Abnormalities of WM integrity in adult ADHD
One novel finding of this study is that bilateral orbitofrontal WM changes in adult patients with ADHD were seen compared with matched healthy control subjects (Fig. 1). These areas include fronto-striatal fibre tracts connecting prefrontal cortices with putamen and caudate nucleus. The uncinate fasciculus connects orbitofrontal and subcortical limbic regions, which have been shown to modulate emotional behaviour and stress responses (Drevets, 2000; Beyer et al., 2005). Disturbed WM microstructure of the limbic-thalamic-cortical circuits has already been demonstrated in mood disorders (Drevets, 2000; Versace et al., 2008). Several MRI studies in patients with ADHD showed volume reductions in prefrontal cortices (Seidman et al., 2005; Valera et al., 2007) and in the orbitofrontal cortex (Hesslinger et al., 2002). Makris et al. (2007) found significant cortical thinning in ADHD in the right hemisphere involving the inferior parietal lobule, the dorsolateral prefrontal and the ACCs. Casey et al. (2007) performed a multimodal functional MRI and DTI study, and demonstrated that FA in right prefrontal fibre tracts was correlated with functional activity in the inferior frontal gyrus and caudate nucleus, though they did not describe FA differences between patients with ADHD and controls. A DTI study in women with borderline personality disorder (BPD) and comorbid ADHD investigated inferior frontal WM, but did not find differences between patients and healthy control subjects (Rusch et al., 2007). In addition, there is also convergent evidence from neuropsychological, genetics and neurochemical studies pointing to the involvement of the fronto-striatal network in the pathophysiology of ADHD (for review, see: Emond et al., 2009).
Our results of reduced FA in the right ACB are in line with previous findings in adult patients with ADHD showing reduced FA in the ACB and SLF in the right hemisphere (Makris et al., 2008). The ACB is part of the attentional network and involved in cognitive processing (Mesulam, 1990; Baird et al., 2006; Mulert et al., 2008). Moreover, several volumetric MRI studies in adult patients with ADHD showed reduced regional brain volume predominantly in the ACC, prefrontal cortex, cerebellum, caudate and CC (Seidman et al., 2006; Valera et al., 2007). Though there is a discrepancy between our results and the DTI studies in children and adolescents with ADHD. Ashtari et al. (2005) performed a voxel-based DTI analysis in children and adolescents with ADHD and showed significantly decreased FA in the right premotor cortex, right anterior limb of the internal capsule, right cerebral peduncle, middle cerebellar peduncle, left cerebellum and left parietooccipital region. Another recent DTI study in children and adolescents with ADHD investigated eight fibre tracts including the cingulum, inferior longitudinal fasciculus and SLF (Pavuluri et al., 2009): MD was significantly higher in patients with ADHD in these regions, but no difference was observed for FA values (Pavuluri et al., 2009). Moreover, decreased FA in the SLF and in the corticospinal tract in children and adolescents with ADHD has been demonstrated (Hamilton et al., 2008).
Our findings of increased FA bilaterally in frontotemporal WM connections point to an involvement of widespread brain areas in the pathophysiology of ADHD. While temporal structural abnormalities have not yet been described in previous MRI and DTI studies, a recent functional MRI study demonstrated bilateral temporal lobe dysfunction in boys with ADHD (Rubia et al., 2007).
Possible reasons for the discrepancy with respect to the results of DTI studies in childhood and adolescence could be the sample heterogeneity between studies, the medication status of the investigated patients and the different diffusion imaging parameters between studies. In contrast to the majority of imaging studies in ADHD, we only included never-medicated patients in our study. Particularly, none of the patients had received any ADHD-specific treatment before such as psychostimulant medication. We are therefore able to exclude potential medication effects on imaging results as well as on neuropsychological findings. In addition, we have excluded patients with ADHD with acute psychiatric comorbidity. Although we did not include medicated patients and patients with acute psychiatric comorbidity, symptom severeness of our patients as measured with the BADDS was quite high (Brown, 1996; Table 1).
For completeness, it also needs to be mentioned that the possibility of false positive results in our study cannot be entirely excluded. In fact, taking into account the relatively weak group differences in our study, which would not survive a correction for multiple comparisons, and also the findings in DTI studies conducted by other groups in (adult) ADHD (Casey et al., 2007; Makris et al., 2008), replication studies would be desirable to confirm these findings.
Correlation of diffusion parameters with attentional performance
To our knowledge, this is the first study demonstrating a direct association between microstructural integrity and measures of attention in adult patients with ADHD. The correlation analyses between diffusion parameters and the ADHD score, which reflects the ability to focus attention (Greenberg & Kindschi, 1996), demonstrated significant findings in the right SLF. This specific fibre pathway together with the cingulum bundle connects frontal areas and cortical regions at the right temporo-occipito-parietal junction, which are considered to play a key role in processing information related to attentional functions (Makris et al., 2008). Even if there is a lack of structural MRI studies investigating correlations of brain (micro-) structure and attentional performance, there are convergent data from functional MRI studies adopting tasks of attention: among the most reported findings is reduced activation in the dorsal ACC, the frontal cortex and the basal ganglia, but also in right hemispheric temporal and parietal brain regions (Emond et al., 2009; Rubia et al., 2009). Moreover, cortical thinning in patients with ADHD compared with matched controls has been demonstrated in the right hemisphere involving the inferior parietal lobule, the dorsolateral prefrontal and the ACCs (Makris et al., 2007).
Taken together, our finding of significant correlation between ADHD score and diffusion parameters in the right SLF suggests that structural dysconnectivity may – at least in part – underlie the described functional deficits in cortical areas connected by the right SLF.
Correlation of diffusion parameters with impulsivity
In our study, we demonstrated a significant correlation of FA and a measure of impulsivity (number of commission errors) in right fronto-striatal fibre tracts connecting the orbitofrontal cortex to the basal ganglia and limbic regions. We were therefore able to confirm in part the findings by Casey et al. (2007), who demonstrated a correlation of FA bilaterally in prefrontal fibre tracts and a measure of impulsivity (performance in a go/no-go task) in parent–child diads with ADHD. Impulsivity due to impaired inhibitory control functions of the fronto-striatal circuit have been described previously (Jentsch & Taylor, 1999; Uhlikova et al., 2007). In this context, it is also noteworthy that a DTI study in women with BPD and comorbid ADHD demonstrated a correlation of MD in inferior frontal WM with dysfunctional affect regulation and other clinical symptoms of BPD (Rusch et al., 2007). A MRI study adopting a fibre-tracking algorithm demonstrated that fronto-striatal microstructural properties predicted RT, and this correlation grew stronger for trials expected to require greater control (Liston et al., 2006). The authors suggest that fronto-striatal connectivity may contribute to developmental and individual differences in the efficient recruitment of cognitive control (Liston et al., 2006). This is of particular interest as there is a strong relation between cognitive control and impulsivity, and a lack of cognitive control has been described as an underlying deficit in ADHD that affects cognitive functioning and behaviour (Randall et al., 2009). Deficiencies in the control of cognitive resources may be causal for ADHD symptoms such as inattention and impulsivity rather than impaired cognitive resources per se (Doyle et al., 2005).
We were able to show a positive correlation of MD and impulsivity bilaterally in the lingual gyrus, which is difficult to interpret. The lingual gyrus is connected to the limbic system by neural pathways, but there are no direct connections to the fronto-striatal system, although there is some evidence from literature for correlations of DTI measures of the lingual gyrus and impulsivity in schizophrenia (Hoptman et al., 2004). Taken together, our findings particularly emphasize the impact of structural integrity of fronto-striatal fibre tracts on impulsivity in adult patients with ADHD.
Neuroanatomical correlates of DTI measures
It is difficult to tell what biological processes exactly account for the observed abnormality of FA and MD values in patients with ADHD as the neuroanatomical and physiological correlates of diffusion parameters are not yet entirely understood (Beaulieu, 2002; Versace et al., 2008). In our study, lower FA and higher MD in orbitofrontal areas of patients with ADHD may correlate with myelination deficits, changes in axonal integrity, lower packing density of fibres or more obliquely oriented fibres. However, higher FA and lower MD localized in frontotemporal WM, where fibres of several tracts (IFO, inferior longitudinal fasciculus, uncinate fasciculus) are crossing (Mori et al., 2005), might rather be the result of less fibre crossings in this area. While higher FA in fibre tracts usually correlates with higher structural integrity, this correlation may not be correct in brain areas containing a particular high amount of fibre crossings, which results in lower FA values. In these areas, a higher number of fibres and thus a larger number of fibre crossings may result in higher connectivity of the involved brain areas and thus may lead to lower FA (Beaulieu, 2002). This may explain increased FA in patients with ADHD in frontotemporal WM clusters. In this context, it has to be mentioned that age effects on FA and MD have been previously described in healthy adults (Sullivan & Pfefferbaum, 2006), although age effects are unlikely to account for the observed group differences in our study, because both groups did not differ significantly in age.