Synopsis
The substantia nigra/ventral tegmental area (SN/VTA) is central to the modulation of dopaminergic networks implicated in Attention Deficit Hyperactivity Disorder (ADHD). However, little is known of its specific contribution to the disorder. Whilst motivational abnormalities and impulsivity are known to be related to the structure, it is not clear whether SN/VTA subcomponents differentially contribute to these deficits. Using diffusion MRI tractography parcellation of the SN/VTA, we show that increased waiting impulsivity in ADHD is related to the microstructure of the mesolimbic SN/VTA, whilst trait motivation is related to the nigrostriatal component. Unlike previous reports in unmedicated ADHD, we detect no motivational abnormalities in this medicated cohort. However, we report that patients who have been medicated longer show alterations in microstructure consonant with increased motivation.Purpose
The substantia nigra/ventral tegmental area
(SN/VTA) is central to dopaminergic modulation of networks involved in Attention
deficit hyperactivity disorder (ADHD). However, due to limitations in
non-invasive midbrain imaging little is known of its role in the disorder.
Recent accounts have suggested the SN/VTA may have a central role in
impulsivity
1 and motivation
2 abnormalities in the disorder, though such
findings have not had sufficient anatomical resolution to assess the
contribution of its functionally distinct subcomponents. We therefore employ diffusion
MRI tractography to parcellate the (i) nigrostriatal and (ii) mesolimbic SN/VTA
according to their connectivity with the following target regions: (i) dorsal
striatum and the (ii) nucleus accumbens, amygdala and hippocampus.
We then sought to assess how incentive motivation and waiting impulsivity are
related to these subcomponents.
Methods
Thirty
patients with ADHD, and 30 age, IQ, gender and handedness matched controls were
scanned using a 1.5T Siemens Avanto scanner. For diffusion MR
imaging a multi-slice twice refocused spin echo echo-planar imaging (EPI)
acquisition was used (60 slices, 2.5mm3 resolution, TE 86ms, TR
7.7s, B 1500 s/mm-1, 60 diffusion weighted volumes and 7 B0). MT
maps optimised for SN/VTA4 were calculated
from a multi-parameter protocol adapted from a 3D multi-echo fast low angle
shot (FLASH) sequence.5
SN/VTA
seed regions were manually traced blind to diagnosis on MT saturation images,
and target regions were segmented using Freesurfer. Diffusion volumes were corrected
for eddy currents and motion distortion. FA maps were generated from fitting the
diffusion tensor at each voxel. A persistent angular structure (PAS) model of
diffusion was then estimated at each voxel, and up to 3 principal directions
(PDs) of diffusion were extracted at each point. FA maps were used to calculate
an initial Affine (Taff) and non-linear diffeomorphic (Tdiff)
warp to each subjects MT saturation image. Due to the small size of the SN/VTA,
tractography analyses were performed at the upsampled resolution of the MT
data. To simplify the PD rotation required for this transformation, diffusion
data were upsampled by applying Taff (rather than Taff +
Tdiff) to all diffusion data. PDs were transformed to dyadic
tensors before Taff transformation to preserve
directional information, and then extracted from the tensors.7 ROIs were
transformed into this common space by applying the inverse Tdiff.
Probabilistic tractography was performed for 5000 iterations per PD per voxel
with an angle threshold of >80°. A winner-takes-all strategy was implemented
across directions, with each voxel assigned its identity according to maximum
PiCO connectivity to either target (i: dorsal striatum; ii: nucleus accumbens,
amygdala, and hippocampus).
Trait
motivation was indexed using the ‘Achievement’ subscale of the Multidimensional
personality questionnaire as in Volkow et al.,2 and the
‘Persistence’ subscale of the Tridimensional Personality Questionnaire. Twenty-eight
of the ADHD patients and 25 healthy controls also completed the 4-choice serial
reaction time task to index waiting impulsivity.7,8
Results
Parcellation produced results similar to
previous reports
10 and in line with animal tracer studies (Figure
1). Participants with ADHD had greater waiting impulsivity which was related to reduced FA (
r = -0.55,
p = 0.012) and MT (
r = -0.49,
p = 0.028) in the right mesolimbic
SN/VTA. In contrast to previous reports of motivation abnormalities in
medication naïve ADHD patients, we observe no differences in incentive
motivation. However, reduced FA in the right nigrostriatal SN/VTA was related
to both increased motivation (MPQ:
rho = -0.50, p = 0.014; TPQ:
rho = -0.39, p = 0.066) and longer treatment with stimulant medication (
r =
-0.50,
p = 0.012),
suggesting that medication may have a normalising effect.
Discussion
These results suggest that waiting impulsivity
is heightened in ADHD, and that this relates to reductions in FA and MT
saturation in the right mesolimbic SN/VTA. By contrast we observe no deficits
in trait motivation in this medicated cohort, although this may reflect long-term
therapeutic effects of stimulant medication on the nigrostriatal SN/VTA. These
results suggest dissociable effects of midbrain dopaminergic subcomponents to
ADHD, and a potentially therapeutic effect of medication on the midbrain correlates of incentive motivation.
Acknowledgements
No acknowledgement found.References
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