Publications by authors named "Matthew Howard"

430 Publications

The association between pain-induced autonomic reactivity and descending pain control is mediated by the periaqueductal grey.

J Physiol 2021 Oct 13. Epub 2021 Oct 13.

Department of Neuroimaging, King's College London, London, UK.

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.
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http://dx.doi.org/10.1113/JP282013DOI Listing
October 2021

Credentialing and certification: Overview, science, and impact on policy, regulation, and practice.

Int Nurs Rev 2021 Sep 30. Epub 2021 Sep 30.

Executive Nursing Administration, Office of Evidence Based Practice and Nursing Research, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Aim: To engage the global nursing community in sharing knowledge, experiences, and lessons learned about credentialing of individual nurses to improve nursing practice, patient safety, and quality of care.

Background: Although the United States has a long and robust history of credentialing individual nurses, the opportunity exists to expand the dialogue globally, and is supported by globally focused governing bodies who call for increased or expanded investment in nursing certification and credentialing. Foundational work to define and operationalize certification for research purposes and develop an administrative home for stakeholders interested in certification can be leveraged by countries and regions globally. Existing frameworks for credentialing research may be used to drive theory-based research in the future.

Sources Of Evidence: PubMed, International Council of Nurses, National Academies of Sciences, Engineering, and Medicine, World Health Organization, American Nurses Association, American Nurses Credentialing Center, and the authors' own experiences.

Discussion: Credentialing as a form of self-governance, as a method for public protection, and as a foundational element in the increasingly new forms of healthcare delivery is intensifying in importance. Credentials provide an opportunity to evaluate relationships between key elements such as nursing practice, environments where nursing care is delivered, and nursing programs with outcomes of interest for the profession such as safety, quality of care, and patient outcomes.

Conclusions: Establishing rigorous credentials for nurses demonstrates a commitment to excellence. Credentialing frameworks that are universally applied could enable nurses to move seamlessly across geographic boundaries, permit regulators and employers of nurses to have a common set of standards and expectations, and ensure a level of competency for nursing practice that can be interpreted and trusted by various stakeholders.

Implications For Nursing Policy: Policymakers have a pivotal role in advancing credentialing in nursing worldwide. Countries developing credentialing programs in nursing need to study their results to help inform how practice might be required to change over time.
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http://dx.doi.org/10.1111/inr.12721DOI Listing
September 2021

Transcriptional and cellular signatures of cortical morphometric remodelling in chronic pain.

Pain 2021 Sep 23. Epub 2021 Sep 23.

Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, UK Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School Wolfson CARD, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE1 1UL.

Abstract: Chronic pain is a highly debilitating and difficult to treat condition, which affects the structure of the brain. While 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 three independent small cohorts of patients with distinct chronic pain syndromes (knee osteoarthritis, low back pain and fibromyalgia) and age 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 FDR 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 suggests 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.
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http://dx.doi.org/10.1097/j.pain.0000000000002480DOI Listing
September 2021

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

Proc Natl Acad Sci U S A 2021 Sep;118(36)

Department of Neurological Surgery, University of California, San Francisco, CA 94143;

Adults can learn to identify nonnative speech sounds with training, albeit with substantial variability in learning behavior. Increases in behavioral accuracy are associated with increased separability for sound representations in cortical speech areas. However, it remains unclear whether individual auditory neural populations all show the same types of changes with learning, or whether there are heterogeneous encoding patterns. Here, we used high-resolution direct neural recordings to examine local population response patterns, while native English listeners learned to recognize unfamiliar vocal pitch patterns in Mandarin Chinese tones. We found a distributed set of neural populations in bilateral superior temporal gyrus and ventrolateral frontal cortex, where the encoding of Mandarin tones changed throughout training as a function of trial-by-trial accuracy ("learning effect"), including both increases and decreases in the separability of tones. These populations were distinct from populations that showed changes as a function of exposure to the stimuli regardless of trial-by-trial accuracy. These learning effects were driven in part by more variable neural responses to repeated presentations of acoustically identical stimuli. Finally, learning effects could be predicted from speech-evoked activity even before training, suggesting that intrinsic properties of these populations make them amenable to behavior-related changes. Together, these results demonstrate that nonnative speech sound learning involves a wide array of changes in neural representations across a distributed set of brain regions.
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http://dx.doi.org/10.1073/pnas.2101777118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433551PMC
September 2021

The autonomic brain: Multi-dimensional generative hierarchical modelling of the autonomic connectome.

Cortex 2021 10 23;143:164-179. Epub 2021 Jul 23.

Queen Square Institute of Neurology, University College London, UK.

The autonomic nervous system governs the body's multifaceted internal adaptation to diverse changes in the external environment, a role more complex than is accessible to the methods-and data scales-hitherto used to illuminate its operation. Here we apply generative graphical modelling to large-scale multimodal neuroimaging data encompassing normal and abnormal states to derive a comprehensive hierarchical representation of the autonomic brain. We demonstrate that whereas conventional structural and functional maps identify regions jointly modulated by parasympathetic and sympathetic systems, only graphical analysis discriminates between them, revealing the cardinal roles of the autonomic system to be mediated by high-level distributed interactions. We provide a novel representation of the autonomic system-a multidimensional, generative network-that renders its richness tractable within future models of its function in health and disease.
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http://dx.doi.org/10.1016/j.cortex.2021.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500219PMC
October 2021

Imaging Brain Glx Dynamics in Response to Pressure Pain Stimulation: A H-fMRS Study.

Front Psychiatry 2021 28;12:681419. Epub 2021 Jul 28.

Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom.

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 . Functional magnetic resonance spectroscopy (H-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 H-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 ( = 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 H-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.
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http://dx.doi.org/10.3389/fpsyt.2021.681419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357306PMC
July 2021

Regional cerebral blood flow as predictor of response to occipital nerve block in cluster headache.

J Headache Pain 2021 Aug 12;22(1):91. Epub 2021 Aug 12.

Department of Neuroimaging, King's College London, Institute of Psychiatry, Psychology and Neuroscience, Box 89, De Crespigny Park, London, SE5 8AF, UK.

Background: Cluster 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.

Methods: 21 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.

Results: Following 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.

Conclusions: We 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.
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http://dx.doi.org/10.1186/s10194-021-01304-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359299PMC
August 2021

Affordable Embroidered EMG Electrodes for Myoelectric Control of Prostheses: A Pilot Study.

Sensors (Basel) 2021 Aug 3;21(15). Epub 2021 Aug 3.

Department of Engineering, King's College London, London WC2R 2LS, UK.

Commercial myoelectric prostheses are costly to purchase and maintain, making their provision challenging for developing countries. Recent research indicates that embroidered EMG electrodes may provide a more affordable alternative to the sensors used in current prostheses. This pilot study investigates the usability of such electrodes for myoelectric control by comparing online and offline performance against conventional gel electrodes. Offline performance is evaluated through the classification of nine different hand and wrist gestures. Online performance is assessed with a crossover two-degree-of-freedom real-time experiment using Fitts' Law. Two performance metrics (Throughput and Completion Rate) are used to quantify usability. The mean classification accuracy of the nine gestures is approximately 98% for subject-specific models trained on both gel and embroidered electrode offline data from individual subjects, and 97% and 96% for general models trained on gel and embroidered offline data, respectively, from all subjects. Throughput (0.3 bits/s) and completion rate (95-97%) are similar in the online test. Results indicate that embroidered electrodes can achieve similar performance to gel electrodes paving the way for low-cost myoelectric prostheses.
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http://dx.doi.org/10.3390/s21155245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347069PMC
August 2021

De novo isolated myeloid sarcoma: comparative analysis of survival in 19 consecutive cases.

Br J Haematol 2021 Aug 3. Epub 2021 Aug 3.

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.

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.
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http://dx.doi.org/10.1111/bjh.17742DOI Listing
August 2021

Corrigendum to "Oscillatory correlates of auditory working memory examined with human electrocorticography" [Neuropsychologia 150 (2021) 107691].

Neuropsychologia 2021 Aug 8;159:107950. Epub 2021 Jul 8.

Newcastle University Medical School, Newcastle Upon Tyne, Tyne and Wear, NE2 4HH, UK; Department of Neurosurgery, The University of Iowa, Iowa City, IA, 52242, USA; Wellcome Centre for Human Neuroimaging, University College London, London, WC1N 3BG, UK.

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http://dx.doi.org/10.1016/j.neuropsychologia.2021.107950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350140PMC
August 2021

Evaluation of Sagittal Spinopelvic Balance in Spinal Cord Stimulator Patients.

Neuromodulation 2021 Jun 9. Epub 2021 Jun 9.

Department of Neurosurgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA.

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.
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http://dx.doi.org/10.1111/ner.13481DOI Listing
June 2021

RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis.

Nat Commun 2021 05 18;12(1):2901. Epub 2021 May 18.

Sigmund Freud University Vienna, Vienna, Austria.

Proliferative chronic myelomonocytic leukemia (pCMML), an aggressive CMML subtype, is associated with dismal outcomes. RAS pathway mutations, mainly NRAS, define the pCMML phenotype as demonstrated by our exome sequencing, progenitor colony assays and a Vav-Cre-Nras mouse model. Further, these mutations promote CMML transformation to acute myeloid leukemia. Using a multiomics platform and biochemical and molecular studies we show that in pCMML RAS pathway mutations are associated with a unique gene expression profile enriched in mitotic kinases such as polo-like kinase 1 (PLK1). PLK1 transcript levels are shown to be regulated by an unmutated lysine methyl-transferase (KMT2A) resulting in increased promoter monomethylation of lysine 4 of histone 3. Pharmacologic inhibition of PLK1 in RAS mutant patient-derived xenografts, demonstrates the utility of personalized biomarker-driven therapeutics in pCMML.
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http://dx.doi.org/10.1038/s41467-021-23186-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131698PMC
May 2021

Using a Secure, Continually Updating, Web Source Processing Pipeline to Support the Real-Time Data Synthesis and Analysis of Scientific Literature: Development and Validation Study.

J Med Internet Res 2021 05 6;23(5):e25714. Epub 2021 May 6.

PanSurg Collaborative, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.

Background: The scale and quality of the global scientific response to the COVID-19 pandemic have unquestionably saved lives. However, the COVID-19 pandemic has also triggered an unprecedented "infodemic"; the velocity and volume of data production have overwhelmed many key stakeholders such as clinicians and policy makers, as they have been unable to process structured and unstructured data for evidence-based decision making. Solutions that aim to alleviate this data synthesis-related challenge are unable to capture heterogeneous web data in real time for the production of concomitant answers and are not based on the high-quality information in responses to a free-text query.

Objective: The main objective of this project is to build a generic, real-time, continuously updating curation platform that can support the data synthesis and analysis of a scientific literature framework. Our secondary objective is to validate this platform and the curation methodology for COVID-19-related medical literature by expanding the COVID-19 Open Research Dataset via the addition of new, unstructured data.

Methods: To create an infrastructure that addresses our objectives, the PanSurg Collaborative at Imperial College London has developed a unique data pipeline based on a web crawler extraction methodology. This data pipeline uses a novel curation methodology that adopts a human-in-the-loop approach for the characterization of quality, relevance, and key evidence across a range of scientific literature sources.

Results: REDASA (Realtime Data Synthesis and Analysis) is now one of the world's largest and most up-to-date sources of COVID-19-related evidence; it consists of 104,000 documents. By capturing curators' critical appraisal methodologies through the discrete labeling and rating of information, REDASA rapidly developed a foundational, pooled, data science data set of over 1400 articles in under 2 weeks. These articles provide COVID-19-related information and represent around 10% of all papers about COVID-19.

Conclusions: This data set can act as ground truth for the future implementation of a live, automated systematic review. The three benefits of REDASA's design are as follows: (1) it adopts a user-friendly, human-in-the-loop methodology by embedding an efficient, user-friendly curation platform into a natural language processing search engine; (2) it provides a curated data set in the JavaScript Object Notation format for experienced academic reviewers' critical appraisal choices and decision-making methodologies; and (3) due to the wide scope and depth of its web crawling method, REDASA has already captured one of the world's largest COVID-19-related data corpora for searches and curation.
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http://dx.doi.org/10.2196/25714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104004PMC
May 2021

Impact of Intracerebral Hematoma Evacuation During Decompressive Hemicraniectomy on Functional Outcomes.

Stroke 2021 Mar 28;52(3):1105-1108. Epub 2021 Jan 28.

Department of Neurosurgery (L.L., V.A.M., S.C.S., M.Z., M.A.H., J.D.G., D.M.H., E.C.L.), University of Iowa.

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 (=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.
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http://dx.doi.org/10.1161/STROKEAHA.120.032224DOI Listing
March 2021

MRI monitoring of macaque monkeys in neuroscience: Case studies, resource and normative data comparisons.

Neuroimage 2021 04 23;230:117778. Epub 2021 Jan 23.

Comparative Biology Centre, Newcastle University, Newcastle upon Tyne, United Kingdom. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063182PMC
April 2021

Communicating Expectations: Developing a Rubric for Peer Reviewers.

J Contin Educ Nurs 2021 Feb;52(2):64-66

The peer-review process is a form of self-regulation by qualified members of the profession to evaluate works done by one or more individuals. However, without a clear structure, the peer-review process can be problematic. Rubrics have been shown to increase peer reviewer satisfaction and author compliance, but only when they convey clear and specific descriptions for task-specific criteria. Sigma developed a peer-review rubric to provide consistency in judging scientific abstracts. An asynchronous provider-directed, provider-paced educational activity can be used to successfully educate peer reviewers on the benefit and use of a peer-review rubric. [J Contin Educ Nurs. 2021;52(2):64-66.].
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http://dx.doi.org/10.3928/00220124-20210114-04DOI Listing
February 2021

Common fronto-temporal effective connectivity in humans and monkeys.

Neuron 2021 03 21;109(5):852-868.e8. Epub 2021 Jan 21.

Biosciences Institute, Newcastle University Medical School, Newcastle upon Tyne, UK. Electronic address:

Human brain pathways supporting language and declarative memory are thought to have differentiated substantially during evolution. However, cross-species comparisons are missing on site-specific effective connectivity between regions important for cognition. We harnessed functional imaging to visualize the effects of direct electrical brain stimulation in macaque monkeys and human neurosurgery patients. We discovered comparable effective connectivity between caudal auditory cortex and both ventro-lateral prefrontal cortex (VLPFC, including area 44) and parahippocampal cortex in both species. Human-specific differences were clearest in the form of stronger hemispheric lateralization effects. In humans, electrical tractography revealed remarkably rapid evoked potentials in VLPFC following auditory cortex stimulation and speech sounds drove VLPFC, consistent with prior evidence in monkeys of direct auditory cortex projections to homologous vocalization-responsive regions. The results identify a common effective connectivity signature in human and nonhuman primates, which from auditory cortex appears equally direct to VLPFC and indirect to the hippocampus. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.neuron.2020.12.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927917PMC
March 2021

Prescription opioid misusers exhibit blunted parasympathetic regulation during inhibitory control challenge.

Psychopharmacology (Berl) 2021 Mar 7;238(3):765-774. Epub 2021 Jan 7.

University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

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 computed. 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 = .16) and slowed reaction times (p = .045, η = .09) compared to neutral and positive affective images, respectively. Though no between-group 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 = .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-group 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.
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http://dx.doi.org/10.1007/s00213-020-05729-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914222PMC
March 2021

Innovative Opportunities for Civility: Professional Development in a Time of COVID-19.

J Contin Educ Nurs 2021 Jan;52(1):11-12

The impact of the COVID-19 pandemic on nursing professional development has spurred innovative teaching efforts by educators. The application of new technology provided innovative support for participant engagement and allowed for evaluation of civility education learning outcomes. A technology expert provided necessary support in a live virtual environment. A planned dress rehearsal prior to the live event ensured the functionality of the virtual platform. The versatility of the new technology allowed breakout rooms and interactive software applications. Nursing professional development practitioners can use these tips to reimagine other face-to-face educational activities into a virtual platform. [J Contin Educ Nurs. 2021;52(1):11-12.].
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http://dx.doi.org/10.3928/00220124-20201215-05DOI Listing
January 2021

Novel t(1;8)(p31.3;q21.3) NFIA-RUNX1T1 Translocation in an Infant Erythroblastic Sarcoma.

Am J Clin Pathol 2021 06;156(1):129-138

Divisions of Pediatrics, MemorialCare, Miller Children's and Women's Hospital, Long Beach, CA.

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.
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http://dx.doi.org/10.1093/ajcp/aqaa216DOI Listing
June 2021

Focal Cortical Surface Cooling is a Novel and Safe Method for Intraoperative Functional Brain Mapping.

World Neurosurg 2021 03 8;147:e118-e129. Epub 2020 Dec 8.

Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA. Electronic address:

Objective: Electric cortical stimulation (ECS) has been the gold standard for intraoperative functional mapping in neurosurgery, yet it carries the risk of induced seizures. We assess the safety of focal cortical cooling (CC) as a potential alternative to ECS.

Methods: We reviewed 40 patients (13 with tumor and 27 with mesial temporal lobe epilepsy) who underwent intraoperative CC at the University of Iowa Hospital and Clinics (CC group), of whom 38 underwent ECS preceding CC. Intraoperative and postoperative seizure incidence, postoperative neurologic deficits, and new postoperative radiographic findings were collected to assess CC safety. Fifty-five patients who underwent ECS mapping without CC (ECS-alone group) were reviewed as a control cohort. Another 25 patients who underwent anterior temporal lobectomy (ATL) without CC or ECS (no ECS/no CC-ATL group) were also reviewed to evaluate long-term effects of CC.

Results: Seventy-nine brain sites in the CC group were cooled, comprising inferior frontal gyrus (44%), precentral gyrus (39%), postcentral gyrus (6%), subcentral gyrus (4%), and superior temporal gyrus (6%). The incidence of intraoperative seizure(s) was 0% (CC group) and 3.6% (ECS-alone group). The incidence of seizure(s) within the first postoperative week did not significantly differ among CC (7.9%), ECS-alone (9.0%), and no ECS/no CC-ATL groups (12%). There was no significant difference in the incidence of postoperative radiographic change between CC (7.5%) and ECS-alone groups (5.5%). Long-term seizure outcome (Engel I+II) for mesial temporal epilepsy did not differ among CC (80%), ECS-alone (83.3%), and no ECS/no CC-ATL groups (83.3%).

Conclusions: CC when used as an intraoperative mapping technique is safe and may complement ECS.
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http://dx.doi.org/10.1016/j.wneu.2020.11.164DOI Listing
March 2021

Magnetic resonance imaging (MRI) of pharmacological ascorbate-induced iron redox state as a biomarker in subjects undergoing radio-chemotherapy.

Redox Biol 2021 01 19;38:101804. Epub 2020 Nov 19.

Department of Radiology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA. Electronic address:

Pharmacological ascorbate (P-AscH) combined with standard of care (SOC) radiation and temozolomide is being evaluated in a phase 2 clinical trial (NCT02344355) in the treatment of glioblastoma (GBM). Previously published data demonstrated that paramagnetic iron (Fe) catalyzes ascorbate's oxidation to form diamagnetic iron (Fe). Because paramagnetic Fe may influence relaxation times observed in MR imaging, quantitative MR imaging of P-AscH-induced changes in redox-active Fe was assessed as a biomarker for therapy response. Gel phantoms containing either Fe or Fe were imaged with T2* and quantitative susceptibility mapping (QSM). Fifteen subjects receiving P-AscH plus SOC underwent T2* and QSM imaging four weeks into treatment. Subjects were scanned: pre-P-AscH infusion, post-P-AscH infusion, and post-radiation (3-4 h between scans). Changes in T2* and QSM relaxation times in tumor and normal tissue were calculated and compared to changes in Fe and Fe gel phantoms. A GBM mouse model was used to study the relationship between the imaging findings and the labile iron pool. Phantoms containing Fe demonstrated detectable changes in T2* and QSM relaxation times relative to Fe phantoms. Compared to pre-P-AscH, GBM T2* and QSM imaging were significantly changed post-P-AscH infusion consistent with conversion of Fe to Fe. No significant changes in T2* or QSM were observed in normal brain tissue. There was moderate concordance between T2* and QSM changes in both progression free survival and overall survival. The GBM mouse model showed similar results with P-AscH inducing greater changes in tumor labile iron pools compared to the normal tissue. CONCLUSIONS: T2* and QSM MR-imaging responses are consistent with P-AscH reducing Fe to Fe, selectively in GBM tumor volumes and represent a potential biomarker of response. This study is the first application using MR imaging in humans to measure P-AscH-induced changes in redox-active iron.
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http://dx.doi.org/10.1016/j.redox.2020.101804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708874PMC
January 2021

Pain in the neurodegenerating brain: insights into pharmacotherapy for Alzheimer disease and Parkinson disease.

Pain 2021 04;162(4):999-1006

Wolfson Centre for Age Related Diseases, The Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom.

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http://dx.doi.org/10.1097/j.pain.0000000000002111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977618PMC
April 2021

Oscillatory correlates of auditory working memory examined with human electrocorticography.

Neuropsychologia 2021 01 21;150:107691. Epub 2020 Nov 21.

Newcastle University Medical School, Newcastle Upon Tyne, Tyne and Wear NE2 4HH, UK; Department of Neurosurgery, The University of Iowa, Iowa City, IA, 52242, USA; Wellcome Centre for Human Neuroimaging, University College London, London, WC1N 3BG, UK.

This work examines how sounds are held in auditory working memory (AWM) in humans by examining oscillatory local field potentials (LFPs) in candidate brain regions. Previous fMRI studies by our group demonstrated blood oxygenation level-dependent (BOLD) response increases during maintenance in auditory cortex, inferior frontal cortex and the hippocampus using a paradigm with a delay period greater than 10s. The relationship between such BOLD changes and ensemble activity in different frequency bands is complex, and the long delay period raised the possibility that long-term memory mechanisms were engaged. Here we assessed LFPs in different frequency bands in six subjects with recordings from all candidate brain regions using a paradigm with a short delay period of 3 s. Sustained delay activity was demonstrated in all areas, with different patterns in the different areas. Enhancement in low frequency (delta) power and suppression across higher frequencies (beta/gamma) were demonstrated in primary auditory cortex in medial Heschl's gyrus (HG) whilst non-primary cortex showed patterns of enhancement and suppression that altered at different levels of the auditory hierarchy from lateral HG to superior- and middle-temporal gyrus. Inferior frontal cortex showed increasing suppression with increasing frequency. The hippocampus and parahippocampal gyrus showed low frequency increases and high frequency decreases in oscillatory activity. This work demonstrates sustained activity patterns during AWM maintenance, with prominent low-frequency increases in medial temporal lobe regions.
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http://dx.doi.org/10.1016/j.neuropsychologia.2020.107691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884909PMC
January 2021

Electrophysiology of the Human Superior Temporal Sulcus during Speech Processing.

Cereb Cortex 2021 01;31(2):1131-1148

Department of Neurosurgery, The University of Iowa, Iowa City, IA 52242, USA.

The superior temporal sulcus (STS) is a crucial hub for speech perception and can be studied with high spatiotemporal resolution using electrodes targeting mesial temporal structures in epilepsy patients. Goals of the current study were to clarify functional distinctions between the upper (STSU) and the lower (STSL) bank, hemispheric asymmetries, and activity during self-initiated speech. Electrophysiologic properties were characterized using semantic categorization and dialog-based tasks. Gamma-band activity and alpha-band suppression were used as complementary measures of STS activation. Gamma responses to auditory stimuli were weaker in STSL compared with STSU and had longer onset latencies. Activity in anterior STS was larger during speaking than listening; the opposite pattern was observed more posteriorly. Opposite hemispheric asymmetries were found for alpha suppression in STSU and STSL. Alpha suppression in the STS emerged earlier than in core auditory cortex, suggesting feedback signaling within the auditory cortical hierarchy. STSL was the only region where gamma responses to words presented in the semantic categorization tasks were larger in subjects with superior task performance. More pronounced alpha suppression was associated with better task performance in Heschl's gyrus, superior temporal gyrus, and STS. Functional differences between STSU and STSL warrant their separate assessment in future studies.
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http://dx.doi.org/10.1093/cercor/bhaa281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786351PMC
January 2021

Quantitative Assessment of Ventriculostomy-Related Hemorrhage: A Volume-Based Classification System to Predict New Neurological Symptoms.

Oper Neurosurg (Hagerstown) 2021 01;20(2):198-205

Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City, Iowa.

Background: 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.

Objective: To correlate quantitative volumetric measurements of VRH with new neurological symptoms.

Methods: 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.

Results: 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 volume <1.10 cc has 91.7% sensitivity to rule out symptomatic VRH, whereas a volume >7.59 cc has 95.5% specificity to predict symptomatic VRH.

Conclusion: Approximately 6% of patients developed postprocedural VRH, but only 0.4% were symptomatic. VRH volumes <1 cc are extremely unlikely to become symptomatic, whereas volumes >7.5 cc may predict development of new neurological deficits.
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http://dx.doi.org/10.1093/ons/opaa319DOI Listing
January 2021

Linking Pain Sensation to the Autonomic Nervous System: The Role of the Anterior Cingulate and Periaqueductal Gray Resting-State Networks.

Front Neurosci 2020 27;14:147. Epub 2020 Feb 27.

Department of Neuroimaging, King's College London, London, United Kingdom.

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.
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http://dx.doi.org/10.3389/fnins.2020.00147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527240PMC
February 2020
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