Mental health and wellbeing coordinators in primary schools to support student mental health: protocol for a quasi-experimental cluster study.

BACKGROUND: Half of mental health disorders begin before the age of 14, highlighting the importance of prevention and early-intervention in childhood. Schools have been identified globally by policymakers as a platform to support good child mental health; however, the majority of the research is focused on secondary schools, with primary schools receiving very little attention by comparison. The limited available evidence on mental health initiatives in primary schools is hindered by a lack of rigorous evaluation. This quasi-experimental cluster study aims to examine the implementation and effectiveness of a Mental Health and Wellbeing Co-ordinator role designed to build mental health capacity within primary schools. METHODS: This is a primary (ages 5-12) school-based cluster quasi-experimental study in Victoria, Australia. Before baseline data collection, 16 schools selected by the state education department will be allocated to intervention, and another 16 matched schools will continue as 'Business as Usual'. In intervention schools, a mental health and well-being coordinator will be recruited and trained, and three additional school staff will also be selected to receive components of the mental health training. Surveys will be completed by consenting staff (at 2-, 5-, 10- and 17-months post allocation) and by consenting parents/carers (at 3-, 10- and 17-months post allocation) in both intervention and business as usual schools. The primary objective is to assess the change in teacher's confidence to support student mental health and wellbeing using the School Mental Health Self-Efficacy Teacher Survey. Secondary objectives are to assess the indirect impact on systemic factors (level of support, prioritisation of child mental health), parent and teachers' mental health literacy (stigma, knowledge), care access (school engagement with community-based services), and student mental health outcomes. Implementation outcomes (feasibility, acceptability, and fidelity) and costs will also be evaluated. DISCUSSION: The current study will examine the implementation and effectiveness of having a trained Mental Health and Wellbeing Coordinator within primary schools. If the intervention increases teachers' confidence to support student mental health and wellbeing and builds the capacity of primary schools it will improve student mental health provision and inform large-scale mental health service reform. TRIAL REGISTRATION: The trial was retrospectively registered in the Australian New Zealand Clinical Trials Registry (ANZCTR) on July 6, 2021. The registration number is ACTRN12621000873820 .

Vortioxetine reduces BOLD signal during performance of the N-back working memory task: a randomised neuroimaging trial in remitted depressed patients and healthy controls.

Cognitive dysfunction is common in depression during both acute episodes and remission. Vortioxetine is a novel multimodal antidepressant that has improved cognitive function including executive function in depressed patients in randomised placebo-controlled clinical trials. However, it is unclear whether vortioxetine is able to target directly the neural circuitry implicated in the cognitive deficits in depression. Remitted depressed (n=48) and healthy volunteers (n=48) were randomised to receive 14 days treatment with 20 mg vortioxetine or placebo in a double-blind design. The effects of treatment on functional magnetic resonance imaging responses during an N-back working memory task were assessed at baseline and at the end of treatment. Neuropsychological measures of executive function, speed and information processing, attention and learning and memory were examined with the Trail Making Test (TMT), Rey Auditory Learning Test and Digit Symbol Substitution Test before and after treatment; subjective cognitive function was assessed using the Perceived Deficits Questionnaire (PDQ). Compared with placebo, vortioxetine reduced activation in the right dorsolateral prefrontal cortex and left hippocampus during the N-back task compared with placebo. Vortioxetine also increased TMT-A performance and self-reported cognitive function on the PDQ. These effects were seen across both subject groups. Vortioxetine modulates neural responses across a circuit subserving working memory in a direction opposite to the changes described in depression, when performance is maintained. This study provides evidence that vortioxetine has direct effects on the neural circuitry supporting cognitive function that can be dissociated from its effects on the mood symptoms of depression.

Abnormal gangliosides are localized in lipid rafts in Sanfilippo (MPS3a) mouse brain.

Allogenic stem cell transplantation can reduce lysosomal storage of heparan sulfate-derived oligosaccharides by up to 27 % in Sanfilippo MPS3a brain, but does not reduce the abnormal storage of sialolactosylceramide (G(M3)) or improve neurological symptoms, suggesting that ganglioside storage is in a non-lysosomal compartment. To investigate this further we isolated the Triton X100-insoluble at 4 °C, lipid raft (LR) fraction from a sucrose-density gradient from cerebral hemispheres of a 7 month old mouse model of Sanfilippo MPS3a and age-matched control mouse brain. HPLC/MS/MS analysis revealed the expected enrichment of normal complex gangliosides, ceramides, galatosylceramides and sphingomyelin enrichment in this LR fraction. The abnormal HS-derived oligosaccharide storage material was in the Triton X100-soluble at 4 °C fractions (8-12),whereas both GM3 and sialo[GalNAc]lactosylceramide (GM2) were found exclusively in the LR fraction (fractions 3 and 4) and were >90 % C18:0 fatty acid, suggesting a neuronal origin. Further analysis also revealed a >threefold increase in the late-endosome marker bis (monoacylglycerol) phosphate (>70 % as C22:6/22:6-BMP) in non-LR fractions 8-12 whereas different forms of the proposed BMP precursor, phosphatidylglycerol (PG) were in both LR and non-LR fractions and were less elevated in MPS3a brain. Thus heparan sulfate-derived oligosaccharide storage is associated with abnormal lipid accumulation in both lysosomal (BMP) and non-lysosomal (GM3 and GM2) compartments.

Theory of Mind and social functioning among neuropsychiatric disorders: A transdiagnostic study.

Social dysfunction is commonly present in neuropsychiatric disorders of schizophrenia (SZ) and Alzheimer's disease (AD). Theory of Mind (ToM) deficits have been linked to social dysfunction in disease-specific studies. Nevertheless, it remains unclear how ToM is related to social functioning across these disorders, and which factors contribute to this relationship. We investigated transdiagnostic associations between ToM and social functioning among SZ/AD patients and healthy controls, and explored to what extent these associations relate to information processing speed or facial emotion recognition capacity. A total of 163 participants were included (SZ: n=56, AD: n=50 and age-matched controls: n=57). Social functioning was assessed with the Social Functioning Scale (SFS) and the De Jong-Gierveld Loneliness Scale (LON). ToM was measured with the Hinting Task. Information processing speed was measured by the Digit Symbol Substitution Test (DSST) and facial emotion recognition capacity by the facial emotion recognition task (FERT). Case-control deficits in Hinting Task performance were larger in AD (rrb = -0.57) compared to SZ (rrb = -0.35). Poorer Hinting Task performance was transdiagnostically associated with the SFS (ßHinting-Task = 1.20, p<0.01) and LON (ßHinting-Task = -0.27, p<0.05). DSST, but not FERT, reduced the association between the SFS and Hinting Task performance, however the association remained significant (ßHinting-Task = 0.95, p<0.05). DSST and FERT performances did not change the association between LON and Hinting Task performance. Taken together, ToM deficits are transdiagnostically associated with social dysfunction and this is partly related to reduced information processing speed.

High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility.

Autism spectrum disorders are a group of highly heritable neurodevelopmental disorders with a complex genetic etiology. The International Molecular Genetic Study of Autism Consortium previously identified linkage loci on chromosomes 7 and 2, termed AUTS1 and AUTS5, respectively. In this study, we performed a high-density association analysis in AUTS1 and AUTS5, testing more than 3000 single nucleotide polymorphisms (SNPs) in all known genes in each region, as well as SNPs in non-genic highly conserved sequences. SNP genotype data were also used to investigate copy number variation within these regions. The study sample consisted of 127 and 126 families, showing linkage to the AUTS1 and AUTS5 regions, respectively, and 188 gender-matched controls. Further investigation of the strongest association results was conducted in an independent European family sample containing 390 affected individuals. Association and copy number variant analysis highlighted several genes that warrant further investigation, including IMMP2L and DOCK4 on chromosome 7. Evidence for the involvement of DOCK4 in autism susceptibility was supported by independent replication of association at rs2217262 and the finding of a deletion segregating in a sib-pair family.

Isolation of novel virus-like sequences associated with human hepatitis.

Two viruses, GB virus A (GBV-A) and GB virus B (GBV-B), were recently identified in the GB hepatitis agent. Human sera containing antibodies that recognize GBV-A and/or GBV-B recombinant proteins were subjected to polymerase chain reaction studies with degenerate oligonucleotides capable of amplifying a segment of the putative helicase genes from GBV-A, GBV-B or hepatitis C virus. Novel sequences related to members of the Flaviviridae were identified in sera from 12 individuals including 4 individuals with hepatitis. The limited nucleotide sequence identity between GBV-A, GBV-B and HCV sequences suggests that a novel virus, tentatively named GB virus C, may be responsible for some cases of non-A, non-B, non-C, non-D, non-E hepatitis.

Mutations in the TSGA14 gene in families with autism spectrum disorders.

Linkage to 7q has been the most robust genetic finding in familial autism. A previous scan of multiplex families with autism spectrum disorders found a linkage signal of genome-wide significance at D7S530 on 7q32. We searched a candidate imprinted region at this location for genetic variants in families with positive linkage scores. Using exon resequencing, we identified three rare potentially pathogenic variants in the TSGA14 gene, which encodes a centrosomal protein. Two variants were missense mutations (c.664C>G; p.P206A and c.766T>G; p.C240G) that changed conserved residues in the same protein domain; the third variant (c.192+5G>A) altered splicing, which resulted in a protein with an internal deletion of 16 residues and a G33D substitution. These rare TSGA14 variants are enriched in the affected subjects (6/348 patients versus 2/670 controls, Fisher's exact two tailed P = 0.022). This is the first report of a possible link of a gene with a centrosomal function with familial autism.

Infant EEG theta modulation predicts childhood intelligence.

Intellectual functioning is a critical determinant of economic and personal productivity. Identifying early neural predictors of cognitive function in infancy will allow us to map the neurodevelopmental pathways that underpin individual differences in intellect. Here, in three different cohorts we investigate the association between a putative neurophysiological indicator of information encoding (change in frontal theta during a novel video) in infancy and later general cognitive outcome. In a discovery cohort of 12-month-old typically developing infants, we recorded EEG during presentation of dynamic movies of people and objects. Frontal theta power (3-6 Hz) significantly increased during the course of viewing each video. Critically, increase in frontal theta during viewing of a video was associated with a differential response to repetition of that specific video, confirming relation to learning. Further, individual differences in the magnitude of change in frontal theta power were related to concurrent nonverbal cognitive level. We then sought to extend this association in two independent samples enriched for variation in cognitive outcome due to the inclusion of infants at familial risk for autism. We observed similar patterns of theta EEG change at 12 months, and found a predictive relation to verbal and nonverbal cognitive skills measured at 2, 3 and 7 years of age. For the subset of high-risk infants later diagnosed with autism, infant theta EEG explained over 80% of the variance in nonverbal skills at age 3 years. We suggest that EEG theta change in infancy is an excellent candidate predictive biomarker that could yield substantial insight into the mechanisms that underlie individual differences in childhood intelligence, particularly in high risk populations.

Racial Bias in National Football League Officiating.

Racial bias in sport is a prevalent research topic. Much of the previous research regarding bias among referees in sport focused on sports such as baseball, basketball, hockey, and soccer. Professional American football is unique because race is more clearly defined when compared to these other sports. Additionally, by examining holding penalties, which are known to be more subjective and called predominately by a single official on the field (i.e., the umpire), racial bias in officiating can be more efficiently analyzed in professional American football. The purpose of this study is to examine potential racial bias regarding holding penalties in the National Football League (NFL). Three years of data from the 2013 to 2014 through 2015 to 2016 NFL seasons were used, including the races of officials and players involved in holding penalties. Results showed no evidence of racial bias in the calling of holding penalties by White officials. However, Black umpires were found to call more holding penalties when led by a White referee. Additionally, Black players were more likely to have holding penalties called on them earlier in the game by all officials.

Lactosyl ceramidosis: catabolic enzyme defect of glycosphingolipid metabolism.

A 3-year-old Negro female showed clinical evidence of a neurovisceral storage disorder that has been characterized by the specific elevation of lactosyl ceramide in erythrocytes, plasma, bone marrow, urine sediment, liver biopsy, and brain biopsy. A galactosyl hydrolase deficiency was demonstrated by the inability to cleave lactosyl ceramide labeled with tritium in the terminal galactose. The enzyme deficiency may be the primary cause of this previously unreported sphingolipidosis.

Oligodendrocyte adhesion activates protein kinase C-mediated phosphorylation of myelin basic protein.

When isolated adult oligodendrocytes adhere to a substratum myelinogenesis occurs. Investigation of the mechanism by which this happens indicated that the oligodendrocyte-substratum interaction activated protein kinase C-dependent phosphorylation of myelin basic protein and promoted the synthesis of myelin basic protein. In addition, when agents that activate protein kinase C (second messenger diacylglycerol or a tumor-promoting phorbol ester) were added to nonattached oligodendrocytes, they mimicked the influence of the substratum by inducing phosphorylation of myelin basic protein; and reagents that increase cellular adenosine 3', 5'-monophosphate (cyclic AMP) inhibited phosphorylation of myelin basic protein. Thus, at least in vitro, the interaction between oligodendrocytes and the substratum may mediate myelinogenic events, and phosphorylation of myelin basic protein may be an early requirement in the sequence of steps that ultimately results in myelin formation.

Glycolipid and mucopolysaccharide abnormality in fibroblasts of fabry's disease.

Cultures of skin fiibroblasts from a patient with Fabry's disease showed an accumulation of the glycolipid, galactosyl-galactosyl-glucosyl ceramide. Such cells also showed metachromasia on staining with toluidine blue and a markedly elevated acid mucopolysaccharide content.

Lactosyl ceramidosis: normal activity for two lactosyl ceramide beta-galactosidases.

Lactosyl ceramide beta-galactosidase activities in the fibroblasts from the previously described patient with so-called "lactosyl ceramidosis" were reexamined with the two recently developed assay methods which appear to measure two genetically distinct enzymes that can degrade this substrate. No deficiency of either of the lactosyl ceramide-cleaving enzymes was observed. In addition, sphingomyelinase activity was only one-sixth of normal, while all other enzymes examined were within the normal ranges.

Age-related neural activity during allocentric spatial memory.

Age-related decline in allocentric (viewer-independent) spatial memory is seen across species. We employed a virtual reality analogue of the Morris Water Maze to study the effect of healthy ageing on neural activity during allocentric spatial memory using functional magnetic resonance imaging. Voxel-based morphometry was used to ascertain hippocampal volumetric integrity. A widespread neural network comprising frontal, parietal, occipital, thalamic, and cerebellar regions was activated in young and older adults, but only young adults significantly activated bilateral hippocampus and left parahippocampus, as well as right frontal pole and dorso-lateral prefrontal cortex (DLPFC) during encoding and right DLPC during retrieval. Hippocampal grey matter volume was unchanged in older adults; however, prefrontal and parahippocampal functional attenuation was accompanied by volumetric reduction. We conclude that the decline in allocentric spatial memory with age is associated with attenuated hippocampal function, as well as compromised function and structure of prefrontal and parahippocampal regions.

Enhancing Low-Intensity Coaching in Parent Implemented Early Start Denver Model Intervention for Early Autism: A Randomized Comparison Treatment Trial.

Short-term low intensity parent implemented intervention studies for toddlers with autism spectrum disorder (ASD) have found it difficult to demonstrate significantly improved developmental scores or autism severity compared to community treatment. We conducted a randomized comparative intent-to-treat study of a parent implemented intervention to (1) test the effects of an enhanced version on parent and child learning, and (2) evaluate the sensitivity to change of proximal versus distal measures of child behavior. We randomized 45 children with ASD, 12-30 months of age, into one of two versions of parent-implemented Early Start Denver Model (P-ESDM), the basic model, in which we delivered 1.5 h of clinic-based parent coaching weekly, and an enhanced version that contained three additions: motivational interviewing, multimodal learning tools, and a weekly 1.5-h home visit. We delivered the intervention for 12 weeks and measured child and parent change frequently in multiple settings. We found a time-by-group interaction: parents in the enhanced group demonstrated significantly greater gains in interaction skills than did parents in the non-enhanced group. Both interventions were associated with significant developmental acceleration; however, child outcomes did not differ by group. We found a significant relationship between degree of change in parental interaction skill and rate of children's improvement on our proximal measure. Parents in both groups reported satisfaction with the intervention. These findings suggest that parent skills improved more in the enhanced group than the comparison group. Children in the two groups showed similar improvements. Rate of individual parent learning was associated with greater individual child progress on a measure quite proximal to the treatment, though not on standardized assessments.

Alpha2-containing GABA(A) receptors are involved in mediating stimulant effects of cocaine.

alpha2 subunit-containing GABA(A) receptors are involved in incentive learning associated with cocaine, and in cocaine addiction. Deletion of alpha2-containing receptors abolishes cocaine-induced behavioural sensitisation (BS), while selective activation of alpha2 receptors, achieved using Ro 15-4513's agonist properties in alpha2(H101R) mice, induced BS. Here, we investigate further the mechanisms underlying Ro 15-4513-induced behavioural sensitisation in alpha2(H101R) mice. alpha2(H101R) mice sensitised to Ro 15-4513 (10 mg/kg) showed an enhanced stimulant response to cocaine (10 mg/kg). In contrast, cocaine (10 mg/kg)-sensitised alpha2(H101R) mice did not show enhanced sensitivity to the stimulant effects of Ro 15-4513 (1, 3 and 10 mg/kg), suggesting that the neural adaptations underlying Ro 15-4513 induced BS are related to, but not identical with those associated with cocaine-induced plasticity. Secondly, we investigated whether alpha2-containing receptors are involved in mediating the ability of BZs to facilitate cocaine-induced activity. The non-selective (i.e., alpha1, alpha2, alpha3 and alpha5 subtype) benzodiazepine GABA(A) receptor agonist midazolam (10 and 30 mg/kg) potentiated cocaine (10 mg/kg) hyperactivity in wildtype mice, but not in alpha2(H101R) mice, in which alpha2-containing receptors are insensitive to benzodiazepines. To determine where alpha2 receptors are localised we compared BZ-insensitive sites between wildtype (alpha4 and alpha6) and alpha2(H101R) (alpha2, alpha4 and alpha6) mice, using quantitative autoradiography to estimate [(3)H]Ro 15-4513 binding in the presence of 10 muM diazepam. alpha2 receptors were found in projection areas of the mesolimbic dopamine pathway including accumbens, central amygdala, and basolateral amygdala as well as CA1 and CA3 areas of the hippocampus. The involvement of the alpha2-containing receptor in mediating BZ's potentiating effect on cocaine hyperactivity suggests that the locomotor stimulant effects of BZs and psychostimulants may be mediated by a common neural system, but the lack of cross sensitisation to Ro 15-4513 in cocaine-sensitised alpha2(H101R) mice, suggests that this form of BS may occur downstream of plastic events underlying cocaine sensitisation.

Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype.

Inhibitory neurotransmission in the brain is largely mediated by GABA(A) receptors. Potentiation of GABA receptor activation through an allosteric benzodiazepine (BZ) site produces the sedative, anxiolytic, muscle relaxant, anticonvulsant and cognition-impairing effects of clinically used BZs such as diazepam. We created genetically modified mice (alpha1 H101R) with a diazepam-insensitive alpha1 subtype and a selective BZ site ligand, L-838,417, to explore GABA(A) receptor subtypes mediating specific physiological effects. These two complimentary approaches revealed that the alpha1 subtype mediated the sedative, but not the anxiolytic effects of benzodiazepines. This finding suggests ways to improve anxiolytics and to develop drugs for other neurological disorders based on their specificity for GABA(A) receptor subtypes in distinct neuronal circuits.

Sensory hypersensitivity predicts enhanced attention capture by faces in the early development of ASD.

Sensory sensitivity is prevalent among young children with ASD, but its relation to social communication impairment is unclear. Recently, increased sensory hypersensitivity has been linked to greater activity of the neural salience network (Green et al., 2016). Increased neural sensitivity to stimuli, especially social stimuli, could provide greater opportunity for social learning and improved outcomes. Consistent with this framework, in Experiment 1 we found that parent report of greater sensory hypersensitivity at 2 years in toddlers with ASD (N=27) was predictive of increased neural responsiveness to social stimuli (larger amplitude event-related potential/ERP responses to faces at P1, P400 and Nc) at 4 years, and this in turn was related to parent report of increased social approach at 4 years. In Experiment 2, parent report of increased perceptual sensitivity at 6 months in infants at low and high familial risk for ASD (N=35) predicted larger ERP P1 amplitude to faces at 18 months. Increased sensory hypersensitivity in early development thus predicted greater attention capture by faces in later development, and this related to more optimal social behavioral development. Sensory hypersensitivity may index a child's ability to benefit from supportive environments during development. Early sensory symptoms may not always be developmentally problematic for individuals with ASD.

Glycopeptide storage in skin fibroblasts cultured from a patient with alpha-mannosidase deficiency.

Patients with mannosidosis, an inherited deficiency of lysosomal alpha-mannosidase, accumulate large amounts of mannose-rich oligosaccharides (the "core" of the carbohydrate units of many glocoproteins) in brain and liver and excrete these partial degradation products in their urine. A profound alpha-mannosidase deficiency was demonstrated in fibroblasts cultured from a skin biopsy obtained from a child with mannosidosis. Further, abnormal glycopeptides rich in mannose and similar to oligosaccharides found in the patient's urine were isolated from fibroblast extracts by a variety of chromatographic procedures and by virtue of their binding to a concanavalin A-Sepharose 4B affinity column. This storage material contained mannose, N-acetylglucosamine, and asparagine in the ratio 3 : 1 : 1 together with a few toher amino acids and had a molecular weight of approximately 1,100. There was no evidence for excretion of storage material by mannosidosis fibroblasts or for any abnormality in cell surface glycoprotein composition. The glycopeptide nature of the storage material isolated from cultured skin fibroblasts may be attributed to the low level of N-aspartyl-beta-glucosamindase (EC 3.5.1.-) activity in these cells.

Shape mapping of the hippocampus in young children with autism spectrum disorder.

BACKGROUND AND PURPOSE: We hypothesized the occurrence of characteristic hippocampal-shape alterations in young children with autistic spectrum disorder (ASD) who also exhibit deficits on neuropsychologic tests of medial temporal lobe (MTL) function. MATERIALS AND METHODS: Coronal 3D MR images were acquired from 3- to 4-year-old children with ASD (n = 45) and age-matched children with typical development (n = 13). Children with ASD were further subclassified into those with autism disorder (AD, n = 29) or pervasive developmental disorder-not otherwise specified (PDD-NOS) (n = 16). Variations in hippocampal shape were evaluated by using large-deformation high-dimensional brain mapping. RESULTS: Hippocampal shape measures distinguished children with ASD from those with typical development; within the ASD sample, children with AD were distinguished from those with PDD-NOS. Hippocampal-shape alterations in children with ASD were correlated with degree of mental retardation and performance deficits on tests of MTL function. CONCLUSIONS: Children with ASD exhibited an alteration of hippocampal shape consistent with inward deformation of the subiculum. This pattern of hippocampal-shape deformations in the children with ASD was accentuated in the more severely affected subgroup of children with AD and was associated with deficits on neuropsychologic tests of MTL but not prefrontal function. Hippocampal-shape deformation in the children with ASD was observed to be similar to a pattern of hippocampal shape deformation previously reported in adults with MTL epilepsy. Although the children with ASD, and those with AD in particular, PDD-NOS are at high risk for epilepsy as they enter adolescence, the specificity and causal relationship of this pattern of hippocampal-shape deformation to the development of seizures is not yet known.