Acute Post-Concussive Assessments of Brain Tissue Magnetism Using Magnetic Resonance Imaging.

Recent studies have demonstrated the promising capabilities of magnetic resonance imaging (MRI)-based quantitative susceptibility maps (QSM) in producing biomarkers of brain injury. The present study aims to further explore acute QSM changes in athletes after sports concussion and investigate prognostication capabilities of QSM-derived imaging metrics. The QSM were derived from neurological MRI data acquired on a cohort (n = 78) of concussed male American football athletes within 48 h of injury. The MRI-derived QSM values in subcortical gray and white matter compartments after concussion showed differences relative to a matched uninjured control group (white matter: z = 3.04, p = 0.002, subcortical gray matter: z = -2.07, p = 0.04). Subcortical gray matter QSM MRI measurements also correlated strongly with duration of symptoms (ρ = -0.46, p = 0.002) within a subcohort of subjects who had symptom durations for at least one week (n = 39). The acute QSM MRI metrics showed promising prognostication capabilities, with subcortical gray matter compartment QSM values yielding a mean classification area under the curve performance of 0.78 when predicting symptoms of more than two weeks in duration. The results of the study reproduce previous acute post-concussion group QSM findings and provide promising initial prognostication capabilities of acute QSM measurements in a post-concussion setting.

Mechanisms of Below-Level Pain Following Spinal Cord Injury (SCI).

Mechanisms of below-level pain are discoverable as neural adaptations rostral to spinal injury. Accordingly, the strategy of investigations summarized here has been to characterize behavioral and neural responses to below-level stimulation over time following selective lesions of spinal gray and/or white matter. Assessments of human pain and the pain sensitivity of humans and laboratory animals following spinal injury have revealed common disruptions of pain processing. Interruption of the spinothalamic pathway partially deafferents nocireceptive cerebral neurons, rendering them spontaneously active and hypersensitive to remaining inputs. The spontaneous activity among these neurons is disorganized and unlikely to generate pain. However, activation of these neurons by their remaining inputs can result in pain. Also, injury to spinal gray matter results in a cascade of secondary events, including excitotoxicity, with rostral propagation of excitatory influences that contribute to chronic pain. Establishment and maintenance of below-level pain results from combined influences of injured and spared axons in the spinal white matter and injured neurons in spinal gray matter on processing of nociception by hyperexcitable cerebral neurons that are partially deafferented. A model of spinal stenosis suggests that ischemic injury to the core spinal region can generate below-level pain. Additional questions are raised about demyelination, epileptic discharge, autonomic activation, prolonged activity of C nocireceptive neurons, and thalamocortical plasticity in the generation of below-level pain. PERSPECTIVE: An understanding of mechanisms can direct therapeutic approaches to prevent development of below-level pain or arrest it following spinal cord injury. Among the possibilities covered here are surgical and other means of attenuating gray matter excitotoxicity and ascending propagation of excitatory influences from spinal lesions to thalamocortical systems involved in pain encoding and arousal.

Medulloblastoma in childhood: What effects on neurocognitive functions?

PUPOSE: Medulloblastoma is the most common primary malignant central nervous system tumor in childhood, accounting for 16-25% of cases (1). New treatment approaches have led to improved survival rates; however toxicities are still a major concern. PATIENTS AND METHODS: Participants were selected from the records of patients who were treated with craniospinal irradiation for medulloblastoma. Between January 2008 and December 2012, 62 patients were diagnosed with medulloblastoma at the national institute of oncology Rabat, 27 patients were still alive at the time of the study, of which n=16 patients were included in the study. The mean age of patients at the time of the study was 9.6 years. All children were treated with radiation therapy and chemotherapy, according to standard protocols. Median follow-up between treatment and evaluation was 4 years. All the children were assessed with the Wechsler Intelligence Scale for Children - fourth Edition (WISC-IV) three to five years after completion of radiotherapy. The test was administered by two well-trained psychologists in a distraction-free environment. The scoring was then reviewed by a psychologist from Brooklyn College. RESULTS: The mean standard score Full-Scale Intelligence Quotient (FSIQ) (M=63, SD=12.6) was found to be in the extremely low range and in the 1st percentile rank (PR), compared to the general population. All the measured primary index scales were below typical performance: verbal comprehension (M=67.7, SD=13.1), perceptual reasoning (M=63.5, SD=13.8) and processing speed (M=62.7, SD=15.5) were all found to be in the extremely low range, while xorking memory (M=75.5, SD=10.8) was found to be in the borderline range compared to the general population. To identify factors influencing the results, we performed both univariate and multivariate analyses. Age at the time of radiotherapy, initial clinical stage, total cranial radiotherapy dose, socioeconomic status, and the time of evaluation were identified as significantly impacting cognitive scores in the univariate analysis. In the multivariate analysis, only age at the time of radiotherapy and initial clinical stage remained factors significantly impacting cognitive outcomes with P=0.001 and P<0.001 respectively. CONCLUSION: Our study is evidence that tremendous efforts are still to be made in low-income countries to correctly measure neurocognitive dysfunction in medulloblastoma survivors and to prepare those patients to a typical life after the completion of treatment.

A Novel Gradient Echo Plural Contrast Imaging Method Detects Brain Tissue Abnormalities in Patients With TBI Without Evident Anatomical Changes on Clinical MRI: A Pilot Study.

RESEARCH OBJECTIVES: It is widely accepted that mild traumatic brain injury (mTBI) causes injury to the white matter, but the extent of gray matter (GM) damage in mTBI is less clear. METHODS: We tested 26 civilian healthy controls and 14 civilian adult subacute-chronic mTBI patients using quantitative features of MRI-based Gradient Echo Plural Contrast Imaging (GEPCI) technique. GEPCI data were reconstructed using previously developed algorithms allowing the separation of R2t*, a cellular-specific part of gradient echo MRI relaxation rate constant, from global R2* affected by BOLD effect and background gradients. RESULTS: Single-subject voxel-wise analysis (comparing each mTBI patient to the sample of 26 control subjects) revealed GM abnormalities that were not visible on standard MRI images (T1w and T2w). Analysis of spatial overlap for voxels with low R2t* revealed tissue abnormalities in multiple GM regions, especially in the frontal and temporal regions, that are frequently damaged after mTBI. The left posterior insula was the region with abnormalities found in the highest proportion (50%) of mTBI patients. CONCLUSIONS: Our data suggest that GEPCI quantitative R2t* metric has potential to detect abnormalities in GM cellular integrity in individual TBI patients, including abnormalities that are not detectable by a standard clinical MRI.

Effects of virtual reality therapy on upper limb function after stroke and the role of neuroimaging as a predictor of a better response.

OBJECTIVE: Virtual reality therapy (VRT) is an interactive intervention that induces neuroplasticity. The aim was to evaluate the effects of VRT associated with conventional rehabilitation for an upper limb after stroke, and the neuroimaging predictors of a better response to VRT. METHODS: Patients with stroke were selected, and clinical neurological, upper limb function, and quality of life were evaluated. Statistical analysis was performed using a linear model comparing pre- and post-VRT. Lesions were segmented in the post-stroke computed tomography. A voxel-based lesion-symptom mapping approach was used to investigate the relationship between the lesion and upper limb function. RESULTS: Eighteen patients were studied (55.5 ± 13.9 years of age). Quality of life, functional independence, and dexterity of the upper limb showed improvement after VRT (p < 0.001). Neuroimaging analysis showed negative correlations between the internal capsule lesion and functional recovery. CONCLUSION: VRT showed benefits for patients with stroke, but when there was an internal capsule lesion, a worse response was observed.

Effects of virtual reality therapy on upper limb function after stroke and the role of neuroimaging as a predictor of a better response / Efeitos da terapia de realidade virtual na função do membro superior após AVC e o papel da neuroimagem como preditor de melhor resposta

ABSTRACT Background: Virtual reality therapy (VRT) is an interactive intervention that induces neuroplasticity. The aim was to evaluate the effects of VRT associated with conventional rehabilitation for an upper limb after stroke, and the neuroimaging predictors of a better response to VRT. Methods: Patients with stroke were selected, and clinical neurological, upper limb function, and quality of life were evaluated. Statistical analysis was performed using a linear model comparing pre- and post-VRT. Lesions were segmented in the post-stroke computed tomography. A voxel-based lesion-symptom mapping approach was used to investigate the relationship between the lesion and upper limb function. Results: Eighteen patients were studied (55.5 ± 13.9 years of age). Quality of life, functional independence, and dexterity of the upper limb showed improvement after VRT (p < 0.001). Neuroimaging analysis showed negative correlations between the internal capsule lesion and functional recovery. Conclusion: VRT showed benefits for patients with stroke, but when there was an internal capsule lesion, a worse response was observed.

RESUMO Introdução: A realidade virtual (RV) é uma intervenção interativa que induz a neuroplasticidade. O objetivo deste estudo foi avaliar os efeitos da RV associado à reabilitação convencional na função do membro superior após o AVC e as características preditores de neuroimagem de melhor resposta a esta terapia. Métodos: os pacientes com AVC foram selecionados, e as características neurológicas, a função do membro superior e a qualidade de vida foram avaliadas. A análise estatística foi realizada por meio de modelo linear geral comparando resultados pré e pós-intervenção. As lesões foram segmentadas na tomografia computadorizada após o AVC. A abordagem de mapeamento da lesão-sintoma baseada em voxel foi utilizada para avaliar a relação entre a lesão e a função do membro superior. Resultados: Foram estudados 18 pacientes (8 mulheres, 55,5 ± 13,9 anos). A qualidade de vida, independência funcional, características funcionais e destreza do membro superior apresentaram melhora após RV (p < 0,001). A análise de imagem mostrou correlações negativas principalmente entre a cápsula interna e a recuperação funcional do membro superior. Conclusão: A RV mostrou benefícios para pacientes com AVC, mas quando houve lesão da cápsula interna apresentaram pior resposta à terapia.

Brain structure alterations and cognitive impairment following repetitive mild head impact: An in vivo MRI and behavioral study in rat.

Mild traumatic brain injury (mTBI) or concussion is a common health issue. Several people repeatedly experience head impact milder than that causing concussion. The present study aimed to confirm the effects of such repeated impact on the brain structure and cognitive abilities. Rat models were established by closed skull weight-drop injury. The animals were anesthetized, subjected to single (s)-sham, s-mTBI, repetitive (r)-sham, and r-mTBI, and recovery times were recorded. MRI, including T2-weighted and diffusion tensor imaging (DTI), as well as, neurological severity scores (mNSS) were assessed for the dynamics of the brain structure and neurological function. Morris water maze (MWM) was used to evaluate the cognitive function. The histological examination of r-mTBI rats revealed the basis of structural changes in the brain. There was no significant difference in the recovery time, MRI, mNSS, and MWM between the s-sham and the s-mTBI groups. Compared with r-sham, r-mTBI induced significant differences in the following aspects. The recovery time was prolonged and beam balance test (BBT) in mNSS increased from day 5. MWM performances were worse even after the BBT was recovered. The volumes of the cortex (CT), hippocampus (HP), and lateral ventricle had changed from day 5, which reached a maximum at day 14. Abnormal DTI parameters were observed in CT, corpus callosum, and HP. Histological analyses showed that both in CT and HP, neuron counts reduced at the end of the experiment. Altogether, these findings indicate that non-symptomatic head injury may result in brain atrophy and cognitive impairment when occurred repeatedly.

Concussion induces focal and widespread neuromorphological changes.

Concussion induces transient, and oftentimes chronic, lingering impairment to mental functioning, which must be driven by some underlying neurobiological perturbation - however, the physical changes related to sequelae are difficult to detect. Previous imaging studies on concussion have focused on alterations to cortical anatomy, but few have examined the cerebrum, subcortex, and cerebellum. Here, we present an analysis of these structures in a single cohort (all males, 21 patients, 22 controls) using MRI and diagnosed with a single-concussive episode in the acute and sub-acute stages of injury. Structural images were segmented into 78 cortical brain regions and 81,924 vertices using the CIVET algorithm. Subcortical volumetric analyses of the cerebellum, thalamus, globus pallidus, caudate and putamen were conducted following segmentation. Participants with concussion were found to have reduced white and grey matter volume, total cortical volume, as well as cortical thinning, primarily in left frontal areas. No differences were observed in the cerebellum or subcortical structures. In conclusion, just a single concussive episode induces measurable changes in brain structure manifesting as diffuse and local patterns of altered neuromorphometry.

Sensitivity of diffusion MRI to perilesional reactive astrogliosis in focal ischemia.

Reactive astrogliosis is a response to injury in the central nervous system that plays an essential role in inflammation and tissue repair. It is characterized by hypertrophy of astrocytes, alterations in astrocyte gene expression and astrocyte proliferation. Reactive astrogliosis occurs in multiple neuropathologies, including stroke, traumatic brain injury and Alzheimer's disease, and it has been proposed as a possible source of the changes in diffusion magnetic resonance imaging (dMRI) metrics observed with these diseases. In this study, the sensitivity of dMRI to reactive astrogliosis was tested in an animal model of focal acute and subacute ischemia induced by the vasoconstricting peptide, endothelin-1. Reactive astrogliosis in perilesional cortex was quantified by calculating the astrocyte surface density as determined with a glial fibrillary acidic protein (GFAP) antibody, whereas perilesional diffusion changes were measured in vivo with diffusional kurtosis imaging. We found substantial changes in the surface density of GFAP-positive astrocyte processes and modest changes in dMRI metrics in the perilesional motor cortex following stroke. Although there are time point-specific correlations between dMRI and histological measures, there is no definitive evidence for a causal relationship.

Multimodality MRI assessment of grey and white matter injury and blood-brain barrier disruption after intracerebral haemorrhage in mice.

In this study, we examined injury progression after intracerebral haemorrhage (ICH) induced by collagenase in mice using a preclinical 11.7 Tesla MRI system. On T2-weighted MRI, lesion and striatal volumes were increased on day 3 and then decreased from days 7 to 28. On day 3, with an increase in striatal water content, vasogenic oedema in the perihaematomal region presented as increased T2 and increased apparent diffusion coefficient (ADC) signal. With a synchronous change in T2 and ADC signals, microglial activation peaked on day 3 in the same region and decreased over time. Iron deposition appeared on day 3 around the haematoma border but did not change synchronously with ADC signals. Vascular permeability measured by Evans blue extravasation on days 1, 3, and 7 correlated with the T1-gadolinium results, both of which peaked on day 3. On diffusion tensor imaging, white matter injury was prominent in the corpus callosum and internal capsule on day 3 and then partially recovered over time. Our results indicate that the evolution of grey/white matter injury and blood-brain barrier disruption after ICH can be assessed with multimodal MRI, and that perihaematomal vasogenic oedema might be attributable to microglial activation, iron deposition, and blood-brain barrier breakdown.

Theory of mind mediates the prospective relationship between abnormal social brain network morphology and chronic behavior problems after pediatric traumatic brain injury.

Childhood and adolescence coincide with rapid maturation and synaptic reorganization of distributed neural networks that underlie complex cognitive-affective behaviors. These regions, referred to collectively as the 'social brain network' (SBN) are commonly vulnerable to disruption from pediatric traumatic brain injury (TBI); however, the mechanisms that link morphological changes in the SBN to behavior problems in this population remain unclear. In 98 children and adolescents with mild to severe TBI, we acquired 3D T1-weighted MRIs at 2-8 weeks post-injury. For comparison, 33 typically developing controls of similar age, sex and education were scanned. All participants were assessed on measures of Theory of Mind (ToM) at 6 months post-injury and parents provided ratings of behavior problems at 24-months post-injury. Severe TBI was associated with volumetric reductions in the overall SBN package, as well as regional gray matter structural change in multiple component regions of the SBN. When compared with TD controls and children with milder injuries, the severe TBI group had significantly poorer ToM, which was associated with more frequent behavior problems and abnormal SBN morphology. Mediation analysis indicated that impaired theory of mind mediated the prospective relationship between abnormal SBN morphology and more frequent chronic behavior problems. Our findings suggest that sub-acute alterations in SBN morphology indirectly contribute to long-term behavior problems via their influence on ToM. Volumetric change in the SBN and its putative hub regions may represent useful imaging biomarkers for prediction of post-acute social cognitive impairment, which may in turn elevate risk for chronic behavior problems.

Astrocyte reactivity after brain injury-: The role of galectins 1 and 3.

Astrocytes react to brain injury in a heterogeneous manner with only a subset resuming proliferation and acquiring stem cell properties in vitro. In order to identify novel regulators of this subset, we performed genomewide expression analysis of reactive astrocytes isolated 5 days after stab wound injury from the gray matter of adult mouse cerebral cortex. The expression pattern was compared with astrocytes from intact cortex and adult neural stem cells (NSCs) isolated from the subependymal zone (SEZ). These comparisons revealed a set of genes expressed at higher levels in both endogenous NSCs and reactive astrocytes, including two lectins-Galectins 1 and 3. These results and the pattern of Galectin expression in the lesioned brain led us to examine the functional significance of these lectins in brains of mice lacking Galectins 1 and 3. Following stab wound injury, astrocyte reactivity including glial fibrillary acidic protein expression, proliferation and neurosphere-forming capacity were found significantly reduced in mutant animals. This phenotype could be recapitulated in vitro and was fully rescued by addition of Galectin 3, but not of Galectin 1. Thus, Galectins 1 and 3 play key roles in regulating the proliferative and NSC potential of a subset of reactive astrocytes.

Grey matter injury patterns in cerebral palsy: associations between structural involvement on MRI and clinical outcomes.

AIMS: In a population cohort of children with grey matter injury (GMI) and cerebral palsy (CP), we aimed to describe and classify magnetic resonance imaging characteristics specific to GMI, and to identify key structure-function associations that serve as a basis for rating GMI in clinically relevant ways. METHOD: Symmetry, extent of cerebral injury, and pathological pattern for 54 children (37 males, 17 females) with CP and a predominant GMI pattern on chronic-phase magnetic resonance imaging were related to gross motor function, motor type and topography, epilepsy, intellectual disability, blindness, and deafness. RESULTS: Relative to mild GMI where there was no pallidal abnormality, severe GMI, comprising pallidal abnormality alone or in conjunction with other deep nuclear and generalized cortical-subcortical involvement, was strongly associated with Gross Motor Function Classification System levels IV to V (OR 35.7 [95% CI 3.5, 368.8]). Involvement of the basal ganglia was associated with non-spastic/mixed motor types, but predominantly where cortical-subcortical grey and white matter involvement was not extensive. The prevalence of epilepsy was highest where there was diffuse cortical-subcortical involvement and white matter loss. INTERPRETATION: Better understanding of structure-function relationships in CP and GMI, and how to rate the severity of GMI, will be helpful in the clinical context and also as a basis for investigation of causal pathways in CP.

Development of cerebral gray and white matter injury and cerebral inflammation over time after inflammatory perinatal asphyxia.

Antenatal inflammation is associated with increased severity of hypoxic-ischemic (HI) encephalopathy and adverse outcome in human neonates and experimental rodents. We investigated the effect of lipopolysaccharide (LPS) on the timing of HI-induced cerebral tissue loss and gray matter injury, white matter injury and integrity, and the cerebral inflammatory response. On postnatal day 9, mice underwent HI by unilateral carotid artery occlusion followed by systemic hypoxia which resulted in early neuronal damage (MAP2 loss) at 3 h that did not increase up to day 15. LPS injection 14 h before HI (LPS+HI) significantly and gradually aggravated MAP2 loss from 3 h up to day 15, resulting in an acellular cystic lesion. LPS+HI increased white matter damage, reduced myelination in the corpus callosum and increased white matter fiber coherency in the cingulum. The number of oligodendrocytes throughout the lineage (Olig2-positive) was increased whereas more mature myelinating (CNPase-positive) oligodendrocytes were strongly decreased after LPS+HI. LPS+HI induced an increased and prolonged expression of cerebral cytokines/chemokines compared to HI. Additionally, LPS+HI increased macrophage/microglia activation and influx of neutrophils in the brain compared to HI. This study demonstrates the sensitizing effect of LPS on neonatal HI brain injury for an extended time-frame up to 15 days postinsult. LPS before HI induced a gradual increase in gray and white matter deficits, including reduced numbers of more mature myelinating oligodendrocytes and a decrease in white matter integrity. Moreover, LPS+HI prolonged and intensified the cerebral inflammatory response, including cellular infiltration. In conclusion, as the timing of damage and/or involved pathways are changed when HI is preceded by inflammation, experimental therapies might require modifications in the time window, dosage or combinations of therapies for efficacious neuroprotection.

Spatial patterns of whole brain grey and white matter injury in patients with occult spastic diplegic cerebral palsy.

Spastic diplegic cerebral palsy (SDCP) is a common type of cerebral palsy (CP), which presents as a group of motor-impairment syndromes. Previous conventional MRI studies have reported abnormal structural changes in SDCP, such as periventricular leucomalacia. However, there are roughly 27.8% SDCP patients presenting normal appearance in conventional MRI, which were considered as occult SDCP. In this study, sixteen patients with occult SDCP and 16 age- and sex-matched healthy control subjects were collected and the data were acquired on a 3T MR system. We applied voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) analysis to investigate whole brain grey and white matter injury in occult SDCP. By using VBM method, the grey matter volume reduction was revealed in the bilateral basal ganglia regions, thalamus, insula, and left cerebral peduncle, whereas the white matter atrophy was found to be located in the posterior part of corpus callosum and right posterior corona radiata in the occult SDCP patients. By using TBSS, reduced fractional anisotropy (FA) values were detected in multiple white matter regions, including bilateral white matter tracts in prefrontal lobe, temporal lobe, internal and external capsule, corpus callosum, cingulum, thalamus, brainstem and cerebellum. Additionally, several regions of white matter tracts injury were found to be significantly correlated with motor dysfunction. These results collectively revealed the spatial patterns of whole brain grey and white matter injury in occult SDCP.