Hemispheric Dominance and Neurodevelopmental Disorders: Global Effects for Intensive Motor Training on White Matter Plasticity.

Cerebral maturation is characterized by different age-dependent molecular and cellular processes and follows a different course for grey matter (GM) and white matter (WM). During brain development, a crucial point seems to be represented by the establishment of a hemispheric specialization with the left hemisphere dominant for language and motor control and the right hemisphere dominant for visuospatial processing and attention. Therefore, motor and cognitive development are strongly connected. Atypical motor development and lateralization can be associated with neurodevelopmental disorders, such as Language Disorder, Learning Disorders (Dysgraphia and Dyslexia), Attention Deficit Hyperactivity Disorder and Autism Spectrum Disorder. The aim of our research was to investigate the possible effects of intensive motor training on WM plasticity and writing skills in children with Developmental Dysgraphia through a tractography study of the main WM tracts. Considering the effect of training for the Mean Diffusivity (MD) over 18 WM tracts, in 6 collaborating dysgraphic patient MD decrease (-4.3%) and in 3 not. Intensive motor training affects both stimulated and not stimulated WM tracts and showed a double not-specificity: for not stimulated hemilate and for not directly stimulated WM tracts. Intensive motor training improves both some lateralized brain functions and intra- and inter-hemispheric connectivity in our patients with good compliance with motor treatment. Moreover, our findings have shown that WM plasticity improvement concerned cortical areas responsible for both motor and cognitive functions.

Attention Deficits Influence the Development of Motor Abnormalities in High Functioning Autism.

Early attentional dysfunction is one of the most consistent findings in autism spectrum disorder (ASD), including the high functioning autism (HFA). There are no studies that assess how the atypical attentional processes affect the motor functioning in HFA. In this study, we evaluated attentional and motor functioning in a sample of 15 drug-naive patients with HFA and 15 healthy children (HC), and possible link between attentional dysfunction and motor impairment in HFA. Compared to HC, HFA group was seriously impaired in a considerable number of attentional processes and showed a greater number of motor abnormalities. Significant correlations between attention deficits and motor abnormalities were observed in HFA group. These preliminary findings suggest that deficit of attentional processes can be implied in motor abnormalities in HFA.

A Child with a c.6923_6928dup (p.Arg2308_Met2309dup) SPTAN1 Mutation Associated with a Severe Early Infantile Epileptic Encephalopathy.

Early infantile epileptic encephalopathies (EIEEs) are a group of neurological disorders characterized by early-onset refractory seizures, severe electroencephalographic abnormalities, and developmental delay or intellectual disability. Recently, genetic studies have indicated that a significant portion of previously cryptogenic EIEEs are single-gene disorders. SPTAN1 is among the genes whose mutations are associated with EIEE development (OMIM# 613477). Here, a case of the c.6923_6928dup (p.Arg2308_Met2309dup) SPTAN1 mutation associated with a severe EIEE is reported. This case shows that mutations in the α20 repeat in the C-terminal of αII spectrin can be associated with EIEE. Duplication seems essential to cause EIEE. This causation is not demonstrated for amino acid deletions in the same spectrin residues. Reportedly, children with p.(Asp2303_Leu2305del) and p.(Gln2304_Gly2306del) deletions have childhood-onset epilepsy and no or marginal magnetic resonance imaging abnormalities, suggesting that not only the location but also the type of mutation plays a role in conditioning nervous system damage. Further studies are needed for a better understanding of the phenotype/genotype correlation in SPTAN1-related encephalopathies.

The Decrease in Human Endogenous Retrovirus-H Activity Runs in Parallel with Improvement in ADHD Symptoms in Patients Undergoing Methylphenidate Therapy.

Increasing scientific evidence demonstrated the deregulation of human endogenous retroviruses (HERVs) expression in complex diseases, such as cancer, autoimmune, psychiatric, and neurological disorders. The dynamic regulation of HERV activity and their responsiveness to a variety of environmental stimuli designate HERVs as genetic elements that could be modulated by drugs. Methylphenidate (MPH) is widely used in the treatment of attention deficit hyperactivity disorder (ADHD). The aim of this study was to evaluate the time course of human endogenous retrovirus H (HERV-H) expression in peripheral blood mononuclear cells (PBMCs) with respect to clinical response in ADHD patients undergoing MPH therapy. A fast reduction in HERV-H activity in ADHD patients undergoing MPH therapy was observed in parallel with an improvement in clinical symptoms. Moreover, when PBMCs from drug-naïve patients were cultured in vitro, HERV-H expression increased, while no changes in the expression levels were found in ADHD patients undergoing therapy. This suggests that MPH could affect the HERV-H activity and supports the hypothesis that high expression levels of HERV-H could be considered a distinctive trait of ADHD patients.

A Small Supernumerary Marker Derived from the Pericentromeric Region of Chromosome 5: Case Report and Delineation of Partial Trisomy 5p Phenotype.

A 17-year-old girl presented with a distinct phenotype mainly featuring craniofacial dysmorphism, including a disproportioned large, round, elongated face; hypertelorism; deep-set eyes with short palpebral fissures; obesity (BMI 37), and a neuropsychiatric disorder with high-functioning autism. Postnatal conventional cytogenetic analyses from peripheral blood revealed a mosaic small supernumerary marker chromosome (sSMC) with a mos 47,XX,+mar[7]/46,XX[43] karyotype. By cenM-FISH technique, the sSMC was identified as a ring derivative of chromosome 5. Metaphase FISH analysis with a set of dedicated probes defined its origin from the pericentromeric region of chromosome 5, including the NIPBL gene at 5p13.2. Such sSMCs, exceedingly rare in the literature, underlie proximal trisomy 5p. In order to delineate a core phenotype of proximal trisomy 5p, we compared our patient's features with those of 6 patients found in the literature with similar der(5) chromosomes. Furthermore, a dozen individuals with 5p13 (micro)duplication syndrome was compared and discussed. We identified highly distinctive craniofacial dysmorphism, obesity, and intellectual disability and/or autism spectrum disorder as typical features of proximal 5p trisomy. In the critical region (band 5p13), the NIPBL gene is likely to be a major determinant of the neurobehavioral phenotype, and its presence at the sSMC level may be relevant to predict clinical outcome.

Dysfunctional personality traits in adolescence: effects on alerting, orienting and executive control of attention.

The present study examined attentional networks performance in 39 adolescents with dysfunctional personality traits, split into two group, Group < 10 and Group ≥ 10, according to the number of criteria they met at the Structured Clinical Interview for DSM-IV Axis II Personality Disorders. The attentional performance has been tested by means of a modified version of the Attentional Network Test (ANTI-V) which allows testing both phasic and tonic components of the alerting system, the exogenous aspect of the orienting system, the executive network and their interactions. Results showed that the orienting costs of having an invalid spatial cue were reduced in the Group ≥ 10 criteria compared to the Group < 10. Moreover, adolescents included in the Group ≥ 10 showed lower conflict when attention was cued to the target location (valid trials) but showed normal interference when there was no overpowering focus of attention (invalid trials). The results found with ANOVA after splitting the sample into two categorical groups were also observed in a complementary correlation analysis keeping intact the continuous nature of such variables. These findings are consistent with the notion that dysfunctional features of personality disorders may represent the psychological manifestations of a neuropsychological abnormality in attention and executive functioning. Finally, we discuss the implications of this attentional anomaly for dysfunctional personality traits and behaviour.

Neurological soft signs are associated with attentional dysfunction in children with attention deficit hyperactivity disorder.

INTRODUCTION: Inattention is one of the core symptoms of Attention Deficit Hyperactivity Disorder (ADHD). Most of patients with ADHD show motor impairment, consisting in the persistence of neurological soft signs (NSS). Our aim was to evaluate attentional and motor functioning in an ADHD sample and healthy children (HC) and possible link between attentional dysfunction and motor impairment in ADHD. METHOD: Twenty-seven drug-naive patients with ADHD and 23 HC were tested with a test battery, measuring different aspects of attention. Motor evaluation has provided three primary variables: overflow movements (OM), dysrhythmia and total speed of timed activities. RESULTS: Compared to HC, patients were impaired in a considerable number of attentional processes and showed a greater number of NSS. Significant correlations between disturbances of attention and motor abnormalities were observed in ADHD group. CONCLUSION: Our findings suggest that attentional processes could be involved in the pathophysiology of the NSS and add scientific evidence to the predictive value of NSS as indicators of the severity of functional impairment in ADHD. Given the marked improvement or complete resolution of NSS following treatment with methylphenidate, we suggest that evaluation of NSS is useful to monitor the effectiveness of pharmacological treatment with MPH in ADHD.

First evidence of HERV-H transcriptional activity reduction after methylphenidate treatment in a young boy with ADHD.

Human endogenous retroviruses (HERVs) have been associated with many complex diseases including neuropsychiatric diseases, such as attention deficit hyperactivity disorder (ADHD). In ADHD an over-expression of HERV-H family in peripheral blood mononuclear cells has been documented. It has been hypothesized that HERVs may represent the link between genetic and environmental risk factors, contributing to the clinical onset and/or to the progression of the neurodevelopmental disease. The effect of pharmacological treatment on HERV transcriptional activity in psychiatric disorders has been attracting attention. Using a real-time RT-PCR we investigated the influence of methylphenidate on HERV transcription in peripheral blood mononuclear cells of a young patient with ADHD. In this clinical case we describe for the first time the reduction of HERV-H expression and the significant improvement of ADHD symptoms after 6 months of methylphenidate treatment.

Impaired reflexive orienting to social cues in attention deficit hyperactivity disorder.

The present study investigated whether another person's social attention, specifically the direction of their eye gaze, and non-social directional cues triggered reflexive orienting in individuals with Attention Deficit Hyperactivity Disorder (ADHD) and age-matched controls. A choice reaction time and a detection tasks were used in which eye gaze, arrow and peripheral cues correctly (congruent) or incorrectly (incongruent) signalled target location. Independently of the type of the task, differences between groups were specific to the cue condition. Typically developing individuals shifted attention to the location cued by both social and non-social cues, whereas ADHD group showed evidence of reflexive orienting only to locations previously cued by non-social stimuli (arrow and peripheral cues) but failed to show such orienting effect in response to social eye gaze cues. The absence of reflexive orienting effect for eye gaze cues observed in the participants with ADHD may reflect an attentional impairment in responding to socially relevant information.

Impairment in flexible regulation of speed and accuracy in children with ADHD.

Attention deficit hyperactivity disorder (ADHD) is characterized by poor adaptation of behavior to environmental demands, including difficulties in flexibly regulating behavior. To understand whether ADHD is associated with a reduction of strategic flexibility in modulating speed and accuracy, we used a perceptual decision-making task that required participants to randomly stress either fast or accurate responding. Thirty-one drug-free boys with ADHD combined-type (mean age: 10.2 years) and 33 healthy control boys (mean age: 10.7 years), matched for age and IQ, participated. Both reaction time and accuracy data were analyzed. Our findings demonstrated significantly lower accuracy in ADHD children than in controls when switching from speed to accuracy instructions. This deficit was directly associated with hyperactivity symptoms but not with inattention. Our results showed that ADHD is associated with a deficit in dynamically switching response strategy according to task demands on a trial-to-trial basis.

Presence of neurologic signs in children with neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis type 1 is a common neurogenetic disorder affecting nervous system, caused by germiline mutations of the NF1 gene. Although the clinical diagnosis of NF1 is defined by presence of cafe-au-laits spots, freckling and benign tumors (neurofibromatosis), neurocognitive impairment and neuropsychiatric disorders are reported in comorbidity. Children with NF1 show higher incidence of executive deficits, such attention, response inhibition, executive planning and problem solving, working memory, and learning impairment. In this study we examine the presence of neurological soft signs and planning function in subjects with NF1. The NSS are minor motor and sensory abnormalities without focal brain damage. METHODS: Eleven drug naïve children between 7-15 years with clinical and molecular diagnosis of NF are matched to 11 healthy controls to ass the presence of neurological soft signs and planning executive functions. NSS were assessed using Physical and Neurological Examination for Subtle Signs and the Tower of London task is performance test to assess the capacity of planning, organization and execution of a work. RESULTS: Our results revealed highest rate of NSS and planning deficit in children with NF1 compared to healthy controls. CONCLUSIONS: The motor abnormalities and planning deficit are possible markers to confirm that NF1 could be considering a neurodevelopmental disorder.

Motor examination in children with Attention-deficit/hyperactivity Disorder and Asperger Syndrome.

AIM: Evaluating whether motor skills could differentiate drug-naive subjects with two neurodevelopmental disorders: Attention-Deficit Hyperactivity Disorder (ADHD) and Asperger Syndrome (AS). METHODS: Thirty-six boys (12 with ADHD, 12 with AS and 12 with typical development) aged 8-12 were evaluated using the Physical and Neurological Examination for Subtle Signs. Three primary outcome variables were obtained as follows: (i) total speed of timed activities, (ii) total overflow and (iii) total dysrhythmia. RESULTS: Children with AS performed more slowly than those with ADHD and healthy children independently of age and IQ. Total dysrhythmia differentiates ADHD and AS children from controls. CONCLUSION: Dysfunction of the fronto-striatal-cerebellar networks related to motor control could be the physiopathological basis of the reported findings.

Detecting anxiety symptoms in children and youths with neurofibromatosis type I.

Children with Neurofibromatosis type 1 (NF1) are known to have cognitive, social, and behavioral deficits. Fifteen NF1-subjects (5 boys, 10 girls, mean age = 13.4), and 15 healthy controls matched for age and sex were assessed on the presence of anxiety symptoms, using the Multidimensional Anxiety Scale for Children (MASC), self-report questionnaire. Significant group differences emerged with regard to MASC total (Z = -2.058, P = 0.041) and anxiety disorder index (ADI; Z = -2.202, P = 0.026), but not with regard to single scales. When the severity and visibility of NF1 were considered, correlation between severity and social anxiety, and severity and MASC total was found. This is the first study assessing anxiety symptoms in NF1 children and youths. A precocious psychological survey and intervention in NF1 subjects, may contribute to reduce the risk of psychiatric disorders in adulthood.

New Insights on the Effects of Methylphenidate in Attention Deficit Hyperactivity Disorder.

This narrative review describes an overview of the multiple effects of methylphenidate (MPH) in attention-deficit/hyperactivity disorder (ADHD) and its potential neurobiological targets. It addressed the following aspects: 1) MPH effects on attention and executive functions in ADHD; 2) the relation between MPH efficacy and dopamine transporter gene (DAT) polymorphism; and 3) the role of MPH as an epigenetic modulator in ADHD. Literature analysis showed that MPH, the most commonly used psychostimulant in the therapy of ADHD, acts on multiple components of the disorder. Marked improvements in attentional and executive dysfunction have been observed in children with ADHD during treatment with MPH, as well as reductions in neurological soft signs. MPH efficacy may be influenced by polymorphisms in the DAT, and better responses to treatment were associated with the 10/10 genotype. Innovative lines of research have suggested that ADHD etiopathogenesis and its neuropsychological phenotypes also depend on the expression levels of human endogenous retrovirus (HERV). In particular, several studies have revealed that ADHD is associated with HERV-H over-expression and that MPH administration results in decreased expression levels of this retroviral family and a reduction in the main symptoms of the disorder. In conclusion, there is a confirmed role for MPH as an elective drug in the therapy of ADHD alone or in association with behavioral therapy. Its effectiveness can vary based on DAT polymorphisms and can act as a modulator of HERV-H gene expression, pointing to targets for a precision medicine approach.

Rett Syndrome in Males: The Different Clinical Course in Two Brothers with the Same Microduplication MECP2 Xq28.

Rett syndrome (RTT) is a neurodevelopmental disorder with a genetic basis that is associated with the mutation of the X-linked methyl-CpG binding protein 2 (MECP2) gene in approximately 90% of patients. RTT is characterized by a brief period of normal development followed by loss of acquired skills and evolution towards impairment of brain and motor functions and multi-organ dysfunction. Originally, RTT was considered lethal in males as it has an X-linked dominant inheritance. However, although this syndrome has a higher incidence in females, rare cases are also documented in males. Here, we describe the case of an 11-year-old male patient with a microduplication MECP2 Xq28. Our patient is currently living, while his older brother with the same mutation died at the age of 9 years. We showed that the role of MECP2 as an epigenetic modulator and the X-chromosome inactivation pattern can explain the lethal clinical form of the older brother with the same microduplication MECP2 Xq28 presented by our patient who is still alive. Given the limited case history of RTT in males, further studies are needed to better characterize this syndrome in males and consequently improve the currently available therapeutic strategies.

22q11 microdeletion syndrome and ultra-high risk for psychosis: The role of neurological soft signs as an independent marker of vulnerability for psychosis.

AIM: 22q11 microdeletion syndrome has an increased risk for psychosis, similar to subjects at ultra-high risk for psychosis. Neurological soft signs are considered an endophenotype of psychotic disorders and a marker of vulnerability to Schizophrenia, consisting of overflow movements, dysrhythmia and speed of timed activities. To date, there are no studies that have evaluated the presence of the neurological soft signs in subjects with 22q11 microdeletion syndrome and there are a few studies that have analysed this issue in subjects at ultra-high risk. METHODS: We sought to measure neurological soft signs in these two conditions, compared to healthy controls and to analyse the possible correlation between neurological soft signs and positive/negative symptoms both in 22q11 microdeletion syndrome and ultra-high-risk groups. 54 drug-naive patients (29 with 22q11 microdeletion syndrome and 25 at ultra-high risk for psychosis) and 25 healthy controls were evaluated for neurological soft signs. RESULTS: Both clinical groups showed a greater number of neurological soft signs compared to healthy control, although the two clinical groups did not differ for the number of neurological soft signs. Positive correlation between speed of timed activities and negative symptoms was found in subjects at ultra-high risk. CONCLUSION: Neurological soft signs could represent a marker of atypical neurodevelopment in the two populations examined. Since we did not found a strong correlation between neurological soft signs and positive/negative symptoms, we suggest that neurological soft signs could be indicators of vulnerability to psychosis independent from the psychopathology.

Antipsychotics Do Not Influence Neurological Soft Signs in Children and Adolescents at Ultra-High Risk for Psychosis: A Pilot Study.

OBJECTIVE: Ultra-high risk for psychosis (UHR) is considered as the condition that temporally precedes the onset of psychotic symptoms. In addition to the core symptoms, patients with schizophrenia show motor abnormalities, also known as neurological soft signs (NSS), that are considered an endophenotype for psychotic disorders and particularly for schizophrenia. Antipsychotic medications do not appear to influence NSS in individuals with schizophrenia. However, NSS in UHR subjects have been poorly studied and, to date, we do not know what effects antipsychotics have in early treated UHR subjects. Therefore, we evaluated NSS in treated UHR subjects in comparison with drug-naive UHR subjects and a group of healthy control subjects and the effect of pharmacological treatment on early treated UHR children and adolescents. PATIENTS AND METHODS: Fifteen UHR subjects receiving pharmacological treatment, 15 drug-naive UHR subjects, and 25 healthy control subjects were evaluated for NSS to analyze any differences between clinical subjects and healthy controls and to evaluate the effect of antipsychotic medications in early treated UHR subjects. RESULTS: Both clinical groups showed a greater number of NSS compared with the healthy control subjects. However, no significant differences in NSS were found between treated and drug-naive UHR subjects. CONCLUSIONS: Consistent with what has been observed in the population of patients with a first psychotic episode and/or with schizophrenia, our results support the conclusion that antipsychotic medications do not influence NSS in children and adolescents who are at high risk for psychosis.

The complex roles of neurosteroids in depression and anxiety disorders.

The role of neurosteroids in neuropsychiatric disorders has been thoroughly investigated in many research studies that have stressed their significant pathophysiological function in neuropsychiatry. In this review, we will focus mainly on the steroids active on the GABA(A) receptors studied in anxiety and depression. The aim is to discuss the controversial results reported in research on anxiety and depressive disorders. We suggest the combined use of biological parameters linked to psychopathological dimensions to make more homogeneous diagnoses and to develop more precise therapies for the treatment of depression and anxiety disorders. We discuss the role of neurosteroids in the pathophysiology and therapy of anxiety and depression. Finally, we consider the possibility of using quantification of mRNA expression of steroidogenic enzymes from peripheral sources in neuropsychiatry.

Scientific Evidence for the Evaluation of Neurological Soft Signs as Atypical Neurodevelopment Markers in Childhood Neuropsychiatric Disorders.

Motor dysfunction is commonly present in children with neurodevelopmental disorders. Developmental changes in voluntary control of motor skills include improvements in speed and motor coordination as well as reduced frequency of neurological soft signs (NSS) that are commonly observed in typically developing younger children. NSS are motor and sensory conditions that cannot be linked to specific cerebral lesions. The persistence of NSS into later childhood and adolescence is linked with an increased risk of psychiatric disorders. This finding gives support to the neurodevelopmental model of NSS in which minor neurological impairments may be viewed as potential signs of deviant brain development and might represent trait markers of vulnerability for neurodevelopmental disorders. Given that NSS are easily detectable, it is important that clinicians increase their knowledge of the clinical presentation and research implications of the relationship between NSS and childhood neurodevelopmental disorders. To the best of our knowledge, this is the first review article to give an updated overview of the current knowledge of NSS in the most common neuropsychiatric disorders of childhood/adolescence, such as attention-deficit/hyperactivity disorder, autism spectrum disorder, obsessive-compulsive disorder, bipolar disorder, and first episode of psychosis. The article also presents key points for future research studies on this topic.

Recurrent Renal Colic in a Patient with Munchausen Syndrome.

BACKGROUND: In most of the cases regarding children, factitious disorders (FDs) are intentionally produced by parents. Less attention is paid to FDs in which a child or adolescent intentionally induces or falsifies the disease to attain a patient's role. CASE PRESENTATION: A 13-year-old immigrated and adopted boy previously underwent an operation for renal joint syndrome and was affected by recurrent episodes of renal colic. The boy was admitted reporting acute left flank pain with scars on the mucous face of his prepuce and had a recent previous hospitalization for the same reason. Laboratory tests and radiological findings did not reveal any morphological or functional alterations. Self-induced FD was suspected, and a psychiatric consultation was performed. After psychiatric consultation and remission of the symptoms with a placebo, a diagnosis of Munchausen syndrome was suspected. The patient's uncle was not initially convinced of the diagnosis. Some videos clearly showed that the boy was handling his prepuce to excrete stones, explaining the scars. A therapeutic plan with psychiatrist support was later accepted with a positive outcome. No further signs and symptoms of renal colic were reported. CONCLUSIONS: It is recommended that paediatricians include FD in the differential diagnosis of a persistent and unexplained medical condition. If suspicion arises, confirmation and long-term therapy by a group of qualified specialists, including psychiatrists, should be planned.