Deficits In Sensorimotor Function Research Articles

Primary cilia signaling in astrocytes mediates development and regional-specific functional specification.

Astrocyte diversity is greatly influenced by local environmental modulation. Here we report that the majority of astrocytes across the mouse brain possess a singular primary cilium localized to the cell soma. Comparative single-cell transcriptomics reveals that primary cilia mediate canonical SHH signaling to modulate astrocyte subtype-specific core features in synaptic regulation, intracellular transport, energy and metabolism. Independent of canonical SHH signaling, primary cilia are important regulators of astrocyte morphology and intracellular signaling balance. Dendritic spine analysis and transcriptomics reveal that perturbation of astrocytic cilia leads to disruption of neuronal development and global intercellular connectomes in the brain. Mice with primary ciliary-deficient astrocytes show behavioral deficits in sensorimotor function, sociability, learning and memory. Our results uncover a critical role for primary cilia in transmitting local cues that drive the region-specific diversification of astrocytes within the developing brain.

Efficacy of novel SPAK inhibitor ZT-1a derivatives (1c, 1d, 1g & 1h) on improving post-stroke neurological outcome and brain lesion in mice

SPAK inhibitor ZT-1a was previously shown to be neuroprotective in murine ischemic stroke models. In this study, we further examined the efficacy of four ZT-1a derivatives (ZT-1c, -1d, -1g and -1h) on reducing stroke-induced sensorimotor function impairment and brain lesions. Vehicle control (Veh) or ZT-1 derivatives were administered via osmotic pump to adult C57BL/6J mice during 3–21 h post-stroke. Neurological behavior of these mice was assessed at days 1, 3, 5, and 7 post-stroke and MRI T2WI and DTI analysis was subsequently conducted in ex vivo brains. Veh-treated stroke mice displayed sensorimotor function deficits compared to Sham mice. In contrast, mice receiving ZT-1a derivatives displayed significantly lower neurological deficits at days 3–7 post-stroke (p < 0.05), with ZT-1a, ZT-1c and ZT-1d showing greater impact than ZT-1h and ZT-1g. ZT-1a treatment was the most effective in reducing brain lesion volume on T2WI and in preserving NeuN + neurons (p < 0.01), followed by ZT-1d > -1c > -1g > -1h. The Veh-treated stroke mice displayed white matter tissue injury, reflected by reduced fractional anisotropy (FA) or axial diffusivity (AD) values in external capsule, internal capsule and hippocampus. In contrast, only ZT-1a-as well as ZT-1c-treated stroke mice exhibited significantly higher FA and AD values. These findings demonstrate that post-stroke administration of SPAK inhibitor ZT-1a and its derivatives (ZT-1c and ZT-1d) is effective in protecting gray and white matter tissues in ischemic brains, showing a potential for ischemic stroke therapy development.

Amide Proton Transfer-Weighted Magnetic Resonance Imaging for Detecting Severity and Predicting Outcome after Traumatic Brain Injury in Rats.

After traumatic brain injury (TBI), early assessment of secondary injury severity is critically important for estimating prognosis and treatment stratification. Currently, secondary injury severity is difficult to estimate. The objective of this study was to investigate the capacity of non-invasive amide proton transfer-weighted (APTw) magnetic resonance imaging (MRI) techniques to assess TBI injury in different brain regions and predict long-term neurobehavior outcomes. Fifty-five male and female rats were subjected to a controlled cortical impact with one of three different impactor depths to produce different degrees of TBI. Multi-parameter MRI data were acquired on a 4.7-Tesla scanner at 1 h, 1 day, and 3 days. Immunofluorescence staining was used to detect activated microglia at 3 days, and neurobehavioral tests were performed to assess long-term outcomes after 28 days. The APTw signal in the injury core at 1 day correlated with deficits in sensorimotor function, the sucrose preference test (a test for anhedonia), and spatial memory function on the Barnes maze. The APTw signal in the perilesion ipsilateral cortex gradually increased after TBI, and the value at 3 days correlated with microglia density at 3 days and with spatial memory decline and anhedonia at 28 days. The correlation between APTw and activated microglia was also observed in the ipsilateral thalamus, and its correlation to memory deficit and depression was evident in other ipsilateral sites. These results suggest that APTw imaging can be used for detecting secondary injury and as a potential predictor of long-term outcomes from TBI.

Mild-to-Moderate Traumatic Brain Injury: A Review with Focus on the Visual System.

Traumatic Brain Injury (TBI) is a major global public health problem. Neurological damage from TBI may be mild, moderate, or severe and occurs both immediately at the time of impact (primary injury) and continues to evolve afterwards (secondary injury). In mild (m)TBI, common symptoms are headaches, dizziness and fatigue. Visual impairment is especially prevalent. Insomnia, attentional deficits and memory problems often occur. Neuroimaging methods for the management of TBI include computed tomography and magnetic resonance imaging. The location and the extent of injuries determine the motor and/or sensory deficits that result. Parietal lobe damage can lead to deficits in sensorimotor function, memory, and attention span. The processing of visual information may be disrupted, with consequences such as poor hand-eye coordination and balance. TBI may cause lesions in the occipital or parietal lobe that leave the TBI patient with incomplete homonymous hemianopia. Overall, TBI can interfere with everyday life by compromising the ability to work, sleep, drive, read, communicate and perform numerous activities previously taken for granted. Treatment and rehabilitation options available to TBI sufferers are inadequate and there is a pressing need for new ways to help these patients to optimize their functioning and maintain productivity and participation in life activities, family and community.

Interhemispheric Inhibition Between Primary Sensory Cortices is not Influenced by Acute Muscle Pain

Bilateral deficits in sensorimotor function have been observed in unilateral musculoskeletal pain conditions. Altered interhemispheric inhibition (IHI) between primary sensory cortices (S1s) is one mechanism that could explain this phenomenon. However, IHI between S1s in response to acute muscle pain, and the relationship between IHI and pressure pain sensitivity in the unaffected limb have not been examined. In 21 healthy individuals, IHI was assessed using somatosensory evoked potentials in response to paired median nerve electrical stimulation at: 1) baseline; 2) immediately following pain resolution; and 3) at 30-minutes follow-up. Acute muscle pain was induced by injection of hypertonic saline into the right abductor pollicis brevis (APB) muscle. Pressure pain thresholds were assessed at the right and left APB muscles before and 30-minutes after pain resolution. Compared to baseline, IHI from the affected to unaffected S1 was unaltered in response to acute muscle pain immediately following pain resolution, or at 30-minutes follow-up. Pressure pain thresholds were reduced over the right (P = .001) and left (P = .001) APB muscles at 30-minutes follow-up. These findings suggest IHI between S1s is unaffected by acute, short-lasting muscle pain, despite the development of increased sensitivity to pressure in the unaffected APB muscle. PerspectiveIHI from the affected S1 (contralateral to the side of pain) to unaffected S1 is unaltered following the resolution of acute muscle pain. This finding suggests that IHI between S1s may not be relevant in the development of bilateral sensorimotor symptoms in unilateral pain conditions.

The effect of exercise on early sensorimotor performance alterations in the 3xTg-AD model of Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by a progressive decline in cognitive function; however, recent evidence suggests that non-cognitive sensorimotor and psychomotor symptoms accompany early stages of the disease in humans and AD models. Although exercise is emerging as an important therapeutic to combat AD progression, little is known about the effect of exercise on sensorimotor domain functions. The purpose of this study was to determine if early sensorimotor symptoms accompany deficits in Morris water maze (MWM) performance in the 3xTg-AD model, and investigate if exercise could protect against early behavioral decline. 3xTg-AD and wild-type (WT) control mice were subjected to 12 weeks of moderate intensity wheel running or remained sedentary. At 6 months of age, animals underwent a series of sensorimotor and MWM testing. 3xTg-AD mice displayed deficits in sensorimotor function (beam traversal, spontaneous activity, and adhesive removal) and MWM performance. Interestingly, 3xTg-AD animals exhibited increased freezing and unusual shaking/tremoring behaviors not displayed by WT controls. Exercise improved beam traversal, adhesive removal, and reduced the unusual motor-related behaviors in 3xTg-AD mice. Our study shows that sensorimotor symptoms coincide with deficits in MWM performance, and suggest that exercise may mitigate deficits associated with early disease in 3xTg-AD mice.

Center of pressure (COP) measurement in patients with confirmed successful outcomes following shoulder surgery show significant sensorimotor deficits

PurposeTo determine the sensorimotor and clinical function of patients with confirmed successful outcome after either undergoing acromioclavicular joint (ACJ) stabilization, Bankart repair (BR), or rotator cuff repair (RC), and to compare these measures to the contralateral, healthy side without history of previous injuries or surgeries of the upper extremity. It was hypothesized that patients of each interventional group would have inferior sensorimotor function of the shoulder joint compared to the contralateral, healthy side, while presenting with successful clinical and functional outcomes.MethodsThree intervention groups including ten patients who had confirmed successful clinical and functional outcomes after either undergoing ACJ stabilization, BR, or RC were evaluated postoperatively at an average follow-up of 31.7 ± 11.6 months. Additionally, a healthy control group (CG) of ten patients was included. Clinical outcomes were assessed using the Constant–Murley (CM) and American Shoulder and Elbow Surgeons (ASES) Score. Pain was evaluated using the visual analogue scale (VAS). Sensorimotor function was assessed by determining the center of pressure (COP) of the shoulder joint in a one-handed support task in supine position on a validated pressure plate.ResultsEach interventional group demonstrated excellent clinical outcome scores including the CM Score (ACJ 83.3 ± 11.8; BR 89.0 ± 10.3; RC 81.4 ± 8.8), ASES Score (ACJ 95.5 ± 7.0; BR 92.5 ± 9.6; RC 96.5 ± 5.2), and VAS (ACJ 0.5 ± 0.9; BR 0.5 ± 0.8; RC 0.5 ± 0.8). Overall, the CG showed no significant side-to-side difference in COP, whereas the ACJ-group and the BR-group demonstrated significantly increased COP compared to the healthy side (ACJ 103 cm vs. 98 cm, p = 0.049; BR: 116 cm vs. 102 cm, p = 0.006). The RC-group revealed no significant side-to-side difference (120 cm vs. 108 cm, n.s.).ConclusionCentre of pressure measurement detected sensorimotor functional deficits following surgical treatment of the shoulder joint in patients with confirmed successful clinical and functional outcomes. This may indicate that specific postoperative training and rehabilitation protocols should be established for patients who underwent surgery of the upper extremity. These results underline that sensorimotor training should be an important component of postoperative rehabilitation and physiotherapeutic activities to improve postoperative function and joint control.Level of evidenceIV.

Intercellular Adhesion Molecule-1-Induced Posttraumatic Brain Injury Neuropathology in the Prefrontal Cortex and Hippocampus Leads to Sensorimotor Function Deficits and Psychological Stress.

Intercellular adhesion molecule-1 (ICAM-1) promotes adhesion and transmigration of circulating leukocytes across the blood-brain barrier (BBB). Traumatic brain injury (TBI) causes transmigrated immunocompetent cells to release mediators [function-associated antigen (LFA)-1 and macrophage-1 antigen (Mac-1)] that stimulate glial and endothelial cells to express ICAM-1 and release cytokines, sustaining neuroinflammation and neurodegeneration. Although a strong correlation exists between TBI-mediated inflammation and impairment in functional outcome following brain trauma, the role of ICAM-1 in impairing functional outcome by inducing neuroinflammation and neurodegeneration after TBI remains inconclusive. The experimental TBI was induced in vivo by fluid percussion injury (FPI; 10 and 20 psi) in wild-type (WT) and ICAM-1−/− mice and in vitro by stretch injury (3 psi) in brain endothelial cells. We manipulate ICAM-1 pharmacologically and genetically and conducted several biochemical analyses to gain insight into the mechanisms underlying ICAM-1-mediated neuroinflammation and performed rotarod, grid-walk, sucrose preference, and light-dark tests to assess functional outcome. TBI-induced ICAM-1-mediated neuroinflammation and cell death occur via LFA-1 or Mac-1 signaling pathways that rely on oxidative stress, matrix metalloproteinase (MMP), and vascular endothelial growth factor (VEGF) pathways. The deletion or blocking of ICAM-1 resulted in a better outcome in attenuating neuroinflammation and cell death as marked by the markers such as NF-kB, IL-1β, TNF-α, cleaved-caspase-3 (cl-caspase-3), Annexin V, and by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and Trypan blue staining. ICAM-1 deletion in TBI improves sensorimotor, depression, and anxiety-like behavior with significant upregulation of norepinephrine (NE), dopamine (DA) D1 receptor (DAD1R), serotonin (5-HT)1AR, and neuropeptide Y (NPY). This study could establish the significance of ICAM-1 as a novel therapeutic target against the pathophysiology to establish functional recovery after TBI.

Sensorimotor dysfunction in a mild mouse model of cortical contusion injury without significant neuronal loss is associated with increases in inflammatory proteins with innate but not adaptive immune functions.

Traumatic brain injury is a leading cause of mortality and morbidity in the United States. Acute trauma to the brain triggers chronic secondary injury mechanisms that contribute to long-term neurological impairment. We have developed a single, unilateral contusion injury model of sensorimotor dysfunction in adult mice. By targeting a topographically defined neurological circuit with a mild impact, we are able to track sustained behavioral deficits in sensorimotor function in the absence of tissue cavitation or neuronal loss in the contused cortex of these mice. Stereological histopathology and multiplex enzyme-linked immunosorbent assay proteomic screening confirm contusion resulted in chronic gliosis and the robust expression of innate immune cytokines and monocyte attractant chemokines IL-1β, IL-5, IL-6, TNFα, CXCL1, CXCL2, CXCL10, CCL2, and CCL3 in the contused cortex. In contrast, the expression of neuroinflammatory proteins with adaptive immune functions was not significantly modulated by injury. Our data support widespread activation of innate but not adaptive immune responses, confirming an association between sensorimotor dysfunction with innate immune activation in the absence of tissue or neuronal loss in our mice.

Slower reaction and response times and impaired hand-eye coordination in individuals with neck pain

BackgroundNeck pain is associated with sensorimotor dysfunction. Research is sparse of the effect of neck pain on reaction and response times and hand-eye coordination. ObjectivesTo investigate hand and foot reaction and response times and hand-eye coordination in individuals with neck pain and to determine any relationships with clinical features of neck pain. MethodsSixty individuals with neck pain and 60 controls of similar age and gender were recruited. Tests of simple reaction and response time were measured on the dominant hand and foot. Hand-eye coordination was measured by tracing a variety of coordination patterns with different levels of difficulty. Clinical features measured were intensity and duration of pain, and neck disability. ResultsHand and foot reaction and response times were significantly slower in the neck pain group compared to controls (all p < 0.001). The neck pain group took longer to trace the hand-eye coordination task at the hardest level (p = 0.03). Neck disability scores correlated with hand reaction time (r = 0.4, p = 0.005) and time taken in hand-eye coordination tasks (r = 0.2 for all levels, p < 0.05). Reaction and response times were correlated with time taken in the hand-eye coordination test (r = 0.2–0.4, p < 0.01). ConclusionsIndividuals with neck pain had slower hand and foot reaction and response times and impaired hand-eye coordination, suggesting deficits in sensorimotor function. Training speed, as a function of acuity, and hand-eye coordination might be considered in clinical assessment. Further research is needed to identify potential underlying mechanisms of the slower and less well coordinated movement.

Functional neuroimaging of sensorimotor cortices in postmenopausal women with type II diabetes.

.Significance: Deficits in sensorimotor function in persons with type II diabetes mellitus (PwDM) have traditionally been considered a result of peripheral nerve damage. Emerging evidence has suggested that factors outside of nerve damage due to type II diabetes mellitus, such as impaired hemodynamic function, contribute significantly to both sensory and motor deficits in PwDM.Aim: The focus of the current study was to evaluate functional cortical hemodynamic activity during sensory and motor tasks in PwDM.Approach: Functional near-infrared spectroscopy was used to monitor oxyhemoglobin (HbO) and deoxyhemoglobin (HbR) across the cortex during sensory and motor tasks involving the hands.Results: Decline in HbO across sensory and motor regions of interest was found in PwDM with simultaneous deficits in manual motor tasks, providing the first evidence of functional cortical hemodynamic activity deficits relating to motor dysfunction in PwDM. Similar deficits were neither specifically noted in HbR nor during evaluation of sensory function. Health state indices, such as , blood pressure, body mass index, and cholesterol, were found to clarify group effects.Conclusions: Further work is needed to clarify potential sex-based differences in PwDM during motor tasks as well as the root of reduced cortical HbO indices but unchanged HbR indices in PwDM.

Longitudinal Assessment of Sensorimotor Function after Controlled Cortical Impact in Mice: Comparison of Beamwalk, Rotarod, and Automated Gait Analysis Tests.

Traumatic brain injury (TBI) patients are reported to experience long-term sensorimotor dysfunction, with gait deficits evident up to 2 years after the initial brain trauma. Experimental TBI including rodent models of penetrating ballistic-like brain injury and severe controlled cortical impact (CCI) can induce impairments in static and dynamic gait parameters. It is reported that the majority of deficits in gait-related parameters occur during the acute phase post-injury, as functional outcomes return toward baseline levels at chronic time points. In the present study, we carried out a longitudinal analysis of static, temporal and dynamic gait patterns following moderate-level CCI in adult male C57Bl/6J mice using the automated gait analysis apparatus, CatWalk. For comparison, we also performed longitudinal assessment of fine-motor coordination and function in CCI mice using more traditional sensorimotor behavioral tasks such as the beamwalk and accelerating rotarod tasks. We determined that longitudinal CatWalk analysis did not detect TBI-induced deficits in static, temporal, or dynamic gait parameters at acute or chronic time points. In contrast, the rotarod and beamwalk tasks showed that CCI mice had significant motor function impairments as demonstrated by deficits in balance and fine-motor coordination through 28 days post-injury. Stereological analysis confirmed that CCI produced a significant lesion in the parietal cortex at 28 days post-injury. Overall, these findings demonstrate that CatWalk analysis of gait parameters is not useful for assessment of long-term sensorimotor dysfunction after CCI, and that more traditional neurobehavioral tests should be used to quantify acute and chronic deficits in sensorimotor function.

Concussion Recovery Evaluation Using the Inertial Sensor Instrumented Y Balance Test.

The current sports concussion assessment paradigm lacks reliability, has learning effects, and is not sufficiently challenging for athletes. As a result, subtle deficits in sensorimotor function may be unidentified, increasing the risk of future injury. This study examined if the inertial-sensor instrumented Y Balance test could capture concussion-induced alterations in dynamic movement control. A cohort of 226 elite Rugby Union, American football, and ice hockey athletes were evaluated using the inertial-sensor instrumented Y balance test. Dynamic balance performance was quantified using normalized reach distance, jerk magnitude root-mean-squared (Jerk Mag RMS), and gyroscope magnitude sample entropy (Gyro Mag SEn). Concussed athletes who consented to follow-up were evaluated 24 to 48 h post-injury, and at the point of return to full contact training (RTP). Seventeen athletes sustained a concussion and consented to both the 24- to 48-h and RTP follow-up testing. Twenty uninjured control athletes were re-tested 6 months following initial screening. Concussed athletes had reductions in normalized reach distance (Cohens D = 0.66-1.16) and Jerk Mag (Cohens D = 0.57-1.14) 24 to 48 h post-injury, which returned to pre-injury levels by the point of RTP. There was no significant difference in performance between the baseline and 6-month follow-up in the 20 uninjured athletes (Cohens D = 0.06-0.51). There was a statistically significant linear association between Jerk Mag RMS 24 to 48 h post-injury and the natural log of RTP duration (R2 = 0.27 to 0.33). These results indicate that concussed athletes possessed alterations in dynamic movement control 24 to 48 h post-concussion, which typically returns to pre-injury levels by the point of RTP. Further, evaluation of dynamic movement control 24 to 48 h post-injury may aid in the evaluation of recovery prognosis.

Interhemispheric Inhibition Is Reduced in Response to Acute Muscle Pain: A Cross-Sectional Study Using Transcranial Magnetic Stimulation

Bilateral deficits in sensorimotor function have been observed in unilateral musculoskeletal pain conditions. Evidence suggests a reduction in interhemispheric inhibition (IHI) from the “affected” (contralateral to the side of pain) to the “unaffected” primary motor cortex (M1) could contribute. However, the effect of short-lasting acute muscle pain on IHI, and whether any changes are related to early sensorimotor changes in the unaffected limb, is unknown. Using a cross-sectional study design, IHI was investigated in 20 healthy individuals before, immediately after, and 30 minutes after the induction of acute muscle pain in the right first dorsal interosseous muscle via a bolus injection of hypertonic saline. Transcranial magnetic stimulation was used to assess corticomotor excitability and short and long latency IHI. Pain intensity and quality were recorded using an 11-point numerical rating scale and the McGill Pain Questionnaire. Pressure pain thresholds were assessed in the affected and unaffected first dorsal interosseous and both tibialis anterior muscles. Participants reported an average pain intensity of 4.8 points (standard deviation = 1.3 points). Compared with baseline, corticomotor excitability was decreased at all time points in the affected but not the unaffected M1. IHI was decreased at all time points from the affected to the unaffected M1. Pressure pain thresholds were decreased over both first dorsal interosseous muscles at 30 minutes of follow-up. These findings suggest a decrease in IHI from the affected to the unaffected M1 that occurs rapidly after the onset of acute pain and could contribute to the development of bilateral symptoms. PerspectiveThe affected M1 (contralateral to the side of pain) releases inhibition over the unaffected M1 within minutes after the onset of acute muscle pain. This finding could have relevance for the development of bilateral sensorimotor symptoms in unilateral pain conditions.

Severe-combined immunodeficient rats can be used to generate a model of perinatal hypoxic-ischemic brain injury to facilitate studies of engrafted human neural stem cells.

Cerebral palsy (CP) encompasses a group of non-progressive brain disorders that are often acquired through perinatal hypoxic-ischemic (HI) brain injury. Injury leads to a cascade of cell death events, resulting in lifetime motor and cognitive deficits. There are currently no treatments that can repair the resulting brain damage and improve functional outcomes. To date, preclinical research using neural precursor cell (NPC) transplantation as a therapy for HI brain injury has shown promise. To translate this treatment to the clinic, it is essential that human-derived NPCs also be tested in animal models, however, a major limitation is the high risk of xenograft rejection. A solution is to transplant the cells into immune-deficient rodents, but there are currently no models of HI brain injury established in such a cohort of animals. Here, we demonstrate that a model of HI brain injury can be generated in immune-deficient Prkdc knockout (KO) rats. Long-term deficits in sensorimotor function were similar between KO and wildtype (WT) rats. Interestingly, some aspects of the injury were more severe in KO rats. Additionally, human induced pluripotent stem cell derived (hiPSC)-NPCs had higher survival at 10 weeks post-transplant in KO rats when compared to their WT counterparts. This work establishes a reliable model of neonatal HI brain injury in Prkdc KO rats that will allow for future transplantation, survival, and long-term evaluation of the safety and efficacy of hiPSC-NPCs for neonatal brain damage. This model will enable critical preclinical translational research using human NPCs.

Long-Lasting Effects of Prenatal Ethanol Exposure on Fear Learning and Development of the Amygdala

Prenatal ethanol exposure (PrEE) produces developmental abnormalities in brain and behavior that often persist into adulthood. We have previously reported abnormal cortical gene expression, disorganized neural circuitry along with deficits in sensorimotor function and anxiety in our CD-1 murine model of fetal alcohol spectrum disorders, or FASD (El Shawa et al., 2013; Abbott et al., 2016). We have proposed that these phenotypes may underlie learning, memory, and behavioral deficits in humans with FASD. Here, we evaluate the impact of PrEE on fear memory learning, recall and amygdala development at two adult timepoints. PrEE alters learning and memory of aversive stimuli; specifically, PrEE mice, fear conditioned at postnatal day (P) 50, showed deficits in fear acquisition and memory retrieval when tested at P52 and later at P70–P72. Interestingly, this deficit in fear acquisition observed during young adulthood was not present when PrEE mice were conditioned later, at P80. These mice displayed similar levels of fear expression as controls when tested on fear memory recall. To test whether PrEE alters development of brain circuitry associated with fear conditioning and fear memory recall, we histologically examined subdivisions of the amygdala in PrEE and control mice and found long-term effects of PrEE on fear memory circuitry. Thus, results from this study will provide insight on the neurobiological and behavioral effects of PrEE and provide new information on developmental trajectories of brain dysfunction in people prenatally exposed to ethanol.

Sensorimotor and executive function slowing in anesthesiology residents after overnight shifts

Study objectiveMedical residents working overnight call shifts experience sleep deprivation and circadian clock disruption. This leads to deficits in sensorimotor function and increases in workplace accidents. Using quick tablet-based tasks, we investigate whether measureable executive function differences exist following a single overnight call versus routine shift, and whether factors like stress, rest and caffeine affect these measures. DesignA prospective, observational, longitudinal, comparison study was conducted. SettingAn academic tertiary hospital's main operating room suite staffed by attending anesthesiologists, anesthesiology residents, anesthesiologist assistants and nurse anesthetists. PatientsSubjects were 30 anesthesiology residents working daytime shifts and 30 peers working overnight call shifts from the University of Texas Health Science Center at Houston. InterventionsBefore and after their respective work shifts, residents completed the Stanford Sleepiness Scale (SSS) and the ProPoint and AntiPoint tablet-based tasks. These latter tasks are designed to measure sensorimotor and executive functions, respectively. MeasurementsThe SSS is a self-reported measure of sleepiness. Response times (RTs) are measured in the pointing tasks. Main resultsCall residents exhibited increased RTs across their shifts (post–pre) on both ProPoint (p=0.002) and AntiPoint (p<0.002) tasks, when compared to Routine residents. Increased stress was associated with decreases in AntiPoint RT for Routine (p=0.007), but with greater increases in sleepiness for Call residents (p<0.001). Further, whether or not a Call resident consumed caffeine habitually was associated with ProPoint RT changes; with Call residents who habitually drink caffeine having a greater Pre-Post difference (i.e., more slowing, p<0.001) in ProPoint RT. ConclusionsThese results indicate that (1) overnight Call residents demonstrate both sensorimotor and cognitive slowing compared to routine daytime shift residents, (2) sensorimotor slowing is greater in overnight Call residents who drink caffeine habitually, and (3) increased stress during a shift reduces (improves) cognitive RTs during routine daytime but not overnight call shifts.

CD47 deficiency improves neurological outcomes of traumatic brain injury in mice

CD47 is a receptor for signal-regulatory protein alpha (SIRPα) in self-recognition by the innate immune system, and a receptor of thrombospondin-1 (TSP-1) contributing to vascular impairment in response to stress. However, the roles of CD47 in traumatic brain injury (TBI) have not been investigated. In this study we aimed to test our hypothesis that CD47 mediates early neutrophil brain infiltration and late brain vascular remodeling after TBI. Mice were subjected to TBI using a controlled cortical impact (CCI) device. We examined early phase neutrophil infiltration, and late phase brain vessel density, pro-angiogenic markers VEGF and Ang-1 protein expression, neurological function deficits and lesion volumes for up to three weeks after TBI. Our results show that mice deficient in CD47 (CD47 Knockout) had significantly less brain neutrophil infiltration at 24h, upregulated VEGF expression in peri-lesion cortex at 7 and 14days, and increased blood vessel density at 21days after TBI, compared to wild type (WT) mice. CD47 knockout also significantly decreased sensorimotor function deficits and reduced brain lesion volume at 21days after TBI. We conclude that CD47 may play pathological roles in brain neutrophil infiltration, progression of brain tissue damage, impairment of cerebrovascular remodeling and functional recovery after TBI.

P.1.j.016 - Spatial memory impairments following excitotoxic lesions of the basal forebrain noncholinergic neuronal ensembles

The previous articles in this series 4, 9 have shown that unilateral AMPA lesions of the nucleus basalis magnocellularis (nbm) produced widepread morphological and functional changes to the forebrain cholinergic projection system that could be reversed by transplants of fetal cholinergic tissue. At earlier postgraft time points, the effects of cholinergic grafts were specific to the neocortical region (frontal or parietal cortex) into which the grafts were targeted. Here we report that nbm lesion-induced spatial learning and memory deficits in the Morris water maze were reversed at 6–8 weeks postsurgery only by cholinergic grafts placed in the frontal cortex or frontal and parietal cortices combined. Similar grafts to parietal cortex only and noncholinergic fetal transplants to any cortical site were ineffective. In contrast, using separate groups of animals, deficits in sensorimotor function could be reversed in only one measure (open field turning) by cholinergic transplants targeted to the parietal (somatosensory) cortex or frontal and parietal cortex combined. These behavioural dissociations demonstrate that the frontal cortical cholinergic innervation from the nbm is necessary for effective spatial cognitive performance.

Etifoxine improves sensorimotor deficits and reduces glial activation, neuronal degeneration, and neuroinflammation in a rat model of traumatic brain injury.

BackgroundTraumatic brain injury (TBI) results in important neurological impairments which occur through a cascade of deleterious physiological events over time. There are currently no effective treatments to prevent these consequences. TBI is followed not only by an inflammatory response but also by a profound reorganization of the GABAergic system and a dysregulation of translocator protein 18 kDa (TSPO). Etifoxine is an anxiolytic compound that belongs to the benzoxazine family. It potentiates GABAergic neurotransmission, either through a positive allosteric effect or indirectly, involving the activation of TSPO that leads to an increase in neurosteroids synthesis. In several models of peripheral nerve injury, etifoxine has been demonstrated to display potent regenerative and anti-inflammatory properties and to promote functional recovery. Prior study also showed etifoxine efficacy in reducing brain edema in rats. In light of these positive results, we used a rat model of TBI to explore etifoxine treatment effects in a central nervous system injury, from functional outcomes to the underlying mechanisms.MethodsMale Sprague-Dawley rats received contusion (n = 18) or sham (n = 19) injuries centered laterally to bregma over the left sensorimotor cortex. They were treated with etifoxine (50 mg/kg, i.p.) or its vehicle 30 min following injury and every day during 7 days. Rats underwent behavioral testing to assess sensorimotor function. In another experiment, injured rats (n = 10) or sham rats (n = 10) received etifoxine (EFX) (50 mg/kg, i.p.) or its vehicle 30 min post-surgery. Brains were then dissected for analysis of neuroinflammation markers, glial activation, and neuronal degeneration.ResultsBrain-injured rats exhibited significant sensorimotor function deficits compared to sham-injured rats in the bilateral tactile adhesive removal test, the beam walking test, and the limb-use asymmetry test. After 2 days of etifoxine treatment, behavioral impairments were significantly reduced. Etifoxine treatment reduced pro-inflammatory cytokines levels without affecting anti-inflammatory cytokines levels in injured rats, reduced macrophages and glial activation, and reduced neuronal degeneration.ConclusionsOur results showed that post-injury treatment with etifoxine improved functional recovery and reduced neuroinflammation in a rat model of TBI. These findings suggest that etifoxine may have a therapeutic potential in the treatment of TBI.