A. Differential improvement in depression as a function of rTMS frequency
Within the 19 patients who received both high and low frequency active rTMS, a strong inverse relationship to the degree of antidepressant response was noted (r = –0.66, n = 19, p < 0.002) as illustrated in . Those who improved on one frequency tended to worsen on the other. The 12 unipolar patients showed a relatively equal distribution of those improving on 1 versus 20-Hz and deteriorating on the other rTMS frequency, whereas the 7 bipolar depressed patients improved on 20-Hz. There was no effect of rTMS order and demographic and clinical illness characteristics revealed no striking correlates of response to 20- versus 1-Hz rTMS.
Figure 1 Inverse relationship (r = −0.66) between the degree of antidepressant response (change in HAM-D) achieved with 1-Hz versus 20-Hz rTMS at 100% MT in each patient. Those improving on 20-Hz rTMS tended to worsen on 1-Hz rTMS, while those who improved (more ...)
In the third active phase, patients were allowed to revisit the frequency of rTMS to which they had previously responded best. This was followed by attempts at response optimization during a continuation phase. During this average period of 6.1 weeks, and average number of treatments of 26.1 ± 11.8 (range 7–42), additional degrees of clinical improvement were not consistently observed. Baseline HAM-D ratings averaged 30.3 ± 5.9 at baseline, increased to 32.6 ± 9.8 on 1-Hz and decreased to 27.2 ± 4.6 on 20-Hz and increased to 31.8 ± 9.5 on sham. However, at the end of the continuation phase on 1-Hz, HAM-D rating averaged 21.6 ± 10.8 and on 20-Hz averaged 29.6 ± 5.1.
B. Association of response to baseline PET activity
Given the large individual difference in responsivity to high versus low frequency rTMS within different patients, and the large variations in baseline activity on PET in both unipolar and bipolar patients, we sought to re-examine the possibility of predicting better responsivity based on patterns of cerebral activity assessed at baseline with PET procedures (Kimbrell et al., 1999
). We first examined the data in the 13 patients who participated in both the FDG and H215
O PET studies to determine whether they were “matched” to their predicted optimal rTMS frequency (i.e., hypoactive with 20-Hz and hyperactive with 1-Hz). Significantly greater improvement occurred during “matched” than “unmatched” phases as evaluated by baseline perfusion, but not metabolism.
In order to examine the predictive relationships in the larger group of all patients who had a baseline H215O scan and a subsequent active rTMS phase, we compared the 11 patients hypoperfused at baseline (, left side) with the eight who were hyperperfused at baseline (, right side). Depressed patients with baseline presentations of hypoperfusion showed greater improvement (–4.5 ± 2.5 HAM-D points) when they received 20-Hz rTMS (matched), whereas they showed an exacerbation of their depressive mood (+2.8 ± 1.5 points) when treated with 1-Hz rTMS (p < 0.01), which would be expected to further decrease their baseline hypoperfusion (i.e., a mismatch).
Figure 2 Using all 19 patients who had PET scans, baseline cerebral hypoperfusion (n = 11) predicted clinical response to 20-Hz rTMS and worsening on 1-Hz rTMS (left side). Baseline hyperperfusion (n = 8) did not show such a differential response to 1- vs. 20-Hz (more ...)
In contrast, in the eight patients who were hyperperfused at baseline (, right side), the degree of improvement was not significantly different, as predicted. However, when examining all patients when “matched” to the expected frequency, the improvement on the HAM-D was still greater (-3.7 ± 2.5) than when they were mismatched (0.7 ± 1.6; p < 0.04).
In a second more discrete regional analysis the degree of baseline hyperperfusion was significantly correlated with the predicted better degrees of responsivity to 1-Hz rTMS in a number of regions, including: bilateral dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, medial and lateral temporal lobe, and thalamus; midbrain regions encompassing red nucleus and substantia nigra; cerebellum; and right amygdala, and large areas of frontal to occipital cortices However, the magnitude of baseline hypoperfusion (from idealized control) in any specific cortical area lacked substantial relationships to the magnitude of clinical improvement on 20-Hz rTMS. The relationships of the degree of responsivity to 1-Hz rTMS to FDG measures of regional hyper- metabolism were not as striking as those of rCBF.