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1. Reduced Reelin Expression in the Hippocampus after Traumatic Brain Injury

   https://doi.org/10.3390/biom10070975  

   Dal Pozzo, Valentina ; Crowell, Beth ; Briski, Nicholas ; Crockett, David P. ; D’Arcangelo, Gabriella ( July 2020 , Biomolecules)

   null (Ed.)

   Traumatic brain injury (TBI) is a relatively common occurrence following accidents or violence, and often results in long-term cognitive or motor disability. Despite the high health cost associated with this type of injury, presently there are no effective treatments for many neurological symptoms resulting from TBI. This is due in part to our limited understanding of the mechanisms underlying brain dysfunction after injury. In this study, we used the mouse controlled cortical impact (CCI) model to investigate the effects of TBI, and focused on Reelin, an extracellular protein that critically regulates brain development and modulates synaptic activity in the adult brain. We found that Reelin expression decreases in forebrain regions after TBI, and that the number of Reelin-expressing cells decrease specifically in the hippocampus, an area of the brain that plays an important role in learning and memory. We also conducted in vitro experiments using mouse neuronal cultures and discovered that Reelin protects hippocampal neuronal cells from glutamate-induced neurotoxicity, a well-known secondary effect of TBI. Together our findings suggest that the loss of Reelin expression may contribute to neuronal death in the hippocampus after TBI, and raise the possibility that increasing Reelin levels or signaling activity may promote functional recovery. 

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2. Brain Trauma Disrupts Hepatic Lipid Metabolism: Blame It on Fructose?

   https://doi.org/10.1002/mnfr.201801054  

   Rege, Shraddha D. ; Royes, Luiz ; Tsai, Brandon ; Zhang, Guanglin ; Yang, Xia ; Gomez‐Pinilla, Fernando ( June 2019 , Molecular Nutrition & Food Research)

   The action of brain disorders on peripheral metabolism is poorly understood. The impact of traumatic brain injury (TBI) on peripheral organ function and how TBI effects can be influenced by the metabolic perturbation elicited by fructose ingestion are studied.

   It is found that TBI affects glucose metabolism and signaling proteins for insulin and growth hormone in the liver; these effects are exacerbated by fructose ingestion. Fructose, principally metabolized in the liver, potentiates the action of TBI on hepatic lipid droplet accumulation. Studies in isolated cultured hepatocytes identify GH and fructose as factors for the synthesis of lipids. The liver has a major role in the synthesis of lipids used for brain function and repair. TBI results in differentially expressed genes in the hypothalamus, primarily associated with lipid metabolism, providing cues to understand central control of peripheral alterations. Fructose‐fed TBI animals have elevated levels of markers of inflammation, lipid peroxidation, and cell energy metabolism, suggesting the pro‐inflammatory impact of TBI and fructose in the liver.

   Results reveal the impact of TBI on systemic metabolism and the aggravating action of fructose. The hypothalamic‐pituitary‐growth axis seems to play a major role in the regulation of the peripheral TBI pathology.

    

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3. Intranasal Delivery of Cell-Penetrating Therapeutic Peptide Enhances Brain Delivery, Reduces Inflammation, and Improves Neurologic Function in Moderate Traumatic Brain Injury

   https://doi.org/10.3390/pharmaceutics16060774  

   Yanamadala, Yaswanthi ; Roy, Ritika ; Williams, Afrika Alake ; Uppu, Navya ; Kim, Audrey Yoonsun ; DeCoster, Mark A ; Kim, Paul ; Murray, Teresa Ann ( June 2024 , Pharmaceutics)

   Following traumatic brain injury (TBI), secondary brain damage due to chronic inflammation is the most predominant cause of the delayed onset of mood and memory disorders. Currently no therapeutic approach is available to effectively mitigate secondary brain injury after TBI. One reason is the blood–brain barrier (BBB), which prevents the passage of most therapeutic agents into the brain. Peptides have been among the leading candidates for CNS therapy due to their low immunogenicity and toxicity, bioavailability, and ease of modification. In this study, we demonstrated that non-invasive intranasal (IN) administration of KAFAK, a cell penetrating anti-inflammatory peptide, traversed the BBB in a murine model of diffuse, moderate TBI. Notably, KAFAK treatment reduced the production of proinflammatory cytokines that contribute to secondary injury. Furthermore, behavioral tests showed improved or restored neurological, memory, and locomotor performance after TBI in KAFAK-treated mice. This study demonstrates KAFAK’s ability to cross the blood–brain barrier, to lower proinflammatory cytokines in vivo, and to restore function after a moderate TBI.

    

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4. Noninvasive and reliable automated detection of spreading depolarization in severe traumatic brain injury using scalp EEG

   https://doi.org/10.1038/s43856-023-00344-3  

   Chamanzar, Alireza ; Elmer, Jonathan ; Shutter, Lori ; Hartings, Jed ; Grover, Pulkit ( December 2023 , Communications Medicine)

   Spreading depolarizations (SDs) are a biomarker and a potentially treatable mechanism of worsening brain injury after traumatic brain injury (TBI). Noninvasive detection of SDs could transform critical care for brain injury patients but has remained elusive. Current methods to detect SDs are based on invasive intracranial recordings with limited spatial coverage. In this study, we establish the feasibility of automated SD detection through noninvasive scalp electroencephalography (EEG) for patients with severe TBI.

   Building on our recent WAVEFRONT algorithm, we designed an automated SD detection method. This algorithm, with learnable parameters and improved velocity estimation, extracts and tracks propagating power depressions using low-density EEG. The dataset for testing our algorithm contains 700 total SDs in 12 severe TBI patients who underwent decompressive hemicraniectomy (DHC), labeled using ground-truth intracranial EEG recordings. We utilize simultaneously recorded, continuous, low-density (19 electrodes) scalp EEG signals, to quantify the detection accuracy of WAVEFRONT in terms of true positive rate (TPR), false positive rate (FPR), as well as the accuracy of estimating SD frequency.

   WAVEFRONT achieves the best average validation accuracy using Delta band EEG: 74% TPR with less than 1.5% FPR. Further, preliminary evidence suggests WAVEFRONT can estimate how frequently SDs may occur.

   We establish the feasibility, and quantify the performance, of noninvasive SD detection after severe TBI using an automated algorithm. The algorithm, WAVEFRONT, can also potentially be used for diagnosis, monitoring, and tailoring treatments for worsening brain injury. Extension of these results to patients with intact skulls requires further study.

    

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5. Time-dependent homeostatic mechanisms underlie brain-derived neurotrophic factor action on neural circuitry

   https://doi.org/10.1038/s42003-023-05638-9  

   O’Neill, Kate_M ; Anderson, Erin_D ; Mukherjee, Shoutik ; Gandu, Srinivasa ; McEwan, Sara_A ; Omelchenko, Anton ; Rodriguez, Ana_R ; Losert, Wolfgang ; Meaney, David_F ; Babadi, Behtash ; et al ( December 2023 , Communications Biology)

   Plasticity and homeostatic mechanisms allow neural networks to maintain proper function while responding to physiological challenges. Despite previous work investigating morphological and synaptic effects of brain-derived neurotrophic factor (BDNF), the most prevalent growth factor in the central nervous system, how exposure to BDNF manifests at the network level remains unknown. Here we report that BDNF treatment affects rodent hippocampal network dynamics during development and recovery from glutamate-induced excitotoxicity in culture. Importantly, these effects are not obvious when traditional activity metrics are used, so we delve more deeply into network organization, functional analyses, and in silico simulations. We demonstrate that BDNF partially restores homeostasis by promoting recovery of weak and medium connections after injury. Imaging and computational analyses suggest these effects are caused by changes to inhibitory neurons and connections. From our in silico simulations, we find that BDNF remodels the network by indirectly strengthening weak excitatory synapses after injury. Ultimately, our findings may explain the difficulties encountered in preclinical and clinical trials with BDNF and also offer information for future trials to consider.

    

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