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Aims: Low-frequency transcranial magnetic stimulation (TMS) to the right prefrontal cortex has been shown to be effective in treatment-resistant depression. The aim of the present study was to investigate changes in regional cerebral blood flow (rCBF) after low-frequency right prefrontal stimulation (LFRS), and neuroanatomical correlates of therapeutic efficacy of LFRS in treatment-resistant depression.
Methods: Twenty-six patients with treatment-resistant depression received five 60-s 1-Hz trains over the right prefrontal cortex, and 12 treatment sessions were administered during 3 weeks. Brain scans were acquired before and after LFRS using single photon emission computed tomography with 99mTc-ethyl cysteinate dimer. Severity of depression was assessed on the Hamilton Depression Rating Scale (HDRS).
Results: Significant decreases in rCBF after LFRS were seen in the prefrontal cortex, orbitofrontal cortex, subgenual cingulate cortex, globus pallidus, thalamus, anterior and posterior insula, and midbrain in the right hemisphere. Therapeutic efficacy of LFRS was correlated with decreases in rCBF in the right prefrontal cortex, bilateral orbitofrontal cortex, right subgenual cingulate cortex, right putamen, and right anterior insula.
Conclusion: The antidepressant effects of LFRS in treatment-resistant depression may be associated with decreases in rCBF in the orbitofrontal cortex and the subgenual cingulate cortex via the right prefrontal cortex.
TRANSCRANIAL MAGNETIC STIMULATION (TMS) is a non-invasive technique for stimulating the cerebral cortex and altering cortical and subcortical activities.1–3 High-frequency stimulation (5–20 Hz) has been shown to enhance cortical excitability, and low-frequency stimulation (1 Hz) to inhibit cortical excitability.4–7 Most studies of TMS for depression have used high-frequency stimulation over the left dorsolateral prefrontal cortex,8–10 and a number of recent double-blind, randomized, sham-controlled trials support antidepressant effects of high-frequency left prefrontal TMS.11–14 Several studies have shown that low-frequency stimulation to the right dorsolateral prefrontal cortex has antidepressant effects.11,15,16 The potential advantages of low-frequency stimulation are that it may be better tolerated and safer than high-frequency stimulation, because low-frequency stimulation produces less site discomfort during stimulation and has a considerably lower risk of seizure induction by TMS.11,17,18 Although the effects of TMS on neuroanatomical activity differ according to the frequency (high vs low) of the stimulation, high-frequency left prefrontal stimulation (HFLS) and low-frequency right prefrontal stimulation (LFRS) have both been shown to be effective in treatment-resistant depression.11,19–22 Therefore, LFRS may be a sensible first-line TMS for the treatment of depression in terms of tolerability and safety.
Functional imaging studies found abnormalities in the prefrontal cortex in patients with depression, particularly decreased activity in the dorsolateral prefrontal and medial regions,23–26 and for the treatment of depression, high-frequency stimulation has been used, targeting the left dorsolateral prefrontal cortex as the stimulation site. Single photon emission computed tomography and positron emission tomography (PET) studies of depression using TMS indicate that HFLS increases regional cerebral blood flow (rCBF) in the prefrontal cortex and the limbic–paralimbic regions,5,27 and therapeutic efficacy of HFLS is correlated with increased rCBF in the left prefrontal cortex, bilateral orbitofrontal cortex, anterior cingulate, left subgenual cingulate, bilateral anterior insula, and basal ganglia.27 In contrast, LFRS decreases rCBF in several brain regions,28 but neuroanatomical correlates of therapeutic efficacy of LFRS have still not been elucidated and it would differ from those of HFLS.
The aim of the present study was to investigate changes in rCBF after LFRS, and neuroanatomical correlates of therapeutic efficacy of LFRS in treatment-resistant depression.
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Twenty-six right-handed patients with major depression (treatment-resistant unipolar depression) participated in the present study. Twenty-five patients completed the entire study, but one patient withdrew consent for study participation during the trial because she had experienced no change in severity of depression. Eleven of 26 patients (six male, five female) were responders who had 50% reduction in the total HDRS score from baseline to week 5. Fifteen of 26 patients (eight male, seven female) were non-responders. Four of 11 responders went into remission, which was defined as a score <8 on the total HDRS.
For changes in the HDRS score, one-way repeated-measures anova was used to determine the main effect of time (F = 80.647, d.f. = 2, 48, P < 0.001). Multiple comparisons using the Bonferroni correction showed that the mean score on the HDRS decreased significantly from 22.65 ± 3.77 at baseline to 13.64 ± 4.60 at week 3, and to 11.92 ± 4.99 at week 5, respectively (P < 0.001).
Areas of significantly decreased rCBF after LFRS are given in Table 1 and Fig. 1 (height P < 0.05, extent P < 0.05). There was no area of significantly increased rCBF after LFRS, however. Areas that involved a correlation between therapeutic efficacy of LFRS and changes in rCBF due to LFRS are given in Table 2 and Fig. 2 (height P < 0.005, extent P < 0.005). The results indicate that therapeutic efficacy of LFRS was correlated with decreased rCBF in these brain regions. No area of increased rCBF, however, was correlated with therapeutic efficacy of LFRS.
Table 1. Changes in rCBF in treatment-resistant depression after low-frequency right prefrontal TMS
|Brain region||Hemisphere||Z score||Talairach coordinates||Brodmann area|
|Areas of decrease|
|Frontal white matter||Right||2.58||36||28||24|| |
|Globus pallidus||Right||3.34||18||−4||4|| |
Figure 1. Areas of decreased regional cerebral blood flow in patients with treatment-resistant depression after low-frequency right prefrontal transcranial magnetic stimulation.
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Table 2. Brain regions correlating with therapeutic efficacy of low-frequency right prefrontal TMS and changes in rCBF
|Brain region||Z score||Talairach coordinates||Brodmann area|
|Areas of decrease|
|Frontal white matter||Left||4.00||−10||23||−3|| |
Figure 2. Areas of correlates of therapeutic efficacy of low-frequency right prefrontal transcranial magnetic stimulation and changes in regional cerebral blood flow.
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