Journal of Neuroscience Research

BackgroundFetal Alcohol Spectrum Disorders (FASD) encompass a group of highly prevalent conditions resulting from prenatal alcohol exposure. Alcohol exposure during the third trimester of pregnancy overlapping with the brain growth spurt is detrimental to white matter growth and myelination, particularly in the corpus callosum, ultimately affecting tissue integrity in adolescence. Traditional neuroimaging techniques have been essential for assessing neurodevelopment in affected youth; however, these methods are limited in their capacity to track subtle microstructural alterations to white matter, thus restricting their effectiveness in monitoring therapeutic intervention. In this preliminary study we use a highly sensitive and clinically translatable Magnetic Resonance Elastography (MRE) protocol for assessing brain tissue microstructure through its mechanical properties following an exercise intervention in a rat model of FASD. MethodsRat pups were divided into two groups: alcohol-exposed (AE) pups which received alcohol in milk substitute (5.25 g/kg/day) via intragastric intubation on postnatal days (PD) four through nine during the rat brain growth spurt (Dobbing and Sands, 1979), or sham-intubated (SI) controls. In adolescence, on PD 30, half AE and SI rats were randomly assigned to either a modified home cage with free access to a running wheel or to a new home cage for 12 days (Gursky and Klintsova, 2017). Previous studies conducted in the lab have shown that 12 days of voluntary exercise intervention in adolescence immediately ameliorated callosal myelination in AE rats (Milbocker et al., 2022, 2023). MRE was used to measure longitudinal changes to mechanical properties of the whole brain and the corpus callosum at intervention termination and one-month post-intervention. Histological quantification of precursor and myelinating oligoglia in corpus callosum was performed one-month post-intervention. ResultsPrior to intervention, AE rats had lower forebrain stiffness in adolescence compared to SI controls (p = 0.02). Exercise intervention immediately mitigated this effect in AE rats, resulting in higher forebrain stiffness post-intervention in adolescence. Similarly, we discovered that forebrain damping ratio was lowest in AE rats in adolescence (p < 0.01), irrespective of intervention exposure. One-month post-intervention in adulthood, AE and SI rats exhibited comparable forebrain stiffness and damping ratio (p > 0.05). Taken together, these MRE data suggest that adolescent exercise intervention supports neurodevelopmental "catch-up" in AE rats. Analysis of the stiffness and damping ratio of the body of corpus callosum revealed that these measures increased with age. Finally, histological quantification of myelinating oligodendrocytes one-month post-intervention revealed a negative rebound effect of exercise cessation on the total estimate of these cells in the body of corpus callosum, irrespective of treatment group which was not convergent with noninvasive MRE measures. ConclusionsThis is the first application of MRE to measure changes in brain mechanical properties in a rodent model of FASD. MRE successfully captured alcohol-related changes to forebrain stiffness and damping ratio in adolescence. These preliminary findings expand upon results from previous studies which used traditional diffusion neuroimaging to identify structural changes to the adolescent brain in rodent models of FASD (Milbocker et al., 2022; Newville et al., 2017). Additionally, in vivo MRE identified an exercise-related alteration to forebrain stiffness that occurred in adolescence, immediately post-intervention.

Despite the fundamental importance of understanding impaired brain activity exhibited in post-traumatic epilepsy and other neurological impairments associated with traumatic brain injury (TBI), knowledge of how brain injury affects neuronal activity remains remarkably incomplete. We describe a whole-brain imaging and analysis approach to identify alterations in neuronal activity after TBI as a complementary method to conventional two-dimensional (2D) histological approaches. Here we report an easy-to-follow experimental pipeline to quantify changes in the whole mouse brain using tissue clearing, light sheet microscopy (LSM) and an optimised open-access atlas registration workflow. We validated the outcome of the pipeline using high throughput image analysis software and a secondary atlas registration method. Using the CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration) TBI model, TRAP2 mice were subjected to repeated mild TBI or sham treatment followed by tamoxifen injection to lock c-Fos activity after TBI. Brains were SHIELD fixed and passively cleared for imaging of c-Fos+ cells throughout the rostro-caudal axis of the brain using a light sheet microscope equipped with a specialized whole-brain imaging chamber. Volumetric images were stitched and 3D rendered using Arivis Vision4D image analysis software. For quantitative analysis, 2D image stacks were exported to segment c-Fos+ cells and register them to the Allen Mouse Brain Atlas using the BrainQuant3D python package. As a result, c-Fos+ cell counts were estimated throughout the brain and heatmaps were generated. We identified a brain-wide reduction in c-Fos cell density in the TBI group compared to sham controls, indicative of TBI-induced changes in whole brain neuronal activity. Further studies using multi-dimensional imaging coupled with analysis tools will deepen our understanding of post-TBI brain-wide dynamics.

Of the 2.8 million individuals who seek medical attention for traumatic brain injury (TBI) each year, nearly 300,000 require hospitalization, with up to 60% of these needing intensive care. Intensive care treatment of TBI involves stressful events such as sleep disruption, noise, and painful procedures, potentially leading to chronic stress in patients undergoing such treatment. Given that physiologic stress can exacerbate neuroinflammation and impair normal neural function, we hypothesized that chronic variable stress (CVS) following TBI would exacerbate behavioral and pathological outcomes. We tested this hypothesis by subjecting adolescent male mice to blunt TBI, followed by two weeks of CVS or control conditions. We assessed brain pathologic responses to injury 2-, 5-, 20-, and 28-weeks post-injury. We found chronic optic tract degeneration by Fluoro-jade B staining in TBI groups. Unexpectedly, CVS+TBI mice did not show evidence of optic tract axon degeneration 20 weeks after injury, but did at the other time points. CVS led to increased microglial phagocytic markers early after injury, regardless of TBI status, and TBI led to increased microglial phagocytic markers in a delayed fashion as well. Notably, microglial phagocytosis markers were not elevated in TBI+CVS groups compared to TBI only groups 20 weeks post-injury. There was no effect of TBI or CVS on behavioral measures taken at the end of CVS. These findings suggest a delayed, but not permanent, protective effect on axonal degeneration after TBI, potentially related to altered microglial and astrocytic phagocytic activity.

Subconcussive impacts are highly prevalent in contact sports and are thought to increase concussion risk. However, the specific conditions under which these subconcussive impacts influence concussion outcomes are uncertain, limiting our understanding of the mechanisms behind repetitive head trauma. Given that subconcussive impacts elicit a microglial response, and microglial morphology offers insight into function, we examined how subconcussive preconditioning affects microglial morphology and cognitive outcome after concussion. To investigate this question, we developed and validated a scalable, closed-head controlled cortical impact model. Using this approach, we found that although concussion elicited features of hypersurveillant microglia at 1 day post-injury, they resolve by 9 days post-injury, and subconcussive impacts only produced microglial changes at 9 days post-injury. When subconcussive impacts preceded a concussive impact (i.e., preconditioned concussion) no changes in microglial morphology appeared at either 1 or 9 days after injury. Interestingly, subconcussive preconditioning eliminated concussion-associated cognitive deficits in novel object recognition and this cognitive protection was time dependent: preconditioning impacts were only protective if delivered within 2 minutes of concussion, and had no effect if delivered over a 48-hour window. These results suggest that some types of subconcussive impacts may offer protection against subsequent concussion and mitigate changes in microglial morphology. Understanding this timing window could inform strategies for minimizing cognitive impairments in athletes exposed to repetitive head trauma.

Brain injury is heterozygous in nature and no single scheme is ideal for diagnosis and prognosis. Assessing proteins in cerebrospinal fluid is limited or not applicable after surgery whereas plasma biomarkers can only report occurrence of injury. The lack of regeneration markers renders the difficulty during drug discovery. This study aims to establish a potential reporter that correlates the regeneration progress of injured brain neurons. According to our recent publication, treatment of mitochondrial uncoupler carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) could rescue motor function deficit of mice after traumatic brain injury. We thus measured the local field potential (LFP) at sites proximal to the injury region. The recorded neuronal activity reported stimulation of right forelimb of mice. Our experimental results indicate that the recovery of evoked LFP correlates with FCCP treatment and could potentially be used as a regeneration biomarker. These promising findings suggest future application of a wireless, non-invasive recording system as a potential companion diagnosis device during drug development.

IntroductionSpecific diseases such as Alzheimers, schizophrenia and multiple sclerosis have been associated with environmental changes, including changes in season. The relationship between changes in season or photoperiod and brain volume has been widely studied in animals. However, the relationship between changes in season and brain volume in humans is not yet well established. Here, we aim to provide a comprehensive and systematic review of magnetic resonance imaging (MRI) studies examining the effects of changes in season or photoperiod on brain volume. MethodsWe used a systematic review approach to study reports on the relationship between changes in season or photoperiod and brain volume using MRI. PubMed database and Google Scholar search engines were used to locate appropriate. PRISMA was used in selection of appropriate studies on season or photoperiod and brain volume using MRI. ResultsFive studies were included in the current review: three examined the relationship between changes in photoperiod and brain volumes while two studies examined the relationship between changes in season and brain volume. ConclusionWhen studying other variables like changes in temperature and humidity on how they affect brain volume, no effect was observed. It was, however, observed from studies that hydration status changed brain volumes when measured using MRI. Overall, we found evidence demonstrating differences in human brain volumes across different seasons. We suggest future longitudinal research to prove changes in brain volume across different seasons.

Respiratory chemosensitivity is an important mechanism by which the brain senses changes in blood partial pressure of CO2 (PCO2). It is proposed that special neurons (and astrocytes) in various brainstem regions play key roles as CO2 central respiratory chemosensors in rodents. Although common marmosets (Callithrix jacchus), New-World non-human primates, show similar respiratory responses to elevated inspired CO2 as rodents, the chemosensitive regions in marmoset brain have not been defined yet. Here, we used c-fos immunostainings to identify brain-wide CO2-activated brain regions in common marmosets. In addition, we mapped the location of the retrotrapezoid nucleus (RTN) and raphe nuclei in the marmoset brainstem based on colocalization of CO2-induced c-fos immunoreactivity with Phox2b, and TPH immunostaining, respectively. Our data also indicated that, similar to rodents, marmoset RTN astrocytes express Phox2b and have complex processes that create a meshwork structure at the ventral surface of medulla. Our data highlight some cellular and structural regional similarities in brainstem of the common marmosets and rodents.

ObjectiveIn this study we explored how neuroimaging and blood biomarkers relate to cognitive recovery in traumatic brain injury (TBI) patients. MethodsSixteen participants with moderate to severe traumatic brain injury (TBI) were enrolled, with blood samples, MRI, and diffusion tensor imaging (DTI) collected at enrollment and six months. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Disability Rating Scale, and Montreal Cognitive Assessment (MoCA) were also administered at both time points to evaluate neuropsychological and functional outcomes. ResultsFractional anisotropy (FA) in the genu (rs = 0.937, p = 0.002) and splenium of the corpus callosum (rs = 0.955, p < 0.001) was strongly correlated with changes in RBANS - Attention scores. Fornix FA was correlated with changes in RBANS - Total (rs = 0.928, p = 0.008), and left tapetum FA was correlated with changes in RBANS - Visuospatial scores (rs = 0.964, p < 0.001). Right temporal fusiform cortex grey matter (GM) volume was correlated with changes in RBANS - Attention scores (rs = 0.975, p = 0.005). Blood biomarkers did not show significance. ConclusionImaging markers like FA and GM volume appear to help predict cognitive recovery in TBI, supporting the potential use of neuroimaging to guide rehabilitation strategies.

Traumatic brain injuries (TBIs) result from impact to or rapid displacement of the brain and can lead to various neurological deficits involving working memory, decision-making, and anxiety. While large-scale effects of brain damage are well-described for more severe TBIs, less is known about the extent and duration of cognitive deficits at the mild level. Interval timing can provide a helpful window into cognition in mice and humans. Interval-timing behavior is impaired in a wide range of neuropsychiatric disease states, such as Parkinsons disease. Furthermore, novel object recognition (NOR) and the Barnes maze (BM) tests are valuable assays for evaluating spatial learning, working memory, and anxiety-like behavior in mice. Here, we employed a weight-drop model of mild TBI (mTBI) to investigate changes in internal cognitive states resulting from mTBI treatment. mTBI mice were not significantly impaired in either interval timing or NOR, but they demonstrated impaired spatial memory in the Barnes Maze. Interestingly, within-sex comparisons revealed impairments in male mTBI mice in the interval-timing task and the NOR, suggesting that male and female mice may be differently affected by mTBIs.

Traumatic brain injury (TBI), particularly sports- and recreational activity related mild TBI (mTBI), is common in young adults and can be followed by persistent attentional and executive complaints. This study investigated chronic ([&ge;]6 months post-injury) structural brain alterations in gray matter (GM) and white matter (WM) and their associations with self-reported inattentive and hyperactive/impulsive symptoms, with a focus on sex-differentiated patterns. Structural brain properties in gray matter (GM) and white matter (WM) were acquired from 44 subjects with TBI and 45 matched controls, by utilizing structural MRI and diffusion tensor imaging techniques. Behavioral measures assessing severities of post TBI inattentive and hyperactive/impulsive symptoms were collected from each participant. Between-group and sex-specific differences of these brain and behavioral measures were conducted. Interactions among the TBI-induced significant brain- and behavioral-alterations, and their sex-specific patterns, were assessed as well. Male-dominated pattern of increased cortical thickness in superior parietal lobule (SPL) and female-dominated pattern of higher superior longitudinal fasciculus and superior fronto-occipital fasciculus (sFOF) fractional anisotropy (FA) were observed in the TBI group, when compared to controls. In males with TBI, greater SPL cortical thickness was significantly correlated with increased inattentive behaviors. In females with TBI, higher FA of sFOF was significantly correlated with decreased hyperactive/impulsive behaviors. Findings suggest that TBI-induced superior parietal cortical GM abnormalities may significantly cause attention deficits in patients with TBI, especially in males; while optimal post-TBI WM recovery in sFOF significantly contributes to maintenance of inhibitive control in patients with TBI, especially in females.

There is a critical unmet need for concussion biomarkers for injury prognosis and cognitive recovery. Existing traumatic brain injury (TBI) biomarkers are largely focused on acute cellular damage and reactivity, rather than the cellular repair mechanisms that contribute to differential concussion outcomes. Neuron-derived extracellular vesicles (EVs) are an emerging alternative to traditional protein biomarkers, providing a brain-specific molecular signature that can inform mechanistic insights and subsequent therapeutic intervention. Although neuroinflammation plays a key role in injury repair and cognitive recovery, its influence on neuronal EV signatures is unknown. In this work, we examine the role of inflammation in subacute neuronal EV biomarkers for differential concussion recovery in male mice. In particular, we identify general diagnostic biomarkers for concussion using miRNAs from neuronal EVs in blood serum, and then subtyped concussion based on prior injury history. Using PLX5622 to diminish the brains inflammatory response, we find that acute inflammation significantly contributes to differential cognitive recovery post-concussion and can enhance or impede recovery based on injury history. Furthermore, we find that removing microglia prior to injury eliminates diagnostic biomarkers of concussion. Finally, we identify a general panel of EV-derived miRNA biomarkers associated with cognitive recovery across all experimental conditions. Together, we not only identify putative biomarkers for post-acute concussion diagnosis, injury history, and cognitive recovery, but also define a novel role for neuron-derived EVs in indirectly surveilling brain inflammation. Broadly, these findings could inform efforts to subtype concussion patients and identify more precise recovery profiles for individual concussion patients.

Long-term total sleep deprivation induces changes in cortical - and hippocampal microglial morphology that closely resemble the microglial response to the gram-negative bacterial cell wall component lipopolysaccharide (LPS). A recent study found evidence that microglia could modify vigilance-states/sleep, but only few studies investigated microglial throughout the diurnal behavioral inactivity/activity pattern or the naturally occurring sleep-wake cycle, and those who have, only concentrated on the cortical or hippocampal microglia. As microglia demonstrate regional heterogeneity, we compared microglial diurnal morphological alterations in the somatosensory cortex (SC) and dorsal hippocampus (HC) to the basal forebrain (BF), which is a subcortical brain area involved in the regulation of vigilance states. We collected mouse brain samples every 3h throughout the 24h light-dark-cycle and applied a 3D reconstruction method for the acquired confocal microscopy images for each brain area separately. While microglial regional heterogeneity was evident, stimulation of microglia with LPS caused comparable microglial responses in all brain areas. When comparing microglial features between the 12h light- and dark periods, regional heterogeneity re-appeared. As most of the morphological alterations occurred during the light period-the habitual sleeping period of the mice, we performed polysomnography to study the possible interaction of microglial morphology and sleep. We found that cortical-, but not HC- or BF microglial territory and volume negatively correlated with sleep slow wave activity (SWA), an electroencephalic feature of non-REM sleep (NREMS). Since microglia are sensitive to neuronal activity, we propose that the regional differences reflect vigilance-state specific neuronal activity patterns. Table of contents image O_FIG O_LINKSMALLFIG WIDTH=184 HEIGHT=200 SRC="FIGDIR/small/482976v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@112d346org.highwire.dtl.DTLVardef@ecc138org.highwire.dtl.DTLVardef@1817331org.highwire.dtl.DTLVardef@1b1b47c_HPS_FORMAT_FIGEXP M_FIG C_FIG Main PointsMicroglia show morphological differences between the somatosensory cortex (SC), hippocampus (HC) and basal forebrain (BF) under physiological conditions. Cortical-, but not HC- or BF microglial cell volume negatively correlates with non-REM sleep slow wave activity.

Moderate-to-severe traumatic brain injury (msTBI) is recognized as a chronic and evolving neurological condition characterized by progressive structural brain changes and persistent cognitive impairment. While prior studies have demonstrated widespread atrophy following msTBI, less is known regarding the longitudinal trajectory of gray matter (GM) changes during recovery and post-rehabilitation. The current study used longitudinal voxel-based morphometry (VBM) to characterize GM volume changes over a period of 9 months, in individuals with msTBI relative to healthy controls (HC). Associations between regional GM volume and neuropsychological functioning were examined. Twenty-eight participants (14 msTBI, 14 HC) completed MRI and neuropsychological assessments across three timepoints spanning outpatient rehabilitation and follow-up. Longitudinal VBM analyses revealed significant group and time interactions within subcortical and limbic regions. Relative to HC, individuals with msTBI showed lower GM volume in these regions at baseline, with trajectories that converged toward HC values (right hippocampus) or increased relative to HC over the rehabilitation period (bilateral pulvinar), whereas the right amygdala and inferior cerebellar vermis remained persistently reduced. Significant longitudinal improvements in memory and psychomotor speed during the rehabilitation period were demonstrated in msTBI. Greater (preserved) GM volume within the right hippocampus, thalamus, and bilateral pulvinar was associated with better performance across measures of verbal memory, processing speed, executive functioning, and cognitive flexibility. These findings suggest that msTBI is associated with dynamic structural brain changes involving subcortical, limbic, and cerebellar networks, and that the rehabilitation period was accompanied by relative volumetric stabilization in these regions and by meaningful cognitive improvement.

Social isolation is a profound form of psychological stress that impacts the mental health of a large proportion of society. Other experimental models of stress and injury have demonstrated microglia activation and alterations in neural activity. Microglia and neural activity undergo coordinated changes under physiological and pathological states. However, the effect of social isolation on microglia and neural activity has not been thoroughly investigated. Here we show that the dorsal medial hypothalamus and hippocampal CA2 region of male mice undergo an increased microglia volume and branching following social isolation, whereas females exhibit this increase in the hypothalamus only. The prefrontal cortex, central amygdala, nucleus accumbens shell, and visual cortex did not exhibit changes in microglia structure in either male or female mice. The home cage resting level of neural activity, as measured by the immediate early gene c-fos, was reduced in CA2 and the prefrontal cortex of female but not male mice following isolation. However, the co-variation in neural activity across brain regions was abolished in male but not female isolated mice. These data show that different brain regions undergo independent and dissociable changes in microglia structure and network activity following social isolation which may account for changes in cognition and behavior associated with this form of psychological stress.

BackgroundRepetitive blast-related mild traumatic brain injury (mTBI) caused by exposure to high explosives is increasingly common among warfighters as well as civilians. While women have been serving in military positions with increased risk of blast exposure since 2016, there are few published reports examining sex as a biological variable in models of blast mTBI, greatly limiting diagnosis and treatment capabilities. As such, here we examined acute and chronic outcomes of repetitive blast trauma in female and male mice in relation to potential behavioral, inflammatory, microbiome, and vascular dysfunction. MethodsIn this study we utilized a well-established blast overpressure model to induce repetitive (3x) blast-mTBI in both female and male mice. Acutely following repetitive exposure, we measured serum and brain cytokine levels, blood-brain barrier (BBB) disruption, fecal microbial abundance, and locomotion and anxiety-like behavior in the open field assay. Chronically, in female and male mice we assessed behavioral correlates of mTBI and PTSD-related symptoms commonly reported by Veterans with a history of blast-mTBI using the elevated zero maze, acoustic startle, and conditioned odorant aversion paradigms. ResultsRepetitive blast exposure resulted in both similar and disparate patterns of acute serum and brain cytokine as well as gut microbiome changes in female and male mice. Acute BBB disruption following repetitive blast exposure was apparent in both sexes. While female and male blast mice both exhibited acute locomotor and anxiety-like deficits in the open field assay, only male mice exhibited chronic adverse behavioral outcomes. DiscussionRepresenting a novel survey of potential sex differences following repetitive blast trauma, our results demonstrate unique similar yet divergent patterns of blast-induced dysfunction in female vs. male mice and highlight novel targets for future diagnosis and therapeutic development.

Human brain organoids are emerging as relevant models for the study of human brain health and disease. However, it has not been shown whether human brain organoids exhibit a proteoform profile similar to the human brain. Herein, we demonstrate that unguided brain organoids exhibit minimal batch-to-batch variability in cell composition and metabolism when generated from induced pluripotent stem cells (iPSCs) derived from male-female siblings. We then show that profiles of select proteins in these brain organoids are more similar to autopsied human cortical and cerebellar profiles than to those in mouse cortical samples. Brain organoids derived from sibling iPSCs do not exhibit any sex differences in protein proportions. By benchmarking human brain organoid proteoforms against human parenchymal tissue, we establish the foundation for future studies that could investigate, for example, how well brain organoids can model any of the known sex-dependent differences in cellular function, including responses of drug-receptor interactions. HighlightsO_LIBrain organoids (BOs) display protein banding similar to human parenchymal lysates C_LIO_LIProtein banding differs between mouse and human brain parenchyma lysates C_LIO_LISibling-derived BOs have similar cell composition and metabolism at day 90 C_LIO_LISibling-derived BOs exhibit similar protein banding at day 90 C_LI

AbstractThe objective of this secondary analysis of a prior investigation was to determine if prolonged exposure to the anesthetics isoflurane and dexmedetomidine during MRI was associated with a higher proportion of axons with myelin decompaction. 16 mice underwent an MRI protocol in which they had prolonged exposure to isoflurane and dexmedetomidine, while 10 mice did not undergo this protocol. All mice were sacrificed and electron microscope images were taken of various brain regions including the right prefrontal cortex (anterior cingulate and prelimbic area), the nucleus accumbens, the amygdala, and the ventral hippocampus.. Proportion of decompacted axons was calculated for each mouse, and an inter-rater reliability score of 80% was achieved. Welchs t-tests were used to test the hypothesis that mice undergoing MRI with prolonged anesthesia had greater levels of myelin decompaction than mice that did not experience prolonged anesthesia. Mice with prolonged anesthetic exposure during MRI had significantly higher proportions of decompacted axons than mice that did not experience prolonged anesthesia (p-value of 0.00003642). Prolonged exposure to anesthetics, particularly isoflurane, may be associated with myelin decompaction. These findings, if replicated, have potential to impact future anesthesia use in clinical work and scientific research. Significance StatementProlonged exposure to the anesthetics isoflurane and dexmedetomidine during brain imaging may lead to myelin decompaction in adult rodents. Myelin is a protective sheath around nerve fibers that ensures efficient transmission of electrical signals in the nervous system. Decompaction of myelin can disrupt these signals, potentially leading to neurological issues. This discovery is significant because it highlights potential risks associated with these anesthetics, which are commonly used in fMRI studies of rodents and in veterinary and medical procedures.

Cerebrovascular reactivity (CVR) reflects the ability of blood vessels to dilate or constrict in response to a vasoactive stimulus, and allows researchers to assess the brains vascular health. Individuals with spinal cord injury (SCI) are at an increased risk for autonomic dysfunction in addition to cognitive impairments, which have been linked to a decline in CVR; however, there is currently a lack of brain-imaging studies that investigate how CVR is altered after SCI. In this study, we used a breath-holding hypercapnic stimulus and functional near-infrared spectroscopy (fNIRS) to investigate CVR alterations in individuals with SCI (n = 20, 14M, 6F, mean age = 46.3 {+/-} 10.2 years) as compared to age- and sex-matched able-bodied (AB) controls (n = 25, 19M, 6F, mean age = 43.2 {+/-} 12.28 years). CVR was evaluated by its amplitude and delay components separately by using principal component analysis and cross-correlation analysis, respectively. We observed significantly delayed CVR in the right inferior parietal lobe in individuals with SCI compared to AB controls (linear mixed-effects model, fixed-effects estimate = 6.565, Satterthwaites t-test, t = 2.663, p = 0.008), while the amplitude of CVR was not significantly different. The average CVR delay in the SCI group in the right inferior parietal lobe was 14.21 s (sd: 6.60 s), and for the AB group, the average delay in the right inferior parietal lobe was 7.08 s (sd: 7.39 s). CVR delays were also associated with the duration since injury in individuals with SCI, in which a longer duration since injury was associated with a shortened delay in CVR in the right inferior parietal region (Pearsons r-correlation, r = -0.59, p = 0.04). This study shows that fNIRS can be used to quantify changes in CVR in individuals with SCI, and may be further used in rehabilitative settings to monitor the cerebrovascular health of individuals with SCI.

Meta-analysis shows that sub-clusters defined by affected domains of psychosocial functioning capture PTSD subtypes better than symptom clusters defined in the DSM-IV. This pilot study investigated the association between symptom sub-clusters and brain volume in twelve persons with PTSD (females, mean age 40.9 years). Structural magnetic resonance imaging (MRI) images were acquired, and voxel-based morphometry (VBM) was used to estimate local gray matter volume throughout the brain. Participants gray matter volume was correlated with both overall PTSD severity and sub-cluster severities. In this preliminary study examining sub-clusters and brain morphometry, we found that neuronal changes associated with sub-clusters may provide a more complete understanding of the neuroanatomical changes that occur in PTSD beyond what can be ascertained using overall disorder severity or comparisons with control subjects. The results of our study suggest that the neurobiological changes resulting from severe trauma depend on the specific sub-clusters of symptoms experienced by individuals with PTSD.

Alzheimers Disease is a chronic progressive neurodegenerative disorder that impairs the cerebral lymphatic system and compartmental fluid exchange leading to a decline in cognitive function. Due to the lack of disease modifying medications, non-pharmacological Cranial Osteopathic Manipulation (COM) is evolving as a potential minimally invasive treatment choice. In this work, the effect of quantified COM treatment, using a nanosensor glove, on 3-month-old (Yg) and 18-month-old transgenic (Tg) rat model of Alzheimers Disease were studied using the Morris Water Maze (MWM), Western Blots, and Proteomics and Transcriptomics assays. The results revealed that COM had minimal to no significant difference in the behavioral and biochemical parameters in the Yg rats, suggesting COM treatment was harmless. While COM exhibited no significant differences in Tg rat MWM escape latency, navigation to the platform was significantly different on testing days 5 and 6, with p-values of signed initial heading error were 0.014 and 0.034 respectively. This indicates a difference in learning and spatial working memory. A proteomic assay on Tg rat hippocampus identified 51 significantly differentially expressed proteins with 34 associated with neurological disorders, while transcriptome remained indifferent. In this study, for the first time we have established a technique to quantify the force applied during COM treatment on an animal model of AD, offering a more objective approach for evaluating the effect of such treatments. Our results indicate that a quantifiable COM can be applied to rodents and to study the resulting behavioral and biochemical phenotypes.