Bumetanide has been reported to alter synaptic excitation-inhibition (E-I) balance by potentiating the action of γ-aminobutyric acid (GABA), thereby attenuating the severity of autism spectrum disorder (ASD) in animal models. However, clinical evidence of its efficacy in young patients with ASD is limited. This was investigated in the present clinical trial of 83 patients, randomised to the bumetanide group (bumetanide treatment, 0.5 mg twice daily) or the control group (no bumetanide treatment). Primary [Children Autism Rating Scale (CARS)], secondary [Clinical Global Impressions (CGI)], and exploratory [inhibitory (γ-aminobutyric acid, GABA) and excitatory (glutamate, Glx) neurotransmitter concentrations measured in the insular cortex (IC) and visual cortex (VC) by magnetic resonance spectroscopy (MRS)] outcome measures were evaluated at baseline and at the 3-month follow-up. Side effects were monitored throughout the treatment course. Compared with the control group, the bumetanide group showed significant reduction in symptom severity, as indicated by both total CARS score and number of items assigned a score ≥ 3. The improvement in clinical symptoms was confirmed by CGI. GABA/Glx ratio in both the IC and VC decreased more rapidly over the 3-month period in the bumetanide group than that in the control group. This decrease in the IC was associated with the symptom improvement in the bumetanide group. Our study confirmed the clinical efficacy of bumetanide on alleviating the core symptoms of ASD in young children and it is the first demonstration that the improvement is associated with reduction in GABA/Glx ratios. This study suggests that the GABA/Glx ratio measured by MRS may provide a neuroimaging biomarker for assessing treatment efficacy for bumetanide.
Objective: As two common neurodevelopmental disorders, autistic spectrum disorder and attention deficit hyperactivity disorder frequently occur together. Until now, only a few studies have investigated the co-occurrence of attention deficit hyperactivity disorder and autistic spectrum disorder, this is due to restrictions associated with previous Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Most previous research has focused on the developmental trajectories for autistic spectrum disorder and attention deficit hyperactivity disorder separately, while the neural mechanisms underpinning the co-occurrence of autistic spectrum disorder and attention deficit hyperactivity disorder remain largely unknown. Methods:We studied 162 autistic spectrum disorder individuals (including 79 co-attention deficit hyperactivity disorder and 83 non-attention deficit hyperactivity disorder patients) and 177 typical developing individuals using resting-state functional magnetic resonance imaging data from the Autism Brain Imaging Data Exchange II, an aggregated magnetic resonance imaging dataset from 19 centers. Independent component analysis was used to extract sub-networks from the classic resting-state networks. Functional connectivity values within (intra-iFC) and between (inter-iFC) these networks were then determined. Subsequently, we compared the ASD_coADHD group with the ASD_nonADHD group in relation to the abnormal intra-iFC and inter-iFC of autistic spectrum disorder group relative to the typical developing group. Results:The ASD_coADHD group showed more severe social impairment and decreased intra-iFC in the bilateral posterior cingulate cortex of the default mode network (independent component 17) and increased inter-iFC between the default mode network (independent component 8) and the somatomotor networks (independent component 2) compared to the ASD_nonADHD group. In addition, the strength of the intra-iFC in the default mode network was associated with the severity of autistic traits across the entire autistic spectrum disorder group and particularly the ASD_coADHD group. Conclusion:Our results showed that dysfunction of the default mode network is a central feature in the co-occurrence of autistic spectrum disorder and attention deficit hyperactivity disorder, including connectivity within the default mode network as well as between the default mode network and the somatomotor networks, thus supporting the existence of a clinically combined phenotype (autistic spectrum disorder + attention deficit hyperactivity disorder).
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