Evaluating peripheral neuromuscular function with brief movement-evoked pain.

Movement-evoked pain is an understudied manifestation of musculoskeletal conditions that contributes to disability, yet little is known about how the neuromuscular system responds to movement-evoked pain. The present study examined whether movement-evoked pain impacts force production, electromyographic (EMG) muscle activity, and the rate of force development (RFD) during submaximal muscle contractions. Fifteen healthy adults (9 males; age = 30.3 ± 10.2 yr, range = 22-59 yr) performed submaximal isometric first finger abduction contractions without pain (baseline) and with movement-evoked pain induced by laser stimulation to the dorsum of the hand. Normalized force (% maximal voluntary contraction) and RFD decreased by 11% (P < 0.001) and 15% (P = 0.003), respectively, with movement-evoked pain, without any change in normalized peak EMG (P = 0.77). Early contractile RFD, force impulse, and corresponding EMG amplitude computed within time segments of 50, 100, 150, and 200 ms relative to the onset of movement were also unaffected by movement-evoked pain (P > 0.05). Our results demonstrate that movement-evoked pain impairs peak characteristics and not early measures of submaximal force production and RFD, without affecting EMG activity (peak and early). Possible explanations for the stability in EMG with reduced force include antagonist coactivation and a reorganization of motoneuronal activation strategy, which is discussed here.NEW & NOTEWORTHY We provide neurophysiological evidence to indicate that peak force and rate of force development are reduced by movement-evoked pain despite a lack of change in EMG and early rapid force development in the first dorsal interosseous muscle. Additional evidence suggests that these findings may coexist with a reorganization in motoneuronal activation strategy.

Regional variations in cingulate cortex glutamate levels: A magnetic resonance spectroscopy study at 3T.

Regional variations in glutamate levels across the cingulate cortex, decreasing rostral-to-caudal, have been observed previously in healthy volunteers using proton magnetic resonance spectroscopy (1H-MRS) at 7T. This study sought to explore cingulate cortex glutamate trends further by investigating whether a similar gradient could be detected at 3T, the effect of sex, as well as whether individual variations gave rise to more than one regional glutamate pattern. 1H-MRS at 3T (Phillips Elition, semi-Localization by Adiabatic Selective Refocusing, TE/TR = 32/5000) was acquired in four cingulate regions: the anterior, mid-anterior, mid-posterior, and posterior cortices, in 50 healthy participants (26F) scanned at a fixed time of day and with controlled food intake. K-means clustering was used to characterize the presence of distinct regional patterns, which were then compared between sex and clusters. In addition, cortical thickness was compared between clusters, and in relation to glutamate. Aligned with 7T findings, we demonstrated that average glutamate levels decreased rostral-to-caudal in the healthy cingulate cortex. No effect of sex was found, suggesting similar resting glutamate levels in both sexes. Interestingly, the majority of participants were characterized by glutamate levels that did not significantly change across the cingulate (65%). Different regional patterns in cortical thickness between clusters offer further evidence into these distinct glutamate variations and suggest both a neuroanatomical and functional role may lead to these findings. This study provides a much needed foundation for further research to determine the implications of neurotransmission patterns in health and disease.

Pain-related gamma band activity is dependent on the features of nociceptive stimuli: a comparison of laser and contact heat.

Painful contact heat and laser stimulation offer an avenue to characterize nociceptive pathways involved in acute pain processing, by way of evoked potentials. Direct comparisons of radiant laser and contact heat are limited, particularly in context of examining time-frequency responses to stimulation. This is important in light of recent evidence to suggest that gamma band oscillations (GBOs) represent a functionally heterogeneous measure of pain. The purpose of the current study was to investigate differences in GBOs generated in response to laser and contact heat stimulation of the nondominant forearm. Following intensity matching to pain ratings, evoked electroencephalography (EEG) responses to laser and contact heat stimulation were examined in the time-frequency domain in the same participants (19 healthy adults) across two sessions. At ∼200 ms, both contact heat and laser stimulation resulted in significant, group-level event-related synchronization (ERS) in the low gamma band (i.e., 30-60 Hz) in central electrode locations (Cc, Cz, Ci). Laser stimulation also generated ERS in the 60-100 Hz range (i.e., high gamma), at ∼200 ms, while contact heat led to a significant period of desynchronization in the high gamma range between 400 and 600 ms. Both contact heat and laser GBOs were stronger on the central electrodes contralateral to the stimulated forearm, indicative of primary somatosensory cortex involvement. Based on our findings, and taken in conjunction with previous studies, laser and contact heat stimulation generate characteristically different responses in the brain, with only the former leading to high-frequency GBOs characteristic of painful stimuli.NEW & NOTEWORTHY Despite matching pain perception between noxious laser and contact heat stimuli, we report notable differences in gamma band oscillations (GBO), measured via electroencephalography. GBOs produced following contact heat more closely resembled that of nonnoxious stimuli, while GBOs following laser stimuli were in line with previous reports. Taken together, laser and contact heat stimulation generate characteristically different responses in the brain, with only the former leading to high-frequency GBOs characteristic of painful stimuli.

Physical pain among Indigenous Peoples in Canada: a scoping review.

PURPOSE: Pain is a multifaceted experience shaped by various factors including context of pain, previous life events, and ongoing ethnocultural circumstances. Moreover, the definition of pain is inconsistent across cultures. Western medicine views physical pain (e.g., associated with a bone fracture) and nonphysical mental pain (e.g., depression) as two distinct conditions. Indigenous perspectives are often more wholistic, encompassing mental, spiritual, emotional, and physical hurt. The subjective nature of pain invites ample opportunity for discrimination in both its assessment and management. As such, it is important to consider Indigenous perspectives of pain in research and clinical practice. To investigate which aspects of Indigenous pain knowledge are currently considered by Western research, we conducted a scoping review of the literature on pain in Indigenous Peoples of Canada. SOURCE: In June 2021, we searched nine databases and downloaded 8,220 papers after removal of duplicates. Two independent reviewers screened abstracts and full-text articles. PRINCIPLE FINDINGS: Seventy-seven papers were included in the analysis. Using grounded theory, five themes emerged: pain measures/scales (n = 7), interventions (n = 13), pharmaceuticals (n = 17), pain expression/experiences (n = 45), and pain conditions (n = 70). CONCLUSION: This scoping review shows that there is a paucity of research on pain measurement in Indigenous Peoples of Canada. This finding is concerning in light of numerous studies reporting that Indigenous Peoples experience their pain as ignored, minimized, or disbelieved. Furthermore, a clear disconnect emerged between pain expression in Indigenous Peoples and assessment in medical professionals. We hope that this scoping review will serve to translate current knowledge to other non-Indigenous academics and to initiate meaningful collaboration with Indigenous partners. Future research led by Indigenous academics and community partners is critically needed to better address pain needs in Canada.

RéSUMé: OBJECTIF: La douleur est une expérience multidimensionnelle façonnée par divers facteurs, notamment le contexte de la douleur, les événements antérieurs de la vie et les circonstances ethnoculturelles courantes. De plus, la définition de la douleur change d'une culture à l'autre. La médecine occidentale considère la douleur physique (par exemple, celle associée à une fracture osseuse) et la douleur mentale non physique (par exemple, la dépression) comme deux conditions distinctes. Les perspectives autochtones sont souvent plus holistiques, englobant les blessures mentales, spirituelles, émotionnelles et physiques. La nature subjective de la douleur ouvre la voie à de nombreuses possibilités de discrimination tant dans son évaluation que dans sa prise en charge. C'est pourquoi il est important de tenir compte des perspectives autochtones en matière de douleur dans la recherche et la pratique clinique. Afin d'étudier quels aspects des connaissances autochtones concernant la douleur sont actuellement pris en compte par la recherche occidentale, nous avons réalisé une étude de portée de la littérature sur la douleur chez les peuples autochtones du Canada. SOURCES: En juin 2021, nous avons consulté neuf bases de données et téléchargé 8220 articles après suppression des doublons. Deux personnes ont passé en revue et évalué de manière indépendante les résumés et textes intégraux. CONSTATATIONS PRINCIPALES: Soixante-dix-sept articles ont été inclus dans l'analyse. À l'aide de la théorie ancrée, cinq thèmes sont ressortis : les mesures/échelles de la douleur (n = 7), les interventions (n = 13), les produits pharmaceutiques (n = 17), l'expression/les expériences de la douleur (n = 45), et les conditions de douleur (n = 70). CONCLUSION: Cette étude de portée démontre le peu de recherches sur la mesure de la douleur chez les peuples autochtones du Canada. Cette conclusion est préoccupante à la lumière de nombreuses études indiquant que les peuples autochtones voient leur douleur ignorée, minimisée ou discréditée. De plus, un décalage évident est apparu entre l'expression de la douleur chez les peuples autochtones et l'évaluation par les professionnels de la santé. Nous espérons que cette étude de portée servira à transférer les connaissances actuelles à d'autres chercheurs et chercheuses non autochtones et à établir une collaboration significative avec des partenaires autochtones. Les recherches futures menées par des universitaires autochtones et des partenaires de la collectivité sont essentielles pour mieux répondre aux besoins en matière de douleur au Canada.

Supraspinal facilitation to repetitive painful stimulation: a laser-evoked potential study.

To better characterize central modulation mechanisms involved in the processing of daily repetitive painful stimulation, laser-evoked potentials (LEPs) were recorded at and away from the conditioning area in healthy participants. In addition, we aimed to evaluate a repetitive painful stimulation paradigm that could be conducted in a shorter time frame than previous studies. Collectively, continuous pain rating, warm and heat pain threshold results suggest that sensitivity to pain was reduced 24 h after the shortened repeated painful stimulation. Laser-evoked potentials revealed a significant increase in the contralateral arm to where the conditioning stimulus was applied. This finding was specific to noxious conditioning (i.e., not seen in the control brush experiment). These results provide neurophysiological evidence of pain facilitation resulting from prolonged exposure to painful heat, potentially arising in supraspinal structures.NEW & NOTEWORTHY We provide evidence for supraspinal faciliation measured via laser-evoked potentails in response to a shortened and methodologically improved repetitive painful stimulation paradigm, serving the broader scientific community, insofar as providing a paradigm can feasibly be completed in a caldendar week. These findings provide new evidence using laser-evoked potentials indicating increased activation of the anterior cingulate cortex during prolonged pain processing.

A data-driven T2 relaxation analysis approach for myelin water imaging: Spectrum analysis for multiple exponentials via experimental condition oriented simulation (SAME-ECOS).

PURPOSE: The decomposition of multi-exponential decay data into a T2 spectrum poses substantial challenges for conventional fitting algorithms, including non-negative least squares (NNLS). Based on a combination of the resolution limit constraint and machine learning neural network algorithm, a data-driven and highly tailorable analysis method named spectrum analysis for multiple exponentials via experimental condition oriented simulation (SAME-ECOS) was proposed. THEORY AND METHODS: The theory of SAME-ECOS was derived. Then, a paradigm was presented to demonstrate the SAME-ECOS workflow, consisting of a series of calculation, simulation, and model training operations. The performance of the trained SAME-ECOS model was evaluated using simulations and six in vivo brain datasets. The code is available at https://github.com/hanwencat/SAME-ECOS. RESULTS: Using NNLS as the baseline, SAME-ECOS achieved over 15% higher overall cosine similarity scores in producing the T2 spectrum, and more than 10% lower mean absolute error in calculating the myelin water fraction (MWF), as well as demonstrated better robustness to noise in the simulation tests. Applying to in vivo data, MWF from SAME-ECOS and NNLS was highly correlated among all study participants. However, a distinct separation of the myelin water peak and the intra/extra-cellular water peak was only observed in the mean T2 spectra determined using SAME-ECOS. In terms of data processing speed, SAME-ECOS is approximately 30 times faster than NNLS, achieving a whole-brain analysis in 3 min. CONCLUSION: Compared with NNLS, the SAME-ECOS method yields much more reliable T2 spectra in a dramatically shorter time, increasing the feasibility of multi-component T2 decay analysis in clinical settings.

Single-trial averaging improves the physiological interpretation of contact heat evoked potentials.

Laser and contact heat evoked potentials (LEPs and CHEPs, respectively) provide an objective measure of pathways and processes involved in nociception. The majority of studies analyzing LEP or CHEP outcomes have done so based on conventional, across-trial averaging. With this approach, evoked potential components are potentially confounded by latency jitter and ignore relevant information contained within single trials. The current study addressed the advantage of analyzing nociceptive evoked potentials based on responses to noxious stimulations within each individual trial. Single-trial and conventional averaging were applied to data previously collected in 90 healthy subjects from 3 stimulation locations on the upper limb. The primary analysis focused on relationships between single and across-trial averaged CHEP outcomes (i.e., N2P2 amplitude and N2 and P2 latencies) and subject characteristics (i.e., age, sex, height, and rating of perceived intensity), which were examined by way of linear mixed model analysis. Single-trial averaging lead to larger N2P2 amplitudes and longer N2 and P2 latencies. Age and ratings of perceived intensity were the only subject level characteristics associated with CHEPs outcomes that significantly interacted with the method of analysis (conventional vs single-trial averaging). The strength of relationships for age and ratings of perceived intensity, measured by linear fit, were increased for single-trial compared to conventional across-trial averaged CHEP outcomes. By accounting for latency jitter, single-trial averaging improved the associations between CHEPs and physiological outcomes and should be incorporated as a standard analytical technique in future studies.

Serum albumin as a predictor of neurological recovery after spinal cord injury: a replication study.

STUDY DESIGN: This was a secondary analysis on an observational cohort study. OBJECTIVE: To determine if serum albumin significantly associates with long-term neurological outcome (i.e., 1-year post-injury) in a contemporary cohort of individuals with spinal cord injury. SETTING: Six rehabilitation centers across the United States. METHODS: A secondary analysis of neurological outcomes and serum albumin concentrations was performed on data from the Spinal Cord Injury Rehabilitation study. Data was accessed from the Archive of Data on Disability to Enable Policy and research (ADDEP). The primary analysis applied unbiased recursive partitioning to examine the relationship between serum albumin, injury severity, and long-term outcomes. The analysis is accessible via https://rpubs.com/AnhKhoaVo/586028 . RESULTS: Serum albumin concentration was significantly associated with lower extremity motor scores (LEMS) and American Spinal Injury Association Impairment Scale (AIS) grade at admission to rehabilitation. Serum albumin concentrations alone were also significantly associated with change of LEMS and marked recovery (improvement of at least 2 AIS grades and/or recovery to walking) at 1-year post injury. However, after adjusting for admission to rehabilitation LEMS and AIS grade, serum albumin was not significant. CONCLUSION: The current study partially confirms our previous observations that serum albumin concentrations are associated with neurological outcome after spinal cord injury. As a crude prognostic biomarker, serum albumin concentration could be useful in cases where injury severity cannot be accurately assessed.

Clinical trials and tribulations: lessons from spinal cord injury studies registered on ClinicalTrials.gov.

STUDY DESIGN: Article. OBJECTIVE: ClinicalTrials.gov is an online trial registry that provides public access to information on past, present, and future clinical trials. While increasing transparency in research, the quality of the information provided in trial registrations is highly variable. The objective of this study is to assess key areas of information on ClinicalTrials.gov in interventional trials involving people with spinal cord injuries. SETTING: Interventional trials on ClinicalTrials.gov involving people with spinal cord injuries. METHODS: A subset of data on interventional spinal cord injury trials was downloaded from ClinicalTrials.gov. Reviewers extracted information pertaining to study type, injury etiology, spinal cord injury characteristics, timing, study status, and results. RESULTS: Of the interventional trial registrations reviewed, 62.5%, 58.6%, and 24.3% reported injury level, severity, and etiology, respectively. The timing of intervention relative to injury was reported in 72.8% of registrations. Most trials identified a valid study status (89.2%), but only 23.5% of those completed studies had posted results. CONCLUSIONS: Our review provides a snapshot of interventional clinical trials conducted in the field of spinal cord injury and registered in ClinicalTrials.gov. Areas for improvement were identified with regards to reporting injury characteristics, as well as posting results.

Excitatory and inhibitory responses in the brain to experimental pain: A systematic review of MR spectroscopy studies.

BACKGROUND: The role of the brain in processing pain has been extensively investigated using various functional imaging techniques coupled with well controlled noxious stimuli. Studies applying experimental pain have also used proton magnetic resonance spectroscopy (1H-MRS). The advantage of MRS compared to other techniques is the capacity to non-invasively examine metabolites involved in neurotransmission of pain, including glutamate, γ-aminobutyric acid (GABA), glutamate â€‹+ â€‹glutamine (Glx), and glutamine. OBJECTIVE: To systematically review MRS studies used in the context of studying experimental pain in healthy human participants. DATA SOURCES: PubMed, Ovid Medline, and Embase databases were searched using pre-specified search terms. ELIGIBILITY CRITERIA: Studies investigating glutamate, GABA, Glx and/or glutamine in relation to experimental pain (e.g., heat) in healthy participants via MRS. APPRAISAL CRITERIA: Each study was evaluated with a modified quality criterion (used in previous imaging systematic reviews) as well as a risk of bias assessment. RESULTS: From 5275 studies, 14 met the selection criteria. Studies fell into two general categories, those examining changes in metabolites triggered by noxious stimulation or examining the relationship between sensitivity to pain and resting metabolite levels. In five (out of ten) studies, glutamate, Glx and/or glutamine increased significantly in response to experimental pain (compared to baseline) in three different brain areas. To date, there is no evidence to suggest Glx, glutamate or glutamine levels decrease, suggesting an overall effect in favour of increased excitation to pain. In addition to no changes, both increases and decreases were reported for levels of GABA+ (=GABA â€‹+ â€‹macromolecules). A positive correlation between pain sensitivity and resting glutamate and Glx levels were reported across three studies (out of three). Further research is needed to examine the relationship of GABA+ and pain sensitivity. LIMITATIONS: A major limitation of our review was a limited number of studies that used MRS to examine experimental pain. In light of this and major differences in study design, we did not attempt to aggregate results in a meta-analysis. As for the studies we reviewed, there was a limited number of brain areas were examined by studies included in our review. Moreover, the majority of studies included lacked an adequate control condition (i.e., non-noxious stimulation) or blinding, which represent a major source of potential bias. CONCLUSION: MRS represents a promising tool to examine the brain in pain, functionally, and at rest with support for increased glutamate, glutamine and Glx levels in relation to pain. IMPLICATIONS: Resting and functional MRS should be viewed as complementary to existing neuroimaging techniques, and serve to investigate the brain in pain. Systematic review registration number- CRD42018112917.

Adaptive trial designs for spinal cord injury clinical trials directed to the central nervous system.

STUDY DESIGN: Narrative review. PURPOSE: To provide an overview of adaptive trial designs, and describe how adaptive methods can address persistent challenges encountered by randomized controlled trials of people with spinal cord injury (SCI). RESULTS: With few exceptions, adaptive methodologies have not been incorporated into clinical trial designs of people with SCI. Adaptive methods provide an opportunity to address high study costs, slow recruitment, and excessive amount of time needed to carry out the trial. The availability of existing SCI registries are well poised to support modeling and simulation, both of which are used extensively in adaptive trial designs. Eight initiatives for immediate advancement of adaptive methods in SCI were identified. CONCLUSION: Although successfully applied in other fields, adaptive clinical trial designs in SCI clinical trial programs have been narrow in scope and few in number. Immediate application of several adaptive methods offers opportunity to improve efficiency of SCI trials. Concerted effort is needed by all stakeholders to advance adaptive clinical trial design methodology in SCI.

A pragmatic randomized controlled trial testing the effects of the international scientific SCI exercise guidelines on SCI chronic pain: protocol for the EPIC-SCI trial.

STUDY DESIGN: Protocol for a pragmatic randomized controlled trial (the Exercise guideline Promotion and Implementation in Chronic SCI [EPIC-SCI] Trial). PRIMARY OBJECTIVES: To test if home-/community-based exercise, prescribed according to the international SCI exercise guidelines, significantly reduces chronic bodily pain in adults with SCI. SECONDARY OBJECTIVES: To investigate: (1) the effects of exercise on musculoskeletal and neuropathic chronic pain; (2) if reduced inflammation and increased descending inhibitory control are viable pathways by which exercise reduces pain; (3) the effects of chronic pain reductions on subjective well-being; and (4) efficiency of a home-/community-based exercise intervention. SETTING: Exercise in home-/community-based settings; assessments in university-based laboratories in British Columbia, Canada. METHOD: Eighty-four adults with chronic SCI, reporting chronic musculoskeletal or neuropathic pain, and not meeting the current SCI exercise guidelines, will be recruited and randomized to a 6-month Exercise or Wait-List Control condition. Exercise will occur in home/community settings and will be supported through behavioral counseling. All measures will be taken at baseline, 3-months and 6-months. Analyses will consist of linear mixed effect models, multiple regression analyses and a cost-utility analysis. The economic evaluation will examine the incremental costs and health benefits generated by the intervention compared with usual care. ETHICS AND DISSEMINATION: The University of British Columbia Clinical Research Ethics Board approved the protocol (#H19-01650). Using an integrated knowledge translation approach, stakeholders will be engaged throughout the trial and will co-create and disseminate evidence-based recommendations and messages regarding the use of exercise to manage SCI chronic pain.

Correction: A pragmatic randomized controlled trial testing the effects of the international scientific SCI exercise guidelines on SCI chronic pain: protocol for the EPIC-SCI trial.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Ecological fallacy as a novel risk factor for poor translation in neuroscience research: A systematic review and simulation study.

BACKGROUND: Translational neuroscience is largely concerned with establishing causal links between biological processes and functional outcomes. Exciting new methods have emerged and top-tier biomedical journals are placing increasingly high demand for experiments that link outcomes. One pitfall to making these connections is the "ecological fallacy"-establishing a relationship between outcomes based on aggregate (averaged) results (a distinct issue from correlation vs causation). METHODS: To showcase the ecological fallacy, we first used simulated data to define and demonstrate the problem. Next, we performed a systematic review to determine the prevalence of the fallacy in top-tier biomedical journals (Science, Nature Medicine, Neuron, Nature, Nature Neuroscience, Cell). Based on our own research interests and specializations, we specifically focused on recent publications in the area of spinal cord injury and regenerative medicine. RESULTS: Of the articles reviewed which examined a relationship between central nervous system regeneration and a behavioural outcome, 100% (21/21) were subject to possible ecological fallacy. CONCLUSIONS: Ecological fallacy is highly prevalent in neuroscience research and could partially account for translation failures in this field. Reporting guidelines for in vivo experiments should include subject-level correlation analyses for the primary outcomes.

Application of electrophysiological measures in spinal cord injury clinical trials: a narrative review.

STUDY DESIGN: Narrative review. OBJECTIVES: To discuss how electrophysiology may contribute to future clinical trials in spinal cord injury (SCI) in terms of: (1) improvement of SCI diagnosis, patient stratification and determination of exclusion criteria; (2) the assessment of adverse events; and (3) detection of therapeutic effects following an intervention. METHODS: An international expert panel for electrophysiological measures in SCI searched and discussed the literature focused on the topic. RESULTS: Electrophysiology represents a valid method to detect, track, and quantify readouts of nerve functions including signal conduction, e.g., evoked potentials testing long spinal tracts, and neural processing, e.g., reflex testing. Furthermore, electrophysiological measures can predict functional outcomes and thereby guide rehabilitation programs and therapeutic interventions for clinical studies. CONCLUSION: Objective and quantitative measures of sensory, motor, and autonomic function based on electrophysiological techniques are promising tools to inform and improve future SCI trials. Complementing clinical outcome measures, electrophysiological recordings can improve the SCI diagnosis and patient stratification, as well as the detection of both beneficial and adverse events. Specifically composed electrophysiological measures can be used to characterize the topography and completeness of SCI and reveal neuronal integrity below the lesion, a prerequisite for the success of any interventional trial. Further validation of electrophysiological tools with regard to their validity, reliability, and sensitivity are needed in order to become routinely applied in clinical SCI trials.

Neuropathic pain following traumatic spinal cord injury: Models, measurement, and mechanisms.

Neuropathic pain following spinal cord injury (SCI) is notoriously difficult to treat and is a high priority for many in the SCI population. Resolving this issue requires animal models fidelic to the clinical situation in terms of injury mechanism and pain phenotype. This Review discusses the means by which neuropathic pain has been induced and measured in experimental SCI and compares these with human outcomes, showing that there is a substantial disconnection between experimental investigations and clinical findings in a number of features. Clinical injury level is predominantly cervical, whereas injury in the laboratory is modeled mainly at the thoracic cord. Neuropathic pain is primarily spontaneous or tonic in people with SCI (with a relatively smaller incidence of allodynia), but measures of evoked responses (to thermal and mechanical stimuli) are almost exclusively used in animals. There is even the question of whether pain per se has been under investigation in most experimental SCI studies rather than simply enhanced reflex activity with no affective component. This Review also summarizes some of the problems related to clinical assessment of neuropathic pain and how advanced imaging techniques may circumvent a lack of patient/clinician objectivity and discusses possible etiologies of neuropathic pain following SCI based on evidence from both clinical studies and animal models, with examples of cellular and molecular changes drawn from the entire neuraxis from primary afferent terminals to cortical sensory and affective centers. © 2016 Wiley Periodicals, Inc.

Challenges for defining minimal clinically important difference (MCID) after spinal cord injury.

STUDY DESIGN: This is a review article. OBJECTIVES: This study discusses the following: (1) concepts and constraints for the determination of minimal clinically important difference (MCID), (2) the contrasts between MCID and minimal detectable difference (MDD), (3) MCID within the different domains of International Classification of Functioning, disability and health, (4) the roles of clinical investigators and clinical participants in defining MCID and (5) the implementation of MCID in acute versus chronic spinal cord injury (SCI) studies. METHODS: The methods include narrative reviews of SCI outcomes, a 2-day meeting of the authors and statistical methods of analysis representing MDD. RESULTS: The data from SCI study outcomes are dependent on many elements, including the following: the level and severity of SCI, the heterogeneity within each study cohort, the therapeutic target, the nature of the therapy, any confounding influences or comorbidities, the assessment times relative to the date of injury, the outcome measurement instrument and the clinical end-point threshold used to determine a treatment effect. Even if statistically significant differences can be established, this finding does not guarantee that the experimental therapeutic provides a person living with SCI an improved capacity for functional independence and/or an increased quality of life. The MDD statistical concept describes the smallest real change in the specified outcome, beyond measurement error, and it should not be confused with the minimum threshold for demonstrating a clinical benefit or MCID. Unfortunately, MCID and MDD are not uncomplicated estimations; nevertheless, any MCID should exceed the expected MDD plus any probable spontaneous recovery. CONCLUSION: Estimation of an MCID for SCI remains elusive. In the interim, if the target of a therapeutic is the injured spinal cord, it is most desirable that any improvement in neurological status be correlated with a functional (meaningful) benefit.

Differences in cortical coding of heat evoked pain beyond the perceived intensity: an fMRI and EEG study.

Imaging studies have identified a wide network of brain areas activated by nociceptive stimuli and revealed differences in somatotopic representation of highly distinct stimulation sites (foot vs. hand) in the primary (S1) and secondary (S2) somatosensory cortices. Somatotopic organization between adjacent dermatomes and differences in cortical coding of similarly perceived nociceptive stimulation are less well studied. Here, cortical processing following contact heat nociceptive stimulation of cervical (C4, C6, and C8) and trunk (T10) dermatomes were recorded in 20 healthy subjects using functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). Stimulation of T10 compared with the C6 and C8 revealed significant higher response intensity in the left S1 (contralateral) and the right S2 (ipsilateral) even when the perceived pain was equal between stimulation sites. Accordingly, contact heat evoked potentials following stimulation of T10 showed significantly higher N2P2 amplitudes compared to C6 and C8. Adjacent dermatomes did not reveal a distinct somatotopical representation. Within the assessed cervical and trunk dermatomes, nociceptive cortical processing to heat differs significantly in magnitude even when controlling for pain perception. This study provides evidence that controlling for pain perception is not sufficient to compare directly the magnitude of cortical processing [blood oxygen level dependence (BOLD) response and amplitude of evoked potentials] between body sites.

Next-gen spinal cord injury clinical trials: lessons learned and opportunities for future success.

Despite promising basic science discoveries and a surge in clinical trials, the quest for effective treatments that restore neurological function after spinal cord injury lags on. While "failed" in a conventional sense, emerging solutions to longstanding challenges represent promising steps towards a future with effective interventions. In this personal view, we highlight clinical trials implementing new solutions and their impact on the field. Our perspective is that, ultimately, the integration of shared knowledge, adaptive designs, and a deeper understanding of the intricacies of spinal cord injury holds promise of unlocking of major breakthroughs, leading to improved outcomes for people with spinal cord injury.

The myelin water imaging transcriptome: myelin water fraction regionally varies with oligodendrocyte-specific gene expression.

Identifying sensitive and specific measures that can quantify myelin are instrumental in characterizing microstructural changes in neurological conditions. Neuroimaging transcriptomics is emerging as a valuable technique in this regard, offering insights into the molecular basis of promising candidates for myelin quantification, such as myelin water fraction (MWF). We aimed to demonstrate the utility of neuroimaging transcriptomics by validating MWF as a myelin measure. We utilized data from a normative MWF brain atlas, comprised of 50 healthy subjects (mean age = 25 years, range = 17-42 years) scanned at 3 Tesla. Magnetic resonance imaging data included myelin water imaging to extract MWF and T1 anatomical scans for image registration and segmentation. We investigated the inter-regional distributions of gene expression data from the Allen Human Brain Atlas in conjunction with inter-regional MWF distribution patterns. Pearson correlations were used to identify genes with expression profiles mirroring MWF. The Single Cell Type Atlas from the Human Protein Atlas was leveraged to classify genes into gene sets with high cell type specificity, and a control gene set with low cell type specificity. Then, we compared the Pearson correlation coefficients for each gene set to determine if cell type-specific gene expression signatures correlate with MWF. Pearson correlation coefficients between MWF and gene expression for oligodendrocytes and adipocytes were significantly higher than for the control gene set, whereas correlations between MWF and inhibitory/excitatory neurons were significantly lower. Our approach in integrating transcriptomics with neuroimaging measures supports an emerging technique for understanding and validating MRI-derived markers such as MWF.