1H MRSI of middle frontal gyrus in pediatric ADHD

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Abstract

Neuroimaging studies in multiple modalities have implicated the left or right dorsolateral prefrontal cortex (here, middle frontal gyrus) in attentional functions, in ADHD, and in dopamine agonist treatment of ADHD. The far lateral location of this cortex in the brain, however, has made it difficult to study with magnetic resonance spectroscopy (MRS). We used the smaller voxel sizes of the magnetic resonance spectroscopic imaging (MRSI) variant of MRS, acquired at a steep coronal-oblique angle to sample bilateral middle frontal gyrus in 13 children and adolescents with ADHD and 13 age- and sex-matched healthy controls. Within a subsample of the ADHD patients, aspects of attention were also assessed with the Trail Making Task. In right middle frontal gyrus only, mean levels of N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (tNAA), creatine + phosphocreatine (Cr), choline-compounds (Cho), and myo-inositol (mI) were significantly lower in the ADHD than in the control sample. In the ADHD patients, lower right middle frontal Cr was associated with worse performance on Trails A and B (focused attention, concentration, set-shifting), while the opposite relationship held true for the control group on Trails B. These findings add to evidence implicating right middle frontal cortex in ADHD. Lower levels of these multiple species may reflect osmotic adjustment to elevated prefrontal cortical perfusion in ADHD and/or a previously hypothesized defect in astrocytic production of lactate in ADHD resulting in decelerated energetic metabolism (Cr), membrane synthesis (Cho, mI), and acetyl-CoA substrate for NAA synthesis. Lower Cr levels may indicate attentional or executive impairments.

Introduction

Attention Deficit Hyperactivity Disorder (ADHD) is a neurobehavioral condition affecting 3–9% of children and 4–6% of adults worldwide (McCracken, 1998; Kessler et al., 2006). Consistent inattention, impulsivity, and hyperactivity are the core symptoms of ADHD (American Psychiatric Association, 2000). These symptoms (Jensen et al., 2001), along with impaired neurocognitive performance on multiple instruments (Aron et al., 2003; Bedard et al., 2003, 2002), respond to stimulant treatment, popularly methylphenidate. Methylphenidate decreases synaptic dopamine reuptake in the brain (Seeman and Madras, 1998) in part by inhibiting the dopamine transporter (DAT) (Volkow et al., 1998). Therefore, neuroimaging studies of ADHD have targeted brain structures in dopamine-rich frontostriatal circuits (Cheon et al., 2003), especially since these circuits are implicated in attention and other neurocognitive functions impaired in ADHD. One such structure is the “dorsolateral prefrontal cortex” (DLPFC), target of the present investigation.

The human DLPFC is described by various authors as the dorsal half of the middle frontal cortex, the entire middle frontal cortex, or the middle frontal plus superior frontal cortex. This report concerns specifically the “middle frontal gyrus” and avoids the term “DLPFC”. Evidence from multiple modalities (neurocognitive, neuropharmacological, neuroimaging) in pediatric (Barkley and Grodzinsky, 1994; Loo et al., 2004; Weber et al., 2005, 2007; Barnett et al., 2009; Gau et al., 2009; Gau and Shang, 2010) and adult (Mehta et al., 2000; Moll et al., 2002; Moser et al., 2002; Owen et al., 1996; Zakzanis et al., 2005) ADHD implicates this region in ADHD, its dopaminergic treatment, or neurocognitive functions impaired in ADHD. But this region has been little studied using proton magnetic resonance spectroscopy (1H MRS), a method that characterizes regional neurometabolism.

Previous MRS investigations of ADHD (reviewed in O’Neill et al., in press; Perlov et al., 2009) have emphasized basal ganglia (Liew and Yan, 2006; Carrey et al., 2003, 2007), white matter (Fayed and Modergo, 2005; Yeo et al., 2003), and cingulate cortex (Colla et al., 2008; Kronenberg et al., 2008; Perlov et al., 2007; Courvoisie et al., 2004; MacMaster et al., 2003; Sparkes et al., 2001) rather than middle frontal gyrus. These studies have identified effects of ADHD or of stimulant treatment involving the metabolite signals for N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (tNAA), glutamate + glutamine (Glx), creatine + phosphocreatine (Cr), and choline compounds (Cho). In several cases effects restricted to left or right cerebrum were found. It should be noted, however, that many of these studies deployed large MRS voxel sizes suffering from the ‘partial-voluming problem’ (inclusion of multiple different brain structures in a single acquisition volume) and/or expressed their results as metabolite ratios rather than absolute levels. Partial voluming makes assignment of effects to a single structure ambiguous while ratios make assignment of effects to a single metabolite signal ambiguous. One exception was Colla et al. (2008) who studied the cingulate using absolute metabolite levels and identified above-normal Cho in the subjects with ADHD in the left and in combined left + right anterior middle cingulate cortex (aMCC). This group used the magnetic resonance spectroscopic imaging (MRSI) variant of MRS which, in contrast to single-voxel MRS, acquires data from an array of multiple voxels simultaneously, typically with higher spatial resolution, i.e., smaller voxel-size. We are aware of only two MRS studies of DLPFC in any of its definitions (Soliva et al., 2010; Hesslinger et al., 2001). One (Soliva et al., 2010) measured below-normal Cr in right middle frontal gyrus using single-voxel MRS in a pediatric ADHD sample; the other, (Hesslinger et al., 2001) again using single-voxel MRS, found lower tNAA in left middle frontal gyrus in ADHD than in attention deficit disorder (ADD) or healthy controls in adult subjects. Thus, there is evidence for below-normal MRS metabolite levels in middle frontal gyrus in ADHD, but the region remains understudied.

The present study examined the bilateral middle frontal gyri in pediatric ADHD using MRSI and absolute metabolites. An unconventional coronal-oblique prescription was used to enable access to this anatomic site. As a further novelty, and in contrast to Colla et al. (2008), we used short echo-time (short-TE) MRSI, which measures more metabolites and stronger signals of most metabolites relative to long-TE. Based on the above literature, we anticipated below-normal levels of tNAA and Cr in patients with ADHD, possibly more severely in the right hemisphere. These levels might also correlate with attentional functions.

Section snippets

Methods

Thirteen children meeting the DSM-IV diagnosis for ADHD (8 boys, 5 girls; mean age ± SD, 12.3 ± 1.5 years) and 13 healthy control subjects (8 boys, 5 girls; 12.2 ± 2.7 years) were recruited to participate. Four ADHD patients were of the Inattentive subtype, 7 of Combined subtype, and 2 were ADHD NOS. Subjects were screened for neurological, psychiatric, language, or hearing disorders by clinical interview and developmental history. Mean full-scale IQ (Wechsler, 1974) was 85.6 ± 18.1 for the

Results

The ADHD and control groups did not differ significantly in age (t(20.1) = 0.28, p = 0.785) or full-scale IQ (t(20.0) = −0.98, p = 0.338). Group mean ± standard deviation scores for the ADHD subsample undergoing neurocognitive assessment were 94.9 ± 12.4 (standard score, range: 74–118) on Trails A and 99.1 ± 23.7 (range: 52–126) on Trails B. For the control subsample the scores were 101.6 ± 9.8 (range: 81–113) on Trails A and 98.8 ± 10.3 (range: 78–113) on Trails B. The scores did not differ

Discussion

This study found below-normal levels of four major MRSI metabolites (tNAA, Cr, Cho, and mI) in the middle frontal gyrus of children and adolescents with ADHD compared to age- and sex-matched healthy controls. Significant deficits in these neurometabolites were confined to the right cerebral hemisphere. Lower right cerebral levels of one neurometabolite (Cr) in ADHD subjects were related to worse performance on two neurocognitive tests of attention. These deficits may be related to ADHD or to

Contributors

Drs. Levitt and McCracken conceived of the study in collaboration with Dr. O'Neill. Drs. Levitt and McCracken conducted the recruitment, diagnostic assessment, and scanning of all subjects. Drs. O'Neill and Alger designed the MR acquisition and post-processing protocols. Dr. Levitt conducted the structural analysis and Dr. O'Neill, with Mr. Tafazoli's and Mr. Bejjani's assistance, conducted the spectroscopic analysis of the MR data. Mr. Tafazoli wrote much of the first draft of the manuscript

Role of the funding source

This study was supported by NIMH RC1 MH088507 (Levitt), by the NIH Pediatric MRI Database (Levitt/McCracken), NIH R01 MH081864 (O'Neill/Piacentini), and by NIH P01 MH63357 (Strickland).

Conflicts of interest

Dr. McCracken reports receiving consultant honoraria from Shionogi, Roche, Novartis, Noven, PharmaNet, and BioMarin; Dr. McCracken also reports research grant support from Seaside Therapeutics.

Mr. Tafazoli, Dr. O’Neill, Mr. Bejjani, Mr. Ly, Dr. Salamon, Dr. Alger, and Dr. Levitt report no conflicts of interest.

Acknowledgments

We are grateful to the faculty, researchers, and staff at Charles R. Drew University for their past collaboration on this study and for their role in the recruitment, screening, and neuropsychological testing administration for our research participants.

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