1. Reduction of Functional Brain Connectivity in Chronic Cocaine Users ? ? Previous neuroimaging studies have shown significant reductions in metabolism, functional activity and/or gray matter density in several brain regions including prefrontal cortex (PFC), anterior cingulate cortex (ACC), ventral striatum, and meso-temporal lobes of human cocaine addicts. However, whether chronic use of cocaine affects the interactions among these brain regions is not known. In the present study, we use resting-state fMRI to test the hypothesis that system specific functional connectivity is altered in cocaine addicts compared to healthy controls. Resting-state fMRI experiments were performed on 20 cocaine users and 20 gender, age and education matched healthy controls. Regions of interest (ROIs) were selected in the amygdala, anterior cingulate, hippocampus, medial-dorsal thalamus, and sensorimotor cortex corresponding to the hand. Mean time courses were obtained from these seed ROIs and were utilized as templates for calculating cross-correlation coefficients (CC) for all voxels across the brain. A general reduction in functional connectivity was seen in cocaine addicts compared with matched control subjects. For example, when the seed point was in the amygdala, significant reductions in functional connectivity was found in a large area of the medial prefrontal cortices (mPFC), inferior prefrontal cortex (iPFC), orbital cortex, posterior cingulate cortices (PCC) in the cocaine group. The reduced connections among brain regions in the reward circuitry may help explain brain deficits associated with chronic cocaine addiction, and point to a powerful new tool to study cocaine-induced neuronal dysfunction or dysregulation. ? ? ? 2. Lower Glutamate Levels in the Anterior Cingulate Cortex of Chronic Cocaine Users? ? In this study, we used a recently developed MRS technique (TE-averaged PRESS) to determine the consequences of long term, chronic cocaine use on Glu and other metabolites in the anterior cingulate cortex (ACC) of human brain. Fifteen healthy volunteers and seventeen age-matched chronic cocaine users participated in this study. Data were acquired on a Siemens Allegra 3T scanner, and were quantified using LCModel. Since creatine (Cr) has been shown to be stable in the frontal gray matter of cocaine users and healthy controls, statistical analyses were conducted on the ratios of NAA/Cr, Cho/Cr, Glu/Cr, and Ins/Cr between the two groups. Our results showed that Glu/Cr ratio was significantly lower (12%) in the cocaine-user group compared with the controls (F1,29=4.2; p < 0.05). Additionally, while the NAA/Cr significantly decreased with age (F1,29=9.1; p < 0.005), there was no significant difference as a function of group (F1,29=1.5, n.s.). Regression analyses showed a significant positive correlation between Glu/Cr and NAA/Cr (t29=2.2; p<0.05), accounting for age. A decrease in Glu is consistent with evidence from animal studies that showed chronic cocaine self-administration significantly decreases the turnover rate of Glu in many reward-related brain regions including the NAc and cingulate cortex, suggesting a possible reduction in synaptic density or neurotransmitter synthetic capacity. As NAA is thought to be a marker of neuronal integrity, the correlation between Glu/Cr and NAA/Cr may reflect decreased ability of ACC neurons to produce Glu. A decrease in the enzyme glutamate carboxypeptidase II (CGPII) or III (CGPIII), which catabolizes N-acetyl-aspartylglutamate (NAAG) to NAA and Glu, could also lead to a reduction in Glu. In either case, a loss of ACC glutaminergic output may provide a mechanistic explanation for the impaired cognitive functions previously seen in cocaine addicts. ? ? ? 3. Reduction of White Matter Integrity in Cocaine Uses Revealed by Diffusion MRI? ? In this study, we tested the hypothesis that white matter integrity is altered in cocaine addicts compared to healthy controls using a voxelwise group analysis on diffusion tensor imaging (DTI) data. DTI data were acquired from 12 cocaine dependent individuals and 12 matched healthy controls on a Siemens 3T Allegra scanner. Fractional anisotropy (FA), mean diffusivity (MD), and 3 eigenvalues (1, 2, and 3) of the diffusion tensor were calculated in each voxel. Comparing DTI data of a cocaine group (n=12) with a control group (n=12), a number of brain regions demonstrated a reduction of FA in cocaine addicts compared, and theses regions generally appeared in a bilateral pattern. In Talairach coordinates (LPI), significant reduction of FA was found in pontine crossing tract, substantia nigra, subcallosal gyrus, superior cerebella peduncle, anterior cingulate, middle temporal gyrus, inferior frontal gyrus, medial frontal gyrus, superior frontal gyrus, anterior limb of internal capsule, amygdala, parahippocampal gyrus, corpus callosum, precentral gyrus, and superior occipital gyrus. A few regions of FA increase were also found, including in middle cerebella peduncle, posterior limb of internal capsule, superior temporal gyrus, middle occipital gyrus and angular gyrus. Meanwhile, a global increase of mean diffusivity (MD) was found in the cocaine users. These results suggest that chronic cocaine abuse may affect the white matter integrity in brain regions associated with drug addition.? ? ? 4. Quantification of BOLD Effect in CBV-Weighted fMRI at 9.4T? ? In CBV-weighted fMRI employing superparamagnetic contrast agent, iron dose and BOLD contamination are two important issues for experimental design and CBV quantification. Bothe BOLD and CBV-weighted fMRI are based upon the susceptibility effect, to which spin-echo and gradient-echo MRI sequence have different sensitivities. In the present study, CBV-weighted fMRI was conducted using spin echo and gradient echo sequences at 9.4T by systematically changing the doses of contrast agent. Results suggest that BOLD contamination is a significant component in CBV-weighted fMRI at high field, particularly when relatively low dose of contrast agent is administered. A mathematical model was developed to quantify the extra-vascular (EV) BOLD effect. With a TE of 35ms, the EV BOLD effect was estimated to account for 76 12% of the observed spin echo fMRI signal at 9.4T. These data suggest that correcting BOLD effect may be necessary for accurately quantifying activation-induced CBV changes at high field.? ? ? 5. Mechanisms of Resting-State fMRI: Electrophysiology and fMRI on Rats? ? Synchronized spontaneous fluctuations of the fMRI signal have been applied to reveal large-scale neuronal networks of the brain in the absence of specific task instructions. However, the underlying neural mechanisms of these fluctuations in fMRI remain largely unknown. We have recently developed an animal model to investigate these mechanisms by integrating electrophysiological and fMRI signals at the resting rat brain. By employing cerebral blood volume(CBV)-weighted fMRI with a superparamagnetic contrast agent, we achieved enhanced sensitivity and functional specificity, and were able to detect, for the first time, region-specific and anesthetic dose-dependent synchronized fMRI fluctuations in the primary somatosensory cortex (S1FL) of the resting rat brain. Epidural electroencephalographic (EEG) signals were recorded from bilateral S1FL electrodes using the same animal model. Results demonstrate that, unlike the evoked fMRI response that correlates with power changes in high frequency bands, power coherence in low frequency bands, particularly the delta band, correlates with the resting-state fMRI signal, and does so in a region-specific and dose-dependent fashion. These results add a novel dimension and new insight into the linkage between neuronal activity and hemodynamic response-based fMRI signal.
