Connectivity-based functional analysis of dopamine release in the striatum using diffusion-weighted MRI and positron emission tomography

Abstract

The striatum acts in conjunction with the cortex to control and execute functions that are impaired by abnormal dopamine neurotransmission in disorders such as Parkinson's and schizophrenia. To date, in vivo quantification of striatal dopamine has been restricted to structure-based striatal subdivisions. Here, we present a multimodal imaging approach that quantifies the endogenous dopamine release following the administration of d-amphetamine in the functional subdivisions of the striatum of healthy humans with [(11)C]PHNO and [(11)C]Raclopride positron emission tomography ligands. Using connectivity-based (CB) parcellation, we subdivided the striatum into functional subregions based on striato-cortical anatomical connectivity information derived from diffusion magnetic resonance imaging (MRI) and probabilistic tractography. Our parcellation showed that the functional organization of the striatum was spatially coherent across individuals, congruent with primate data and previous diffusion MRI studies, with distinctive and overlapping networks. d-amphetamine induced the highest dopamine release in the limbic followed by the sensory, motor, and executive areas. The data suggest that the relative regional proportions of D2-like receptors are unlikely to be responsible for this regional dopamine release pattern. Notably, the homogeneity of dopamine release was significantly higher within the CB functional subdivisions in comparison with the structural subdivisions. These results support an association between local levels of dopamine release and cortical connectivity fingerprints.

Keywords: diffusion-weighted image; dopamine receptors; positron emission tomography; probabilistic tractography; striatum.

Figure 1.

(A) Cortical subdivisions. Purple corresponds to the frontal lobe, magenta to the parietal lobe, gray to the temporal lobe, and orange to the occipital lobe. Yellow corresponds to the executive, red to the limbic, green to the rostral-motor, and blue to the caudal-motor. (B) Methods overview. To obtain the CB functional regions in each subject, a 2-step procedure was applied: (Phase I) the projections from the 4 brain lobes (frontal, parietal, occipital, and temporal) to the striatum were calculated, and the striatal areas associated with each lobe were established. (Phase II) The frontal lobe was subdivided into 4 anatomical ROIs, each associated with a particular functional specialization (limbic, executive, rostral-motor, and caudal-motor), and projections between these anatomical ROIs and the striatal area associated with the frontal lobe were estimated

Figure 2.

(A) Group average projections from the 4 frontal lobe target to the striatum. Each anatomical target is associated with a specific function; limbic (first column), executive (second), rostral-motor (third), and caudal-motor (fourth) functions. The rows correspond to different coronal planes (top row corresponds to rostral striatum and bottom row to caudal striatum). A threshold of 50 samples was applied to the image in order to discard noise and voxels with low connection probabilities. (B) Individual functional subdivisions in 4 randomly selected subjects (MNI space—coronal planes). Each column corresponds to a subject starting from rostral (top row) to caudal (bottom row). To obtain the functional subdivision for each subject, a 2-step procedure was applied. First, the projections from the 4 brain lobes (frontal, parietal, occipital, and temporal) were calculated and each lobe's dominant area was established. Subsequently, the frontal lobe was subdivided into 4 anatomical ROIs, each associated with a specific function (limbic, executive, rostral-motor, and caudal-motor), and the projection of each target to the frontal lobe dominant area was estimated. Each voxel was assigned to the target that gave the highest connection probability.

Figure 3.

(A) Group averaged functional subdivision of the striatum (MNI space—coronal planes). First column corresponds to the precommissural and second column to the postcommissural striatum. (B) Overlapping projections in the striatum (MNI space—coronal planes). The columns correspond to overlaps between: 1) limbic and executive (first column); 2) executive and rostral-motor (second column); 3) executive and caudal-motor (third column); and 4) rostral-motor and caudal-motor (fourth column). A threshold of 50 samples was applied to the projections and, subsequently, the overlapping areas were determined

Figure 4.

Dopamine release measured as the percentage change of [¹¹C]PHNO BP_ND (column A) and [¹¹C]Raclopride BP_ND (column C) within the exclusive CB functional ROIs (CB, top row), the structural-derived functional ROIs (SBf, middle row), and the structural subdivisions of the striatum (SB, bottom row). Columns B and D correspond to the dopamine release %COV for each region for [¹¹C]PHNO and [¹¹C]Raclopride, respectively. Abbreviations correspond to: lim = limbic, exe = executive, rMt = rostral-motor, cMt = caudal-motor, par = parietal, sLim = structural-limbic, sExe = structural-executive, sSm = structural-sensorimotor, VST = ventral striatum, CD = caudate, PU = putamen.