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Neurophysiological and behavioral correlates of alertness impairment and compensatory processes in ADHD evidenced by the Attention Network Test.

ABSTRACT: In Attention Deficit Hyperactivity disorder (ADHD), fMRI studies show asymmetric alterations: widespread hypoactivation in anterior cortical areas and hyperactivation in some posterior regions, and the latter is considered to be related to compensatory processes. In Posner's attentional networks, an important role is attributed to functional interhemispheric asymmetries. The psychophysiological Attention Network Test (ANT), which measures the efficiency of the alerting, orienting, and executive networks, seems particularly informative for ADHD. Potentials related to ANT stimuli (ANT-RPs) have revealed reduced cognitive potential P3 in ADHD. However, there are no studies associated with asymmetry of ANT-RPs. In the present study, conducted with 20 typically developing boys and 19 boys with ADHD, aged 11-13 years, the efficiency of the three Posner's networks regarding performance and amplitude asymmetries in ANT-RPs was evaluated according to the arithmetic difference of these parameters between different cue and target presentation conditions. The results were correlated to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) scores. Regarding accuracy and intraindividual variation in reaction time, ADHD subjects showed lower efficiency of executive and alerting network, and this effect was correlated with DSM. Regarding alerting network, ANT-RPs in ADHD did not have the right-side amplitude prevalence in the temporal regions, which was observed in controls. In all ANT conditions, significantly higher asymmetries were observed in ADHD than in controls in the occipital regions 40-200 ms after target onset. Their amplitude in ADHD subjects was inversely proportional to DSM scores of inattentiveness and directly proportional to accuracy and efficiency of the executive network. The results suggest impaired alerting and executive networks in ADHD and compensatory occipital mechanisms.

SUBMITTER: Abramov DM

PROVIDER: S-EPMC6657843 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:UnlabelledSchizophrenia is a chronic, disabling neuropsychiatric disorder with complex genetic origins. The development of strategies for genome manipulation in rodents provides a platform for understanding the pathogenic role of genes and for testing novel therapeutic agents. Neuregulin 1 (NRG1), a critical developmental neurotrophin, is associated with schizophrenia. The NRG1 gene undergoes extensive alternative splicing and, to date, little is known about the neurobiology of a novel NRG1 isoform, NRG1-IV, which is increased in the brains of individuals with schizophrenia and associated with genetic risk variation. Here, we developed a transgenic mouse model (NRG1-IV/NSE-tTA) in which human NRG1-IV is selectively overexpressed in a neuronal specific manner. Using a combination of molecular, biochemical, electrophysiological, and behavioral analyses, we demonstrate that NRG1-IV/NSE-tTA mice exhibit abnormal behaviors relevant to schizophrenia, including impaired sensorimotor gating, discrimination memory, and social behaviors. These neurobehavioral phenotypes are accompanied by increases in cortical expression of the NRG1 receptor, ErbB4 and the downstream signaling target, PIK3-p110δ, along with disrupted dendritic development, synaptic pathology, and altered prefrontal cortical excitatory-inhibitory balance. Pharmacological inhibition of p110δ reversed sensorimotor gating and cognitive deficits. These data demonstrate a novel role for NRG1-IV in learning, memory, and neural circuit formation and a potential neurobiological mechanism for schizophrenia risk; show that deficits are pharmacologically reversible in adulthood; and further highlight p110δ as a target for antipsychotic drug development.Significance statementSchizophrenia is a disabling psychiatric disorder with neurodevelopmental origins. Genes that increase risk for schizophrenia have been identified. Understanding how these genes affect brain development and function is necessary. This work is the first report of a newly generated humanized transgenic mouse model engineered to express human NRG1-IV, an isoform of the NRG1 (Neuregulin 1) gene that is increased in the brains of patients with schizophrenia in association with genetic risk. Using behavioral neuroscience, molecular biology, electrophysiology, and pharmacology, we identify a role for NRG1-IV in learning, memory, and cognition and determine that this relates to brain excitatory-inhibitory balance and changes in ErbB4/PI3K/AKT signaling. Moreover, the study further highlights the potential of targeting the PI3K pathway for the treatment of schizophrenia.

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Neurophysiological and behavioral correlates of alertness impairment and compensatory processes in ADHD evidenced by the Attention Network Test.

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