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Keywords:

  • brain imaging;
  • depression;
  • transcranial magnetic stimulation

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

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.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Subjects

Patients with DSM-IV-TR criteria of major depressive disorder (unipolar depression) who had failed to respond to a minimum of two courses of antidepressant medications in different chemical classes29 in the current episode and scored >18 on the 21-item Hamilton Depression Rating Scale30 (HDRS) participated in the present study. The patients were recruited from the outpatient department at Kyorin University Hospital and by referral from several medical institutions. Exclusion criteria for the study included bipolar disorders, neurological disorders, convulsive disorders, significant medical diseases, a history of substance abuse or dependence, and active suicidal ideation. Thirty-two patients were screened by an expert psychiatrist, and six patients were excluded because they did not meet the diagnostic criteria or included the exclusion criteria. The 26 patients (14 male, 12 female) enrolled in the study were all right-handed and had no history of psychosis. The mean patient age was 46.19 ± 13.80 years and the age at onset of depression was 39.04 ± 13.33 years. The number of previous depressive episodes was 3.12 ± 1.11 and the duration of current depressive episode was 11.42 ± 6.35 months. The mean HDRS score at baseline was 22.65 ± 3.77. The Thase–Rush stage of treatment-resistant depression29 was as follows: three patients, stage II; 23 patients, stage III. Medical treatments administered were not allowed to have changed in the 4 weeks before the start of the first TMS session or during the trial. Twenty-four patients were taking medications during the trial and some patients were receiving several antidepressants: nine were taking selective serotonin re-uptake inhibitors (fluvoxamine, paroxetine, sertraline), eight were taking serotonin norepinephrine re-uptake inhibitors (milnacipran), eight were taking tricyclics (amitriptyline, clomipramine, amoxapine), seven were taking other antidepressants (trazodone, mianserin, sulpiride), five were taking lithium carbonate, one was taking antipsychotics (olanzapine), and 16 were taking benzodiazepines.

All patients provided written informed consent for participation in the study after receiving a full explanation of the procedures, and the study was approved by the ethics committee of Kyorin University School of Medicine.

Transcranial magnetic stimulation

TMS was administered using a magstim super rapid (Magstim, Whitland, UK) with stand-held 70-mm figure eight coils. At the first TMS session, the resting motor threshold was measured using standard visual methods.31 The right dorsolateral prefrontal cortex was the stimulation site during the TMS sessions and was defined by a point 5 cm anterior in a parasagittal line to the motor threshold location. Five 60-s trains at 1 Hz and at 100% of the resting motor threshold were applied in each session with a 60-s interval between the trains. Twelve treatment sessions were administered during 3 weeks (total pulses, 3600). Patients sat in a reclining chair with a headrest during the TMS sessions and the 70-mm figure eight coil was held in place using the coil stand. The resting motor threshold and the stimulation site were determined by an experienced psychiatrist.

Clinical assessment and analyses

All patients were assessed at baseline, at week 3, and at week 5 (2 weeks after the TMS sessions) with the 21-item HDRS. The rate of improvement in severity of depression was estimated from the scores on the HDRS at baseline and at week 5 (decrease [%] = [score at baseline–score at week 5]/score at baseline). One-way repeated-measures analysis of variance (anova) was used to compare changes in the HDRS score and to estimate the effect of time. Statistical analysis was conducted using SPSS for Windows 14.0 (SPSS, Chicago, IL, USA), with the level of statistical significance set at P < 0.05.

Brain scan and image analyses

Brain scans were acquired within 24–72 h before the first TMS session and after the last TMS session. All patients rested in the supine position in a quiet room with their eyes closed and their ears unplugged. The image acquisition started approximately 10 min after the injection of 600 MBq 99mTc-ethyl cysteinate dimer in the resting state via a venous cannula previously inserted into the right arm, using a triple-detector gamma camera GCA-9300A/HG (Toshiba, Tokyo, Japan) with low-energy super-high-resolution fan beam collimators. The matrix size was 128 × 128, and data were collected in 30 frames at 4° steps over 120° with a pixel width of 1.72 mm and a slice thickness of 3.45 mm. Scanned data were prefiltered using a Butterworth filter (order 8 and a cut-off at 0.08–0.09 cycles/pixel) and reconstructed with a Ramp filter. Scatter and attenuation corrections were performed using the triple-energy window correction and Sorenson methods, respectively.

Statistical analysis was conducted on a voxel-by-voxel basis with statistical parametric mapping (SPM for Windows).32,33 The images were realigned and spatially normalized to the standard stereotactic space, which was based on the ECD2 template, and smoothed with an isotropic 12-mm full-width half-maximum Gaussian filter to improve the signal-to-noise ratio. To investigate changes in rCBF after LFRS, we examined the difference for each patient before and after the treatment session using SPM for Windows. To investigate neuroanatomical correlates of therapeutic efficacy of LFRS and changes in rCBF by LFRS, we examined the difference for each patient before and after the treatment session, using SPM for Windows, with decrease (%) on the HDRS score as the variable of interest, and patient age as a confounding variable. Height and extent of brain areas were assessed using P < 0.05 or 0.005, respectively, after correction for multiple comparisons. Stereotactic coordinates were based on Talairach atlas coordinates converted from Montreal Neurological Institute coordinates.34

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

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 regionHemisphereZ scoreTalairach coordinatesBrodmann area
xyz
  1. rCBF, regional cerebral blood flow; TMS, transcranial magnetic stimulation.

Areas of decrease
Dorsolateral prefrontalRight3.2240402410/46
Right2.683424438
Right2.623823349
Ventrolateral prefrontalRight2.354639546
OrbitofrontalRight3.522215−1147
Right2.863452−1111
Frontal white matterRight2.58362824 
Right2.19322123 
Subgenual cingulateRight3.331220−1825
Globus pallidusRight3.3418−44 
ThalamusRight3.178−134 
Anterior insulaRight2.2630141413
Posterior insulaRight2.6534−191213
MidbrainRight2.034−22−4 
image

Figure 1. Areas of decreased regional cerebral blood flow in patients with treatment-resistant depression after low-frequency right prefrontal transcranial magnetic stimulation.

Download figure to PowerPoint

Table 2.  Brain regions correlating with therapeutic efficacy of low-frequency right prefrontal TMS and changes in rCBF
Brain regionZ scoreTalairach coordinatesBrodmann area
xyz
  1. rCBF, regional cerebral blood flow; TMS, transcranial magnetic stimulation.

Areas of decrease
PremotorRight3.49324506
Right3.273816516/8
Dorsolateral prefrontalRight3.324022438
OrbitofrontalLeft3.64−624−2111
Left2.68−434−2211
Right3.16226−2511
Right2.901022−1811
Frontal white matterLeft4.00−1023−3 
Right3.19261723 
Subgenual cingulateRight2.83821−925/32
PutamenRight3.902221−4 
Anterior insulaRight3.003018513
Right2.6528161413
image

Figure 2. Areas of correlates of therapeutic efficacy of low-frequency right prefrontal transcranial magnetic stimulation and changes in regional cerebral blood flow.

Download figure to PowerPoint

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

To our knowledge this is the first study to elucidate neuroanatomical correlates of therapeutic efficacy of low-frequency right prefrontal TMS in treatment-resistant depression.

Changes in rCBF after LFRS

Brain regions of changes in rCBF after low-frequency TMS to the prefrontal cortex differ between the laterality of the stimulation site. Therefore, the findings of earlier brain imaging studies are not consistent with each other. Low-frequency TMS to the left dorsolateral prefrontal cortex of 10 patients with depression decreased rCBF in the right prefrontal cortex, left medial temporal cortex, left basal ganglia, and left amygdala.5 To the right dorsolateral prefrontal cortex of 14 depressed patients, low-frequency stimulation decreased rCBF in the bilateral prefrontal cortex, orbitofrontal cortex, anterior insula, right subgenual cingulate cortex, and left parietal cortex, according to our previous preliminary study.28 Although there were some differences in rCBF changes between the preliminary study28 and the present study, this discrepancy might be due to differences in the number of subjects and clinical characteristics such as sex, clinical symptoms, and treatment response. In the previous study the subjects consisted only of depressed male patients, and several patients, although they met the DSM-IV diagnostic criteria for major depression, proved to have some atrophy of the brain.28 The present results show that areas of significantly decreased rCBF after LFRS were seen in the right prefrontal cortex, right subgenual cingulate cortex, and limbic–paralimbic regions, and these significant changes in rCBF were seen in the right hemisphere. There was no area, however, of significantly increased rCBF after LFRS. Significant rCBF decreases in the ipsilateral prefrontal cortex, orbitofrontal cortex, subgenual cingulate cortex, globus pallidus, thalamus, anterior and posterior insula, and midbrain suggest the presence of neuroanatomical connectivity among these brain regions, and that the effects of LFRS on the stimulation site can elicit activity changes in local and distant brain regions via the neural pathways.

Correlates of therapeutic efficacy of LFRS and changes in rCBF

The present study indicates that there is a correlation between therapeutic efficacy of LFRS and decreases in rCBF in the right prefrontal cortex, bilateral orbitofrontal cortex, right subgenual cingulate cortex, right putamen, and right anterior insula. Brain imaging studies have shown that increased activity in the orbitofrontal cortex and the subgenual cingulate cortex was involved in the pathophysiology of depression.35–38 Mayberg and colleagues found that the subgenual cingulate cortex (BA25) is metabolically overactive in patients with treatment-resistant depression, and reported that deep brain stimulation to the subgenual cingulate cortex ameliorated the clinical features of depression, with decreases in CBF in the orbitofrontal cortex and the subgenual cingulate cortex.38–40 Taken together, these findings suggest that therapeutic efficacy of LFRS is correlated with decreases in rCBF in the orbitofrontal cortex and the subgenual cingulate cortex. Additionally, Drevets et al. noted that the reduction in CBF and metabolism in the orbital cortex and ventrolateral prefrontal cortex during antidepressant drug treatment and electroconvulsive therapy may not constitute a primary mechanism for ameliorating depressive symptoms; instead, direct inhibition of pathological limbic activity in areas such as the amygdala and subgenual anterior cingulate cortex may be more essential to correcting the pathophysiology associated with mediating depressive symptoms.41

Limitations

There were several limitations in the present study. Subjects enrolled in the study were patients with treatment-resistant depression and some of them were receiving medical treatment during the trial. The medications administered might have affected changes in rCBF and depressed mood. According to a PET study of depression by Bench et al., there was no significant difference in rCBF between medicated patients and non-medicated patients, compared with normal controls.42 In the present study the patients were recruited from the outpatient department at Kyorin University Hospital and voluntarily participated in the study, and therefore were not a general population sample of subjects with depression. We did not measure rCBF in healthy subjects in the present study. Therefore, it was not clear whether rCBF in the patients before TMS treatment showed hyperperfusion or hypoperfusion compared with the healthy subjects.

The main outcome of the present study suggests that 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. Efficacy of HFLS in treatment-resistant depression has been shown to be correlated with increases in rCBF in several brain regions, particularly in the left prefrontal cortex.27 Therefore, there are some differences in neuroanatomical correlates of therapeutic efficacy between LFRS and HFLS. These findings may contribute to the treatment of depression using TMS.

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  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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