Joint analysis of frontal theta synchrony and white matter following mild traumatic brain injury

Brain Imaging and Behavior - Some of the most disabling aspects of mild traumatic brain injury (mTBI) include lingering deficits in executive functioning. It is known that mTBI can damage white...     

Myelin loss and oligodendrocyte pathology in white matter tracts following traumatic brain injury in the rat

Axonal injury is an important contributor to the behavioral deficits observed following traumatic brain injury (TBI). Additionally, loss of myelin and/or oligodendrocytes can negatively influence signal transduction and axon integrity. Apoptotic oligodendrocytes, changes in the oligodendrocyte progenitor cell (OPC) population and loss of myelin were evaluated at 2, 7 and 21 days following TBI. We used the central fluid percussion injury model (n = 18 and three controls) and the lateral fluid percussion injury model (n = 15 and three controls). The external capsule, fimbriae and corpus callosum were analysed. With Luxol Fast Blue and RIP staining, myelin loss was observed in both models, in all evaluated regions and at all post‐injury time points, as compared with sham‐injured controls (P ≤ 0.05). Accumulation of β‐amyloid precursor protein was observed in white matter tracts in both models in areas with preserved and reduced myelin staining. White matter microglial/macrophage activation, evaluated by isolectin B4 immunostaining, was marked at the early time points. In contrast, the glial scar, evaluated by glial fibrillary acidic protein staining, showed its highest intensity 21 days post‐injury in both models. The number of apoptotic oligodendrocytes, detected by CC1/caspase‐3 co‐labeling, was increased in both models in all evaluated regions. Finally, the numbers of OPCs, evaluated with the markers Tcf4 and Olig2, were increased from day 2 (Olig2) or day 7 (Tcf4) post‐injury (P ≤ 0.05). Our results indicate that TBI induces oligodendrocyte apoptosis and widespread myelin loss, followed by a concomitant increase in the number of OPCs. Prevention of myelin loss and oligodendrocyte death may represent novel therapeutic targets for TBI.     

Ethyl pyruvate improves white matter remodeling in rats after traumatic brain injury

BackgroundSevere traumatic brain injury (TBI) results in long‐term neurological deficits associated with white matter injury (WMI). Ethyl pyruvate (EP) is a simple derivative of the endogenous energy substrate pyruvate with neuroprotective properties, but its role in recovery from WMI has not been explored.AimsThis study examines the effect of EP treatment on rats following TBI using behavioral tests and white matter histological analysis up to 28 days post‐injury.Materials and MethodsAnaesthetised adult rats were subjected to TBI by controlled cortical impact. After surgery, EP or Ringers solution (RS) was administrated intraperitoneally at 15 min after TBI and again at 12, 24, 36, 48, and 60 h after TBI. Sensorimotor deficits were evaluated up to day 21 after TBI by four independent tests. Immunofluorescence and transmission electron microscopy (TEM) were performed to assess white matter injury. Microglia activation and related inflammatory molecules were examined up to day 14 after TBI by immunohistochemistry or real‐time PCR.ResultsHere, we demonstrate that EP improves sensorimotor function following TBI as well as improves white matter outcomes up to 28 d after TBI, as shown by reduced myelin loss. Furthermore, EP administration during the acute phase of TBI recovery shifted microglia polarization toward the anti‐inflammatoryM2 phenotype, modulating the release of inflammatory‐related factors.ConclusionEP treatment may protect TBI‐induced WMI via modulating microglia polarization toward M2.     

Evidence for white matter disruption in traumatic brain injury without macroscopic lesions

Background

Non‐missile traumatic brain injury (nmTBI) without macroscopically detectable lesions often results in cognitive impairments that negatively affect daily life.

Aim

To identify abnormal white matter projections in patients with nmTBI with cognitive impairments using diffusion tensor magnetic resonance imaging (DTI).

Methods

DTI scans of healthy controls were compared with those of 23 patients with nmTBI who manifested cognitive impairments but no obvious neuroradiological lesions. DTI was comprised of fractional anisotropy analysis, which included voxel‐based analysis and confirmatory study using regions of interest (ROI) techniques, and magnetic resonance tractography of the corpus callosum and fornix.

Results

A decline in fractional anisotropy around the genu, stem and splenium of the corpus callosum was shown by voxel‐based analysis. Fractional anisotropy values of the genu (0.47), stem (0.48), and splenium of the corpus callosum (0.52), and the column of the fornix (0.51) were lower in patients with nmTBI than in healthy controls (0.58, 0.61, 0.62 and 0.61, respectively) according to the confirmatory study of ROIs. The white matter architecture in the corpus callosum and fornix of patients with nmTBI were seen to be coarser than in the controls in the individual magnetic resonance tractography.

Conclusions

Disruption of the corpus callosum and fornix in patients with nmTBI without macroscopically detectable lesions is shown. DTI is sensitive enough to detect abnormal neural fibres related to cognitive dysfunction after nmTBI.Cognitive and vocational sequelae are common complications after non‐missile traumatic brain injury (nmTBI) without obvious neuroradiological lesions.^1,2 They may present as memory disturbance, impairments in multitask execution and loss of self‐awareness.³ These symptoms have been attributed to diffuse brain injury and the diffuse loss of white matter or neural networks in the brain.^4,5,6 Currently no accurate method is available for diagnosing and assessing the distribution and severity of diffuse axonal injury. As computed tomography and magnetic resonance imaging (MRI) findings underestimate the extent of diffuse axonal injury and correlate poorly with the final neuropsychological outcome,^7,8 this dysfunction tends to be clinically underdiagnosed or overlooked. Indirect evidence for loss of functional connectivity after nmTBI has been provided by both morphometric and functional neuroimaging studies. Morphometric analysis of nmTBI has shown the relationship between atrophy of the corpus callosum and fornix and the neuropsychological outcome.⁹ Most functional neuroimaging studies conducted after nmTBI have shown that cognitive and behavioural disorders are correlated, with some degree of secondary hypometabolism or hypoperfusion in regions of the cortex.⁵ To date, however, there has been no direct in vivo demonstration of structural disconnections without macroscopically detectable lesions in patients with nmTBI.Diffusion tensor magnetic resonance imaging (DTI), which measures diffusion anisotropy in vivo, is a promising method for the non‐invasive detection of the degree of fibre damage in various disease processes affecting the white matter.^10,11 In biological systems, the diffusional motion of water is impeded by tissue structures, such as cell membranes, myelin sheaths, intracellular microtubules and associated proteins. Motion parallel to axons or myelin sheaths is inhibited to a lesser degree than perpendicular motion, a phenomenon known as diffusion anisotropy.¹² Fractional anisotropy was applied to evaluation of post‐traumatic diffuse axonal injury¹³ and its clinical usefulness described. In a previous study,¹⁴ fractional anisotropy score in the acute stage as an index of injury to white matter showed promise in predicting outcome in patients with traumatic brain injury, by using the regions of interest (ROIs) techniques. MRI voxel‐based analysis, a statistical normalising method, has been developed to reduce interindividual variability and to evaluate the whole brain objectively.^15,16,17 We investigated the regions in the whole brain that are commonly injured in patients having nmTBI with cognitive impairments but no macroscopic lesions, using voxel‐based analysis of fractional anisotropy, referred to as diffusion anisotropy. The advent of DTI has allowed inter‐regional fibre tracking, called magnetic resonance tractography, which reconstructs the three‐dimensional trajectories of white matter tracts.^11,18,19 We also investigated whether magnetic resonance tractography sensitively recognises degeneration of the corpus callosum and fornix in individual patients with nmTBI.     

Microglia/macrophage polarization dynamics in white matter after traumatic brain injury

Mononuclear phagocytes are a population of multi-phenotypic cells and have dual roles in brain destruction/reconstruction. The phenotype-specific roles of microglia/macrophages in traumatic brain injury (TBI) are, however, poorly characterized. In the present study, TBI was induced in mice by a controlled cortical impact (CCI) and animals were killed at 1 to 14 days post injury. Real-time polymerase chain reaction (RT–PCR) and immunofluorescence staining for M1 and M2 markers were performed to characterize phenotypic changes of microglia/macrophages in both gray and white matter. We found that the number of M1-like phagocytes increased in cortex, striatum and corpus callosum (CC) during the first week and remained elevated until at least 14 days after TBI. In contrast, M2-like microglia/macrophages peaked at 5 days, but decreased rapidly thereafter. Notably, the severity of white matter injury (WMI), manifested by immunohistochemical staining for neurofilament SMI-32, was strongly correlated with the number of M1-like phagocytes. In vitro experiments using a conditioned medium transfer system confirmed that M1 microglia-conditioned media exacerbated oxygen glucose deprivation–induced oligodendrocyte death. Our results indicate that microglia/macrophages respond dynamically to TBI, experiencing a transient M2 phenotype followed by a shift to the M1 phenotype. The M1 phenotypic shift may propel WMI progression and represents a rational target for TBI treatment.     

Changes in white matter late after severe traumatic brain injury in childhood

Severe traumatic brain injury in childhood, particularly that complicated by raised intracranial pressure, has significant long-term effects on the brain. Since magnetic resonance imaging provides a means of visualizing neuroanatomic structure in exquisite detail, the scope of this review is to revisit the pathology of traumatic brain injury described in recent clinical imaging studies. Acute imaging provides insight into the acute mechanism of focal and diffuse injury. There is some reduction in threshold for white matter pathology in the hemisphere ipsilateral to injury. After injury, there may be long-term effects on white matter architecture and the potential for brain growth. In this context, the pattern of hippocampal rather than parahippocampal gyrus tissue loss provides insight into the likely cause of white matter injury being cerebral hypoperfusion.     

Measurement and prediction of subjective fatigue following traumatic brain injury.

Numerous outcome studies have found fatigue to be a common problem following traumatic brain injury (TBI). This study examined the magnitude, causes and impact of fatigue following TBI using three subjective fatigue scales, and investigated its relationship with demographic and injury-related factors, and mood. Forty-nine controls and 49 TBI participants (36.2% with GCS score of 13-15, 29.8% with GCS score of 9-12, and 34% with GCS score of 3-8) were seen at a mean of approximately 8 months post injury. All participants completed three subjective fatigue measures, including the Fatigue Severity Scale (FSS), Visual Analogue Scale-Fatigue (VAS-F) and Causes of Fatigue Questionnaire (COF). TBI participants reported a significantly greater impact of fatigue on their lifestyle on the FSS relative to controls, and reported activities requiring physical and mental effort as more frequent causes of fatigue on the COF. There were, however, no significant group differences on subscales of the VAS-F. Greater time since injury and higher education levels were associated with higher fatigue levels, independent of the effects of mood. Injury severity and age were not found to be significant predictors of subjective fatigue severity in TBI participants.     

Psychosis following traumatic brain injury

Psychosis is a relatively infrequent but potentially serious and debilitating consequence of traumatic brain injury (TBI), and one about which there is considerable scientific uncertainty and disagreement. There are several substantial clinical, epidemiological, and neurobiological differences between the post-traumatic psychoses and the primary psychotic disorders. The recognition of these differences may facilitate identification and treatment of patients whose psychosis is most appropriately regarded as post-traumatic. In the service of assisting psychiatrists and other mental health clinicians in the diagnosis and treatment of persons with post-traumatic psychoses, this article will review post-traumatic psychosis, including definitions relevant to describing the clinical syndrome, as well as epidemiologic, neurobiological, and neurogenetic factors attendant to it. An approach to evaluation and treatment will then be offered, emphasizing identification of the syndrome of post-traumatic psychosis, consideration of the differential diagnosis of this condition, and careful selection and administration of treatment interventions.     

High mobility group box protein 1 and white matter injury following traumatic brain injury: perspectives on mechanisms and therapeutic strategies

Traumatic brain injury(TBI)is a major cause of morbidity and mortality worldwide.Despite significant medical advances over recent decades,many survivors of TBI develop long term neuro-cognitive deficits.Previously,only moderate and severe injuries were thought to account for the devastating consequences of TBI.However,there is increasing evidence that even milder injuries may result in problematic lifelong cognitive and affective disturbances.TBI is typically characterized by an an acute physical injury followed by a protracted innate neuro-inflammatory response.These reponses,mediated via neuronal,astrocyte and microglial cells,amongst others,and may result in widespread neuronal death and a micro-environment that is not conducive to brain repair(Manivannan et al.,2021).Whilst the primary physical injury often evades intervention from a medical perspective,the subsequent neuro-inflammatory response offers a potential therapeutic target.Nonetheless,effective pharmacological strategies continue to elude clinicians and scientists due to the complex underlying pathogenesis and difficulties of modelling such a heterogeneous disease.However,the majority of research to date has focused on investigating the effects of post-traumatic neuro-inflammation on grey matter injury rather than the consequences upon white matter(WM),which contributes greatly to cognitive dysfunction across many neurological diseases(Filly and Kelly,2018).Herein,we will briefly discuss:(i)high mobility group box protein 1(HMGB1)as a potential therapeutic target;(ii)the relevance of WM injury in TBI and current understanding of WM repair following injury;and(iii)perspectives on how HMGB1 may play a role.     

Irritability following traumatic brain injury

This study was undertaken to identify the clinical and pathoanatomical correlates of irritability in patients with closed head injuries. A consecutive series of 66 patients was assessed in hospital and at 3, 6, 9, and 12-month follow-ups. Patients fulfilling criteria for irritability were divided into 2 groups based on the immediate or delayed onset of their irritability and compared with patients without irritability for background characteristics, impairment variables, and lesion characteristics. There were 12 patients (18.2%) with acute onset irritability and 10 (15.1%) with delayed onset irritability. Acute onset irritability patients had a higher frequency of left cortical lesions. Delayed onset irritability patients showed a strong association with poor social functioning and greater impairment in activities of daily living. The findings suggest that post-brain injury irritability may have different causes and treatment in the acute and chronic stages.     

Psychosis following traumatic brain injury

Psychosis is a relatively infrequent but potentially serious and debilitating consequence of traumatic brain injury (TBI), and one about which there is considerable scientific uncertainty and disagreement. There are several substantial clinical, epidemiological, and neurobiological differences between the post-traumatic psychoses and the primary psychotic disorders. The recognition of these differences may facilitate identification and treatment of patients whose psychosis is most appropriately regarded as post-traumatic. In the service of assisting psychiatrists and other mental health clinicians in the diagnosis and treatment of persons with post-traumatic psychoses, this article will review post-traumatic psychosis, including definitions relevant to describing the clinical syndrome, as well as epidemiologic, neurobiological, and neurogenetic factors attendant to it. An approach to evaluation and treatment will then be offered, emphasizing identification of the syndrome of post-traumatic psychosis, consideration of the differential diagnosis of this condition, and careful selection and administration of treatment interventions.     

Regression-based prediction of long-term outcome following multidisciplinary rehabilitation for traumatic brain injury

Studied 100 patients (62 males, 38 females) who had sustained traumatic brain injuries (TBI) in an automobile accident. Patients were a mean age of 27 years (SD = 16.8) and were 6.2 years (SD = 1.7) postinjury. All patients were covered by no-fault automobile insurance in the state of Michigan and had unlimited access to services and treatments as mandated by state law. Patient files were randomly selected from a catastrophic claims office, a reinsuring association established by the Michigan legislature in conjunction with auto no-fault law. Time postinjury was inversely related to virtually all outcome domains assessed. Treatment variables considering both duration and costs, produced little or no significant increase in the prediction of long-term functional outcome, and in the majority of cases were inversely related to outcome. Patients receiving the longest duration of treatment and accumulating the greatest treatment costs displayed the poorest outcome ratings in this sample; some shorter durations of treatment were associated with modest improvements in outcome. The best single predictors of outcome were coma/vegetative state duration and age at accident.     

Mood disorders following traumatic brain injury

Mood disorders are a frequent complication of traumatic brain injury that exerts a deleterious effect on the recovery process and psychosocial outcome of brain injured patients. Prior psychiatric history and impaired social support have been consistently reported as risk factors for developing mood disorders after traumatic brain injury (TBI). In addition, biological factors such as the involvement of the prefrontal cortex and probably other limbic and paralimbic structures may play a significant role in the complex pathophysiology of these disorders. Preliminary studies have suggested that selective serotonin reuptake inhibitors such as sertraline, mood stabilizers such as sodium valproate, as well as stimulants and ECT may be useful in treating these disorders. Mood disorders occurring after TBI are clearly an area of neuropsychiatry in which further research in etiology as well as treatment is needed.     

Persisting insomnia following traumatic brain injury

Persisting insomnia secondary to traumatic brain injury, rarely reported and documented, is described in an adult male following head injury. The neuronal mechanisms underlying this sleep disorder as well as the neuropsychological concomitants and therapeutic approaches are discussed.     

Recurrent hypersomnia following traumatic brain injury

BackgroundRecurrent hypersomnia (RH) following a traumatic brain injury (TBI) is a rare form of RH. According to the International Classification of Sleep Disorders, 2nd edition (ICSD-2), RH must be considered in the differential diagnosis as secondary to an organic insult of the central nervous system and not as the clinical subtype of RH, Kleine–Levin syndrome (KLS). The aim of our study was to investigate if cases of RH following TBI should be considered in the differential diagnosis of RH as indicated by the International Classification of Sleep Disorders, 2nd edition or as genuine, or indicated by ICSD-2, RH must cases of KLS.MethodsTwelve cases of RH developed after TBI were collected and analyzed for circumstance at onset, severity of TBI, delay between TBI and occurrence of first episode of RH, symptoms of RH, duration and cycle length of episodes of hypersomnia, physical signs, and brain morphological imaging at the time of hypersomnia episodes.ResultsFactors such as the delay between TBI and the first episode of RH, the presence of other triggering factors and potential genetic factors, the degree of the severity of TBI, the presence or absence of any consistent brain imaging abnormality, provided the following results: (1) two of the cases could be considered as symptomatic of the underlying pathological brain process, (2) eight of the cases could be considered as simply triggered by TBI in patients at risk for KLS, and (3) two cases could be considered neither symptomatic nor triggered by TBI, due to the long delay between TBI and occurrence of symptoms.ConclusionCases of RH following TBI do not present under a single mechanism. Clinical assessment and laboratory tests are necessary to correctly classify them.     

Mood disorders following traumatic brain injury

Mood disorders are a frequent complication of traumatic brain injury that exerts a deleterious effect on the recovery process and psychosocial outcome of brain injured patients. Prior psychiatric history and impaired social support have been consistently reported as risk factors for developing mood disorders after traumatic brain injury (TBI). In addition, biological factors such as the involvement of the prefrontal cortex and probably other limbic and paralimbic structures may play a significant role in the complex pathophysiology of these disorders. Preliminary studies have suggested that selective serotonin reuptake inhibitors such as sertraline, mood stabilizers such as sodium valproate, as well as stimulants and ECT may be useful in treating these disorders. Mood disorders occurring after TBI are clearly an area of neuropsychiatry in which further research in etiology as well as treatment is needed.     

Major depression following traumatic brain injury

BACKGROUND: Major depression is a frequent psychiatric complication among patients with traumatic brain injury (TBI). To our knowledge, however, the clinical correlates of major depression have not been extensively studied. OBJECTIVE: To determine the clinical, neuropsychological, and structural neuroimaging correlates of major depression occurring after TBI. DESIGN: Prospective, case-controlled, surveillance study conducted during the first year after the traumatic episode occurred.Settings University hospital level I trauma center and a specialized rehabilitation unit. METHODS: The study group consisted of 91 patients with TBI. In addition, 27 patients with multiple traumas but without evidence of central nervous system injury constituted the control group. The patients' conditions were evaluated at baseline and at 3, 6, and 12 months after the traumatic episode. Psychiatric diagnosis was made using a structured clinical interview and DSM-IV criteria. Neuropsychological testing and quantitative magnetic resonance imaging were performed at the 3-month follow-up visit. RESULTS: Major depressive disorder was observed in 30 (33%) of 91 patients during the first year after sustaining a TBI. Major depressive disorder was significantly more frequent among patients with TBI than among the controls. Patients with TBI who had major depression were more likely to have a personal history of mood and anxiety disorders than patients who did not have major depression. Patients with major depression exhibited comorbid anxiety (76.7%) and aggressive behavior (56.7%). Patients with major depression had significantly greater impairment in executive functions than their nondepressed counterparts. Major depression was also associated with poorer social functioning at the 6-and 12-month follow-up, as well as significantly reduced left prefrontal gray matter volumes, particularly in the ventrolateral and dorsolateral regions. CONCLUSIONS: Major depression is a frequent complication of TBI that hinders a patient's recovery. It is associated with executive dysfunction, negative affect, and prominent anxiety symptoms. The neuropathological changes produced by TBI may lead to deactivation of lateral and dorsal prefrontal cortices and increased activation of ventral limbic and paralimbic structures including the amygdala.