Innovations: Using telemedicine to improve care of predominantly non-white youth with suboptimal insulin dependent diabetes control.

AIM: Despite advances in diabetes treatments, youth commonly fail to meet glucose targets. Telehealth support may help youth meet diabetes related goals. The objective of the project was to assess whether intensive telehealth support in a group of poorly controlled youth with diabetes would help improve glycated hemoglobin (HbA1c) levels and decrease hospitalization rates over a 12-month time frame. METHODS: This quality improvement project included youth aged 8-18 with suboptimal insulin dependent diabetes control and Medicaid insurance, who were willing to use continuous glucose monitoring (CGM). Participants received weekly contact (phone or video) with a certified diabetes educator and monthly video visits with a nurse practitioner. RESULTS: Youth (N = 27, 63 % female, 89 % Non-Hispanic Black), diabetes duration 6.2 ± 4.3 years, had baseline mean HbA1c 12.4 ± 1.8 % (112 mmol/mol); 22 % were on pump therapy (majority were non-automated insulin delivery systems). There was a sustained improvement between baseline HbA1c (mean 12.4 %±1.8) (112 mmol/mol) and 3 months (mean 11.5 %±2.8) (102 mmol/mol) (p = 0.03), 6 months (mean 11.1 %±2.1) (98 mmol/mol) (p = 0.01), 9 months (mean 11.4 %±2.3) (101 mmol/mol) (p = 0.04) and 12 months (mean 10.8 %±2.2) (95 mmol/mol) (p = 0.02). CONCLUSION: This intensive telehealth intervention provided interim glycemic improvement in a high-risk patient cohort. Further efforts to increase connection in vulnerable pediatric patient groups could help long-term diabetes management.

Barriers to oral health care for transgender and gender nonbinary populations.

BACKGROUND: Despite health disparities and barriers to medical care being well documented in the literature, transgender and gender nonbinary (TGNB) people's experiences and expectations with regard to oral health care remain understudied. The authors examined gender identity-related factors influencing experiences in the dental setting, aspects of subjective oral health, and avoidance of oral health care. METHODS: One-hundred eighteen TGNB people aged 13 through 70 years completed a 32-item questionnaire designed for this study. Data analysis relied on descriptive methods and bivariate comparisons using a conventional P < .05 statistical significance criterion. Qualitative description analysis was used to identify emerging themes from responses to an open-ended question. RESULTS: One-third of participants reported misgendering (that is, had been addressed by their incorrect name and pronouns in the dental setting). Although refusal of oral health care was rare in this sample of TGNB participants, more than one-half felt that their usual source of oral health care was not equipped to provide gender-appropriate care. Participants' avoidance due to gender identity was significantly associated with measures of self-reported suboptimal oral health. Common themes related to participants' oral health care experiences included gender insensitivity, awkward interactions, avoidance of care, and lack of gender-affirming providers. CONCLUSIONS: Discrepancies between TGNB patients' expectations and actual experiences suggest that their needs are often unmet in the dental setting, possibly contributing to gender identity-associated dental avoidance and oral health disparities. PRACTICAL IMPLICATIONS: Although these results need to be verified in larger and more diverse samples, they provide actionable information for improvement to this population's oral health and management.

Understanding and Caring for LGBTQ+ Youth by the Oral Health Care Provider.

With growing visibility, there is an increasing prevalence of lesbian, gay, bisexual, transgender, and queer (LGBTQ+) youth who feel empowered to own their true identity. Members of the oral health team frequently do not receive sufficient education in their training to recognize the nuance that treating this population may require. Although the tooth-level treatment does not materially change, a deeper appreciation of development of sexuality and gender identity, transgender medicine, and the health disparities LGBTQ+ youth face can promote more meaningful, trusting clinical relationships with this vulnerable population. This article aims to provide members of the oral health team with the requisite knowledge to deliver culturally competent care to LGBTQ+ youth.

Differences in Patient and Parent Informant Reports of Depression and Anxiety Symptoms in a Clinical Sample of Transgender and Gender Diverse Youth.

Purpose: We assessed characteristics of patients at a pediatric gender clinic and investigated if reports of mental health concerns provided by transgender and gender diverse (TGD) youth patients differed from reports provided by a parent informant on their behalf. Methods: This cross-sectional study included 259 TGD patients 8 to 22 years of age attending a pediatric gender clinic in the southeast United States from 2015 to 2020. Pearson correlations and paired sample t-tests compared patient-reported mental health concerns at patient intake with those provided by a parent informant. Clinical symptom severity was assessed with standardized T-scores. Level 2 Patient-Reported Outcomes Measurement Information System (PROMIS) Emotional Distress-Depression Scale and Level 2 PROMIS Emotional Distress-Anxiety Scale assessed depression and anxiety symptoms of patients. Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Parent/Guardian-Rated Level 1 Cross-Cutting Symptom Measure was used with parents. Results: Patients had a mean age of 14.9 at first visit, with most identifying as White (85.5%), non-Hispanic (91.1%), and as a boy or man (63.6%). Half had moderate-to-severe depression (51.2%) or anxiety (47.9%) symptoms. There was a moderate, positive correlation between patient-reported and parent-reported depression symptoms, with no correlation for anxiety symptoms. Informant type differences were statistically significant (patients reporting greater depression and anxiety symptoms). Conclusions: TGD youth patients reported more severe depression and anxiety symptoms compared with parent informants. Despite moderate agreement on depression symptoms, parents did not accurately detect their child's anxiety symptoms. These discrepancies highlight a need for interventions which increase parental recognition of child mental health status.

Complement Drives Synaptic Degeneration and Progressive Cognitive Decline in the Chronic Phase after Traumatic Brain Injury.

Cognitive deficits following traumatic brain injury (TBI) remain a major cause of disability and early-onset dementia, and there is increasing evidence that chronic neuroinflammation occurring after TBI plays an important role in this process. However, little is known about the molecular mechanisms responsible for triggering and maintaining chronic inflammation after TBI. Here, we identify complement, and specifically complement-mediated microglial phagocytosis of synapses, as a pathophysiological link between acute insult and a chronic neurodegenerative response that is associated with cognitive decline. Three months after an initial insult, there is ongoing complement activation in the injured brain of male C57BL/6 mice, which drives a robust chronic neuroinflammatory response extending to both hemispheres. This chronic neuroinflammatory response promotes synaptic degeneration and predicts progressive cognitive decline. Synaptic degeneration was driven by microglial phagocytosis of complement-opsonized synapses in both the ipsilateral and contralateral brain, and complement inhibition interrupted the degenerative neuroinflammatory response and reversed cognitive decline, even when therapy was delayed until 2 months after TBI. These findings provide new insight into our understanding of TBI pathology and its management; and whereas previous therapeutic investigations have focused almost exclusively on acute treatments, we show that all phases of TBI, including at chronic time points after TBI, may be amenable to therapeutic interventions, and specifically to complement inhibition.SIGNIFICANCE STATEMENT There is increasing evidence of a chronic neuroinflammatory response after traumatic brain injury (TBI), but little is known about the molecular mechanisms responsible for triggering and maintaining chronic inflammation. We identify complement, and specifically complement-mediated microglial phagocytosis of synapses, as a pathophysiological link between acute insult and a chronic neurodegenerative response, and further that this response is associated with cognitive decline. Complement inhibition interrupted this response and reversed cognitive decline, even when therapy was delayed until 2 months after injury. The data further support the concept that TBI should be considered a chronic rather than an acute disease condition, and have implications for the management of TBI in the chronic phase of injury, specifically with regard to the therapeutic application of complement inhibition.

Comparative Enhancement of Motor Function and BDNF Expression Following Different Brain Stimulation Approaches in an Animal Model of Ischemic Stroke.

BACKGROUND: Combinatory intervention such as high-frequency (50-100 Hz) excitatory cortical stimulation (ECS) given concurrently with motor rehabilitative training (RT) improves forelimb function, except in severely impaired animals after stroke. Clinical studies suggest that low-frequency (≤1 Hz) inhibitory cortical stimulation (ICS) may provide an alternative approach to enhance recovery. Currently, the molecular mediators of CS-induced behavioral effects are unknown. Brain-derived neurotrophic factor (BDNF) has been associated with improved recovery and neural remodeling after stroke and thus may be involved in CS-induced behavioral recovery. OBJECTIVE: To investigate whether inhibitory stimulation during RT improves functional recovery of severely impaired rats, following focal cortical ischemia and if this recovery alters BDNF expression (study 1) and depends on BDNF binding to TrkB receptors (study 2). METHODS: Rats underwent ECS + RT, ICS + RT, or noCS + RT treatment daily for 3 weeks following a unilateral ischemic lesion to the motor cortex. Electrode placement for stimulation was either placed ipsilateral (ECS) or contralateral (ICS) to the lesion. After treatment, BDNF expression was measured in cortical tissue samples (study 1). In study 2, the TrkB inhibitor, ANA-12, was injected prior to treatment daily for 21 days. RESULTS: ICS + RT treatment significantly improved impaired forelimb recovery compared with ECS + RT and noCS + RT treatment. CONCLUSION: ICS given concurrently with rehabilitation improves motor recovery in severely impaired animals, and alters cortical BDNF expression; nevertheless, ICS-mediated improvements are not dependent on BDNF binding to TrkB. Conversely, inhibition of TrkB receptors does disrupt motor recovery in ECS + RT treated animals.

Community perspectives on difference of sex development (DSD) diagnoses: A crowdsourced survey.

INTRODUCTION AND OBJECTIVES: Differences of sex development (DSD) engender ethical, social and psychosexual complexities that can complicate medical decision-making. We performed a web-based pilot study to estimate the utility value of a DSD diagnosis and to identify community concerns regarding DSD management. METHODS: A cross-sectional survey was posted on Amazon's Mechanical Turk, an online crowdsourcing platform. Respondents were ≥18y and were randomized to receive information on one of three common DSD conditions: Congenital Adrenal Hyperplasia (CAH), Mixed Gonadal Dysgenesis (MGD), and Partial Androgen Insensitivity Syndrome (PAIS). Time trade-off methodology was used to estimate utility values. Likert scale and statement-ranking questions were used to assess respondent perceptions. RESULTS: Of 1,628 respondents, median age was 34y; most respondents were parents (59.1%), white (77.1%), and previously unfamiliar with DSD (60.4%). The median overall utility value was 0.70 (IQR 0.50-0.90), similar to moderately severe chronic health conditions. Utility estimates varied based on the DSD scenario presented (0.80 CAH vs. 0.70 MGD vs. 0.80 PAIS, p = 0.0006), respondent gender (p < 0.0001), race (p = 0.002), religion (p = 0.005), and prior knowledge of DSD (p < 0.0001). Reported concerns included gender identity (23.4%), urinary function (20.5%) and surgical complications (17.4%). Most (67.5%) supported early surgical intervention at 6-18 mo; 10.4% thought surgery should occur ≥18 y. COMMENT: Limitations of this study include that survey participants were aware of the nature of the study, thus some respondents may have participated to skew the results. Given the nature of this pilot study, the representation of families with children with DSD within the study is severely limited given the rarity of DSDs. This means that their opinions may be diluted by the large sample size. However, because utility values are classically estimated according to community opinions, the utility data presented should be taken to reflect that of the specific sample studied and is not reflective of that of families with a vested interest in such cases. CONCLUSIONS: Community-based respondents perceived that DSD conditions were associated with a reduction in utility values (0.70-0.80), on par with moderately severe chronic health conditions. Estimates varied based on respondents' gender, race, religion and prior knowledge of DSD. Gender identity was the most concerning aspect for respondents.

Longitudinal Changes in Depression Symptoms and Glycemia in Adults With Type 1 Diabetes.

OBJECTIVE: This study assessed longitudinal change in depression symptoms over ≥4 years in adults with type 1 diabetes and examined the association between change in depression symptom status and glycemia. RESEARCH DESIGN AND METHODS: Adults in the T1D Exchange registry with HbA1c and Patient Health Questionnaire (PHQ-8) at 1 year (baseline) and 5 years post-enrollment (follow-up; n = 2,744, mean age, 42 years; 57% female, 92% white; mean HbA1c, 7.6% [58 mmol/mol]) were included. Depression status was defined as Persistent Elevated Depression Symptoms (EDS) (EDS at baseline and follow-up), Resolved EDS (EDS at baseline, no EDS at follow-up), New Onset EDS (no EDS at baseline, EDS at follow-up), and Not Depressed (no EDS at baseline or follow-up). RESULTS: Overall, 131 (5%) had Persistent EDS, 122 (4%) had Resolved EDS, 168 (6%) had New Onset EDS, and 2,323 (85%) were Not Depressed. Of those with EDS (PHQ ≥ 10) at baseline, 53% had EDS at follow-up; of those not depressed at baseline, 7% had EDS at follow-up. An increase in PHQ-8 was associated with an increase in HbA1c (P < 0.001). Although HbA1c increased in all groups, the increase was less in the Resolved EDS and Not Depressed groups (P = 0.001). Persistent EDS and New Onset EDS groups were more likely to experience diabetic ketoacidosis (DKA) (P < 0.001). CONCLUSIONS: T1D Exchange registry data provide evidence for relationships over time between persistently, and newly developing EDSs and worsening glycemic control, and suggest relationships between depression symptoms and the occurrence of severe hypoglycemia and DKA. Successful treatment of depression symptoms may lead to better long-term diabetes outcomes.

Best Practices in Transgender Health: A Clinician's Guide.

Providing culturally competent and medically knowledgeable care to the transgender community is increasingly falling within the realms of practice for primary care providers. The purpose of this article is to provide an overview of best practices as they relate to transgender care. This article is by no means a comprehensive guide, but rather a starting point for clinicians as they provide high-quality care to their transgender patients.

Acute Complement Inhibition Potentiates Neurorehabilitation and Enhances tPA-Mediated Neuroprotection.

Because complement activation in the subacute or chronic phase after stroke was recently shown to stimulate neural plasticity, we investigated how complement activation and complement inhibition in the acute phase after murine stroke interacts with subsequent rehabilitation therapy to modulate neuroinflammation and neural remodeling. We additionally investigated how complement and complement inhibition interacts with tissue plasminogen activator (tPA), the other standard of care therapy for stroke, and a U.S. Food and Drug Administration preclinical requirement for translation of an experimental stroke therapy. CR2fH, an injury site-targeted inhibitor of the alternative complement pathway, significantly reduced infarct volume, hemorrhagic transformation, and mortality and significantly improved long-term motor and cognitive performance when administered 1.5 or 24 h after middle cerebral artery occlusion. CR2fH interrupted a poststroke inflammatory process and significantly reduced inflammatory cytokine release, microglial activation, and astrocytosis. Rehabilitation alone showed mild anti-inflammatory effects, including reduced complement activation, but only improved cognitive recovery. CR2fH combined with rehabilitation significantly potentiated cognitive and motor recovery compared with either intervention alone and was associated with higher growth factor release and enhanced rehabilitation-induced neuroblast migration and axonal remodeling. Similar outcomes were seen in adult, aged, and female mice. Using a microembolic model, CR2fH administered in combination with acute tPA therapy improved overall survival and enhanced the neuroprotective effects of tPA, extending the treatment window for tPA therapy. A human counterpart of CR2fH has been shown to be safe and nonimmunogenic in humans and we have demonstrated robust deposition of C3d, the CR2fH targeting epitope, in ischemic human brains after stroke.SIGNIFICANCE STATEMENT Complement inhibition is a potential therapeutic approach for stroke, but it is not known how complement inhibition would interact with current standards of care. We show that, after murine ischemic stroke, rehabilitation alone induced mild anti-inflammatory effects and improved cognitive, but not motor recovery. However, brain-targeted and specific inhibition of the alternative complement pathway, when combined with rehabilitation, significantly potentiated cognitive and motor recovery compared with either intervention alone via mechanisms involving neuroregeneration and enhanced brain remodeling. Further, inhibiting the alternative pathway of complement significantly enhanced the neuroprotective effects of thrombolytic therapy and markedly expanded the therapeutic window for thrombolytic therapy.

Characterizing the corticomotor connectivity of the bilateral ankle muscles during rest and isometric contraction in healthy adults.

The investigation of the corticomotor connectivity (CMC) to leg muscles is an emerging research area, and establishing reliability of measures is critical. This study examined the measurement reliability and the differences between bilateral soleus (SOL) and tibialis anterior (TA) CMC in 21 neurologically intact adults. Using single pulse transcranial magnetic stimulation (TMS), each muscle's CMC was assessed twice (7 ±â€¯2 days apart) during rest and active conditions. CMC was quantified using a standardized battery of eight measures (4/condition): motor threshold during resting (RMT), motor evoked potential amplitude and latency (raw and normalized to height) in both conditions, contralateral silent period (CSP) during active. Using two reliability metrics (intraclass correlation coefficient and coefficient of variation of method error; good reliability: ≥0.75 and ≤15, respectively) and repeated-measures ANOVA, we investigated the reliability and Muscle X Body Side interaction. For both muscles, RMT, resting raw and normalized latencies, and active raw latency demonstrated good reliability, while CSP had good reliability only for TA. Amplitude did not demonstrate good reliability for both muscles. SOL CMC was significantly different from TA CMC for all measures but CSP; body side had no significant effect. Therefore, only certain measures may reliably quantify SOL and TA CMC while different CMC (except CSP) between SOL and TA suggests dissimilar corticospinal drive to each muscle regardless of the side.

Identifying the Role of Complement in Triggering Neuroinflammation after Traumatic Brain Injury.

The complement system is implicated in promoting acute secondary injury after traumatic brain injury (TBI), but its role in chronic post-traumatic neuropathology remains unclear. Using various injury-site targeted complement inhibitors that block different complement pathways and activation products, we investigated how complement is involved in neurodegeneration and chronic neuroinflammation after TBI in a clinically relevant setting of complement inhibition. The current paradigm is that complement propagates post-TBI neuropathology predominantly through the terminal membrane attack complex (MAC), but the focus has been on acute outcomes. Following controlled cortical impact in adult male mice, we demonstrate that although inhibition of the MAC (with CR2-CD59) reduces acute deficits, inhibition of C3 activation is required to prevent chronic inflammation and ongoing neuronal loss. Activation of C3 triggered a sustained degenerative mechanism of microglial and astrocyte activation, reduced dendritic and synaptic density, and inhibited neuroblast migration several weeks after TBI. Moreover, inhibiting all complement pathways (with CR2-Crry), or only the alternative complement pathway (with CR2-fH), provided similar and significant improvements in chronic histological, cognitive, and functional recovery, indicating a key role for the alternative pathway in propagating chronic post-TBI pathology. Although we confirm a role for the MAC in acute neuronal loss after TBI, this study shows that upstream products of complement activation generated predominantly via the alternative pathway propagate chronic neuroinflammation, thus challenging the current concept that the MAC represents a therapeutic target for treating TBI. A humanized version of CR2fH has been shown to be safe and non-immunogenic in clinical trials.SIGNIFICANCE STATEMENT Complement, and specifically the terminal membrane attack complex, has been implicated in secondary injury and neuronal loss after TBI. However, we demonstrate here that upstream complement activation products, generated predominantly via the alternative pathway, are responsible for propagating chronic inflammation and injury following CCI. Chronic inflammatory microgliosis is triggered by sustained complement activation after CCI, and is associated with chronic loss of neurons, dendrites and synapses, a process that continues to occur even 30 d after initial impact. Acute and injury-site targeted inhibition of the alternative pathway significantly improves chronic outcomes, and together these findings modify the conceptual paradigm for targeting the complement system to treat TBI.

Contemporary Demographic, Treatment, and Geographic Distribution Patterns for Disorders of Sex Development.

This study aimed to describe the demographic characteristics, hospital utilizations, patterns of inpatient surgical management, and the overall state/regional variation in surgery rate among patients with disorders of sex development (DSD). We analyzed the Nationwide Inpatient Sample from 2001 to 2012 for patients younger than 21 years. DSD-related diagnoses and procedures were identified via International Classification of Diseases, Ninth Revision (ICD-9) codes. We identified a total of 43,968 DSD-related admissions. Of these, 73.4% of the admissions were designated as female and 642 (1.9%) were inpatient surgical admissions. Among neonates, less than 1% underwent any type of genital surgery. Nonsurgical admissions were associated with longer length of stay and higher cost. There was no significant regional variation in the rate of DSD surgeries, but we observed higher concentrations of DSD surgeries in states associated with tertiary referral centers.

Preclinical and Clinical Evidence on Ipsilateral Corticospinal Projections: Implication for Motor Recovery.

Motor impairment is the most common complication after stroke, and recovery of motor function has been shown to be dependent on the extent of lesion in the ipsilesional corticospinal tract (iCST) and activity within ipsilesional primary and secondary motor cortices. However, work from neuroimaging research has suggested a role of the contralesional hemisphere in promoting recovery after stroke potentially through the ipsilateral uncrossed CST fibers descending to ipsilateral spinal segments. These ipsilateral fibers, sometimes referred to as "latent" projections, are thought to contribute to motor recovery independent of the crossed CST. The aim of this paper is to evaluate using cumulative evidence from animal models and human patients on whether an uncrossed CST component is present in mammals and conserved through primates and humans, and whether iCST fibers have a functional role in hemiparetic/hemiplegic human conditions. This review highlights that an ipsilateral uncrossed CST exists in human during development, but the evidence on a functionally relevant iCST component in adult humans is still elusive. In addition, this review argues that whereas activity within the ipsilesional cortex is essential for enhancing motor recovery after stroke, the role of iCST projections specifically is still controversial. Finally, conclusions from current literature emphasize the importance of activity in the ipsilesional cortex and the integrity of crossed CST fibers as major determinants of motor recovery after brain injury.

Sensitivity of diffusion MRI to perilesional reactive astrogliosis in focal ischemia.

Reactive astrogliosis is a response to injury in the central nervous system that plays an essential role in inflammation and tissue repair. It is characterized by hypertrophy of astrocytes, alterations in astrocyte gene expression and astrocyte proliferation. Reactive astrogliosis occurs in multiple neuropathologies, including stroke, traumatic brain injury and Alzheimer's disease, and it has been proposed as a possible source of the changes in diffusion magnetic resonance imaging (dMRI) metrics observed with these diseases. In this study, the sensitivity of dMRI to reactive astrogliosis was tested in an animal model of focal acute and subacute ischemia induced by the vasoconstricting peptide, endothelin-1. Reactive astrogliosis in perilesional cortex was quantified by calculating the astrocyte surface density as determined with a glial fibrillary acidic protein (GFAP) antibody, whereas perilesional diffusion changes were measured in vivo with diffusional kurtosis imaging. We found substantial changes in the surface density of GFAP-positive astrocyte processes and modest changes in dMRI metrics in the perilesional motor cortex following stroke. Although there are time point-specific correlations between dMRI and histological measures, there is no definitive evidence for a causal relationship.

Intra- and interregional coregulation of opioid genes: broken symmetry in spinal circuits.

Regulation of the formation and rewiring of neural circuits by neuropeptides may require coordinated production of these signaling molecules and their receptors that may be established at the transcriptional level. Here, we address this hypothesis by comparing absolute expression levels of opioid peptides with their receptors, the largest neuropeptide family, and by characterizing coexpression (transcriptionally coordinated) patterns of these genes. We demonstrated that expression patterns of opioid genes highly correlate within and across functionally and anatomically different areas. Opioid peptide genes, compared with their receptor genes, are transcribed at much greater absolute levels, which suggests formation of a neuropeptide cloud that covers the receptor-expressed circuits. Surprisingly, we found that both expression levels and the proportion of opioid receptors are strongly lateralized in the spinal cord, interregional coexpression patterns are side specific, and intraregional coexpression profiles are affected differently by left- and right-side unilateral body injury. We propose that opioid genes are regulated as interconnected components of the same molecular system distributed between distinct anatomic regions. The striking feature of this system is its asymmetric coexpression patterns, which suggest side-specific regulation of selective neural circuits by opioid neurohormones.-Kononenko, O., Galatenko, V., Andersson, M., Bazov, I., Watanabe, H., Zhou, X. W., Iatsyshyna, A., Mityakina, I., Yakovleva, T., Sarkisyan, D., Ponomarev, I., Krishtal, O., Marklund, N., Tonevitsky, A., Adkins, D. L., Bakalkin, G. Intra- and interregional coregulation of opioid genes: broken symmetry in spinal circuits.

Striatal Mitochondrial Disruption following Severe Traumatic Brain Injury.

Traumatic brain injury (TBI) results in oxidative stress and calcium dysregulation in mitochondria. However, little work has examined perturbations of mitochondrial homeostasis in peri-injury tissue. We examined mitochondrial homeostasis after a unilateral controlled cortical impact over the sensorimotor cortex in adult male rats. There was a significant reduction in peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) messenger RNA (mRNA) at post-injury days 3 and 6 and a transient reduction in mitochondrial DNA copy number at 3 days post-injury that recovered by 6 days in the ipsi-injury striatum. In ipsilateral cortex, PGC-1α mRNA was reduced only at 6 days post-injury. Additionally, expression of mitochondrial-encoded mRNAs, cytochrome c oxidase subunit 1 and NADH dehydrogenase subunit 1, was decreased at 3 and 6 days post-injury in ipsilesional striatum and at 6 days post-injury in ipsilesional cortex. There was no observable decrease in nuclear-encoded mRNAs mitochondrial transcription factor A or NADH dehydrogenase (ubiquinone) Fe-S protein 1. We detected an acute increase in superoxide dismutase 2 mRNA expression, as well as an induction of microRNA (miR)-21 and miR-155, which have been previously demonstrated to disrupt mitochondrial homeostasis. Behaviorally, rats with TBI exhibited marked error rates in contrainjury forelimb performance on the ladder test. These findings reveal that there may be differential susceptibilities of various peri-injury brain structures to mitochondrial dysfunction and associated behavioral deficits, and that molecular pathways demonstrated to interfere with mitochondrial homeostasis and function are activated subacutely post-TBI.

Disrupted mitochondrial genes and inflammation following stroke.

AIMS: Determine the subacute time course of mitochondria disruption, cell death, and inflammation in a rat model of unilateral motor cortical ischemic stroke. MAIN METHODS: Rats received unilateral ischemia of the motor cortex and were tested on behavioral tasks to determine impairments. Animals were euthanized at 24h, 72h and 144h and mRNA expression of key mitochondria proteins and indicators of inflammation, apoptosis and potential regenerative processes in ipsilesion cortex and striatum, using RT-qPCR. Mitochondrial proteins were examined at 144h using immunoblot analysis. KEY FINDINGS: Rats with stroke induced-behavioral deficits had sustained, 144h post-lesion, decreases in mitochondrial-encoded electron transport chain proteins NADH dehydrogenase subunit-1 and cytochrome c oxidase subunit-1 (mRNA and protein) and mitochondrial DNA content in perilesion motor and sensory cortex. Uncoupling-protein-2 gene expression, but not superoxide dismutase-2, remained elevated in ipsilateral cortex and striatum at this time. Cortical inflammatory cytokine, interleukin-6, was increased early and was followed by increased macrophage marker F4/80 after stroke. Cleaved caspase-3 activation was elevated in cortex and growth associated protein-43 was elevated in the cortex and striatum six days post-lesion. SIGNIFICANCE: We identified a relationship between three disrupted pathways, (1) sustained loss of mitochondrial proteins and mitochondrial DNA copy number in the cortex linked to decreased mitochondrial gene transcription; (2) early inflammatory response mediated by interleukin- 6 followed by macrophages; (3) apoptosis in conjunction with the activation of regenerative pathways. The stroke-induced spatial and temporal profiles lay the foundation to target pharmacological therapeutics to these three pathways.

Enhanced Motor Recovery After Stroke With Combined Cortical Stimulation and Rehabilitative Training Is Dependent on Infarct Location.

BACKGROUND: Cortical electrical stimulation of the motor cortex in combination with rehabilitative training (CS/RT) has been shown to enhance motor recovery in animal models of focal cortical stroke, yet in clinical trials, the effects are much less robust. The variability of stroke location in human patient populations that include both cortical and subcortical brain regions may contribute to the failure to find consistent effects clinically. OBJECTIVE: This study sought to determine whether infarct location influences the enhanced motor recovery previously observed in response to CS/RT. The efficacy of CS/RT to promote improvements in motor function was examined in 2 different rat models of stroke that varied the amount and location of cortical and subcortical damage. METHODS: Ischemic infarctions were induced by injecting the vasoconstricting peptide endothelin-1 either (1) onto the middle cerebral artery (MCA) producing damage to the frontal cortex and lateral striatum or (2) into a subcortical region producing damage to the posterior thalamus and internal capsule (subcortical capsular ischemic injury [SCII]). Daily CS/RT or RT alone was then given for 20 days, during which time performance on a skilled reaching task was assessed. RESULTS: Animals with MCA occlusion infarctions exhibited enhanced improvements on a skilled reaching task in response to CS/RT relative to RT alone. No such enhancement was observed in animals with SCII infarctions across the 20 days of treatment. CONCLUSIONS: The efficacy of CS for enhancing motor recovery after stroke may depend in part on the extent and location of the ischemic infarct.

Cortical Stimulation Concurrent With Skilled Motor Training Improves Forelimb Function and Enhances Motor Cortical Reorganization Following Controlled Cortical Impact.

BACKGROUND: Electrical and magnetic brain stimulation can improve motor function following stroke in humans, rats, and nonhuman primates, especially when paired with rehabilitative training (RT). Previously, we found in rodent stroke models that epidural electrical cortical stimulation (CS) of the ipsilesional motor cortex (MC) combined with motor RT enhances motor function and motor cortical plasticity. It was unknown whether CS following experimental traumatic brain injury (TBI) would have similar effects. OBJECTIVE: To test the effects of CS combined with motor training after moderate/severe TBI on behavioral outcome and motor cortical organization. METHODS: Following unilateral controlled cortical impact (CCI) over the caudal forelimb area of the MC in adult male rats, forelimb reach training was administered daily for 9 weeks concurrently with subthreshold, 100-Hz monopolar CS or no-stimulation control procedures. The rate and magnitude of behavioral improvements and changes in forelimb movement representations in the injured MC as revealed by intracortical microstimulation were measured. RESULTS: CCI resulted in severe motor impairments persisting throughout the 9 weeks of training in both groups, but CS-treated animals had significantly greater behavioral improvements. CS also increased wrist motor cortical representation, one of the main movements used in the training task, when compared with RT alone. However, the overall recovery level was modest, leaving animals still extremely impaired. CONCLUSIONS: These data suggest that CS may be useful for improving rehabilitation efficacy after TBI but also raise the possibility that the CS parameters that are highly effective following stroke are suboptimal after moderate/severe TBI.