Chronic Stress Alters Striosome-Circuit Dynamics, Leading to Aberrant Decision-Making.

Effective evaluation of costs and benefits is a core survival capacity that in humans is considered as optimal, "rational" decision-making. This capacity is vulnerable in neuropsychiatric disorders and in the aftermath of chronic stress, in which aberrant choices and high-risk behaviors occur. We report that chronic stress exposure in rodents produces abnormal evaluation of costs and benefits resembling non-optimal decision-making in which choices of high-cost/high-reward options are sharply increased. Concomitantly, alterations in the task-related spike activity of medial prefrontal neurons correspond with increased activity of their striosome-predominant striatal projection neuron targets and with decreased and delayed striatal fast-firing interneuron activity. These effects of chronic stress on prefronto-striatal circuit dynamics could be blocked or be mimicked by selective optogenetic manipulation of these circuits. We suggest that altered excitation-inhibition dynamics of striosome-based circuit function could be an underlying mechanism by which chronic stress contributes to disorders characterized by aberrant decision-making under conflict. VIDEO ABSTRACT.

Characteristics and associations of ocular and non-ocular manifestations of shaken baby syndrome.

OBJECTIVES: Shaken baby syndrome (SBS), a subset of abusive head trauma, results from non-accidental, violent head shaking. Most survivors suffer permanent neurological sequelae. Accurate diagnosis is imperative and remains challenging. The purpose of this study is to describe ocular injuries and associated neurotrauma in suspected SBS. METHODS: We retrospectively surveyed the National Trauma Data Bank 2008-2014 for patients ≤ 3 years old admitted for suspected SBS. Statistical analysis was performed with SPSS software. Significance was set at p < 0.05. RESULTS: Three hundred forty-seven (13.9%) of 2495 patients who were ≤ 3 years old were admitted with abusive head trauma and ocular injuries which resulted from suspected SBS. Most were < 1 year old (87.9%) and male (54.2%). Common eye injuries were retinal hemorrhages (30.5%), eye/adnexa contusion (14.7%), and retinal edema (10.7%). Common neurotrauma were subdural (75.5%), subarachnoid (23.9%), and intracerebral hemorrhage (ICH) (10.4%). Mean (SD) Injury Severity Score was severe, 20.2 (8.2), and Glasgow Coma Score was moderate, 9.2 (12.8). The mortality rate was 16.7%. Retinal hemorrhages were not significantly associated with one type of neurotrauma over others. Ocular/adnexa contusion (OR 4.06; p < 0.001) and commotio retinae/Berlin's edema (OR 5.27; p < 0.001) had the greatest association with ICH than other neurotrauma. Optic neuropathy (OR 21.33; p < 0.001) and ICH (OR 3.34; p < 0.001) had the highest associated with mortality. CONCLUSIONS: Our study supports previous studies showing that retinal and subdural hemorrhages were the most common ocular injury and neurotrauma in SBS, respectively. However, we did not find a significant propensity for their concurrence. Commotio retinae/Berlin's edema was significantly associated with both intracerebral and subdural hemorrhages.

The Role of Insulin-like Growth Factor-1 and Its Receptor in the Eye: A Review and Implications for IGF-1R Inhibition.

PURPOSE: FDA approval of teprotumumab for thyroid eye disease in January 2020 reinforced interest in the pharmacologic potential of insulin-like growth factor-1 (IGF-1) and its receptor, IGF-1R. Despite recent approval and adaptation for ophthalmic use, IGF-1R inhibitors are not a new therapeutic class. In 1986, Yamashita described aIR3, a monoclonal antibody to IGF-1R (anti-IGF-1R), that inhibited the effect of IGF-1 on growth hormone release. Given the widespread presence of IGF-1R, interrupting this receptor can lead to systemic physiologic effects, some adverse. We aim to review what is known about IGF-1/IGF-1R in the eye and consider the possible local side effects, unintended consequences, and potential uses of this medication class. METHODS: A PubMed database search utilizing the keywords "insulin-like growth factor-1, eye, inhibitor, antibody, side effect" was performed to identify publications discussing IGF-1 in the human eye from January 2011 to August 2021. Criteria for acceptance included studies discussing human subjects or human tissue specifically related to the eye. RESULTS: Out of a total of 230 articles, 47 were organized in 3 subject groups for discussion: thyroid-associated orbitopathy, cornea and the ocular surface, and the retina and neovascularization. Review of the literature demonstrated that IGF-1 affects growth and development of the eye, epithelial proliferation, retinal angiogenesis, inflammation, and is associated with thyroid-associated orbitopathy. CONCLUSIONS: IGF-1R exists throughout in the human body, including the cornea, retina, and orbit. Research regarding ocular effects of IGF-1/IGF-1R outside thyroid eye disease is limited. Carefully designed studies and clinical assessments of patients undergoing treatment with anti-IGF-1R may identify ocular side effects and foster consideration of the role of anti-IGF-1R in ocular therapeutics. Given the increasing use of anti-IGF-1R antibodies, understanding their ocular effects, side effects, and potential systemic implications for use in disease is critical.

A comparison of pediatric ocular injuries based on intention in patients admitted with trauma.

PURPOSE: Pediatric ocular trauma is a major source of morbidity and blindness and the number of epidemiological studies is incommensurate with its significance. We sought to determine differences in epidemiologic patterns of pediatric ocular injuries based on intention. METHODS: A retrospective review of the National Trauma Data Bank (2008-2014) was performed and patients < 21 years old, admitted with trauma and ocular injury, were identified using ICD-9CM codes. Demographic data, types of injury and external circumstances including intention were tabulated and analyzed with students' t and chi-squared tests and logistic regression. Statistical significance was set at p < 0.05. RESULTS: Fifty-eight thousand seven hundred sixty-five pediatric patients were admitted for trauma and ocular injuries. The mean(SD) age was 11.9(6.9) years. Most patients were male (68.7%) and White (59.1%). Unintentional injuries (76.3%) were mostly associated with falls (OR = 13.4, p < 0.001), assault (16.3%) with firearms (OR = 9.15, p < 0.001) and self-inflicted trauma (0.7%) also with firearms (OR = 44.66, p < 0.001). There was increasing mean(SD) age from unintentional, 12.9(6.6) years and assault 12.3(8.1) years to self-inflicted trauma, 17(3.4) years. The 0-3 year age group had highest odds of open adnexa wounds (OR = 30.45, p < 0.001) from unintentional trauma, and traumatic brain injury (TBI) (OR = 5.77, p < 0.001) and mortality (OR = 8.52, p < 0.001) from assault. The oldest 19-21 year group, had highest odds visual pathway injuries (OR = 8.34, p < 0.001) and TBI (OR = 1.54, p = 0.048) from self-inflicted trauma and mortality (OR = 2.08, p < 0.001) from unintentional trauma. CONCLUSION: Sight-threatening injuries were mostly associated with unintentional trauma in the youngest group and self-inflicted trauma in the oldest group. Patterns emerged of associations between demographic groups, mechanisms, types of injury and associated TBI with intention of trauma.

Cannabidiol as an Adjunct to Botulinum Toxin in Blepharospasm - A Randomized Pilot Study.

Purpose: The purpose of this study was to evaluate the safety and efficacy of low dose cannabidiol (CBD; Epidiolex) as adjunctive therapy for idiopathic adult-onset blepharospasm (BPS), as well as develop a novel objective assessment methodology to gauge response. Methods: Prospective, randomized, double-masked, placebo-controlled crossover design of 6 months duration of 12 patients with BPS undergoing routine maximal botulinum toxin (BTX) therapy and experiencing breakthrough symptoms. Participants received their standard BTX every 3 months and were randomized to group A = CBD daily in cycle 1, followed by placebo in cycle 2 or group B = placebo followed by CBD. Videos recorded at days 0, 45, and 90 of each cycle were analyzed to quantify eyelid kinematics. The Jankovic Rating Scale (JRS) was used to provide a clinical rating. Results: All 12 patients completed the study without adverse events. CBD decreased median eyelid closure amplitude by 19.1% (-1.66 mm, confidence interval [CI] = -3.19 to -0.14 mm, P = 0.03), decreased median eyelid closure duration by 15.8% (-18.35 ms, CI = -29.37 to -7.32 ms, P = 0.001), and increased the maximum eyelid closure velocity by 34.8% (-13.26 mm/ms, CI = -20.93 to -5.58 mm/ms, P = 0.001). The JRS showed a 0.5 reduction in severity and frequency, which was not statistically significant. Conclusions: Low dose CBD was safely tolerated and improved several BPS kinematic parameters. The clinical scale suggested a direction of effect but may have been underpowered. Further studies are needed to better quantify the clinical relevance. Translational Relevance: This work describes a novel assessment methodology and therapeutic approach to bBPS.

Firearm-associated ocular injuries: analysis of national trauma data.

PURPOSE: The United States of America has the highest gun ownership rate of all high-income nations, and firearms have been identified as a leading cause of ocular trauma and visual impairment. The purpose of this study was to characterize firearm-associated ocular injury and identify at-risk groups. METHODS: Patients admitted with firearm-associated ocular injury were identified from the National Trauma Data Bank (2008-2014) using the International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic codes and E-codes for external causes. Statistical analysis was performed using the SPSS 24 software. Significance was set at p<0.05. RESULTS: Of the 235,254 patients, 8,715 (3.7%) admitted with firearm-associated trauma had ocular injuries. Mean (standard deviation) age was 33.8 (16.9) years. Most were males (85.7%), White (46.6%), and from the South (42.9%). Black patients comprised 35% of cases. Common injuries were orbital fractures (38.6%) and open globe injuries (34.7%). Frequent locations of injury were at home (43.8%) and on the street (21.4%). Black patients had the highest risk of experiencing assault (odds ratio [OR]: 9.0; 95% confidence interval [CI]: 8.02-10.11; p<0.001) and street location of injury (OR: 3.05; 95% CI: 2.74-3.39; p<0.001), while White patients had the highest risk of self--inflicted injury (OR: 10.53; 95% CI: 9.39-11.81; p<0.001) and home location of injury (OR: 3.64; 95% CI: 3.33-3.98; p<0.001). There was a steadily increasing risk of self-inflicted injuries with age peaking in those >80 years (OR: 12.01; 95% CI: 7.49-19.23; p<0.001). Mean (standard deviation) Glasgow Coma Scale and injury severity scores were 10 (5.5) and 18.6 (13.0), respectively. Most injuries (53.1%) were classified as severe or very severe injury, 64.6% had traumatic brain injury, and mortality occurred in 16% of cases. CONCLUSION: Most firearm-associated ocular injuries occurred in young, male, White, and Southern patients. Blacks were disproportionally affected. Most firearm-associated ocular injuries were sight--threatening and associated with traumatic brain injury. The majority survived, with potential long-term disabilities. The demographic differences identified in this study may represent potential targets for prevention.

Gender of Presenters at Ophthalmology Conferences Between 2015 and 2017.

PURPOSE: To analyze the proportion of women presenting at 9 major ophthalmology conferences over 3 years. DESIGN: Retrospective observational study. METHODS: Conference brochures from 9 national ophthalmology conferences from 2015 to 2017 were analyzed. Genders of first author presenters of papers and non-papers (moderators, presenters at symposia, panel discussions, workshops/instructional courses) were recorded. Comparisons were made to the gender ratio of board-certified ophthalmologists. Student t test and Cochran-Armitage trend test was used for analysis, with significance at P < .05. RESULTS: Of 14,214 speakers, 30.5% were female, statistically higher than the expected 25.4% (P < .001). Paper presenters were 33.1% female (P < .001) and non-paper presenters were 28.5% female (P < .001). When stratified to general or subspecialty conference, general conferences had a higher proportion of women compared to the American Board of Ophthalmology (ABO) expected rates (P < .001) for paper and non-paper presentations. The rates of female presenters increased over the 3 years only at the Association for Research in Vision and Ophthalmology (P = .009). Subgroup analysis showed that women presented 33.1% of papers but only 28.5% of non-paper presentations, which is lower than expected (P < .001). CONCLUSIONS: Our results highlight positive trends: the overall proportions of female speakers exceed ABO estimates of female ophthalmologists. However, the gender gap remains at many subspecialty conferences, especially for non-papers, which are more likely to require invitations rather than being self-submitted. As demographics continue to change, further efforts are needed to assure equitable selection of conference presenters.

Visual Pathway Injuries in Pediatric Ocular Trauma-A Survey of the National Trauma Data Bank From 2008 to 2014.

BACKGROUND: Traumatic visual pathway injuries are often associated with severe head trauma and can have profound deleterious effects in developing children and their rehabilitation. We sought to elucidate the epidemiology of pediatric visual pathway injuries in the United States. MATERIALS AND METHODS: This study is a retrospective evaluation of pediatric patients (less than 21 years of age) with visual pathway injuries that were submitted to the National Trauma Data Bank between 2008 to 2014. Patients were identified using the International Classification of Diseases, Ninth Revision Clinical Modification codes. Statistical analysis was performed with SPSS software. Variables were correlated using Student t test, chi-squared test, and logistic regression analyses. RESULTS: Of the 58,765 pediatric patients (1.7%) who were admitted with ocular injuries, 970 had visual pathway injuries. The majority of these patients were male (69.2%), and the mean age was 11.6 years (±7.2). Traumatic optic neuropathy was the most common (86.1%) visual pathway injury. It had the greatest odds of occurring with oculomotor nerve injury (odds ratio = 3.84; P < 0.001). Associated ocular injuries were open adnexal wounds (87.4%) and orbital fractures (23%). Common mechanisms were motor vehicle occupant (21.5%) and firearms (15.6%). Motor vehicle occupants were most likely white and firearms injury, black. In the zero to three years age group, most injuries were due to falls; injuries in the 19 to 21 years age group had the greatest association with firearms. Overall mortality was 17.6%. CONCLUSIONS: Visual pathway injuries may have devastatating sequelae and should be considered in pediatric ocular injuries. The clear majority were traumatic optic neuropathies. The common mechanisms, motor vehicle occupant and firearms, revealed age and race disparities.

Pediatric traumatic brain injury and ocular injury.

PURPOSE: Traumatic brain injury (TBI) is a leading cause of pediatric disability and mortality. Together with sight-threatening ocular injuries, TBIs may lead to devastating consequences in developing children and complicate rehabilitation. We sought to investigate this relationship in pediatric patients admitted with major trauma. METHODS: The records of pediatric patients admitted with ocular injury and concomitant TBI were reviewed retrospectively using the National Trauma Data Bank (2008-2014). RESULTS: Of 58,765 pediatric patients admitted for trauma and also had ocular injuries, 32,173 were diagnosed with TBI. Mean patient age was 12.3 ± 7 years. Most were male (69.8%) and White (61.2%). The most frequent injuries were contusion of the eye/adnexa (39.1%) and orbital fractures (35.8%). The youngest age groups had greatest odds of falls in home locations, whereas older groups were more likely to suffer motor vehicle trauma as occupants (MVTO), struck by or against (SBA) injuries, and firearms injuries in street locations (P < 0.001). Blacks and Hispanics were most likely to suffer assault (P < 0.001) and Whites, unintentional (P < 0.001) and self-inflicted (P < 0.012) injury. Blacks were at a higher risk of firearms injury, Whites of MVTO, and Hispanics of motor vehicles as pedestrians (P < 0.001). CONCLUSIONS: TBI frequently is experienced by trauma patients with concomitant ocular injury and should be considered in children admitted with major trauma. Resultant demographic patterns may help identify patients that have a higher risk of TBI leading to earlier diagnosis and treatment.

Firearm-associated ocular injuries: analysis of national trauma data / Lesões oculares relacionadas a armas de fogo: análise de dados nacionais de traumas nos EUA

ABSTRACT Purpose: The United States of America has the highest gun ownership rate of all high-income nations, and firearms have been identified as a leading cause of ocular trauma and visual impairment. The purpose of this study was to characterize firearm-associated ocular injury and identify at-risk groups. Methods: Patients admitted with firearm-associated ocular injury were identified from the National Trauma Data Bank (2008-2014) using the International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic codes and E-codes for external causes. Statistical analysis was performed using the SPSS 24 software. Significance was set at p<0.05. Results: Of the 235,254 patients, 8,715 (3.7%) admitted with firearm-associated trauma had ocular injuries. Mean (standard deviation) age was 33.8 (16.9) years. Most were males (85.7%), White (46.6%), and from the South (42.9%). Black patients comprised 35% of cases. Common injuries were orbital fractures (38.6%) and open globe injuries (34.7%). Frequent locations of injury were at home (43.8%) and on the street (21.4%). Black patients had the highest risk of experiencing assault (odds ratio [OR]: 9.0; 95% confidence interval [CI]: 8.02-10.11; p<0.001) and street location of injury (OR: 3.05; 95% CI: 2.74-3.39; p<0.001), while White patients had the highest risk of self-­inflicted injury (OR: 10.53; 95% CI: 9.39-11.81; p<0.001) and home location of injury (OR: 3.64; 95% CI: 3.33-3.98; p<0.001). There was a steadily increasing risk of self-inflicted injuries with age peaking in those >80 years (OR: 12.01; 95% CI: 7.49-19.23; p<0.001). Mean (standard deviation) Glasgow Coma Scale and injury severity scores were 10 (5.5) and 18.6 (13.0), respectively. Most injuries (53.1%) were classified as severe or very severe injury, 64.6% had traumatic brain injury, and mortality occurred in 16% of cases. Conclusion: Most firearm-associated ocular injuries occurred in young, male, White, and Southern patients. Blacks were disproportionally affected. Most firearm-associated ocular injuries were sight-­threatening and associated with traumatic brain injury. The majority survived, with potential long-term disabilities. The demographic differences identified in this study may represent potential targets for prevention.

RESUMO Objetivo: Os Estados Unidos têm a maior taxa de posse de armas de fogo de todos os países de alta renda e essas armas foram identificados como uma das maiores causas de trauma ocular e deficiência visual. O objetivo deste estudo foi caracterizar as lesões oculares associadas a armas de fogo e identificar grupos de risco. Métodos: Foram identificados pacientes hospitalizados com lesões oculares associadas a armas de fogo no período de 2008 a 2014, a partir do Banco de Dados Nacional de Trauma (National Trauma Data Bank), usando os códigos de diagnósticos da CID9MC e códigos "E" para causas externas. A análise estatística foi efetuada usando o programa SPSS. O nível de significância considerado foi de p<0,05. Resultados: De um total de 235.254 pacientes hospitalizados com trauma associado a armas de fogo, 8.715 (3,7%) tinham lesões oculares. A média de idade foi de 33,8 (DP 16,9) anos. A maioria foi de homens (85,7%), brancos (46,6%) e da região Sul (42,9%); 35% dos pacientes eram negros. As lesões mais comuns foram fraturas de órbita (38,6%) e lesões de globo aberto (34,7%). Os locais mais frequentes foram a residência (43,8%) e a rua (21,4%). Pacientes negros tiveram maior probabilidade de sofrer agressões (RP=9,0, IC 95%=8,02-10,11; p<0,001) e da ocorrência ser na rua (RP=3,05, IC 95%=2,74-3,39; p<0,001), enquanto pacientes brancos tiveram maior probabilidade de lesões autoprovocadas (RP=10,53, IC 95%=9,39-11,81; p<0,001) e da ocorrência ser na residência (RP=3,64, IC 95%=3,33-3,98; p<0,001). A probabilidade de lesões autoprovocadas aumentou com a idade de forma consistente, atingindo o máximo em pacientes com mais de 80 anos (RP=12,01, IC 95%=7,49-19,23; p<0,001). A pontuação média na escala de coma de Glasgow foi 10 (DP 5,5) e na escala de severidade da lesão foi 18,6 (DP 13,0). A maioria das lesões (53,1%) foi classificada como severa ou muito severa. Dentre os pacientes, 64,6% tiveram lesão cerebral traumática e 16% evoluíram a óbito. Conclusão: A maior parte das lesões oculares relacionadas a armas de fogo ocorreu em pacientes jovens, do sexo masculino, brancos e sulistas. Negros foram afetados desproporcionalmente. A maior parte das lesões oculares relacionadas a armas de fogo apresentou riscos à visão e foi associada a lesões cerebrais traumáticas. A maioria dos pacientes sobreviveu, mas com potencial para invalidez no longo prazo. As diferenças demográficas identificadas podem ser potencialmente alvos de ações preventivas.

Oxidative Stress in Caenorhabditis elegans: Protective Effects of Spartin.

Troyer syndrome is caused by a mutation in the SPG20 gene, which results in complete loss of expression of the protein spartin. We generated a genetic model of Troyer syndrome in worms to explore the locomotor consequences of a null mutation of the Caenorhabditis elegans SPG20 orthologue, F57B10.9, also known as spg-20. Spg-20 mutants showed decreased length, crawling speed, and thrashing frequency, and had a shorter lifespan than wild-type animals. These results suggest an age-dependent decline in motor function in mutant animals. The drug paraquat was used to induce oxidative stress for 4 days in the animals. We measured survival rate and examined locomotion by measuring crawling speed and thrashing frequency. After 4 days of paraquat exposure, 77% of wild-type animals survived, but only 38% of spg-20 mutant animals survived. Conversely, animals overexpressing spg-20 had a survival rate of 95%. We also tested lifespan after a 1 hour exposure to sodium azide. After a 24 hour recovery period, 87% of wild type animals survived, 57% of spg-20 mutant animals survived, and 82% of animals overexpressing spg-20 survived. In the behavioral assays, spg-20 mutant animals showed a significant decrease in both crawling speed and thrashing frequency compared with wild-type animals. Importantly, the locomotor phenotype for both crawling and thrashing was rescued in animals overexpressing spg-20. The animals overexpressing spg-20 had crawling speeds and thrashing frequencies similar to those of wild-type animals. These data suggest that the protein F57B10.9/SPG-20 might have a protective role against oxidative stress.