Neuromotor Deficits Research Articles

Egg White Hydrolysate Mitigates Cadmium-induced Neurological Disorders and Oxidative Damage

We aimed to investigate whether the consumption of Egg White Hydrolysate (EWH) acts on nervous system disorders induced by exposure to Cadmium (Cd) in rats. Male Wistar rats were divided into (a) Control (Ct): H2O by gavage for 28 days + H2O (i.p. − 15th − 28th day); (b) Cadmium (Cd): H2O by gavage + CdCl2 − 1 mg/kg/day (i.p. − 15th − 28th day); (c) EWH 14d: EWH 1 g/kg/day by gavage for 14 days + H2O (i.p.- 15th − 28th day); (d) Cd + EWH cotreatment (Cd + EWHco): CdCl2 + EWH for 14 days; (e) EWH 28d: EWH for 28 days; (f) EWHpre + Cd: EWH (1st − 28th day) + CdCl2 (15th − 28th day). At the beginning and the end of treatment, neuromotor performance (Neurological Deficit Scale); motor function (Rota-Rod test); ability to move and explore (Open Field test); thermal sensitivity (Hot Plate test); and state of anxiety (Elevated Maze test) were tested. The antioxidant status in the cerebral cortex and the striatum were biochemically analyzed. Cd induces anxiety, and neuromotor, and thermal sensitivity deficits. EWH consumption prevented anxiety, neuromotor deficits, and alterations in thermal sensitivity, avoiding neuromotor deficits both when the administration was performed before or during Cd exposure. Both modes of administration reduced the levels of reactive species, and the lipid peroxidation increased by Cd and improved the striatum’s antioxidant capacity. Pretreatment proved to be beneficial in preventing the reduction of SOD activity in the cortex. EWH could be used as a functional food with antioxidant properties capable of preventing neurological damage induced by Cd.

Loss of SLC30A10 manganese transporter alters expression of neurotransmission genes and activates hypoxia-inducible factor signaling in mice.

The essential metal manganese (Mn) induces neuromotor disease at elevated levels. The manganese efflux transporter SLC30A10 regulates brain Mn levels. Homozygous loss-of-function mutations in SLC30A10 induce hereditary Mn neurotoxicity in humans. Our prior characterization of Slc30a10 knockout mice recapitulated the high brain Mn levels and neuromotor deficits reported in humans. But, mechanisms of Mn-induced motor deficits due to SLC30A10 mutations or elevated Mn exposure are unclear. To gain insights into this issue, we characterized changes in gene expression in the basal ganglia, the main brain region targeted by Mn, of Slc30a10 knockout mice using unbiased transcriptomics. Compared with littermates, >1000 genes were upregulated or downregulated in the basal ganglia sub-regions (i.e. caudate putamen, globus pallidus, and substantia nigra) of the knockouts. Pathway analyses revealed notable changes in genes regulating synaptic transmission and neurotransmitter function in the knockouts that may contribute to the motor phenotype. Expression changes in the knockouts were essentially normalized by a reduced Mn chow, establishing that changes were Mn dependent. Upstream regulator analyses identified hypoxia-inducible factor (HIF) signaling, which we recently characterized to be a primary cellular response to elevated Mn, as a critical mediator of the transcriptomic changes in the basal ganglia of the knockout mice. HIF activation was also evident in the liver of the knockout mice. These results: (i) enhance understanding of the pathobiology of Mn-induced motor disease; (ii) identify specific target genes/pathways for future mechanistic analyses; and (iii) independently corroborate the importance of the HIF pathway in Mn homeostasis and toxicity.

Patterned Sensory Enhancement, a Music Rehabilitation Therapy for Elderly Patients with Neuromotor Deficit during the COVID-19 Pandemic: A Pilot Study.

(1) Background: The Patterned Sensory Enhancement (PSE) technique refers to a music-based rehabilitation therapy strategy used in neurological pathologies. (2) Methods: This study aims at developing a music-drill protocol for recovery in elderly patients with neuromuscular degenerative pathologies. Each music drill is based on a number of specific music-composition parameters. The conclusions represent suggestions for further enhancing the PSE technique through collaborations between the rehabilitation team and the musicians involved due to the importance of the music stimuli used as a therapy. (3) Results: The music-composition parameters used in this study relate to the existence of music homogeneity factors such as the key signature and rhythm; the importance of the major scale and the tonal system in general; the obvious music suggestions of movement, repetition or absence of movement; the importance of rhythm; the introduction of musical instruments in order to harmonize the music material as much as possible; the connection between PSE music along with patients' musical taste and the musical recording as a therapy during patient outcare; (4) Conclusions: The therapy efficiency was observed by measurements taken before and after the therapeutic intervention by means of a Takei dynamometer. The present study asserts that for a patient undergoing the PSE technique, the researcher should compose personalized music material adapted to each patient's peculiarities.

Degenerative cervical myelopathy: establishing severity thresholds for neuromotor dysfunction in the aging spine using the NIH Toolbox Assessment Scale.

Degenerative cervical myelopathy (DCM) is a leading cause of age-related non-traumatic spinal cord disorders resulting from chronic degeneration of the cervical spine. While traditional clinical assessments rely on patient-reported measures, this study used the NIH Toolbox Motor Battery (NIHTBm) as an objective, quantitative measure to determine DCM severity. The objective is to define NIHTBm cutoff values that can accurately classify the severity of DCM neuromotor dysfunction. A case-controlled pilot study of patients with DCM and age-matched controls. The focus was an in-depth quantitative motor assessment using the NIHTBm to understand the severity of neuromotor deficits due to degenerative spine disease. Motor assessments, dexterity, grip strength, balance, and gait speed were measured in 45 DCM patients and 37 age-matched healthy subjects (HC). Receiver operating curve (ROC) analysis determined cutoff values for mild and moderate-to-severe myelopathy which were validated by comparing motor assessment scores with disability scores. The ROC curves identified thresholds for mild dexterity impairment (T-score range 38.4 - 33.5, AUC 0.77), moderate-to-severe dexterity impairment (< 33.5, AUC 0.70), mild grip strength impairment (47.4 - 32.0, AUC 0.80), moderate-to-severe grip strength impairment (< 32.0, AUC 0.75), mild balance impairment (36.4 - 33.0, AUC 0.61), and moderate-to-severe balance impairment (< 33.0, AUC 0.78). Mild gait speed impairment was defined as 0.78-0.6m/sec (AUC 0.65), while moderate-to-severe gait speed impairment was < 0.6m/sec (AUC 0.65). The NIHTB motor score cutoff points correlated negatively with the DCM neck disability index (NDI) and showed balance and dexterity measures as independent indicators of DCM dysfunction. The use of NIHTB allows for precise delineation of DCM severity by establishing cutoff values corresponding to mild and moderate-to-severe myelopathy. The use of NIHTB in DCM allows enhanced clinical precision, enabling clinicians to better pinpoint specific motor deficits in DCM and other neurological disorders with motor deficits, including stroke and traumatic brain injury (TBI). Furthermore, the utility of objective assessment, NIHTB, allows us to gain a better understanding of the heterogeneity of DCM, which will enhance treatment strategies. This study serves as a foundation for future research to facilitate the discovery of innovative treatment strategies for DCM and other neurological conditions.

Adjuvant Radiotherapy in Atypical Meningioma: Are the Risks Worth the Benefit?

Adjuvant radiotherapy (RT) improves progression-free survival (PFS) in atypical meningiomas. Herein, we assess whether the treatment-related acute and long-term toxicity of upfront RT in atypical meningioma patients versus surveillance merits the PFS benefit. In our prior single institution retrospective study of 230 patients with resected intracranial atypical meningiomas between 2000-2015, adjuvant RT was associated with a significantly lower risk of progression/recurrence compared to surveillance (HR = 0.21 [95% CI 0.11-0.41]; p<0.01), with 36% of surveillance patients eventually requiring salvage RT. In the current study, the acute (≤6 months) and long term (>6 months) RT-related toxicities from the same patient cohort for those who received adjuvant RT (n = 51) were evaluated and compared to those who received salvage RT (n = 64) in the surveillance group. Additionally, overall treatment-related toxicity at time of last follow up was obtained for comparison between the adjuvant RT (n = 51) vs surveillance (n = 179) group. All toxicities were graded per CTCAE v5.0. Kaplan-Meier analysis was used to calculate the cumulative incidence of toxicities; Pearson's chi-squared and log-rank test were used for comparison. Adjuvant RT as compared to salvage RT was generally associated with greater RT-related toxicities both in the acute (90% vs 69%, p = 0.006) and long term (57% vs 33%, p = 0.010). While there was no significant difference in grade 3-4 acute toxicities, long term grade 3-4 toxicities (including headache, seizure, vision loss, neuromotor deficit, and neurocognitive deficit) were present in 14% of adjuvant vs 3% of salvage RT group (p = 0.035). Radionecrosis occurred in 18% of adjuvant RT vs 8% of salvage RT group (p = 0.11). Between adjuvant RT vs surveillance groups, any-treatment related toxicity at last follow up was greater with adjuvant RT (31% vs 15%; p = 0.006), with trend towards greater grade 3-4 toxicities (including headache, vision loss, neuromotor deficit, neurocognitive deficit, and cerebral edema) as well (8% vs 3%; p = 0.101). Cumulative incidence of treatment-related neuromotor deficit (any grade) was significantly greater in the adjuvant RT vs surveillance group with 14% vs 2% at 10 years (p = 0.004). There was no difference in rate of cerebrovascular accident between adjuvant RT (6%) vs surveillance (4%) groups (p = 0.83). Adjuvant RT for patients with atypical meningioma was associated with greater acute and long-term treatment toxicities. Potential RT-related toxicity and impact on quality-of-life should thus be carefully weighed against the tumor control benefit of RT in deciding the optimal use and timing of RT.

Upper-Limb Rehabilitation of Patients with Neuromotor Deficits Using Impedance-Based Control of a 6-DOF Robot.

This paper presents a study on the use of impedance-based control of a 6-degree-of-freedom robot for upper-limb rehabilitation of patients with neuromotor deficits. The control strategy is based on impedance and does not require external force sensors at the end-effector for implementation. The experimental setup involved using the control algorithm to move the robot to a desired position, follow a desired trajectory while being moved out of the trajectory by the user, and reproduce three different rehabilitation exercises (passive, isometric, and ADL). The results suggest that the parameters of the control strategy can be adjusted to set the robot's compliance and support force according to the patient's needs. Ultimately, the study concluded that the proposed control strategy can serve as a foundation for rehabilitation robots, which could potentially improve access to continued upper-limb rehabilitation for stroke patients and reduce the number of healthcare professionals required per patient.Clinical Relevance- This paper proposes a human-robot interaction control scheme to be used in a robotic rehabilitation tool, with the goal of assisting both clinicians and patients during the rehabilitation exercises and ultimately reducing the load on healthcare system. This platform can be potentially used in telemedicine solutions for upper-limb rehabilitation of a wide range of patients with neuromotor deficits such as stroke.

Inherent Susceptibility to Acquired Epilepsy in Selectively Bred Rats Influences the Acute Response to Traumatic Brain Injury.

Traumatic brain injury (TBI) often causes seizures associated with a neuroinflammatory response and neurodegeneration. TBI responses may be influenced by differences between individuals at a genetic level, yet this concept remains understudied. Here, we asked whether inherent differences in one's vulnerability to acquired epilepsy would determine acute physiological and neuroinflammatory responses acutely after experimental TBI, by comparing selectively bred "seizure-prone" (FAST) rats with "seizure-resistant" (SLOW) rats, as well as control parental strains (Long Evans and Wistar rats). Eleven-week-old male rats received a moderate-to-severe lateral fluid percussion injury (LFPI) or sham surgery. Rats were assessed for acute injury indicators and neuromotor performance, and blood was serially collected. At 7 days post-injury, brains were collected for quantification of tissue atrophy by cresyl violet (CV) histology, and immunofluorescent staining of activated inflammatory cells. FAST rats showed an exacerbated physiological response acutely post-injury, with a 100% seizure rate and mortality within 24 h. Conversely, SLOW rats showed no acute seizures and a more rapid neuromotor recovery compared with controls. Brains from SLOW rats also showed only modest immunoreactivity for microglia/macrophages and astrocytes in the injured hemisphere compared with controls. Further, group differences were apparent between the control strains, with greater neuromotor deficits observed in Long Evans rats compared with Wistars post-TBI. Brain-injured Long Evans rats also showed the most pronounced inflammatory response to TBI across multiple brain regions, whereas Wistar rats showed the greatest extent of regional brain atrophy. These findings indicate that differential genetic predisposition to develop acquired epilepsy (i.e., FAST vs. SLOW rat strains) determines acute responses after experimental TBI. Differences in the neuropathological response to TBI between commonly used control rat strains is also a novel finding, and an important consideration for future study design. Our results support further investigation into whether genetic predisposition to acute seizures predicts the chronic outcomes after TBI, including the development of post-traumatic epilepsy.

SLC30A10 manganese transporter in the brain protects against deficits in motor function and dopaminergic neurotransmission under physiological conditions.

Loss-of-function mutations in SLC30A10 induce hereditary manganese (Mn)-induced neuromotor disease in humans. We previously identified SLC30A10 to be a critical Mn efflux transporter that controls physiological brain Mn levels by mediating hepatic and intestinal Mn excretion in adolescence/adulthood. Our studies also revealed that in adulthood, SLC30A10 in the brain regulates brain Mn levels when Mn excretion capacity is overwhelmed (e.g. after Mn exposure). But, the functional role of brain SLC30A10 under physiological conditions is unknown. We hypothesized that, under physiological conditions, brain SLC30A10 may modulate brain Mn levels and Mn neurotoxicity in early postnatal life because body Mn excretion capacity is reduced in this developmental stage. We discovered that Mn levels of pan-neuronal/glial Slc30a10 knockout mice were elevated in specific brain regions (thalamus) during specific stages of early postnatal development (postnatal day 21), but not in adulthood. Furthermore, adolescent or adult pan-neuronal/glial Slc30a10 knockouts exhibited neuromotor deficits. The neuromotor dysfunction of adult pan-neuronal/glial Slc30a10 knockouts was associated with a profound reduction in evoked striatal dopamine release without dopaminergic neurodegeneration or changes in striatal tissue dopamine levels. Put together, our results identify a critical physiological function of brain SLC30A10-SLC30A10 in the brain regulates Mn levels in specific brain regions and periods of early postnatal life, which protects against lasting deficits in neuromotor function and dopaminergic neurotransmission. These findings further suggest that a deficit in dopamine release may be a likely cause of early-life Mn-induced motor disease.

Thiolutin attenuates ischemic stroke injury via inhibition of NLRP3 inflammasome: an in vitro and in vivo study.

A recent study confirmed that thiolutin is effective in the treatment of nucleotide-binding domain-like receptor protein 3 (NLRP3)-related inflammatory diseases. Nevertheless, whether thiolutin (THL) is involved in the regulation of NLRP3 inflammasome in ischemic stroke is not known. The murine neuronal cell oxygen-glucose deprivation (OGD) model was first established, and then different concentrations (25nM and 50nM) of THL were administered for 48h incubation, respectively. Subsequently, cell viability and toxicity, and the levels of intracellular inflammatory factors interleukin-1β (IL-1β), interleukin-18 (IL-18), oxidative stress factors superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) and malondialdehyde (MDA), and NLRP3 inflammasome activation-related proteins pro-caspase, caspase-1, apoptosis-associated speck like-protein (ASC) and NLRP3 were examined, respectively. We further established the mouse middle cerebral artery occlusion (MCAO) model to evaluate the therapeutic effects of THL on cerebral infarction like behaviors in mice and the preventive effects on NLRP3 inflammasome activation in vivo. Cell cytotoxic, and the levels of inflammatory factors and oxidative stress were conspicuously increased, and NLRP3 inflammasome was materially activated in the OGD-induced cell model and MCAO-established mouse model, which were partially countered by THL treatment. Besides, intraperitoneal injection of THL could prominently reduce the cerebral infarct volume and neuromotor deficit scores in MCAO mice. The present study confirmed that THL attenuated neuronal and cerebral inflammatory injury caused by OGD and MCAO models in mice through restraining NLRP3 inflammasome activation in vitro and in vivo.

Suprafoveal condylar arthroplasty in unilateral disc displacement without reduction – A retrospective study

The aim of this study was to evaluate the efficacy of suprafoveal condylar arthroplasty (SFCA) in the management of patients with unilateral temporomandibular joint (TMJ) disc displacement without reduction (DDWoR). A retrospective study comprising patients who underwent unilateral SFCA for clinically and radiologically confirmed unilateral DDWoR from 2008 to 2020 was conducted. Patients older than 18 years at the time of diagnosis with a minimum of 6 months of unsuccessful non-surgical and minimally invasive management (including diet and life style modification, physiotherapy, appliance therapy, pharmacotherapy, arthrocentesis and arthroscopic lysis and lavage) before undergoing surgery with a minimum of 1 year follow-up post-surgery were included in the study. Patients with other articular and extra-articular causes of restricted mouth opening, prior history of mandibular surgery and/or trauma, growth abnormalities, systemic, metabolic, infective, neoplastic conditions affecting TMJ, including gross occlusal disharmony, untreated existing para-functional habits and bilateral DDWoR, were excluded from the study. Patients were assessed in terms pain on a visual analog scale (VAS), interincisal mouth opening (MO) and subjective assessment of mandibular range of movements including deviation of mouth opening, protrusion and ability for contralateral laterotrusion. 23 patients (10 males and 13 female) were included in the study, with a mean age of 35.09 years and mean follow up period of 37.7 months (range = 12–58; SD = 15.3). The mean pain scores on the VAS reduced from 6.35 preoperatively to 1.13 postoperatively and were found to be statistically significant (p < 0.0001). The improvement of the mean pre-operative mouth opening of 21.83 mm to a mean post-operative mouth opening of 42.09 mm was also found to be statistically significant (p < 0.0001). The subjective improvement in protrusive (p = 0.0003), laterotrusive (p = 0.0005) and opening movements (p = 0.0001) after 1 year were also found to be statistically significant. No patient developed any significant changes in occlusion post-operatively. Four of 23 (17.3%) patients developed transient neuromotor deficit of the temporal branch of the facial nerve. Within the limitations of the study, it seems that SFCA (without addressing the disc) might be an alternative to less invasive treatment approaches, if the latter turned out not to be successful.

Identification of risk factors in pre-term infants with abnormal general movements.

This study aimed to investigate the relationship between prenatal, perinatal, and postnatal risk factors for neurodevelopmental impairment (NDI) with the outcomes of General Movement (GM) Assessment (GMA) in pre-term infants at 3-5 months of age. We sought to identify the risk factors associated with the predictors of psychomotor development in pre-term newborns, such as normal fidgety movements (FMs), absent FMs, or abnormal FMs, assessed during the fidgety period of motor development. The SYNAGIS program (prophylactic of Respiratory Syncytial Virus Infection) was used to identify risk factors for the development of neuromotor deficits in 164 pre-term infants who were at high risk of developing these deficits. Based on the GMA, all participants were divided into three groups of infants who presented: (1) normal FMs; (2) absent FMs; and (3) abnormal FMs. The results of the current study suggest that abnormal GMs not only indicate commonly known factors like birth asphyxia (BA), respiratory distress syndrome (RDS), periventricular leukomalacia (PVL), intraventricular hemorrhage (IVH) grades 3-4, but also predict the development of motor impairments. In the present study, several specific risk factors including bronchopulmonary dysplasia (BPD), infertility treatments, maternal acute viral/bacterial infections during pregnancy, and elevated bilirubin levels were identified as attributes of an atypical fidgety movement pattern. Additional clinical data, such as risk factors for NDI associated with early predictors of psychomotor development in pre-term newborns, i.e., absent or abnormal FMs, may be helpful in predicting neurological outcomes in pre-term infants with developmental concerns in the 1st month of life.

Neuromotor deficits and altered physiological responses to repeated exertional heat stroke exposures in mice.

Exertional heat stroke (EHS) is a life-threatening illness that can lead to negative health outcomes. Using a "severe" preclinical mouse model of EHS, we tested the hypotheses that one EHS exposure results in altered susceptibility to a subsequent EHS and reduced neuromotor performance. Female C57BL/6 mice underwent two protocols, 2 wk apart, either an EHS trial (EHS) or a sham exercise control trial (EXC). For EHS, mice ran in a forced running wheel at 37.5°C/40% relative humidity until loss of consciousness, followed by a slow cooling protocol (2 h recovery at 37.5°C). EXC mice exercised equally but in ∼22°C. Mice were randomized into three groups: 1) EXC-EXC (two consecutive EXC, n = 6, 2) EHS-EXC (EHS followed by EXC, n = 5), and 3) EHS-EHS (repeated EHS, n = 9). Mice underwent noninvasive neuromotor and behavioral tests during recovery and isolated soleus force measurements at the end of recovery. At the first EHS, mice reached average peak core temperatures (Tc,max) of 42.4°C, (46% mortality). On the second EHS, average Tc,max was reduced by ∼0.7°C (P < 0.05; mortality 18%). After the first EHS, both EHS-EX and EHS-EHS showed significant reductions in maximum strength (24 h and 1 wk post). After the second EHS, strength, horizontal rotation, hindlimb tone, suspended hindlimb splay, trunk curl, and provoked biting continued to decline in the EHS-EHS group. In conclusion, exposure to a second EHS after 2 wk leads to increased exercise times in the heat, symptom limitation at a lower Tc,max, and greater deficits in neuromotor and behavioral function during recovery.

Rapid Synthesis of the Literature on the Evolution of Gamification in Distal Radial Fracture Rehabilitation.

Distal radial fractures (DRF) are often encountered in upper limb fractures globally, and their associated complications affect the functional independence of the individual following the injury. The potential of gamification in applied rehabilitation is expanding its horizons in the rehabilitation of conditions ranging from neuromotor deficits to cognitive impairments. However, the synthesis of the literature is aimed at analyzing and summarizing the evolution of gamification in DRF rehabilitation. A comprehensive search and extraction of relevant literature were conducted and reviewed for the applicability of population analysis, interventional methodology, comparative factors, outcome measures, and the type of study. Thirteen studies were included and evaluated, including randomized controlled trials (RCTs), literature reviews, systematic reviews, meta-analyses, and bibliometric analyses. The conclusions demonstrated an improvement with gamification and addressed it as an effective rehabilitation method. Based on the analysis of the data that was extracted, the conclusion supports the use of gamification in the rehabilitation of DRF and looks into how it can help improve the person's functional capacity.

Modified Kickstand Rod Technique for the Correction of Adult Idiopathic Scoliosis

Adult idiopathic scoliosis (ADIS) is the delayed form of adolescent idiopathic scoliosis (AIS) which is defined as a three-dimensional deformity with a lateral curvature of more than 10°in adults with prior history of AIS.Surgery is necessary for patients with symptoms of chronic pain, neuromotor deficits and cardiopulmonary problems with a Cobb angle exceeding 45°. In untreated patients, AIS may lead to ADIS which can cause serious problems like osteoarthritis, progressive deformity and spinal stenosis. In recent years, the kickstand rod technique has been introduced in addition to posterior transpedicular stabilization.A kickstand rod is an additional rod which is placed on a supporting iliac screw which is placed on the superior lateral edge of the ilium on the concave side of the deformity (or in other words on the ipsilateral side of the trunk shift)and is connected with a domino connector to the thoracolumbar junction.The rod is then distracted with the screw nuts locked on the contralateral side to achieve coronal correction. The classic kickstand works as a an additional aid to keep the spine in place during maneuvering.We established a modified kickstand rod technique where we put the rod on the concave side and apply compressionbetween the rod on the screw heads and the kickstandto bring the concavity to the midline.The kickstand was used as a temporary tool like a lever to push the spine medially with compression. We believe that our technique can be a useful alternative for correction of coronal imbalance besides the classic one.

Neuromotor Development in the Shank3 Mouse Model of Autism Spectrum Disorder.

Although autism spectrum disorder (ASD) is mainly characterized by developmental delay in social and communication skills, it has been shown that neuromotor deficits are an early component of ASD. The neuromotor development of B6.129-Shank3tm2Gfng/J (Shank3B−/−) mice as an animal model of autism has not been analyzed yet. The aim of this study was to compare the early neuromotor development of Shank3B−/− to wild-type mice. The mice underwent a multitude of neurodevelopmental tests and observations from postnatal day 1 (PND = 1) to weaning. Shank3B−/− mice opened their eyes later than their wild-type litter mates (p < 0.01). Shank3B−/− mice were also slower in the negative geotaxis test from PND = 13 to PND = 16 (p < 0.001) in both sexes. The results of this study indicate neurodevelopmental deficits in Shank3B−/− mice. The test is partially dependent on truncal motor control, and these lines of evidence suggest a phenotype of developmental hypotonia, which corresponds with the phenotypes seen in patients with Phelan-McDermid Syndrome. There was no observable effect of sex in any of the tests. There were no observed differences in upper and lower incisor eruption, ear unfolding, air righting, surface righting and ear twitch reflexes. Further studies should prove whether the delay in neuromotor development is linked to social or communication deficits, and thus, whether it may serve as an early indicator of autistic-like phenotype in mice.

Traumatic Lower Extremity Vascular Injuries and Limb Salvage in a Civilian Urban Trauma Center

Data on management of traumatic lower extreity arterial injuries comes largely from military experience and involves few civilian centers. This study reports on the experience of an urban trauma center and factors associated with limb loss. A retrospective review of lower extremity arterial injuries between 2013 and 2020 at an academic urban level 1 trauma center was completed. Patients with lower extremity revascularization were included in the final data analysis. Demographics, clinical variables, operative details, type of revascularization, as well as 30-day morbidity and postoperative outcomes were analyzed. The primary outcome of interest was 30-day limb loss. Secondary outcomes included postoperative complications and functional outcomes. Seventy-five patients were included in our analysis. Sixty-nine were male (92%), mean age 33 ± 15 years, 50 patients had penetrating trauma (67%), mean injury severity score was 15 ± 9. Thirty-day limb loss was reported in 8 (11%). Factors associated with limb loss included female sex (P=0.001), high body mass index (P=0.001), blunt injury (P=0.001), associated fractures (P=0.005), significant soft tissue injury (P=0.007), delayed repair after shunt placement (P=0.003), bypass revascularization (P=0.001), initial revascularization failure (P=0.019), and wound complications (P < 0.001). Fifty-five patients had at least one return to the operating room (ROR), including 24 patients (32%) for complications related to their revascularization. These included delayed compartment syndrome (n=7), revascularization failure (n=9), bleeding (n=3), and vascular surgical wound complications (n=5). Mean length of hospital stay (LOS) for the cohort was 24 ± 20 days with 3 ± 3 ROR, in contrast patients who ultimately required amputation had LOS of 57 ± 21 days with 8 ± 4 ROR. Fifty-seven patients (76%) followed in clinic for a median 36 [14-110] days, with only 32 (43%) at >30 days. Twenty-three reported ambulation without assistance, 9 neuromotor deficit including 1 patient that had delayed amputation. Patients with blunt trauma and associated fracture and/or extensive soft tissue injury are at risk of limb loss. These injuries are often associated with postoperative wound complications, requiring aggressive soft tissue care that substantially increases ROR and LOS; Expectations for limb salvage in these patients should be tempered when the other associated factors with limb loss mentioned above are also present. When limb salvage is achieved, regaining full limb function remains a challenge.

Characterizing Cycling Smoothness and Rhythm in Children With and Without Cerebral Palsy.

Stationary cycling is a practical exercise modality in children with cerebral palsy (CP) that lack the strength for upright exercises. However, there is a lack of robust, sensitive metrics that can quantitatively assess the motor control during cycling. The purpose of this brief report was to characterize the differences in motor control of cycling in children with CP and with typical development by developing novel metrics to quantify cycling smoothness and rhythm. Thirty one children with spastic diplegic CP and 10 children with typical development cycled on a stationary cycle. Cycling smoothness was measured by cross-correlating the crank angle with an ideal cycling pattern generated from participant-specific cadence and cycling duration. Cycling rhythmicity was assessed by evaluating the revolution-to-revolution variability in the time required to complete a revolution. Statistically significant differences (p < 0.001) using the Wilcoxon Rank Sum test were found between the two groups for both the metrics. Additionally, decision tree analysis revealed thresholds of smoothness <0.01 and rhythm <0.089–0.115 s for discriminating a less smooth, irregular cycling pattern characteristic of CP from typical cycling. In summary, the objective measures developed in this study indicate significantly less smoothness and rhythm of cycling in children with CP compared to children with typical development, suggestive of altered coordination and poor motor control. Such quantitative assessments of cycling motion in children with CP provide insights into neuromotor deficits that prevent them from cycling at intensities required for aerobic benefits and for participating in cycling related physical activities with their peers.

A-64 Neuropsychological Assessment in Bilateral Perisylvian Polymicrogyria: A Tool for Data-Driven Intervention

Abstract Objective This case study examined neurocognitive features associated with a rare genetic/neurological disorder impacting the cerebral cortex. Bilateral perisylvian polymicrogyria (BPP) is characterized by abnormal embryonic growth affecting both sides of the brain near the Sylvian fissure. BPP occurs randomly though researchers suspect an underlying genetic abnormality that may have autosomal recessive inheritance. Neurodevelopmental manifestations include neurocognition marked by EEG abnormalities, impaired motor function, and deficits in speech articulation, language development, learning and memory, and adaptive skills. Method A 13-year 7-month-old male with BPP, detected at 24 months by MRI, was seen for neuropsychological assessment to guide habilitative, academic and adaptive interventions. Relevant medical history includes stimulant medication and pharyngeal flap surgery. Parental concerns include the provision of appropriate special education services and withdrawal behaviors. Results Assessment revealed a complex neuropsychological profile characterized by nonverbal versus verbal intellectual strengths, receptive-expressive language impairment, underlying deficits in phonemic awareness, diminished fine motor speed, and diminished verbal fluency. Verbal list learning, semantic memory, and attention were intact. Mild elevations were evident for anxiety symptoms. Conclusion BPP, a rare genetic disorder, represents significant challenges for affected children. In this case study, a 13-year 7-month-old youngster’s assessment revealed underlying neurocognitive and neuromotor deficits most pronounced in aspects of language, speech articulation, select domains of executive functioning and academic skills. Areas of strength, including verbal memory and semantic recall, were indicated and merit consideration in developing appropriate interventions. This case study illustrates the value of neuropsychological assessment in guiding therapeutic interventions, pharmacotherapy, and appropriate educational services in this rare neurological disorder.

Up-regulation of the manganese transporter SLC30A10 by hypoxia-inducible factors defines a homeostatic response to manganese toxicity

Manganese (Mn) is an essential metal that induces incurable parkinsonism at elevated levels. However, unlike other essential metals, mechanisms that regulate mammalian Mn homeostasis are poorly understood, which has limited therapeutic development. Here, we discovered that the exposure of mice to a translationally relevant oral Mn regimen up-regulated expression of SLC30A10, a critical Mn efflux transporter, in the liver and intestines. Mechanistic studies in cell culture, including primary human hepatocytes, revealed that 1) elevated Mn transcriptionally up-regulated SLC30A10, 2) a hypoxia response element in the SLC30A10 promoter was necessary, 3) the transcriptional activities of hypoxia-inducible factor (HIF) 1 or HIF2 were required and sufficient for the SLC30A10 response, 4) elevated Mn activated HIF1/HIF2 by blocking the prolyl hydroxylation of HIF proteins necessary for their degradation, and 5) blocking the Mn-induced up-regulation of SLC30A10 increased intracellular Mn levels and enhanced Mn toxicity. Finally, prolyl hydroxylase inhibitors that stabilize HIF proteins and are in advanced clinical trials for other diseases reduced intracellular Mn levels and afforded cellular protection against Mn toxicity and also ameliorated the in vivo Mn-induced neuromotor deficits in mice. These findings define a fundamental homeostatic protective response to Mn toxicity-elevated Mn levels activate HIF1 and HIF2 to up-regulate SLC30A10, which in turn reduces cellular and organismal Mn levels, and further indicate that it may be possible to repurpose prolyl hydroxylase inhibitors for the management of Mn neurotoxicity.

Allogenic C57B/6->B6D2F1 Transplantation As a Model for Graft Versus Host Disease in the Brain

Bone marrow transplants are a common and reliable treatment for many disorders; however, in roughly 50% of patients, graft versus host disease (GvHD) occurs, causing significant morbidity and mortality. GvHD is an immune mediated disorder in which donor T cells recognize host antigens as foreign, causing donor T cells to proliferate and attack healthy host tissue. Though the pathogenesis of GvHD in organs such as the skin and colon has been well-documented, little is known about the effects of GvHD on the brain. Some clinical case studies have associated extensive neurological issues with onset of GvHD, with symptoms such as seizures, cognitive dysfunction, and cerebellar impairment including hemiparesis. Yet research involving the brain in GvHD lags behind research in other tissues. Our lab, working with a MHCII mismatched GvHD murine model, has studied GvHD in the brain in an effort to better understand the neurological effects of GvHD.It has been established that an increase in CD4+ and CD8+ T cells in GvHD causes much of the autoimmune reaction associated with the disease. Because of this, we sought to determine if these cell types infiltrate the brain, and if so, where. Using histochemical staining in a C57BL/6->B6D2F1 model (syngenically transplanted B6D2F1 mice were healthy controls), we saw significantly increased populations of CD3+ T cells (p<0.0001) in perivascular, periventricular, and meningeal locations. CD3+ cells are rarely observed in healthy mice and indicate an abnormal immune response in the brain. There was a significant increase in CD8+ (p=0.0316), but not in CD4+, cell counts in brains of GvHD mice as compared to brains of healthy control mice. These T cell populations were not found in parenchymal locations except proximal to micro vessels. The location of infiltrating T cells suggests that the epithelial cells lining neural blood vessels and the ependymal cells lining the ventricles are likely the target of inflammatory attack.Since an increase in CD8+ T cell populations suggests a pro-inflammatory Th1 immune response, we also investigated B226+ (B-cell) and IBA1+ (macrophage/microglia) cell populations in the brain. B-cells are associated with a Th2 response, while Th1 responses increase IBA1+ cell populations. We found no increase in numbers of B226+ cells in GvHD vs healthy mice, but found a significant increase in the number of IBA1+ cells (p<0.0001) in brains of GvHD mice, indicative of a Th1 immune response. Further, using a luminex multiplex assay, we found decreased serum levels of IL-4 (p = 0.0011) as well as increased levels of VEGF (p=0.0012) and ICAM-1 (p=0.0222) in GvHD mice as compared to healthy controls. The decreased level of IL-4 is consistent with the activation of a Th1 response and suppression of an anti-inflammatory Th2 response. The increase in ICAM-1, a molecule that regulates vascular permeability, indicates that GvHD induces increases in proteins important to vascular integrity, possibly allowing T cells to enter the brain via the blood brain barrier. Past studies have found increased levels of VEGF, and likewise of angiogenesis, in other organs affected by GVHD. Interestingly there is often a spike in VEGF-A levels following central nervous system injury, and the increase observed in our GvHD model may be a result of GvHD injury to the brain.Finally, since behavioral changes are often the first indicator of neurological involvement in GvHD, we wanted to assess whether our GvHD mouse model showed any notable changes in behavior. We found no motor deficits as measured through inverted grid and pole walk, nor did we see any difference in Morris Water Maze learning and recall between GvHD and control mice. However, we saw slower swimming speeds for GvHD mice (p<0.0001), correlating with signs of generalized somatic illness associated with GvHD, such as weight loss, signs of dehydration, and whisker barbering which may indicate stress. It is likely that the decrease in swimming speed is a result of generalized illness, rather than a neuromotor deficit caused by GvHD.In conclusion, our data suggest that the epithelial and ependymal cells surrounding the brain are a target of GvHD. Additionally, we found data supporting the theory that acute GvHD is associated with a Th1 response, as well as elevated serum ICAM-1 and VEGF levels. Our data indicate that GvHD may play a role in the brain of GvHD patients, an organ that has not previously been implicated in the pathology of GvHD. DisclosuresNo relevant conflicts of interest to declare.