Neuroimaging-Aided Prediction of the Effect of Methylphenidate in Children with Attention-Deficit Hyperactivity Disorder: A Randomized Controlled Trial

Abstract

Although methylphenidate hydrochloride (MPH) is a first-line treatment for children with attention-deficit hyperactivity disorder (ADHD), the non-response rate is 30%. Our aim was to develop a supplementary neuroimaging biomarker for predicting the clinical effect of continuous MPH administration by using near-infrared spectroscopy (NIRS). After baseline assessment, we performed a double-blind, placebo-controlled, crossover trial with a single dose of MPH, followed by a prospective 4-to-8-week open trial with continuous MPH administration, and an ancillary 1-year follow-up. Twenty-two drug-naïve and eight previously treated children with ADHD (NAÏVE and NON-NAÏVE) were compared with 20 healthy controls (HCs) who underwent multiple NIRS measurements without intervention. We tested whether NIRS signals at the baseline assessment or ΔNIRS (single dose of MPH minus baseline assessment) predict the Clinical Global Impressions-Severity (CGI-S) score after 4-to-8-week or 1-year MPH administration. The secondary outcomes were the effect of MPH on NIRS signals after single-dose, 4-to-8-week, and 1-year administration. ΔNIRS significantly predicted CGI-S after 4-to-8-week MPH administration. The leave-one-out classification algorithm had 81% accuracy using the NIRS signal. ΔNIRS also significantly predicted CGI-S scores after 1 year of MPH administration. For secondary analyses, NAÏVE exhibited significantly lower prefrontal activation than HCs at the baseline assessment, whereas NON-NAÏVE and HCs showed similar activation. A single dose of MPH significantly increased activation compared with the placebo in NAÏVE. After 4-to-8-week administration, and even after MPH washout following 1-year administration, NAÏVE demonstrated normalized prefrontal activation. Supplementary NIRS measurements may serve as an objective biomarker for clinical decisions and monitoring concerning continuous MPH treatment in children with ADHD.

Application of Functional Near-Infrared Spectroscopy to the Study of Brain Function in Humans and Animal Models

“…ADHD is characterized by the persistent symptoms of inattention, hyperactivity, and impulsivity ( Faraone et al, 2005 ). By using behavioral tasks requiring attentiveness and concentration, fNIRS imaging has demonstrated that these ADHD-related symptoms are associated with low cerebral cortical activity in a number of regions, including the PFC, inferior prefrontal gyrus, middle prefrontal gyrus, supra-marginal gyrus, and angular gyrus ( Araki et al, 2015 ; Ichikawa et al, 2014 ; Inoue et al, 2012 ; Ishii-Takahashi et al, 2015 ; Kochel et al, 2015 ; Monden et al, 2015 ; Moser et al, 2009 ; Nagashima et al, 2014a ; 2014b ; 2014c ; Negoro et al, 2010 ; Schecklmann et al, 2011b ; Tsujimoto et al, 2013 ; Weber et al, 2005 ; Xiao et al, 2012 ; Yasumura et al, 2014 ). Similarly, frontal hypoactivity has been observed in ASD patients during behavioral tasks designed to assess social relations and communicative abilities that are dysfunctional or inappropriate in these patients ( Iwanaga et al, 2013 ; Kajiume et al, 2013 ; Kita et al, 2011 ; Kuwabara et al, 2006 ; Minagawa-Kawai et al, 2009 ; Tamura et al, 2012 ; Xiao et al, 2012 ; Yasumura et al, 2014 ).…”

Fat mass and obesity-associated (FTO) rs9939609 polymorphism modifies the relationship between body mass index and affective symptoms through the life course: a prospective birth cohort study

“…Thus, the FTO genotype-related increase in BMI in adolescence and young adulthood would be essential for physical development, which could lead to or result from better psychological health. Second, the rs9939609 A allele is protective of child emotional problems and attention deficits and hyperactivity disorder symptoms 65 , which is thought to be due to an altered reward response in dopaminergic neuron in the prefrontal cortex 66 . Conversely, the mouse knock-out FTO gene within the midbrain dopaminergic system showed hyperactivity and aberrant sensitivity to dopamine stimulants 23 .…”

Application of functional near-infrared spectroscopy in the healthcare industry: A review

“…27 A longitudinal study showed that ADHD patients exhibited improved prefrontal responses after a single dose of methylphenidate, and its long-term use yielded an activation equivalent to that of a healthy person. 61…”