illustrates fMRI activation maps of hallucination events and sites targeted for rTMS for 2 patients with intermittent hallucinations. illustrates fMRI maps of correlations referenced to Wernicke’s area and corresponding rTMS sites for 2 continuous hallucinators.
Figure 2 fMRI activation maps of hallucination events for 2 patients with intermittent hallucinations. Images are in the axial oblique orientation. Arrows illustrate the rTMS sites selected. Numbers next to arrows are Brodmann areas per Talairach and Tournoux (more ...)
Figure 3 Representative fMRI maps of correlations relative to Wernicke’s area for 2 patients with continuous hallucinations. Left side of the brain corresponds to the right side of images. (A) Subject in the 3-site version of the protocol. As expected, (more ...)
Figures and illustrate changes in hallucination scores for cortical sites probed with active rTMS for subjects with intermittent hallucinations and continuous hallucinations, respectively. Quantitative comparisons of clinical outcomes for rTMS delivered to ROIs are summarized in . Only rTMS directed to the left temporoparietal region produced a greater rate of clinical improvement relative to sham stimulation (Wilcoxon signed ranks test, z = 2.60, P = 0.009, estimated effect size = 1.01). Greater rate of improvement was also observed for rTMS delivered to this region compared with rTMS delivered to anterior temporal regions (Wilcoxon signed ranks test, z = 2.20, P = 0.028, estimated effect size = 1.27).
Cortical maps of rates of improvement/worsening of AVHs associated with rTMS delivered to alternative sites for all patients with intermittent hallucinations. Left supramarginal (l. sm.) region and Wernicke’s (W) region are circled.
Cortical maps of rates of improvement/worsening of AVHs associated with rTMS delivered to alternative sites for all patients with continuous hallucinations. Left supramarginal (l. sm.) region and Wernicke’s (W) region are circled.
Figure 6 (A) Data generated under double-masked conditions averaged across all subjects receiving stimulation at designated site. Ant. Temp., anterior superior temporal regions including BA 41/42 and anterior BA 22 bilaterally; Broca’s, BA 44/45 bilaterally; (more ...)
It is possible that rTMS response for sites probed late in the sequence for a given subject expressed carryover effects arising from stimulating prior sites. If left temporoparietal sites clustered late in the order of sites, this may have contributed to improved response rates in this region. This possibility was assessed by comparing rate of response relative to site order probed with rTMS (). For the 10 patients probed in at least 4 sites, the fourth site probed was associated with greater improvement than the first site (Wilcoxon signed rank test, z = 2.02, P = 0.043). The number of subjects receiving rTMS directed to left temporoparietal sites at different steps in the sequence was as follows: first in sequence (5), second in sequence (3), third in sequence (4), and fourth in sequence (3). These data indicate that sequential order of left temporoparietal rTMS did not appear to contribute to elevated response rate observed for this region.
ROI data for fMRI maps were assessed as possible predictors of rate of improvement while receiving left temporoparietal rTMS. For intermittent hallucinators alone (N = 6), negative correlations with rate of improvement for rTMS delivered to this region were significant for hallucination-related activation in Broca’s region (Spearman rank rho = –0.93, P = 0.008, ) and the right-sided homologous region (Spearman rank rho = −.87, P = 0.024) but not for activation in the left temporoparietal region itself (Spearman rank rho = −0.70, P = 0.12). The correlation with Broca’s hallucination-related activation remained significant after Bonferroni correction (activation variables utilized in this analysis corresponded to left and right Broca’s, anterior temporal, and temporoparietal ROIs yielding a total of 6 variables) with adjusted P value = 0.008 × 6 = 0.048. Confounding effects of 2 factors that may have influenced detected level of activation as well as rTMS response were considered. Number of scanning runs, which could influence robustness of activation maps, may have been influenced by symptom severity (patients with greater symptoms may tolerate extended scanning with more difficulty), which, in turn, could have altered rTMS response. Similarly, frequency of hallucination events during scanning is an index of hallucination severity that could have influenced robustness of activation maps as well as rTMS response. Correlations with rate of improvement for left temporoparietal rTMS for these 2 variables did not, however, approach statistical significance (for number of scan runs per subject, Spearman rank rho = −0.26, P = 0.62; for frequency of AVHs during scanning, Spearman rank rho = .32, P = 0.54).
Figure 7 The y axis shows percent improvement in hallucination severity expressed as average hallucination change score reductions per each left temporoparietal (TP) rTMS session. Each plot represents an independent set of 6 patients. Scale of x axis in upper (more ...)
Correlations between temporoparietal rTMS response and functional coupling in ROIs linked to Wernicke’s area were assessed for continuous hallucinators (N = 6). A robust negative correlation was detected between level of Wernicke’s coupling to right Broca’s area and left temporoparietal rTMS response (Spearman rank rho = −1.0, P = 0.001, ) but not for coupling to left Broca’s area (Spearman rank rho = −0.60, P = 0.20). Insofar as all continuously hallucinating patients completed an identical number of scan runs (=6), this variable was not a confound influencing these correlational findings. Hallucination frequency in these cases was also identical, that is, continuous.
Patients tolerated active rTMS without significant difficulties. Two patients experienced significant pain during rTMS when stimulating over Broca’s region that required reductions of stimulation strength to 70% motor threshold.