Comorbidity between ADHD and anxiety disorders across the lifespan.

Objectives: Attention deficit/hyperactivity disorder (ADHD) and anxiety disorders are among the most common psychiatric disorders with a 25% comorbidity rate with each other. In this study, we overview the comorbidity between ADHD and anxiety disorders in a longitudinal perspective across the lifespan and we discuss possible therapeutic strategies.Methods: A literature search was performed using PubMed to identify clinical studies assessing comorbidity between ADHD and anxiety disorders from childhood to adulthood.Results: Anxiety disorders may substantially change the presentation, the prognosis, and the treatment of ADHD itself. In childhood, the presence of generalised anxiety disorder, could prevent the typical inhibitory dysfunction present in ADHD, in adolescence may increase the deficit of working memory, and in adulthood may enhance the presence of sleep problems. Individuals with comorbid ADHD and anxiety disorders would benefit from adjunctive psychosocial or adjunctive pharmacotherapy interventions to cognitive behavioural treatment.Conclusions: The management of individuals with comorbid ADHD and anxiety disorders could be challenging for clinicians, and assessing the developmental course is crucial in order to shed light on individualised treatment.KeypointsThe comorbidity between ADHD and anxiety disorders changes the clinical presentation, the prognosis and treatment of patients with ADHD across lifespan.ADHD and anxiety disorders shared common neurobiological dysfunctions but have also different neurobiological abnormalities suggesting that they are different diagnoses.These patients are less likely to benefit from cognitive behavioural treatment strategies alone and often need adjunctive pharmacological treatments.Studies that evaluated the response to MPH reported conflicting results. These patients could respond less well and get more unpleasant arousal side-effects, but these findings need to be confirmed.For his unique mechanism of action, low dose aripiprazole treatment in adolescents and adults with this comorbid condition could be an intriguing avenue of exploration.

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.

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.

Motor cortical inhibition in ADHD: modulation of the transcranial magnetic stimulation-evoked N100 in a response control task.

The N100 component, evoked by transcranial magnetic stimulation (TMS) and electroencephalography is associated with the activation of inhibitory cortical circuits and has recently been suggested as a potential marker of inhibition in attention-deficit/hyperactivity disorder (ADHD). The aim of the present ADHD study was to investigate the modulation of the TMS-N100 in go and nogo trials of a response control task considering stages of response preparation, activation, execution and inhibition. Eighteen children with ADHD and 19 typically developing children, aged 10-14 years, were assessed. TMS was delivered over the left motor cortex, the TMS-N100 was measured at electrode P3. The TMS-N100 was determined at rest and at different time points (50 ms before S2; 150, 300 and 500 ms after S2) in a cued go/nogo task (S1-S2 paradigm). Correlations between the TMS-N100 measures, MEP-related TMS measures (e.g., short-interval intracortical inhibition) and performance measures were calculated. At rest, the amplitude of TMS-N100 was not found to be significantly reduced in the ADHD group. During the go/nogo task, children with ADHD showed a smaller increase of TMS-N100 amplitude in go trials and a smaller decrease after inhibiting a response. In go trials, a lower TMS-N100 was associated with a smaller variability of reaction times. A smaller TMS-N100 modulation extends the picture of cortical inhibition deficits in ADHD. Findings suggest a functional involvement of the mechanisms underlying the TMS-N100 at the motor output stage.

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.

Attention impairment in childhood absence epilepsy: an impulsivity problem?

Although attention problems have often been described in children with childhood absence epilepsy (CAE), the use of different methodological approaches, neuropsychological tests, and heterogeneous experimental groups has prevented identification of the selective areas of attention deficit in this population. In this study, we investigated several components of attention in children with CAE using a unique computerized test battery for attention performance. Participants included 24 patients with CAE and 24 controls matched for age and sex. They were tested with a computerized test battery, which included the following tasks: selective attention, impulsivity, focused attention, divided attention, alertness, and vigilance. Compared with healthy controls, patients with CAE made more commission errors in the Go/No-Go task and more omission errors in the divided attention task. Childhood absence epilepsy patients also showed decreased reaction times in measures of selective attention and a great variability of reaction times in alertness and Go/No-Go tasks. Our findings suggest that patients with CAE were impaired in tonic and phasic alertness, divided attention, selective attention, and impulsivity.

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.

Benign childhood epilepsy with centrotemporal spikes and the multicomponent model of attention: a matched control study.

Although the high risk of cognitive impairments in benign childhood epilepsy with centrotemporal spikes (BCECTS) is now well established, there is no clear definition of a uniform neurocognitive profile. This study was based on a neuropsychological model of attention that assessed various components of attention in 21 children with BCECTS and 21 healthy children. All participants were tested with a computerized test battery using the multicomponent model of attention performance. In comparison with healthy participants, the children with BCECTS showed significant impairment in the measure of selectivity and in one measure of intensity of attention (arousal). Our results did not correlate with the electroclinical variables of age at onset of seizures and spike index on sleep EEGs. To the best of our knowledge, this is the first study in which the multicomponent model of attentional function has been used in children with BCECTS to provide a clearer neuropsychological profile of these patients.

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.

Neurological soft signs, but not theory of mind and emotion recognition deficit distinguished children with ADHD from healthy control.

Attention Deficit Hyperactivity Disorder (ADHD) is associated with social cognition impairment, executive dysfunction and motor abnormalities, consisting in the persistence of neurological soft signs (NSS). Theory of mind (ToM) and emotion recognition (ER) deficit of children with ADHD have been interpreted as a consequence of their executive dysfunction, particularly inhibitory control deficit. To our knowledge, there are not studies that evaluate the possible correlation between the ToM and ER deficit and NSS in the population with ADHD, while this association has been studied in other psychiatric disorders, such as schizophrenia. Therefore, the aim of this study was to evaluate ToM and ER and NSS in a sample of 23 drug-naïve children with ADHD and a sample of 20 healthy children and the possible correlation between social cognition dysfunction and NSS in ADHD. Our findings suggest that ToM and ER dysfunction is not a constant feature in the population with ADHD, while NSS confirmed as a markers of atypical neurodevelopment and predictors of the severity of functional impairment in children with ADHD.

Comorbidity of ADHD and High-functioning Autism: A Pilot Study on the Utility of the Overflow Movements Measure.

OBJECTIVES: Children with attention-deficit/hyperactivity disorder (ADHD) and high-functioning autism (HFA) commonly show neurological soft signs (NSS) and impairment in executive functioning (EF). Many children with HFA may experience ADHD-like symptoms, and the 2 disorders may be comorbid. Evaluating NSS and EF in drug-naive subjects with ADHD, HFA, and ADHD+HFA compared with healthy children may be critical in understanding and differentiating the biological substrates and cognitive phenotypes associated with these disorders. The goal of this study was to evaluate possible differences among these groups in motor and EF and the effects of comorbidity. METHODS: Thirty-eight drug-naive patients (13 with ADHD, 13 with HFA, 12 with ADHD+HFA) and 13 healthy controls (HC) were evaluated on measures of planning, verbal working memory, and response inhibition. Evaluation of NSS involved 3 primary variables: overflow movements (OM), dysrhythmia, and speed of timed activities. RESULTS: The group with ADHD and the group with HFA both showed impairment on measures of planning, response inhibition, and verbal working memory compared with the HC group. Moreover, the group with ADHD showed a greater number of NSS compared with the HC group, whereas the group with HFA showed greater dysrhythmia and slowness compared with the HC group. The group with ADHD+HFA showed deficits of planning and response inhibition and a greater number of NSS compared with the HC group. The group with ADHD+HFA showed greater impairment of planning compared with the other clinical groups and greater dysrhythmia compared with the group with ADHD. CONCLUSION: According to our data, the OM measure revealed a gradient in which ADHD was at one extreme (more OM) and HFA at the other extreme (less OM), whereas ADHD+HFA showed a number of OM that fell in the middle between the numbers for the ADHD and HFA groups.

Planning deficit in children with neurofibromatosis type 1: a neurocognitive trait independent from attention-deficit hyperactivity disorder (ADHD)?

Neurofibromatosis type 1 is associated with executive dysfunctions and comorbidity with attention-deficit hyperactivity disorder (ADHD) in 30% to 50% of children. This study was designed to clarify the neurocognitive phenotype observed in neurofibromatosis type 1 by testing the hypothesis that children with neurofibromatosis type 1 have specific planning deficits independently from intellectual level and ADHD comorbidity. Eighteen children with neurofibromatosis type 1 were pair-matched to 18 children with ADHD and 18 healthy controls. All groups were assessed on the presence of ADHD symptoms (Conners Scales) and planning deficits (Tower of London). Compared with control group, groups with neurofibromatosis type 1 and ADHD demonstrated significant impairment of planning and problem solving. The lack of correlation between Tower of London results and Conners subscale scores in neurofibromatosis type 1 group confirmed that the planning and problem-solving deficit is not directly related to inattention level. These findings suggested that the executive impairment probably represents a peculiar trait of neurofibromatosis type 1 neurocognitive phenotype.

Human endogenous retroviruses and ADHD.

OBJECTIVES: Several lines of evidences suggest that human endogenous retroviruses (HERVs) are implicated in the development of many complex diseases with a multifactorial aetiology and a strong heritability, such as neurological and psychiatric diseases. Attention deficit hyperactivity Disorder (ADHD) is a neurodevelopmental disorder that results from a complex interaction of environmental, biological and genetic factors. Our aim was to analyse the expression levels of three HERV families (HERV-H, K and W) in patients with ADHD. METHODS: The expression of retroviral mRNAs from the three HERV families was evaluated in peripheral blood mononuclear cells (PBMCs) from 30 patients with ADHD and 30 healthy controls by quantitative RT-PCR. RESULTS: The expression levels of HERV-H are significantly higher in patients with ADHD compared to healthy controls, while there are no differences in the expression levels of HERV-K and W. CONCLUSIONS: Since the ADHD aetiology is due to a complex interaction of environmental, biological and genetic factors, HERVs may represent one link among these factors and clinical phenotype of ADHD. A future confirmation of HERV-H overexpression in a larger number of ADHD patients will make possible to identify it as a new parameter for this clinical condition, also contributing to deepen the study on the role of HERVs in the neurodevelopment diseases.

Neuroleptic treatments and overflow movements in schizophrenia: are they independent?

Neurological soft signs (NSS) are minor neurological abnormalities that can be revealed by a clinical examination focused on sensory and motor information processing. NSS include overflow movements (OMs), which are defined as involuntary movements that may accompany the production of voluntary movements. OM is generally considered to be a characteristic feature of schizophrenia. White matter abnormalities might be involved in the pathogenesis of OMs. Dopamine receptors play a role in oligodendrocytes development. There is a direct link between antipsychotic agents that bind to dopamine receptors on oligodendrocytes and the development of oligodendrocytes and myelin formation. In this paper, we review the current knowledge of the effects of antipsychotic agents on NSS in schizophrenic patients. As a result of this critical review we hypothesize that the neuroleptic actions described in this paper could explain why antipsychotic agents have no effect on the resolution of NSS in patients with schizophrenia.

Attention and executive functions profile in childhood absence epilepsy.

Childhood absence epilepsy (CAE) has been associated with executive functions and attention deficits. To clarify the issue of neurocognitive impairments in CAE, we investigated whether specific executive functions and attention deficit patterns were present in a well-defined group of children with CAE who were taking valproic acid. Participants included 15 children with CAE and 15 healthy controls aged 8-15 years and matched for sex, age and IQ. We compared the performances of the two groups in the following neuropsychological domains: planning and problem solving (TOL), verbal fluency (FAS and CAT), verbal short-term memory (DSF), verbal working memory (DSB), visuospatial memory (Corsi Block Tapping Test) and sustained and divided attention (TMT-A and TMT-B). No differences were found between the two groups on measures of intellectual functioning, verbal short-term memory and visuospatial memory. By contrast, significant differences were found in total time of planning task, phonological and category fluency and sustained and divided attention. Future studies that systematically examine different aspects of attention and executive functions are needed to outline a clear and specific neuropsychological profile in CAE.

ADHD and genetic syndromes.

A high rate of Attention Deficit/Hyperactivity Disorder (ADHD)-like characteristics has been reported in a wide variety of disorders including syndromes with known genetic causes. In this article, we review the genetic and the neurobiological links between ADHD symptoms and some genetic syndromes such as: Fragile X Syndrome, Neurofibromatosis 1, DiGeorge Syndrome, Tuberous Sclerosis Complex, Turner Syndrome, Williams Syndrome and Klinefelter Syndrome. Although each syndrome may arise from different genetic abnormalities with multiple molecular functions, the effects of these abnormalities may give rise to common effects downstream in the biological pathways or neural circuits, resulting in the presentation of ADHD symptoms. Early diagnosis of ADHD allows for earlier treatment, and has the potential for a better outcome in children with genetic syndromes.

Neurosteroids as neuromodulators in the treatment of anxiety disorders.

Anxiety disorders are the most common psychiatric disorders. They are frequently treated with benzodiazepines, which are fast acting highly effective anxiolytic agents. However, their long-term use is impaired by tolerance development and abuse liability. In contrast, antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are considered as first-line treatment but have a slow onset of action. Neurosteroids are powerful allosteric modulators of GABA(A) and glutamate receptors. However, they also modulate sigma receptors and they are modulated themselves by SSRIs. Both pre-clinical and clinical studies have shown that neurosteroid homeostasis is altered in depression and anxiety disorders and antidepressants may act in part through restoring neurosteroid disbalance. Moreover, novel drugs interfering with neurosteroidogenesis such as ligands of the translocator protein (18 kDa) may represent an attractive pharmacological option for novel anxiolytics which lack the unwarranted side effects of benzodiazepines. Thus, neurosteroids are important endogenous neuromodulators for the physiology and pathophysiology of anxiety and they may constitute a novel therapeutic approach in the treatment of these disorders.