Quantitative sensory testing in a magnetic resonance environment: considerations for thermal sensitivity and patient safety.

Introduction: Quantitative sensory testing (QST) is often used to understand the perceptual basis of acute and chronic conditions, including pain. As the need grows for developing a mechanistic understanding of neurological pathways underlying perception in the basic and clinical sciences, there is a greater need to adapt techniques such as QST to the magnetic resonance (MR) environment. No studies have yet evaluated the impact of the MR environment on the perception of thermal stimuli. This study aimed to evaluate the differences in temperature sensitivity outside an MR environment and during an MRI scanning session. We hypothesized that there would be a difference in how participants reported their pain sensitivity between the two environments. Methods: Healthy participants underwent thermal QST outside the MR scanning environment, where they were asked to rate the temperature of a noxious stimulus at which they perceived their pain to be 7/10, using a Likert scale ranging from 0 to 10. Participants repeated this procedure inside a 3.0 T MRI approximately 30 min later. We repeated our investigation in a clinical cohort of participants with a chronic pain condition. Results: There were statistically significant changes of 1.1°C in thermal sensitivity between environments. This increase in pain threshold was found in healthy participants and replicated in the clinical cohort. Discussion: Findings can be applied toward improving MR safety, the resolution of brain pathways underlying pain mechanisms, and to more broadly comment on the impact of the MR environment on investigations that integrate perception-influenced processes.

Sensorimotor Integration and Pain Perception: Mechanisms Integrating Nociceptive Processing. A Systematic Review and ALE-Meta Analysis.

Pain treatment services and clinical indicators of pain chronicity focus on afferent nociceptive projections and psychological markers of pain perception with little focus on motor processes. Research supports a strong role for the motor system both in terms of pain related disability and in descending pain modulation. However, there is little understanding of the neurological regions implicated in pain-motor interactions and how the motor and sensory systems interact under conditions of pain. We performed an ALE meta-analysis on two clinical cohorts with atypical sensory and motor processes under conditions of pain and no pain. Persons with sensory altered processing (SAP) and no pain presented with greater activity in the precentral and supplementary motor area relative to persons with self-reported pain. In persons with motor altered processing (MAP), there appeared to be a suppression of activity in key pain regions such as the insula, thalamus, and postcentral gyrus. As such, activation within the motor system may play a critical role in dampening pain symptoms in persons with SAP, and in suppressing activity in key pain regions of the brain in persons with MAP. Future research endeavors should focus on understanding how sensory and motor processes interact both to understand disability and discover new treatment avenues.

Alterations in the structure and function of the brain in adolescents with new daily persistent headache: A pilot MRI study.

OBJECTIVE: The purpose of this study was to explore brain morphological and functional connectivity alterations in adolescents with new daily persistent headache (NDPH) compared to pain-free, healthy controls. BACKGROUND: NDPH is one of the most disabling and least understood primary headache conditions. To date, no studies have considered the role of brain function and structure in pediatric patients with NDPH. METHODS: In this cross-sectional study, resting-state functional and structural images were acquired for 13 patients with NDPH (M age = 15.9, standard deviation [SD] ± 1.4) and 13 age- and sex-matched controls (M age = 16.2, SD ± 1.8) using magnetic resonance imaging. Participants were recruited from the Pediatric Headache Program at Boston Children's Hospital and from the Greater Boston area. In patients, clinical features of NDPH, including disease duration, pain intensity ratings, pain sensitivity, and functional disability were also assessed, and their associations with functional and structural brain alterations were explored. RESULTS: Compared to controls, patients with NDPH demonstrated reduced cortical thickness in the bilateral superior temporal gyrus, left superior, and middle frontal gyrus areas (p < 0.05, Monte Carlo corrected for multiple comparisons). Furthermore, reduced cortical thickness of the left superior frontal gyrus was related to elevated pain sensitivity in NDPH (r = -0.79, p = 0.006). Patients showed altered functional connectivity between regions involved in emotional and cognitive networks of pain, including the amygdala, insula, frontal regions, and cerebellar subregions. CONCLUSION: The present study provides the first preliminary evidence of functional and structural brain differences in pediatric patients with NDPH compared to controls. Identifying alterations in cortical thickness and resting-state connectivity between specific brain regions could provide characteristics of NDPH and probable mechanisms that may guide personalized therapeutic interventions.

Evidence of Chronic Complement Activation in Asymptomatic Pediatric Brain Injury Patients: A Pilot Study.

Physical insult from a mild Traumatic Brain Injury (mTBI) leads to changes in blood flow in the brain and measurable changes in white matter, suggesting a physiological basis for chronic symptom presentation. Post-traumatic headache (PTH) is frequently reported by persons after an mTBI that may persist beyond the acute period (>3 months). It remains unclear whether ongoing inflammation may contribute to the clinical trajectory of PTH. We recruited a cohort of pediatric subjects with PTH who had an acute or a persistent clinical trajectory, each around the 3-month post-injury time point, as well as a group of age and sex-matched healthy controls. We collected salivary markers of mRNA expression as well as brain imaging and psychological testing. The persistent PTH group showed the highest levels of psychological burden and pain symptom reporting. Our data suggest that the acute and persistent PTH cohort had elevated levels of complement factors relative to healthy controls. The greatest change in mRNA expression was found in the acute-PTH cohort wherein the complement cascade and markers of vascular health showed a prominent role for C1Q in PTH pathophysiology. These findings (1) underscore a prolonged engagement of what is normally a healthy response and (2) show that a persistent PTH symptom trajectory may parallel a poorly regulated inflammatory response.

Biological laterality and peripheral nerve DTI metrics.

BACKGROUND AND PURPOSE: Clinical comparisons do not usually take laterality into account and thus may report erroneous or misleading data. The concept of laterality, well evaluated in brain and motor systems, may also apply at the level of peripheral nerves. Therefore, we sought to evaluate the extent to which we could observe an effect of laterality in MRI-collected white matter indices of the sciatic nerve and its two branches (tibial and fibular). MATERIALS AND METHODS: We enrolled 17 healthy persons and performed peripheral nerve diffusion weighted imaging (DWI) and magnetization transfer imaging (MTI) of the sciatic, tibial and fibular nerve. Participants were scanned bilaterally, and findings were divided into ipsilateral and contralateral nerve fibers relative to self-reporting of hand dominance. Generalized estimating equation modeling was used to evaluate nerve fiber differences between ipsilateral and contralateral legs while controlling for confounding variables. All findings controlled for age, sex and number of scans performed. RESULTS: A main effect of laterality was found in radial, axial, and mean diffusivity for the tibial nerve. Axial diffusivity was found to be lateralized in the sciatic nerve. When evaluating mean MTR, a main effect of laterality was found for each nerve division. A main effect of sex was found in the tibial and fibular nerve fiber bundles. CONCLUSION: For the evaluation of nerve measures using DWI and MTI, in either healthy or disease states, consideration of underlying biological metrics of laterality in peripheral nerve fiber characteristics need to considered for data analysis. Integrating knowledge regarding biological laterality of peripheral nerve microstructure may be applied to improve how we diagnosis pain disorders, how we track patients' recovery and how we forecast pain chronification.

DTI and MTR Measures of Nerve Fiber Integrity in Pediatric Patients With Ankle Injury.

Acute peripheral nerve injury can lead to chronic neuropathic pain. Having a standardized, non-invasive method to evaluate pathological changes in a nerve following nerve injury would help with diagnostic and therapeutic assessments or interventions. The accurate evaluation of nerve fiber integrity after injury may provide insight into the extent of pathology and a patient's level of self-reported pain. The aim of this investigation was to evaluate the extent to which peripheral nerve integrity could be evaluated in an acute ankle injury cohort and how markers of nerve fiber integrity correlate with self-reported pain levels in afferent nerves. We recruited 39 pediatric participants with clinically defined neuropathic pain within 3 months of an ankle injury and 16 healthy controls. Participants underwent peripheral nerve MRI using diffusion tensor (DTI) and magnetization transfer imaging (MTI) of their injured and non-injured ankles. The imaging window was focused on the branching point of the sciatic nerve into the tibial and fibular division. Each participant completed the Pain Detection Questionnaire (PDQ). Findings demonstrated group differences in DTI and MTI in the sciatic, tibial and fibular nerve in the injured ankle relative to healthy control and contralateral non-injured nerve fibers. Only AD and RD from the injured fibular nerve correlated with PDQ scores which coincides with the inversion-dominant nature of this particular ankle injuruy cohort. Exploratory analyses highlight the potential remodeling stages of nerve injury from neuropathic pain. Future research should emphasize sub-acute time frames of injury to capture post-injury inflammation and nerve fiber recovery.

A lateralized model of the pain-depression dyad.

Chronic pain and depression are two frequently co-occurring and debilitating conditions. Even though the former is treated as a physical affliction, and the latter as a mental illness, both disorders closely share neural substrates. Here, we review the association of pain with depression, especially when symptoms are lateralized on either side of the body. We also explore the overlapping regions in the forebrain implicated in these conditions. Finally, we synthesize these findings into a model, which addresses gaps in our understanding of comorbid pain and depression. Our lateralized pain-depression dyad model suggests that individuals diagnosed with depression should be closely monitored for pain symptoms in the left hemibody. Conversely, for patients in pain, with the exception of acute pain with a known source, referrals in today's pain centers for psychological evaluation should be part of standard practice, within the framework of an interdisciplinary approach to pain treatment.

Commentary: Novel Use of Offset Analgesia to Assess Adolescents and Adults with Treatment Resistant Endometriosis-Associated Pain.

BACKGROUND AND OBJECTIVE: Endometriosis, affecting approximately 176 million adults and adolescents worldwide, is a debilitating condition in which uterine tissue grows outside the uterus. The condition costs the US economy approximately $78 billion annually in pain-related disability. By understanding the neural underpinnings of endometriosis-associated pain (EAP) and risk factors for chronification, translational research methods could lessen diagnostic delays and maximize successful pain remediation. This can be accomplished by the novel use of a known method, offset analgesia (OA), to better elucidate the neural mechanisms that may contribute to and maintain EAP. This commentary will provide justification and rationale for the use of OA in the study of EAP. CONCLUSION: Utilizing an OA paradigm in patients with endometriosis, especially adolescents, may (1) provide insight into neural mechanisms contributing to pain maintenance, which could capture those at-risk for the transition to chronic pelvic pain, (2) provide a metric for the development of future centrally mediated treatment options for this population, and (3) elucidate the brain changes that result in resistance to treatment and pain chronification.

Clinical features and sex differences in pediatric post-traumatic headache: A retrospective chart review at a Boston area concussion clinic.

BACKGROUND: Often concussion/mTBI triggers a chronic headache syndrome called persistent post-traumatic headache (P-PTH) that can last from months to years post-injury, and produce significant disruption of childhood education, social interaction and development. Although prevalent and highly disabling, P-PTH is underrepresented in headache and pain research and lacks clear definition and pathophysiology. Clinical presentation of P-PTH frequently resembles that of other headache disorders, like migraine, yet the pathophysiological mechanisms are distinct and not fully understood, making the disorder difficult to treat in the clinical setting. METHODS: In a retrospective analysis of 1506 pediatric patients attending Boston Children's Hospital clinics, demographic trends, symptom features, and the influence of sex on clinical presentation of PTH are presented. We compare clinical characteristics of P-PTH with a published cohort of migraine patients to evaluate the clinical features that are unique to P-PTH. RESULTS: Findings show that despite equivalent representation of sex in the clinic, P-PTH is expressed more in females than males and is weighted towards somatic symptoms. Relative to migraine, PTH is less associated with a family history of headache. CONCLUSIONS: The ability to identify persons with PTH can help manage risk factors and identify persons likely to develop persistent post-concussion symptoms.

Delineating conditions and subtypes in chronic pain using neuroimaging.

Differentiating subtypes of chronic pain still remains a challenge-both from a subjective and objective point of view. Personalized medicine is the current goal of modern medical care and is limited by the subjective nature of patient self-reporting of symptoms and behavioral evaluation. Physiology-focused techniques such as genome and epigenetic analyses inform the delineation of pain groups; however, except under rare circumstances, they have diluted effects that again, share a common reliance on behavioral evaluation. The application of structural neuroimaging towards distinguishing pain subtypes is a growing field and may inform pain-group classification through the analysis of brain regions showing hypertrophic and atrophic changes in the presence of pain. Analytical techniques such as machine-learning classifiers have the capacity to process large volumes of data and delineate diagnostically relevant information from neuroimaging analysis. The issue of defining a "brain type" is an emerging field aimed at interpreting observed brain changes and delineating their clinical identity/significance. In this review, 2 chronic pain conditions (migraine and irritable bowel syndrome) with similar clinical phenotypes are compared in terms of their structural neuroimaging findings. Independent investigations are compared with findings from application of machine-learning algorithms. Findings are discussed in terms of differentiating patient subgroups using neuroimaging data in patients with chronic pain and how they may be applied towards defining a personalized pain signature that helps segregate patient subgroups (eg, migraine with and without aura, with or without nausea; irritable bowel syndrome vs other functional gastrointestinal disorders).

Evaluating task-based brain network activity in pediatric subjects with an mTBI: mechanisms of functional compensation are symptom-level dependent.

The diagnosis of a mild traumatic brain injury (mTBI) places large emphasis on patient-reported symptoms which has restricted our ability to evaluate patients. Task-based functional magnetic resonance imaging has the potential to act as an objective measurement of abnormal brain activity and inform clinical decision-making; however, there is little research evaluating pediatric subjects as a function of mTBI-related symptoms. The objective of this study was to evaluate the extent to which brain activity during a spatial navigation task is different between children with mTBI and a group of healthy controls (HCs) based on symptom reporting. A group of patients with mTBI (n = 27) were divided into low- and high-symptom cohorts and compared with HCs (n = 27) on a task that required participants to locate specific landmarks. No difference was found in the level of symptoms reported between patients with low-symptom participants and HCs despite the low-symptom group showing increased activity within the frontal and occipital cortices. In participants with high-symptoms, an increase in the number of reported symptoms was found relative to HCs alongside an increase in the number of active brain regions. Findings suggest that persons with an mTBI may display unique symptom-dependent patterns of altered task-related brain activity.

GABA and glutamate levels correlate with MTR and clinical disability: Insights from multiple sclerosis.

Converging areas of research have implicated glutamate and γ-aminobutyric acid (GABA) as key players in neuronal signalling and other central functions. Further research is needed, however, to identify microstructural and behavioral links to regional variability in levels of these neurometabolites, particularly in the presence of demyelinating disease. Thus, we sought to investigate the extent to which regional glutamate and GABA levels are related to a neuroimaging marker of microstructural damage and to motor and cognitive performance. Twenty-one healthy volunteers and 47 people with multiple sclerosis (all right-handed) participated in this study. Motor and cognitive abilities were assessed with standard tests used in the study of multiple sclerosis. Proton magnetic resonance spectroscopy data were acquired from sensorimotor and parietal regions of the brains' left cerebral hemisphere using a MEGA-PRESS sequence. Our analysis protocol for the spectroscopy data was designed to account for confounding factors that could contaminate the measurement of neurometabolite levels due to disease, such as the macromolecule signal, partial volume effects, and relaxation effects. Glutamate levels in both regions of interest were lower in people with multiple sclerosis. In the sensorimotor (though not the parietal) region, GABA concentration was higher in the multiple sclerosis group compared to controls. Lower magnetization transfer ratio within grey and white matter regions from which spectroscopy data were acquired was linked to neurometabolite levels. When adjusting for age, normalized brain volume, MTR, total N-acetylaspartate level, and glutamate level, significant relationships were found between lower sensorimotor GABA level and worse performance on several tests, including one of upper limb motor function. This work highlights important methodological considerations relevant to analysis of spectroscopy data, particularly in the afflicted human brain. These findings support that regional neurotransmitter levels are linked to local microstructural integrity and specific behavioral abilities that can be affected in diseases such as multiple sclerosis.

Combined structural and functional patterns discriminating upper limb motor disability in multiple sclerosis using multivariate approaches.

A structural or functional pattern of neuroplasticity that could systematically discriminate between people with impaired and preserved motor performance could help us to understand the brain networks contributing to preservation or compensation of behavior in multiple sclerosis (MS). This study aimed to (1) investigate whether a machine learning-based technique could accurately classify MS participants into groups defined by upper extremity function (i.e. motor function preserved (MP) vs. motor function impaired (MI)) based on their regional grey matter measures (GMM, cortical thickness and deep grey matter volume) and inter-regional functional connection (FC), (2) investigate which features (GMM, FC, or GMM + FC) could classify groups more accurately, and (3) identify the multivariate patterns of GMM and FCs that are most discriminative between MP and MI participants, and between each of these groups and the healthy controls (HCs). With 26 MP, 25 MI, and 21 HCs (age and sex matched) underwent T1-weighted and resting-state functional MRI at 3 T, we applied support vector machine (SVM) based classification to learn discriminant functions indicating regions in which GMM or between which FCs were most discriminative between groups. This study demonstrates that there exist structural and FC patterns sufficient for correct classification of upper limb motor ability of people with MS. The classifier with GMM + FC features yielded the highest accuracy of 85.61 % (p < 0.001) to distinguish between the MS groups using leave-one-out cross-validation. It suggests that a machine-learning approach combining structural and functional features is useful for identifying the specific neural substrates that are necessary and sufficient to preserve motor function among people with MS.

Abnormal functional connectivity and cortical integrity influence dominant hand motor disability in multiple sclerosis: a multimodal analysis.

Functional reorganization and structural damage occur in the brains of people with multiple sclerosis (MS) throughout the disease course. However, the relationship between resting-state functional connectivity (FC) reorganization in the sensorimotor network and motor disability in MS is not well understood. This study used resting-state fMRI, T1-weighted and T2-weighted, and magnetization transfer (MT) imaging to investigate the relationship between abnormal FC in the sensorimotor network and upper limb motor disability in people with MS, as well as the impact of disease-related structural abnormalities within this network. Specifically, the differences in FC of the left hemisphere hand motor region between MS participants with preserved (n = 17) and impaired (n = 26) right hand function, compared with healthy controls (n = 20) was investigated. Differences in brain atrophy and MT ratio measured at the global and regional levels were also investigated between the three groups. Motor preserved MS participants had stronger FC in structurally intact visual information processing regions relative to motor impaired MS participants. Motor impaired MS participants showed weaker FC in the sensorimotor and somatosensory association cortices and more severe structural damage throughout the brain compared with the other groups. Logistic regression analysis showed that regional MTR predicted motor disability beyond the impact of global atrophy whereas regional grey matter volume did not. More importantly, as the first multimodal analysis combining resting-state fMRI, T1-weighted, T2-weighted and MTR images in MS, we demonstrate how a combination of structural and functional changes may contribute to motor impairment or preservation in MS. Hum Brain Mapp 37:4262-4275, 2016. © 2016 Wiley Periodicals, Inc.

Cortical Damage and Disability in Multiple Sclerosis: Relation to Intracortical Inhibition and Facilitation.

BACKGROUND: Multimodal research combining biomarkers of intracortical activity and cortical damage could shed light on pathophysiological and adaptive neural processes related to the clinical severity of neurological conditions such as multiple sclerosis (MS). OBJECTIVE: Among people with relapsing-remitting and progressive forms of MS, we assessed the extent to which transcranial magnetic stimulation (TMS)-based biomarkers of excitatory and inhibitory cortical activity are related to cortical damage and clinical impairment. METHODS: Participants included 18 healthy individuals and 36 people with MS who had a relapsing-remitting or progressive clinical course. Using TMS, intracortical facilitation (ICF), short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI), and cortical silent period (CSP) were obtained. Cortical volume and cortical magnetization transfer ratio (MTR) were quantified. Disability was assessed with Multiple Sclerosis Functional Composite (MSFC). RESULTS: Lower mean MTR within the cerebral cortex correlated with shorter CSP among MS participants with a progressive, but not a relapsing-remitting, clinical course. Within the cortical hand knob region targeted with TMS, lower MTR was correlated with lower SICI only among individuals with relapsing-remitting MS. Longer CSP, higher ICF, lower cortical MTR, and sex were all independent significant predictors of poor upper extremity motor performance, while only cortical MTR was a significant independent predictor of total MSFC score among people with MS. CONCLUSIONS: Cortical damage and cortical activity (both inhibitory and excitatory) may contribute to the severity of motor disability experienced by people with MS. When interpreting TMS-based outcomes, cortical integrity, clinical course, and symptom type should be considered.

Intracortical inhibition abnormality during the remission phase of multiple sclerosis is related to upper limb dexterity and lesions.

OBJECTIVE: The impact of inhibitory cortical activity on motor impairment of people with relapsing-remitting multiple sclerosis (RRMS) has not been fully elucidated despite its relevance to neurorehabilitation. The present study assessed the extent to which transcranial magnetic stimulation (TMS)-based metrics of intracortical inhibition are related to motor disability and brain damage. METHODS: Participants included forty-three persons with RRMS in the remitting phase and twenty-nine healthy controls. We stimulated the dominant hemisphere and recorded from the dominant hand to assess short-interval intracortical inhibition (SICI) and cortical silent period (CSP) duration. Disability was evaluated with the Multiple Sclerosis Functional Composite (MSFC). Regional cortical thickness and lesion volume were measured. RESULTS: RRMS participants with dominant upper limb dexterity impairments had prolonged CSP, but equivalent SICI, compared to participants with preserved function. CSP was not related to walking or cognitive performance. Higher normalized lesion volume correlated with longer CSP duration. When adjusting for normalized lesion volume, longer CSP significantly predicted worse dominant upper extremity impairment. CONCLUSIONS: High intracortical inhibition possibly contributes to (or prevents remission from) motor impairment. Lesions may be associated with intracortical inhibition shifts. SIGNIFICANCE: CSP duration and lesion burden should be considered when developing interventions aiming to mitigate motor impairment.

Assessing aggression following traumatic brain injury: a systematic review of validated aggression scales.

BACKGROUND: Every year, millions of people worldwide suffer traumatic brain injuries (TBIs). Aggressive behavior, a known psychological symptom following TBI, has been regarded as an obstacle toward rehabilitation. Having measures that accurately assess aggression during rehabilitation is critical toward proper evaluation. OBJECTIVE: To undertake a systematic review of the validated scales used to assess aggression in the postacute stage (≥3 months) after sustaining a TBI in the adult population. A comprehensive search was performed and studies meeting the inclusion criteria were reviewed in full. Quality and validity of supporting articles were assessed via the Downs and Black and QUADAS checklists along with their supporting statistics. RESULTS: A total of 1329 articles were reviewed from the literature. Thirty-two were reviewed in detail and 6 studies eventually passed the exclusion criteria. Of these, 6 neuropsychological scales were represented pertaining to the measurement of aggressive behavior; however, only 1 directly addressed the validity of their scale's aggression component. CONCLUSIONS: Further research is required to establish the validity of scales that specifically address aggression for use in the adult TBI population which could be used to support rehabilitation and social reintegration strategies.

Distinct visual cues mediate aperture shaping for grasping and pantomime-grasping tasks.

The authors examined whether the top-down requirements of dissociating the spatial relations between stimulus and response in a goal-directed grasping task renders the mediation of aperture trajectories via relative visual information. To address that issue, participants grasped differently sized target objects (i.e., grasping condition) and also grasped to a location that was dissociated from the target object (i.e., pantomime-grasping condition). Just noticeable difference (JND) values associated with the early through late stages of aperture shaping were computed to examine the extent to which motor output adhered to, or violated, the psychophysical principles of Weber's law. As expected, JNDs during the late stages of the grasping condition violated Weber's law: a result evincing the use of absolute visual information. In contrast, JNDs for the pantomime-grasping condition produced a continuous adherence to Weber's law. Such a result indicates that dissociating a stimulus from a response is a perception-based task and results in aperture shaping via relative visual information.