correlation of cerebral blood flow and treatment effects of repetitive transcranial magnetic...

Psychiatry Research Neuroimaging 115(2002) 1–14

0925-4927/02/$ - see front matter� 2002 Elsevier Science Ireland Ltd. All rights reserved.PII: S0925-4927Ž02.00032-X

Correlation of cerebral blood flow and treatment effects ofrepetitive transcranial magnetic stimulation in depressed patients�

Felix M. Mottaghy , Christian E. Keller , Massimo Gangitano , Jennifer Ly , Mark Thall ,a,b a a a a

J. Anthony Parker , Alvaro Pascual-Leone *c a,

Laboratory for Magnetic Brain Stimulation, Department of Neurology,a

Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, 330 Brookline Avenue, Kirstein Building KS 452,Boston, MA 02215, USA

Department of Nuclear Medicine (KME), Research Center Julich, 52426 Julich, Germanyb ¨ ¨Division of Nuclear Medicine, Department of Radiology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston,c

MA 02215, USA

Received 3 October 2001; received in revised form 5 April 2002; accepted 30 April 2002

Abstract

The aims of this study were to:(1) assess the effects of repetitive transcranial magnetic stimulation(rTMS) onbrain activity in depressed patients as measured by single photon emission tomography(SPECT); (2) evaluate thepredictive value of brain SPECT on the antidepressant efficacy of rTMS. Patients(ns17) received 1600 rTMSstimuli at a rate of 10 Hz, 5 days per week for 2 weeks to the left dorsolateral prefrontal cortex. Whole brain SPECTdata were acquired using Tc99m–Bicisate. Regional cerebral blood flow(rCBF) was correlated with the % changein the 28-item Hamilton Depression Rating Scale Score(D-HDRS) and a semiquantitative region of interest(ROI)analysis was conducted. Prior to rTMS there was a significant left–right asymmetry favoring the right, whereas 2weeks after the rTMS treatment this asymmetry was reversed. The rCBF in limbic structures was negatively correlatedwith the outcome and rCBF in several neocortical areas was positively correlated. Brain SPECT can provideinformation about mechanisms of action of rTMS and may have predictive value for the antidepressant efficacy ofrTMS. � 2002 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Depression; Transcranial magnetic stimulation; Single photon emission tomography

� The work was carried out at affiliations a and c. The work was presented in part at the 56th Annual Meeting of the Societyof Biological Psychiatry in New Orleans, May 3–5, 2001.

*Corresponding author. Tel.:q1-617-667-0203; fax:q1-617-975-5322.E-mail address: [email protected](A. Pascual-Leone).

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1. Introduction

In the past several years, a growing number ofstudies have reported on the antidepressant effectsof repetitive transcranial magnetic stimulation(rTMS) and its therapeutic potential in majordepression(for review, see George et al., 1999;Post et al., 1999; Sackeim, 2000; Wassermann andLisanby, 2001). The results of these studies havebeen quite variable, but more work is neededbefore rTMS can be considered a therapeutic toolof clinical utility in depression. Similarly, furtherstudies to elucidate the mechanisms underlying theantidepressant effects of rTMS are needed.Repetitive TMS appears to have similar antide-

pressant effects when applied at high frequency(5–20 Hz) to the left dorsolateral prefrontal cortex(DLPFC) (George et al., 1999) or at low frequen-cies(1 Hz) to the right DLPFC(Pascual-Leone etal., 1998; Klein et al., 1999). Some studies inves-tigated the effects of high and low rTMS frequen-cies in crossover designs looking at the change inregional glucose uptake(Kimbrell et al., 1999) orin regional cerebral blood flow(rCBF) (Speer etal., 2000). The former study suggested a relationbetween pretreatment cerebral metabolism andstimulation frequency(Kimbrell et al., 1999). Thelatter revealed a persistent increase of rCBF afterhigh frequency rTMS in widespread cortical andsubcortical brain areas, whereas low frequencyrTMS resulted in circumscribed decreases in thetargeted left prefrontal cortex(Speer et al., 2000).Several neurophysiological studies showed thatdifferent rTMS frequencies exert different effectson the activity of the stimulated cortical area(Menkes et al., 1999). Low frequency rTMS(1Hz) tends to suppress cortical excitability(Chenet al., 1997; Muellbacher et al., 2000), whilehigher frequency rTMS(5–20 Hz) increases it inmost subjects(Maeda et al., 2000a). Taken togeth-er, the studies(George et al., 1999; Pascual-Leoneet al., 1998; Klein et al., 1999) on rTMS treatmenteffects dependent on frequency and site suggest acritical asymmetry in the hemispheric contributionsto depressive symptoms.Imaging studies bearing on this issue in

depressed patients have shown divergent results.Some have shown hemispheric asymmetry in brain

metabolism, especially in the prefrontal cortex,favoring the right(Kocmur et al., 1998) or theleft side (Baxter et al., 1989; Tutus et al., 1998).Other studies have found a general ‘hypofrontality’in depressed patients(Iidaka et al., 1997). A recentmeta-analysis on 23 different studies investigatingpatients with unipolar major depression demon-strated a diffuse cortical reduction in neuronalactivity with no clear anterior–posterior gradientor left–right asymmetry(Nikolaus et al., 2000).These divergent findings might be due to thephenotypic heterogeneity of depression and itsunderlying pathophysiology in different patientgroups but could also be attributed to technicalissues of image acquisition, data analysis(e.g.selection of reference region) and study design(e.g. differences in the subjects’ medication statusor behavioral condition during scanning(Drevets,2000)).If the brain activity underlying depression is

different in different patients, individualization ofthe rTMS parameters(frequency, intensity and siteof stimulation) according to the underlying corticaldysfunction(left or right hypofrontality)may max-imize the antidepressant effects of rTMS. Maedaet al. (2000b) found that the modulatory effectsof rTMS on cortical excitability do indeed show aprominent inter-individual variability. In a follow-up study, they revealed a positive correlationbetween baseline interhemispheric cortical excita-bility as measured by positron emission tomogra-phy and antidepressant effects of rTMS to the leftDLPFC (Maeda et al., 2002). Eschweiler et al.(2000) demonstrated that the increase in leftDLPFC activity during a mental task as measuredby near infrared spectroscopy is predictive of theantidepressant effects of subsequent rTMS. Kim-brell et al.(1999) found evidence for a correlationbetween pretreatment cerebral glucose metabolismas measured by positron emission tomography andoutcome in a crossover trial using 1 Hz or 20 HzrTMS as two different treatment strategies. In asmall group of patients it was found recently thatrTMS leads to a local increase in rCBF in thetargeted left prefrontal cortex(Catafau et al.,2001). These results support the idea of activation-dependent targeting of rTMS location(Eschweileret al., 2000). In the present pilot study on a small

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Table 1Demographic data of the studied patients(ns17)

Patient Gender Age Education MDD duration No. of episodes Episode duration Axis II Melancholic ECT SPECT(years) (years) (years) (years)

Pre Post

1 M 50 12 15 3 5 NyA N N q q2 F 51 16 10 NyA Chronic Borderline N Y q q3 M 49 12 24 NyA Chronic NyA N Y q4 M 68 21 30 5 4 OCD N Y q q5 F 43 16 32 4 3 NyA N N q6 F 37 14 25 NyA Chronic Borderline N Y q q7 M 56 18 35 5 3 NyA N N q8 M 18 12 6 2 4 Avoidant Y Y q9 F 27 16 15 NyA Chronic Borderline N N q10 F 58 16 25 NyA Chronic NyA N N q11 F 61 12 35 NyA Chronic NyA N Y q q12 F 37 16 25 NyA Chronic NyA N Y q13 F 51 20 30 NyA Chronic NyA N N q14 F 33 16 12 NyA Chronic Borderline N N q q15 M 48 12 20 4 2–3 NyA N N q q16 F 44 16 12 NyA Chronic NyA N N q q17 F 38 16 17 NyA Chronic NyA N Y q q

The gender(msmale; fsfemale), years of education and duration since the unipolar major depression was first diagnosed(MDD duration) as well as the numberof episodes(NyA if chronic depression) and the duration of the current episode in years are displayed. Axis II diagnoses are shown where available and the type ofdepression(melancholic, non-melancholic) as well as whether the patients had received ECT in the past. Finally it is indicated whether pre(all patients) or post(ninepatients) SPECT scanning was performed.


Table 2Results: The prefrontalywhole brain ratio for the left prefrontal cortex(left pre; left post) as well as for the right prefrontal cortex(right pre; right post) are shown for all patients before(* pre) and for 9 patients(* post) after the rTMS treatment

Left pre Right pre Left post Right post Pre HDRS Post HDRS %-HDRS

1 0.98 0.99 0.98 0.97 36 28 222 0.94 1.02 0.86 0.88 38 16 583 1.01 1.02 28 27 44 0.94 1.04 0.90 0.99 34 36 y65 0.97 0.99 31 25 196 1.00 1.01 0.87 0.94 27 18 337 0.98 1.01 26 28 y88 0.97 0.98 33 11 679 0.98 1.00 31 31 0

10 1.06 1.00 34 23 3211 0.97 1.00 1.11 1.07 42 47 y1212 0.92 0.96 29 4 8613 0.97 1.02 29 16 4514 1.02 1.01 0.95 0.98 28 22 2115 0.88 1.02 0.84 0.86 25 25 016 0.92 1.03 0.97 0.94 28 9 6817 0.93 1.00 0.92 0.91 26 11 58Mean 0.97 1.01 0.93 0.95 30.88 22.18 28.65P-value 0.004 0.280 0.002

Pre HDRS, Hamilton Depression Rating Scale(Hamilton, 1967) before the treatment trial; post HDRS,d-HDRS after the rTMStreatment; %-HDRS, percentage of the change from pre to post HDRS. Positive values indicate a decrease ind-HDRS, negativevalues an increase.

cohort of patients, we followed up on this notionby studying the possible correlation betweenregional cerebral blood flow as measured by singlephoton emission computed tomography(SPECT)and the antidepressant effects of rTMS to the leftDLPFC.

2. Methods

2.1. Patients

The patients for the present experiment wererecruited from outpatients participating in ourrTMS treatment trial for unipolar recurrent majordepressive disorder(MDD). This trial is a parallelgroup design in which patients are randomized toreceive high(10 Hz) or low (1 Hz) frequencyrTMS to the right or left DLPFC. Previous to thestudy the patients were naıve about other treatment¨trials, in this way a possible placebo effect incorrelation with the expectation that left-sided highfrequency rTMS would be most effective wasminimized. For the purpose of the present report,

we recruited 17 consecutive patientswsix males;45"13 years; mean"standard deviation(S.D.)xwho were randomized to the ‘high frequency rTMSto the left DLPFC group. Three of the 17 patientswere left-handed(Oldfield, 1971). EEGs andthree-dimensional brain magnetic resonance imag-es (MRI) were done or reviewed from clinicallyobtained studies in the patients prior to entry intothe trial. All patients had to have normal EEGsand MRIs in order to be admitted to(or retainedin) the study. All had a normal neurological examand no contraindications for rTMS according tocurrent guidelines(Wassermann, 1998). All had alongstanding history of treatment-refractorydepression(22"9 years; ranging between twoepisodes and chronic state) having failed at leasttwo medication trials of different classes(appro-priate doses and duration) for the present depres-sion episode(duration of present episode between2 years and chronic state). Some of the patientsalready had received ECT(eighty17) in the past.MDD diagnosis was determined by the StructuredDiagnostic Interview(SCID) (First et al., 1995)

5F.M. Mottaghy et al. / Psychiatry Research Neuroimaging 115 (2002) 1–14

according to the Diagnostic and Statistical Manualfor Mental Disorders, version IV(DSM-IV) cri-teria (American Psychiatric Association, 1994).Diagnosis was confirmed by a board-certified psy-chiatrist through review of psychiatric records anda clinical interview. All patients had unipolarrecurrent depression(12 of the patients did nothave a clear inter-episode recovery and were diag-nosed to have double depression: i.e. underlyingdysthymia with major depressive disorder), addi-tional axis II diagnoses included borderline(four),obsessive-compulsive disorder(one) and avoidantpersonality. This information was gathered frompsychiatrists’ diagnoses in their medical records.In the recruitment interview of this study, a SCIDII was not done. Only one patient showed amelancholic type of depression; the others wereall non-melancholic(Table 1). Prior to inclusioninto the protocol, all patients underwent a carefultapering off of their medications and a 14-daywashout period(4 weeks in the case of fluoxetine).Therefore the SPECT studies and the rTMS trialwere conducted on medication-free patients.The reason to restrict the recruitment for this

experiment to only one arm of the parallel trial isthe capacity of our Nuclear Medicine(SPECT)service. We were only able to obtain two SPECTsper week and could not have accommodated allpatients from all treatment groups. Prior to therandomization, all patients were informed aboutthe SPECT scanning and that they would receiveone scan before and after the rTMS treatment ifthe schedule permitted. This was done to avoidsubjective expectations that could possibly accountfor placebo effects. The local Institutional ReviewBoard approved the study. The repetitive magneticstimulator was used under an InvestigationalDevice Exemption from the Food and DrugAdministration (FDA). All patients gave writteninformed consent following full explanation of theprocedures and risks(Wassermann, 1998).SPECT scans were obtained immediately before

the 10-day course of rTMS(Monday to Friday for2 consecutive weeks). Of the 17 patients, nine alsohad a second SPECT scan 2 weeks after the rTMStreatment(six females; 48"11 years) before theywere restarted on their previous medication.Because of scheduling problems, the other eight

subjects were not able to participate in the secondSPECT study.

2.2. rTMS

Repetitive TMS was performed with a MagstimSuper Rapid Stimulator(Magstim Company Ltd.,UK) equipped with a commercially available 70-mm figure-of-eight coil. Prior to stimulation themotor threshold for the right abductor policisbrevis muscle(APB) was established using stan-dard electromyographic techniques and followingthe recommendation of the International Federationfor Clinical Neurophysiology. The resting motorthreshold(RMT) was defined for each patient, asthe minimal intensity of stimulator output capableof inducing magnetically evoked potentials greaterthan 50mV peak-to-peak amplitude in at least 6out of 10 consecutive trials when TMS was appliedto the optimal scalp position with an interstimulusinterval of at least 7 s in order to avoid ‘carry-over’ effects. The location for the rTMS stimula-tion in the prefrontal cortex was determined 5 cmanterior in the same parasagittal plane as the APBspot (Pascual-Leone et al., 1996). The coil wascentered over this position and the handle of thecoil was placed 458 pointing posterior and lateralwith respect to the midsagittal line. rTMS wasapplied in twenty 8-s trains at 90% of RMT for1600 stimuli per day. The intertrain interval wasset at 52 s.

2.3. HDRS pre and post 2 weeks of treatment

The 28-item Hamilton Rating Scale for Depres-sion (HDRS) (Hamilton, 1967) was obtained atbaseline and at the end of the treatment. A board-certified psychiatrist, tested for inter-rater reliabil-ity and unaware of the patients’ treatment status,completed the ratings. The HDRS scores wereused to calculate improvement between the begin-ning and the end of the rTMS treatment(d-HDRSscore). Clinically significant response wasassumed if the decrease in HDRS score wasG50%.

2.4. SPECT imaging

Baseline whole-brain resting single photon emis-sion computed tomography(SPECT) imaging was


performed 3 days prior to the 2-week rTMStreatment in all patients. At this time, patients hadalready completed at least an 11-day washout ofmedications. In nine patients a second SPECT scanwas obtained 2 weeks after the rTMS treatment.Patients were kept in a quiet and dimly lighted

room for at least 10 min after placementof an intravenous line. A sample of 20–25 mCi(740–925 MBq) of Technetium-99m-bicisate(eth-yl cystine dimer, Tc-99m-ECD, Neurolite, DuPont-Merck Pharmaceutical Co.) was injectedintravenously and imaging was performed 20 minafter injection. While waiting for the tracer tosettle, patients were instructed to keep their eyesclosed and to relax while reclining on their backs.Sixty-four images with 128=128 pixel matriceswere obtained using a Trionix Biad gamma camera(equipped with fan beam collimators(LEURFAN)). The slice distance was 2.5 mm, and theinplane resolution 2.3 mm. A circular orbit wasused. Images were reconstructed in axial, coronal,and sagittal projections using filtered back projec-tion with a Butterworth filter order 5, cut-off 0.6.First order Chang attenuation correction was cal-culated using an elliptical region positioned toinclude the edge of the reconstructed activity. Forfurther analysis SPECT images were transferredinto analyze format using MRIcro(Chris Rorden,UK Version 1.23).

2.5. Analysis

Image analysis was performed on a standard PCequipped with a 700-MHz processor and 256 MBRAM using MatLab (Version 5.3.1 MathWorksInc, Natick, MA, USA) and the SPM99 software(The Wellcome Department of Cognitive Neurol-ogy, London, http:yywww.fil.ion.bpmf.ac.uk). TheSPECT data sets were transformed into a standard-ized stereotactic space(Talairach and Tournoux,1988). Within this normalization, the voxels of thethree-dimensional image were transformed to anisotropic voxel size of 2=2=2 mm. A Gaussianfilter with a full width at half maximums15 mmwas applied to smooth each image and to compen-sate for inter-subject differences and suppress highfrequency noise in the images.

One aim of the present study was to investigate% relationships between rCBF andd-HDRS scorein order to identify features of the SPECT imageobtained prior to the rTMS treatment, which couldbe predictive of response. Therefore, we correlatedthe improvement in HDRS score with rCBF fromthe SPECT data. Data were analyzed by using agray matter threshold of 0.8(i.e. all voxels above80% of the mean voxel value were included in theanalysis, thereby extracting mainly voxels withinthe gray matter) and a grand mean of 50 forproportional scaling. In the first step a correctedthreshold ofP-0.05 with a cluster size thresholdof 20 voxels(ks20) was used. In a hypothesisdriven approach the data were evaluated with anuncorrected more lenient threshold(P-0.05; ks20). We chose the second step because of thesmall number of patients. We were aware of thefact that this approach might lead to an arbitrarycorrelation pattern and therefore considered eachcorrelated region with respect to its relevance indepression research.In another part of the analysis SPECT data were

semi-quantitatively analyzed employing a regionof interest (ROI)-based method using OSIRIS(Vers. 3.1.2: Ligier et al., 1994). Symmetricalmultiple elliptical ROIs were placed in the graymatter of the frontal lobes across all slices display-ing the prefrontal cortex and a mean pixel valuewas calculated. To correct the individual pixelvalue, a whole-brain ROI was determined and forevery individual a ROIywhole-brain ratio wascalculated(Table 2). In the nine patients in whomwe could obtain a post SPECT, we compared theratio within and across hemispheres before andafter the rTMS treatment using pairedt-tests. Theresearcher(C.E.K.) performing the ROI analysiswas blind to the treatment outcome of the individ-ual patients.

3. Results

3.1. Clinical response

Prior to the rTMS treatment the mean HDRSscore was 30.9"4.7 ("S.D.). After the treatmentthe mean HDRS dropped to 22.2"10.9. This


Fig. 1. The correlation maxima are superimposed on a standard rendered brain. Green shows the negative correlations between rCBFandd-HDRS; red indicates region that are positively correlated(P-0.05; ks20).

change indicates a statistically significant(thoughclinically rather modest) overall improvement(paired t-testP-0.002). Only five (one male) ofthe 17 patients showed an improvement, whichmet our clinical response criterion. One of the left-handed patients was among the responders. Table

2 summarizes the results for all patients. Three ofthe patients experienced a mild worsening inHDRS scores(6–12% above baseline) followingthe rTMS course, two had no change and sixshowed a mild(not significant) clinical improve-ment(Table 2).


Table 3Stereotactic coordinates(Talairach and Tournoux, 1988) of thepositive and negative center-of-mass correlations betweend-HDRS change and regional cerebral blood flow(rCBF) areshown

Region Stereotactic Significancecoordinates

X Y z Z

Positive correlationInferior parietal left y38 y62 40 2.64Periinsular left y36 y30 14 2.65Periinsular right 36 y26 16 3.67Middle temporal left y54 y20 y10 2.54Middle temporal right 56 y38 y6 3.13Inferior frontal left y40 26 0 2.43Orbitofrontal 6 42 y16 2.26

Negative correlationParahippocampal left y26 y34 y18 2.96Thalamus 10 y4 12 2.41Precentral right 20 y8 65 2.42Anterior cingulate left y12 40 4 2.36

Only the positive correlation in the right periinsular cortexsurvived the rigorous analysis corrected for multiple compari-sons(bold). Positive correlations indicate a positive treatmenteffect if rCBF in these regions is high before the treatment orvice versa. Negative correlations indicate a positive effect ifrCBF is low before rTMS and vice versa. The significancethreshold was set atP-0.05 with a minimum cluster size ofcorrelated voxels of 20(ks20).

Fig. 2. The ratio between mean rCBF of the prefrontal cortex(DLPFC) and the whole brain are shown for all 17 patientsbefore the rTMS treatment. There was a significant differencebetween left and right in favor of the right prefrontal cortex(P-0.004). (b) The same ratio is shown for the nine patientsin whom a second SPECT scan after the rTMS treatment wasobtained.Pre stands for the SPECT scan before the rTMS treat-ment session, andpost for the scan after the treatment. Therewas a significant difference between hemispheres in these ninepatients before the treatment(P-0.008), whereas after therTMS treatment this asymmetry was no longer present.

3.2. Correlation analysis

When a corrected threshold was used, only therCBF in the right periinsular cortex correlatedsignificantly with the treatment outcome. Thiscorrelation was positive. In the less conservativeapproach with an uncorrected threshold, additionalpositive correlations were found in the right middletemporal cortex, the left periinsular, the middletemporal cortex, the inferior parietal cortex, theleft inferior frontal cortex and the midline orbitof-rontal cortex(Fig. 1; Table 3). A positive corre-lation means that the higher the measured rCBFin these areas before the rTMS treatment, thegreater the antidepressant response to the rTMScourse to the left DLPFC at a frequency of 10 Hz.There was no area showing a negative correla-

tion betweend-HDRS and rCBF using a correctedthreshold. Using a more lenient threshold, wefound in some areas that the lower the measured

rCBF before the rTMS treatment, the greater wasthe antidepressant effect of the applied rTMScourse. Negative correlations between rCBF andd-HDRS were found in the left parahippocampalregion, the thalamus, the left anterior cingulatecortex, and the right precentral cortex(Fig. 1;Table 3).

3.3. Hemispheric asymmetry

The semi-quantitative ROI analysis of the rCBFin the frontal lobe revealed a significant asymmetryprior to the rTMS treatment, favoring the rightside (mean left ratio 0.97 and mean right 1.01;d.f.s16; ts3.34; P-0.004; Table 2). Only twoof the 17 patients showed an opposite asymmetrypattern. In the nine patients in whom a secondSPECT scan was obtained 2 weeks after thetreatment, there was a significant differencebetween the two frontal lobes before the treatment


(left 0.95 and right 1.01; d.f.s8; ts3.48; P-0.008; Table 2), which vanished 2 weeks after therTMS treatment(left 0.93 and right 0.95). Com-paring within hemisphere across the different time-points, there was no significant difference for theleft but a significant decrease of right frontal rCBF(Table 2; Fig. 2).Five of the 17 patients(;29%) showed a

clinically significant response to rTMS(G50%decrease in HDRS score). All clinical respondershad a significantly lower rCBF in the left frontallobe with respect to the right side before rTMS(d.f.s4; ts3.44; P-0.03). In two of the threeresponders who were scanned 2 weeks after rTMS,a reversed asymmetry pattern was found and thethird displayed an approximation of right rCBF toleft rCBF (Table 2), suggesting a correlation ofasymmetry with treatment response. But in thisstudy a reversal of hemispheric asymmetry wasnot significantly correlated with a positive treat-ment effect (Table 2) as the other six patientsshowed comparable effects on hemisphericasymmetry.

4. Discussion

This study revealed brain areas where baselinerCBF was correlated with the antidepressant effectsof 2 weeks of rTMS at a frequency of 10 Hz tothe left DLPFC. The change in the HDRS scorewas positively correlated to the rCBF in neocorti-cal structures such as temporal, parietal, and peri-insular regions. The higher the baseline rCBF inthese areas, the more the patients benefited from10-Hz rTMS to the left DLPFC. Among these theperiinsular cortex of the right hemisphere was theonly region surviving a corrected-for-multiple-comparisons approach. Blood flow in areas belong-ing to allocortical structures, i.e. the limbic system(anterior cingulate, parahippocampal gyrus andthalamus), correlated negatively to the clinicaloutcome. The higher the baseline rCBF in theseareas, the less the antidepressant efficacy of therTMS treatment, or equivalently, the lower therCBF in the limbic system, the higher the thera-peutic effect of rTMS applied at 10 Hz to the leftDLPFC. None of the negatively correlated brainregions reached a statistical threshold corrected for

multiple comparisons. Therefore the results of thecorrelation analysis per se have to be consideredcarefully. All the brain areas we found correlatedto the antidepressant effects of rTMS have beenpreviously related to depression(Baxter et al.,1989; Nobler et al., 1994), altered emotional states(Papez, 1937; Robinson, 1997) or self-inducedemotions in healthy subjects(Lane et al., 1997;Damasio et al., 2000). For this reason we assumethat our approach using an uncorrected thresholdfor the correlation analysis did not lead to anarbitrary pattern of activation. Nevertheless, it isclear that a follow-up study with a larger cohortof patients is warranted and that the present find-ings can only be considered pilot data.The evaluation of hemispheric asymmetry using

a semiquantitative ROI analysis revealed a signif-icant hemispheric asymmetry within the prefrontalcortices favoring the right hemisphere. Theseresults are comparable with some previous studies(e.g. Baxter et al., 1989; Kocmur et al., 1998).Unmedicated unipolar depressed patients showeda significantly lower rCBF in the left frontal cortexin comparison to the right frontal cortex, whichwas adjusted during treatment(Kocmur et al.,1998). Similar to this study, the hemispheric asym-metry in our study was no longer detectable in theSPECT data obtained 2 weeks after the rTMStreatment. All patients included in our study weretreatment-resistant unipolar depressed patients andresponded to the rTMS treatment with a significantthough clinically moderate decrease in the HDRS,which potentially could be attributed to a placeboeffect. However, the subgroup of patients that werescanned after the rTMS treatment showed a rever-sal of hemispheric asymmetry in cortical activitycomparable to the reversal seen in medicationtreatment studies(e.g. Kocmur et al., 1998), whichis an indication against a placebo effect. Thiseffect on the prefrontal asymmetry could be dueto an increase in left prefrontal activity or due toa trans-synaptic reduction in right-sided prefrontalcortex activity by rTMS. However, our studydesign does not allow us to conclude that thechanges in rCBF are related to direct rTMS effects.It is possible that changes in the emotional stateand depressive symptoms may secondarily lead tothe measured changes in rCBF(Drevets, 2000).


Such changes would then be an index of thedepressive state, rather than reveal mechanisms ofaction of rTMS. The fact that we had fewertreatment responders in the current study than insome previous studies(e.g. Pascual-Leone et al.,1996; Figiel et al., 1998) makes it rather unlikelythat the observed effects can only be attributed toa placebo effect. Further studies comparing acuteeffects of single rTMS trains with sustained effectsfollowing 2 weeks of stimulation may be revealingin this regard. While there is still a lot of uncer-tainty about the mechanism of action of rTMS indepression(Wassermann and Lisanby, 2001), somestudies made mere placebo effects unlikely(Pas-cual-Leone et al., 1996; Klein et al., 1999; Georgeet al., 2000). A recent study expanded on thelasting effect of rTMS in a small group of patients.Besides a significant lasting increase in rCBF inthe targeted left prefrontal cortex, there was noother region that showed a consistent effect. In thegroup of seven patients there was no significantcorrelation between rCBF and clinical outcome asmeasured by the HDRS. Sham rTMS led to nomeasurable effects on the rCBF in the left prefron-tal cortex (Catafau et al., 2001). The advantagesof our study over the study by Catafau et al.(2001) are that: (1) we studied a homogenousgroup of patients(all had unipolar MDD); and(2)all of the patients were studied without any currentanti-depressant medication.Several studies combining rTMS and functional

neuroimaging have demonstrated that beyond localeffects in the directly targeted cortical region,rTMS exerts effects in anatomically or functionallyconnected areas(Paus et al., 1997; Fox et al.,1997; Ilmoniemi et al., 1997; Paus et al., 1998;Bohning et al., 1999, 2000; Mottaghy et al., 2000).Our stimulation site in the left prefrontal cortex isdetermined by moving 5 cm anterior to a function-ally defined area(the optimal scalp position foractivation of the right APB) that correlates wellwith the central sulcus and the primary motorcortex (Wassermann et al., 1996). In an unpubli-shed MRI study of a large number of subjects,Tomas Paus has found that this stimulation sitetargets the posterior third of the middle frontalgyrus, most likely Brodmann area 9y46 (TomasPaus, personal communication). Another recent

study also evaluated this approach to position theTMS coil in 22 subjects using a frameless stereo-tactic system(Herwig et al., 2001). In all subjectsthe posterior third of the middle frontal gyrus wastargeted; however, the variability in the corre-sponding Brodmann areas of the data that weretransformed into a normalized brain is noteworthy,but in contrast to the conclusion in the article wasstill within the anatomically and functionallydefined DLPFC. The DLPFC is highly intercon-nected with the anterior cingulate, the orbitofrontal,the temporal, and the parietal cortex(e.g. Barbas,2000). Thus our finding that the efficacy of rTMSis not correlated with the activity in the targetedleft DLPFC but mainly with the activity in func-tionally connected cortical and subcortical struc-tures is reasonable. Indeed, combining rTMS withPET, Wassermann et al.(1997) have shown acontralateral effect in the homologous area bystimulating the DLPFC and Paus et al.(2001)found suppression of activity in the anterior cin-gulate when activity in the DLPFC was increased.The middle temporal as well as the periinsular

cortex are active during different emotional states(Lane et al., 1997; Damasio et al., 2000; Liotti etal., 2000). The insular cortex has been portrayedas an integrator for sensory, affective and cognitivecomponents, all of which are necessary for normalresponse to external stimuli and normal emotionalbehavior. In unmedicated depressed patients theperiinsular cortex shows an abnormally relativeincrease in comparison to the remitted phase(forreview see Drevets, 2000). In our study we founda positive correlation between the antidepressantefficacy of rTMS and the rCBF in these structures,predominantly in the right hemisphere. The orbi-tofrontal cortex and the rostral part of the anteriorcingulate cortex receive robust projections fromthe amygdala, associated with emotional memory(Barbas, 2000). In this study we found a positivecorrelation between outcome and rCBF in theorbitofrontal cortex. Based on its multiple efferentand afferent connections to allo- and neocorticalstructures the orbitofrontal cortex is probably oneof the important key players in the ‘control’ ofemotion(Barbas, 2000; Drevets, 2000).Particularly interesting are the findings correlat-

ing antidepressant outcome and rCBF in limbic


structures(Papez, 1937) not directly targeted byrTMS. In a recent study Mayberg et al.(2000)found that chronic treatment and clinical responseto fluoxetine are associated with a pattern ofsubcortical and limbic hypometabolism and corti-cal hypermetabolism. Consistent with these find-ings, in our study we found that the lower theactivity in allocortical regions and the higher theactivity in cortical areas, the more likely was theantidepressant effect of rTMS. In the hypothesis-driven approach we found a negative correlationbetween treatment effects and baseline rostral ante-rior cingulate activity. The ‘affective’ part of theanterior cingulate is more rostral with regard tothe ‘cognitive’ part(Bush et al., 2000). These twosub-territories are distinguishable, based on con-vergent data from cytoarchitectural, lesion, electro-physiology, and imaging studies(Devinsky et al.,1995; Mayberg et al., 1997; Bush et al., 2000).The anterior cingulate cortex has been describedas the only specific region with a potential to bepredictive for drug treatment response in depressedpatients(Mayberg et al., 1997). Mayberg et al.(1997) found that a relative hypermetabolism inthe rostral part of the anterior cingulate allowsdifferentiating eventual treatment responders fromnon-responders. They argue that cingulate hyper-metabolism may represent an adaptive response todepression and failure of this adaptation may leadto poor outcome(Mayberg et al., 1997). A com-parable correlation was found for treatmentresponders to sleep deprivation(Wu et al., 1999).For our study we only recruited patients who hadfailed at least two medication trials and wouldtherefore be classified as a poor outcome group.Therefore, comparison with Mayberg et al.’s orWu et al.’s findings is difficult. Indeed, our find-ings may seem to contradict these results sinceamong our treatment-resistant patients, the lowerthe rCBF as an indirect marker of metabolism(Lou et al., 1987) in the anterior cingulate, thehigher the likelihood of an antidepressant effect ofrTMS and vice versa. Nevertheless, considered ina different way, our results appear more in linewith Mayberg’s hypothesis. Our findings revealthat the greater the ability of rTMS to trans-synaptically increase activity in the anterior cin-gulate area, the greater could be the eventual

antidepressant effects. Due to the small number ofresponders we were not able to obtain statisticalcomparisons of the anterior cingulate rCBF pre vs.post that could confirm this hypothesis. But Pauset al. have shown that rTMS to the DLPFC doesindeed increase the activity in the anterior cingu-late in this manner(Paus et al., 2001). Therefore,it seems reasonable to hypothesize that the DLPFCis a window for trans-synaptic effects of rTMSonto anterior cingulate and other allocortical struc-tures and that it is the modulation of activity inthese subcortical regions that accounts for theantidepressant effects. This hypothesis is also inline with the results of a recent rTMS trial thatdemonstrated that in depressed adults, 10 days ofprefrontal TMS selectively affected prefrontal andlimbic activity (Teneback et al., 1999) in respond-ers and less in non-responders.The fact that only five of the 17 patients showed

a clinically significant effect of the 2-week rTMSprotocol with left prefrontal cortex stimulationcould account for the statistically rather weakresults in the current study. Only the right periin-sular cortex survived the correction for multiplecomparisons. Therefore the results have to beconsidered as hypothesis-driven pilot data. Furtherdouble-blind and placebo-controlled studies onlarger cohorts of patients have to be carried out toconfirm or disprove the current results.

Acknowledgments

We thank Meredith Hickory, Julian Keenan,Fumiko Maeda, Dawn Mechanic, Margaret O’Con-nor, Rafael Romero, Shirlene Sampson, Jose M.Tormos, and Bernard Vaccaro for their help withdifferent aspects of the rTMS trial. FMM wassupported by a grant of the Deutsche Forschungs-gemeinschaft(DFG MO 871y3-1). Our researchwas supported by the National Institute of MentalHealth (RO1MH60734, RO1MH57980), theNational Alliance for Research in Schizophreniaand Depression, the Stanley Vada Foundation, andthe General Clinical Research Center at Beth IsraelDeaconess Medical Center(NCRR MO1RR01032).


References

American Psychiatric Association, 1994. DSM-IV: Diagnosticand Statistical Manual of Mental Disorders, 4 ed. Americanth

Psychiatric Press, Washington, DC.Barbas, H., 2000. Connections underlying the synthesis of

cognition, memory, and emotion in primate prefrontal cor-tices. Brain Research Bulletin 52, 319–330.

Baxter, L.R., Schwartz, J.M., Phelps, M.E., Mazziotta, J.C.,Guze, B.H., Selin, C.E., Gerner, R.H., Sumida, R.M., 1989.Reduction of prefrontal cortex glucose metabolism commonto three types of depression. Archives of General Psychiatry46, 243–250.

Bohning, D.E., Shastri, A., McConnell, K.A., Nahas, Z.,Lorberbaum, J.P., Roberts, D.R., Teneback, C., Vincent,D.J., George, M.S., 1999. A combined TMSyfMRI study ofintensity-dependent TMS over motor cortex. BiologicalPsychiatry 45, 385–394.

Bohning, D.E., Shastri, A., Wassermann, E.M., Ziemann, U.,Lorberbaum, J.P., Nahas, Z., Lomarev, M.P., George, M.S.,2000. BOLD-fMRI response to single-pulse transcranialmagnetic stimulation(TMS). Journal of Magnetic Reso-nance Imaging 11, 569–574.

Bush, G., Luu, P., Posner, M.I., 2000. Cognitive and emotionalinfluences in anterior cingulate cortex. Trends in CognitiveScience 4, 215–222.

Catafau, A.M., Perez, V., Gironell, A., Martin, J.C., Kulisevsky,J., Estorch, M., Carrio, I., Alvarez, E., 2001. SPECTmapping of cerebral activity changes induced by repetitivetranscranial magnetic stimulation in depressed patients. Apilot study. Psychiatry Research: Neuroimaging 106,151–160.

Chen, R., Classen, J., Gerloff, C., Celnik, P., Wassermann,E.M., Hallett, M., Cohen, L.G., 1997. Depression of motorcortex excitability by low-frequency transcranial magneticstimulation. Neurology 48, 1398–1403.

Damasio, A.R., Grabowski, T.J., Bechara, A., Damasio, H.,Ponto, L.L., Parvizi, J., Hichwa, R.D., 2000. Subcorticaland cortical brain activity during the feeling of self-gener-ated emotions. Nature Neuroscience 3, 1049–1056.

Devinsky, O., Morrell, M.J., Vogt, B.A., 1995. Contributionsof anterior cingulate cortex to behaviour. Brain 118,279–306.

Drevets, W.C., 2000. Neuroimaging studies of mood disorders.Biological Psychiatry 48, 813–829.

Eschweiler, G.W., Wegerer, C., Schlotter, W., Spandl, C.,Stevens, A., Bartels, M., Buchkremer, G., 2000. Left pre-frontal activation predicts therapeutic effects of repetitivetranscranial magnetic stimulation(rTMS) in major depres-sion. Psychiatry Research: Neuroimaging 99, 161–172.

Figiel, G.S., Epstein, C., McDonald, W.M., Amazon-Leece, J.,Figiel, L., Saldivia, A., Glover, S., 1998. The use of rapid-rate transcranial magnetic stimulation(rTMS) in refractorydepressed patients. Journal of Neuropsychiatry and ClinicalNeuroscience 10, 20–25.

First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B.W., 1995.Structured Clinical Interview for DSM-IV Axis I Disorders

(SCID-I) Version 2.0. Biometrics Research Department,New York State Psychiatric Institute, New York.

Fox, P., Ingham, R., George, M.S., Mayberg, H., Ingham, J.,Roby, J., Martin, C., Jerabek, P., 1997. Imaging humanintra-cerebral connectivity by PET during TMS. Neuro-Report 8, 2787–2791.

George, M.S., Lisanby, S.H., Sackeim, H.A., 1999. Transcran-ial magnetic stimulation: applications in neuropsychiatry.Archives of General Psychiatry 56, 300–311.

George, M.S., Nahas, Z., Molloy, M., Speer, A.M., Oliver,N.C., Li, X.B., Arana, G.W., Risch, S.C., Ballenger, J.C.,2000. A controlled trial of daily left prefrontal cortex TMSfor treating depression. Biological Psychiatry 48, 962–970.

Hamilton, M., 1967. Development of a rating scale for primarydepressive illness. British Journal of Social and ClinicalPsychology 6, 278–296.

Herwig, U., Padberg, F., Unger, J., Spitzer, M., Schonfeldt-Lecuona, C., 2001. Transcranial magnetic stimulation intherapy studies: examination of the reliability of ‘standard’coil positioning by neuronavigation. Biological Psychiatry50, 58–61.

Iidaka, T., Nakajima, T., Suzuki, Y., Okazaki, A., Maehara, T.,Shiraishi, H., 1997. Quantitative regional cerebral flowmeasured by Tc-99M HMPAO SPECT in mood disorder.Psychiatry Research: Neuroimaging 68, 143–154.

Ilmoniemi, R.J., Virtanen, J., Ruohonen, J., Karhu, J., Aronen,H.J., Naatanen, R., Katila, T., 1997. Neuronal responses tomagnetic stimulation reveal cortical reactivity and connec-tivity. NeuroReport 8, 3532–3537.

Kimbrell, T.A., Little, J.T., Dunn, R.T., Frye, M.A., Greenberg,B.D., Wassermann, E.M., Repella, J.D., Danielson, A.L.,Willis, M.W., Benson, B.E., Speer, A.M., Osuch, E., George,M.S., Post, R.M., 1999. Frequency dependence of antide-pressant response to left prefrontal repetitive transcranialmagnetic stimulation(rTMS) as a function of baselinecerebral glucose metabolism. Biological Psychiatry 46,1603–1613.

Klein, E., Kreinin, I., Chistyakov, A., Koren, D., Mecz, L.,Marmur, S., Ben-Shachar, D., Feinsod, M., 1999. Therapeu-tic efficacy of right prefrontal slow repetitive transcranialmagnetic stimulation in major depression: a double-blindcontrolled study. Archives of General Psychiatry 56,315–320.

Kocmur, M., Milcinski, M., Budihna, N.V., 1998. Evaluationof brain perfusion with technetium-99m bicisate single-photon emission tomography in patients with depressivedisorder before and after drug treatment. European Journalof Nuclear Medicine 25, 1412–1414.

Lane, R.D., Reiman, E.M., Ahern, G.L., Schwartz, G.E.,Davidson, R.J., 1997. Neuroanatomical correlates of happi-ness, sadness, and disgust. American Journal of Psychiatry154, 926–933.

Liotti, M., Mayberg, H.S., Brannan, S.K., McGinnis, S.,Jerabek, P., Fox, P.T., 2000. Differential limbic–corticalcorrelates of sadness and anxiety in healthy subjects: impli-cations for affective disorders. Biological Psychiatry 48,


30–42.Ligier, Y., Ratib, O., Logean, M., Girard, C., 1994. OSIRIS: a

medical image manipulation system. M.D. Computing Jour-nal 11, 212–218.

Lou, H.C., Edvinsson, L., MacKenzie, E.T., 1987. The conceptof coupling blood flow to brain function: revision required?Annals of Neurology 22, 289–297.

Maeda, F., Keenan, J.P., Tormos, J.M., Topka, H., Pascual-Leone, A., 2000. Modulation of corticospinal excitability byrepetitive transcranial magnetic stimulation. Clinical Neu-rophysiology 111, 800–805.

Maeda, F., Keenan, J.P., Tormos, J.M., Topka, H., Pascual-Leone, A., 2000. Interindividual variability of the modula-tory effects of repetitive transcranial magnetic stimulationon cortical excitability. Experimental Brain Research 133,425–430.

Maeda, F., Keenan, J.P., Freund, S., Sampson, S., Vaccaro, B.,Birnbaum, R., Pascual-Leone, A., 2002. Transcranial mag-netic stimulation(TMS) in the treatment of depression:predictive value of modulatory effects on cortico-spinalexcitability, Submitted.

Mayberg, H.S., Brannan, S.K., Mahurin, R.K., Jerabek, P.A.,Brickman, J.S., Tekell, J.L., Silva, J.A., McGinnis, S., Glass,T.G., Martin, C.C., Fox, P.T., 1997. Cingulate function indepression: a potential predictor of treatment response.NeuroReport 8, 1057–1061.

Mayberg, H.S., Brannan, S.K., Tekell, J.L., Silva, J.A., Mahu-rin, R.K., McGinnis, S., Jerabek, P.A., 2000. Regionalmetabolic effects of fluoxetine in major depression: serialchanges and relationship to clinical response. BiologicalPsychiatry 48, 830–843.

Menkes, D.L., Bodnar, P., Ballesteros, R.A., Swenson, M.R.,1999. Right frontal lobe slow frequency repetitive transcran-ial magnetic stimulation(SF r-TMS) is an effective treat-ment for depression: a case-control pilot study of safety andefficacy. Journal of Neurology, Neurosurgery and Psychiatry67, 113–115.

Mottaghy, F.M., Krause, B.J., Kemna, L.J., Topper, R., Tell-mann, L., Beu, M., Pascual-Leone, A., Muller-Gartner, H.W.,2000. Modulation of the neuronal circuitry subserving work-ing memory in healthy human subjects by repetitive trans-cranial magnetic stimulation. Neuroscience Letters 280,167–170.

Muellbacher, W., Ziemann, U., Boroojerdi, B., Hallett, M.,2000. Effects of low-frequency trans-cranial magnetic stimulation on motor excitability and basicmotor behavior. Clinical Neurophysiology 111, 1002–1007.

Nikolaus, S., Larisch, R., Beu, M., Vosberg, H., Muller-Gartner, H.W., 2000. Diffuse cortical reduction of neuronalactivity in unipolar major depression: a retrospective anal-ysis of 337 patients and 321 controls. Nuclear MedicineCommunications 21, 1119–1125.

Nobler, M.S., Sackeim, H.A., Prohovnik, I., Moeller, J.R.,Mukherjee, S., Schnur, D.B., Prudic, J., Devanand, D.P.,1994. Regional cerebral blood flow in mood disorders, III.Treatment and clinical response. Archives of General Psy-chiatry 51, 884–897.

Oldfield, R.C., 1971. The assessment and analysis of handed-ness: the Edinburgh Inventory. Neuropsychologia, 997–1013.

Papez, J.W., 1937. A proposed mechanism of emotion.Archives of Neurological Psychology 38, 725–743.

Pascual-Leone, A., Rubio, B., Pallardo, F., Catala, M.D., 1996.Rapid-rate transcranial magnetic stimulation of left dorso-lateral prefrontal cortex in drug-resistant depression. Lancet348, 233–237.

Pascual-Leone, A., Tormos, J.M., Keenan, J., Tarazona, F.,Canete, C., Catala, M.D., 1998. Study and modulation ofhuman cortical excitability with transcranial magnetic stim-ulation. Journal of Clinical Neurophysiology 15, 333–343.

Paus, T., Jech, R., Thompson, C.J., Comeau, R., Peters, T.,Evans, A.C., 1997. Transcranial magnetic stimulation duringpositron emission tomography: a new method for studyingconnectivity of the human cerebral cortex. Journal of Neu-roscience 17, 3178–3184.

Paus, T., Jech, R., Thompson, C.J., Comeau, R., Peters, T.,Evans, A.C., 1998. Dose-dependent reduction of cerebralblood flow during rapid-rate transcranial magnetic stimula-tion of the human sensorimotor cortex. Journal of Neuro-physiology 79, 1102–1107.

Paus, T., Castro-Alamancos, M., Petrides, M., 2001. Cortico-cortical connectivity of the human mid-dorsolateral frontalcortex and its modulation by repetitive transcranial magneticstimulation. European Journal of Neuroscience 14,1405–1411.

Post, R.M., Kimbrell, T.A., McCann, U.D., Dunn, R.T., Osuch,E.A., Speer, A.M., Weiss, S.R., 1999. Repetitive transcranialmagnetic stimulation as a neuropsychiatric tool: presentstatus and future potential. Journal of ECT 15, 39–59.

Robinson, R.G., 1997. Mood disorders secondary to stroke.Seminars in Clinical Neuropsychiatry 2, 244–251.

Sackeim, H.A., 2000. Repetitive transcranial magnetic stimu-lation: what are the next steps? Biological Psychiatry 48,959–961.

Speer, A.M., Kimbrell, T.A., Wassermann, E.M., Di Repella,J., Willis, M.W., Herscovitch, P., Post, R.M., 2000. Oppositeeffects of high and low frequency rTMS on regional brainactivity in depressed patients. Biological Psychiatry 48,1133–1141.

Talairach, J., Tournoux, P., 1988. Co-planar Stereotactic Atlasof the Human Brain: Three-dimensional Proportional Sys-tem: An Approach to Cerebral Imaging. Thieme, Stuttgart.

Teneback, C.C., Nahas, Z., Speer, A.M., Molloy, M., Stallings,L.E., Spicer, K.M., Risch, S.C., George, M.S., 1999. Chang-es in prefrontal cortex and paralimbic activity in depressionfollowing two weeks of daily left prefrontal TMS. Journalof Neuropsychiatry and Clinical Neuroscience 11, 426–435.

Tutus, A., Simsek, A., Sofuoglu, S., Nardali, M., Kugu, N.,Karaaslan, F., Gonul, A.S., 1998. Changes in regionalcerebral blood flow demonstrated by single photon emissioncomputed tomography in depressive disorders: comparisonof unipolar vs. bipolar subtypes. Psychiatry Research: Neu-roimaging 83, 169–177.


Wassermann, E.M., 1998. Risk and safety of repetitive trans-cranial magnetic stimulation: report and suggested guide-lines from the International Workshop on the Safety ofRepetitive Transcranial Magnetic Stimulation, June 5–7,1996. Electroencephalography and Clinical Neurophysiolo-gy 108, 1–16.

Wassermann, E.M., Lisanby, S.H., 2001. Therapeutic applica-tion of repetitive transcranial magnetic stimulation: a review.Clinical Neurophysiology 112, 1367–1377.

Wassermann, E.M., Wang, B., Zeffiro, T.A., Sadato, N., Pas-cual-Leone, A., Toro, C., Hallett, M., 1996. Locating the

motor cortex on the MRI with transcranial magnetic stimu-lation and PET. Neuroimage 3, 1–9.

Wassermann, E.M., Kimbrell, T.A., George, M.S., et al., 1997.Local and distant changes in cerebral glucose metabolismduring repetitive transcranial magnetic stimulation(rTMS).Neurology 48, A107.

Wu, J., Buchsbaum, M.S., Gillin, J.C., Tang, C., Cadwell, S.,Wiegand, M., Najafi, A., Klein, E., Hazen, K., Bunney,W.E., Fallon, J.H., Keator, D., 1999. Prediction of antide-pressant effects of sleep deprivation by metabolic rates inthe ventral anterior cingulate and medial prefrontal cortex.American Journal of Psychiatry 156, 1149–1158.

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