Cognitive MR spectroscopy of anterior cingulate cortex in ADHD: Elevated choline signal correlates with slowed hit reaction times

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Abstract

The anterior cingulate cortex (ACC) plays a major role in modulating executive control of attention. Here, 15 medication-naı¨ve patients with attention deficit/hyperactivity disorder (ADHD) and 10 carefully matched healthy controls were studied with 2D 1H-magnetic resonance spectroscopic imaging (MRSI) of the ACC [Brodmann areas 24b′-c′ and 32′]. Attentional skills were assessed using the identical pairs version of the continuous performance task (CPT-IP). Analysis of regional brain spectra revealed a significantly increased signal of choline-containing compounds (Ch) in the ACC of ADHD patients (p < 0.05). Across and within groups, the Ch signal showed high correlations with slowed hit reaction times on the CPT-IP. No group differences in N-acetyl-aspartate (NAA) and creatine (tCr) were detectable. The combination of performance deficits and elevated Ch levels in the ACC supports the hypothesis that subtle structural abnormalities underlie the functional alterations in ACC activation previously observed in ADHD patients.

Introduction

The anterior cingulate cortex (ACC) is connected with the prefrontal and parietal cortices as well as the motor system and the frontal eye fields rendering it a crucial regulator of top-down and bottom-up information processing (Posner et al., 1997). The ACC plays an important role in monitoring conflict (e.g. Barch et al., 2000). The conflict-monitoring hypothesis constitutes a pre-eminent concept of cognitive control (Carter et al., 2000, Botvinick et al., 2001). The hypothesis asserts that the conflict occurs primarily at the response selection stage and is set off by the simultaneous availability of competing tendencies. Whereas the ACC implements an evaluative function that signals the need for control, recruitment of the prefrontal cortex is responsible for the execution of cognitive control (Kerns et al., 2004). Not surprisingly, a number of studies have specifically implicated the ACC in the speed of a reaction. Following bilateral anterior cingulotomy, slower response times and increased interference on the Stroop task have been observed (Ochsner et al., 2001). Similarly, subjects with superior medial lesions including the anterior cingulate also showed lengthened reaction times on a variant of the Stroop interference paradigm (Alexander et al., 2007). In a group of children aged 5–16 years, Casey et al. demonstrated a significant correlation between attentional measures assessed with a visual discrimination paradigm and the volume of the right ACC (faster and more accurate performance in children with larger right anterior cingulate volumes; Casey et al., 1997). Increased ACC activation as assessed by regional cerebral blood flow (simple reaction time tasks) or low resolution electromagnetic tomography (auditory choice reaction paradigm) has been associated with a gain in reaction speed (Naito et al., 2000, Mulert et al., 2003).

Attention-deficit/hyperactivity disorder (ADHD) is a common childhood disorder that frequently persists into adulthood. The clinical syndrome is characterized by significant levels of inattentive, hyperactive and/or impulsive behavior. In contrast to childhood and adolescence, hyperactivity may decrease over time, whereas problems with attention and deficits in executive functioning tend to be more persistent (Wender et al., 2001, Wasserstein, 2005). A large cross-sectional study on maturational changes of executive control in ADHD recently reported impairments in psychomotor speed and reaction times across the investigated age range (10–29 years) in the patient group. In both normals and ADHD patients performance improved with age. However, control group participants improved their performance with shorter reaction times whereas ADHD patients adopted a less efficient strategy with increased response latencies with age (Gualtieri and Johnson, 2006).

Magnetic resonance spectroscopy is emerging as a powerful new tool in cognitive neuroscience research (Ross and Sachdev, 2004). In this study, three markers of brain metabolism, N-acetyl-aspartate (NAA), choline containing compounds (Ch) and total creatine (tCr; i.e., creatine and phosphocreatine) were evaluated. NAA is primarily present in neurons and is regarded as an indicator of neuronal viability and functioning. The choline resonance is constituted of metabolites of phosphatidylcholine (Boulanger et al., 2000). As a crucial buffer capacity in the energy metabolism of the cell the creatine signal is usually thought to be relatively stable (Sartorius et al., 2003).

So far, comparatively few spectroscopic studies have been carried out in adult ADHD and a clear pattern of neurochemical alterations associated with the disorder has not yet been firmly established. Elevated frontal-striatal glutamatergic resonances in pediatric ADHD and a decrease in the striatal glutamate/creatine ratio with treatment have been reported (MacMaster et al., 2003). Some recent studies in children have also implicated altered membrane metabolism in the etiopathogenesis of ADHD with a choline rise in basal ganglia (Jin et al., 2001, Margari et al., 2006) and lower phosphomonoester levels in prefrontal cortex and basal ganglia (Stanley et al., 2006). Results on NAA concentrations in ADHD have been discordant between children and adults (e.g. Hesslinger et al., 2001, MacMaster et al., 2003). To our knowledge, only two spectroscopic studies to date have specifically investigated the anterior cingulate cortex in ADHD. Moore et al. (2006) reported a significantly higher ratio of glutamate plus glutamine to myo-inositol-containing compounds in the ACC of children with ADHD as compared to healthy children. While this study was under review, Perlov et al. reported significantly increased right Ch/creatine and reduced glutamate + glutamine/creatine ratios in adult ADHD patients (Perlov et al., 2006).

The current study was undertaken to determine if: (1) distinct biochemical changes would be apparent in the ACC of adult ADHD patients, and (2) if these changes could be shown to exert an influence on CPT-IP measures, in particular reaction times. CPT performance has previously been shown to increase regional cerebral blood flow in the ACC (Benedict et al., 1998) and, – particularly in children – numerous studies have documented poorer CPT performance associated with ADHD (e.g. O’Dougherty et al., 1984, Losier et al., 1996). Remarkably, a recently published study that investigated relations between various CPT variables and ADHD behaviors found that one variable, namely reaction time for hits, was related to ADHD symptoms as a whole (Epstein et al., 2003).

Section snippets

Participants

Patients were recruited from the Central Institute of Mental Health ADHD outpatient clinic. The diagnosis of adult ADHD according to DSM-IV criteria was established by an experienced senior psychiatrist after at least three consecutive visits. Patients’ self-reported complaints had to be corroborated by a second report for current and childhood symptoms of ADHD. Inclusion criteria included a score of >46 on the Wender Utah Rating Scale (Ward et al., 1993) and of 24+ on the Conners’ Parent

Study population

Fifteen patients with a diagnosis of adult ADHD and 10 healthy controls matched for age, gender and education were enrolled into the study. Participants were administered the CPT-IP, MWT-B and LPS and were then investigated in MRI on a single day. Patients and controls did not differ regarding sociodemographic variables or IQ estimates (Table 1).

Neuropsychological and clinical assessment

Patients and controls differed significantly on ADHD symptom checklist scores (I-score: 16.2 ± 3.7 vs. 4.1 ± 1.1, F1, 23 = 98.4, p < 0.0001; HI-score: 14.6 ± 3.2

Discussion

In a hypothesis-driven approach, we here used proton magnetic resonance spectroscopy to evaluate the cerebral metabolic pattern in the ACC of adult ADHD patients. The ACC has been implicated in attentional processing both by monitoring competing response tendencies and by allocating attentional resources to task-relevant stimuli (e.g. MacDonald et al., 2000, Botvinick et al., 2001, Dreher and Berman, 2002). In a sample of medication-naı¨ve adults with established ADHD we document increased ACC

Acknowledgement

The authors thank Ulrike Kersting for assistance in neuropsychological testing.

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