Hypotheses
We hypothesize that behavioral differences (increased discounting of delayed rewards) between MA-dependent subjects and normal controls reflect (1) greater sensitivity of MA patients to magnitude of immediate reward as well as cognitive control deficits in the MA group; i.e., the MA group will show a greater difference in activation of the affective circuit than controls when evaluating immediate as opposed to delayed rewards. Furthermore, we hypothesize that (2) during discounting, the MA group will show disproportionate recruitment of the amygdala when choosing either immediate losses or delayed rewards.
Specific Aims
Specific Aim 1: Use a Working Memory Delay Discounting (WMDD) task to separate valuation of stimulus valence from stimulus comparison. The task partially separates the choices from the stimulus to choose. This aim has been accomplished and leads directly to Aim 2.
Progress on Aim 1: A total of 10 MA-dependent subjects and 10 controls completed screening and have been analyzed to date with task 1. The groups differed substantially on the standard administration of the delay discounting task, with ln(k) = -6.3 ± 0.9 and -3.7 ± 1.7 [t(19) = 4.19, p < .001 (corresponding to k of 0.0019 and 0.024)] in the Control and MA groups, respectively.
The first of two options in a delay discounting stimulus pair was presented separately, followed by 1 to 2 s fixation and then the presentation of the second option. In some trials, the second option was not presented. Immediate vs. Delayed rewards were presented as the first option with equal probability in pseudorandom order.
 The data were collected and analyzed according to the methods and plan set out in the component protocol. Three GLMs were run to investigate the neurobiological basis of the decision task. The first analysis examined predictors aligned at the decision point. A contrast of trials in which choice of immediate reward was contrasted with choice of delayed reward is shown in Figure 1. The analysis suggests that choice of an immediate reward is associated with activation of sub-genual anterior cingulate cortex, L-amygdala, R middle frontal gyrus and middle temporal gyrus.
 When the trials were separated according to whether the immediate reward option was offered initially, markedly different patterns emerged. When the immediate option was presented first, there were few differences between immediate choice and delayed choice trials (Figure 2), but when the delayed option was presented first, there were more dramatic and informative differences (Figure 3).  Trials in which the subject chose the immediate reward showed activation in sub-genual ACC, R MTG and Posterior Parietal Cortex (not shown). Trials in which the subject chose the delayed reward showed activation in dorsal ACC, anterior insula and R MFG.
Examination of the responses to the initial option presentation (Figures 4 and 5) are helpful in understanding the decision- making part of the trial. Figure 5 shows regions where activity correlated strongly with length of delay. The sub-genual ACC identified in this contrast is the same as that associated with choice of an immediate reward. The response to initial presentation of an immediate reward option shows that magnitude of the reward is correlated with activity in visual cortex, basal ganglia and motor cortex. Activation of this region is associated with subsequent choice of an immediate reward, whereas subsequent choice of a delayed reward is associated with insular and LOFC activation.
Specific Aim 2.1:
Calculate the optimum method of adjusting the DD task and its variants.
Progress on Specific Aim 2.1:
A version of the DD task is currently being piloted that performs the standard administration, calculates k, graphs the result and then allows the experimenter to adjust the maximum delay time to better center the discounting curve in the response space. Preliminary results indicate that the task works as planned and that changing the maximum delay does not, within the limits of (30 days < Tmax < 1800 days), change the discounting behavior of the subject. We plan to pilot this method in the scanner in the next quarter.
Specific Aim 2.2:
Derive functional anatomical maps of specificity of Delayed Loss Discounting, Probability Discounting (PD) and (DLD) Double Delay Discounting (D3) in recovering MA-dependent individuals and controls.
Progress on Specific Aim 2.2:
These tasks have been programmed and are being piloted outside the scanner. The methods will be piloted in the scanner starting in the 3rd quarter of the coming year of funding.
Specific Aim 2.3:
Map the neural response to a Delay Discounting task in which the sign of discounting, loss vs. gain, is unknown until after both choices have been displayed.
Progress on Specific Aim 2.3:
This task is due to be piloted outside the scanner in the 4th quarter of the next funding year and moved to the scanner in the first quarter of the following year.
Specific Aim 3.1 (Future Aim):
Develop methods for determination of the anatomical and functional connectivity of the regions determined statistically in Specific Aims 1 and 2 using Diffusion Tensor Imaging (DTI) and Independent Components Analysis (ICA).
Progress on Specific Aim 3.1:
The DTI sequence is working well and data have been collected and analyzed on 4 subjects. The images will be carefully examined in the next quarter.
Significance
The initial aim demonstrates that immediate and delayed rewards are processed differently and that MA subjects process the comparison differently from normals. Further work will establish the detailed nature of the difference.
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