Network modulation following sham surgery in Parkinson's disease

Abstract

Patient responses to placebo and sham effects are a major obstacle to the development of therapies for brain disorders, including Parkinson's disease (PD). Here, we used functional brain imaging and network analysis to study the circuitry underlying placebo effects in PD subjects randomized to sham surgery as part of a double-blind gene therapy trial. Metabolic imaging was performed prior to randomization, then again at 6 and 12 months after sham surgery. In this cohort, the sham response was associated with the expression of a distinct cerebello-limbic circuit. The expression of this network increased consistently in patients blinded to treatment and correlated with independent clinical ratings. Once patients were unblinded, network expression declined toward baseline levels. Analogous network alterations were not seen with open-label levodopa treatment or during disease progression. Furthermore, sham outcomes in blinded patients correlated with baseline network expression, suggesting the potential use of this quantitative measure to identify "sham-susceptible" subjects before randomization. Indeed, Monte Carlo simulations revealed that a priori exclusion of such individuals substantially lowers the number of randomized participants needed to demonstrate treatment efficacy. Individualized subject selection based on a predetermined network criterion may therefore limit the need for sham interventions in future clinical trials.

Figure 6. PDRP expression and natural history.

(A) The previously characterized PDRP (11, 13, 49). This network is associated with increased (red) pallidal, thalamic, cerebellar, and motor cortical metabolic activity, with relative reductions (blue) in the lateral premotor and parieto-occipital regions. The displayed voxel loadings on the pattern were shown to be reliable (P < 0.001) by bootstrap estimation. (B) Voxel-wise correlation of standardized regional loadings on the SSRP and PDRP topographies exhibited no spatial correspondence between the 2 networks. Less than 0.0001% of the total voxel weight variation was shared by these patterns (P = 0.957, adjusted for autocorrelation; ref. 42). (C) PDRP expression values computed in the 23 SHAM subjects (right) increased significantly over time (r² = 0.223, P < 0.001, Bland-Altman correlation). The network progression in this group was continuous (dotted line) with the progression line (r² = 0.540, P < 0.001) that was determined independently in 15 subjects (left) with early-stage PD (13). The slope of PDRP progression did not significantly differ between the early-stage PD subjects (left, b = 0.141; 95% CI: 0.087–0.194) and those who underwent SHAM (right, b = 0.406; 95% CI: 0.175–0.636).

Figure 5. Effects of unblinding on network expression.

(A) Eleven sham (SHAM_R) and 6 gene therapy (GAD_R) responders were rescanned at 12 months after unblinding (see text). The time course of SSRP expression differed for the 2 groups [F(1,15) = 6.900, P = 0.019, group × time interaction, RMANOVA]. Unblinding was associated with a significant decline in network expression in the sham-operated subjects (P = 0.031, LSD test) but not in their gene therapy counterparts (P = 0.152). Outliers (greater than the mean +1.5 × SD) are shown by white circles. (B) After unblinding, the majority of SHAM_R subjects (8 of 11 = 72.7%) exhibited a decline in network expression (left), with values falling in the range (dashed line) seen over a comparable time interval in an unblinded disease progression cohort (see text). By contrast, SSRP expression remained above this level (right) in the 4 SHAM_R subjects who were still under the blind at 12 months. Dashed line represents 1.5 SD above the mean change in SSRP expression observed in an independent cohort composed of 15 PD subjects scanned twice over a 2-year period (see Supplemental Figure 2B). (C) Six of the 13 gene therapy responders (GAD_R) who underwent repeat metabolic imaging at 12 months were unblinded prior to the final imaging session. Unblinding had no significant effect on SSRP expression in these subjects. Indeed, in 5 of the unblinded GAD_R subjects (left), network activity at 12 months was in the open-label progression range (dashed line). Similar network values were observed (right) for the GAD_R subjects who remained under the blind at the final imaging time point.

Figure 4. Effects of treatment on network modulation under the blind.

Changes in SSRP expression (light gray bars) were computed under the blind at 6 months in the 16 sham responders and 14 STN AAV-GAD gene therapy responders (see text). Concurrent changes in UPDRS motor scores (dark gray bars) are presented for comparison. Motor outcomes under the blind did not differ for the GAD_R and SHAM_R subjects [t(28) = 1.213, P = 0.235]. Nonetheless, a significant difference in SSRP modulation was observed in the 2 groups [t(28) = 3.379, P = 0.002].

Figure 3. Clinical outcome under the blind correlates with baseline network expression.

(A) Baseline SSRP expression in the SHAM subjects (n = 23) correlated with motor outcome under the blind at 6 months (r = 0.459, P = 0.028, Pearson’s correlation). (B) Accordingly, baseline SSRP expression was lower [t(21) = 3.96, P = 0.001] in the SHAM_R subjects as compared with that in the SHAM_NR subjects. Baseline network values were similar [t(37) = 0.113, P = 0.910] for the subjects who subsequently received gene therapy and for those who received SHAM (see text). The middle lines, boxes, and whiskers represent the median, lower and upper quartiles, and range, respectively. (C) Monte Carlo simulations were performed to estimate the sample size needed to detect a group difference in motor outcome based on the data obtained under the blind in the STN AAV-GAD trial (ref. , and see Methods). The results of 10,000 random trials are depicted for simulations of varying sample size for the 2 groups. The simulations indicated that at least 192 randomized subjects were needed to detect a significant group difference (P = 0.05, 2-tailed Student’s t test) in 95% of the trials. Nonetheless, the number of participants needed to demonstrate the same treatment effect fell to 84 by a priori exclusion of subjects with baseline SSRP expression below the prespecified criterion. For this analysis, we chose the median baseline SSRP expression in sham responders (–0.75; dashed lines in A and B). Participants with baseline SSRP values below this criterion exhibited more pronounced sham responses. Therefore, excluding all such sham-susceptible individuals before randomization lowered the required number of sham surgeries by greater than 50%.

Figure 2. Network changes: relationship to the sham response.

(A) A significant difference in UPDRS motor outcomes (dark gray bars) was evident across the 3 testing groups [(F(2,21) = 20.095, P < 0.001, ANOVA]. As expected, motor improvement was similar for the sham responders in the testing set and for the subjects who received open-label levodopa treatment (P = 0.730, post-hoc LSD); these changes differed from those seen in the sham nonresponders (P < 0.001). Significant differences were also seen for network activity measurements (light gray bars) in the 3 groups [F(2,21) = 4.156, P = 0.030]. In contrast to the motor changes, SSRP modulation was greater in the sham responders than in either the sham nonresponders (P = 0.014) or the individuals receiving open-label levodopa treatment (P = 0.036). (B) A significant correlation was observed between changes in SSRP expression in the SHAM cohort (n = 23) and concurrent motor outcomes under the blind at 6 months (r = –0.749, P < 0.001, Pearson’s correlation).

Figure 1. SSRP.

Network analysis of metabolic images obtained for 8 PD patients scanned at baseline and again, under the blind, 6 months after SHAM (see text). (A) The resulting SSRP was characterized by increased metabolic activity in the anterior cingulate cortex (BA 32/24), subgenual cingulate gyrus (BA 25), inferior temporal cortex, hippocampus, amygdala, and posterior cerebellar vermis. ACC, anterior cingulate cortex; LOB, lobule; SubCAL, subcallosal gyrus. Pattern is displayed as a bootstrap reliability map thresholded at z =|1.64|, 1-tailed P < 0.05; 1,000 iterations. (B) SSRP also included contributions from the head of the caudate and anterior putamen (top) and from the VA thalamic nucleus. While voxel weights for these clusters significantly contributed to this network (Table 1), these loadings did not meet the prespecified bootstrap reliability criteria (z = 1.575, 1.472, and 1.348 for the 3 regions, respectively; 1,000 iterations). (C) A significant ordinal trend in SSRP expression (left) was seen in the 8 responders to SHAM who were used to identify the pattern. Each subject exhibited an increase in network expression under the blind at 6 months (P < 0.01, binomial test). A similar ordinal trend in SSRP expression under the blind (P < 0.01, binomial test) was evident in the 8 remaining sham responders (middle) who were not used for pattern identification. An ordinal trend was not observed under the blind (P = 1.0) for the 7 sham nonresponders (right). Three violations were evident in this group, whereas no violations were present in either SHAM_R group.