At the beginning of fMRI experiments, lifetime cumulative cocaine doses were 27 and 75
mg/kg in monkeys M1 and M2, respectively. By the end of these experiments, cumulative doses were 75 and 102
mg/kg. During fMRI and training sessions, the timing and cumulative doses of cocaine were dependent on behavior, but animals typically received about two infusions per minute. This infusion rate approximately equals the rate of cocaine infusions by self-administration using single bar presses with this unit dose of drug (Flory and Woods, 2003
). During the 15
min of cocaine availability allowed within each fMRI run, cumulative cocaine doses per fMRI run were 0.51±0.10
mg/kg (mean±SD) in monkey M1 and 0.42±0.07
mg/kg in monkey M2.
shows the temporal responses of whole putamen to cocaine infusion in the two monkeys using a single 15-min block of cocaine availability in monkey M1 () and repeated on–off blocks of drug availability in monkey M2 (). Data are presented in 30-s time bins to simplify presentation. Analysis regressors (solid lines) were derived from shifted summations of a parametric response curve that was determined from the measured response induced by a larger non-contingent dose of cocaine (). Clearly, the assumption of temporal linearity proved to be accurate for this dose regimen, as the shape of the analysis regressor provided an excellent fit to data in basal ganglia.
The response to repetitive cocaine stimulation using this small unit dose showed little indication of acute tolerance across fMRI runs within each session, as illustrated by . Because subtle effects of acute tolerance within runs can be lost in corrections for signal drift, we additionally analyzed data by employing three separate regressors to fit cocaine-induce responses during each of the three periods of drug availability for monkey M2. In this analysis, responses to the second and third infusion trains were reduced progressively relative to those from the first period by 11±10 and 20±12%, respectively, but these effects did not reach significance across sessions.
Contingent and non-contingent cocaine infusion produced similar spatial patterns of CBV reduction throughout basal ganglia and motor cortex (). Both maps show all positive and negative cocaine-induced CBV changes that reached statistical significance using a blue-green color range for negative changes in CBV and a red-yellow color range for positive changes. Note that the non-contingent map in uses a fourfold larger range of CBV changes than used for the contingent data in this or other figures. shows the response of CBV in putamen during all self-administration sessions; points and error bars were derived from the first-level GLM analysis and represent peak response magnitudes of the regressors that were fit to the data (see ). Responses were consistent between the two monkeys and across imaging sessions.
shows the cocaine-induced functional response using a mosaic format of 15 transverse slices across basal ganglia from +9 to +20
mm in a standard stereotaxic coordinate system (Saleem and Logothetis, 2006
). Data were registered to the multi-subject macaque brain template (McLaren et al, 2009
) that underlies the functional map in the figure, and outlines of putamen, caudate, and accumbens were defined using T1- and T2-based image contrast from the averaged MRI brain template in conjunction with coordinates from the stereotaxic atlas. Assuming a coupling between fMRI and metabolic responses, all regions of basal ganglia exhibit pronounced functional inhibition. In addition, decreases in CBV were clearly evident in motor and premotor cortex.
Figure 3 A spatial map of the peak magnitude of the cocaine-induced response averaged across animals, transposed onto a population-averaged rhesus brain (McLaren et al, 2009), and reported as a percentage change in CBV, with negative changes using the blue-green (more ...)
Responses to cocaine in prefrontal cortex were smaller and more variable across monkeys. depicts the subject-averaged cocaine-induced response in frontal cortex on a partially inflated cortical surface. Brodmann boundaries rely on the probabilistic atlases of Lewis and Van Essen (2000)
together with Ferry et al (2000)
. Although bilateral cocaine-induced reductions of CBV were pronounced throughout premotor cortex (BA 6 in the figure) and motor cortex posterior to BA 6, orbital frontal cortex (BA 11, BA 12) and dorsolateral prefrontal cortex (BA 46, BA 45 inside sulcus) showed smaller and more lateralized reductions of CBV.
Figure 4 Functional activation in the frontal cortex measured as the percentage change in CBV (color scale) for regions that responded significantly by a random-effects analysis across fMRI sessions and monkeys. Activity is shown on right and left partially inflated (more ...)
quantifies regional changes in both monkeys. Using a conservative across-session analysis, cocaine infusion decreased CBV significantly throughout basal ganglia in each monkey, including the anterior and posterior putamen, caudate, and nucleus accumbens (p<0.01 after correction for multiple comparisons using Dunnett's method). When averaged across animals, all regions listed in the figure exhibited significant decreases in CBV, except for primary visual cortex, ACC and PCC, and amygdala. No regions responded differently between monkeys (p>0.05). No cocaine-induced increases in CBV were observed in any regions that reached significance by conservative random-effects statistical analysis within or across monkeys.
Figure 5 Functional changes in CBV (mean±standard error) associated with cocaine infusion. Asterisks indicate significance (p<0.01) in each monkey across sessions after correction for multiple comparisons. Plus signs indicate significance averaged (more ...)
The spatiotemporal response to cocaine was specific to injection of drug. In two sessions in monkey M2, the pump was turned off during alternating periods of cocaine availability to compare responses with and without infusion of drug. In two sessions in monkey M1 and three sessions in monkey M2 that occurred after all cocaine-reinforcement studies, saline was substituted for cocaine. Pooling these data to create a control group for an analysis of regional effects across monkeys owing to infusion of drug, the same regions shown in reached significance, except for DLPFC.