MR Imaging-Detectable Metabolic Alterations in Attention Deficit/Hyperactivity Disorder: From Preclinical to Clinical Studies

Abstract

MR spectroscopy represents one of the most suitable in vivo tool to assess neurochemical dysfunction in several brain disorders, including attention deficit/hyperactivity disorder. This is the most common neuropsychiatric disorder in childhood and adolescence, which persists into adulthood (in approximately 30%-50% of cases). In past years, many studies have applied different MR spectroscopy techniques to investigate the pathogenesis and effect of conventional treatments. In this article, we review the most recent clinical and preclinical MR spectroscopy results on subjects with attention deficit/hyperactivity disorder and animal models, from childhood to adulthood. We found that the most investigated brain regions were the (pre)frontal lobes and striatum, both involved in the frontostriatal circuits and networks that are known to be impaired in this pathology. Neurometabolite alterations were detected in several regions: the NAA, choline, and glutamatergic compounds. The creatine pool was also altered when an absolute quantitative protocol was adopted. In particular, glutamate was increased in children with attention deficit/hyperactivity disorder, and this can apparently be reversed by methylphenidate treatment. The main difficulties in reviewing MR spectroscopy studies were in the nonhomogeneity of the analyzed subjects, the variety of the investigated brain regions, and also the use of different MR spectroscopy techniques. As for possible improvements in future studies, we recommend the use of standardized protocols and the analysis of other brain regions of particular interest for attention deficit hyperactivity disorder, like the hippocampus, limbic structures, thalamus, and cerebellum.ABBREVIATIONS: ACC ϭ anterior cingulate cortex; ADHD ϭ attention deficit/hyperactivity disorder; Cho ϭ total choline (phosphorylcholine ϩ glycerolphosphorylcholine); GABA ϭ ␥-aminobutyric acid; PFC ϭ prefrontal cortex; PRESS ϭ point-resolved spectroscopy sequence; tCr ϭ total creatine (creatine ϩ phosphorylcreatine) A ttention deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disease in children and adolescents. Marked differences in the ADHD prevalence are thought to exist among countries. In fact, the estimated prevalence is 4%-7% in the United States and 1%-3% in Europe.1 ADHD, which is 2-4 times more frequent in males than in females, is characterized by traits of inattention, impulsivity, and motor hyperactivity. These can significantly impact many aspects of behavior in children and adolescents and can affect their performance, both at school and at home. The symptoms of ADHD have a negative impact on the individual throughout childhood, adolescence, and well into adult life, especially if not managed optimally. In approximately 80% of children with ADHD, symptoms persist into adolescence and may persist into adulthood in approximately 30%-50% of cases. ADHD adolescents and adults retain from infancy the traits of inattention and impulsivity. Moreover, they start to show a propensity for ...

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“…Furthermore, the dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC) as well as their connections with striatal and parietal cortical regions appear to be hypoactive [30] (reviews: [31–33]. These regions and pathways are thought to be important in the mechanisms of maintaining and shifting attention as well as processing and filtering sensory input and, therefore, would seem to be critical in the aetiology of ADHD; interestingly, methylphenidate normalizes the hypoactivities observed in ADHD (reviews: [34, 35]). As the primary target of methylphenidate is dopamine transport including the dopamine transporter DAT1 [1, 6–8] changes in dopamine transport (perhaps involving altered expression of DAT1) would seem to be the most probable culprit in the development of ADHD.…”

Biomarkers, Genetics, and Epigenetic Studies to Explore the Neurocognitive Effects of Anesthesia in Children

“…This is an intriguing idea that should be considered for this disease process (38). MR imaging, for example, provides a reliable non-invasive technique that allows determination of brain morphology and quantification of neurochemical compounds in vivo (39). Thus, it is possible that such technology could be used to permit identification of imaged-based phenotypes in immature animals and children following anesthetic exposure prior to manifestation of neurological symptoms.…”

“…Moreover, MR spectroscopy permits measurement and detection of brain metabolic signatures and neurometabolites such as alanine, aspartate, creatine, GABA, glucose, glutamate, glutamine, glycerol-phosphoryl-choline, guanidoacetate, phosphoryl-choline, myo-inositol, lactate, N -acetylaspartate (NAA), N- acetylaspartylglutamate, phosphor-creatine, scyllo-inositol, and taurine (39). This imaging modality has been used to detect alterations in neurometabolites within several brain regions in children with attention deficit/hyperactivity disorder, for example (39).…”

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