CPM association. CPM response magnitude was also negatively with vmPFC GM volumes. Our multi-modal approach, using behavioural, physiological, and MRI measures, provides important new evidence of interactions between ANS and descending pain mechanisms. ANS dysregulation and dysfunctional descending pain modulation are characteristics of chronic pain. We suggest that further investigation of body-brain interactions in chronic pain patients may catalyse the development of new treatments. Abstract figure. The aim of this study is to investigate which brain regions mediate the association between the Autonomic Nervous System (ANS) and descending pain modulating mechanisms. To achieve so, healthy controls underwent a Conditioned Pain Modulation paradigm, with the aim to explore the functioning of their descending pain modulating mechanisms. In a subgroup of these participants, we also acquired structural and functional MRI data, alongside with physiological data (i.e. Heart Rate Variability during cold pain). Overall, we observed that the CPM response was negatively associated with ventro-medial prefrontal cortex grey matter (vmPFC) and positively associated with the strength of functional connectivity between the periaqueductal gray area (PAG) and the vmPFC. Importantly, PAG-vmPFC functional connectivity mediated the strength of the association between HRV and CPM. This article is protected by copyright. All rights reserved.

Background Sphenoid wing meningiomas are a challenging surgical disease with relatively high perioperative morbidity. Most studies to date have focused on resection strategies as it relates to disease recurrence. Few have examined the optimal strategy as it relates to overall patient survival. We retrospectively reviewed our case series and evaluated extent of resection and perioperative stroke as it relates to all cause and disease-specific survival. Patients/Methods Ninety-four patients were included in the study. Demographics, clinical features, operative features and clinical course, and time to mortality evaluation were collected. Extent of resection (EOR) was defined as gross total (GTR, 100%), near total (NTR, ≥ 95%), and subtotal (STR, Results The overall mean EOR was 94.5% with 70.2% of cases achieving GTR, 12.8% achieved NTR, and 17% achieved STR. Postoperative stroke only occurred with GTR or NTR (p = 0.041). Age alone was significant on Cox regression analysis for all cause mortality (p = 0.042, HR 1.054 [95% CI 1.002 – 1.109]). Postoperative stroke was associated with worse disease-specific mortality (p = 0.046, HR 23.337 [95% CI 1.052 – 517.782) with no impact from extent of resection (p = 0.258). Conclusions Although maximizing resection and minimizing recurrence is ideal, GTR or NTR confer a significantly higher stroke risk. Most patients do not die from their meningioma, as all cause mortality was associated only with age. However, perioperative stroke conferred decreased survival throughout follow up. This series demonstrates that an overly aggressive surgical philosophy negatively impacted disease specific survival.

Institutional database search (1999-2020) for acute myeloid leukaemia (AML) identified 109 cases of myeloid sarcoma (MS), of which 19 were isolated and presented de novo. The latter displayed longer survival (median 78 months), compared to MS with synchronous intramedullary AML (n = 32; median 16 months) and de novo AML without MS (n = 729; median 22 months; P = 0·13). However, the difference in survival was no longer apparent after accounting for bone marrow cytogenetic risk status (P = 0·67). Treatment-induced MS tumour resolution was not affected by the presence of intramedullary disease (P = 0·61). The current study clarifies the prognosis of de novo isolated MS, in the context of AML.

BackgroundCluster headache is an excruciating disorder with no cure. Greater occipital nerve blockades can transiently suppress attacks in approximately 50% of patients, however, its mechanism of action remains uncertain, and there are no reliable predictors of treatment response. To address this, we investigated the effect of occipital nerve blockade on regional cerebral blood flow (rCBF), an index of brain activity, and differences between treatment responders and non-responders. Finally, we compared baseline perfusion maps from patients to a matched group of healthy controls.Methods21 male, treatment-naive patients were recruited while in a cluster headache bout. During a pain-free phase between headaches, patients underwent pseudo-continuous arterial spin labelled MRI assessments to provide quantitative indices of rCBF. MRIs were performed prior to and 7-to-21 days following treatment. Patients also recorded the frequency of their headache attacks in a daily paper diary. Neuropsychological assessment including anxiety, depression and quality of life measures was performed in a first, scanning free session for each patient.ResultsFollowing treatment, patients demonstrated relative rCBF reductions in posterior temporal gyrus, cerebellum and caudate, and rCBF increases in occipital cortex. Responders demonstrated relative rCBF increases, compared to non-responders, in medial prefrontal cortex and lateral occipital cortex at baseline, but relative reductions in cingulate and middle temporal cortices. rCBF was increased in patients compared to healthy controls in cerebellum and hippocampus, but reduced in orbitofrontal cortex, insula and middle temporal gyrus.ConclusionsWe provide new mechanistic insights regarding the aetiology of cluster headache, the mechanisms of action of occipital nerve blockades and potential predictors of treatment response. Future investigation should determine whether observed effects are reproducible and extend to other headache disorders.

Background and Purpose: Decompressive hemicraniectomy has been used to treat spontaneous intracerebral hemorrhage, but the benefit of evacuating the hematoma during the procedure is unclear. We aim to evaluate the utility of performing clot evacuation during hemicraniectomy for spontaneous intracerebral hemorrhage. Methods: Retrospective cohort of consecutive patients (2010–2019) treated with decompressive hemicraniectomy for a spontaneous supratentorial intracerebral hemorrhage at the University of Iowa. We compared hemicraniectomy alone to hemicraniectomy plus hematoma evacuation. We analyzed clinical features and hematoma characteristics. The outcomes at 6 months were dichotomized into unfavorable (Glasgow Outcome Scale score 1–3) and favorable (Glasgow Outcome Scale score 4–5). Results: Eighty-three patients underwent decompressive hemicraniectomy for spontaneous intracerebral hemorrhage, 52 with hematoma evacuation, and 31 without hematoma evacuation. There were no statistically significant differences in clinical and radiographic characteristics between the 2 groups. Evacuating the hematoma in addition to hemicraniectomy did not change the odds of favorable outcome at 6 months ( P =0.806). Conclusions: In this retrospective study, the performance of hematoma evacuation during decompressive hemicraniectomy for spontaneous intracerebral hemorrhage may not change functional outcomes over performing the hemicraniectomy alone.

Pure erythroid leukemia (PEL) is a rare, aggressive subtype of acute myeloid leukemia with a poor prognosis. The diagnosis of PEL is often medically urgent, quite challenging, and is typically a diagnosis of exclusion requiring meticulous distinction from non-neoplastic erythroid proliferations, particularly florid erythroid hyperplasia/regeneration. Given the frequency of TP53 mutations in the molecular signature of PEL, we hypothesize that differential p53 expression by immunohistochemistry (IHC) may be useful in distinguishing PEL versus non-neoplastic erythroid conditions. We performed p53 IHC on 5 normal bone marrow, 46 reactive erythroid proliferations, and 27 PEL cases. We assessed the positivity and intensity of nuclear staining in pronormoblasts and basophilic normoblasts using a 0–3+ scale with 0 being absent (with internal positive controls) and 3 being strong nuclear positivity. A total of 26/27 PEL cases showed strong, uniform, diffuse intense staining by the neoplastic pronormoblasts versus 0/5 and 0/46 normal and reactive controls, respectively. The control cases show various staining patterns ranging from 0 to 3+ in scattered erythroid precursor cells. Uniform, strong p53 positivity is unique to PEL and discriminates this entity from a benign erythroid mimic. Thus, p53 IHC may be a useful marker in urgent medical cases to assist in the confirmation of a malignant PEL diagnosis while awaiting the results of additional ancillary studies such as cytogenetics.

Objective The treatment failure rate for spinal cord stimulators (SCS) remains unacceptably high, with reports of removal in up to 30% of patients. The purpose of this study is to perform survival and multivariate regression analyses of patients who have undergone SCS explantation in order to identify patient characteristics that may predict treatment failure. Materials and methods We identified 253 patients who underwent SCS placement using current procedural terminology codes in a private health insurance data base spanning 2003-2016. Patient demographics, opioid use, surgical indications, as well as comorbidities were noted. At least 6 months of continuous claims data before and after implantation were required for inclusion. Patients who underwent explantation were defined as those who underwent removal without replacement within 90 days and had at least 90 days of continuous insurance eligibility following removal. Those who underwent removal for infectious reasons were identified with corresponding diagnosis codes. Results Of the 252 patients who met the inclusion criteria, 17 (6.7%) underwent SCS explantation. Median follow-up time was 2.0 years. Of those who had their system explanted, six patients (2.8%) had their systems removed for infection and 11 (4.3%) for noninfectious reasons. Bivariate analysis revealed that younger age and tobacco use were associated with an increased likelihood of explantation. The Cox proportional hazards analysis demonstrated that younger age, tobacco use, and the presence of "other" mental health disorders were predictive of explantation. Conclusions In a cohort of SCS patients from multiple institutions, this study demonstrates that explantation for noninfectious reasons is more likely in younger patients, tobacco users, and those with certain psychiatric conditions. With an estimated 10% of patients opting to have their devices removed within 5 years of implantation, refining the ability of clinicians to predict who will see benefit from SCS treatment remains necessary.

Objectives Pure erythroid leukemia (PEL) is exceptionally rare in the pediatric setting. Four pediatric PEL cases with t(1;16)(p31;q24) NFIA-CBFA2T3 were reported previously. We present a case of an infant with PEL presenting with erythroblastic sarcoma and harboring a novel t(1;8)(p31.3;q21.3) NFIA-RUNX1T1 fusion detected by RNA sequencing and conventional karyotype. Methods Bone marrow (BM) and abdominal mass biopsies from the patient were evaluated with extensive immunohistochemical, flow cytometric, cytogenetic, and molecular studies. Results The patient was a female infant who presented between 2 and 5 months of age with cytopenias and an enlarging abdominal mass. Blasts in the BM and abdominal mass expressed CD71 and CD117 with focal expression of CD43, E-cadherin, epithelial membrane antigen, and hemoglobin A. They were negative for additional myeloid, lymphoid, and nonhematolymphoid markers. These findings were most consistent with PEL and erythroblastic sarcoma. RNA sequencing revealed the novel NFIA-RUNX1T1 fusion. Conclusions Along with the previously reported PELs with NFIA-CBFA2T3 fusions, we describe a subset of PELs that occur in children, that frequently display extramedullary disease, and that harbor rearrangements of NFIA with core binding factor genes. We hypothesize that, together, these cases represent a rare but distinct clinicopathologic group of pediatric PELs with recurrent genetic abnormality.

Background We are developing an intradural approach to spinal cord stimulation, where the thin electrode array is affixed stably to the underside of the thoracic spinal dura mater without leakage of cerebrospinal fluid. As part of the design and testing process, we sought to evaluate the potential risk of inadvertent contact of the array with the pial surface of the spinal cord during variations in spinal loading. Methods As part of the risk assessment process, a 2-part study was undertaken. First, a retrospective review of the imaging studies of 25 patients was done in the supine, 45- and 90-degree positions to measure the positional shift between the T9 and T10 vertebral bodies as a function of spinal angulation. Second, similar measurements were made on a cadaveric model, with and without a prototype intradural stimulator implanted at the T9–T10 position and with and without 13.8 kg (30 lb) of axial spinal loading at the 90-degree orientation. Results In all cases, the measured relative displacement of the dura mater towards the spinal cord in both the imaging and the cadaveric arms of the study was less than 1 mm. Conclusions The implantation method for the thin intradural array of the prototype device will ensure that the anatomic separation between it and the pial surface of the spinal cord will be the same as that of the dura mater. Therefore the risk of inadvertent contact will be no greater than that due to the mass effects of standard epidural stimulator implants.

Background: A significant proportion of individuals seeking treatment for substance use disorders (SUDs) have experienced sexual victimization, which has been shown to disrupt the efficacy of SUD t...

Introduction We are developing a novel intradural spinal cord stimulator for treatment of neuropathic pain and spasticity. A key feature is the means by which it seals the dura mater to prevent leakage of cerebrospinal fluid (CSF). We have built and employed a test rig that enables evaluation of candidate seal materials. Methods To guide the design of the test rig, we reviewed the literature on neurosurgical durotomies. The test rig has a mock durotomy slot with a dural substitute serving as the surrogate dura mater and water as the CSF. The primary experimental goal was to evaluate the effectiveness of candidate gasket materials as seals against CSF leakage in an implanted prototype device, at both normal and super-physiologic pressures. A secondary goal was to measure the transmembrane flows in a representative dural substitute material, to establish its baseline aqueous transport properties. Results The seals prevented leakage of water at the implantation site over periods of ≈ ten days, long enough for the scar tissue to form in the clinical situation. The seals also held at water pressure transients approaching 250 mm Hg. The residual volumetric flux of water through the dura substitute membrane (Durepair®) was δVT /A ≈ 0.24 mm3 /min/cm2 , consistent with expectations for transport through the porous membrane prior to closure and equalization of internal/external pressures. Conclusions We have demonstrated the workability of obtaining robust seal against leakage at the implantation site of a novel intradural stimulator using a custom-designed test rig. Extension of the method to in vivo testing in a large animal model will be the next step.

Vagus nerve stimulation (VNS) is being used increasingly to treat a wide array of diseases and disorders. This growth is driven in part by the putative ability to stimulate the nerve non-invasively. Despite decades of use and a rapidly expanding application space, we lack a complete understanding of the acute effects of VNS on human cortical neurophysiology. Here, we investigated cortical responses to sub-perceptual threshold cervical implanted (iVNS) and transcutaneous auricular (taVNS) vagus nerve stimulation using intracranial neurophysiological recordings in human epilepsy patients. To understand the areas that are modulated by VNS and how they differ depending on invasiveness and stimulation parameters, we compared VNS-evoked neural activity across a range of stimulation modalities, frequencies, and amplitudes. Using comparable stimulation parameters, both iVNS and taVNS caused subtle changes in low-frequency power across broad cortical networks, which were not the same across modalities and were highly variable across participants. However, within at least some individuals, it may be possible to elicit similar responses across modalities using distinct sets of stimulation parameters. These results demonstrate that both invasive and non-invasive VNS cause evoked changes in activity across a set of highly distributed cortical networks that are relevant to a diverse array of clinical, rehabilitative, and enhancement applications.

Glutamate signalling is increasingly implicated across a range of psychiatric, neurological and pain disorders. Reliable methodologies are needed to probe the glutamate system and understand glutamate dynamics in vivo. Functional magnetic resonance spectroscopy (1H-fMRS) is a technique that allows measurement of glutamatergic metabolites over time in response to task conditions including painful stimuli. In this study, 18 healthy volunteers underwent 1H-fMRS during a pressure-pain paradigm (8 blocks of REST and 8 blocks of PAIN) across two separate sessions. During each session, estimates of glutamate + glutamine (Glx), scaled to total creatine (tCr = creatine + phosphocreatine) were determined for averaged REST and PAIN conditions within two separate regions of interest: the anterior cingulate cortex (ACC) and dorsal ACC (dACC). A two-way repeated measures analysis of variance determined a significant main effect of CONDITION (p = 0.025), with higher Glx/tCr during PAIN compared to REST across combined sessions, in the dACC ROI only. However, increases in dACC Glx/tCr during PAIN compared to REST showed limited reliability and reproducibility across sessions. Future test-retest 1H-fMRS studies should examine modified or alternative paradigms to determine more reliable methodologies to challenge the glutamate system that may then be applied in patient groups and experimental medicine studies.

The effects of neurodegeneration on the experience of pain remain poorly understood, despite the risk of suffering from both pain and neurodegenerative diseases rising concurrently with age.63,75Given the anticipated increase in magnitude and median age of the global population,76,152the interaction of these 2 clinically unmet needs will become an increasingly pressing challenge. In particular, a significant proportion of patients with Alzheimer disease (AD) and Parkinson disease (PD), the 2 most prevalent neurodegenerative diseases, suffer chronic pain of variable origin (Box 1). As such, they have been the most extensively studied and, for brevity, will be the focus of this review. Persistent pain in AD and PD is partially attributable to various concomitant disease manifestations and comorbidities (Fig. 1).43,117In addition, disease-specific neurodegenerative changes may affect a multitude of regions implicated in the perceptual and cognitive processes underlying pain. Despite this, the precise perceptual sequelae of neurodegenerative pathophysiology in these 2 diseases remain equivocal, and whether this may result in differential responses to analgesic treatment remains largely unexplored

Information from Magnetic Resonance Imaging (MRI) is useful for diagnosis and treatment management of human neurological patients. MRI monitoring might also prove useful for non-human animals involved in neuroscience research provided that MRI is available and feasible and that there are no MRI contra-indications precluding scanning. However, MRI monitoring is not established in macaques and a resource is urgently needed that could grow with scientific community contributions. Here we show the utility and potential benefits of MRI-based monitoring in a few diverse cases with macaque monkeys. We also establish a PRIMatE MRI Monitoring (PRIME-MRM) resource within the PRIMatE Data Exchange (PRIME-DE) and quantitatively compare the cases to normative information drawn from MRI data from typical macaques in PRIME-DE. In the cases, the monkeys presented with no or mild/moderate clinical signs, were well otherwise and MRI scanning did not present a significant increase in welfare impact. Therefore, they were identified as suitable candidates for clinical investigation, MRI-based monitoring and treatment. For each case, we show MRI quantification of internal controls in relation to treatment steps and comparisons with normative data in typical monkeys drawn from PRIME-DE. We found that MRI assists in precise and early diagnosis of cerebral events and can be useful for visualising, treating and quantifying treatment response. The scientific community could now grow the PRIME-MRM resource with other cases and larger samples to further assess and increase the evidence base on the benefits of MRI monitoring of primates, complementing the animals' clinical monitoring and treatment regime.

Background Accurate identification of cranial midline structures is essential for many targeting techniques that use repetitive transcranial magnetic stimulation (rTMS), including the Beam F3 method used for depression treatment. Objective Evaluate whether a novel, laser-sighted device will assist with more accurate identification of the cranial midline relative to standard scalp-based measurement procedures. Methods Three trained TMS technicians performed repeated scalp-based measurements to identify the inion and vertex on five subjects (n = 54 measurements). Measurements were compared to points identified with the midline localizer device and the true midline as defined by MRI midline structures. Results Use of the midline localizer was more accurate for midline identification than technician measurement (p = 0.00025) and the ratio of localizing the midline within 5 mm was higher (78% versus 54%, p = 0.008). Conclusion Use of a laser-sighted midline localizer device can improve the accuracy of scalp measurements associated with target localization for rTMS treatment protocols.

OBJECTIVECervical myelopathy (CM) is a common and debilitating form of spinal cord injury caused by chronic compression; however, little is known about the in vivo mechanics of the healthy spinal cord during motion and how these mechanics are altered in CM. The authors sought to measure 3D in vivo spinal cord displacement and strain fields from MR images obtained during physiological motion of healthy individuals and cervical myelopathic patients.METHODSNineteen study participants, 9 healthy controls and 10 CM patients, were enrolled in the study. All study participants had 3T MR images acquired of the cervical spine in neutral, flexed, and extended positions. Displacement and strain fields and corresponding principal strain were obtained from the MR images using image registration.RESULTSThe healthy spinal cord displaces superiorly in flexion and inferiorly in extension. Principal strain is evenly distributed along the spinal cord. The CM spinal cord displaces less than the healthy cord and the magnitude of principal strain is higher, at the midcervical levels.CONCLUSIONSIncreased spinal cord compression during cervical myelopathy limits motion of the spinal cord and increases spinal cord strain during physiological motion. Future studies are needed to investigate how treatment, such as surgical intervention, affects spinal cord mechanics.

Substance use disorders (SUDs) are a pervasive public health problem with deleterious consequences for individuals, families, and society. Furthermore, SUD intervention is complicated by the continuous possibility of relapse. Despite decades of research, SUD relapse rates remain high, underscoring the need for more effective treatments. Scientific findings indicate that SUDs are driven by dysregulation of neural processes underlying reward learning and executive functioning. Emerging evidence suggests that mindfulness training can target these neurocognitive mechanisms to produce significant therapeutic effects on SUDs and prevent relapse. The purpose of this manuscript is to review the cognitive, affective, and neural mechanisms underlying the effects of mindfulness-based interventions (MBIs) on SUDs. We discuss the etiology of addiction and neurocognitive processes related to the development and maintenance of SUDs. We then explore evidence supporting use of MBIs for intervening in SUDs and preventing relapse. Finally, we provide clinical recommendations about how these therapeutic mechanisms might be applied to intervening in SUDs and preventing relapse.

Introduction The intrathecal space remains underutilized for diagnostic testing, invasive monitoring or as a pipeline for the delivery of neurological therapeutic agents and devices. The latter including drug infusions, implants for electrical modulation, and a means for maintaining the physiologic pressure column. The reasons for this are many but include unfamiliarity with the central nervous system and the historical risks that continue to overshadow the low complication rates in modern clinical series. Materials and Methods Our intent in this review is to explore the access devices currently on the market, assess the risk associated with breaching the intrathecal space, and propose a research model for bringing to patients the next generation of intrathecal hardware. For this purpose, we reviewed both historical and contemporary literature that pertains to the access devices and catheters intended for both temporary and permanent implantation and the complications thereof. Results There are few devices that are currently marketed in the United States or Europe for intrathecal use. Most hew to a relatively fixed design pattern predicated on the dimensions and properties of the thecal sac. All are typically composed of soft silicone, and employ a Tuohy needle for access despite design limitations. In general, these catheters are engineered for durability, ease of use, and regional deployment. Devices on the market with steerability or targeted intrathecal fixation are not yet available. Complications, once a legitimate concern, are now quite rare when recommended techniques are followed. Conclusions Over the next decade, advances in intrathecal catheter design, access techniques, imaging, and greater understanding of the spinal cord neurophysiology will usher in an era where the intrathecal space is recognized as a highly valued diagnostic and therapeutic target. We anticipate that this will occur in several concurrent phases, each with the potential to accelerate the growth of the others.

Chronic pain is a highly debilitating and poorly understood condition. Here, we attempt to advance our understanding of the brain mechanisms driving chronic pain by investigating alterations in morphometric similarity (MS) and corresponding transcriptomic and cellular signatures, in three cohorts of patients with distinct chronic pain syndromes (knee osteoarthritis, low back pain and fibromyalgia). We uncover a novel pattern of cortical MS remodelling involving mostly MS increases in the insula and limbic cortex, which cuts across the boundaries of specific pain syndromes. We show that cortical MS remodelling in chronic pain spatially correlates with the brain-wide expression of genes involved in the glial immune response and neuronal plasticity. Cortical remodelling in chronic pain might involve a disruption of multiple elements of the cellular architecture of the brain. Therefore, multi-target therapeutic approaches tackling both glial activation and neuronal hyperexcitability might better encompass the full neurobiology of chronic pain.

Objective Spinal cord stimulation (SCS) has become a popular nonopioid pain intervention. However, the treatment failure rate for SCS remains significantly high and many of these patients have poor sagittal spinopelvic balance, which has been found to correlate with increased pain and decreased quality of life. The purpose of this study was to determine if poor sagittal alignment is correlated with SCS treatment failure. Materials and methods Comparative retrospective analysis was performed between two cohorts of patients who had undergone SCS placement, those who had either subsequent removal of their SCS system (representing a treatment failure cohort) and those that underwent generator replacement (representing a successful treatment cohort). The electronic medical record was used to collect demographic and surgical characteristics, which included radiographic measurements of lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS). Also included were data on pain medication usage including opioid and nonopioid therapies. Results Eighty-one patients met inclusion criteria, 31 had complete removal, and 50 had generator replacements. Measurement of sagittal balance parameters demonstrated that many patients had poor alignment, with 34 outside normal range for LL (10 vs. 24 in removal and replacement cohorts, respectively), 30 for PI (12 [38.7%] vs. 18 [36.0%]), 46 for PT (18 [58.1%] vs. 28 [56.0%]), 38 for SS (18 [58.1%] vs. 20 [40.0%]), and 39 for PI-LL mismatch (14 [45.2%] vs. 25 [50.0%]). There were no significant differences in sagittal alignment parameters between the two cohorts. Conclusions This retrospective cohort analysis of SCS patients did not demonstrate any relationship between poor sagittal alignment and failure of SCS therapy. Further studies of larger databases should be performed to determine how many patients ultimately go on to have additional structural spinal surgery after failure of SCS and whether or not those patients go on to have positive outcomes.

SUMMARYNon-invasive Gamma ENtrainment Using Sensory stimuli (GENUS) at 40Hz reduced Alzheimer’s disease (AD) pathology, prevented cerebral atrophy and improved performance during behavioral testing in mouse models of AD. We report data from a safety study (NCT04042922) and a randomized, placebo-controlled trial in participants with probable mild AD dementia after 3 months of one-hour daily 40Hz light and sound GENUS (NCT04055376) to assess safety, compliance, entrainment and possible effects on brain structure, function, sleep and cognitive function. GENUS was well-tolerated and compliance was high in both groups. Electroencephalography recordings show that our GENUS device safely and effectively induced 40Hz entrainment in cognitively normal subjects and participants with mild AD. After 3 months of daily stimulation, participants with mild AD in the 40Hz GENUS group showed less ventricular enlargement and stabilization of the hippocampal size compared to the control group. Functional connectivity increased in both the default mode network and the medial visual network after 3 months of stimulation. Circadian rhythmicity also improved with GENUS. Compared to controls, the active group performed better on the face-name association delayed recall test. These results suggest that 40Hz GENUS can be used safely at home daily and shows favorable outcomes on cognitive function, daily rhythms, and structural and functional MRI biomarkers of AD-related degeneration. These results support further evaluation of GENUS in larger and longer clinical trials to evaluate its potential as a disease modifying therapeutic for Alzheimer’s disease.

BackgroundChronic pain is a world-wide clinical challenge. Response to analgesic treatment is limited and difficult to predict. Functional MRI (fMRI) has been suggested as a potential solution. However, while most analgesics target specific neurotransmission pathways, fMRI-based biomarkers are not specific for any neurotransmitter system, limiting our understanding of how they might contribute to predict treatment response.MethodsHere, we sought to bridge this gap by applying Receptor-Enriched Analysis of Functional Connectivity by Targets (REACT) to investigate whether neurotransmission-enriched functional connectivity (FC) mapping can provide insights into the brain mechanisms underlying chronic pain and inter-individual differences in analgesic response after a placebo or duloxetine. Chronic knee osteoarthritis (OA) pain patients (n=56) underwent pre-treatment brain scans in two clinical trials. Study 1 (n=17) was a 2-week single-blinded placebo pill trial. Study 2 (n=39) was a 3-month double-blinded randomized trial comparing placebo to duloxetine, a dual serotonin-noradrenaline reuptake inhibitor.ResultsAcross two independent studies, we found that chronic pain OA patients present FC alterations in the FC related to the serotonin (SERT) and noradrenaline (NET) transporters, when compared to age-matched healthy controls. Placebo responders presented with higher pre-treatment dopamine transporter (DAT)-enriched FC than non-responders. Duloxetine responders presented with higher pre-treatment SERT and NET-enriched FC than non-responders. Pre-treatment SERT and NET-enriched FC achieved predictive positive values of duloxetine response up to 85.71%.ConclusionNeurotransmission-enriched FC mapping might hold promise as a new mechanistic-informed biomarker for functional brain alterations and prediction of response to pharmacological analgesia in chronic pain.

Chronic pain is a highly debilitating and difficult to treat condition, which affects the structure of the brain. Although the development of chronic pain is moderately heritable, how disease-related alterations at the microscopic genetic architecture drive macroscopic brain abnormalities is currently largely unknown. Here, we examined alterations in morphometric similarity (MS) and applied an integrative imaging transcriptomics approach to identify transcriptional and cellular correlates of these MS changes, in 3 independent small cohorts of patients with distinct chronic pain syndromes (knee osteoarthritis, low back pain, and fibromyalgia) and age-matched and sex-matched pain-free controls. We uncover a novel pattern of cortical MS remodelling involving mostly small-to-medium MS increases in the insula and limbic cortex (none of these changes survived stringent false discovery rate correction for the number of regions tested). This pattern of changes is different from that observed in patients with major depression and cuts across the boundaries of specific pain syndromes. By leveraging transcriptomic data from Allen Human Brain Atlas, we show that cortical MS remodelling in chronic pain spatially correlates with the brain-wide expression of genes related to pain and broadly involved in the glial immune response and neuronal plasticity. Our findings bridge levels to connect genes, cell classes, and biological pathways to in vivo imaging correlates of chronic pain. Although correlational, our data suggest that cortical remodelling in chronic pain might be shaped by multiple elements of the cellular architecture of the brain and identifies several pathways that could be prioritized in future genetic association or drug development studies.

Non-invasive Gamma ENtrainment Using Sensory stimuli (GENUS) at 40Hz reduced Alzheimer’s disease (AD) pathology, prevented cerebral atrophy and improved performance during behavioral testing in mouse models of AD. We report data from a safety study (NCT04042922) and a randomized, placebo-controlled trial in participants with probable mild AD dementia after 3 months of one-hour daily 40Hz light and sound GENUS (NCT04055376) to assess safety, compliance, entrainment and possible effects on brain structure, function, sleep and cognitive function. GENUS was well-tolerated and compliance was high in both groups. Electroencephalography recordings show that our GENUS device safely and effectively induced 40Hz entrainment in cognitively normal subjects and participants with mild AD. After 3 months of daily stimulation, participants with mild AD in the 40Hz GENUS group showed less ventricular enlargement and stabilization of the hippocampal size compared to the control group. Functional connectivity increased in both the default mode network and the medial visual network after 3 months of stimulation. Circadian rhythmicity also improved with GENUS. Compared to controls, the active group performed better on the face-name association delayed recall test. These results suggest that 40Hz GENUS can be used safely at home daily and shows favorable outcomes on cognitive function, daily rhythms, and structural and functional MRI biomarkers of AD-related degeneration. These results support further evaluation of GENUS in larger and longer clinical trials to evaluate its potential as a disease modifying therapeutic for Alzheimer’s disease.

ObjectiveElectrical cortical stimulation (ECS) has been the gold standard for intraoperative functional mapping in neurosurgery, yet it carries the risk of induced seizures. Here we assess the safety of focal cortical cooling (CC) as a potential alternative to ECS for functional brain mapping.MethodsWe retrospectively reviewed 40 consecutive subjects (n=13 tumor, 27 mesial temporal lobe epilepsy (MTLE) resection) who underwent intraoperative CC during craniotomy at the University of Iowa Hospital and Clinics from 2007 through 2019 (CC group). Thirty-eight of the 40 subjects had ECS performed along with CC during the same procedure. To assess the safety of CC, intra- and post-operative seizure incidence and post-operative neurological deficits were collected together with new post-operative radiographic findings not related to the surgical procedure itself (i.e. non-mapping portions). As a control cohort, we collected 55 consecutive subjects (n=21 MTLE, 34 tumor/vascular pathology) who underwent awake ECS mapping without CC between 2006 and 2019 (ECS-alone group). To evaluate potential long term effects of mapping techniques (CC and/or ECS), we separately collected another 25 consecutive subjects who underwent anterior temporal lobectomy(ATL) without CC nor ECS between 2007 and 2019 (No ECS/No CC-ATL group).ResultsA total of 79 brain sites were cooled in the 40 CC subjects, including inferior frontal gyrus (44%), precentral gyrus (39%), postcentral gyrus (6%), subcentral gyrus (4%) and superior temporal gyrus (6%). No intraoperative seizures were reported in the CC group, whereas 3.6% of ECS-alone group had intraoperative seizures. The incidence of seizure(s) within the first post-operative week did not significantly differ amongst CC (7.9%), ECS-alone (9.0%) and No ECS/No CC-ATL groups (12%). There was no significante difference in the incidence of postoperative radiographic change between CC (7.5%) and ECS-alone groups (5.5 %). The long term seizure outcome for MTLE subjects did not statistically differ regarding ‘good’ outcomes (Engel I+II): CC group (80%), ECS-alone (83.3%) and No ECS/No CC-ATL group (83.3%).ConclusionsCortical cooling when used as an intraoperative mapping technique is safe, and may complement traditional electrical cortical stimulation.

There is a strict interaction between the autonomic nervous system (ANS) and pain, which might involve descending pain modulatory mechanisms. The periaqueductal grey (PAG) is involved both in descending pain modulation and ANS, but its role in mediating this relationship has not yet been explored.Here, we sought to determine brain regions mediating ANS and descending pain control associations. 30 participants underwent Conditioned Pain Modulation (CPM) assessments, in which they rated painful pressure stimuli applied to their thumbnail, either alone or with a painful cold contralateral stimulation. Differences in pain ratings between ‘pressure-only’ and ‘pressure+cold’ stimuli provided a measure of descending pain control. In 18 of the 30 participants, structural scans and two functional MRI assessments, one pain-free and one during cold-pain, were acquired. Heart Rate Variability (HRV) was simultaneously recorded.Low frequency HRV (LF-HRV) and the CPM score were negatively correlated; individuals with higher LF-HRV during pain reported reductions in pain during CPM. PAG-frontal medial cortex (FMC) and PAG-rostral ventro-medial medulla (RVM) functional connectivity correlated negatively with the CPM. Importantly, PAG-FMC functional connectivity mediated the strength of HRV-CPM association. CPM response magnitude was also negatively associated with PAG and positively associated with FMC grey matter volumes.Our multi-modal approach, using behavioral, physiological and MRI measures, provides important new evidence of interactions between ANS and descending pain mechanisms. ANS dysregulation and dysfunctional descending pain modulation are characteristics of chronic pain. We suggest that further investigation of body-brain interactions in chronic pain patients may catalyse the development of new treatments.

IntroductionThe introduction of successful neuromodulation strategies for managing chronic visceral pain lag behind what is now treatment of choice in refractory chronic back and extremity pain for many providers in the United States and Europe. Changes in public policy and monetary support to identify nonopioid treatments for chronic pain have sparked interest in alternative options. In this review, we discuss the scope of spinal cord stimulation (SCS) for visceral pain, its limitations, and the potential role for new intradural devices of the type that we are developing in our laboratories, which may be able to overcome existing challenges.MethodsA review of the available literature relevant to this topic was performed, with particular focus on the pertinent neuroanatomy and uses of spinal cord stimulation systems in the treatment of malignant and nonmalignant gastrointestinal, genitourinary, and chronic pelvic pain.ResultsTo date, there have been multiple off-label reports testing SCS for refractory gastrointestinal and genitourinary conditions. Though some findings have been favorable for these organs and systems, there is insufficient evidence to make this practice routine. The unique configuration and layout of the pelvic pain pathways may not be ideally treated using traditional SCS implantation techniques, and intradural stimulation may be a viable alternative.ConclusionsDespite the prevalence of visceral pain, the application of neuromodulation therapies, a standard approach for other painful conditions, has received far too little attention, despite promising outcomes from uncontrolled trials. Detailed descriptions of visceral pain pathways may offer several clues that could be used to implement devices tailored to this unique anatomy.

RATIONALE: Among opioid-treated chronic pain patients, response inhibition deficits in emotional contexts may contribute to opioid misuse. OBJECTIVES: Using high frequency heart rate variability (HF-HRV) to index impaired response inhibition, we examined associations between opioid misuse and response inhibition in emotional and neutral contexts in a sample of opioid-treated chronic pain patients. METHOD: Chronic pain patients taking opioid analgesics (N = 97) for ≥ 90 days completed an Emotional Go/NoGo Task that presented an inhibitory control challenge in the context of neutral, opioid, negative affective, and positive affective background images while HF-HRV was recorded. Opioid misuse and craving were assessed. Using a validated cut-point on the Current Opioid Misuse Measure, participants were classified as opioid misusers or non-misusers. Opioid misuse was examined as a predictor of behavioral and HF-HRV metrics of response inhibition. RESULTS: Negative affective and opioid images elicited more errors of commission (p = .002, η(2)(partial) = .16) and slowed reaction times (p = .045, η(2)(partial) = .09) than neutral and positive affective images, respectively. Though no between-groups behavioral differences were observed on the task, opioid misusers exhibited significantly blunted phasic HF-HRV during the task relative to non-misusers (p = .027, η(2)(partial) = .11). HF-HRV during the task was significantly inversely associated with opioid craving. It was not clear whether these autonomic findings reflected a durable phenotypic difference between groups or between-groups differences in opioid dosing and withdrawal. CONCLUSION: Reduced parasympathetic regulation during inhibitory control challenge may indicate heightened opioid misuse risk among opioid-treated chronic pain patients.

Background Total cell counts (TC-BF) and percent polymorphonuclear cells (%PMN) of synovial fluid (SF) aspirates provide important cues for the timely diagnosis and management of septic arthritis. To facilitate faster turnaround time, we compared automated to manual TC-BF and differential counts in order to identify reporting cut-offs for automated TC-BF and %PMN that would allow release of automated results concordant with manual counts and differentials. Methods Automated TC-BF and %PMN counts of a non-validated analyzer (Analyzer-B in STAT laboratory) were compared to a validated analyzer (Analyzer-A) and manual TC-BF counts and cytospin differentials. Concordance and %differences of Analyzer-B versus Analyzer-A and manual counts were assessed by linear regression analysis and Bland-Altman comparison. Results Overall, automated and manual counts displayed good correlation. A majority of samples demonstrated unacceptable (>20%) differences between automated and manual counts at lower TC-BF ( Conclusions Based on good overall correlation and fewer samples with unacceptable (>20%) differences between automated and manual counts, we adopted TC-BF > 10,000 cells/μl and %PMN > 60% as cutoffs for reporting automated counts. These cutoffs minimize differences between automated and manual cell counts and differentials and would allow rapid automated reporting in the vast majority of septic arthritis cases.

Roller compaction (RC) is a dry granulation technique applied to improve the flow and compressibility of drug formulations. RC implementation for high drug load formulations can be challenging due to flow issues and a high consumption of active pharmaceutical ingredient (API) for robust process development. This work addresses these challenges using process modelling for design and scale-up of an RC process on the same equipment and transfer to different equipment. A modified application of existing models incorporating a new description of mass transport in the feed screw is evaluated for guaifenesin formulations with a 90% drug loading. The model is calibrated using low-throughput data on a Vector Freund TF Mini RC and used to predict ribbon density and throughput for various process settings at high-throughput. It is found that the modelling framework can reasonably predict high-throughput behaviour on the same RC but the predictive performance decreases for transfer between equipment.

Hemorrhage is one of the most feared complications following ventriculostomy placement. Current studies have assessed factors associated with increased risk of ventriculostomy-related hemorrhage (VRH). However, the clinical significance of VRH has not been determined.To correlate quantitative volumetric measurements of VRH with new neurological symptoms.A retrospective review of our institutional database of ventriculostomy patients during the last decade was performed. Patients' demographics and procedural details such as indication, number of passes and position of the catheter were recorded. VRH volume was quantified on noncontrast head computed tomography using the Picture Archiving Communication System (Carestream Vue®, Rochester, New York) semi-automated livewire segmentation tool. Patients with new neurological symptoms within 48 h of VRH were considered symptomatic. Several clinical confounders were ruled out. Logistic regression analyses were performed. The best volumetric cut-offs in predicting symptomatic VRH were determined through receiver operating characteristic (ROC) curve analysis.A total of 3090 patients underwent ventriculostomy procedures and 179 (∼6%) developed VRH. A total of 41 (1.06%) patients with VRH developed new neurological symptoms. Only 12 (0.39%) were attributable to a new VRH. Multivariable logistic regression showed that volume of the hemorrhage (OR 1.17, P = .006) is the only significant predictor of symptomatic VRH. ROC curve analysis demonstrated that VRH volume1.10 cc has 91.7% sensitivity to rule out symptomatic VRH, whereas a volume7.59 cc has 95.5% specificity to predict symptomatic VRH.Approximately 6% of patients developed postprocedural VRH, but only 0.4% were symptomatic. VRH volumes1 cc are extremely unlikely to become symptomatic, whereas volumes7.5 cc may predict development of new neurological deficits.

A Human Amygdala Site That Inhibits Respiration and Elicits Apnea in Pediatric Epilepsy Rhone AE, Kovach CK, Harmata GIS, et al. JCI Insight. 2020;5(6):e134852. doi:10.1172/jci.insight.134852Background:Seizure-induced inhibition of respiration plays a critical role in sudden unexpected death in epilepsy (SUDEP). However, the mechanisms underlying seizure-induced central apnea in pediatric epilepsy are unknown.Methods:We studied 8 pediatric patients with intractable epilepsy undergoing intracranial electroencephalography. We recorded respiration during seizures and during electrical stimulation mapping of 174 forebrain sites. A machine learning algorithm was used to delineate brain regions that inhibit respiration.Results:In 2 patients, apnea coincided with seizure spread to the amygdala. Supporting a role for the amygdala in breathing inhibition in children, electrically stimulating the amygdala produced apnea in all 8 patients (3-17 years old). These effects did not depend on epilepsy type and were relatively specific to the amygdala, as no other site affected breathing. Remarkably, patients were unaware that they had stopped breathing, and none reported dyspnea or arousal, findings critical for SUDEP. Finally, a machine learning algorithm based on 45 stimulation sites and 210 stimulation trials identified a focal subregion in the human amygdala that consistently produced apnea. This site, which we refer to as the amygdala inhibition of respiration (AIR) site, includes the medial subregion of the basal nuclei, cortical and medial nuclei, amygdala transition areas, and intercalated neurons.Conclusions:A focal site in the amygdala inhibits respiration and induces apnea (AIR site) when electrically stimulated and during seizures in children with epilepsy. This site may prove valuable for determining those at greatest risk for SUDEP and as a therapeutic target. Seizure-Related Apneas Have an Inconsistent Linkage to Amygdala Seizure Spread Park K, Kanth K, Bajwa S, et al. Epilepsia. 2020;61(6):1253-1260.Objective:Sudden unexpected death in epilepsy (SUDEP) is a frequent cause of death in epilepsy. Respiratory dysfunction is implicated as a critical factor in SUDEP pathophysiology. Human studies have shown that electrical stimulation of the amygdala resulted in apnea, indicating that the amygdala has a role in respiration control. Unilateral amygdala stimulation resulted in immediate onset of respiratory dysfunction occurring only during nose breathing. In small numbers of patients, some but not all spontaneous seizures resulted in apnea occurring shortly after seizure spread to the amygdala. With this study, we aimed to determine whether seizure onset or spread to the amygdala was necessary and sufficient to cause apnea.Methods:We investigated the temporal relationship between apnea/hypopnea (AH) onset and initial seizure involvement within the amygdala in patients with implanted depth electrodes.Results:Data from 17 patients (11 female) with 47 seizures were analyzed. With 7 seizures (3 patients), AH preceded amygdala seizure involvement by 2 to 55 seconds. There was no AH with 4 seizures (3 patients) that involved the amygdala. With 8 seizures (4 patients), AH occurred within 2 seconds following amygdala seizure onset. With 28 seizures, AH started >2 seconds after amygdala seizure onset (range: 3-158 seconds). Following seizure onset, there was a significant difference between AH onset time and amygdala seizure onset (P < .001). The mean ± standard deviation AH onset was 27.8 ± 41.06 seconds, and the mean time to amygdala involvement was 8.83 ± 20.19 seconds.Significance:There is a wide range of AH onset times relative to amygdala seizure involvement. With some seizures, amygdala seizure involvement occurs without AH. With other seizures, AH precedes amygdala seizures, suggesting that, with spontaneous seizures, involvement of the amygdala may not be crucial to induction of AH with all seizures. Other pathophysiology impacting brain stem respiratory networks may be of greater relevance to seizure-triggered apneas.

Objectives We are in the process of designing and testing an intradural stimulation device that will shorten the distance between the location of the electrode array and the targeted neural tissue, thus improving the efficacy of electrical current delivery. Identifying a biomarker that accurately reflects the response to this intervention is highly valued because of the potential to optimize interventional parameters or predict a response before it is clinically measurable. In this report, we summarize the findings pertaining to the study of biomarkers so that we and others will have an up-to-date reference that critically evaluates the current approaches and select one or several for testing during the development of our device. Materials and methods We have conducted a broad survey of the existing literature to catalogue the biomarkers that could be coupled to intradural spinal cord stimulation. We describe in detail some of the most promising biomarkers, existing limitations, and suitability to managing chronic pain. Results Chronic, intractable pain is an all-encompassing condition that is incurable. Many treatments for managing chronic pain are nonspecific in action and intermittently administered; therefore, patients are particularly susceptible to large fluctuations in pain control over the course of a day. The absence of a reliable biomarker challenges assessment of therapeutic efficacy and contributes to either incomplete and inconsistent pain relief or, alternatively, intolerable side effects. Fluctuations in metabolites or inflammatory markers, signals captured during dynamic imaging, and genomics will likely have a role in governing how a device is modulated. Conclusions Efforts to identify one or more biomarkers are well underway with some preliminary evidence supporting their efficacy. This has far-reaching implications, including improved outcomes, fewer adverse events, harmonization of treatment and individuals, performance gains, and cost savings. We anticipate that novel biomarkers will be used widely to manage chronic pain.

There are bi-directional interactions between the autonomic nervous system (ANS) and pain. This is likely underpinned by a substantial overlap between brain areas of the central autonomic network and areas involved in pain processing and modulation. To date, however, relatively little is known about the neuronal substrates of the ANS-pain association. Here, we acquired resting state fMRI scans in 21 healthy subjects at rest and during tonic noxious cold stimulation. As indicators of autonomic function, we examined how heart rate variability (HRV) frequency measures were influenced by tonic noxious stimulation and how these variables related to participants’ pain perception and to brain functional connectivity in regions known to play a role in both ANS regulation and pain perception, namely the right dorsal anterior cingulate cortex (dACC) and periaqueductal gray (PAG). Our findings support a role of the cardiac ANS in brain connectivity during pain, linking functional connections of the dACC and PAG with measurements of low frequency (LF)-HRV. In particular, we identified a three-way relationship between the ANS, cortical brain networks known to underpin pain processing, and participants’ subjectively reported pain experiences. LF-HRV both at rest and during pain correlated with functional connectivity between the seed regions and other cortical areas including the right dorsolateral prefrontal cortex (dlPFC), left anterior insula (AI), and the precuneus. Our findings link cardiovascular autonomic parameters to brain activity changes involved in the elaboration of nociceptive information, thus beginning to elucidate underlying brain mechanisms associated with the reciprocal relationship between autonomic and pain-related systems.

Introduction: The aging of the western population and the increased use of oral anticoagulation (OAC) and antiplatelet drugs (APD) will result in a clinical dilemma on how to balance the recurrence risk of chronic subdural hematoma (cSDH) with the risk of withholding blood thinners. Objective: To identify features that predicts recurrence, thromboembolism (TEE), hospital stay and mortality. To identify the optimal window for resuming APD or OAC. Methods: We performed a retrospective multivariate analysis of a prospectively collected database. We then build machine learning models for outcomes prediction. Results: We identified 596 patients. The rate of recurrence was 22.17%, that of thromboembolism was 0.9% and that of mortality was 14.78%. Smoking, platelet dysfunction, CKD, and alcohol use were independent predictors of higher recurrence, while resolution of the SDH was protective. OAC use had higher odds of developing TEEs. CKD, developing a new neurological deficit or a TEEs were independent predictors of higher mortality. We find the optimal time of resuming OAC to be after 2 days but before 21 days as these patients had the lowest recurrence of bleeding associated with a low risk of stroke. The ML model achieved an accuracy of 93, precision of 0.84 and recall of 0.80 for recurrence prediction. ML models for hospital stay performed poorly (R2 = 0.33). ML model for stroke was overfitted given the low number of events. Conclusion: ML modeling is feasible. However, large well-designed prospective multicenter studies are needed for accurate ML so that clinicians can balance the risks of recurrence with the risk of TEEs, especially for high-risk anticoagulated patients.

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.

Objectives: Hemostasis and dural defect repair are fundamental aspects of neurosurgical procedures. Some significant bleeding may be caused by dural tears (e.g. bleeding from cerebral dural venous sinuses). Various methods have been previously reported for these purposes, utilizing commercially available surgical materials such as gelatin sponge and fibrin glue. We describe a simple, yet versatile and flexible technique with a critical modification to the previously known combined use of gelatin sponge and fibrin glue. We then present a few illustrative cases and discuss the utility and advantages of the described technique. Patients and methods: The described technique involves separate and sequential application of fibrinogen solution followed by thrombin solution of fibrin glue over gelatin sponge, which enables hemostasis or dural defect repair in a localized, controlled manner. Results: We have utilized this technique effectively for hemostasis and dural defect repair in a variety of neurosurgical procedures for over 10 years. We have found the technique to be highly useful and effective, although the effectiveness of this technique may be difficult to quantify objectively and independently of the other standard surgical maneuvers, given that hemostasis and prevention of cerebrospinal fluid leak is multifactorial. We have not encountered any complications specifically attributable to the use of fibrin glue and/or gelatin sponge for this technique. Conclusion: This technique will add to the neurosurgeons' arsenal for hemostasis and dural defect repair, in addition to the more standard and basic surgical maneuvers. Keywords: Cerebral dural venous sinus, CSF leak, Dural closure, Fibrin sealant, Gelfoam, Tisseel

BACKGROUND: Traditional psychometric measures aimed at characterizing the pain experience often show considerable overlap, due to interlinked affective and modulatory processes under central nervous system control. Neuroimaging studies have been employed to investigate this complexity of pain processing, in an attempt to provide a quantifiable, adjunctive description of pain perception. In this exploratory study, we examine psychometric and neuroimaging data from 38 patients with painful osteoarthritis of the carpometacarpal joint. We had two aims; firstly, to utilize principal components analysis (PCA) as a dimension reduction strategy across multiple self-reported endpoints of pain, cognitive and affective functioning; second, to investigate the relationship between identified dimensions and regional cerebral blood flow (rCBF) as an indirect measure of brain activity underpinning their ongoing pain experiences.METHODS: Psychometric data were collected using validated questionnaires. Quantitative estimates of rCBF was acquired using pseudo-continuous arterial spin labelled functional magnetic resonance imaging.RESULTS: Two principal components were identified that accounted for 73% of data variance; one related to pain scores and a second to psychological traits. Voxel-wise multiple regression analysis revealed a significant negative association between the 'pain score' component and rCBF to a right temporal lobe cluster, including the amygdala and the parahippocampal cortex.CONCLUSION: We suggest this association may represent a coping mechanism that aims to reduce fear-related pain-anxiety. Further investigation of central brain processing mechanisms in osteoarthritis-related pain may offer insights into more effective therapeutic strategies.SIGNIFICANCE: This study demonstrates that dimension reduction using PCA allows insight into pain perception and its affective components in relation to brain activation patterns in patients with painful hand osteoarthritis. This article is protected by copyright. All rights reserved.

Objectives Determine ancillary test utilization for the workup of isolated eosinophilia in otherwise morphologically unremarkable bone marrow (BM). Methods We evaluated BM ancillary testing performed in cases with isolated eosinophilia and otherwise morphologically unremarkable BM. Cases with abnormal morphology (eg, dysplasia, basophilia) and/or findings suggestive of a disorder (eg, unexplained thromboses, lymphoma) are specifically excluded. Results A total of 132 cases met inclusion criteria. Ten cases had an ancillary testing abnormality that warranted a more specific hematologic diagnosis: four cases of lymphocytic variant of hypereosinophilic syndrome, three cases of myeloid neoplasm with PDGFRA rearrangement, and one case each of myeloid neoplasm with PDGFRB rearrangement, chronic eosinophilic leukemia, and morphologically occult systemic mastocytosis. No cases revealed a cryptic PDGFRB or BCR/ABL1 rearrangement or JAK2 V617F mutation. Conclusions Findings from our institutional experience support initial testing in isolated eosinophilia with otherwise unremarkable BM to include PDGFRA rearrangement, tryptase/CD25 immunohistochemistry, cytogenetics, and T-cell flow cytometry/receptor gene rearrangement. This approach achieves diagnostic quality and test utilization efficiency in our clinical practice.

OBJECTIVEA convergence of clinical research suggests that the temporal pole (TP) plays an important and potentially underappreciated role in the genesis and propagation of seizures in temporal lobe epilepsy (TLE). Understanding its role is becoming increasingly important because selective resections for medically intractable TLE spare temporopolar cortex (TPC). The purpose of this study was to characterize the role of the TPC in TLE after using dense electrocorticography (ECoG) recordings in patients undergoing invasive monitoring for medically intractable TLE.METHODSChronic ECoG recordings were obtained in 10 consecutive patients by using an array customized to provide dense coverage of the TP as part of invasive monitoring to localize the epileptogenic zone. All patients would eventually undergo cortico-amygdalohippocampectomy. A retrospective review of the patient clinical records including ECoG recordings, neuroimaging studies, neuropathology reports, and clinical outcomes was performed.RESULTSIn 7 patients (70%), the TP was involved at seizure onset; in 7 patients (70%), there were interictal discharges from the TP; and in 1 case, there was early spread to the TP. Seizure onset in the TP did not necessarily correlate with preoperative neuroimaging abnormalities of the TP.CONCLUSIONSThese data demonstrate that TPC commonly plays a crucial role in temporal lobe seizure networks. Seizure onset from the TP would not have been predicted based on available neuroimaging data or interictal discharges. These findings illustrate the importance of thoroughly considering the role of the TP prior to resective surgery for TLE, particularly when selective mesial resection is being considered.

Musicogenic epilepsy (ME) is an extremely rare form of the disorder that is provoked by listening to or playing music, and it has been localized to the temporal lobe. The number of reported cases of ME in which intracranial electroencephalography (iEEG) has been used for seizure focus localization is extremely small, especially with coverage of the superior temporal plane (STP) and specifically, Heschl’s gyrus (HG). The authors describe the case of a 17-year-old boy with a history of medically intractable ME who underwent iEEG monitoring that involved significant frontotemporal coverage as well as coverage of the STP with an HG depth electrode anteriorly and a planum temporale depth electrode posteriorly. Five seizures occurred during the monitoring period, and a seizure onset zone was localized to HG and the STP. The patient subsequently underwent right temporal neocortical resection, involving the STP and including HG, with preservation of the mesial temporal structures. The patient remains seizure free 1 year postoperatively. To the authors’ knowledge, this is the first reported case of ME in which the seizure focus has been localized to HG and the STP with iEEG monitoring. The authors review the literature on iEEG findings in ME, explain their approach to HG depth electrode placement, and discuss the utility of STP depth electrodes in temporal lobe epilepsy.

OBJECTIVEThe differences in symptoms of spinal meningiomas have rarely been discussed from the perspective of tumor characteristics. The main purpose of this paper was to define the differences, if any, in symptoms in patients with spinal meningiomas with respect to tumor size, location, and degree of spinal cord compression. The authors also sought the threshold of spinal cord compression that causes motor weakness.METHODSThe authors conducted a retrospective study of 53 cases of spinal meningiomas that were surgically treated from 2013 to 2018. Symptoms related to the tumor were classified as motor weakness, sensory disturbance, pain, and bowel/bladder dysfunction. Based on MR images, tumor location was classified by spinal level and by its attachment to the dura mater. Tumor dimensions were also measured. Occupation ratios of the tumors to the spinal canal and degree of spinal cord flattening were sought from the axial MR images that showed the highest degree of spinal cord compression.RESULTSMotor weakness and sensory disturbance were significantly more common in thoracic spine meningiomas than in cervical spine meningiomas (p < 0.001 and p = 0.013, respectively), while pain was more common in meningiomas at the craniovertebral junction (p < 0.001). The attachment, height, width, depth, and volume of the tumor showed no significant difference irrespective of the presence or absence of each symptom. In cases of motor weakness and sensory disturbance, occupation ratios and spinal cord flattening ratios were significantly larger. However, these ratios were significantly smaller in the presence of pain. Multivariate logistic regression analysis revealed that occupation ratio independently contributed to motor weakness (OR 1.14, p = 0.035) and pain (OR 0.925, p = 0.034). Receiver operating characteristic curve analysis suggested that occupation ratio with a value of 63.678% is the threshold for the tumor to cause motor weakness.CONCLUSIONSThe study showed the difference in clinical presentation of spinal meningiomas by spinal level, occupation ratio, and spinal cord flattening ratio. An occupation ratio of approximately 64% could be utilized as the threshold value of tumor growth to cause motor weakness. Tumor growth in the cervical spine might cause pain symptoms before causing motor weakness. The relationship between the tumor and its symptomatology should be discussed with respect to tumor size relative to the surrounding spinal canal.

Objectives Lymphoplasmacytic lymphoma (LPL) remains a poorly defined entity, even with the discovery of MYD88L265P mutations and association with Waldenstrom macroglobulinemia (WM). Among bone marrow (BM)-based, low-grade B-cell lymphoma with plasmacytic differentiation (LGBLPD) and immunoglobulin M (IgM) paraproteins, we sought to determine whether MYD88L265P defines a distinct entity and can help refine diagnostic criteria for LPL. Methods BMs diagnosed with LGBLPD or LPL and serum IgM paraprotein were studied (2007-2013). Clinicopathologic features were reviewed and specimens were tested for MYD88L265P. Results In total, 138 (87%) of 159 cases had MYD88L265P, and 158 of 159 were clinically considered WM. MYD88L265P cases had higher disease burden than MYD88WT. Features associated with MYD88L265P include increased mast cells and lymphocyte (not plasma cell)-predominant infiltrate. Hemosiderin, Dutcher bodies, and paratrabecular growth were not associated with MYD88L265P. Conclusions Our data support a clinicopathologic approach to LPL diagnosis and recognition that it may manifest with varying morphologies, phenotypes, and molecular features.

Background Chronic pain is a prevalent condition that causes functional impairment and emotional suffering. To allay pain-induced suffering, opioids are often prescribed for chronic pain management. Yet, chronic pain patients on opioid therapy are at heightened risk for opioid misuse—behaviors that can lead to addiction and overdose. Relatedly, chronic pain patients are at elevated risk for suicidal ideation and suicidal behaviors. Main body Opioid misuse and suicidality are maladaptive processes aimed at alleviating the negative emotional hyperreactivity, hedonic hyporeactivity, and emotion dysregulation experienced by chronic pain patients on opioid therapy. In this review, we explore the role of emotion dysregulation in chronic pain. We then describe why emotionally dysregulated chronic pain patients are vulnerable to opioid misuse and suicidality in response to these negative affective states. Conclusion Emotion dysregulation is an important and malleable treatment target with the potential to reduce or prevent opioid misuse and suicidality among opioid-treated chronic pain patients.