H¹-MR-spectroscopy of cerebellum in adult attention deficit/hyperactivity disorder

Abstract

Introduction

Neurobiological research has implicated the cerebellum as one possible site of neurophysiological dysfunction in ADHD. Latest theoretical conceptualizations of the cerebellum as core site of the brain to model motor as well as cognitive behavior puts further weight to the assumption that it might play a key role in ADHD pathophysiology.

Methods

30 medication free adult ADHD patients and 30 group matched (gender, age and education) healthy controls were investigated using the method of chemical shift imaging (CSI) of the cerebellum. The vermis, left and right cerebellar hemispheres were processed separately.

Results

We found significantly increased glutamate-glutamine (Glx) to creatine (Cre) ratios in the left cerebellar hemisphere. No other differences in measured metabolite concentrations were observed.

Discussion

To our knowledge this is the first evidence for neurochemical alterations in cerebellar neurochemistry in adult ADHD. They relate well to recent hypotheses that the cerebellum might control mental activities by internal models.

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a serious mental problem which begins in childhood and may persist into adult life in a substantial subgroup of patients (Biederman and Faraone, 2005). The prevalence of ADHD in adults is estimated by nearly 4% (Kessler et al., 2006). Since the level of hyperactivity tends to decline from childhood to adulthood the ADHD symptoms in adults are less obvious for the observer (Biederman et al., 2000) but still cause significant impairments in occupational performance and social life. Adult ADHD is associated with low self esteem, higher rates of motor vehicle accidents, higher risks of substance abuse and other co-occurring psychiatric disorders compared to common population (Philipsen et al., 2009, Spencer et al., 2002). The high prevalence, the global impairment and the chronicity of this disorder led the Center for Disease Control and Prevention to identify ADHD as a serious public health problem (Spencer et al., 2002).

The DSM-IV distinguishes three subtypes of attention deficit disorder: the predominantly inattentive subtype (ADD) which is characterized by predominant impairments in attention and concentration, forgetfulness and disorganized behavior, the predominantly hyperactive-impulsive subtype (ADHD) which in contrast is characterized by a combination of hyperactivity and impulsivity, and the combined subtype with symptoms of both subtypes (Biederman et al., 2000, Hesslinger et al., 2001).

The precise etiology of ADHD is not fully understood. Most current theories focus on dysfunction in the prefrontal brain as well as in striatal and thalamic structures (i.e. fronto-striato-thalamo-frontal circuits) (Ashtari et al., 2005, Castellanos et al., 2002, Hynd et al., 1990, Semrud-Clikeman et al., 2000).

However, in structural imaging research cerebellar abnormalities are among the most consistently reported findings in ADHD. Many volumetric studies reported reduced cerebellar volumes and developmental alterations of cerebellum in ADHD children (Berquin et al., 1998, Castellanos et al., 2001, Castellanos et al., 2002, Mackie et al., 2007, Mulder et al., 2008).

Because of its dense connection to the prefrontal cortex and basal ganglia, the cerebellum is thought to play an important role in cognition including verbal working memory, implicit learning, temporal information processing as well as shift in attention and emotional regulation (Ito, 2008, Ivry et al., 2002, Schmahmann and Sherman, 1998, Schmahmann, 2004, Vaidya and Stollstorff, 2008).

Neurochemically, dopamine plays the central role in most pathogenetic models of ADHD (Biederman and Faraone, 2005). This assumption is based on the observation of the good efficacy of the dopaminergic and adrenergic substance methylphenidate in treating ADHD symptoms but also based on clinical and neuroimaging findings (Dougherty et al., 1999, Krause et al., 2000). In a previous study we were able to show increased glutamate signals in the anterior cingulate cortex (ACC) in adult ADHD patients (Perlov et al., 2007). The model of dopaminergic/glutamatergic interaction was developed by Carlsson and coworkers for schizophrenia but seems to be applicable also to ADHD (Perlov et al., 2008a)). To our knowledge the cerebellum of ADHD patients has not been yet investigated using the Magnet-Resonance-Spectroscopy (MRS).

The current study investigates the glutamatergic metabolism in cerebellum of adult ADHD patients using the method of H1-MRS. MRS is a unique non-invasive MRI method to detect metabolites in vivo. Basically MRS uses the different spin-echo signal of the protons differently connected in molecules. Due to the methodological reasons only some of several known metabolites can be detected using the different methods of MRS. The most widely established detectable metabolites in the human brain are: N-acetylaspartate (NAA) – a marker of the cell integrity; choline compounds (Cho) – an important part of cell membranes and to a lesser degree of the energy metabolism; creatine (Cre) – a marker of cell metabolism especially in muscle tissue (due to the fact that it is often regarded as a rahter constant metabolite it is generally used as a denominator for building metabolite ratios if absolute quantification is not possible); myo-inositol (mI) – an important second messenger and glutamate-glutamine (Glx) – the most important excitatory amino acid in the human brain.

Based on our earlier findings in the anterior cingulate cortex (ACC) we hypothesized to observe alterations in glutamate-glutamine signals in adult ADHD patients. In order to maximize the region of interest including the vermis and both hemispheres of the cerebellum we used the method of chemical shift imaging (CSI).