Novel in silico multivariate mapping of intrinsic and anticorrelated connectivity to neurocognitive functional maps supports the maturational hypothesis of ADHD

Abstract

From childhood to adolescence, strengthened coupling in frontal, striatal and parieto-temporal regions associated with cognitive control, and increased anticorrelation between task-positive and task-negative circuits, subserve the reshaping of behavior. ADHD is a common condition peaking in adolescence and regressing in adulthood, with a wide variety of cognitive control deficits. Alternate hypotheses of ADHD emphasize lagging circuitry refinement versus categorical differences in network function. However, quantifying the individual circuit contributions to behavioral findings, and relative roles of maturational versus categorical effects, is challenging in vivo or in meta-analyses using task-based paradigms within the same pipeline, given the multiplicity of neurobehavioral functions implicated. To address this, we analyzed 46 positively-correlated and anticorrelated circuits in a multivariate model in resting-state data from 504 age- and gender-matched youth, and created a novel in silico method to map individual quantified effects to reverse inference maps of 8 neurocognitive functions consistently implicated in ADHD, as well as dopamine and hyperactivity. We identified only age- and gender-related effects in intrinsic connectivity, and found that maturational refinement of circuits in youth with ADHD occupied 3-10x more brain locations than in typical development, with the footprint, effect size and contribution of individual circuits varying substantially. Our analysis supports the maturational hypothesis of ADHD, suggesting lagging connectivity reorganization within specific subnetworks of fronto-parietal control, ventral attention, cingulo-opercular, temporo-limbic and cerebellar sub-networks contribute across neurocognitive findings present in this complex condition. We present the first analysis of anti-correlated connectivity in ADHD and suggest new directions for exploring residual and non-responsive symptoms.

Multilevel Mapping of Sexual Dimorphism in Intrinsic Functional Brain Networks

“…For example, in autism a hypothesis has been advanced that male sex may confer vulnerability, or female sex protective effects, operating at the genetic and/or neural levels. An interesting comparison can be made with our prior work in ADHD, a developmental disorder with a much higher reported incidence in males, where we surveyed a similar set of cognitive control functions and found that the neurocognitive footprint across these functions was much larger in youth with ADHD vs. neurotypical youth (de Lacy et al, 2018). More broadly, our results suggest that sex-related differences in cognitive performance may have intrinsic neural correlates.…”

“…In this final step, we used the output of the multivariate analysis (see Statistical Analysis to Identify Sex-Related Effects in IN Spatial Maps) which identified significant sex-related effects in each IN in each model as the input to a mapping process where we mapped effects of sex in each IN to neurocognitive functional maps using a method which we recently developed and published (de Lacy et al, 2018). The aim of this analysis was to identify and compare the cognitive ‘footprint’ of sex-related differences in IN function across 16 cognitive functions and see how this varied between sexes, cognitive functions and 8-, 24-, and 51-network models of brain function.…”

“…While altered brain function associated with diagnosis has been described in most neuropsychiatric disorders, sex-related differences appear to further mediate disrupted function, suggesting interactions between sex and the requisite developmental or disease process. For example, diagnosis × sex interactions in brain function have been identified in autism (Yang and Lee, 2018) and our own work in ADHD (de Lacy et al, 2018). Similar phenomena occur in aging and dementia.…”

Shared and distinct resting functional connectivity in children and adults with attention-deficit/hyperactivity disorder

“…Extant imaging studies have reported brain structural and functional differences between patients with ADHD and HCs, both in childhood and adulthood. Many functional magnetic resonance imaging (fMRI) findings heavily support that ADHD involves a distributed pattern of brain alterations 3,4 . According to Rubia et al, functional abnormalities in fronto-cortical and fronto-subcortical networks are core deficits in both children and adults with ADHD 5 .…”

Association of Affected Neurocircuitry With Deficit of Response Inhibition and Delayed Gratification in Attention Deficit Hyperactivity Disorder: A Narrative Review

“…Neural impairment is associated with many profound complex issues. For example, the patients with ADHD tend to have the response delayed in many aspects such as in the development of neurological organization and neuroplasticity (Van Doren et al, 2017), network analysis and brain development (de Lacy et al, 2018), cognitive function and motor control integration (Leisman et al, 2014), synergies and motor primitives, retained primitive reflexes (Konicarova et al, 2013) and many other areas that all impinge on which is necessary to build models to help understanding the nature of neurodevelopmental disorders. As ADHD symptoms change over time, linguistic and locomotor maturation cannot reach social maturity at any developmental stage (Giertuga et al, 2017).…”