Impact of Upper Limb Motor Recovery on Functional Independence After Traumatic Low Cervical Spinal Cord Injury.

Cervical spinal cord injury (SCI) causes devastating loss of upper limb function and independence. Restoration of upper limb function can have a profound impact on independence and quality of life. In low-cervical SCI (level C5-C8), upper limb function can be restored via reinnervation strategies such as nerve transfer surgery. The translation of recovered upper limb motor function into functional independence in activities of daily living (ADLs), however, remains unknown in low cervical SCI (i.e., tetraplegia). The objective of this study was to evaluate the association of patterns in upper limb motor recovery with functional independence in ADLs. This will then inform prioritization of reinnervation strategies focused to maximize function in patients with tetraplegia. This retrospective study performed a secondary analysis of patients with low cervical (C5-C8) enrolled in the SCI Model Systems (SCIMS) database. Baseline neurological examinations and their association with functional independence in major ADLs-i.e., eating, bladder management, and transfers (bed/wheelchair/chair)-were evaluated. Motor functional recovery was defined as achieving motor strength, in modified research council (MRC) grade, of ≥ 3 /5 at one year from ≤ 2/5 at baseline. The association of motor function recovery with functional independence at one-year follow-up was compared in patients with recovered elbow flexion (C5), wrist extension (C6), elbow extension (C7), and finger flexion (C8). A multi-variable logistic regression analysis, adjusting for known factors influencing recovery after SCI, was performed to evaluate the impact of motor function at one year on a composite outcome of functional independence in major ADLs. Composite outcome was defined as functional independence measure score of 6 or higher (complete independence) in at least two domains among eating, bladder management, and transfers. Between 1992 and 2016, 1090 patients with low cervical SCI and complete neurological/functional measures were included. At baseline, 67% of patients had complete SCI and 33% had incomplete SCI. The majority of patients were dependent in eating, bladder management, and transfers. At one-year follow-up, the largest proportion of patients who recovered motor function in finger flexion (C8) and elbow extension (C7) gained independence in eating, bladder management, and transfers. In multi-variable analysis, patients who had recovered finger flexion (C8) or elbow extension (C7) had higher odds of gaining independence in a composite of major ADLs (odds ratio [OR] = 3.13 and OR = 2.87, respectively, p < 0.001). Age 60 years (OR = 0.44, p = 0.01), and complete SCI (OR = 0.43, p = 0.002) were associated with reduced odds of gaining independence in ADLs. After cervical SCI, finger flexion (C8) and elbow extension (C7) recovery translate into greater independence in eating, bladder management, and transfers. These results can be used to design individualized reinnervation plans to reanimate upper limb function and maximize independence in patients with low cervical SCI.

Association of upper-limb neurological recovery with functional outcomes in high cervical spinal cord injury.

OBJECTIVE: High cervical spinal cord injury (SCI) results in complete loss of upper-limb function, resulting in debilitating tetraplegia and permanent disability. Spontaneous motor recovery occurs to varying degrees in some patients, particularly in the 1st year postinjury. However, the impact of this upper-limb motor recovery on long-term functional outcomes remains unknown. The objective of this study was to characterize the impact of upper-limb motor recovery on the degree of long-term functional outcomes in order to inform priorities for research interventions that restore upper-limb function in patients with high cervical SCI. METHODS: A prospective cohort of high cervical SCI (C1-4) patients with American Spinal Injury Association Impairment Scale (AIS) grade A-D injury and enrolled in the Spinal Cord Injury Model Systems Database was included. Baseline neurological examinations and functional independence measures (FIMs) in feeding, bladder management, and transfers (bed/wheelchair/chair) were evaluated. Independence was defined as score ≥ 4 in each of the FIM domains at 1-year follow-up. At 1-year follow-up, functional independence was compared among patients who gained recovery (motor grade ≥ 3) in elbow flexors (C5), wrist extensors (C6), elbow extensors (C7), and finger flexors (C8). Multivariable logistic regression evaluated the impact of motor recovery on functional independence in feeding, bladder management, and transfers. RESULTS: Between 1992 and 2016, 405 high cervical SCI patients were included. At baseline, 97% of patients had impaired upper-limb function with total dependence in eating, bladder management, and transfers. At 1 year of follow-up, the largest proportion of patients who gained independence in eating, bladder management, and transfers had recovery in finger flexion (C8) and wrist extension (C6). Elbow flexion (C5) recovery had the lowest translation to functional independence. Patients who achieved elbow extension (C7) were able to transfer independently. On multivariable analysis, patients who gained elbow extension (C7) and finger flexion (C8) were 11 times more likely to gain functional independence (OR 11, 95% CI 2.8-47, p < 0.001) and patients who gained wrist extension (C6) were 7 times more likely to gain functional independence (OR 7.1, 95% CI 1.2-56, p = 0.04). Older age (≥ 60 years) and motor complete SCI (AIS grade A-B) reduced the likelihood of gaining independence. CONCLUSIONS: After high cervical SCI, patients who gained elbow extension (C7) and finger flexion (C8) had significantly greater independence in feeding, bladder management, and transfers than those with recovery in elbow flexion (C5) and wrist extension (C6). Recovery of elbow extension (C7) also increased the capability for independent transfers. This information can be used to set patient expectations and prioritize interventions that restore these upper-limb functions in patients with high cervical SCI.

Clinically meaningful improvement in disabilities of arm, shoulder, and hand (DASH) following cervical spine surgery.

BACKGROUND CONTEXT: Patients with cervical spine disease suffer from upper limb disability. At present, no clinical benchmarks exist for clinically meaningful change in the upper limb function following cervical spine surgery. PURPOSE: Primary: to establish clinically meaningful metrics; the minimal clinically important difference (MCID) and substantial clinical benefit (SCB) of upper limb functional improvement in patients following cervical spine surgery. Secondary: to identify the prognostic factors of MCID and SCB of upper limb function following cervical spine surgery. STUDY DESIGN: Retrospective cohort study. PATIENT SAMPLE: Adult patients ≥18 years of age who underwent cervical spine surgery from 2012 to 2016. OUTCOME MEASURES: Patient-reported outcomes: Neck disability index (NDI) and Disabilities of Arm, Shoulder, and Hand (DASH). METHODS: MCID was defined as minimal improvement and SCB as substantial improvement in the DASH score at last follow-up. The anchor-based methods (ROC analyses) defined optimal MCID and SCB thresholds with area under curve (AUC) in discriminating improved vs. non-improved patients. The MCID was also calculated by distribution-based methods: half standard-deviation (0.5-SD) and standard error of the mean (SEM) method. A multivariable logistic regression evaluated the impact of baseline factors in achieving the MCID and SCB in DASH following cervical spine surgery. RESULTS: Between 2012 and 2016, 1,046 patients with average age of 57±11.3 years, 53% males, underwent cervical spine surgery. Using the ROC analysis, the threshold for MCID was -8 points with AUC of 0.73 (95% CI: 0.67-0.79) and the SCB was -18 points with AUC of 0.88 (95% confidence interval [CI]: 0.85-0.91). The MCID was -11 points by 0.5-SD and -12 points by SEM-method. On multivariable analysis, patients with myelopathy had lower odds of achieving MCID and SCB, whereas older patients and those with ≥6 months duration of symptoms had lower odds of achieving DASH MCID and SCB respectively. CONCLUSIONS: In patients undergoing cervical spine surgery, MCID of -8 points and SCB of -18 points in DASH improvement may be considered clinically significant. These metrics may enable evaluation of minimal and substantial improvement in the upper extremity function following cervical spine surgery.

In Vivo Imaging of Cerebrospinal Fluid Transport through the Intact Mouse Skull using Fluorescence Macroscopy.

Cerebrospinal fluid (CSF) flow in rodents has largely been studied using ex vivo quantification of tracers. Techniques such as two-photon microscopy and magnetic resonance imaging (MRI) have enabled in vivo quantification of CSF flow but they are limited by reduced imaging volumes and low spatial resolution, respectively. Recent work has found that CSF enters the brain parenchyma through a network of perivascular spaces surrounding the pial and penetrating arteries of the rodent cortex. This perivascular entry of CSF is a primary driver of the glymphatic system, a pathway implicated in the clearance of toxic metabolic solutes (e.g., amyloid-ß). Here, we illustrate a new macroscopic imaging technique that allows real-time, mesoscopic imaging of fluorescent CSF tracers through the intact skull of live mice. This minimally-invasive method facilitates a multitude of experimental designs and enables single or repeated testing of CSF dynamics. Macroscopes have high spatial and temporal resolution and their large gantry and working distance allow for imaging while performing tasks on behavioral devices. This imaging approach has been validated using two-photon imaging and fluorescence measurements obtained from this technique strongly correlate with ex vivo fluorescence and quantification of radio-labeled tracers. In this protocol, we describe how transcranial macroscopic imaging can be used to evaluate glymphatic transport in live mice, offering an accessible alternative to more costly imaging modalities.

When the air hits your brain: decreased arterial pulsatility after craniectomy leading to impaired glymphatic flow.

OBJECTIVECranial neurosurgical procedures can cause changes in brain function. There are many potential explanations, but the effect of simply opening the skull has not been addressed, except for research into syndrome of the trephined. The glymphatic circulation, by which CSF and interstitial fluid circulate through periarterial spaces, brain parenchyma, and perivenous spaces, depends on arterial pulsations to provide the driving force for bulk flow; opening the cranial cavity could dampen this force. The authors hypothesized that a craniectomy, without any other pathological insult, is sufficient to alter brain function due to reduced arterial pulsatility and decreased glymphatic flow. Furthermore, they postulated that glymphatic impairment would produce activation of astrocytes and microglia; with the reestablishment of a closed cranial compartment, the glymphatic impairment, astrocytic/microglial activation, and neurobehavioral decline caused by opening the cranial compartment might be reversed.METHODSUsing two-photon in vivo microscopy, the pulsatility index of cortical vessels was quantified through a thinned murine skull and then again after craniectomy. Glymphatic influx was determined with ex vivo fluorescence microscopy of mice 0, 14, 28, and 56 days following craniectomy or cranioplasty; brain sections were immunohistochemically labeled for GFAP and CD68. Motor and cognitive performance was quantified with rotarod and novel object recognition tests at baseline and 14, 21, and 28 days following craniectomy or cranioplasty.RESULTSPenetrating arterial pulsatility decreased significantly and bilaterally following unilateral craniectomy, producing immediate and chronic impairment of glymphatic CSF influx in the ipsilateral and contralateral brain parenchyma. Craniectomy-related glymphatic dysfunction was associated with an astrocytic and microglial inflammatory response, as well as with the development of motor and cognitive deficits. Recovery of glymphatic flow preceded reduced gliosis and return of normal neurological function, and cranioplasty accelerated this recovery.CONCLUSIONSCraniectomy causes glymphatic dysfunction, gliosis, and changes in neurological function in this murine model of syndrome of the trephined.

Aquaporin-4-dependent glymphatic solute transport in the rodent brain.

The glymphatic system is a brain-wide clearance pathway; its impairment contributes to the accumulation of amyloid-ß. Influx of cerebrospinal fluid (CSF) depends upon the expression and perivascular localization of the astroglial water channel aquaporin-4 (AQP4). Prompted by a recent failure to find an effect of Aqp4 knock-out (KO) on CSF and interstitial fluid (ISF) tracer transport, five groups re-examined the importance of AQP4 in glymphatic transport. We concur that CSF influx is higher in wild-type mice than in four different Aqp4 KO lines and in one line that lacks perivascular AQP4 (Snta1 KO). Meta-analysis of all studies demonstrated a significant decrease in tracer transport in KO mice and rats compared to controls. Meta-regression indicated that anesthesia, age, and tracer delivery explain the opposing results. We also report that intrastriatal injections suppress glymphatic function. This validates the role of AQP4 and shows that glymphatic studies must avoid the use of invasive procedures.

Transcranial optical imaging reveals a pathway for optimizing the delivery of immunotherapeutics to the brain.

Despite the initial promise of immunotherapy for CNS disease, multiple recent clinical trials have failed. This may be due in part to characteristically low penetration of antibodies to cerebrospinal fluid (CSF) and brain parenchyma, resulting in poor target engagement. We here utilized transcranial macroscopic imaging to noninvasively evaluate in vivo delivery pathways of CSF fluorescent tracers. Tracers in CSF proved to be distributed through a brain-wide network of periarterial spaces, previously denoted as the glymphatic system. CSF tracer entry was enhanced approximately 3-fold by increasing plasma osmolality without disruption of the blood-brain barrier. Further, plasma hyperosmolality overrode the inhibition of glymphatic transport that characterizes the awake state and reversed glymphatic suppression in a mouse model of Alzheimer's disease. Plasma hyperosmolality enhanced the delivery of an amyloid-ß (Aß) antibody, obtaining a 5-fold increase in antibody binding to Aß plaques. Thus, manipulation of glymphatic activity may represent a novel strategy for improving penetration of therapeutic antibodies to the CNS.

The Glymphatic System in Central Nervous System Health and Disease: Past, Present, and Future.

The central nervous system (CNS) is unique in being the only organ system lacking lymphatic vessels to assist in the removal of interstitial metabolic waste products. Recent work has led to the discovery of the glymphatic system, a glial-dependent perivascular network that subserves a pseudolymphatic function in the brain. Within the glymphatic pathway, cerebrospinal fluid (CSF) enters the brain via periarterial spaces, passes into the interstitium via perivascular astrocytic aquaporin-4, and then drives the perivenous drainage of interstitial fluid (ISF) and its solute. Here, we review the role of the glymphatic pathway in CNS physiology, the factors known to regulate glymphatic flow, and the pathologic processes in which a breakdown of glymphatic CSF-ISF exchange has been implicated in disease initiation and progression. Important areas of future research, including manipulation of glymphatic activity aiming to improve waste clearance and therapeutic agent delivery, are also discussed.

Understanding the functions and relationships of the glymphatic system and meningeal lymphatics.

Recent discoveries of the glymphatic system and of meningeal lymphatic vessels have generated a lot of excitement, along with some degree of skepticism. Here, we summarize the state of the field and point out the gaps of knowledge that should be filled through further research. We discuss the glymphatic system as a system that allows CNS perfusion by the cerebrospinal fluid (CSF) and interstitial fluid (ISF). We also describe the recently characterized meningeal lymphatic vessels and their role in drainage of the brain ISF, CSF, CNS-derived molecules, and immune cells from the CNS and meninges to the peripheral (CNS-draining) lymph nodes. We speculate on the relationship between the two systems and their malfunction that may underlie some neurological diseases. Although much remains to be investigated, these new discoveries have changed our understanding of mechanisms underlying CNS immune privilege and CNS drainage. Future studies should explore the communications between the glymphatic system and meningeal lymphatics in CNS disorders and develop new therapeutic modalities targeting these systems.

Why have we not yet developed a simple blood test for TBI?

In recent years, traumatic brain injury (TBI) has emerged as a rapidly growing public health challenge. Annually, approximately 1.7 million people will sustain a TBI in the USA and WHO has named TBI the leading cause of death and disability in young adults worldwide, predicting it will become the third leading cause of death in the general population by 2020. The medical community currently relies on clinical examination and various neuroimaging modalities for the diagnosis of TBI; however, these methodologies are often confounded by altered patient mental status and are particularly poor at identifying mild-to-moderate injury. Despite decades of basic and clinical research, and the identification of hundreds of biochemical markers, presently there is no blood test to objectively assess TBI severity. Recent work suggests treatment-induced variance in the brain's glymphatic clearance may be responsible for the breakdown between biomarker discovery and clinical translation.

Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system.

The nonspecific and variable presentation of traumatic brain injury (TBI) has motivated an intense search for blood-based biomarkers that can objectively predict the severity of injury. However, it is not known how cytosolic proteins released from traumatized brain tissue reach the peripheral blood. Here we show in a murine TBI model that CSF movement through the recently characterized glymphatic pathway transports biomarkers to blood via the cervical lymphatics. Clinically relevant manipulation of glymphatic activity, including sleep deprivation and cisternotomy, suppressed or eliminated TBI-induced increases in serum S100ß, GFAP, and neuron specific enolase. We conclude that routine TBI patient management may limit the clinical utility of blood-based biomarkers because their brain-to-blood transport depends on glymphatic activity.

Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury.

Traumatic brain injury (TBI) is an established risk factor for the early development of dementia, including Alzheimer's disease, and the post-traumatic brain frequently exhibits neurofibrillary tangles comprised of aggregates of the protein tau. We have recently defined a brain-wide network of paravascular channels, termed the "glymphatic" pathway, along which CSF moves into and through the brain parenchyma, facilitating the clearance of interstitial solutes, including amyloid-ß, from the brain. Here we demonstrate in mice that extracellular tau is cleared from the brain along these paravascular pathways. After TBI, glymphatic pathway function was reduced by ∼60%, with this impairment persisting for at least 1 month post injury. Genetic knock-out of the gene encoding the astroglial water channel aquaporin-4, which is importantly involved in paravascular interstitial solute clearance, exacerbated glymphatic pathway dysfunction after TBI and promoted the development of neurofibrillary pathology and neurodegeneration in the post-traumatic brain. These findings suggest that chronic impairment of glymphatic pathway function after TBI may be a key factor that renders the post-traumatic brain vulnerable to tau aggregation and the onset of neurodegeneration.

Impairment of paravascular clearance pathways in the aging brain.

OBJECTIVE: In the brain, protein waste removal is partly performed by paravascular pathways that facilitate convective exchange of water and soluble contents between cerebrospinal fluid (CSF) and interstitial fluid (ISF). Several lines of evidence suggest that bulk flow drainage via the glymphatic system is driven by cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular CSF pathways. The objective of this study was to evaluate whether the efficiency of CSF-ISF exchange and interstitial solute clearance is impaired in the aging brain. METHODS: CSF-ISF exchange was evaluated by in vivo and ex vivo fluorescence microscopy and interstitial solute clearance was evaluated by radiotracer clearance assays in young (2-3 months), middle-aged (10-12 months), and old (18-20 months) wild-type mice. The relationship between age-related changes in the expression of the astrocytic water channel aquaporin-4 (AQP4) and changes in glymphatic pathway function was evaluated by immunofluorescence. RESULTS: Advancing age was associated with a dramatic decline in the efficiency of exchange between the subarachnoid CSF and the brain parenchyma. Relative to the young, clearance of intraparenchymally injected amyloid-ß was impaired by 40% in the old mice. A 27% reduction in the vessel wall pulsatility of intracortical arterioles and widespread loss of perivascular AQP4 polarization along the penetrating arteries accompanied the decline in CSF-ISF exchange. INTERPRETATION: We propose that impaired glymphatic clearance contributes to cognitive decline among the elderly and may represent a novel therapeutic target for the treatment of neurodegenerative diseases associated with accumulation of misfolded protein aggregates.

Tree stand falls: A persistent cause of neurological injury in hunting.

AIM: To characterize and compare our current series of patients to prior reports in order to identify any changes in the incidence of neurological injury related to hunting accidents in Rochester, New York. METHODS: All tree stand-related injuries referred to our regional trauma center from September 2003 through November 2011 were reviewed. Information was obtained from the hospital's trauma registry and medical records were retrospectively reviewed for data pertaining to the injuries. RESULTS: Fifty-four patients were identified. Ninety-six percent of patients were male with a mean age of 47.9 years (range 15-69). The mean Injury Severity Score was 12.53 ± 1.17 (range 2-34). The average height of fall was 18.2 feet (range 4-40 feet). All patients fell to the ground with the exception of one who landed on rocks, and many hit the tree or branches on the way down. A reason for the fall was documented in only 13 patients, and included tree stand construction (3), loss of balance (3), falling asleep (3), structural failure (2), safety harness breakage (3) or light-headedness (1). The most common injuries were spinal fractures (54%), most commonly in the cervical spine (69%), followed by the thoracic (38%) and lumbar (21%) spine. Eight patients required operative repair. Head injuries occurred in 22%. Other systemic injuries include rib/clavicular fractures (47%), pelvic fractures (11%), solid organ injury (23%), and pneumothorax or hemothorax (19%). No patient deaths were reported. The average hospital length of stay was 6.56 ± 1.07 d. Most patients were discharged home without (72%) or with (11%) services and 17% required rehabilitation. CONCLUSION: Falls from hunting tree stands are still common, with a high rate of neurological injury. Compared to a decade ago we have made no progress in preventing these neurological injuries, despite an increase in safety advances. Neurosurgeons must continue to advocate for increased safety awareness and participate in leadership roles to improve outcomes for hunters.

Neurologic injury in snowmobiling.

BACKGROUND: Snowmobiles are increasingly popular recreational, all-terrain utility vehicles that require skill and physical strength to operate given their inherent maneuverability, acceleration, and top speed capabilities. These same characteristics increase the risk of injury with the operation of these vehicles, particularly neurological injury. We characterize our series of 107 patients involved in snowmobiling accidents. METHODS: From January 2004 to January 2012, all snowmobiling-related injuries referred to our regional trauma center were reviewed. Information had been recorded in the hospital's trauma registry and medical records were retrospectively reviewed for data pertaining to the injuries, with particular emphasis on neurological injuries and any associated details. RESULTS: A total of 107 patients were identified. Ninety percent of injured riders were male. The mean age was 34.4 years (range 10-70), with 7% younger than age 16. The mean Injury Severity Score was 12.0 ± 0.69 (range 1-34). Although not documented in all patients, alcohol use was found in 7.5% of the patients and drug use found in one patient. Documentation of helmet use was available for only 31 of the patients; of which 13% were not helmeted. Causes included being thrown, flipped, or roll-over (33%), striking a stationary object (27%), being struck by a snowmobile (9%), striking another snowmobile (5.5%) or a car, train, or truck (5.5%), being injured by the machine itself (9%), other (2%) or unspecified (18%). Head injuries occurred in 35% patients, including concussion, subarachnoid hemorrhage, subdural hematoma, contusion, and facial/skull fracture. Spinal fractures occurred in 21% of the patients. Fractures to the thoracic spine were the most common (50%), followed by the cervical (41%) and lumbar (36%) spine. There were also three brachial plexus injuries, one tibial nerve injury, and one internal carotid artery dissection. Average length of stay was 4.98 ± 0.56 days. Disposition was home (78%), home with services (12%), rehabilitation placement (9%), and one death. Details regarding other systemic injuries will also be reviewed. CONCLUSIONS: Snowmobiles are a significant source of multi-trauma, particularly neurological injury. Neurosurgeons can play key roles in advocating for neurological safety in snowmobiling.

Straight from the horse's mouth: neurological injury in equestrian sports.

OBJECTIVES: Equestrian sports can result in a variety of injuries to the nervous system due to many factors. We describe our series of 80 patients with injuries sustained during participation in equestrian sports. METHODS AND RESULTS: All patients seen at the regional trauma center with injuries associated with equestrian sports between 2003 and 2011 were reviewed; 80 patients were identified. Fifty-four per cent were female and the average age was 37 years (2·2-79·3). The mean injury severity score (ISS) was 9·9 ± 0·7. Only two patients had documented helmet use. Glasgow coma score (GCS) was 15 in 93% of patients. The most common neurosurgical injuries were to the cranial vault (28%), including concussions, intracranial hematomas and hemorrhages, and skull, facial, and spine fractures (10%), with the majority (63%) being transverse process fractures. The mechanisms of injury varied: 55% were kicked or stepped on, 28% were thrown or fell off, and 21% were injured by the horse falling on them. The causes ranged from carelessness and lack of attention to animal factors including inadequate training of horses and animal fear. Fourteen per cent required surgery. There were no mortalities and average length of stay was 3·7 ± 0·35 days. All patients were discharged home with 95% requiring no services. DISCUSSION: Equestrian sports convey special risks for its participants. With proper protection and precautions, a decrease in the incidence of central nervous system injuries may be achieved. Neurosurgeons can play key roles in advocating for neurologic safety in equestrian sports.

A novel technique for morphometric quantification of subarachnoid hemorrhage-induced microglia activation.

BACKGROUND: Subarachnoid hemorrhage (SAH) is a neurologic catastrophe and poor outcome is typically attributed to vasospasm; however, there is also evidence that SAH causes a pro-inflammatory state and these two phenomena may be interrelated. SAH causes activation of microglia, but the time course and degree of microglial activation after SAH and its link to poor patient outcome and vasospasm remains unknown. NEW METHOD: Transgenic mice expressing eGFP under the control of the CX3CR1 locus, in which microglia are endogenously fluorescent, were randomly assigned to control or SAH groups. Immunohistochemistry for CD-68 and CD-31 was performed at different time points after SAH. Using confocal microscopy and MatLab software, we have developed a novel technique to detect and quantify the stages of microglial activation and return to quiescence using an automated computerized morphometric analysis. RESULTS: We detected a statistically significant decrease in microglial process complexity 2 and 7 days following SAH. In addition, we detected a statistically significant increase in microglial domain volume 1 day following SAH; however, microglial domain volume returned to baseline by 2 days. COMPARISON WITH EXISTING METHOD: Most techniques for microglia assessment are qualitative, not quantitative, and are therefore inadequate to address the effects of anti-inflammatory drug treatment or other therapies after SAH. CONCLUSIONS: Using novel image analysis techniques we were able to reproducibly quantify activation of microglia following SAH, which will improve our ability to study the biology of microglial activation, and may ultimately improve management of disease progression and response to therapies directed at microglial activation.

The spectrum of neurobehavioral sequelae after repetitive mild traumatic brain injury: a novel mouse model of chronic traumatic encephalopathy.

There has been an increased focus on the neurological sequelae of repetitive mild traumatic brain injury (TBI), particularly neurodegenerative syndromes, such as chronic traumatic encephalopathy (CTE); however, no animal model exists that captures the behavioral spectrum of this phenomenon. We sought to develop an animal model of CTE. Our novel model is a modification and fusion of two of the most popular models of TBI and allows for controlled closed-head impacts to unanesthetized mice. Two-hundred and eighty 12-week-old mice were divided into control, single mild TBI (mTBI), and repetitive mTBI groups. Repetitive mTBI mice received six concussive impacts daily for 7 days. Behavior was assessed at various time points. Neurological Severity Score (NSS) was computed and vestibulomotor function tested with the wire grip test (WGT). Cognitive function was assessed with the Morris water maze (MWM), anxiety/risk-taking behavior with the elevated plus maze, and depression-like behavior with the forced swim/tail suspension tests. Sleep electroencephalogram/electromyography studies were performed at 1 month. NSS was elevated, compared to controls, in both TBI groups and improved over time. Repetitive mTBI mice demonstrated transient vestibulomotor deficits on WGT. Repetitive mTBI mice also demonstrated deficits in MWM testing. Both mTBI groups demonstrated increased anxiety at 2 weeks, but repetitive mTBI mice developed increased risk-taking behaviors at 1 month that persist at 6 months. Repetitive mTBI mice exhibit depression-like behavior at 1 month. Both groups demonstrate sleep disturbances. We describe the neurological sequelae of repetitive mTBI in a novel mouse model, which resemble several of the neuropsychiatric behaviors observed clinically in patients sustaining repetitive mild head injury.