Secondary thalamic neuroinflammation after focal cortical stroke and traumatic injury mirrors corticothalamic functional connectivity

Necula, Deanna; Cho, Frances S.; He, Andrea; Paz, Jeanne T.

doi:10.1002/cne.25259

Cited by 13 publications

(17 citation statements)

References 138 publications

(184 reference statements)

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“…Similarly, in two mouse models of injury-unilateral photothrombotic stroke or controlled cortical impact in the somatosensory cortex (a model of TBI)-GFAP was elevated in the thalamus, without gross hippocampal damage (Fig. 1B), in agreement with previous findings (10)(11)(12)(13)34).…”

Section: Thalamic Astrogliosis Is Observed In Postmortem Human Tissue...supporting

confidence: 91%

Enhancing GAT-3 in thalamic astrocytes promotes resilience to brain injury in rodents

et al. 2022

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Inflammatory processes induced by brain injury are important for recovery; however, when uncontrolled, inflammation can be deleterious, likely explaining why most anti-inflammatory treatments have failed to improve neurological outcomes after brain injury in clinical trials. In the thalamus, chronic activation of glial cells, a proxy of inflammation, has been suggested as an indicator of increased seizure risk and cognitive deficits that develop after cortical injury. Furthermore, lesions in the thalamus, more than other brain regions, have been reported in patients with viral infections associated with neurological deficits, such as SARS-CoV-2. However, the extent to which thalamic inflammation is a driver or by-product of neurological deficits remains unknown. Here, we found that thalamic inflammation in mice was sufficient to phenocopy the cellular and circuit hyperexcitability, enhanced seizure risk, and disruptions in cortical rhythms that develop after cortical injury. In our model, down-regulation of the GABA transporter GAT-3 in thalamic astrocytes mediated this neurological dysfunction. In addition, GAT-3 was decreased in regions of thalamic reactive astrocytes in mouse models of cortical injury. Enhancing GAT-3 in thalamic astrocytes prevented seizure risk, restored cortical states, and was protective against severe chemoconvulsant-induced seizures and mortality in a mouse model of traumatic brain injury, emphasizing the potential of therapeutically targeting this pathway. Together, our results identified a potential therapeutic target for reducing negative outcomes after brain injury.

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Section: Thalamic Astrogliosis Is Observed In Postmortem Human Tissue...supporting

confidence: 91%

Enhancing GAT-3 in thalamic astrocytes promotes resilience to brain injury in rodents

et al. 2022

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“…183 In animal models, both blood-brain barrier breakdown and entrance of TGFβ into the brain and neuroinflammation associated with thalamic circuit reorganization and seizure generation after cortical stroke are implicated in epilepsy. 186,187 However, precise inflammatory mechanisms that can successfully be targeted in humans have not been identified.…”

Section: Long-term Sequelaementioning

confidence: 99%

Immune Pathways in Etiology, Acute Phase, and Chronic Sequelae of Ischemic Stroke

Endres

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Nolte

et al. 2022

Circulation Research

116

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Inflammation and immune mechanisms are crucially involved in the pathophysiology of the development, acute damage cascades, and chronic course after ischemic stroke. Atherosclerosis is an inflammatory disease, and, in addition to classical risk factors, maladaptive immune mechanisms lead to an increased risk of stroke. Accordingly, individuals with signs of inflammation or corresponding biomarkers have an increased risk of stroke. Anti-inflammatory drugs, such as IL (interleukin)-1β blockers, methotrexate, or colchicine, represent attractive treatment strategies to prevent vascular events and stroke. Lately, the COVID-19 pandemic shows a clear association between SARS-CoV2 infections and increased risk of cerebrovascular events. Furthermore, mechanisms of both innate and adaptive immune systems influence cerebral damage cascades after ischemic stroke. Neutrophils, monocytes, and microglia, as well as T and B lymphocytes each play complex interdependent roles that synergize to remove dead tissue but also can cause bystander injury to intact brain cells and generate maladaptive chronic inflammation. Chronic systemic inflammation and comorbid infections may unfavorably influence both outcome after stroke and recurrence risk for further stroke. In addition, stroke triggers specific immune depression, which in turn can promote infections. Recent research is now increasingly addressing the question of the extent to which immune mechanisms may influence long-term outcome after stroke and, in particular, cause specific complications such as poststroke dementia or even poststroke depression.

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“…Since the DWI may need a few days to reach the complete extent of the lesions [ 25 ], thalami showed lower scores, being among the first to suffer from hypoxic-ischemic injury. This data is corroborated by studies on stroke patients, since primary injuries may disrupt functional connections, resulting in the development of secondary injuries, such as thalamic damage, which impair patients’ recovery [ 26 , 27 ].…”

Section: Discussionmentioning

confidence: 65%

Predictive Value of MRI in Hypoxic-Ischemic Encephalopathy Treated with Therapeutic Hypothermia

et al. 2023

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Background: Hypoxic-ischemic encephalopathy (HIE) is a severe pathology, and no unique predictive biomarker has been identified. Our aims are to identify associations of perinatal and outcome parameters with morphological anomalies and ADC values from MRI. The secondary aims are to define a predictive ADC threshold value and detect ADC value fluctuations between MRIs acquired within 7 days (MR0) and at 1 year (MR1) of birth in relation to perinatal and outcome parameters. Methods: Fifty-one term children affected by moderate HIE treated with hypothermia and undergoing MRI0 and MRI1 were recruited. Brain MRIs were evaluated through the van Rooij score, while ADC maps were co-registered on a standardized cerebral surface, on which 29 ROIs were drawn. Statistical analysis was performed in Matlab, with the statistical significance value at 0.05. Results: ADC0 < ADC1 in the left and right thalami, left and right frontal white matter, right visual cortex, and the left dentate nucleus of children showing abnormal perinatal and neurodevelopmental parameters. At ROC analysis, the best prognostic ADC cut-off value was 1.535 mm2/s × 10−6 (sensitivity 80%, specificity 86%) in the right frontal white matter. ADC1 > ADC0 in the right visual cortex and left dentate nucleus, positively correlated with multiple abnormal perinatal and neurodevelopmental parameters. The van Rooij score was significantly higher in children presenting with sleep disorders. Conclusions: ADC values could be used as prognostic biomarkers to predict children’s neurodevelopmental outcomes. Further studies are needed to address these crucial topics and validate our results. Early and multidisciplinary perinatal evaluation and the subsequent re-assessment of children are pivotal to identify physical and neuropsychological disorders to guarantee early and tailored therapy.

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Secondary thalamic neuroinflammation after focal cortical stroke and traumatic injury mirrors corticothalamic functional connectivity

Cited by 13 publications

References 138 publications

Enhancing GAT-3 in thalamic astrocytes promotes resilience to brain injury in rodents

Enhancing GAT-3 in thalamic astrocytes promotes resilience to brain injury in rodents

Immune Pathways in Etiology, Acute Phase, and Chronic Sequelae of Ischemic Stroke

Predictive Value of MRI in Hypoxic-Ischemic Encephalopathy Treated with Therapeutic Hypothermia

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