Dimensional Neuroimaging Endophenotypes: Neurobiological Representations of Disease Heterogeneity Through Machine Learning.

Machine learning has been increasingly used to obtain individualized neuroimaging signatures for disease diagnosis, prognosis, and response to treatment in neuropsychiatric and neurodegenerative disorders. Therefore, it has contributed to a better understanding of disease heterogeneity by identifying disease subtypes with different brain phenotypic measures. In this review, we first present a systematic literature overview of studies using machine learning and multimodal magnetic resonance imaging to unravel disease heterogeneity in various neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease, schizophrenia, major depressive disorder, autism spectrum disorder, and multiple sclerosis, as well as their potential in a transdiagnostic framework, where neuroanatomical and neurobiological commonalities were assessed across diagnostic boundaries. Subsequently, we summarize relevant machine learning methodologies and their clinical interpretability. We discuss the potential clinical implications of the current findings and envision future research avenues. Finally, we discuss an emerging paradigm called dimensional neuroimaging endophenotypes. Dimensional neuroimaging endophenotypes dissects the neurobiological heterogeneity of neuropsychiatric and neurodegenerative disorders into low-dimensional yet informative, quantitative brain phenotypic representations, serving as robust intermediate phenotypes (i.e., endophenotypes), presumably reflecting the interplay of underlying genetic, lifestyle, and environmental processes associated with disease etiology.

Genetic predisposition of BDNF (rs6265) gene is susceptible to Schizophrenia: A prospective study and updated meta-analysis / Asociación entre el gen BDNF (rs6265) y predisposición a la esquizofrenia: estudio prospectivo y metaanálisis actualizado

Introduction: Genetic polymorphism in the BDNF gene has been found to cause neuronal alterations and has been identified as a causal factor for many neuropsychiatric disorders. Therefore, various neurological case–control studies and meta-analyses have been conducted to find the possible link between BDNF and susceptibility to schizophrenia. Method: This meta-analysis gathered data from 25 case–control studies including a total of 8384 patients with schizophrenia and 8821 controls in order to identify the relationship between the rs6265 single nucleotide polymorphism and the disease, evaluating the combined odds ratio and 95% confidence intervals under 5 different genetic models. Validation followed the “Leave one out” method, and we used the Egger test and Begg's funnel plot to identify publication bias. Results: Research into the rs6265 (G/A) polymorphism revealed a non-significant association with schizophrenia in all 5 genetic models; in the subgroup analysis, no association was found between white and Asian populations, with a p value > .05. Conclusions: Overall, the updated meta-analysis revealed that rs6265 exonic polymorphisms do not increase susceptibility to this disease. However, to better understand the pathogenesis of the disease, there is a need for further case–control studies into the BDNF polymorphism including larger sample sizes and different ethnic groups.(AU)

Introducción: Se sabe que los polimorfismos del gen BDNF provocan alteraciones neuronales y parecen ser un factor causal en muchos trastornos neuropsiquiátricos. Es por ello que se han llevado a cabo varios metaanálisis y estudios de casos y controles con el objetivo de evaluar la posible relación entre BDNF y la esquizofrenia. Método: Realizamos un metaanálisis de 25 estudios de casos y controles, que incluyó un total de 8.384 pacientes con esquizofrenia y 8.821 controles. Se analizó la relación entre el polimorfismo de nucleótido simple rs6265 y la esquizofrenia mediante odds ratios combinados y sus intervalos de confianza del 95% con 5 modelos genéticos diferentes. Utilizamos el método de validación cruzada dejando uno fuera («leave one out»), la prueba de Egger y el gráfico en embudo de Begg para identificar posibles sesgos de publicación. Resultados: Los estudios sobre el polimorfismo rs6265 (G/A) muestran una asociación no significativa con la esquizofrenia en los 5 modelos genéticos. En el análisis por subgrupos, no se encontró relación con las poblaciones caucásica y asiática (p > 0,05). Conclusiones: La presencia de polimorfismos rs6265 no aumenta la predisposición a desarrollar esquizofrenia. Sin embargo, se deben realizar más estudios de casos y controles sobre polimorfismos de BDNF, con muestras más numerosas y con individuos de diferentes grupos étnicos, para comprender mejor los mecanismos patogénicos de la enfermedad.(AU)

The association between attention deficit hyperactivity disorder and pregnancy, delivery and neonatal outcomes-an evaluation of a population database.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is one of the more common neuropsychiatric disorders in women of reproductive age. Our objective was to compare perinatal outcomes between women with an ADHD diagnosis and those without. METHODS: A retrospective population-based cohort study utilizing the Healthcare Cost and Utilization Project, Nationwide Inpatient Sample (HCUP-NIS) United States database. The study included all women who either delivered or experienced maternal death from 2004 to 2014. Perinatal outcomes were compared between women with an ICD-9 diagnosis of ADHD and those without. RESULTS: Overall, 9,096,788 women met the inclusion criteria. Amongst them, 10,031 women had a diagnosis of ADHD. Women with ADHD, compared to those without, were more likely to be younger than 25 years of age; white; to smoke tobacco during pregnancy; to use illicit drugs; and to suffer from chronic hypertension, thyroid disorders, and obesity (p < 0.001 for all). Women in the ADHD group, compared to those without, had a higher rate of hypertensive disorders of pregnancy (HDP) (aOR 1.36, 95% CI 1.28-1.45, p < 0.001), cesarean delivery (aOR 1.19, 95% CI 1.13-1.25, p < 0.001), chorioamnionitis (aOR 1.34, 95% CI 1.17-1.52, p < 0.001), and maternal infection (aOR 1.33, 95% CI 1.19-1.5, p < 0.001). Regarding neonatal outcomes, patients with ADHD, compared to those without, had a higher rate of small-for-gestational-age neonate (SGA) (aOR 1.3, 95% CI 1.17-1.43, p < 0.001), and congenital anomalies (aOR 2.77, 95% CI 2.36-3.26, p < 0.001). CONCLUSION: Women with a diagnosis of ADHD had a higher incidence of a myriad of maternal and neonatal complications, including cesarean delivery, HDP, and SGA neonates.

Genetic predisposition of BDNF (rs6265) gene is susceptible to Schizophrenia: A prospective study and updated meta-analysis.

INTRODUCTION: Genetic polymorphism in the BDNF gene has been found to cause neuronal alterations and has been identified as a causal factor for many neuropsychiatric disorders. Therefore, various neurological case-control studies and meta-analyses have been conducted to find the possible link between BDNF and susceptibility to schizophrenia. METHOD: This meta-analysis gathered data from 25 case-control studies including a total of 8384 patients with schizophrenia and 8821 controls in order to identify the relationship between the rs6265 single nucleotide polymorphism and the disease, evaluating the combined odds ratio and 95% confidence intervals under 5 different genetic models. Validation followed the "Leave one out" method, and we used the Egger test and Begg's funnel plot to identify publication bias. RESULTS: Research into the rs6265 (G/A) polymorphism revealed a non-significant association with schizophrenia in all 5 genetic models; in the subgroup analysis, no association was found between white and Asian populations, with a p value>.05. CONCLUSIONS: Overall, the updated meta-analysis revealed that rs6265 exonic polymorphisms do not increase susceptibility to this disease. However, to better understand the pathogenesis of the disease, there is a need for further case-control studies into the BDNF polymorphism including larger sample sizes and different ethnic groups.

Neurobiological evidence and criminal competencies.

Neuroimaging and other neurobiological evidences are increasingly introduced in criminal litigation, especially when a neuropsychiatric disorder is suspected. Evaluations of criminal competencies are the most common type of criminal forensic assessment in forensic psychiatry and psychology. Given this, it is critical for forensic evaluators to understand how neuropsychiatric disorders may affect a defendant's criminal competencies and how neurobiological data may be used in competency determinations. This paper reviews the use of neurobiological data, particularly neuroimaging, while considering the limitations and potential misuse of such data in criminal competency evaluations.

The Risk Genes for Neuropsychiatric Disorders negr1 and opcml Are Expressed throughout Zebrafish Brain Development.

The immunoglobulin LAMP/OBCAM/NTM (IgLON) family of cell adhesion molecules comprises five members known for their involvement in establishing neural circuit connectivity, fine-tuning, and maintenance. Mutations in IgLON genes result in alterations in these processes and can lead to neuropsychiatric disorders. The two IgLON family members NEGR1 and OPCML share common links with several of them, such as schizophrenia, autism, and major depressive disorder. However, the onset and the underlying molecular mechanisms have remained largely unresolved, hampering progress in developing therapies. NEGR1 and OPCML are evolutionarily conserved in teleosts like the zebrafish (Danio rerio), which is excellently suited for disease modelling and large-scale screening for disease-ameliorating compounds. To explore the potential applicability of zebrafish for extending our knowledge on NEGR1- and OPCML-linked disorders and to develop new therapeutic strategies, we investigated the spatio-temporal expression of the two genes during early stages of development. negr1 and opcml are expressed maternally and subsequently in partially distinct domains of conserved brain regions. Other areas of expression in zebrafish have not been reported in mammals to date. Our results indicate that NEGR1 and OPCML may play roles in neural circuit development and function at stages earlier than previously anticipated. A detailed functional analysis of the two genes based on our findings could contribute to understanding the mechanistic basis of related psychiatric disorders.

Dimensional Neuroimaging Endophenotypes: Neurobiological Representations of Disease Heterogeneity Through Machine Learning.

Machine learning has been increasingly used to obtain individualized neuroimaging signatures for disease diagnosis, prognosis, and response to treatment in neuropsychiatric and neurodegenerative disorders. Therefore, it has contributed to a better understanding of disease heterogeneity by identifying disease subtypes that present significant differences in various brain phenotypic measures. In this review, we first present a systematic literature overview of studies using machine learning and multimodal MRI to unravel disease heterogeneity in various neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease, schizophrenia, major depressive disorder, autism spectrum disorder, multiple sclerosis, as well as their potential in transdiagnostic settings. Subsequently, we summarize relevant machine learning methodologies and discuss an emerging paradigm which we call dimensional neuroimaging endophenotype (DNE). DNE dissects the neurobiological heterogeneity of neuropsychiatric and neurodegenerative disorders into a low-dimensional yet informative, quantitative brain phenotypic representation, serving as a robust intermediate phenotype (i.e., endophenotype) largely reflecting underlying genetics and etiology. Finally, we discuss the potential clinical implications of the current findings and envision future research avenues.

A novel ternary pattern-based automatic psychiatric disorders classification using ECG signals.

Neuropsychiatric disorders are one of the leading causes of disability. Mental health problems can occur due to various biological and environmental factors. The absence of definitive confirmatory diagnostic tests for psychiatric disorders complicates the diagnosis. It's critical to distinguish between bipolar disorder, depression, and schizophrenia since their symptoms and treatments differ. Because of brain-heart autonomic connections, electrocardiography (ECG) signals can be changed in behavioral disorders. In this research, we have automatically classified bipolar, depression, and schizophrenia from ECG signals. In this work, a new hand-crafted feature engineering model has been proposed to detect psychiatric disorders automatically. The main objective of this model is to accurately detect psychiatric disorders using ECG beats with linear time complexity. Therefore, we collected a new ECG signal dataset containing 3,570 ECG beats with four categories. The used categories are bipolar, depression, schizophrenia, and control. Furthermore, a new ternary pattern-based signal classification model has been proposed to classify these four categories. Our proposal contains four essential phases, and these phases are (i) multileveled feature extraction using multilevel discrete wavelet transform and ternary pattern, (ii) the best features selection applying iterative Chi2 selector, (iii) classification with artificial neural network (ANN) to calculate lead wise results and (iv) calculation the voted/general classification accuracy using iterative majority voting (IMV) algorithm. tenfold cross-validation is one of the most used validation techniques in the literature, and this validation model gives robust classification results. Using ANN with tenfold cross-validation, lead-by-lead and voted results have been calculated. The lead-by-lead accuracy range of the proposed model using the ANN classifier is from 73.67 to 89.19%. By deploying the IMV method, the general classification performance of our ternary pattern-based ECG classification model is increased from 89.19 to 96.25%. The findings and the calculated classification accuracies (single lead and voted) clearly demonstrated the success of the proposed ternary pattern-based advanced signal processing model. By using this model, a new wearable device can be proposed.

Cerebellar Heterotopia: Broadening the Neuroradiological Spectrum of KBG Syndrome.

KBG syndrome is a rare genetic disorder caused by heterozygous pathogenic variants in ANKRD11. Affected individuals have developmental delay, short stature, characteristic facial features, and other dysmorphic findings. To date, a spectrum of unspecific neuroradiological defects has been reported in KBG patients, such as cortical defects, white matter abnormalities, corpus callosum, and cerebellar vermis hypoplasia.Deep clinical and neuroradiological phenotyping and genotype of a patient presenting with mild cognitive and behavioral problems were obtained after written informed consent.We herein describe the first KBG patient presenting with cerebellar heterotopia, a heterogeneous malformation characterized by the presence of clusters of neurons within the white matter of cerebellar hemispheres.This novel association broadens the neuroradiological spectrum of KBG syndrome, and further prompts to investigate the potential functions of ANKRD11 in cerebellar development.

Gut microbiota connects the brain and the heart: potential mechanisms and clinical implications.

Nowadays, high morbidity and mortality of cardiovascular diseases (CVDs) and high comorbidity rate of neuropsychiatric disorders contribute to global burden of health and economics. Consequently, a discipline concerning abnormal connections between the brain and the heart and the resulting disease states, known as psychocardiology, has garnered interest among researchers. However, identifying a common pathway that physicians can modulate remains a challenge. Gut microbiota, a constituent part of the human intestinal ecosystem, is likely involved in mutual mechanism CVDs and neuropsychiatric disorder share, which could be a potential target of interventions in psychocardiology. This review aimed to discuss complex interactions from the perspectives of microbial and intestinal dysfunction, behavioral factors, and pathophysiological changes and to present possible approaches to regulating gut microbiota, both of which are future directions in psychocardiology.

Spatio-molecular profiles shape the human cerebellar hierarchy along the sensorimotor-association axis.

Cerebellar involvement in both motor and non-motor functions manifests in specific regions of the human cerebellum, revealing the functional heterogeneity within it. One compelling theory places the heterogeneity within the cerebellar functional hierarchy along the sensorimotor-association (SA) axis. Despite extensive neuroimaging studies, evidence for the cerebellar SA axis from different modalities and scales was lacking. Thus, we establish a significant link between the cerebellar SA axis and spatio-molecular profiles. Utilizing the gene set variation analysis, we find the intermediate biological principles the significant genes leveraged to scaffold the cerebellar SA axis. Interestingly, we find these spatio-molecular profiles notably associated with neuropsychiatric dysfunction and recent evolution. Furthermore, cerebello-cerebral interactions at genetic and functional connectivity levels mirror the cerebral cortex and cerebellum's SA axis. These findings can provide a deeper understanding of how the human cerebellar SA axis is shaped and its role in transitioning from sensorimotor to association functions.

Vagus Nerves Stimulation: Clinical Implication and Practical Issue as a Neuropsychiatric Treatment.

Vagus nerve stimulation (VNS) has been approved as an adjunctive treatment for epilepsy and depression. As the progress of VNS treatment for these neuropsychiatric disorders continues, its applications have expanded to a wide range of conditions, including inflammatory diseases to cognitive dysfunctions. The branches of the vagal nerves directly or indirectly innervate the anatomical structures implicated in these neuropsychiatric conditions, which has led to promising results regarding the effectiveness of VNS. Previous studies investigating the effectiveness of VNS have mostly utilized invasive forms of stimulation. However, current preclinical and clinical research indicates that non-invasive forms of VNS, such as transcutaneous vagus nerve stimulation, hold the promise for treating various neuropsychiatric conditions. This review aims to delve into relevant clinical studies of VNS in various illness states, different methods of VNS, and the potential mechanisms underlying the therapeutic effects in these neuropsychiatric conditions.

Unraveling the Role of miR-200b-3p in Attention-Deficit/Hyperactivity Disorder (ADHD) and Its Therapeutic Potential in Spontaneously Hypertensive Rats (SHR).

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder in children with unknown etiology. Impaired learning ability was commonly reported in ADHD patients and has been associated with dopamine uptake in the striatum of an animal model. Another evidence also indicated that micro-RNA (miR)-200b-3p is associated with learning ability in various animal models. However, the association between miR-200b-3p and ADHD-related symptoms remains unclear. Therefore, the current study investigated the role of miR-200b-3p in ADHD-related symptoms such as inattention and striatal inflammatory cytokines. To verify the influence of miR-200b-3p in ADHD-related symptoms, striatal stereotaxic injection of miR-200b-3p antagomir (AT) was performed on spontaneously hypertensive rats (SHR). The antioxidant activity and expressions of miR-200b-3p, slit guidance ligand 2 (Slit2), and inflammatory cytokines in the striatum of SHR were measured using quantitative real-time polymerase chain reaction (RT-qPCR), immunohistochemistry (IHC), immunoblotting, and enzyme-linked immunosorbent assay (ELISA). The spontaneous alternation of SHR was tested using a three-arm Y-shaped maze. The administration of miR-200b-3p AT or taurine significantly decreased striatal tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 in SHR, along with increased super-oxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and significantly higher spontaneous alternation. In this paper, we show that miR-200b-3p AT and taurine alleviates ADHD-related symptoms in SHR. These findings provide insights into ADHD's molecular basis and suggest miR-200b-3p as a potential therapeutic target. Concurrently, this study also suggests broad implications for treating neurodevelopmental disorders affecting learning activity such as ADHD.

Sensory processing in children with Paediatric Acute-onset Neuropsychiatric Syndrome.

INTRODUCTION: Previous research indicates that children with Paediatric Acute-onset Neuropsychiatric Syndrome (PANS) experience sensory reactivity differences that impact occupational performance. The purpose of this study was to determine whether there are differences in sensory reactivity in these children across two different time points; during exacerbation and during remission, using the Sensory Processing Measure (SPM) Home-Form. The study also sought to investigate whether children with PANS experience sensory differences during remission periods, when compared with SPM Home-Form norms. METHODS: A two-period bidirectional case-crossover design was used, and an online assessment was conducted to measure sensory reactivity. Parents of children aged 4.6 to 13.1 years with a diagnosis of PANS were recruited from various sites across Australia, USA, England, Ireland, Scotland, Canada, and New Zealand. The SPM Home-Form was used to measure sensory reactivity at two time points, when PANS was in remission (T-R) and in exacerbation (T-E). Study entry was permitted at either T-E or T-R. Participant exacerbation status was monitored over a maximum 12-month period, and a follow-up SPM Home-Form was sent when a change in exacerbation status was indicated. A linear mixed model was used to assess the difference between SPM Home-Form norm-referenced scores during exacerbation and remission. RESULTS: The study included 82 participants, with 80 providing data at study entry, and 27 providing data at follow-up. Results showed a statistically significant decline in performance across the SPM Home-Form domains of Hearing, Social Participation, Planning and Ideas, and Total Sensory Systems T-scores during exacerbation when compared with remission data. Results also demonstrated atypical sensory reactivity across Vision, Hearing, Touch, Balance and Motion, and Total Sensory Systems domains during periods of remission compared with SPM Home-Form norms. CONCLUSION: This study found that children with PANS experience significant sensory reactivity differences during exacerbation and remission across multiple sensory domains, with a decline in performance during exacerbation. Where there are occupational performance challenges, occupational therapists should consider administering sensory assessments so that effective intervention plans addressing the unique sensory reactivity needs of children with PANS can be developed.

Neuropsychiatric manifestations of tuberous sclerosis in a young man in a psychiatric hospital in Botswana: a case report.

Tuberous sclerosis complex (TSC), first described in 1880, is a disorder that affects multiple systems. Its symptoms include seizures, intellectual disability, and angiofibromas. TSC is caused by mutations in the TSC1 and TSC2 genes and is inherited in an autosomal dominant manner. The present report describes the case of a patient with an unusual psychological presentation who was evaluated in a psychiatric hospital. A man with poorly managed epilepsy was brought to Botswana's only psychiatric hospital. After clinical assessment, a diagnosis of tuberous sclerosis complex was made, which was later confirmed through neuroimaging and genetic tests. Some of the patient's relatives also showed similar neuropsychiatric symptoms. Given that psychiatry may be the first medical contact for TSC patients, especially in low-resource settings, clinicians need to be knowledgeable of various neuropsychiatric conditions and be aware of the possibility of TSC in patients that present with neurocutaneous manifestations. A multidisciplinary team approach is vital for the investigation and management of such cases.

SynCAMs in Normal Vertebrate Neural Development and Neuropsychiatric Disorders: from the Perspective of the OCAs.

Neuronal synaptic junctions connect neurons to enable neuronal signal transmission in the nervous system. The proper establishment of synaptic connections required many adhesion molecules. Malfunctions of these adhesion molecules can result in neural development disorders and neuropsychiatric disorders. How specific synapses are established by various adhesion molecules for proper neural circuitry is a fundamental question of neuroscience. SynCAMs, also named CADMs, Necl, etc., are among the many adhesion proteins found in synapses. Here, we review the current understanding of the physical properties of SynCAMs and their roles in axon pathfinding, myelination, synaptogenesis, and synaptic plasticity. In addition, we discuss the involvement of SynCAMs in neuropsychiatric disorders. Finally, we propose that SynCAM functions can be better viewed and understood from the perspective of orientational cell adhesions (OCAs). In particular, we discuss the possibilities of how SynCAMs can be regulated at the cell-type specific expression, transcription variants, posttranslational modification, and subcellular localization to modulate the diversity of SynCAMs as OCA molecules. Being major components of the synapses, SynCAMs continue to be an important research topic of neuroscience, and many outstanding questions are waiting to be answered.

Leaky lessons learned: Efflux prone dopamine transporter variant reveals sex and circuit specific contributions of D2 receptor signalling to neuropsychiatric disease.

Aberrant dopamine (DA) signalling has been implicated in various neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), schizophrenia, bipolar disorder (BPD) and addiction. The availability of extracellular DA is sculpted by the exocytotic release of vesicular DA and subsequent transporter-mediated clearance, rendering the presynaptic DA transporter (DAT) a crucial regulator of DA neurotransmission. D2-type DA autoreceptors (D2ARs) regulate multiple aspects of DA homeostasis, including (i) DA synthesis, (ii) vesicular release, (iii) DA neuron firing and (iv) the surface expression of DAT and DAT-mediated DA clearance. The DAT Val559 variant, identified in boys with ADHD or ASD, as well as in a girl with BPD, supports anomalous DA efflux (ADE), which we have shown drives tonic activation of D2ARs. Through ex vivo and in vivo studies of the DAT Val559 variant using transgenic knock-in mice, we have uncovered a circuit and sex-specific capacity of D2ARs to regulate DAT, which consequently disrupts DA signalling and behaviour differently in males and females. Our studies reveal the ability of the construct-valid DAT Val559 model to elucidate endogenous mechanisms that support DA signalling, findings that may be of translational and/or therapeutic importance.

Diagnosis of neuropsychiatry disorder in patients with anti-MDA5 antibody dermatomyositis: A case report.

Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis (DM) is a rare disease that can be easily misdiagnosed. Anti-MDA5 dermatomyositis is a subtype of DM. It is distinguished by the presence of significant mucocutaneous characteristics, palmar papules, panniculitis, interstitial lung disease (ILD), and clinically amyopathic dermatomyositis (CADM). When combined with rapidly progressing ILD (RP-ILD), anti-MDA5 DM can be fatal. The literature indicates that nervous system involvement is uncommon in patients with anti-MDA5 DM. We report a case of anti-MDA5 DM with neuropsychiatric abnormalities and ILD. The patient suffered from persistent worsening mental disorders, while his ILD was relatively stable. The patient's neuropsychiatric abnormalities gradually subsided after receiving treatment with glucocorticoids, immunoglobulins, and immunosuppressants, leaving only a slow response and memory loss.

Caregiver Burden, Stress, and Relationship Cohesion Among Self-Identified Caregivers of Children with Pediatric Acute-Onset Neuropsychiatric Syndrome.

Objective: Children with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) experience sudden onset neuropsychiatric symptoms after infection or other triggers. Symptoms range from mild to severe, potentially lasting days, weeks, months, or longer. Exacerbation-related functional decline presents in many aspects of daily life, generally accompanied by family stress and caregiver burden. We sought to investigate the relationship between severity of PANS symptoms and caregiver burden/stress and the relationship between severity of PANS symptoms and degree of caregiver/child cohesion. Methods: This cross-sectional online study surveyed caregivers recruited from PANS-related social media support sites. The Pediatric Acute Neuropsychiatric Symptom Scale - Parent Version (PNSS) measured current severity. Caregiver Burden Inventory (CBI) and Caregiver Self-Assessment Questionnaire (CSAQ) assessed caregiver burden/stress. Inclusion of Other in the Self (IOS) scale determined caregiver-perceived current and desired cohesion with their child(ren) with PANS. Results: Of the 216 respondents 79.6% exceeded CBI threshold indicating need for respite in adult care receiver populations. On the CSAQ, 72.9% expressed high distress, 80.5% reported feeling overwhelmed, and 58.1% reported crying spells, meeting cutoffs for support/respite used in adult care receiver populations. Most caregivers reported not having the desired degree of cohesion with their child on the IOS (85.5%). Parents of children with more severe PNSS symptoms fared significantly worse on all measures (CBI: H = 57.83; CSAQ: F = 29.26; IOS: H = 38.04; p < 0.001 for all). Content analysis of comments revealed five themes: (1) severe caregiver and/or family emotional distress and trauma; (2) caregivers wondering what happened to their child; (3) lack of awareness and support among health and education professionals; (4) relationship strain with family, friends, and significant others; and (5) financial and/or legal struggles because of their child's diagnosis. Conclusion: There is strong need for support and respite for children with PANS and their families. Long-term effects including posttraumatic stress symptoms among family members should be studied.

Precise Therapeutic Targeting of Distinct NRXN1+/- Mutations.

As genetic studies continue to identify risk loci that are significantly associated with risk for neuropsychiatric disease, a critical unanswered question is the extent to which diverse mutations--sometimes impacting the same gene-- will require tailored therapeutic strategies. Here we consider this in the context of rare neuropsychiatric disorder-associated copy number variants (2p16.3) resulting in heterozygous deletions in NRXN1, a pre-synaptic cell adhesion protein that serves as a critical synaptic organizer in the brain. Complex patterns of NRXN1 alternative splicing are fundamental to establishing diverse neurocircuitry, vary between the cell types of the brain, and are differentially impacted by unique (non-recurrent) deletions. We contrast the cell-type-specific impact of patient-specific mutations in NRXN1 using human induced pluripotent stem cells, finding that perturbations in NRXN1 splicing result in divergent cell-type-specific synaptic outcomes. Via distinct loss-of-function (LOF) and gain-of-function (GOF) mechanisms, NRXN1+/- deletions cause decreased synaptic activity in glutamatergic neurons, yet increased synaptic activity in GABAergic neurons. Stratification of patients by LOF and GOF mechanisms will facilitate individualized restoration of NRXN1 isoform repertoires; towards this, antisense oligonucleotides knockdown mutant isoform expression and alters synaptic transcriptional signatures, while treatment with ß-estradiol rescues synaptic function in glutamatergic neurons. Given the increasing number of mutations predicted to engender both LOF and GOF mechanisms in brain disease, our findings add nuance to future considerations of precision medicine.