Development Of Neuropsychiatric Disorders Research Articles

Altered intrahemispheric structural connectivity in Gilles de la Tourette syndrome

Gilles de la Tourette syndrome (GTS) is a common developmental neuropsychiatric disorder characterized by tics and frequent psychiatric comorbidities, often causing significant disability. Tic generation has been linked to disturbed networks of brain areas involved in planning, controlling and execution of actions, particularly structural and functional disorders in the striatum and cortico–striato–thalamo–cortical loops. We therefore applied structural diffusion tensor imaging (DTI) to characterize changes in intrahemispheric white matter connectivity in cortico-subcortical circuits engaged in motor control in 15 GTS patients without psychiatric comorbidities. White matter connectivity was analyzed by probabilistic fiber tractography between 12 predefined cortical and subcortical regions of interest. Connectivity values were combined with measures of clinical severity rated by the Yale Global Tic Severity Scale (YGTSS). GTS patients showed widespread structural connectivity deficits. Lower connectivity values were found specifically in tracts connecting the supplementary motor areas (SMA) with basal ganglia (pre-SMA–putamen, SMA–putamen) and in frontal cortico-cortical circuits. There was an overall trend towards negative correlations between structural connectivity in these tracts and YGTSS scores. Structural connectivity of frontal brain networks involved in planning, controlling and executing actions is reduced in adult GTS patients which is associated with tic severity. These findings are in line with the concept of GTS as a neurodevelopmental disorder of brain immaturity.

Copy number variation at 22q11.2: from rare variants to common mechanisms of developmental neuropsychiatric disorders

Recently discovered genome-wide rare copy number variants (CNVs) have unprecedented levels of statistical association with many developmental neuropsychiatric disorders, including schizophrenia, autism spectrum disorders, intellectual disability and attention deficit hyperactivity disorder. However, as CNVs often include multiple genes, causal genes responsible for CNV-associated diagnoses and traits are still poorly understood. Mouse models of CNVs are in use to delve into the precise mechanisms through which CNVs contribute to disorders and associated traits. Based on human and mouse model studies on rare CNVs within human chromosome 22q11.2, we propose that alterations of a distinct set of multiple, noncontiguous genes encoded in this chromosomal region, in concert with modulatory impacts of genetic background and environmental factors, variably shift the probabilities of phenotypes along a predetermined developmental trajectory. This model can be further extended to the study of other CNVs and may serve as a guide to help characterize the impact of genes in developmental neuropsychiatric disorders.

Brain mechanisms for prepulse inhibition in adults with Tourette syndrome: Initial findings

Prepulse inhibition (PPI) of the startle reflex is disrupted in a number of developmental neuropsychiatric disorders, including Tourette syndrome (TS). This disruption is hypothesized to reflect abnormalities in sensorimotor gating. We applied whole-brain functional magnetic resonance imaging (fMRI) to elucidate the neural correlates of PPI in adult TS subjects using airpuff stimuli to the throat to elicit a tactile startle response. We used a cross-sectional, case-control study design and a blocked-design fMRI paradigm. There were 33 participants: 17 with TS and 16 healthy individuals. As a measure of PPI-related brain activity, we looked for differential cerebral activation to prepulse-plus-pulse stimuli versus activation to pulse-alone stimuli. In healthy subjects, PPI was associated with increased activity in multiple brain regions, of which activation in the left middle frontal gyrus in the healthy controls showed a significant linear correlation with the degree of PPI measured outside of the magnet. Group comparisons identified nine regions where brain activity during PPI differed significantly between TS and healthy subjects. Among the TS subjects, activation in the left caudate was significantly correlated with current tic severity as measured by the total score on the Yale Global Tic Severity Scale. Differential activation of the caudate nucleus associated with current tic severity is consistent with neuropathological data and suggests that portions of cortical–striatal circuits may modulate the severity of tic symptoms in adulthood.

Sex-specific modulation of juvenile social play by vasopressin.

Social play activities among juveniles are thought to contribute to the development of social and emotional skills in humans and animals. Conversely, social play deficits are observed in developmental neuropsychiatric disorders. Importantly, many of these disorders show sex differences in incidence, course of the disease, and severity of symptoms. We hypothesized that sex differences in the neural systems controlling social behavior can contribute to these differences. We therefore studied the involvement of the sexually dimorphic vasopressin and oxytocin systems, which have been implicated in these disorders, in juvenile social play behavior. Single-housed 5-week-old juvenile male and female rats were exposed in their home cage to an age-and sex-matched novel conspecific for 10 min, and social play behaviors were recorded. We found no consistent sex differences in duration or elements of social play in vehicle-treated rats. However, intracerebroventricular injection of the specific vasopressin 1a receptor (V1aR) antagonist (CH2)5Tyr(Me(2))AVP significantly reduced social play behaviors in males while increasing them in females. Intracerebroventricular injection of the specific oxytocin receptor antagonist des-Gly-NH2,d(CH2)5[Tyr(Me)(2),Thr(4)]OVT did not alter social play in either sex. To locate the effects of V1aR blockade on social play, we targeted the lateral septum, a sexually dimorphic brain region showing denser vasopressin fibers in males than in females and an abundant expression of V1aR in both sexes. Surprisingly, blockade of V1aR in the lateral septum increased social play behaviors in males, but decreased them in females. These findings suggest sex- and brain region-specific roles for vasopressin in the regulation of social play behavior in juvenile rats.

Considerations regarding animal research of traditional Chinese medicine on attention deficit hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a common developmental neuropsychiatric disorder. Although ADHD can often be treated with stimulant class medications to alleviate symptoms, such treatments may cause undesirable side effects. Recently, Traditional Chinese medicine (TCM) has been gaining interest with treatment potential for ADHD and the lack of the stimulant-associated undesirable side effects. Animal models are useful for study the efficacy and mechanisms of TCM treatment for ADHD, however, previous studies of TCM on ADHD animal models, in general, have not considered appropriate experiemental designs. There were many concerns regarding the choice and source of the model and control animals, drug administration methods, behavioral and biochemical testing criteria, humane use of animals, and statistical power, etc. In this review, we discuss these issues present in the previous literature of animal research, and propose guidelines for future studies in particular consideration with the unique characteristic of Chinese medicine itself.

No Association Between General Cognitive Ability and Rare Copy Number Variation

There is increasing evidence for the role of rare copy-number variation (CNV) in the development of neuropsychiatric disorders. It is likely that such variants also have an effect on the variation of cognition in what is considered the "normal" phenotypic range. The role of rare CNV (>20 KB in length; frequency <5 %) on general cognitive ability is investigated in a sample of 800 individuals (mean age = 16.5, SD = 1.2) using copy-number variants called from the Illumina 610K SNP genotyping array with the software QuantiSNP. We assessed three measures of CNV burden--total CNV length, number of CNV and average CNV length--for both deletions and duplications in combination and separately. No correlation was found between any of the measures of CNV burden and IQ, or when comparing the top and bottom 10 % of the sample for IQ, both on a genome-wide scale and at individual positions across the genome.

Sex-dependent role of the amygdala in the development of emotional and neuroendocrine reactivity to threatening stimuli in infant and juvenile rhesus monkeys

Amygdala dysfunction and abnormal fear and stress reactivity are common features of several developmental neuropsychiatric disorders. Yet, little is known about the exact role the amygdala plays in the development of threat detection and emotional modulation. The current study examined the effects of neonatal amygdala lesions on defensive, emotional, and neuroendocrine reactivity of infant rhesus monkeys reared with their mothers in large species-typical social groups. Monkeys received either bilateral MRI-guided ibotenic acid amygdala (Neo-A; n=16) or sham (Neo-C; n=12) lesions at 24.8±1.2days of age, or served as behavioral control (Neo-BC; n=3). Defensive and emotional responses were assessed using the Human Intruder paradigm as infants and as juveniles (2.5 and 12months of age, respectively), whereas neuroendocrine reactivity was only examined during the juvenile period. As infants, Neo-A animals expressed similar levels of freezing and hostile behaviors as compared to controls, whereas during the juvenile period Neo-A animals expressed significantly less freezing compared to controls. Interestingly, the sex of the infant modulated the behavioral effects of neonatal amygdalectomy, leading to different patterns of behavior depending on the sex and lesion status of the infant. Unlike controls, Neo-A infants did not modulate their behavioral responses based on the salience of the threat. The impact of neonatal amygdalectomy increased with age, such that Neo-A juveniles exhibited fewer emotional behaviors and increased cortisol response to the stressor as compared to controls. These data indicate that the amygdala plays a critical role in the development of both emotional and neuroendocrine reactivity as well as the expression of sexually dimorphic emotional expression.

The Role of Dentate Gyrus Neurogenesis in Neuropsychiatric Disorders

The Role of Dentate Gyrus Neurogenesis in Neuropsychiatric Disorders

Long-Term Survival, Nutritional Autonomy, and Quality of Life After Intestinal and Multivisceral Transplantation

To assess long-term survival, graft function, and health-related quality of life (QOL) after visceral transplantation. Despite continual improvement in early survival, the long-term therapeutic efficacy of visceral transplantation has yet to be defined. A prospective cross-sectional study was performed on 227 visceral allograft recipients who survived beyond the 5-year milestone. Clinical data were used to assess outcome including graft function and long-term survival predictors. The socioeconomic milestones and QOL measures were assessed by clinical evaluation, professional consultation, and validated QOL inventory. Of 376 recipients, 227 survived beyond 5 years, with conditional survival of 75% at 10 years and 61% at 15 years. With a mean follow-up of 10 ± 4 years, 177 (92 adults, 85 children) are alive, with 118 (67%) recipients 18 years or older. Nonfunctional social support and noninclusion of the liver in the visceral allograft are the most significant survival risk factors. Nutritional autonomy was achievable in 160 (90%) survivors, with current serum albumin level of 3.7 ± 0.5 gm/dL and body mass index of 25 ± 6 kg/m(2). Despite coexistence or development of neuropsychiatric disorders, most survivors were reintegrated to society with self-sustained socioeconomic status. In parallel, most of the psychological, emotional, and social QOL measures significantly (P < 0.05) improved after transplantation. Current morbidities with potential impact on global health included dysmotility (59%), hypertension (37%), osteoporosis (22%), and diabetes (11%), with significantly (P < 0.05) higher incidence among adult recipients. With new tactics to further improve long-term survival including social support measures, visceral transplantation has achieved excellent nutritional autonomy and good QOL.

Complex autism spectrum disorder in a patient with a 17q12 microduplication

Autism spectrum disorders (ASDs) are phenotypically complex developmental neuropsychiatric disorders affecting approximately 0.6% of the population. About 30-70% of affected children are also considered to have intellectual disability (ID). The underlying genetic causes of ASDs are diverse with a defined etiology in 16-20%. Array comparative genomic hybridization (aCGH) has proven useful in identifying sub-microscopic chromosome aberrations in a subset of patients, some of which have been shown to be recurrent. One such aberration is the 1.4 Mb microdeletion at chromosome 17q12, which has been reported to be associated with renal disease, growth restriction, diabetes, cognitive impairment, seizures, and in some cases an ASD. Patients with the reciprocal chromosome 17q12 microduplication typically have also been identified with ID and in some cases seizures and behavioral abnormalities. Here we report a patient with a de novo, 1.4 Mb microduplication diagnosed with significant ID involving complex deficits and autism. To our knowledge, this is the first report of a patient with the 17q12 microduplication and a complex ASD phenotype.

Distinct neuropsychological subgroups in typically developing youth inform heterogeneity in children with ADHD

Research and clinical investigations in psychiatry largely rely on the de facto assumption that the diagnostic categories identified in the Diagnostic and Statistical Manual (DSM) represent homogeneous syndromes. However, the mechanistic heterogeneity that potentially underlies the existing classification scheme might limit discovery of etiology for most developmental psychiatric disorders. Another, perhaps less palpable, reality may also be interfering with progress-heterogeneity in typically developing populations. In this report we attempt to clarify neuropsychological heterogeneity in a large dataset of typically developing youth and youth with attention deficit/hyperactivity disorder (ADHD), using graph theory and community detection. We sought to determine whether data-driven neuropsychological subtypes could be discerned in children with and without the disorder. Because individual classification is the sine qua non for eventual clinical translation, we also apply support vector machine-based multivariate pattern analysis to identify how well ADHD status in individual children can be identified as defined by the community detection delineated subtypes. The analysis yielded several unique, but similar subtypes across both populations. Just as importantly, comparing typically developing children with ADHD children within each of these distinct subgroups increased diagnostic accuracy. Two important principles were identified that have the potential to advance our understanding of typical development and developmental neuropsychiatric disorders. The first tenet suggests that typically developing children can be classified into distinct neuropsychological subgroups with high precision. The second tenet proposes that some of the heterogeneity in individuals with ADHD might be "nested" in this normal variation.

İlk tanısı otizm olan bir becker musküler distrofisi olgusu / A case report of becker’s musculer dystrophy presenting with autistic symptoms

Becker’s muscular dystrophy is a hereditary chronic progressive muscle disease. It is reported that the incidence of autism, a developmental neuropsychiatric disorder in the hereditary muscle diseases is higher than in the normal population. In this paper, a 4 years 3 months old male patient who was diagnosed with autistic symptoms when he was 20-months old and diagnosed with Becker’s muscular dystrophy when he was 3-years-old, is presented.

Developmental changes in human dopamine neurotransmission: cortical receptors and terminators

BackgroundDopamine is integral to cognition, learning and memory, and dysfunctions of the frontal cortical dopamine system have been implicated in several developmental neuropsychiatric disorders. The dorsolateral prefrontal cortex (DLPFC) is critical for working memory which does not fully mature until the third decade of life. Few studies have reported on the normal development of the dopamine system in human DLPFC during postnatal life. We assessed pre- and postsynaptic components of the dopamine system including tyrosine hydroxylase, the dopamine receptors (D1, D2 short and D2 long isoforms, D4, D5), catechol-O-methyltransferase, and monoamine oxidase (A and B) in the developing human DLPFC (6 weeks -50 years).ResultsGene expression was first analysed by microarray and then by quantitative real-time PCR. Protein expression was analysed by western blot. Protein levels for tyrosine hydroxylase peaked during the first year of life (p < 0.001) then gradually declined to adulthood. Similarly, mRNA levels of dopamine receptors D2S (p < 0.001) and D2L (p = 0.003) isoforms, monoamine oxidase A (p < 0.001) and catechol-O-methyltransferase (p = 0.024) were significantly higher in neonates and infants as was catechol-O-methyltransferase protein (32 kDa, p = 0.027). In contrast, dopamine D1 receptor mRNA correlated positively with age (p = 0.002) and dopamine D1 receptor protein expression increased throughout development (p < 0.001) with adults having the highest D1 protein levels (p ≤ 0.01). Monoamine oxidase B mRNA and protein (p < 0.001) levels also increased significantly throughout development. Interestingly, dopamine D5 receptor mRNA levels negatively correlated with age (r = -0.31, p = 0.018) in an expression profile opposite to that of the dopamine D1 receptor.ConclusionsWe find distinct developmental changes in key components of the dopamine system in DLPFC over postnatal life. Those genes that are highly expressed during the first year of postnatal life may influence and orchestrate the early development of cortical neural circuitry while genes portraying a pattern of increasing expression with age may indicate a role in DLPFC maturation and attainment of adult levels of cognitive function.

Stress‐induced anhedonia is associated with an increase in Alzheimer's disease‐related markers

Stress is believed to be associated with the development of neuropsychiatric disorders, including Alzheimer's disease (AD). We have studied mechanisms implicated in vulnerability to stress and the relationship with changes in AD-related markers. Anhedonia induced by a chronic mild stress (CMS) procedure, applied for 6 weeks, was used to select rats vulnerable or resistant to stress. Sucrose intake, the Porsolt forced swimming test and cognitive deficits in the novel object recognition test (NORT) were used to characterize vulnerable and resilient rats. The antidepressant venlafaxine (20 mg·kg(-1) p.o.) or saline was administered daily during the last 2 weeks of CMS. Biochemical markers affected by stress, PKB, ERK and synaptophysin, and those associated with AD, amyloid β-protein (Aβ), β-secretase (BACE1) and τ phosphorylation, were measured in the hippocampus. After CMS, 40% of rats were resistant to the development of anhedonia (CMS-resistant to stress), whereas the remaining were responsive [CMS-anhedonic (CMSA)]. Only CMSA rats displayed significant increases in immobility time in the forced swimming test and cognitive deficits in the NORT, and significant decreases in synaptophysin, phosphorylated PKB and phosphorylated ERK1/2 expression in the hippocampus. Increased levels of Aβ40, BACE1 and τ phosphorylation were also found only in CMSA rats. All these effects in CMSA rats were reverted by treatment with venlafaxine. Vulnerability to stress might constitute a risk factor for the development of AD, and pharmacological treatment with venlafaxine may represent a therapeutic strategy for the treatment of stress-related disorders, including AD.

Nicotinic α5 Subunits Drive Developmental Changes in the Activation and Morphology of Prefrontal Cortex Layer VI Neurons

Nicotinic signaling in prefrontal layer VI pyramidal neurons is important to the function of mature attention systems. The normal incorporation of α5 subunits into α4β2* nicotinic acetylcholine receptors augments nicotinic signaling in these neurons and is required for normal attention performance in adult mice. However, the role of α5 subunits in the development of the prefrontal cortex is not known. We sought to answer this question by examining nicotinic currents and neuronal morphology in layer VI neurons of medial prefrontal cortex of wild-type and α5 subunit knockout (α5(-/-)) mice during postnatal development and in adulthood. In wild-type but not in α5(-/-) mice, there is a developmental peak in nicotinic acetylcholine currents in the third postnatal week. At this juvenile time period, the majority of neurons in all mice have long apical dendrites extending into cortical layer I. Yet, by early adulthood, wild-type but not α5(-/-) mice show a pronounced shift toward shorter apical dendrites. This cellular difference occurs in the absence of genotype differences in overall cortical morphology. Normal developmental changes in nicotinic signaling and dendritic morphology in prefrontal cortex depend on α5-comprising nicotinic acetylcholine receptors. It appears that these receptors mediate a specific developmental retraction of apical dendrites in layer VI neurons. This finding provides novel insight into the cellular mechanisms underlying the known attention deficits in α5(-/-) mice and potentially also into the pathophysiology of developmental neuropsychiatric disorders such as attention-deficit disorder and autism.

Rescue of social behavior impairment by clozapine and alterations in the expression of neuronal receptors in a rat model of neurodevelopmental impairment induced by GRPR blockade

We have previously shown that pharmacological blockade of the gastrin-releasing peptide receptor (GRPR) during the neonatal period in rats produces behavioral features of developmental neuropsychiatric disorders. Here, we show that social interaction deficits in this model are reversed by the atypical antipsychotic clozapine given in the adulthood. In addition, we analyzed the mRNA expression of three neuronal receptors potentially involved in the etiology of disorders of the autism spectrum. Rats were injected with the GRPR antagonist RC-3095 or saline (SAL) from postnatal days 1-10, and tested for social behavior and recognition memory in the adulthood. One hour prior to the behavioral testing, rats were given a systemic injection of clozapine or saline. The mRNA expression of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor, the epidermal growth factor receptor (EGFR), and GRPR was measured in the hippocampus and cortex of a separate set of rats given RC-3095 or SAL neonatally. Rats given neonatal RC-3095 showed decreased social interaction and impaired object recognition memory. Clozapine rescued the social interaction impairment. Neonatal treatment with RC-3095 also resulted in dose-dependent decreases in the expression of GRPR, NR1, and EGFR in the cortex, whereas all three receptor mRNAs were increased in the hippocampus in rats treated with the lower dose of RC-3095. The results contribute to further validate the novel rat model of neurodevelopmental disorders induced by GRPR blockade, and shows alterations in the expression of neuronal receptors in this model.

Essential Fatty Acids and Psychiatric Disorders

Psychiatric disorders are a significant source of disability worldwide. Increasing evidence indicates that disturbances of fatty acids and phospholipid metabolism can play a part in a wide range of psychiatric, neurological, and developmental disorders in adults. Essential fatty acids, ω-3 and ω-6 polyunsaturated fatty acids, play a central role in the normal development and functioning of the brain and central nervous system. The aim of this article is to discuss the overall insight into roles of essential fatty acids in the development of mental disorders (depression, schizophrenia, bipolar disorder) and, in light of the fact that disturbances of fatty acid metabolism can play a part in the above-mentioned disorders, to investigate the current knowledge of lipid abnormalities in posttraumatic stress disorder. The information in this review was obtained after extensive MEDLINE searching of each topic area through relevant published studies from the past 20 years. References from the obtained studies were also used. This review summarizes the knowledge in terms of essential fatty acids intake and metabolism, as well as evidence pointing to potential mechanisms of essential fatty acids in normal brain functioning and development of neuropsychiatric disorders. The literature shows that ω-3 fatty acids provide numerous health benefits and that changes in their concentration in organisms are connected to a variety of psychiatric symptoms and disorders, including stress, anxiety, cognitive impairment, mood disorders, and schizophrenia. Further studies are necessary to confirm ω-3 fatty acids' supplementation as a potential rational treatment in psychiatric disorders.

LPS elicits a much larger and broader inflammatory response than Escherichia coli infection within the hippocampus of neonatal rats

An immune challenge during the neonatal period can significantly affect the development of the nervous and immune systems, such that long-term abnormalities in immune function and behavior persist into adulthood. Given that immune activation and individual cytokines have been linked to the etiology of many developmental neuropsychiatric disorders, a complete characterization of the neonatal immune response within the brain is warranted. In this study, rats were treated peripherally on postnatal day (P) 4 with either a live Escherichia coli (E. coli) infection or lipopolysaccharide (LPS), two common models of neonatal immune activation. Inflammatory gene expression was measured within the hippocampus 2 and 24h later. We determined that E. coli and LPS produce very distinct inflammatory profiles within the brain. Infection with E. coli produced a robust, yet relatively IL-1 pathway focused activation of the neonatal immune system within the brain, while LPS produced a very broad and robust immune response within the brain. This analysis also identified common inflammatory genes up-regulated by both E. coli and LPS treatment.

Altered motor network activation and functional connectivity in adult tourette's syndrome

Tourette's syndrome (TS) is a developmental neuropsychiatric disorder characterized by motor and vocal tics as well as psychiatric comorbidities. Disturbances of the fronto-striatal-thalamic pathways responsible for motor control and impulse inhibition have been previously described in other studies. Although differences in motor performance are well recognized, imaging data elucidating the neuronal correlates are scarce. Here, we examined 19 adult TS patients (13 men, aged 22-52 years, mean = 34.3 years) and 18 age- and sex-matched controls (13 men, aged 24-57 years, mean = 37.6 years) in a functional magnetic resonance imaging study at 1.5 T. We corrected for possible confounds introduced by tics, motion, and brain-structural differences as well as age, sex, comorbidities, and medication. Patients and controls were asked to perform a sequential finger-tapping task using their right, left, and both hands, respectively. Task performance was monitored by simultaneous MR-compatible video recording. Although behavioral data obtained during scanning did not show significant differences across groups, we observed differential neuronal activation patterns depending on both handedness (dominant vs. nondominant) and tapping frequency in frontal, parietal, and subcortical areas. When controlling for open motor performance, a failure of deactivation in easier task conditions was found in the subgenual cingulate cortex in the TS patients. In addition, performance-related functional connectivity of lower- and higher-order motor networks differed between patients and controls. In summary, although open performance was comparable, patients showed different neuronal networks and connectivity patterns when performing increasingly demanding tasks, further illustrating the impact of the disease on the motor system.

Altered amygdala functional connectivity in adult Tourette’s syndrome

Tourette's syndrome (TS) is a developmental neuropsychiatric disorder characterized by motor and vocal tics as well as psychiatric comorbidities. Recently, differences in maturation of cortical networks using functional connectivity metrics have been described for this disorder. However, adult data on subcortical networks are scarce. In particular, the connectivity of the amygdala, for which a role in the pathophysiology of TS has been established, has not been examined so far. We studied 15 adult TS patients (11 male, aged 30.4 ± 9.7y) and 15 age- and sex-matched controls (11 male, aged 32.0 ± 9.3y) in a functional magnetic resonance imaging study at 1.5T using a simple motor task. We corrected for possible confounds introduced by tics, motion and brain-structural differences as well as age, sex, and medication. Task performance was monitored by simultaneous MR-compatible video-recording. Data were analyzed using an independent component approach sensitive to functional connectivity patterns. A stable component comprising both amygdalae could be identified across all subjects. Additionally, we observed a highly significant increase in coupling between/within amygdalae in the TS group when compared to controls, although behavioral data obtained during scanning did not show significant differences. These findings are expected to add to our understanding of the functional architecture of Tourette's syndrome.