High School Sports-Related Concussion and the Effect of a Jugular Vein Compression Collar: A Prospective Longitudinal Investigation of Neuroimaging and Neurofunctional Outcomes.

Sports-related concussion (SRC) can exert serious acute and long-term consequences on brain microstructure, function, and behavioral outcomes. We aimed to quantify the alterations in white matter (WM) microstructure and global network organization, and the decrements in behavioral and cognitive outcomes from pre-season to post-concussion in youth athletes who experienced SRC. We also aimed to evaluate whether wearing a jugular compression neck collar, a device designed to mitigate brain "slosh" injury, would mitigate the pre-season to post-concussion alterations in neuroimaging, behavioral, and cognitive outcomes. A total of 488 high school football and soccer athletes (14-18 years old) were prospectively enrolled and assigned to the non-collar group (n = 237) or the collar group (n = 251). The outcomes of the study were the pre-season to post-concussion neuroimaging, behavioral, and cognitive alterations. Forty-six participants (non-collar: n = 24; collar: n = 22) were diagnosed with a SRC during the season. Forty of these 46 athletes (non-collar: n = 20; collar: n = 20) completed neuroimaging assessment. Significant pre-season to post-concussion alterations in WM microstructural integrity and brain network organization were found in these athletes (corrected p < 0.05). The alterations were significantly reduced in collar-wearing athletes compared to non-collar-wearing athletes (corrected p < 0.05). Concussion and collar main effects were identified for some of the behavioral and cognitive outcomes, but no collar by SRC interaction effects were observed in any outcomes. In summary, young athletes exhibited significant WM microstructural and network organizational, and cognitive alterations following SRC. The use of the jugular vein compression collar showed promising evidence to reduce these alterations in high school contact sport athletes.

Title: Injury characteristics of the Papez circuit in patients with diffuse axonal injury: a diffusion tensor tractography study.

We investigate the characteristics of injury of four portions of the Papez circuit in patients with diffuse axonal injury (DAI), using diffusion tensor tractography (DTT). Thirty-four consecutive patients with DAI and 30 normal control subjects were recruited. Four portions of the Papez circuit were reconstructed: the fornix, cingulum, thalamocingulate tract, and mammillothalamic tract. Analysis of DTT parameters [fractional anisotropy (FA) and tract volume (TV)] and configuration (narrowing, discontinuation, or non-reconstruction) was performed for each portion of the Papez circuit. The Memory Assessment Scale (MAS) was used for the estimation of cognitive function. In the group analysis, decreased fractional anisotropy and tract volume of the entire Papez circuit were observed in the patient group compared with the control group (p < 0.05). In the individual analysis, all four portions of the Papez circuit were injured in terms of DTT parameters or configuration. Positive correlation was observed between TV of the fornix and short-term memory on MAS r = 0.618, p < 0.05), and between FA of the fornix and total memory on MAS (r = 0.613, p < 0.05). We found that all four portions of the Papez circuit in the patient group were vulnerable to DAI, and among four portions of the Papez circuit, the fornix was the most vulnerable portion in terms of injury incidence and severity.

Compound K induces neurogenesis of neural stem cells in thrombin induced nerve injury through LXRα signaling in mice.

Intracerebral hemorrhage (ICH) causes neurological function deficit due to the loss of neurons surrounding the hematoma. Increased neurogenesis of endogenous neural stem cells (EnNSCs) is believed to increase cell proliferation and differentiation, thereby improving the neurological deficit. However, there are still limited drugs that are effective for treating neurological deficit. So, the effects of compound K (CK) in EnNSCs were measured after thrombin-induced mice models both in vivo and in vitro, and investigated the probable mechanisms of CK during pro-neurogenesis. The results revealed that 10 µM CK promotes neurogenesis, proliferation and reduces apoptosis of EnNSCs after induction by thrombin. After that, CK treatment increased the neurogenesis of EnNSCs through liver X receptor α (LXRα) signaling pathway using adeno-associated virus knockdown and knocked out mice of LXRα gene. Finally, intraperitoneal injection of 10 mg/kg CK improved the neurogenesis of subventricular zone (SVZ), myelin repair and behavioral deficit after stereotaxic injection of thrombin in the basal ganglia of mice, and this process involved LXRα. These observations provided evidence regarding the effect of CK in pro-neurogenesis via LXRα activation, and suggested further evaluation of it due to its potential role as an effective modulator in the treatment of ICH.

Exploring of the Unpredicted Effects of Olfactory Network Injuries on Mammary Gland Degeneration: A Preliminary Experimental Study.

Purpose of the study: Hypofunctioning breasts are typically considered a dysfunction of higher brain centers that regulate hormonal feedback, and olfactory information has been proposed as a triggering factor for lactation in the maternal body. However, there are no substantive studies regarding whether olfaction disorders and/or loss of olfactory sense may result in breast gland atrophy by causing diminished olfactory stimulation. To fill this gap in the literature, we studied the histologic features of breast glands as a sample model in animals that had undergone an olfactory bulb lesion (OBL). Materials and methods: This study was conducted on 22 rats. Six, eight, and six of them were used as control, SHAM, and OBL groups, respectively. After 10 weeks, the animals were decapitated. Olfactory bulbs and breast glands were stained with Hematoxylin-eosin and tunnel dye. Specimens were analyzed stereologically to evaluate the loss in volume of the olfactory bulbs, total breast follicle volume (TBFV) and Meissner's corpuscles per cubic centimeter, and these two senior metrics were compared with each other statistically. Results: Olfactory bulb volume loss and breast gland atrophy were both detected in study group. Mean TBFV and OB volumes were measured as: (296 ± 89) × 106 µm3/cm3 and 4.43 ± 0.98 mm3 in control (Group I); (264 ± 63) × 106 µm3/cm3 and 3.86 ± 0.81 mm3 in SHAM (Group II) and (194 ± 52) × 106 µm3/cm3 and 1.52 ± 0.36 mm3 in OBL group (Group III). It was noted that the TBFV was significantly diminished, with apoptotic degradation in the olfactory bulbs and breast glands of OBL-applied animals (p < 0.001). Conclusion: It seems that diminished milk secretion is attributable to the degradation of breast glands that results from olfaction loss in OBL animals.

Autonomic Disturbances in Acute Cerebrovascular Disease.

Autonomic disturbances often occur in patients with acute cerebrovascular disease due to damage of the central autonomic network. We summarize the structures of the central autonomic network and the clinical tests used to evaluate the functions of the autonomic nervous system. We review the clinical and experimental findings as well as management strategies of post-stroke autonomic disturbances including electrocardiographic changes, cardiac arrhythmias, myocardial damage, thermoregulatory dysfunction, gastrointestinal dysfunction, urinary incontinence, sexual disorders, and hyperglycemia. The occurrence of autonomic disturbances has been associated with poor outcomes in stroke patients. Autonomic nervous system modulation appears to be an emerging therapeutic strategy for stroke management in addition to treatments for sensorimotor dysfunction.

Functionality and Robustness of Injured Connectomic Dynamics in C. elegans: Linking Behavioral Deficits to Neural Circuit Damage.

Using a model for the dynamics of the full somatic nervous system of the nematode C. elegans, we address how biological network architectures and their functionality are degraded in the presence of focal axonal swellings (FAS) arising from neurodegenerative disease and/or traumatic brain injury. Using biophysically measured FAS distributions and swelling sizes, we are able to simulate the effects of injuries on the neural dynamics of C. elegans, showing how damaging the network degrades its low-dimensional dynamical responses. We visualize these injured neural dynamics by mapping them onto the worm's low-dimensional postures, i.e. eigenworm modes. We show that a diversity of functional deficits arise from the same level of injury on a connectomic network. Functional deficits are quantified using a statistical shape analysis, a procrustes analysis, for deformations of the limit cycles that characterize key behaviors such as forward crawling. This procrustes metric carries information on the functional outcome of injuries in the model. Furthermore, we apply classification trees to relate injury structure to the behavioral outcome. This makes testable predictions for the structure of an injury given a defined functional deficit. More critically, this study demonstrates the potential role of computational simulation studies in understanding how neuronal networks process biological signals, and how this processing is impacted by network injury.

Hippocampal Damage Increases Deontological Responses during Moral Decision Making.

Complex moral decision making is associated with the ventromedial prefrontal cortex (vmPFC) in humans, and damage to this region significantly increases the frequency of utilitarian judgments. Since the vmPFC has strong anatomical and functional links with the hippocampus, here we asked how patients with selective bilateral hippocampal damage would derive moral decisions on a classic moral dilemmas paradigm. We found that the patients approved of the utilitarian options significantly less often than control participants, favoring instead deontological responses-rejecting actions that harm even one person. Thus, patients with hippocampal damage have a strikingly opposite approach to moral decision making than vmPFC-lesioned patients. Skin-conductance data collected during the task showed increased emotional arousal in the hippocampal-damaged patients and they stated that their moral decisions were based on emotional instinct. By contrast, control participants made moral decisions based on the integration of an adverse emotional response to harming others, visualization of the consequences of one's action, and the rational re-evaluation of future benefits. This integration may be disturbed in patients with either hippocampal or vmPFC damage. Hippocampal lesions decreased the ability to visualize a scenario and its future consequences, which seemed to render the adverse emotional response overwhelmingly dominant. In patients with vmPFC damage, visualization might also be reduced alongside an inability to detect the adverse emotional response, leaving only the utilitarian option open. Overall, these results provide insights into the processes involved in moral decision making and highlight the complementary roles played by two closely connected brain regions. SIGNIFICANCE STATEMENT: The ventromedial prefrontal cortex (vmPFC) is closely associated with the ability to make complex moral judgements. When this area is damaged, patients become more utilitarian (the ends justify the means) and have decreased emotional arousal during moral decision making. The vmPFC is closely connected with another brain region-the hippocampus. In this study we found that patients with selective bilateral hippocampal damage show a strikingly opposite response pattern to those with vmPFC damage when making moral judgements. They rejected harmful actions of any kind (thus their responses were deontological) and showed increased emotional arousal. These results provide new insights into the processes involved in moral decision making and highlight the complementary roles played by two closely connected brain regions.

Traumatic Brain Injury Causes Aberrant Migration of Adult-Born Neurons in the Hippocampus.

Traumatic brain injury (TBI) promotes neural stem/progenitor cell (NSC) proliferation in an attempt to initiate innate repair mechanisms. However, all immature neurons in the CNS are required to migrate from their birthplace to their final destination to develop into functional neurons. Here we assessed the destination of adult-born neurons following TBI. We found that a large percentage of immature neurons migrated past their normal stopping site at the inner granular cell layer (GCL), and became misplaced in the outer GCL of the hippocampal dentate gyrus. The aberrant migration of adult-born neurons in the hippocampus occurred 48 hours after TBI, and lasted for 8 weeks, resulting in a great number of newly generated neurons misplaced in the outer GCL in the hippocampus. Those misplaced neurons were able to become mature and differentiate into granular neurons, but located ectopically in the outer GCL with reduced dendritic complexity after TBI. The adult-born neurons at the misplaced position may make wrong connections with inappropriate nearby targets in the pre-existing neural network. These results suggest that although stimulation of endogenous NSCs following TBI might offer new avenues for cell-based therapy, additional intervention is required to further enhance successful neurogenesis for repairing the damaged brain.

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.

Feedback from visual cortical area 7 to areas 17 and 18 in cats: How neural web is woven during feedback.

To investigate the feedback effect from area 7 to areas 17 and 18, intrinsic signal optical imaging combined with pharmacological, morphological methods and functional magnetic resonance imaging (fMRI) was employed. A spatial frequency-dependent decrease in response amplitude of orientation maps was observed in areas 17 and 18 when area 7 was inactivated by a local injection of GABA, or by a lesion induced by liquid nitrogen freezing. The pattern of orientation maps of areas 17 and 18 after the inactivation of area 7, if they were not totally blurred, paralleled the normal one. In morphological experiments, after one point at the shallow layers within the center of the cat's orientation column of area 17 was injected electrophoretically with HRP (horseradish peroxidase), three sequential patches in layers 1, 2 and 3 of area 7 were observed. Employing fMRI it was found that area 7 feedbacks mainly to areas 17 and 18 on ipsilateral hemisphere. Therefore, our conclusions are: (1) feedback from area 7 to areas 17 and 18 is spatial frequency modulated; (2) feedback from area 7 to areas 17 and 18 occurs mainly ipsilaterally; (3) histological feedback pattern from area 7 to area 17 is weblike.

Removal of perineuronal nets in the medial prefrontal cortex impairs the acquisition and reconsolidation of a cocaine-induced conditioned place preference memory.

Pyramidal neurons in the medial prefrontal cortex (mPFC) critically contribute to cocaine-seeking behavior in humans and rodents. Activity of these neurons is significantly modulated by GABAergic, parvalbumin-containing, fast-spiking interneurons, the majority of which are enveloped by specialized structures of extracellular matrix called perineuronal nets (PNNs), which are integral to the maintenance of many types of plasticity. Using a conditioned place preference (CPP) procedure, we found that removal of PNNs primarily from the prelimbic region of the mPFC of adult, male, Sprague Dawley rats impaired the acquisition and reconsolidation of a cocaine-induced CPP memory. This impairment was accompanied by a decrease in the number of c-Fos-positive cells surrounded by PNNs. Following removal of PNNs, the frequency of inhibitory currents in mPFC pyramidal neurons was decreased; but following cocaine-induced CPP, both frequency and amplitude of inhibitory currents were decreased. Our findings suggest that cocaine-induced plasticity is impaired by removal of prelimbic mPFC PNNs and that PNNs may be a therapeutic target for disruption of cocaine CPP memories.

Functional Connectivity Density and Balance in Young Patients with Traumatic Axonal Injury.

Our previous study provided some evidence for the relationship between abnormal structural connectivity and poor balance performance in young traumatic axonal injury (TAI) patients. An enhanced understanding of the functional connectivity following TAI may allow targeted treatments geared toward improving brain function and postural control. Twelve patients with TAI and 28 normally developing children (aged 9-19 years) performed the sensory organization test (SOT) protocol of the EquiTest (Neurocom). All participants were scanned using resting-state functional magnetic resonance imaging series along with anatomical scans. We applied "functional connectivity density mapping" (FCDM), a voxel-wise data-driven method that calculates individual functional connectivity maps to obtain both short-range and long-range FCD. Findings revealed that the TAI group scored generally lower than the control group on the SOT, especially when proprioceptive feedback was compromised. Between-group maps noted significantly decreased long-range FCD in the TAI group in frontal and subcortical regions and significantly increased short-range FCD in frontal regions, left inferior parietal, and cerebellar lobules. Moreover, lower balance levels in TAI patients were associated with a lower long-range FCD in left putamen and cerebellar vermis. These findings suggest that long-range connections may be more vulnerable to TAI than short-range connections. Moreover, higher values of short-range FCD may suggest adaptive mechanisms in the TAI group. Finally, this study supports the view that FCDM is a valuable tool for selectively predicting functional motor deficits in TAI patients.

Damage to the default mode network disrupts autobiographical memory retrieval.

Functional neuroimaging studies have implicated the default mode network (DMN) in autobiographical memory (AM). Convergent evidence from a lesion approach would help clarify the role of the DMN in AM. In this study, we used a voxelwise lesion-deficit approach to test the hypothesis that regions of the DMN are necessary for AM. We also explored whether the neural correlates of semantic AM (SAM) and episodic AM (EAM) were overlapping or distinct. Using the Iowa Autobiographical Memory Questionnaire, we tested AM retrieval in 92 patients with focal, stable brain lesions. In support of our hypothesis, damage to regions within the DMN (medial prefrontal cortex, mPFC; posterior cingulate cortex, PCC; inferior parietal lobule, IPL; medial temporal lobe, MTL) was associated with AM impairments. Within areas of effective lesion coverage, the neural correlates of SAM and EAM were largely distinct, with limited areas of overlap in right IPL. Whereas SAM deficits were associated with left mPFC and MTL damage, EAM deficits were associated with right mPFC and MTL damage. These results provide novel neuropsychological evidence for the necessary role of parts of the DMN in AM. More broadly, the findings shed new light on how the DMN participates in self-referential processing.

Network measures predict neuropsychological outcome after brain injury.

Hubs are network components that hold positions of high importance for network function. Previous research has identified hubs in human brain networks derived from neuroimaging data; however, there is little consensus on the localization of such hubs. Moreover, direct evidence regarding the role of various proposed hubs in network function (e.g., cognition) is scarce. Regions of the default mode network (DMN) have been frequently identified as "cortical hubs" of brain networks. On theoretical grounds, we have argued against some of the methods used to identify these hubs and have advocated alternative approaches that identify different regions of cortex as hubs. Our framework predicts that our proposed hub locations may play influential roles in multiple aspects of cognition, and, in contrast, that hubs identified via other methods (including salient regions in the DMN) might not exert such broad influence. Here we used a neuropsychological approach to directly test these predictions by studying long-term cognitive and behavioral outcomes in 30 patients, 19 with focal lesions to six "target" hubs identified by our approaches (high system density and participation coefficient) and 11 with focal lesions to two "control" hubs (high degree centrality). In support of our predictions, we found that damage to target locations produced severe and widespread cognitive deficits, whereas damage to control locations produced more circumscribed deficits. These findings support our interpretation of how neuroimaging-derived network measures relate to cognition and augment classic neuroanatomically based predictions about cognitive and behavioral outcomes after focal brain injury.

Axon plasticity in the mammalian central nervous system after injury.

It is widely recognized that severed axons in the adult central nervous system (CNS) have limited capacity to regenerate. However, mounting evidence from studies of CNS injury response and repair is challenging the prevalent view that the adult mammalian CNS is incapable of structural reorganization to adapt to an altered environment. Animal studies demonstrate the potential to achieve significant anatomical repair and functional recovery following CNS injury by manipulating axon growth regulators alone or in combination with activity-dependent strategies. With a growing understanding of the cellular and molecular mechanisms regulating axon plasticity, and the availability of new experimental tools to map detour circuits of functional importance, directing circuit rewiring to promote functional recovery may be achieved.

Damage to the Salience Network and interactions with the Default Mode Network.

Interactions between the Salience Network (SN) and the Default Mode Network (DMN) are thought to be important for cognitive control. However, evidence for a causal relationship between the networks is limited. Previously, we have reported that traumatic damage to white matter tracts within the SN predicts abnormal DMN function. Here we investigate the effect of this damage on network interactions that accompany changing motor control. We initially used fMRI of the Stop Signal Task to study response inhibition in humans. In healthy subjects, functional connectivity (FC) between the right anterior insula (rAI), a key node of the SN, and the DMN transiently increased during stopping. This change in FC was not seen in a group of traumatic brain injury (TBI) patients with impaired cognitive control. Furthermore, the amount of SN tract damage negatively correlated with FC between the networks. We confirmed these findings in a second group of TBI patients. Here, switching rather than inhibiting a motor response: (1) was accompanied by a similar increase in network FC in healthy controls; (2) was not seen in TBI patients; and (3) tract damage after TBI again correlated with FC breakdown. This shows that coupling between the rAI and DMN increases with cognitive control and that damage within the SN impairs this dynamic network interaction. This work provides compelling evidence for a model of cognitive control where the SN is involved in the attentional capture of salient external stimuli and signals the DMN to reduce its activity when attention is externally focused.

Psychosis-related matricide associated with a lesion of the ventromedial prefrontal cortex.

Matricide, the killing of a mother by her biological child, is a rare event. We report a case of matricide associated with a woman who sustained a right ventromedial prefrontal lesion during surgery for nasal polyposis that was performed when she was 40 years old. After her surgery, she developed psychotic symptoms associated with the emergence of antisocial behavior. She committed matricide 22 years later. Neuropsychological evaluation showed decreased frontal-executive deficits, and magnetic resonance imaging revealed a lesion in the right gyrus rectus area of the ventromedial prefrontal region. This case suggests that a secondary psychotic syndrome associated with a lesion in the frontal neural network, which is disturbed in psychopathy, could facilitate homicidal behavior. Furthermore, this case has legal implications for the prosecution of murder associated with a brain lesion.

Synaptic elimination and protection after minimal injury depend on cell type and their prelesion structural dynamics in the adult cerebral cortex.

The axonal and synaptic mechanisms underlying dysfunction and repair of the injured CNS are poorly understood. Unresolved issues include to what degree, when, and how the surviving neurons degenerate and the extent of synaptic remodeling both along the severed axon and in the nearby area. One of the main reasons is the lack of tools to study the complex asynchronous and dynamic features of individual lesioned axon responses in the intact brain. To address these issues, we combined two-photon microscopy and laser microsurgery to image the real-time reorganization of cortical circuitry at synaptic resolution for periods of up to 1 year in the brain of living mice. Injured cortical axons were eliminated proximally through a two-phase retraction process, which continued for at least 3 months postlesion and was independent of the presence of scar tissue. Remarkably, axons which later attempt to regenerate in both the mature and juvenile brain retracted less, raising the possibility that targeting retraction may improve the chances of axon regrowth after axotomy. Comparing prelesion and postlesion dynamics on the same axons over several days and weeks revealed that, although synapse formation rates were unaffected, boutons on injured axons were either rapidly and persistently lost, or extremely resistant, depending on cell-type and their prelesion structural dynamics. Our data suggest a lasting deficiency in synaptic output on surviving injured cortical axons and a surprising difference in the vulnerability of synaptic boutons after axotomy, which depend on cell-type and their recent history.

Motor primitives and synergies in the spinal cord and after injury--the current state of play.

Modular pattern generator elements, also known as burst synergies or motor primitives, have become a useful and important way of describing motor behavior, albeit controversial. It is suggested that these synergy elements may constitute part of the pattern-shaping layers of a McCrea/Rybak two-layer pattern generator, as well as being used in other ways in the spinal cord. The data supporting modular synergies range across species including humans and encompass motor pattern analyses and neural recordings. Recently, synergy persistence and changes following clinical trauma have been presented. These new data underscore the importance of understanding the modular structure of motor behaviors and the underlying circuitry to best provide principled therapies and to understand phenomena reported in the clinic. We discuss the evidence and different viewpoints on modularity, the neural underpinnings identified thus far, and possible critical issues for the future of this area.