Hepatocyte Growth Factor Delivery to Injured Cervical Spinal Cord Using an Engineered Biomaterial Protects Respiratory Neural Circuitry and Preserves Functional Diaphragm Innervation.

A major portion of spinal cord injury (SCI) cases occur in the cervical region, where essential components of the respiratory neural circuitry are located. Phrenic motor neurons (PhMNs) housed at cervical spinal cord level C3-C5 directly innervate the diaphragm, and SCI-induced damage to these cells severely impairs respiratory function. In this study, we tested a biomaterial-based approach aimed at preserving this critical phrenic motor circuitry after cervical SCI by locally delivering hepatocyte growth factor (HGF). HGF is a potent mitogen that promotes survival, proliferation, migration, repair, and regeneration of a number of different cell and tissue types in response to injury. We developed a hydrogel-based HGF delivery system that can be injected into the intrathecal space for local delivery of high levels of HGF without damaging the spinal cord. Implantation of HGF hydrogel after unilateral C5 contusion-type SCI in rats preserved diaphragm function, as assessed by in vivo recordings of both compound muscle action potentials and inspiratory electromyography amplitudes. HGF hydrogel also preserved PhMN innervation of the diaphragm, as assessed by both retrograde PhMN tracing and detailed neuromuscular junction morphological analysis. Furthermore, HGF hydrogel significantly decreased lesion size and degeneration of cervical motor neuron cell bodies, as well as reduced levels surrounding the injury site of scar-associated chondroitin sulfate proteoglycan molecules that limit axon growth capacity. Our findings demonstrate that local biomaterial-based delivery of HGF hydrogel to injured cervical spinal cord is an effective strategy for preserving respiratory circuitry and diaphragm function.

Family caregivers of service members in United States Department of Defense health care report impairment in longitudinal health outcomes.

OBJECTIVE: To examine elevated symptoms on health-related quality of life (HRQOL) measures over 2 years in caregivers of service members with traumatic brain injury (TBI). To compare outcomes to caregivers of veterans. METHOD: Caregivers (N = 315) were classified into two groups: (a) service member caregiver group (n = 55) and (b) veteran caregiver group (n = 260). Caregivers completed 17 HRQOL measures at a baseline evaluation and follow-up evaluation 24 months later. RESULTS: In the service member caregiver group, the highest frequency of clinically elevated T-scores (≥ 60 T) at baseline and follow-up were found on physical and psychological HRQOL measures (16.4%-30.9%). A higher proportion of the veteran caregiver group had clinically elevated scores on nine measures at baseline and seven measures at follow-up. Examining the number of clinically elevated scores simultaneously across all 17 measures, the service member caregiver group had multiple elevated scores (e.g., 4 or more: baseline = 25.5%, follow-up = 27.3%). A higher proportion of the veteran caregiver group had multiple clinically elevated scores for 13 comparisons at baseline (h = .35-.82), but reduced to eight comparisons at follow-up (h = .36-.63). In the service member caregiver group, the proportion of caregivers with clinically elevated scores at baseline and follow-up was equally dispersed across persistent and newly developed symptoms, but higher for persistent symptoms compared to developed symptoms in the veteran caregiver group. CONCLUSIONS: Many caregivers of service members reported clinically elevated scores across HRQOL domains and the prevalence increased over 2 years. More services for caregivers in the Department of Defense may be helpful in reducing the trajectory of newly developed symptoms long term. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Low resilience is associated with worse health-related quality of life in caregivers of service members and veterans with traumatic brain injury: a longitudinal study.

PURPOSE: To examine [a] the association of caregiver health-related quality of life (HRQOL) and service member/veteran (SMV) neurobehavioral outcomes with caregiver resilience; [b] longitudinal change in resilience at the group and individual level; and [c] the magnitude of change at the individual level. METHODS: Caregivers (N = 232) of SMVs with traumatic brain injury completed a resilience measure, and 18 caregiver HRQOL and SMV neurobehavioral outcome measures at a baseline evaluation and follow-up evaluation three years later. Caregivers were divided into two resilience groups at baseline and follow-up: [1] Low Resilience (≤ 45 T, baseline n = 99, follow-up n = 93) and [2] High Resilience (> 45 T, baseline n = 133, follow-up n = 139). RESULTS: At baseline and follow-up, significant effects were found between Low and High Resilience groups for the majority of outcome measures. There were no significant differences in resilience from baseline to follow-up at the group-mean level. At the individual level, caregivers were classified into four longitudinal resilience groups: [1] Persistently Low Resilience (Baseline + Follow-up = Low Resilience, n = 60), [2] Reduced Resilience (Baseline = High Resilience + Follow-up = Low Resilience, n = 33), [3] Improved Resilience (Baseline = Low Resilience + Follow-up = High Resilience, n = 39), and [4] Persistently High Resilience (Baseline + Follow-up = High Resilience, n = 100). From baseline to follow-up, approximately a third of the Reduced and Improved Resilience groups reported a meaningful change in resilience (≥ 10 T). Nearly all of the Persistently High and Persistently Low Resilience groups did not report meaningful change in resilience (< 10 T). CONCLUSION: Resilience was not a fixed state for all caregivers. Early intervention may stall the negative caregiving stress-health trajectory and improve caregiver resilience.

PTEN inhibition promotes robust growth of bulbospinal respiratory axons and partial recovery of diaphragm function in a chronic model of cervical contusion spinal cord injury.

High spinal cord injury (SCI) leads to persistent and debilitating compromise in respiratory function. Cervical SCI not only causes the death of phrenic motor neurons (PhMNs) that innervate the diaphragm, but also damages descending respiratory pathways originating in the rostral ventral respiratory group (rVRG) located in the brainstem, resulting in denervation and consequent silencing of spared PhMNs located caudal to injury. It is imperative to determine whether interventions targeting rVRG axon growth and respiratory neural circuit reconnection are efficacious in chronic cervical contusion SCI, given that the vast majority of individuals are chronically-injured and most cases of SCI involve contusion-type damage to the cervical region. We therefore employed a rat model of chronic cervical hemicontusion to test therapeutic manipulations aimed at reconstructing damaged rVRG-PhMN-diaphragm circuitry to achieve recovery of respiratory function. At a chronic time point post-injury, we systemically administered: an antagonist peptide directed against phosphatase and tensin homolog (PTEN), a central inhibitor of neuron-intrinsic axon growth potential; an antagonist peptide directed against receptor-type protein tyrosine phosphatase sigma (PTPσ), another important negative regulator of axon growth capacity; or a combination of these two peptides. PTEN antagonist peptide (PAP4) promoted partial recovery of diaphragm motor activity out to nine months post-injury (though this effect depended on the anesthetic regimen used during recording), while PTPσ peptide did not impact diaphragm function after cervical SCI. Furthermore, PAP4 promoted robust growth of descending bulbospinal rVRG axons caudal to the injury within the denervated portion of the PhMN pool, while PTPσ peptide did not affect rVRG axon growth at this location that is critical to control of diaphragmatic respiratory function. In conclusion, we find that, when PTEN inhibition is targeted at a chronic time point following cervical contusion, our non-invasive PAP4 strategy can successfully promote significant regrowth of damaged respiratory neural circuitry and also partial recovery of diaphragm motor function.

Activation of fluoride anion as nucleophile in water with data-guided surfactant selection.

A principal component surfactant_map was developed for 91 commonly accessible surfactants for use in surfactant-enabled organic reactions in water, an important approach for sustainable chemical processes. This map was built using 22 experimental and theoretical descriptors relevant to the physicochemical nature of these surfactant-enabled reactions, and advanced principal component analysis algorithms. It is comprised of all classes of surfactants, i.e. cationic, anionic, zwitterionic and neutral surfactants, including designer surfactants. The value of this surfactant_map was demonstrated in activating simple inorganic fluoride salts as effective nucleophiles in water, with the right surfactant. This led to the rapid development (screening 13-15 surfactants) of two fluorination reactions for ß-bromosulfides and sulfonyl chlorides in water. The latter was demonstrated in generating a sulfonyl fluoride with sufficient purity for direct use in labelling of chymotrypsin, under physiological conditions.

Identity Theft, Deep Brain Stimulation, and the Primacy of Post-trial Obligations.

Patient narratives from two investigational deep brain stimulation trials for traumatic brain injury and obsessive-compulsive disorder reveal that injury and illness rob individuals of personal identity and that neuromodulation can restore it. The early success of these interventions makes a compelling case for continued post-trial access to these technologies. Given the centrality of personal identity to respect for persons, a failure to provide continued access can be understood to represent a metaphorical identity theft. Such a loss recapitulates the pain of an individual's initial injury or illness and becomes especially tragic because it could be prevented by robust policy. A failure to fulfill this normative obligation constitutes a breach of disability law, which would view post-trial access as a means to achieve social reintegration through this neurotechnological accommodation.

EphrinB2 knockdown in cervical spinal cord preserves diaphragm innervation in a mutant SOD1 mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron loss. Importantly, non-neuronal cell types such as astrocytes also play significant roles in disease pathogenesis. However, mechanisms of astrocyte contribution to ALS remain incompletely understood. Astrocyte involvement suggests that transcellular signaling may play a role in disease. We examined contribution of transmembrane signaling molecule ephrinB2 to ALS pathogenesis, in particular its role in driving motor neuron damage by spinal cord astrocytes. In symptomatic SOD1G93A mice (a well-established ALS model), ephrinB2 expression was dramatically increased in ventral horn astrocytes. Reducing ephrinB2 in the cervical spinal cord ventral horn via viral-mediated shRNA delivery reduced motor neuron loss and preserved respiratory function by maintaining phrenic motor neuron innervation of diaphragm. EphrinB2 expression was also elevated in human ALS spinal cord. These findings implicate ephrinB2 upregulation as both a transcellular signaling mechanism in mutant SOD1-associated ALS and a promising therapeutic target.

Brain injury, medical progress, and the disability paradox: Towards an Americans with Abilities Act.

It is helpful to think about the needs of patients with moderate to severe brain injury through the lens of disability law. However, there are limitations to current disability law that contribute to ongoing segregation and marginalization of individuals with severe brain injury. Indeed, one of the paradoxes of American jurisprudence is that more clear constitutional protections accrue to those who have definitively immutable conditions. Thus, as neuroscience brings new therapies to those with brain injury, they may become less protected by the constitutional elements of disability law because their conditions have changed and become mutable. This is the clinical progress that brain injury professionals all seek to achieve, but ironically these advances could potentially degrade the legal protections of patients who benefit from emerging treatments. In this paper, we will critically examine this paradox at the interface of medicine and the law and suggest that the Americans with Disabilities Act (ADA) could be nicely complemented by legislation we have named the Americans with Abilities Act (AWAA). Instead of focusing on disabilities that need protection, the AWAA seeks to sustain and foster newfound abilities made possible by the fruits of medicine and neuroscience.

PTEN inhibition promotes robust growth of bulbospinal respiratory axons and partial recovery of diaphragm function in a chronic model of cervical contusion spinal cord injury.

High spinal cord injury (SCI) leads to persistent and debilitating compromise in respiratory function. Cervical SCI not only causes the death of phrenic motor neurons (PhMNs) that innervate the diaphragm, but also damages descending respiratory pathways originating in the rostral ventral respiratory group (rVRG) located in the brainstem, resulting in denervation and consequent silencing of spared PhMNs located caudal to injury. It is imperative to determine whether interventions targeting rVRG axon growth and respiratory neural circuit reconnection are efficacious in chronic cervical contusion SCI, given that the vast majority of individuals are chronically-injured and most cases of SCI involve contusion-type damage to the cervical region. We therefore employed a clinically-relevant rat model of chronic cervical hemicontusion to test therapeutic manipulations aimed at reconstructing damaged rVRG-PhMN-diaphragm circuitry to achieve recovery of respiratory function. At a chronic time point post-injury, we systemically administered: an antagonist peptide directed against phosphatase and tensin homolog (PTEN), a central inhibitor of neuron-intrinsic axon growth potential; an antagonist peptide directed against receptor-type protein tyrosine phosphatase sigma (PTPσ), another important negative regulator of axon growth capacity; or a combination of these two peptides. PTEN antagonist peptide (PAP4) promoted partial recovery of diaphragm motor activity out to nine months post-injury, while PTPσ peptide did not impact diaphragm function after cervical SCI. Furthermore, PAP4 promoted robust growth of descending bulbospinal rVRG axons caudal to the injury within the denervated portion of the PhMN pool, while PTPσ peptide did not affect rVRG axon growth at this location that is critical to control of diaphragmatic respiratory function. In conclusion, we find that, when PTEN inhibition is targeted at a chronic time point following cervical contusion that is most relevant to the SCI clinical population, our non-invasive PAP4 strategy can successfully promote significant regrowth of damaged respiratory neural circuitry and also partial recovery of diaphragm motor function. HIGHLIGHTS: PTEN antagonist peptide promotes partial diaphragm function recovery in chronic cervical contusion SCI.PTPσ inhibitory peptide does not impact diaphragm function recovery in chronic cervical contusion SCI.PTEN antagonist peptide promotes growth of bulbospinal rVRG axons in chronic cervical contusion SCI.PTPσ peptide does not affect rVRG axon growth in chronic cervical contusion SCI.

Timing of treatment for opioid use disorder among birthing people.

BACKGROUND: The number of pregnant women with opioid use disorder (OUD) has increased over time. Although effective treatment options exist, little is known about the extent to which women receive treatment during pregnancy and at what stage of pregnancy care is initiated. METHODS: Using a national private health insurance claims database, we identified women aged 13-49 who gave birth in 2006-2019 and had an OUD or nonfatal opioid overdose (NFOO) diagnosis during the year prior to or at delivery. We then identified women who received their first OUD treatment prior to or during pregnancy. In this cross-sectional study, we investigated how rates and timing of the initial OUD treatment changed over time. Furthermore, we examined factors associated with early initiation of OUD treatment among birthing people. RESULTS: Of the 7057 deliveries from 6747 women with OUD or NFOO, 63.3 % received any OUD treatment. Rates of OUD treatment increased from 42.9 % in 2006 to 69 % in 2019. Of those treated, in 2006, 54.5 % received their first treatment prior to conception and 24.2 % initiated care during the 1st trimester. In 2019, 68.9 % received their first treatment prior to conception, and 15.1 % initiated care during the 1st trimester. The percentage of women who were first treated in the 2nd trimester or later decreased from 21.2 % in 2006 to 16.1 % in 2019. Factors associated with early treatment initiation include being 25 years or older (age 25-34: aOR, 1.51, 95 % CI, 1.28-1.78; age 35-49: aOR, 1.82, 95 % CI, 1.39-2.37), living in urban areas (aOR, 1.28; 95 % CI, 1.05-1.56), having pre-existing behavioral health comorbidities such as anxiety disorders (aOR, 1.8; 95 % CI, 1.40-2.32), mood disorders (aOR, 1.63; 95 % CI, 1.02-2.61), and substance use disorder other than OUD (aOR, 2.56; 95 % CI, 2.03-3.32). CONCLUSION: Overall, rates of OUD treatment increased over time, and more women initiated OUD treatment prior to conception. Despite these improvements, over one-third of pregnant women with OUD/NFOO either received no treatment or did not initiate care until the 3rd trimester in 2019. Future research should examine barriers to OUD treatment initiation among pregnant women.

Inhibition of Aurora-A/N-Myc Protein-Protein Interaction Using Peptidomimetics: Understanding the Role of Peptide Cyclization.

Using N-Myc61-89 as a starting template we showcase the systematic use of truncation and maleimide constraining to develop peptidomimetic inhibitors of the N-Myc/Aurora-A protein-protein interaction (PPI); a potential anticancer drug discovery target. The most promising of these - N-Myc73-94-N85C/G89C-mal - is shown to favour a more Aurora-A compliant binding ensemble in comparison to the linear wild-type sequence as observed through fluorescence anisotropy competition assays, circular dichroism (CD) and nuclear magnetic resonance (NMR) experiments. Further in silico investigation of this peptide in its Aurora-A bound state, by molecular dynamics (MD) simulations, imply (i) the bound conformation is more stable as a consequence of the constraint, which likely suppresses dissociation and (ii) the constraint may make further stabilizing interactions with the Aurora-A surface. Taken together this work unveils the first orthosteric N-Myc/Aurora-A inhibitor and provides useful insights on the biophysical properties and thus design of constrained peptides, an attractive therapeutic modality.

Longitudinal health outcomes in caregivers of military members with traumatic brain injury.

PURPOSE/OBJECTIVE: To examine longitudinal change in health-related quality of life (HRQOL) in caregivers of service members/veterans with traumatic brain injury and factors associated with clinically elevated symptoms. RESEARCH METHOD/DESIGN: Caregivers (N = 220) completed nine HRQOL outcome measures and 10 risk factor measures at a baseline evaluation and follow-up evaluation 3 years later. Caregiver's responses on the nine HRQOL outcome measures were classified into four clinical change categories based on the presence/absence of clinically elevated T-scores (≥ 60 T) at baseline and follow-up: (a) Persistent (baseline ≥ 60T + follow-up ≥ 60 T), (b) Developed (baseline < 60 T + follow-up ≥ 60 T), (c) Improved (baseline ≥ 60 T + follow-up < 60 T), and (d) Asymptomatic (baseline < 60 T + follow-up < 60 T). A clinical change composite score was calculated by summing the number of Persistent or Developed HRQOL outcome measures and used to create three clinical change groups: (a) No Symptoms (n = 69, zero measures), (b) Some Symptoms (n = 88, one to three measures), and (c) Numerous Symptoms (n = 63, four to nine measures). RESULTS: Of the nine HRQOL outcome measures, Bodily Pain, Perceived Stress, Sleep-Related Impairment, and Fatigue were most frequently classified as Persistent or Developed from baseline to follow-up in the entire sample. A linear relationship was found between the vast majority of risk factors across the three clinical change groups at baseline and follow-up (Numerous > Some > None). The risk factors were correlated with the number of elevated HRQOL symptoms at baseline and follow-up. Most Asymptomatic or Persistent caregivers did not have meaningful change (≥ 1 SD) in HRQOL scores. A sizable proportion of Developed or Improved caregivers had either meaningful or no change in HRQOL scores. CONCLUSIONS/IMPLICATIONS: There is a need for ongoing clinical services for military caregivers. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The Scholarly and Pedagogical Benefits of the Legal Laboratory: Lessons from the Consortium for the Advanced Study of Brain Injury at Yale Law School.

In our article, we share the lessons we have learned after creating and running a successful legal laboratory over the past seven years at Yale Law School. Our legal laboratory, which focuses on the intersection of law and severe brain injury, represents a unique pedagogical model for legal academia, and is closely influenced by the biomedical laboratory.

Longitudinal health-related quality of life in military caregivers no longer providing care.

PURPOSE/OBJECTIVE: To examine health-related quality of life (HRQOL) in caregivers when providing care and no longer providing care to service members/veterans with traumatic brain injury. RESEARCH METHOD/DESIGN: Participants included 466 caregivers enrolled in a 15-year longitudinal study. During an annual follow-up evaluation, a subsample of caregivers self-identified as no longer providing care and were retained in the study as a No Longer Caregiving group (n = 48). Scores on HRQOL measures when providing care (baseline) and no longer providing care (follow-up) were examined. Scores on HRQOL measures were also compared with the remaining 418 caregivers (Caregiving group). RESULTS: The most frequent reasons for no longer caregiving were no longer being in a relationship with the SMV and the SMV had recovered/no longer required care. The No Longer Caregiving group at follow-up reported better scores on five measures compared to baseline, and three measures compared to the Caregiving group. There were no differences in the proportion of clinically elevated scores on HRQOL measures for the No Longer Caregiving group between baseline and follow-up. Compared to the Caregiving group, the No Longer Caregiving group reported a higher prevalence of clinical elevated scores on General Life Satisfaction at baseline and follow-up, and worse scores on Caregiving Relationship Satisfaction and the Couples Satisfaction Index at baseline. CONCLUSIONS/IMPLICATIONS: While some improvement in HRQOL was noted when caregivers were no longer providing care, many continued to report elevated scores. Services and supports are required for caregivers when providing care, but also when transitioning out of a caregiving role. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injury.

Following peripheral nerve injury, successful axonal growth and functional recovery require Schwann cell (SC) reprogramming into a reparative phenotype, a process dependent upon c-Jun transcription factor activation. Unfortunately, axonal regeneration is greatly impaired in aged organisms and following chronic denervation, which can lead to poor clinical outcomes. While diminished c-Jun expression in SCs has been associated with regenerative failure, it is unclear whether the inability to maintain a repair state is associated with the transition into an axonal growth inhibition phenotype. We here find that reparative SCs transition into a senescent phenotype, characterized by diminished c-Jun expression and secretion of inhibitory factors for axonal regeneration in aging and chronic denervation. In both conditions, the elimination of senescent SCs by systemic senolytic drug treatment or genetic targeting improved nerve regeneration and functional recovery, increased c-Jun expression and decreased nerve inflammation. This work provides the first characterization of senescent SCs and their influence on axonal regeneration in aging and chronic denervation, opening new avenues for enhancing regeneration and functional recovery after peripheral nerve injuries.

Health outcomes in caregivers of service members and veterans with traumatic brain injury enrolled in the U.S. Veterans Affairs Caregiver Support Program.

To explore health outcomes in caregivers of service members and veterans (SMV) with traumatic brain injury (TBI) enrolled in two programs within the U.S. Department of Veterans Affairs (VA) Caregiver Support Program (CSP) (General and Comprehensive Programs) and those not enrolled. Participants were 290 caregivers classified into three groups: (a) General Program (n = 34); (b) Comprehensive Program (n = 104); and (c) Not Enrolled (n = 152). Main outcome measures assessed caregiver health-related quality of life (HRQOL), SMV functional ability, and caregiver needs. Compared to the Not Enrolled group, the General, and Comprehensive Program groups reported worse scores on five of 25 caregiver HRQOL measures and had a higher proportion of elevated scores on two measures. The Comprehensive Program group reported worse scores on an additional seven HRQOL measures and a higher proportion of elevated scores on three measures compared to the Not Enrolled group. Over 20% of caregivers in each group reported clinically elevated scores on eight HRQOL measures. Few differences between caregiver groups were identified for unmet needs. In the total sample, eight HRQOL measures consistently emerged that were more strongly associated with caregiver needs. Caregivers enrolled in the VA CSP tended to report worse HRQOL and caring for a SMV with worse functional ability compared to those not enrolled. A better understanding of health care utilization for those not enrolled in the CSP and in need of help is required. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Subject and Family Perspectives from the Central Thalamic Deep Brain Stimulation Trial for Traumatic Brain Injury: Part II.

This is the second paper in a two-part series describing subject and family perspectives from the CENTURY-S (CENtral Thalamic Deep Brain Stimulation for the Treatment of Traumatic Brain InjURY-Safety) first-in-human invasive neurological device trial to achieve cognitive restoration in moderate to severe traumatic brain injury (msTBI). To participate, subjects were independently assessed to formally establish decision-making capacity to provide voluntary informed consent. Here, we report on post-operative interviews conducted after a successful trial of thalamic stimulation. All five msTBI subjects met a pre-selected primary endpoint of at least a 10% improvement in completion time on Trail-Making-Test Part B, a marker of executive function. We describe narrative responses of subjects and family members, refracted against that success. Interviews following surgery and the stimulation trial revealed the challenge of adaptation to improvements in cognitive function and emotional regulation as well as altered (and restored) relationships and family dynamics. These improvements exposed barriers to social reintegration made relevant by recoveries once thought inconceivable. The study's success sparked concerns about post-trial access to implanted devices, financing of device maintenance, battery replacement, and on-going care. Most subjects and families identified the need for supportive counseling to adapt to the new trajectory of their lives.