Open rTMS treatment of PD patients with treatment-resistant depression was followed by highly significant improvement in mood scores and anxiety ratings. In participants who returned for evaluation 3-6 weeks post-treatment, improvement in psychiatric measures persisted. The standardized effect sizes of 0.97 and 1.50 for HAMD17 can be cautiously compared to a meta-analysis of left dorsolateral pre-frontal cortex (DLPFC) stimulation for pure depression, which reported a weighted mean effect size of 0.89 (Holtzheimer et al., 2003
). (Note that this meta-analysis included only sham-controlled studies.) Additional improvement was found in motor and cognitive measures, but no change occurred in quality of life ratings. There were no adverse effects attributable to rTMS.
The depression results are consistent with the only previous report of rTMS treatment for depression in PD. This double-blind randomized study of rTMS vs
fluoxetine (Fregni et al., 2004
), found that 15 Hz rTMS over the left DLPFC had antidepressant efficacy comparable to fluoxetine, with fewer adverse effects but no changes in motor performance. Our average mood improvement is similar to that in the prior report. The combined psychiatric outcomes are encouraging, particularly considering that the patients in our study were all treatment resistant; but further confirmation is warranted as neither study included a placebo arm.
Boggio and colleagues found that both rTMS and fluoxetine produced improvement in Stroop test results, in the Hooper visual organization test, and in perseverative errors with the Wisconsin card sorting test (Boggio et al., 2005
). Differences in the test batteries between that study and this make the results difficult to compare, but related indices of attention, initiation, and construction in our patients showed no change. Interestingly, however, both studies failed to find a correlation between measures of cognition and mood, reinforcing the earlier conclusion that improvement in these domains could occur independently (Boggio et al., 2005
). Improvement in the DRS and the near-significant trend towards improvement in the RBANS were notable for involvement of memory function. Although the DRS may conceivably be vulnerable to practice effects, and the memory findings should be considered quite tentative, it is intriguing that the treatment area in the left DLPFC also plays a prominent role in frontal-hippocampal verbal memory systems (Floel et al., 2004
The present study is the first to suggest simultaneous benefit from TMS in psychiatric, cognitive, and motor domains for PD patients. The motor improvement is notable for occurring most prominently in a defined ‘off” state and in the “worst” estimate for H&Y, because the “off” condition is when patients are most debilitated and the practical benefit of treatment might be largest. These results are partially consistent with the hypothesis that a focal treatment in the left prefrontal region might improve motor function along with mood. However, the degree of improvement was not correlated, so we could not infer that alleviation of depression might be the cause
of improved motor and cognitive performance. Interestingly, both prefrontal TMS and placebo treatments are associated with dopamine release in the striatum, implying that relationships among different neuropsychiatric domains may be difficult to untangle even when benefit can be verified (de la Fuente Fernandez et al, (2001
; Keck et al., 2002
Several other studies of rTMS for motor function in PD have reported positive outcomes lasting for weeks or months, some without specifying medication state at the time of treatment or testing. Mally and colleagues (Mally et al., 2004
) conducted an open trial of TMS for motor function in uncomplicated PD, and reported striking and sustained benefit over three years, using low, nonfocal, and infrequent doses of TMS. Several sham-controlled, blinded studies also described improvement in movement measures following TMS of motor regions, DLPFC, or both (Ikeguchi et al., 2003
; Lefaucheur et al., 2004
; Lomarev et al., 2005
). However, Okabe and colleagues (Okabe et al., 2003
), using parameters similar to those of Ikeguchi et al plus a more realistic sham, found no benefit. Most recently, Olmo and colleagues (Olmo et al., 2007
) reported a double-blind sham-controlled trial of DLPFC rTMS for non-depressed patients with PD. UPDRS III “on” did not change in either group. The difference in our results may have been due simply to testing in the off state, since we also failed to find a difference in UPDRS “on” while treating more patients in an open protocol.
There are important caveats to the present results. Although lack of improvement during the delay from initial screening to treatment argues against simple regression to the mean, placebo effects are common in treatment trials of both depression and PD (Goetz et al., 2000
), and the possibility of rater bias could not be prevented. The dropout rate is smaller than reported in some published trials of rTMS for pure depression (Isenberg et al., 2005
), but it is possible that patient dropout might have biased the followup results, by favoring those patients who continued to experience improved mood and were more willing to make the effort to return. This hazard appears difficult to avoid if a comprehensive assessment is to be performed. It also remains possible that a subtle adverse synergy exists between depression and PD, and that improvement in other domains is more easily obtained when PD patients are treated for comorbid depression—even if a clear correlation could not be demonstrated in the data. Conversely, more prolonged treatment might have produced greater benefit, as has been observed in outpatient trials involving depression without PD (Avery et al., 2006
Open studies such as this should always be followed by double-blind trials to confirm the apparent benefits of treatment. As a practical matter, the extensive inpatient assessment protocol was a challenge both for scheduling and for testing many of our subjects. However, the greatest improvement in motor scores occurred off PD medication. Testing during the “off” state may explain the difference between our movement results and some previous studies of TMS in PD. Further studies of TMS in PD appear worthwhile for depression, cognitive, and motor deficits, and should be designed to capture comprehensive measures of movement performance.