RESUMO
Nonpainful tactile sensory stimuli are processed in the cortex, subcortex, and brainstem. Recent functional magnetic resonance imaging studies have highlighted the value of whole-brain, systems-level investigation for examining sensory processing. However, whole-brain functional magnetic resonance imaging studies are uncommon, in part due to challenges with signal to noise when studying the brainstem. Furthermore, differentiation of small sensory brainstem structures such as the cuneate and gracile nuclei necessitates high-resolution imaging. To address this gap in systems-level sensory investigation, we employed a whole-brain, multi-echo functional magnetic resonance imaging acquisition at 3T with multi-echo independent component analysis denoising and brainstem-specific modeling to enable detection of activation across the entire sensory system. In healthy participants, we examined patterns of activity in response to nonpainful brushing of the right hand, left hand, and right foot (n = 10 per location), and found the expected lateralization, with distinct cortical and subcortical responses for upper and lower limb stimulation. At the brainstem level, we differentiated the adjacent cuneate and gracile nuclei, corresponding to hand and foot stimulation respectively. Our findings demonstrate that simultaneous cortical, subcortical, and brainstem mapping at 3T could be a key tool to understand the sensory system in both healthy individuals and clinical cohorts with sensory deficits.
Assuntos
Mapeamento Encefálico , Tronco Encefálico , Imageamento por Ressonância Magnética , Humanos , Tronco Encefálico/fisiologia , Tronco Encefálico/diagnóstico por imagem , Feminino , Masculino , Imageamento por Ressonância Magnética/métodos , Adulto , Mapeamento Encefálico/métodos , Adulto Jovem , Córtex Cerebral/fisiologia , Córtex Cerebral/diagnóstico por imagem , Percepção do Tato/fisiologia , Estimulação Física , Mãos/fisiologiaRESUMO
Therapeutic hypothermia improves outcomes following neonatal hypoxic-ischaemic encephalopathy, reducing cases of death and severe disability such as cerebral palsy compared with normothermia management. However, when cooled children reach early school-age, they have cognitive and motor impairments which are associated with underlying alterations to brain structure and white matter connectivity. It is unknown whether these differences in structural connectivity are associated with differences in functional connectivity between cooled children and healthy controls. Resting-state functional MRI has been used to characterize static and dynamic functional connectivity in children, both with typical development and those with neurodevelopmental disorders. Previous studies of resting-state brain networks in children with hypoxic-ischaemic encephalopathy have focussed on the neonatal period. In this study, we used resting-state fMRI to investigate static and dynamic functional connectivity in children aged 6-8 years who were cooled for neonatal hypoxic-ischaemic without cerebral palsy [n = 22, median age (interquartile range) 7.08 (6.85-7.52) years] and healthy controls matched for age, sex and socioeconomic status [n = 20, median age (interquartile range) 6.75 (6.48-7.25) years]. Using group independent component analysis, we identified 31 intrinsic functional connectivity networks consistent with those previously reported in children and adults. We found no case-control differences in the spatial maps of these intrinsic connectivity networks. We constructed subject-specific static functional connectivity networks by measuring pairwise Pearson correlations between component time courses and found no case-control differences in functional connectivity after false discovery rate correction. To study the time-varying organization of resting-state networks, we used sliding window correlations and deep clustering to investigate dynamic functional connectivity characteristics. We found k = 4 repetitively occurring functional connectivity states, which exhibited no case-control differences in dwell time, fractional occupancy or state functional connectivity matrices. In this small cohort, the spatiotemporal characteristics of resting-state brain networks in cooled children without severe disability were too subtle to be differentiated from healthy controls at early school-age, despite underlying differences in brain structure and white matter connectivity, possibly reflecting a level of recovery of healthy resting-state brain function. To our knowledge, this is the first study to investigate resting-state functional connectivity in children with hypoxic-ischaemic encephalopathy beyond the neonatal period and the first to investigate dynamic functional connectivity in any children with hypoxic-ischaemic encephalopathy.
RESUMO
Non-painful tactile sensory stimuli are processed in the cortex, subcortex, and brainstem. Recent functional magnetic resonance imaging (fMRI) studies have highlighted the value of whole-brain, systems-level investigation for examining pain processing. However, whole-brain fMRI studies are uncommon, in part due to challenges with signal to noise when studying the brainstem. Furthermore, the differentiation of small sensory brainstem structures such as the cuneate and gracile nuclei necessitates high resolution imaging. To address this gap in systems-level sensory investigation, we employed a whole-brain, multi-echo fMRI acquisition at 3T with multi-echo independent component analysis (ME-ICA) denoising and brainstem-specific modeling to enable detection of activation across the entire sensory system. In healthy participants, we examined patterns of activity in response to non-painful brushing of the right hand, left hand, and right foot, and found the expected lateralization, with distinct cortical and subcortical responses for upper and lower limb stimulation. At the brainstem level, we were able to differentiate the small, adjacent cuneate and gracile nuclei, corresponding to hand and foot stimulation respectively. Our findings demonstrate that simultaneous cortical, subcortical, and brainstem mapping at 3T could be a key tool to understand the sensory system in both healthy individuals and clinical cohorts with sensory deficits.
RESUMO
Resting functional magnetic resonance imaging (fMRI) studies have identified intrinsic spinal cord activity, which forms organised motor (ventral) and sensory (dorsal) resting-state networks. However, to facilitate the use of spinal fMRI in, for example, clinical studies, it is crucial to first assess the reliability of the method, particularly given the unique anatomical, physiological, and methodological challenges associated with acquiring the data. Here, we characterise functional connectivity relationships in the cervical cord and assess their between-session test-retest reliability in 23 young healthy volunteers. Resting-state networks were estimated in two ways (1) by estimating seed-to-voxel connectivity maps and (2) by calculating seed-to-seed correlations. Seed regions corresponded to the four grey matter horns (ventral/dorsal and left/right) of C5-C8 segmental levels. Test-retest reliability was assessed using the intraclass correlation coefficient. Spatial overlap of clusters derived from seed-to-voxel analysis between sessions was examined using Dice coefficients. Following seed-to-voxel analysis, we observed distinct unilateral dorsal and ventral organisation of cervical spinal resting-state networks that was largely confined in the rostro-caudal extent to each spinal segmental level, with more sparse connections observed between segments. Additionally, strongest correlations were observed between within-segment ipsilateral dorsal-ventral connections, followed by within-segment dorso-dorsal and ventro-ventral connections. Test-retest reliability of these networks was mixed. Reliability was poor when assessed on a voxelwise level, with more promising indications of reliability when examining the average signal within clusters. Reliability of correlation strength between seeds was highly variable, with the highest reliability achieved in ipsilateral dorsal-ventral and dorso-dorsal/ventro-ventral connectivity. However, the spatial overlap of networks between sessions was excellent. We demonstrate that while test-retest reliability of cervical spinal resting-state networks is mixed, their spatial extent is similar across sessions, suggesting that these networks are characterised by a consistent spatial representation over time.
Assuntos
Medula Cervical , Animais , Humanos , Medula Cervical/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Reprodutibilidade dos Testes , Medula Espinal/diagnóstico por imagem , Substância Cinzenta , Encéfalo/patologiaRESUMO
The application of functional magnetic resonance imaging (fMRI) to the human spinal cord is still a relatively small field of research and faces many challenges. Here we aimed to probe the limitations of task-based spinal fMRI at 3T by investigating the reliability of spinal cord blood oxygen level dependent (BOLD) responses to repeated nociceptive stimulation across two consecutive days in 40 healthy volunteers. We assessed the test-retest reliability of subjective ratings, autonomic responses, and spinal cord BOLD responses to short heat pain stimuli (1s duration) using the intraclass correlation coefficient (ICC). At the group level, we observed robust autonomic responses as well as spatially specific spinal cord BOLD responses at the expected location, but no spatial overlap in BOLD response patterns across days. While autonomic indicators of pain processing showed good-to-excellent reliability, both ß-estimates and z-scores of task-related BOLD responses showed poor reliability across days in the target region (gray matter of the ipsilateral dorsal horn). When taking into account the sensitivity of gradient-echo echo planar imaging (GE-EPI) to draining vein signals by including the venous plexus in the analysis, we observed BOLD responses with fair reliability across days. Taken together, these results demonstrate that heat pain stimuli as short as one second are able to evoke a robust and spatially specific BOLD response, which is however strongly variable within participants across time, resulting in low reliability in the dorsal horn gray matter. Further improvements in data acquisition and analysis techniques are thus necessary before event-related spinal cord fMRI as used here can be reliably employed in longitudinal designs or clinical settings.
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BACKGROUND: Primary adrenal insufficiency (PAI) mortality and morbidity remain unacceptably high, possibly arising as glucocorticoid replacement does not replicate natural physiology. A pulsatile subcutaneous pump can closely replicate cortisol's circadian and ultradian rhythm. OBJECTIVES: To assess the effect of pump therapy on quality of life, mood, functional neuroimaging, behavioural/cognitive responses, sleep and metabolism. METHODS: A 6-week randomised, crossover, double-blinded and placebo-controlled feasibility study of usual dose hydrocortisone in PAI administered as either pulsed subcutaneous or standard care in Bristol, United Kingdom (ISRCTN67193733). Participants were stratified by adrenal insufficiency type. All participants who received study drugs are included in the analysis. The primary outcome, the facial expression recognition task (FERT), occurred at week 6. RESULTS: Between December 2014 and 2017, 22 participants were recruited - 20 completed both arms, and 21 were analysed. The pump was well-tolerated. No change was seen in the FERT primary outcome; however, there were subjective improvements in fatigue and mood. Additionally, functional magnetic resonance imaging revealed differential neural processing to emotional cues and visual stimulation. Region of interest analysis identified the left amygdala and insula, key glucocorticoid-sensitive regions involved in emotional ambiguity. FERT post hoc analysis confirmed this response. There were four serious adverse events (AE): three intercurrent illnesses requiring hospitalisation (1/3, 33.3% pump) and a planned procedure (1/1, 100% pump). There was a small number of expected AEs: infusion site bruising/itching (3/5, 60% pump), intercurrent illness requiring extra (3/7, 42% pump) and no extra (4/6, 66% pump) steroid. CONCLUSIONS: These findings support the administration of hormone therapy that mimics physiology.
Assuntos
Insuficiência Adrenal , Hidrocortisona , Humanos , Insuficiência Adrenal/tratamento farmacológico , Fadiga , Glucocorticoides/efeitos adversos , Hidrocortisona/efeitos adversos , Qualidade de Vida , Ritmo Ultradiano , Estudos de ViabilidadeRESUMO
The investigation of spontaneous fluctuations of the blood-oxygen-level-dependent (BOLD) signal has recently been extended from the brain to the spinal cord, where it has stimulated interest from a clinical perspective. A number of resting-state functional magnetic resonance imaging (fMRI) studies have demonstrated robust functional connectivity between the time series of BOLD fluctuations in bilateral dorsal horns and between those in bilateral ventral horns, in line with the functional neuroanatomy of the spinal cord. A necessary step prior to extension to clinical studies is assessing the reliability of such resting-state signals, which we aimed to do here in a group of 45 healthy young adults at the clinically prevalent field strength of 3T. When investigating connectivity in the entire cervical spinal cord, we observed fair to good reliability for dorsal-dorsal and ventral-ventral connectivity, whereas reliability was poor for within- and between-hemicord dorsal-ventral connectivity. Considering how prone spinal cord fMRI is to noise, we extensively investigated the impact of distinct noise sources and made two crucial observations: removal of physiological noise led to a reduction in functional connectivity strength and reliability - due to the removal of stable and participant-specific noise patterns - whereas removal of thermal noise considerably increased the detectability of functional connectivity without a clear influence on reliability. Finally, we also assessed connectivity within spinal cord segments and observed that while the pattern of connectivity was similar to that of whole cervical cord, reliability at the level of single segments was consistently poor. Taken together, our results demonstrate the presence of reliable resting-state functional connectivity in the human spinal cord even after thoroughly accounting for physiological and thermal noise, but at the same time urge caution if focal changes in connectivity (e.g. due to segmental lesions) are to be studied, especially in a longitudinal manner.
Assuntos
Medula Cervical , Medula Espinal , Adulto Jovem , Animais , Humanos , Reprodutibilidade dos Testes , Medula Espinal/diagnóstico por imagem , Medula Espinal/fisiologia , Medula Cervical/fisiologia , Encéfalo , Corno Dorsal da Medula Espinal , Imageamento por Ressonância Magnética/métodosRESUMO
C-C motif chemokine receptor-like 2 (CCRL2) is a non-signaling 7 transmembrane receptor that binds chemotactic ligands to shape leukocyte recruitment to sites of inflammation. However, there is a lack of consensus on the ligands that directly bind CCRL2 or their functional impact. Studies with CCRL2 knockout mice have demonstrated that neutrophils have impaired degranulation and migration in response to CXCL8, where the underlying molecular mechanism is proposed to be due to the formation of CCRL2 heterodimers with the chemokine receptor CXCR2. Herein, we characterized the ligands that bind directly to CCRL2 and interrogated the impact of CCRL2 neutralization on CXCL8 signaling in neutrophils using pharmacological antibody tools. Using flow cytometry and Surface Plasmon Resonance microscopy (SPRm) cell binding experiments, we confirmed that chemerin, but not previously reported C-C chemokines, binds CCRL2. Furthermore, we identified human and mouse CCRL2 antibodies that neutralized chemerin binding to CCRL2. Unexpectedly, we found that neutralization of CCRL2 with these antibodies did not attenuate CXCL8-induced human neutrophil degranulation nor CXCL8-induced murine neutrophil recruitment to the peritoneum. Based on the observed differences in modulating CCRL2 function with neutralizing antibodies compared to the reported CCRL2 deficient murine models, we hypothesize that the ligand binding function of CCRL2 is dispensable for CXCL8 signaling in neutrophils. Finally, extensive profiling of CCRL2 expression on peripheral blood leukocytes revealed monocytes, dendritic cells (DC), and subpopulations of natural killer T (NKT) cells as additional targets, highlighting potential roles for CCRL2 in human cell types beyond neutrophils that warrants future investigation.
Assuntos
Ativação de Neutrófilo , Receptores CCR , Humanos , Animais , Camundongos , Receptores CCR/metabolismo , Anticorpos Neutralizantes/farmacologia , Ligantes , Transdução de Sinais , Interleucina-8 , Neutrófilos/metabolismoRESUMO
OBJECTIVE: Neonatal imaging studies report corpus callosum abnormalities after neonatal hypoxic-ischaemic encephalopathy (HIE), but corpus callosum development and relation to cognition in childhood are unknown. Using magnetic resonance imaging (MRI), we examined the relationship between corpus callosum size, microstructure and cognitive and motor outcomes at early school-age children cooled for HIE (cases) without cerebral palsy compared to healthy, matched controls. A secondary aim was to examine the impact of HIE-related neonatal brain injury on corpus callosum size, microstructure and growth. METHODS: Participants aged 6-8 years underwent MRI, the Movement Assessment Battery for Children Second Edition and Wechsler Intelligence Scale for Children Fourth Edition. Cross-sectional area, volume, fractional anisotropy and radial diffusivity of the corpus callosum and five subdivisions were measured. Multivariable regression was used to assess associations between total motor score, full-scale IQ (FSIQ) and imaging metrics. RESULTS: Adjusting for age, sex and intracranial volume, cases (N = 40) compared to controls (N = 39) demonstrated reduced whole corpus callosum area (ß = -26.9, 95% confidence interval [CI] = -53.17, -0.58), volume (ß = -138.5, 95% CI = -267.54, -9.56), fractional anisotropy and increased radial diffusivity (P < 0.05) within segments II-V. In cases, segment V area (ß = 0.18, 95% CI = 0.004, 0.35), volume (ß = 0.04, 95% CI = 0.001, 0.079), whole corpus callosum fractional anisotropy (ß = 13.8 95% CI = 0.6, 27.1) and radial diffusivity (ß = -11.3, 95% CI = -22.22, -0.42) were associated with FSIQ. Growth of the corpus callosum was restricted in cases with a FSIQ ≤85, and volume was reduced in cases with mild neonatal multifocal injury compared to white matter injury alone. INTERPRETATION: Following neonatal HIE, morphological and microstructural changes in the corpus callosum are associated with reduced cognitive function at early school age.
Assuntos
Lesões Encefálicas , Cognição , Corpo Caloso , Criança , Humanos , Recém-Nascido , Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Cognição/fisiologia , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/patologia , Imagem de Difusão por Ressonância Magnética , Imageamento por Ressonância Magnética , Estudos de Casos e ControlesRESUMO
AIM: To investigate whether brain volumes were reduced in children aged 6 to 8 years without cerebral palsy, who underwent therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy (patients), and matched controls, and to examine the relation between subcortical volumes and functional outcome. METHOD: We measured regional brain volumes in 31 patients and 32 controls (median age 7 years and 7 years 2 months respectively) from T1-weighted magnetic resonance imaging (MRI). We assessed cognition using the Wechsler Intelligence Scales for Children, Fourth Edition and motor ability using the Movement Assessment Battery for Children, Second Edition (MABC-2). RESULTS: Patients had lower volume of whole-brain grey matter, white matter, pallidi, hippocampi, and thalami than controls (false discovery rate-corrected p < 0.05). Differences in subcortical grey-matter volumes were not independent of total brain volume (TBV). In patients, hippocampal and thalamic volumes correlated with full-scale IQ (hippocampi, r = 0.477, p = 0.010; thalami, r = 0.452, p = 0.016) and MABC-2 total score (hippocampi, r = 0.526, p = 0.004; thalami, r = 0.505, p = 0.006) independent of age, sex, and TBV. No significant correlations were found in controls. In patients, cortical injury on neonatal MRI was associated with reduced volumes of hippocampi (p = 0.001), thalami (p = 0.002), grey matter (p = 0.015), and white matter (p = 0.013). INTERPRETATION: Children who underwent therapeutic hypothermia have reduced whole-brain grey and white-matter volumes, with associations between hippocampal and thalamic volumes and functional outcomes.
Assuntos
Paralisia Cerebral , Hipotermia Induzida , Hipóxia-Isquemia Encefálica , Recém-Nascido , Humanos , Criança , Paralisia Cerebral/diagnóstico por imagem , Paralisia Cerebral/terapia , Paralisia Cerebral/patologia , Hipóxia-Isquemia Encefálica/diagnóstico por imagem , Hipóxia-Isquemia Encefálica/terapia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Cognição , Imageamento por Ressonância MagnéticaRESUMO
AIM: To evaluate mammillary body abnormalities in school-age children without cerebral palsy treated with therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy (cases) and matched controls, and associations with cognitive outcome, hippocampal volume, and diffusivity in the mammillothalamic tract (MTT) and fornix. METHOD: Mammillary body abnormalities were scored from T1-weighted magnetic resonance imaging (MRI) in 32 cases and 35 controls (median age [interquartile range] 7 years [6 years 7 months-7 years 7 months] and 7 years 4 months [6 years 7 months-7 years 7 months] respectively). Cognition was assessed using the Wechsler Intelligence Scale for Children, Fourth Edition. Hippocampal volume (normalized by total brain volume) was measured from T1-weighted MRI. Radial diffusivity and fractional anisotropy were measured in the MTT and fornix, from diffusion-weighted MRI using deterministic tractography. RESULTS: More cases than controls had mammillary body abnormalities (34% vs 0%; p < 0.001). Cases with abnormal mammillary bodies had lower processing speed (p = 0.016) and full-scale IQ (p = 0.028) than cases without abnormal mammillary bodies, and lower scores than controls in all cognitive domains (p < 0.05). Cases with abnormal mammillary bodies had smaller hippocampi (left p = 0.016; right p = 0.004) and increased radial diffusivity in the right MTT (p = 0.004) compared with cases without mammillary body abnormalities. INTERPRETATION: Cooled children with mammillary body abnormalities at school-age have reduced cognitive scores, smaller hippocampi, and altered MTT microstructure compared with those without mammillary body abnormalities, and matched controls. WHAT THIS PAPER ADDS: Cooled children are at higher risk of mammillary body abnormalities than controls. Abnormal mammillary bodies are associated with reduced cognitive scores and smaller hippocampi. Abnormal mammillary bodies are associated with altered mammillothalamic tract diffusivity.
Assuntos
Encefalopatias , Doenças do Recém-Nascido , Recém-Nascido , Humanos , Criança , Lactente , Corpos Mamilares/diagnóstico por imagem , Corpos Mamilares/patologia , Fórnice/patologia , Imagem de Difusão por Ressonância Magnética , Cognição , Imageamento por Ressonância MagnéticaRESUMO
Functional magnetic resonance imaging (fMRI) of the human spinal cord faces many challenges, such as signal loss due to local magnetic field inhomogeneities. This issue can be addressed with slice-specific z-shimming, which compensates for the dephasing effect of the inhomogeneities using a slice-specific gradient pulse. Here, we aim to address outstanding issues regarding this technique by evaluating its effects on several aspects that are directly relevant for spinal fMRI and by developing two automated procedures in order to improve upon the time-consuming and subjective nature of manual selection of z-shims: one procedure finds the z-shim that maximizes signal intensity in each slice of an EPI reference-scan and the other finds the through-slice field inhomogeneity for each EPI-slice in field map data and calculates the required compensation gradient moment. We demonstrate that the beneficial effects of z-shimming are apparent across different echo times, hold true for both the dorsal and ventral horn, and are also apparent in the temporal signal-to-noise ratio (tSNR) of EPI time-series data. Both of our automated approaches were faster than the manual approach, lead to significant improvements in gray matter tSNR compared to no z-shimming and resulted in beneficial effects that were stable across time. While the field-map-based approach performed slightly worse than the manual approach, the EPI-based approach performed as well as the manual one and was furthermore validated on an external corticospinal data-set (N > 100). Together, automated z-shimming may improve the data quality of future spinal fMRI studies and lead to increased reproducibility in longitudinal studies.
Assuntos
Artefatos , Imagem Ecoplanar , Humanos , Imagem Ecoplanar/métodos , Processamento de Imagem Assistida por Computador/métodos , Reprodutibilidade dos Testes , Imageamento por Ressonância Magnética/métodos , Medula Espinal/diagnóstico por imagem , Encéfalo/diagnóstico por imagemRESUMO
BACKGROUND: Physical activity interventions have had varying results on modifying hippocampal volume. METHODS: The Retirement in Action (REACT) study conducted a randomised-controlled trial of a 12-month physical activity and behaviour maintenance intervention in older adults at risk of mobility impairments. The physical activity sessions were delivered twice weekly for the first twelve weeks, and then reduced to once weekly, to groups of 15 participants. Activities included cardiovascular, strength, balance and flexibility exercises. A sub-sample of participants in the physical activity (N = 54) and control arms (N = 48) underwent a 3 T MRI brain scan and cognitive assessments at baseline, 6- and 12-months (mean age = 76.6 years, 6.8 SD). It was hypothesised that the intervention would lead to a reduced rate of decline in hippocampal volume. Group differences in changes in cognition were also examined. RESULTS: As hypothesised, we found a maintenance in left hippocampal volume in the intervention arm, in comparison with the control arm after 12 months (p = 0.027). In a secondary analysis, this effect was attenuated after including age, sex and education level as covariates (p = 0.057). There was no significant between-group difference in the right hippocampus (p = 0.405). Contrary to our hypothesis, we did not find a beneficial effect of the intervention on cognitive outcomes. CONCLUSIONS: Our findings suggest that a community-based physical activity intervention can significantly ward-off hippocampal atrophy in older adults. While the lack of effects on cognition may limit the interpretability of our results, our findings of hippocampal maintenance are promising given the potential clinical relevance of protecting the hippocampus from age-related decline.
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Terapia por Exercício , Exercício Físico , Idoso , Terapia Comportamental , Terapia por Exercício/métodos , Hipocampo/diagnóstico por imagem , Humanos , Imageamento por Ressonância MagnéticaRESUMO
Cerebellar damage during posterior fossa surgery in children can lead to ataxia and risk of cerebellar mutism syndrome. Compartmentalisation of sensorimotor and cognitive functions within the cerebellum have been demonstrated in animal electrophysiology and human imaging studies. Electrophysiological monitoring was carried out under general anaesthesia to assess the limb sensorimotor representation within the human cerebellum for assessment of neurophysiological integrity to reduce the incidence of surgical morbidities. Thirteen adult and paediatric patients undergoing posterior fossa surgery were recruited. Sensory evoked field potentials were recorded in response to mapping (n = 8) to electrical stimulation of limb nerves or muscles. For motor mapping (n = 5), electrical stimulation was applied to the surface of the cerebellum and evoked EMG responses were sought in facial and limb muscles. Sensory evoked potentials were found in two patients (25%). Responses were located on the surface of the right inferior posterior cerebellum to stimulation of the right leg in one patient, and on the left inferior posterior lobe in another patient to stimulation of left forearm. No evoked EMG responses were found for the motor mapping. The present study identifies challenges with using neurophysiological methods to map functional organization within the human cerebellum and considers ways to improve success.
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Mapeamento Encefálico , Cerebelo/fisiologia , Craniotomia , Potencial Evocado Motor , Potenciais Somatossensoriais Evocados , Extremidades/inervação , Monitorização Neurofisiológica Intraoperatória , Contração Muscular , Músculo Esquelético/inervação , Adolescente , Adulto , Anestesia Geral , Criança , Pré-Escolar , Craniotomia/efeitos adversos , Estimulação Elétrica , Eletroencefalografia , Eletromiografia , Músculos Faciais/inervação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Adulto JovemRESUMO
Pain perception is decreased by shifting attentional focus away from a threatening event. This attentional analgesia engages parallel descending control pathways from anterior cingulate (ACC) to locus coeruleus, and ACC to periaqueductal grey (PAG) - rostral ventromedial medulla (RVM), indicating possible roles for noradrenergic or opioidergic neuromodulators. To determine which pathway modulates nociceptive activity in humans, we used simultaneous whole brain-spinal cord pharmacological-fMRI (N = 39) across three sessions. Noxious thermal forearm stimulation generated somatotopic-activation of dorsal horn (DH) whose activity correlated with pain report and mirrored attentional pain modulation. Activity in an adjacent cluster reported the interaction between task and noxious stimulus. Effective connectivity analysis revealed that ACC interacts with PAG and RVM to modulate spinal cord activity. Blocking endogenous opioids with Naltrexone impairs attentional analgesia and disrupts RVM-spinal and ACC-PAG connectivity. Noradrenergic augmentation with Reboxetine did not alter attentional analgesia. Cognitive pain modulation involves opioidergic ACC-PAG-RVM descending control which suppresses spinal nociceptive activity.
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Tronco Encefálico/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Temperatura Alta , Imageamento por Ressonância Magnética/métodos , Percepção da Dor/efeitos dos fármacos , Medula Espinal/diagnóstico por imagem , Adolescente , Adulto , Analgésicos Opioides/administração & dosagem , Encéfalo/efeitos dos fármacos , Tronco Encefálico/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naltrexona/administração & dosagem , Dor/tratamento farmacológico , Medição da Dor , Reboxetina/administração & dosagem , Medula Espinal/efeitos dos fármacos , Adulto JovemRESUMO
ABSTRACT: Fibromyalgia is a prevalent pain condition that is associated with cognitive impairments including in attention, memory, and executive processing. It has been proposed that fibromyalgia may be caused by altered central pain processing characterised by a loss of endogenous pain modulation. We tested whether attentional analgesia, where cognitive engagement diminishes pain percept, was attenuated in patients with fibromyalgia (n = 20) compared with matched healthy controls (n = 20). An individually calibrated, attentional analgesia paradigm with a 2 × 2 factorial design was used with brain and brainstem-focussed functional magnetic resonance imaging. Patients with fibromyalgia had both lower heat pain thresholds and speeds in a visual attention task. When this was taken into account for both attentional task and thermal stimulation, both groups exhibited an equivalent degree of attentional analgesia. Functional magnetic resonance imaging analysis showed similar patterns of activation in the main effects of pain and attention in the brain and brainstem (with the sole exceptions of increased activation in the control group in the frontopolar cortex and the ipsilateral locus coeruleus). The attentional analgesic effect correlated with activity in the periaqueductal gray and rostral ventromedial medulla. These findings indicate that patients with fibromyalgia can engage the descending pain modulatory system if the attentional task and noxious stimulus intensity are appropriately titrated.
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Analgesia , Fibromialgia , Neuralgia , Tronco Encefálico , Fibromialgia/complicações , Humanos , Imageamento por Ressonância Magnética , Manejo da DorRESUMO
Introduction: Diffusion magnetic resonance imaging (MRI) allows noninvasive assessment of white matter connectivity in typical development and of changes due to brain injury or pathology. Probabilistic white matter atlases allow diffusion metrics to be measured in specific white matter pathways, and are a critical component in spatial normalization for group analysis. However, given the known developmental changes in white matter it may be suboptimal to use an adult template when assessing data acquired from children. Methods: By averaging subject-specific fiber bundles from 28 children aged from 6 to 8 years, we created an age-specific probabilistic white matter atlas for 12 major white matter tracts. Using both the newly developed and Johns Hopkins adult atlases, we compared the atlas with subject-specific fiber bundles in two independent validation cohorts, assessing accuracy in terms of volumetric overlap and measured diffusion metrics. Results: Our age-specific atlas gave better overall performance than the adult atlas, achieving higher volumetric overlap with subject-specific fiber tracking and higher correlation of fractional anisotropy (FA) measurements with those measured from subject-specific fiber bundles. Specifically, estimates of FA values for corticospinal tract, uncinate fasciculus, forceps minor, cingulate gyrus part of the cingulum, and anterior thalamic radiation were all significantly more accurate when estimated with an age-specific atlas. Discussion: The age-specific atlas allows delineation of white matter tracts in children aged 6-8 years, without the need for tractography, more accurately than when normalizing to an adult atlas. To our knowledge, this is the first publicly available probabilistic atlas of white matter tracts for this age group.
Assuntos
Substância Branca , Adulto , Fatores Etários , Anisotropia , Encéfalo/diagnóstico por imagem , Criança , Imagem de Difusão por Ressonância Magnética , Imagem de Tensor de Difusão/métodos , Humanos , Substância Branca/diagnóstico por imagemRESUMO
Therapeutic hypothermia reduces the incidence of severe motor disability, such as cerebral palsy, following neonatal hypoxic-ischaemic encephalopathy. However, cooled children without cerebral palsy at school-age demonstrate motor deficits and altered white matter connectivity. In this study, we used diffusion-weighted imaging to investigate the relationship between white matter connectivity and motor performance, measured using the Movement Assessment Battery for Children-2, in children aged 6-8 years treated with therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy at birth, who did not develop cerebral palsy (cases), and matched typically developing controls. Correlations between total motor scores and diffusion properties in major white matter tracts were assessed in 33 cases and 36 controls. In cases, significant correlations (FDR-corrected P < 0.05) were found in the anterior thalamic radiation bilaterally (left: r = 0.513; right: r = 0.488), the cingulate gyrus part of the left cingulum (r = 0.588), the hippocampal part of the left cingulum (r = 0.541), and the inferior fronto-occipital fasciculus bilaterally (left: r = 0.445; right: r = 0.494). No significant correlations were found in controls. We then constructed structural connectivity networks, for 22 cases and 32 controls, in which nodes represent brain regions and edges were determined by probabilistic tractography and weighted by fractional anisotropy. Analysis of whole-brain network metrics revealed correlations (FDR-corrected P < 0.05), in cases, between total motor scores and average node strength (r = 0.571), local efficiency (r = 0.664), global efficiency (r = 0.677), clustering coefficient (r = 0.608), and characteristic path length (r = -0.652). No significant correlations were found in controls. We then investigated edge-level association with motor function using the network-based statistic. This revealed subnetworks which exhibited group differences in the association between motor outcome and edge weights, for total motor scores (P = 0.0109) as well as for balance (P = 0.0245) and manual dexterity (P = 0.0233) domain scores. All three of these subnetworks comprised numerous frontal lobe regions known to be associated with motor function, including the superior frontal gyrus and middle frontal gyrus. The subnetwork associated with total motor scores was highly left-lateralised. These findings demonstrate an association between impaired motor function and brain organisation in school-age children treated with therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy.
Assuntos
Paralisia Cerebral , Pessoas com Deficiência , Transtornos Motores , Substância Branca , Encéfalo/diagnóstico por imagem , Paralisia Cerebral/diagnóstico por imagem , Criança , Imagem de Tensor de Difusão , Humanos , Recém-Nascido , Substância Branca/diagnóstico por imagemRESUMO
Therapeutic hypothermia following neonatal encephalopathy due to birth asphyxia reduces death and cerebral palsy. However, school-age children without cerebral palsy treated with therapeutic hypothermia for neonatal encephalopathy still have reduced performance on cognitive and motor tests, attention difficulties, slower reaction times and reduced visuo-spatial processing abilities compared to typically developing controls. We acquired diffusion-weighted imaging data from school-age children without cerebral palsy treated with therapeutic hypothermia for neonatal encephalopathy at birth, and a matched control group. Voxelwise analysis (33 cases, 36 controls) confirmed reduced fractional anisotropy in widespread areas of white matter in cases, particularly in the fornix, corpus callosum, anterior and posterior limbs of the internal capsule bilaterally and cingulum bilaterally. In structural brain networks constructed using probabilistic tractography (22 cases, 32 controls), graph-theoretic measures of strength, local and global efficiency, clustering coefficient and characteristic path length were found to correlate with IQ in cases but not controls. Network-based statistic analysis implicated brain regions involved in visuo-spatial processing and attention, aligning with previous behavioural findings. These included the precuneus, thalamus, left superior parietal gyrus and left inferior temporal gyrus. Our findings demonstrate that, despite the manifest successes of therapeutic hypothermia, brain development is impaired in these children.
Assuntos
Paralisia Cerebral , Hipotermia Induzida , Substância Branca , Encéfalo/diagnóstico por imagem , Criança , Humanos , Recém-Nascido , Rede NervosaRESUMO
This article reviews and categorises early policy responses to the COVID-19 pandemic, based on a dataset of 496 measures taken by 54 countries between January 1 and April 28 and collected by the OECD from government officials and additional sources. Findings show a large diversity of measures, some of which were urgent and necessary, some that may continue to be beneficial once the pandemic has subsided, while others are potentially disruptive for the functioning of markets or damaging for the environment. National allocations of measures show differences between developed OECD countries, which used more agriculture or support related measures, and emerging economies, which focused on trade policies, information provision or food assistance. A minimum USD 47.6 billion was allocated by OECD governments to the agriculture and food sector, mostly in the form of domestic food assistance and support to agriculture and the food chain.