PV and SST neurons in the anterior cingulate cortex regulate social disorders in adulthood induced by sensory abnormalities in childhood.

OBJECTIVE: Childhood sensory abnormalities experience has a crucial influence on the structure and function of the adult brain. The underlying mechanism of neurological function induced by childhood sensory abnormalities experience is still unclear. Our study was to investigate whether the GABAergic neurons in the anterior cingulate cortex (ACC) regulate social disorders caused by childhood sensory abnormalities experience. METHODS: We used two mouse models, complete Freund's adjuvant (CFA) injection mice and bilateral whisker trimming (BWT) mice in childhood. We applied immunofluorescence, chemogenetic and optogenetic to study the mechanism of parvalbumin (PV) neurons and somatostatin (SST) neurons in ACC in regulating social disorders induced by sensory abnormalities in childhood. RESULTS: Inflammatory pain in childhood leads to social preference disorders, while BWT in childhood leads to social novelty disorders in adult mice. Inflammatory pain and BWT in childhood caused an increase in the number of PV and SST neurons, respectively, in adult mice ACC. Inhibiting PV neurons in ACC improved social preference disorders in adult mice that experienced inflammatory pain during childhood. Inhibiting SST neurons in ACC improved social novelty disorders in adult mice that experienced BWT in childhood. CONCLUSIONS: Our study reveals that PV and SST neurons of the ACC may play a critical role in regulating social disorders induced by sensory abnormalities in childhood.

Cognitive dysfunction, social behavior disorder, cerebellar ataxia, and atypical brain FDG-PET presentation in spinocerebellar ataxia 17: a case report.

BACKGROUND: Spinocerebellar ataxia 17 (SCA17) is a rare autosomal dominant form of inherited ataxia, caused by heterozygous trinucleotide repeat expansions encoding glutamine in the TATA box-binding protein (TBP) gene. CASE DESCRIPTION: We describe the clinical history, neuropsychological, and neuroimaging findings of a 42-year-old patient who presented for medical attention showing prevalent behavioral and cognitive problems along with progressively worsening gait disturbances. The patient's family history indicated the presence of SCA17 in the maternal lineage. Genetic analysis confirmed a heterozygous 52-CAG pathological expansion repeat in TBP (normal interval, 25-40 CAG. Brain 18-fluorodeoxyglucose positron emission tomography (FDG-PET) showed bilateral hypometabolism in the sensorimotor cortex, with a slight predominance on the right, as well as in the striatal nuclei and thalamic hypermetabolism, a finding similar to what is observed in Huntington's disease. The patient also underwent neuropsychological evaluation, which revealed mild cognitive impairment and difficulties in social interaction and understanding other's emotions (Faux Pas Test and Reading the Mind in the Eyes Test). CONCLUSION: Our report emphasizes the importance of considering SCA17 as a possible diagnosis in patients with a prevalent progressive cognitive and behavioral disorders, even with a pattern of FDG-PET hypometabolism not primarily indicative of this disease.

Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder.

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin's effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

Chemogenetic manipulation of the bed nucleus of the stria terminalis counteracts social behavioral deficits induced by early life stress in C57BL/6J mice.

Trauma during critical periods of development can induce long-lasting adverse effects. To study neural aberrations resulting from early life stress (ELS), many studies utilize rodent maternal separation, whereby pups are intermittently deprived of maternal care necessary for proper development. This can produce adulthood behavioral deficits related to anxiety, reward, and social behavior. The bed nucleus of the stria terminalis (BNST) encodes aspects of anxiety-like and social behaviors, and also undergoes developmental maturation during the early postnatal period, rendering it vulnerable to effects of ELS. Mice underwent maternal separation (separation 4 hr/day during postnatal day (PD)2-5 and 8 hr/day on PD6-16) with early weaning on PD17, which induced behavioral deficits in adulthood performance on two-part social interaction task designed to test social motivation (choice between a same-sex novel conspecific or an empty cup) and social novelty preference (choice between the original-novel conspecific vs. a new-novel conspecific). We used chemogenetics to non-selectively silence or activate neurons in the BNST to examine its role in social motivation and social novelty preference, in mice with or without the history of ELS. Manipulation of BNST produced differing social behavior effects in non-stressed versus ELS mice; social motivation was decreased in non-stressed mice following BNST activation, but unchanged following BNST silencing, while ELS mice showed no change in social behavior after BNST activation, but exhibited enhancement of social motivation-for which they were deficient prior-following BNST silencing. Findings emphasize the BNST as a potential therapeutic target for social anxiety disorders instigated by childhood trauma.

Perinatal inflammation is associated with social and motor impairments in preterm children without severe neonatal brain injury.

OBJECTIVE: To test the association between exposure to perinatal inflammation - i.e. clinical chorioamnionitis or early-onset neonatal infection - in preterm children without severe neonatal brain injury and neurodevelopmental outcome at 30 months of corrected age (CA). DESIGN: Cross-sectional study from a French regional cohort of clinical follow-up (SEVE Network). PATIENTS: One hundred sixty-four surviving neonates without severe brain injury - namely, grade III and IV cerebral hemorrhage and cystic periventricular leukomalacia - and without late-onset neonatal inflammation exposure - namely, late-onset neonatal infection and necrotizing enterocolitis -, born at less than 33 weeks of gestational age from November 2011 to June 2015 and enrolled in the SEVE Network. MAIN OUTCOME MEASURE: Global developmental quotient (DQ) score of the revised Brunet-Lézine scale and its four indices measured by the same neuropsychologist at 30 months of CA. RESULTS: After multivariate analysis, exposure to perinatal inflammation was not found significantly associated with a modification of the global DQ score (coefficient -1.7, 95% CI -4.8 to 1.3; p = 0.26). Exposure to perinatal inflammation was associated with a decrease of the gross motor function DQ score (coefficient -6.0, 95% CI -9.9 to -2.1; p < 0.01) and a decrease of the sociability DQ score (coefficient -5.1, 95% CI -9.2 to -0.9; p = 0.02). Language and visuospatial coordination DQ scores were not affected by exposure to perinatal inflammation. CONCLUSION: Exposure to perinatal inflammation in preterm children without severe neonatal brain injury is independently associated with decreased motor and social abilities at 30 months of CA.

GluD1 knockout mice with a pure C57BL/6N background show impaired fear memory, social interaction, and enhanced depressive-like behavior.

The GluD1 gene is associated with susceptibility for schizophrenia, autism, depression, and bipolar disorder. However, the function of GluD1 and how it is involved in these conditions remain elusive. In this study, we generated a Grid1 gene-knockout (GluD1-KO) mouse line with a pure C57BL/6N genetic background and performed several behavioral analyses. Compared to a control group, GluD1-KO mice showed no significant anxiety-related behavioral differences, evaluated using behavior in an open field, elevated plus maze, a light-dark transition test, the resident-intruder test of aggression and sensorimotor gating evaluated by the prepulse inhibition test. However, GluD1-KO mice showed (1) higher locomotor activity in the open field, (2) decreased sociability and social novelty preference in the three-chambered social interaction test, (3) impaired memory in contextual, but not cued fear conditioning tests, and (4) enhanced depressive-like behavior in a forced swim test. Pharmacological studies revealed that enhanced depressive-like behavior in GluD1-KO mice was restored by the serotonin reuptake inhibitors imipramine and fluoxetine, but not the norepinephrine transporter inhibitor desipramine. In addition, biochemical analysis revealed no significant difference in protein expression levels, such as other glutamate receptors in the synaptosome and postsynaptic densities prepared from the frontal cortex and the hippocampus. These results suggest that GluD1 plays critical roles in fear memory, sociability, and depressive-like behavior.

Lifelong consequences of brain injuries during development: From risk to resilience.

Traumatic brain injuries in children represent a major public health issue and even relatively mild injuries can have lifelong consequences. However, the outcomes from these injuries are highly heterogeneous, with most individuals recovering fully, but a substantial subset experiencing prolonged or permanent disabilities across a number of domains. Moreover, brain injuries predispose individuals to other kinds of neuropsychiatric and somatic illnesses. Critically, the severity of the injury only partially predicts subsequent outcomes, thus other factors must be involved. In this review, we discuss the psychological, social, neuroendocrine, and autonomic processes that are disrupted following traumatic brain injury during development, and consider the mechanisms the mediate risk or resilience after traumatic brain injury in this vulnerable population.

Behavioral problems in children of mothers with epilepsy prenatally exposed to valproate, carbamazepine, lamotrigine, or levetiracetam monotherapy.

OBJECTIVE: To examine the behavioral functioning of children prenatally exposed to carbamazepine (CBZ), lamotrigine (LTG), levetiracetam (LEV), or valproate (VPA) monotherapy. METHODS: In collaboration with the European Registry of Antiepileptic Drugs and Pregnancy (EURAP), the Dutch EURAP & Development study was designed, a prospective observational study. Between January 2015 and March 2018, the Child Behavior Checklist and the Social Emotional Questionnaire were used to examine the nature and severity of behavioral problems. VPA-exposed children were compared to children exposed to CBZ, LTG, or LEV, taking potential confounders into account. A direct comparison was also made between LTG and LEV, as these are first-choice treatments for many women with epilepsy of childbearing potential. RESULTS: Of the 405 invited, 181 children were included; 26 were exposed to VPA, 37 to CBZ, 88 to LTG, and 30 to LEV. For most children, both parents completed the behavioral questionnaires. Across all four antiepileptic drug (AED) exposure groups, high percentages of children with clinically relevant behavior problems were found, with behavioral problems occurring in 32% of VPA-exposed children, 14% of CBZ, 16% of LTG, and 14% of LEV. After controlling for potential confounders, VPA-exposed children had significantly more social problems than those exposed to LTG (-2.8, 95% confidence interval [CI] = -5.2 to -0.4; P = 0.022) or LEV (-3.2, CI: -6.1 to -0.3; P = 0.028), and significantly more attention problems than LEV-exposed children (-3.7, CI: -6.7 to -0.8; P = 0.013). LTG-exposed children had significantly more attention deficit (-9.2, CI: -17.3 to 1.1; P = 0.026), but significantly less anxious behavior when compared to LEV-exposed children (9.0, CI: 0.3-17.6; P = 0.042). SIGNIFICANCE: Compared to population norms, a high proportion of children of mothers with epilepsy exposed prenatally to monotherapy with four common AEDs had clinical behavioral problems reported by parents. Different patterns were seen, with some but not all subscales raised for all AED exposure groups. It is important that prenatally AED-exposed children are regularly screened for behavioral problems so that appropriate help can be provided.

Long-term social dysfunction after trauma: What is the prevalence, risk factors, and associated outcomes?

BACKGROUND: Social functioning-the ability to participate in organized or informal family, friend, or peer groups and communal activities-is intertwined with physical and emotional health. Although trauma can have a lasting effect on both the physical and emotional well-being of patients, little is known about the long-term impact of injury on social functioning. We sought to determine the prevalence of, risk factors for, and outcomes associated with long-term social dysfunction after trauma. METHODS: Adults with moderate-to-severe injuries managed at three Level I trauma centers were contacted at 6 to 12 months after injury to inquire about social dysfunction. Demographics, socioeconomic parameters, and injury-related and hospital course information were also obtained. A stepwise backward logistic regression model was fitted to determine independent risk factors of social dysfunction, and multiple logistic regression models were used to determine associations between social dysfunction and post-traumatic stress disorder, functional limitations, and return to work. RESULTS: Of the 805 screened patients, 45.2% reported social dysfunction. Patients with social dysfunction were more likely to be African American, be Medicaid beneficiaries, be of lower education, require mechanical ventilation, be discharged less often to home, have a lower mean age and had longer hospital stays. In multivariable analysis, low education, longer hospital stay, past psychiatric illness, and African-American race independently increased the risk for social dysfunction. Furthermore, patients with social dysfunction were more likely to screen positive for post-traumatic stress disorder (odds ratio: 16.25 [95% confidence interval: 9.49-27.85]), be experiencing functional limitations (odds ratio: 2.80 [95% confidence interval: 1.76-4.44]), and to not have returned to work (odds ratio: 5.65 [95% confidence interval: 3.92-8.14]). CONCLUSION: Lower educational attainment, long hospital stay, past pyschiatric illness, and African-American race appear to predispose to social dysfunction after trauma, which in turn is associated with a positive post-traumatic stress disorder screen, functional limitations, and delayed return to work.

How should we understand the absence of sex differences in the genetic and environmental origins of antisocial behavior?

Available twin-family data on sex differences in antisocial behavior (ASB) simultaneously suggest that ASB is far more prevalent in males than in females, and that its etiology (i.e. the effects of genes, environments, hormones, culture) does not differ across sex. This duality presents a conundrum: How do we make sense of mean sex differences in ASB if not via differences in genes, environments, hormones, and/or cultures? The current selective review and critique explores possible contributions to these seemingly incompatible sets of findings. We asked whether the presence of sex differences in behavior could be smaller than is typically assumed, or confined to a specific set of behaviors. We also asked whether there might be undetected differences in etiology across sex in twin-family studies. We found little evidence that bias or measurement invariance across sex account for phenotypic sex differences in ASB, but we did identify some key limitations to current twin-family approaches. These included the questionable ability of qualitative sex difference analyses to detect gender norms and prenatal exposure to testosterone, and concerns regarding specific analytic components of quantitative sex difference analyses. We conclude that the male preponderance in ASB is likely to reflect a true sex difference in observed behavior. It was less clear, however, that the genetic and environmental contributions to ASB are indeed identical across sex, as argued by prior twin-family studies. It is our hope that this review will inspire the development of new, genetically-informed methods for studying sex differences in etiology.

Trastorno del espectro alcohólico fetal: Un trastorno del neurodesarrollo infradiagnosticado y de pronóstico incierto / Fetal alcohol spectrum disorder. An underdiagnosed neuro-development disorder of uncertain prognosis

La exposición prenatal al alcohol es causa de alteraciones somáticas, cognitivas y conductuales que se agrupan bajo el término de trastorno del espectro alcohólico fetal (TEAF). La evolución a largo plazo de los sujetos afectados a menudo es desfavorable, especialmente a nivel académico y adaptativo social. En el perfil neuropsicológico es característica la disfunción ejecutiva a menudo asociada a trastornos de la conducta que evolucionan en muchos casos hacia la delincuencia a partir de la adolescencia y en la edad adulta. Se han descrito también déficits de las habilidades sociales y la empatía. La exposición prenatal al alcohol constituye la causa más frecuente de trastorno del neurodesarrollo adquirido y prevenible.

Prenatal exposure to alcohol is the cause of cognitive and behavioural disorders grouped under the term fetal alcohol spectrum disorders (FASD). The long-term evolution of subjects with FASD is often unfavourable, especially in social and academic fields. Executive dysfunction is a hallmark deficit for children with FASD with increased rates of externalizing behaviours, such as aggressiveness and frequently delinquency in adolescence and adulthood. Deficits in social skills, empathy and communication ability are frequent observed among FASD. Prenatal exposure to alcohol is the most frequent cause of acquired and preventable neurodevelopmental disorder.

[Fetal alcohol spectrum disorder. An underdiagnosed neuro-development disorder of uncertain prognosis]. / Trastorno del espectro alcohólico fetal. Un trastorno del neurodesarrollo infradiagnosticado y de pronóstico incierto.

Prenatal exposure to alcohol is the cause of cognitive and behavioural disorders grouped under the term fetal alcohol spectrum disorders (FASD). The long-term evolution of subjects with FASD is often unfavourable, especially in social and academic fields. Executive dysfunction is a hallmark deficit for children with FASD with increased rates of externalizing behaviours, such as aggressiveness and frequently delinquency in adolescence and adulthood. Deficits in social skills, empathy and communication ability are frequent observed among FASD. Prenatal exposure to alcohol is the most frequent cause of acquired and preventable neurodevelopmental disorder.

La exposición prenatal al alcohol es causa de alteraciones somáticas, cognitivas y conductuales que se agrupan bajo el término de trastorno del espectro alcohólico fetal (TEAF). La evolución a largo plazo de los sujetos afectados a menudo es desfavorable, especialmente a nivel académico y adaptativo social. En el perfil neuropsicológico es característica la disfunción ejecutiva a menudo asociada a trastornos de la conducta que evolucionan en muchos casos hacia la delincuencia a partir de la adolescencia y en la edad adulta. Se han descrito también déficits de las habilidades sociales y la empatía. La exposición prenatal al alcohol constituye la causa más frecuente de trastorno del neurodesarrollo adquirido y prevenible.

[Encephalitis lethargica. The epidemic at the dawn of neurology]. / Encefalitis letargica. La epidemia en los albores de la neurologia.

Lethargic encephalitis is a neurological illness that shows a wide range of symptoms and signs, including neurological and psychiatric spectrum. It presented in an epidemic way, following influaenza relapses. The last relapse started at the beginning of 20th century and it was deeply described by Constantin von Economo. The illness described first in Europe and North America, was described in many others countries including Chile. There were beautiful descriptions by Chilean physicians like Lea-Plaza, Tello, Iturra and Cienfuegos. Their works showed the complexity of the illness like European physicians did too. The etiology is still unknown; however growing evidence about autoinmune aetiology is gaining force with the use of actual medical technology. In this work, we show encephalitis lethargica, focusing in clinical picture, the beauty of medical descriptions that physicians did at this date.

TITLE: Encefalitis letargica. La epidemia en los albores de la neurologia.La encefalitis letargica es un cuadro neurologico con una variada gama de manifestaciones clinicas en el ambito neurologico y tambien en el psiquiatrico. El cuadro se ha presentado de manera epidemica en brotes que han seguido a los de la gripe. El ultimo brote acaecido a comienzos del siglo XX lo describio en profundidad Constantin von Economo. La epidemia notificada inicialmente en Europa y luego en Norteamerica se presento tambien en otras latitudes, incluyendo Chile. Asi, las descripciones de Lea-Plaza, Tello, Iturra, Cienfuegos y otros medicos chilenos dieron cuenta del cuadro en Chile con toda la complejidad que tambien tuvo en Europa. El origen sigue siendo un misterio, aunque la evidencia creciente de que fuera autoinmune gana fuerza con los hallazgos de la tecnologia medica actual. En este trabajo presentamos el cuadro, privilegiando la riqueza clinica y la belleza de las descripciones realizada por los medicos de la epoca en que esta enfermedad se presento.

Determinants of social behavior deficits and recovery after pediatric traumatic brain injury.

Traumatic brain injury (TBI) during early childhood is associated with a particularly high risk of developing social behavior impairments, including deficits in social cognition that manifest as reduced social interactions, with profound consequences for the individuals' quality of life. A number of pre-injury, post-injury, and injury-related factors have been identified or hypothesized to determine the extent of social behavior problems after childhood TBI. These include variables associated with the individual themselves (e.g. age, genetics, the injury severity, and extent of white matter damage), proximal environmental factors (e.g. family functioning, parental mental health), and more distal environmental factors (e.g. socioeconomic status, access to resources). In this review, we synthesize the available evidence demonstrating which of these determinants influence risk versus resilience to social behavior deficits after pediatric TBI, drawing upon the available clinical and preclinical literature. Injury-related pathology in neuroanatomical regions associated with social cognition and behaviors will also be described, with a focus on findings from magnetic resonance imaging and diffusion tensor imaging. Finally, study limitations and suggested future directions are highlighted. In summary, while no single variable can alone accurately predict the manifestation of social behavior problems after TBI during early childhood, an increased understanding of how both injury and environmental factors can influence social outcomes provides a useful framework for the development of more effective rehabilitation strategies aiming to optimize recovery for young brain-injured patients.

Targeting the Oxytocin System: New Pharmacotherapeutic Approaches.

Deficits in social behavioral domains, such as interpersonal communication, emotion recognition, and empathy, are a characteristic symptom in several neuropsychiatric disorders, including schizophrenia and autism spectrum disorder (ASD). The neuropeptide oxytocin (OT) has emerged as a key regulator of diverse social behaviors in vertebrates and, thus, has been identified as a potential therapeutic target for improving social dysfunction. In recent years, the field of OT research has seen an explosion of scientific inquiry, producing a more comprehensive picture of oxytocinergic signaling and the pathways that regulate its release and degradation in the brain. In this review, we provide an analysis of how this information is being exploited to accelerate the discovery of novel oxytocinergic therapeutics.

Prenatal stress disrupts social behavior, cortical neurobiology and commensal microbes in adult male offspring.

In utero and early neonatal exposure to maternal stress is linked with psychiatric disorders, and the underlying mechanisms are currently being elucidated. We used a prenatal stressor in pregnant mice to examine novel relationships between prenatal stress exposure, changes in the gut microbiome, and social behavior. Here, we show that males exposed to prenatal stress had a significant reduction in social behavior in adulthood, with increased corticosterone release following social interaction. Male offspring exposed to prenatal stress also had neuroinflammation, decreased oxytocin receptor, and decreased serotonin metabolism in their cortex in adulthood, which are linked to decreased social behavior. Finally, we found a significant difference in commensal microbes, including decreases in Bacteroides and Parabacteroides, in adult male offspring exposed to prenatal stress when compared to non-stressed controls. Our findings indicate that gestation is a critical window where maternal stress contributes to the development of aberrant social behaviors and alterations in cortical neurobiology, and that prenatal stress is sufficient to disrupt the male gut-brain axis into adulthood.

A sociocognitive approach to social problem solving in patients with traumatic brain injury: a pilot study.

PRIMARY OBJECTIVE: Patients with traumatic brain injury (TBI) have difficulty dealing with the social world and may display inappropriate social behavior that negatively affects their social and occupational rehabilitation. This difficulty may be explained by a social problem-solving (SPS) impairment, but little is yet known about the cognitive processes involved in the ability to solve social problems. Several publications have demonstrated that executive functions are related to social problem solving, but the role of social cognition needs to be confirmed. The present pilot study examined the expected relationships between SPS ability and both social cognition and social behavioral skills. RESEARCH DESIGN: We compared the performances of 15 patients with TBI on SPS, theory-of-mind and social behavior tasks with those of 25 matched healthy controls. MAIN OUTCOMES AND RESULTS: Our results showed for the first time that impaired social problem solving is associated with a theory-of-mind deficit, but surprisingly not with executive impairment. There was no evidence that SPS deficits predict social behavioral disorders. CONCLUSIONS: Studying social problem solving in patients with TBI may inform the design of more appropriate methods of social rehabilitation.

Recovery of stress-impaired social behavior by an antagonist of the CRF binding protein, CRF6-33, in the bed nucleus of the stria terminalis of male rats.

Social stress is recognized to promote the development of neuropsychiatric and mood disorders. Corticotropin releasing factor (CRF) is an important neuropeptide activated by social stress, and it contributes to neural and behavioral adaptations, as indicated by impaired social interactions and anhedonic effects. Few studies have focused on the role of the CRF binding protein (CRFBP), a component of the CRF system, and its activity in the bed nucleus of stria terminalis (BNST), a limbic structure connecting amygdala and hypothalamus. In this study, animals' preference for sweet solutions was examined as an index of stress-induced anhedonic responses in Wistar rats subjected to four brief intermittent episodes of social defeat. Next, social approach was assessed after local infusions of the CRFBP antagonist, CRF fragment 6-33 (CRF6-33) into the BNST. The experience of brief episodes of social defeat impaired social approach behaviors in male rats. However, intra-BNST CRF6-33 infusions restored social approach in stressed animals to the levels of non-stressed rats. CRF6-33 acted selectively on social interaction and did not alter general exploration in nether stressed nor non-stressed rats. These findings suggest that BNST CRFBP is involved in the modulation of anxiety-like responses induced by social stress.

Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder.

Currently, there are no medications that effectively treat the core symptoms of Autism Spectrum Disorder (ASD). We recently found that the bacterial species Lactobacillus (L.) reuteri reverses social deficits in maternal high-fat-diet offspring. However, whether the effect of L. reuteri on social behavior is generalizable to other ASD models and its mechanism(s) of action remains unknown. Here, we found that treatment with L. reuteri selectively rescues social deficits in genetic, environmental, and idiopathic ASD models. Interestingly, the effects of L. reuteri on social behavior are not mediated by restoring the composition of the host's gut microbiome, which is altered in all of these ASD models. Instead, L. reuteri acts in a vagus nerve-dependent manner and rescues social interaction-induced synaptic plasticity in the ventral tegmental area of ASD mice, but not in oxytocin receptor-deficient mice. Collectively, treatment with L. reuteri emerges as promising non-invasive microbial-based avenue to combat ASD-related social dysfunction.

Risk factors for social withdrawal in amyotrophic lateral sclerosis/motor neurone disease.

BACKGROUND: Greater social withdrawal is related to higher levels of psychological distress and poorer adaptation to a diagnosis of amyotrophic lateral sclerosis. OBJECTIVES: To examine whether demographics and functional deficits can be used to assess which patients may be at risk of social withdrawal and whether symptoms including depression and anxiety can provide additional information for identifying individuals at risk. Furthermore, to examine whether patient-perceived stigma has a role in mediating the effects of any of the predictors of social withdrawal. METHODS: A total of 559 participants in the ongoing Trajectories of Outcomes in Neurological Conditions (TONiC) study completed a questionnaire pack collecting data on demographics and a range of patient reported measures. Multiple regression analysis was employed to assess associations of functional ability, demographics, physical symptoms, anxiety, and depression with social withdrawal. The mediating role of stigma was assessed through the development of a bivariate linear regression model for stigma and social withdrawal. RESULTS: Disability in the bulbar and motor domains, anxiety and depression were found to be significant predictors of social withdrawal. Stigma was the strongest single predictor of social withdrawal and was found to partially mediate the effects of functional deficits and mood on social withdrawal. CONCLUSIONS: Social withdrawal is associated with worse motor disability and poorer bulbar function, as well as increased anxiety and depression. Stigma is a powerful predictor for social withdrawal; further work should investigate whether stigma is a potential target for psychological interventions aimed at reducing social withdrawal and improving quality of life.