Developmental Neuroscience最新文献

Background: Fetal growth restriction (FGR) corresponds to the fetus's inability to achieve an adequate weight gain based on genetic potential and gestational age. It is an important cause of morbidity and mortality.

Summary: In this review, we address the challenges of diagnosis and classification of FGR. We review how chronic fetal hypoxia impacts brain development. We describe recent advances on placental and fetal brain imaging using magnetic resonance imaging and how they offer new noninvasive means to study growth restriction in humans. We go on to review the impact of FGR on brain integrity in the neonatal period, later childhood, and adulthood and review available therapies.

Key messages: FGR consequences are not limited to the perinatal period. We hypothesize that impaired brain reserve, as defined by structure and size, may predict some concerning epidemiological data of impaired cognitive outcomes and dementia with aging in this group of patients.

Background: Fetal growth restriction (FGR) corresponds to the fetus's inability to achieve an adequate weight gain based on genetic potential and gestational age. It is an important cause of morbidity and mortality.

Summary: In this review, we address the challenges of diagnosis and classification of FGR. We review how chronic fetal hypoxia impacts brain development. We describe recent advances on placental and fetal brain imaging using magnetic resonance imaging and how they offer new noninvasive means to study growth restriction in humans. We go on to review the impact of FGR on brain integrity in the neonatal period, later childhood, and adulthood and review available therapies.

Key messages: FGR consequences are not limited to the perinatal period. We hypothesize that impaired brain reserve, as defined by structure and size, may predict some concerning epidemiological data of impaired cognitive outcomes and dementia with aging in this group of patients.

Introduction: Early prediction and timely intervention are particularly essential for high-risk preterm infants. Brain magnetic resonance imaging (BMRI) is frequently used alongside functional evaluations to improve predictions of developmental outcomes. This study aimed to assess voxel-based brain volumetry in extremely preterm infants using BMRI at term equivalent age (TEA) and investigate its association with developmental outcomes.

Methods: From March 2016 to December 2019, high-risk preterm infants (birth weight <1,500 g or gestational age <32 weeks) with BMRI at TEA and follow-up developmental data assessed by Bayley-III were included. For BMRI volumetry, manual tracing and segmentation were performed on T1-weighted scans, and after smoothing, voxels were calculated for each brain segment. Forty-seven subjects were enrolled and categorized into typical/delayed motor groups.

Results: Results revealed a significant difference in ventricle size and ventricle ratio in BMRI at TEA between the groups. Even after controlling for other factors that could influence developmental outcomes, ventricle ratio emerged as a robust, single predictor for future motor development.

Conclusion: This study suggests the potential clinical utility of BMRI volumetry in predicting motor development outcomes.

Introduction: Obsessive-compulsive disorder (OCD) is a mental health disorder characterized by obsessions and compulsions. There is a mounting body of evidence suggesting a link between OCD and inflammation. Neuropsychiatric deteriorations have been reported to follow COVID-19 infections, including OCD. Additionally, symptomatic arthritis has also been reported following COVID-19 infection. We aim to describe post-COVID-19 clinical deteriorations presenting to our multidisciplinary immune behavioral health clinic.

Methods: One hundred and fifty-one prescreened patients were evaluated in our clinic between March 1, 2020 and August 1, 2024. We systematically searched charts for infection with SARS-CoV-2 and found 3 cases of confirmed COVID-19 infection that preceded an abrupt neuropsychiatric deterioration (in the absence of other detected infections). Per our clinic's latest protocol, all patients underwent a full rheumatology and arthritis evaluation (regardless of joint complaints) including ultrasound imaging, which were used to objectively assess for effusions, synovitis, and capsulitis.

Results: Two of the three patients met criteria for a PANS diagnosis. All 3 patients had new-onset OCD or reescalation of OCD with new obsessions/compulsions/rituals post-COVID-19 and all three had imaging findings of effusions +/- synovitis +/- capsulitis despite not having significant complaints of joint pain. Joint pain complaints evolved after psychiatric symptoms improved (because the capacity of the patient to articulate joint pain improved when they were less overwhelmed by intrusive thoughts). Immunomodulatory treatment began with nonsteroidal anti-inflammatory drugs (NSAIDs) and was escalated to disease-modifying antirheumatic drugs (DMARDs) in the 2 patients with synovitis +/- capsulitis. All 3 patients eventually returned to baseline neuropsychiatric health (minimal-to-no OCD and resolution of intense anxiety and mood instability) and also had improvement in arthritic findings after introduction of NSAID +/- DMARDs.

Conclusion: Infections may result in systemic immune activation leading to inflammation. Thus, when patients have an acute neuropsychiatric deterioration (hypothesized to have been triggered by an infection), the situation may warrant evaluation for inflammation in other more accessible sites (e.g., joints). Use of this evidence of inflammation (as a sign of immune activation) is helpful since it is difficult to assess for brain inflammation, as clinical brain imaging has poor sensitivity for inflammation and biopsy of the striatum (and other areas involved in OCD) is difficult and limited by risk. In our cases, early joint imaging not only helped confirm signs of systemic inflammation in the setting of neuropsychiatric symptoms, but it also allowed for earlier initiation of immunomodulatory treatment.

Background: In contemporary medical practice, general anesthesia plays an essential role in pediatric surgical procedures. While modern anesthetic protocols have demonstrated safety and efficacy across various pathological conditions, concerns persist regarding the potential neurotoxic effects associated with early exposure to general anesthesia.

Summary: Current research primarily examines the neurocognitive developmental impacts, with limited focus on neurobehavioral developmental disorders. This review presents a comprehensive analysis of clinical trial results related to five critical neurobehavioral developmental disorders: fine motor disability, attention-deficit hyperactivity disorder, impulse control disorders, autism spectrum disorder, and developmental coordination disorder. Furthermore, this review synthesizes insights from basic research on the potential toxicological mechanisms of general anesthetic agents that could influence clinical neurobehavioral changes. These findings provide valuable guidance for the prudent and safe utilization of anesthetic agents in pediatric patients.

Key messages: This review explores the potential connections between general anesthesia and five neurobehavioral disorders, highlighting the importance of cautious anesthetic use in children in light of current research findings.

Introduction: Pediatric acute-onset neuropsychiatric syndrome (PANS) is an immune-mediated disease characterized by abrupt onset neurobehavioral changes. Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn's disease (CD), chronic conditions characterized by gastrointestinal inflammation. We describe eight individuals with both PANS and IBD.

Methods: All individuals with both IBD and PANS were identified from Stanford Immune Behavioral Health Clinic, Cedars-Sinai Medical Center Pediatric Inflammatory Bowel Disease Program, and Dartmouth Neuroimmune Psychiatric Disorders (NIPD) Clinic. Data were collected by chart review.

Results: Eight cases of PANS with IBD were identified. Five were male. The mean age of onset was 9.3 years for PANS and 15.6 years for IBD. PANS preceded development of IBD in 7 of 8 cases by a mean of 8.4 years. Seven patients (88%) had a first-degree relative with an immune-mediated disease, including 5 with psoriasis or psoriatic arthritis. Five patients themselves had arthralgias or arthritis (63%). All 5 cases where PANS preceded IBD treatment sufficiently for analysis were free of major behavioral relapses after IBD was managed.

Conclusion: The triad of PANS, joint complaints, and family history of autoimmunity, including psoriasis, may represent a subset of PANS at heightened risk for IBD and additional immune-mediated disorders. For children with this triad, clinicians should have a low threshold to evaluate for gastrointestinal inflammation with biomarkers like hemoglobin, CRP, fecal calprotectin, and diagnostic endoscopy when indicated. PANS symptoms may improve with effective treatment of IBD. The high prevalence of joint complaints in our cohort and psoriasis in first-degree family members suggests this subset of PANS may share immune mechanisms with psoriasis and arthritis. Treatment strategies used in IBD and arthritis should be studied for potential application in PANS.

Introduction: Multiple lines of evidence suggest that some cases of obsessive-compulsive disorder (OCD) are underlain by autoimmune and/or inflammatory processes that act on the brain to create neuropsychiatric symptomatology. However, studies of immunomodulatory treatments for such cases are sparse. Here we present consecutive cases of presumed-neuroimmune OCD in youth that have been treated with rituximab +/- adjunctive immunomodulatory treatments.

Methods: Of the 458 cases evaluated by our clinic between September 15, 2012, and January 6, 2023, 23 patients were treated with rituximab +/- adjunctive immunomodulation orchestrated by our team (based on evidence of autoimmunity) and were followed routinely by the outpatient clinic team. Patients who presented for a second opinion and were not diagnosed, treated, and/or followed by our outpatient clinic (n = 5) or did not have OCD (n = 1) are not included. We present the immunological and psychiatric profiles (prior to treatment), selection criteria for the use of rituximab, rituximab treatment protocol, recovery status, and reasons for discontinuation (if applicable). Data were obtained from chart review of clinical records. Determination of recovery status was confirmed by the clinical team caring for the patients; patients were classified as did not recover, partial recovery (PR), or full recovery (FR). Since multiple treatments (psychotherapy, psychiatric medication, and immunomodulation) together contributed to recovery, the team additionally assessed the attribution of response to rituximab and details are documented.

Results: Patients were between the ages of 4 and 20 at initiation of rituximab treatment. All suffered from severe, debilitating neuropsychiatric symptoms prior to rituximab initiation in the context of evidence for systemic autoimmunity. Approximately 70% had an unequivocal recovery following treatment with rituximab (+/- induction and adjunctive immunomodulation) which in most cases allowed the patients to achieve normal levels of function and cease psychotropic medications. Interpretation of attribution in many cases is complicated by the use of induction and adjunct immunomodulation. Most patients experienced transient increases in symptoms before improving; 11 experienced mild self-limited infusion-related reactions, and 14 experienced hypogammaglobulinemia. No patient had an organ or life-threatening reaction or infection following rituximab. One patient developed recurrent sinusitis following rituximab, and thus, rituximab was stopped despite neuropsychiatric improvements, then rituximab was restarted later due to recrudescence of psychiatric symptoms; the approval to use rituximab with intravenous immune globulin (IVIG) permitted its use. Patients who received adjunctive immunomodulation (IVIG, methotrexate, leflunomide, etc.) had a higher likelihood of achieving recovery (FR or PR) after rituximab (Fisher

Introduction: Establishing clear and standardized terminology regarding disease state and course is crucial for enhancing communication, research, and treatment decisions, particularly when there are no clearly identified biological markers, as in the case of pediatric acute-onset neuropsychiatric syndrome (PANS). We aim to propose terminology for assessing disease state and classifying long-term clinical courses in individuals evaluated for PANS, advancing standardization in clinical care and research.

Methods: We drew upon clinical expertise, insights from similar conditions, and a decade of longitudinal clinical data from the Stanford University Immune Behavioral Health (IBH) Clinic to devise terminology for characterizing patient status and clinical progression among patients evaluated for PANS. Utilizing parent- and clinician-reported data spanning from 2012 to 2023, we constructed a comprehensive dataset documenting patients' disease trajectory from initial flare to latest clinical encounter, encompassing intervening recovery periods. This allowed us to apply the proposed terminology to the IBH Clinic patient cohort, offering a detailed phenotypic analysis of PANS flares and clinical courses.

Results: We analyzed 264 patients evaluated for PANS at the IBH Clinic and stratified them based on whether they met PANS criteria at initial flare (51%), after initial flare (24%), or had not met criteria at the time of analysis (25%). The average age at the initial flare ranged from 6.1 to 8.3 years across these patient subgroups. Among patients with PANS, the average isolated flare lasted 3.7-4.1 months and 95% of flares resolved within 1 year. Five years after initial flare, most (77%) patients with PANS had had multiple flares, and nearly half (43%) had experienced a flare that lasted >12 months, approximately half of which occurred at the initial flare.

Conclusions: Patients evaluated for PANS at the IBH Clinic showed diverse clinical presentations and illness courses over the long term, with most experiencing a relapsing-remitting clinical course but some exhibiting persistent symptoms. Many experienced neuropsychiatric flares before meeting PANS classification criteria. This underscores the importance of clinicians being vigilant for new neuropsychiatric symptoms in pediatric patients, even if they do not immediately meet PANS criteria. Based on these data, we propose terms and definitions for characterizing patient status, flares, and clinical course, which we hope the clinical and research communities will build on and refine.

Introduction: Sevoflurane is an extensively used anesthetic for pediatric patients; however, numerous studies showed that sevoflurane (SEVO) may cause long-term neurodevelopmental toxicity. Dexmedetomidine (DEX) has been shown to be protective against SEVO-induced neurotoxicity, but the mechanism remains unclear. The effects and mechanisms of different DEX administration routes on SEVO-induced neurotoxicity and long-term cognitive defects were determined and further investigated the role of sex in these processes.

Methods: Male and female Sprague Dawley rats at postnatal day 7 (PND7) received an intraperitoneal injection of DEX (10 μg/kg) before or after exposure to 2.5% SEVO for 6 h, or before and after SEVO exposure. The respiratory and mortality rates of the pups were recorded during anesthesia. Neuroapoptosis was evaluated by TdT-mediated dUTP nick-end labeling staining. Immunohistochemistry and immunofluorescence were employed to detect the expression of caspase-3 in neuronal cells and neurons. The expression of GSK-3β and DISC1 was determined by Western blotting or RT-qPCR. Morris water maze (MWM) test was used to evaluate the learning and memory ability of rats until they were 3 weeks and 5 weeks old.

Results: Compared with the control group, exposure to 2.5% SEVO resulted in increased neuroapoptosis and decreased the expression of DISC1 at levels of mRNA and protein and phosphorylated GSK-3β in the developing brain. SEVO exposure during critical neurodevelopmental periods could cause persistent cognitive defects in adolescent male and female rats and inhibited DISC1 and phosphorylated GSK-3β protein expression. The neurotoxic impacts of SEVO were lessened by the administration of DEX (10 μg/kg) before or after exposure.

Conclusion: Our findings suggest that DEX (10 μg/kg) mitigates the neurotoxic effects of SEVO on the developing rat brain as well as postnatal cognitive defects by regulating the DISC1/GSK-3β signaling.