Candidate diagnostic biomarkers for neurodevelopmental disorders in children and adolescents: a systematic review.

Neurodevelopmental disorders - including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, communication disorders, intellectual disability, motor disorders, specific learning disorders, and tic disorders - manifest themselves early in development. Valid, reliable and broadly usable biomarkers supporting a timely diagnosis of these disorders would be highly relevant from a clinical and public health standpoint. We conducted the first systematic review of studies on candidate diagnostic biomarkers for these disorders in children and adolescents. We searched Medline and Embase + Embase Classic with terms relating to biomarkers until April 6, 2022, and conducted additional targeted searches for genome-wide association studies (GWAS) and neuroimaging or neurophysiological studies carried out by international consortia. We considered a candidate biomarker as promising if it was reported in at least two independent studies providing evidence of sensitivity and specificity of at least 80%. After screening 10,625 references, we retained 780 studies (374 biochemical, 203 neuroimaging, 133 neurophysiological and 65 neuropsychological studies, and five GWAS), including a total of approximately 120,000 cases and 176,000 controls. While the majority of the studies focused simply on associations, we could not find any biomarker for which there was evidence - from two or more studies from independent research groups, with results going into the same direction - of specificity and sensitivity of at least 80%. Other important metrics to assess the validity of a candidate biomarker, such as positive predictive value and negative predictive value, were infrequently reported. Limitations of the currently available studies include mostly small sample size, heterogeneous approaches and candidate biomarker targets, undue focus on single instead of joint biomarker signatures, and incomplete accounting for potential confounding factors. Future multivariable and multi-level approaches may be best suited to find valid candidate biomarkers, which will then need to be validated in external, independent samples and then, importantly, tested in terms of feasibility and cost-effectiveness, before they can be implemented in daily clinical practice.

The devil is in the detail: exploring the intrinsic neural mechanisms that link attention-deficit/hyperactivity disorder symptomatology to ongoing cognition.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a developmental condition that profoundly affects quality of life. Although mounting evidence now suggests uncontrolled mind-wandering as a core aspect of the attentional problems associated with ADHD, the neural mechanisms underpinning this deficit remains unclear. To that extent, competing views argue for (i) excessive generation of task-unrelated mental content, or (ii) deficiency in the control of task-relevant cognition. METHODS: In a cross-sectional investigation of a large neurotypical cohort (n = 184), we examined alterations in the intrinsic brain functional connectivity architecture of the default mode (DMN) and frontoparietal (FPN) networks during resting state functional magnetic resonance imaging in relation to ADHD symptomatology, which could potentially underlie changes in ongoing thought within variable environmental contexts. RESULTS: The results illustrated that ADHD symptoms were linked to lower levels of detail in ongoing thought while the participants made more difficult, memory based decisions. Moreover, greater ADHD scores were associated with lower levels of connectivity between the DMN and right sensorimotor cortex, and between the FPN and right ventral visual cortex. Finally, a combination of high levels of ADHD symptomology with reduced FPN connectivity to the visual cortex was associated with reduced levels of detail in thought. CONCLUSIONS: The results of our study suggest that the frequent mind-wandering observed in ADHD may be an indirect consequence of the deficient control of ongoing cognition in response to increasing environmental demands, and that this may partly arise from dysfunctions in the intrinsic organisation of the FPN at rest.

Mind wandering perspective on attention-deficit/hyperactivity disorder.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder associated with a range of mental health, neurocognitive and functional problems. Although the diagnosis is based on descriptions of behaviour, individuals with ADHD characteristically describe excessive spontaneous mind wandering (MW). MW in individuals with ADHD reflects constant mental activity which lacks topic stability and content consistency. Based on this review of the neural correlates of ADHD and MW, we outline a new perspective on ADHD: the MW hypothesis. We propose that altered deactivation of the default mode network, and dysfunctional interaction with the executive control network, leads to excessive and spontaneous MW, which underpins symptoms and impairments of ADHD. We highlight that processes linked to the normal neural regulation of MW (context regulation, sensory decoupling, salience thresholds) are deficient in ADHD. MW-related measures could serve as markers of the disease process, as MW can be experimentally manipulated, as well as measured using rating scales, and experience sampling during both cognitive tasks and daily life. MW may therefore be a potential endophenotype.