Transcranial Magnetic Stimulation in the Assessment of Motor Cortex Excitability and Treatment of Drug-Resistant Major Depression

IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING, VOL. 21, NO. 3, MAY 2013 391

Transcranial Magnetic Stimulation in the Assessmentof Motor Cortex Excitability and Treatment of

Drug-Resistant Major DepressionC. Spampinato, Member, IEEE, E. Aguglia, C. Concerto, M. Pennisi, G. Lanza, R. Bella, M. Cantone,

G. Pennisi, I. Kavasidis, and D. Giordano, Member, IEEE

Abstract—Major depression is one of the leading causes of dis-abling condition worldwide and its treatment is often challengingand unsatisfactory, since many patients become refractory topharmacological therapies. Transcranial magnetic stimulation(TMS) is a noninvasive neurophysiological investigation mainlyused to study the integrity of the primary motor cortex excitabilityand of the cortico-spinal tract. The development of paired-pulseand repetitive TMS (rTMS) paradigms has allowed investigatorsto explore the pathophysiology of depressive disorders and otherneuropsychiatric diseases linked to brain excitability dysfunctions.Repetitive transcranial magnetic stimulation has also therapeuticand rehabilitative capabilities since it is able to induce changesin the excitability of inhibitory and excitatory neuronal networksthat may persist in time. However, the therapeutic effects of rTMSon major depression have been demonstrated by analyzing onlythe improvement of neuropsychological performance. The aimof this study was to investigate cortical excitability changes on12 chronically-medicated depressed patients (test group) afterrTMS treatment and to correlate neurophysiological findingsto neuropsychological outcomes. In detail, we assessed differentparameters of cortical excitability before and after active rTMSin the test group, then compared to those of 10 age-matcheddepressed patients (control group) who underwent sham rTMS. Inline with previous studies, at baseline both groups exhibited a sig-nificant interhemispheric difference of motor cortex excitability.This neurophysiological imbalance was then reduced in the pa-tients treated with active rTMS, resulting also in a clinical benefitas demonstrated by the improvement in neuropsychological testscores. On the contrary, after sham rTMS, the interhemisphericdifference was still evident in the control group. The reportedclinical benefits in the test group might be related to the plasticremodeling of synaptic connection induced by rTMS treatment.

Index Terms—Biomedical signal processing, medical informa-tion systems, patient rehabilitation.

Manuscript received October 15, 2011; revised April 05, 2012, July 26, 2012,January 20, 2013; accepted March 07, 2013. Date of publication April 03, 2013;date of current version May 04, 2013.C. Spampinato, I. Kavasidis, and D. Giordano are with the Department of

Electrical, Electronic and Computer Engineering, University of Catania, 95125Catania, Italy (e-mail: [email protected]; [email protected];[email protected]).E. Aguglia and C. Concerto are with Unit of Psychiatry, Department

of Clinical and Molecular Biomedicine, 95123 Catania, Italy (e-mail: [email protected]; [email protected]).M. Pennisi is with the Department of Chemistry, University of Catania,

Catania 95125, Italy (e-mail: [email protected]).G. Lanza, R. Bella, M. Cantone, and G. Pennisi are with the Department GF

Ingrassia, Section of Neurosciences, University of Catania, 95123 Catania, Italy(e-mail: [email protected]; [email protected]; [email protected]; [email protected]).Color versions of one or more of the figures in this paper are available online

at http://ieeexplore.ieee.org.Digital Object Identifier 10.1109/TNSRE.2013.2256432

I. INTRODUCTION

A. Major Depression

M AJOR depression is one of the leading causes of dis-ease burden worldwide. Its impact on society with

regard to human suffering and economic charge is enormousand is even projected to increase in upcoming decades [1].Because of relapses and recurrences, major depression tendsto be a chronic illness and chronic depressive episodes areassociated with disability, functional impairment, and socioe-conomic disadvantage [2]. Treatment is often challengingand often consists of complex multimodal therapies includingpharmacotherapy, psychotherapy, and psychiatric rehabilitationtherapy. However, more than 60% of the treated patients re-spond unsatisfactorily and almost one fifth becomes refractoryto these therapies at long-term follow-up [3].A common problem in pharmacotherapy is the possible non-

response to the first antidepressant treatment: approximately30% of depressed patients do not show sufficient improvementsafter the first course of adequate antidepressant treatment and afurther 20% discontinue due to tolerability problems. Half ofpatients who do not respond adequately to a first course also failto respond to a second antidepressant treatment trial. If severalantidepressant treatment trials have been inefficient, even lowerresponse rates after switching to other drugs may be observed[4]. Given the pervasive nature of depression and the need formore effective, safer, and more socially acceptable therapeuticstrategies, alternative approaches are being investigated, suchas repetitive transcranial magnetic stimulation (rTMS) [5].

B. Transcranial Magnetic Stimulation

Transcranial magnetic stimulation (TMS) has become in-creasingly popular, with its relatively ease of administration,noninvasivity, very few side effects and wide range of potentialapplications. It is used to study the central motor pathways [6],to map motor and cognitive functions, to study neural networks,and to modulate brain function with a potential therapeutic aim[7], [8]. The most traditional use of TMS is to study the centralmotor pathways and motor cortical excitability in healthy sub-jects and in patients with neurological disorders [6], [9], [10].Recent findings on motor system abnormalities in neuropsychi-atric disorders and better insights into the mechanisms of actionof various TMS techniques suggest the systematic explorationof TMS for investigating the pathophysiology of psychiatricdisorders and the assessment of treatment outcomes [11], [12].

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392 IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING, VOL. 21, NO. 3, MAY 2013

A variety of TMS measures of motor cortex excitability canbe obtained, each related to distinct neurobiological processes.Resting motor threshold (rMT) is believed to reflect the mem-brane excitability of corticospinal motor neurons, which ismainly dependent on the ion channel conductivity and on theexcitatory interneurons that project into these neurons [13].Cortical silent period (CSP) refers to a suppression of theelectromyographic activity during a voluntary contraction ofthe target muscle and depends, at least in part, on inhibitorymechanisms at the level of the motor cortex, probably mediatedby gamma-aminobutyric acid (GABA)-b receptors [14]. Thepaired pulse TMS paradigm couples a suprathreshold magneticstimulus with a preceding subthreshold stimulus and the re-sponse to the paired stimuli may be increased (facilitation) ordecreased (inhibition) depending on the interstimulus interval(ISI), measured in milliseconds (ms): at short ISI (1–4 ms) theconditioning stimulus determines an intracortical inhibition(ICI) with respect to the test stimulus, whereas at longer ISI( ms) the effect is an intracortical facilitation (ICF) [11].ICI and ICF interactions are probably related to the balanceof GABAergic, dopaminergic and glutamatergic transmissions[14]. Using the paired pulse TMS technique, inhibitory/facili-tatory curves at various ISI provide useful indications on motorcortex excitability.

C. Repetitive Transcranial Magnetic Stimulation

The principle of rTMS is single TMS pulses delivered intrains, an approach that transiently influences the functionof stimulated and connected brain areas [15], [16], mainlydepending on the frequency of stimulation. Repetitive TMS athigh frequency ( Hz) transiently enhances motor excitability[17], whereas slow rTMS (1 Hz) transiently depresses ex-citability [6]. Both frequencies of stimulation, however, mayhave similar positive effects in some pathological conditions,depending on the site of stimulation [18]. Repetitive TMS hastherapeutic and rehabilitative applications, since the effects ofrepeated sessions may persist in time [19]. Most TMS studies,but not all [20], reported an interhemispheric imbalance offrontal cortex activities in patients with major depression, infavour of a reduced excitability of the motor cortex in the lefthemisphere [21]–[24]. The underlying mechanisms and therelevance of these abnormalities are unclear due to the hetero-geneity of the groups and medication status. These findingshave had practical implications for the development of rTMSprotocols in the treatment of major depression, which is thepsychiatric field where rTMS has received more indications andapprovals worldwide [25]. Most of these rTMS studies haveused high-frequency (5–20 Hz) stimulation targeted on the leftdorsolateral prefrontal cortex (DLPFC). High-frequency rTMShas shown safety and effectiveness in pharmacotherapy-resis-tant major depressed patients compared to simulated (sham)stimulation in several randomized controlled trials [2], [26],[27], [18], [28] and meta-analyses [29]–[31]. Even slow fre-quency stimulation applied to the right DLPFC has shownsimilar responses to left-sided high-frequency rTMS treatment[32], [33]. Recently, new protocols, such as theta-burst stimu-lation (triple-pulse 50 Hz burst given at the rate of 5 Hz), havebeen adopted and demonstrated to be safe, well tolerated and

effective when applied on the left or right DLPFC of depressedpatients [34].In October 2008, the Food and Drug Administration (FDA)

approved rTMS for the add-on treatment of drug-resistant majordepression and gave the first instructions on how to use high-fre-quency TMS [35]. Currently, rTMS in the treatment of pharma-coresistant major depression as an “augmentation” to pharma-cological treatment is one of the most exciting fields of clinicaland research interest [36]. Nevertheless, most previous studieshave evaluated the therapeutic effects of rTMS on depressiononly based on improvement at neuropsychological performance[1]. On the contrary, to the best of our knowledge, no studyhas comprehensively examined changes of cortical excitabilityinduced by rTMS and related such modifications to neuropsy-cological assessment scores. In fact, the existing studies eitherevaluated neurophysiological parameters only before and notafter rTMS [22], [24] or performed a limited assessment ofmotor cortex excitability by only investigating, for instance, thechanges in motor threshold [23]. Therefore, in this study weaim to assess neurophysiological modifications and clinical ef-fects of high-frequency rTMS on the left DLPFC in associationwith pharmacological treatment in a sample of 12 drug-resis-tant major depression patients (test group). In order to have acomprehensive and objective evaluation of the treatment, wemeasured different single and paired-pulse TMS parameters ofcortical excitability. The results of neuropsychological tests be-fore and after active rTMS on the test group were comparedto those of 10 age-matched depressed patients (control group)who underwent sham rTMS. The remainder of the paper is asfollows. The next section describes the subjects assessment, theused procedures for TMS and rTMS and the statistical analysis.Section III discusses the achieved results, whereas Section IVprovides the discussion of the results compared to the literature.Finally, Section V gives the conclusions and the future direc-tions of rTMS in the treatment of drug resistant major depres-sion.

II. MATERIALS AND METHODS

A. Subjects Description

A sample of 12 chronically depressed right-handed subjects(eight males and four females, mean age , meaneducation ) was consecutively recruited betweenJune 2011 and February 2012 from the Unit of Psychiatry, Uni-versity of Catania, Catania, Italy. Mean age at depression onsetwas years, with the last two years of insufficientresponse to pharmacological treatment (mean duration of thecurrent episode months). Including the currentepisode, eight patients had four major depressive episodes, theremaining four patients had five or more episodes. A controlgroup of 10 depressed patients (six males and four females,mean age mean education ) was alsorecruited between October 2011 and February 2012 from theDepartment of Psychiatry. The average age at diagnosis was

, eight patients had four depressive episodes andthe other two had five or more episodes (including the currentepisode). Mean duration of the current episodes was

months.

SPAMPINATO et al.: TRANSCRANIAL MAGNETIC STIMULATION IN THE ASSESSMENT OF MOTOR CORTEX EXCITABILITY AND TREATMENT 393

B. Subjects Assessment

Inclusion criteria were: age 40–65 years; a severe major de-pressive episode meeting Diagnostic and Statistical Manual ofMental Disorders Fourth Edition Text Revision (DSM-IV-TR)criteria (World Health Organization, 1992; American Psychi-atric Association, 2000); a score points to the 21-itemHamilton Rating Scale for Depression (HDRS) [37] or a score

to the Montgomery Asberg Depression Rating Scale(MADRS), [38]; drug-resistance to three adequate courses ofantidepressants from at least two different classes in the currentmajor depressed episode as assessed by the AntidepressantTreatment History Form [39].Exclusion criteria included: presence of current psychotic

features, history of any nonmood psychotic disorder, currentneurological disease, pregnancy, and any contraindicationfor TMS (hypoacusis, tinnitus, severe head trauma, cochlearimplants, metal in the brain, skull, or elsewhere in the body,implanted neurostimulator, cardiac pacemaker or intracardiaclines, medication infusion device, history of epilepsy, predis-position to seizure).General and neurological exams of all participants were

unremarkable. Subsequently, all patients underwent a neu-ropsychological battery of tests for the evaluation of differentfrontal lobe abilities, both before and after rTMS, includingthe Frontal Assessment Battery [40] and the Stroop ColorWord Test interference (normative values collected froman Italian population sample, Stroop T score) [41]. A brainneuroimaging study (computerized tomography or magneticresonance imaging) was acquired to exclude major neurolog-ical diseases. Patients were not withdrawn from psychotropicdrugs, but their doses were required to remain stable in the fourweeks preceding the trial and for its entire duration, except forbenzodiazepines or equivalents, which was changed or addedin case of insomnia (two test group patients and two controlgroup patients took benzodiazepine twice). The test group wastreated with: selective serotonin reuptake inhibitors (SSRI),tricyclic antidepressant, atypical antipsychotic drugs and moodstabilizers (six patients); serotonin noradrenaline reuptake in-hibitors (SNRI), tricyclic antidepressant, atypical antipsychoticdrugs and mood stabilizers (four patients); SNRI, atypicalantipsychotic drugs and mood stabilizers (two patients). Eightpatients were medicated with Lithium and four with Valproate.The control group was treated with: SSRI, Tricyclic antidepres-sant, atypical antipsychotic drugs and mood stabilizers (fivepatients); SNRI, tricyclic antidepressant, atypical antipsychoticdrugs and mood stabilizers (five patients). Eight patients as-sumed Lithium, whereas the other two were medicated withValproate. Table I shows the pharmacological treatment (dailydosages) assumed by each patient of the proposed study.Treatment with mood stabilizers was used as an augmentationtherapy due to the antidepressant drugs resistance. None of thepatients was diagnosed as bipolar.Effectiveness data was gathered at baseline and again at

week four. Clinician-rating of depressive symptoms includedthe HDRS and MADRS. All participants provided writteninformed consent at enrollment and the study was conductedaccording to the latest version of the Declaration of Helsinkiand approved by the local ethic committee.

TABLE ICURRENT PHARMACOLOGICAL TREATMENT (DAILY DOSAGES)

ASSUMED BY EACH PATIENT

C. Transcranial Magnetic Stimulation Procedures

Motor evoked potentials (MEPs) of the right and left firstdorsal interosseous muscles were elicited using a Magstim 200stimulator (The Magstim Company, Whitland, U.K.) connectedto a 70 mm figure-of-eight coil. The coil was applied with thehandle pointing backwards and laterally, at an angle of 45 to thesagittal plane, on the optimum site of stimulation which consis-tently yielded the largest MEP (“hot spot”). Electromyographicactivity was recorded from a silver/silverchloride surface ac-tive electrode placed over the motor point of the target musclewith the reference electrode placed distally at themetacarpopha-langeal joint of the index finger. Motor responses were ampli-fied and filtered (bandwidth 3–3000 Hz) with gains of 100 Vand 5 mV/div. Resting motor threshold (rMT) was defined, ac-cording to the IFCN Committee recommendation [43], as thelowest stimulus intensity able to elicit MEPs of an amplitude

V in at least 5 of 10 trials, with the muscle at rest. Thecortical silent period (CSP) was determined with an approxi-mately 50% of maximum tonic voluntary contraction of the firstdorsal interosseous muscles, induced by single TMS pulses de-livered at 130% of rMT. Themean CSP duration of five rectifiedtrials was calculated. Intracortical inhibition (ICI) and intracor-tical facilitation (ICF) were studied using the conditioning-testparadigm, consisting of applying two magnetic stimuli throughmagnetic stimulators, as described by Kujirai et al. [44]. Theconditioning stimulus was applied at 80% of the subject’s motorthreshold (rMT), and the intensity of the test stimulus was setat 130% of the rMT. The interstimulus intervals (ISIs) testedwere 2, 3, 10, and 15 ms. Ten trials for each ISI, were recordedrandomly with an 8-s interval between each trial. The responseswere expressed as the ratio of the MEP amplitude produced bypaired stimulation to that produced by test stimulation alone.


Fig. 1. Architecture of the system proposed in [42].

Hardware setting, data collection and offline processing/anal-ysis were performed by the tool described in Section II-E. Allmeasurements were conducted while subjects were seated ina comfortable chair with continuous electromyographic mon-itoring to ensure either a constant level of electromyographicactivity during tonic contraction or complete relaxation at rest.The same procedure was performed for all participants after theend of the last rTMS session.

D. Repetitive Transcranial Magnetic Stimulation Protocol

According to FDA recommendations [35], high-frequencyrTMS (10 Hz) was applied on the left dorsolateral prefrontalcortex (DLPFC) using a “Magstim Superapid” stimulator (TheMagstim Company, Whitland, U.K.), connected to a 70 mmfigure-of-eight coil. The stimulation point was identified bymoving the coil 5 cm anteriorly in a parasagittal plane from the“hot spot” for the right first dorsal interosseous (FDI) muscleto the scalp overlying the left DLPFC [45], although thereexist other approaches [46], [47] which, however, make use ofsophisticated hardware. The intensity of the magnetic stimuluswas set at 120% of the rMT.Active rTMS was performed five days per week (from

Monday to Friday), at the same time, for four weeks consecu-tively. Each session of rTMS was delivered as follows: 10 Hz,4-s-train duration, a 26-s inter-train interval, for a total of3000 pulses per session lasting 37.5 min. Coil temperature wascontinuously monitored. All sessions were conducted whilesubjects were relaxed and seated in a comfortable chair.The control group received sham stimulation which was per-

formed by angling the coil at 45 in order to touch but not stim-ulating the skull. All patients remained blind to their allocationfor the duration of the study.

E. Data Acquisition and Processing

To monitor the effects of rTMS we used the data acquisitionand processing tool proposed by Giordano et al. in [42], whichsupported us in all the phases (design, data acquisition, and re-sult analysis) of the proposed study. The architecture of the toolis shown in Fig. 1 and consists of three main modules.• A hardware interaction module responsible for synchro-nizing automatically the magnetic stimuli and acquiringthe resulting response signals. It interfaces the software

with the underlying hardware subsystem (currently, a CED1401 A/D DAQ) in order: 1) to drive the two MagStim200 stimulators interconnected through a BiStim module(The Magstim Company, Whitland, U.K.) for deliveringthe paired stimuli to the patient’s cortex and 2) acquirethe motor evoked potentials MEP (registered by usingsingle-use, low-noise, high conductivity electrodes) re-sulting from the administered TMS stimuli.

• An experiment and patient management module that al-lowed us to define the parameters of the adopted TMSparadigm (ISI, number of repetitions, etc.), the criteria forpatients’ enrollment and the clinical and neuropsycholog-ical variables to be investigated. Fig. 2 shows the graphicaluser interface (GUI) for protocol definition. After parame-ters’ definition, the neurophysiological data of each patientwas acquired by administering the paired-pulse TMS withthe parameters previously set. Fig. 3 shows the user inter-face while administrating paired-pulse TMS (withMEP re-sponses) according to the adopted, previously defined pro-tocol: in the left side the plots of MEP responses for a spe-cific ISI are shown, whereas in the right side the TMS pro-tocol settings are listed together with the monitoring of thesubject’s relaxation status.

• A signal postprocessing module that automatically pro-cessed the acquired muscular responses (MEP) in order toremove noise and other inconsistencies that could affectthe quality of the data, such as coil misalignment and pa-tient relaxation level.

F. Statistical Analysis

To assess the differences on the neuropsychological testscores (HDRS, MADRS, FAB, and Stroop T) between test andcontrol groups at baseline the nonparametric Mann–Whitneytest for unpaired data sets was performed because of thenon-Gaussian distribution of the variables. A two-way ANOVAtest was instead performed to evaluate the differences betweenthe test group and the control group at baseline for the neuro-physiological variables: rMT, CSP, and MEP amplitude at ISI2, 3, 10, 15. Our dependent variables (rMT, CSP, and MEPat the different ISI) were normally distributed for the groupsformed by the combination of the hemisphere and group asassessed by the Shapiro-Wilk test. To test the effects of rTMS


Fig. 2. Graphical user interface for protocol definition. Figure shows some of the variables used in the proposed study.

Fig. 3. Graphical user interface for protocol execution.

treatment a two-way ANOVA with repeated measures was per-formed on the neuropsychological test scores, neurophysiolog-ical variables rMT and CSP and on MEP amplitude at ISI 2,3, 10, 15 both for the test group and for the control group.Spearman’s test was used to examine the correlation between

the neurophysiological measures and the neuropsychologicaltest scores. A p-value lower than 0.05 was considered statisti-cally significant.

III. RESULTS

A. Clinical and Neuropsychological Outcome

The clinical and neuropsychological features for the test andthe control at baseline are summarized in Table II which alsoshows the p-value of the comparison between the two groups.No adverse events were observed and no one dropped out duringthe whole study.


TABLE IICLINICAL FEATURES AND NEUROPSYCHOLOGICAL TEST MEAN SCORES

( SD) OF THE CONTROL AND TEST GROUPS AT BASELINE

A repeated measures ANOVA pointed out a significant de-crease in HDRS ( ; beforeversus after mean difference ), MADRS( ; before versusafter mean difference ) and STROOPT ( , beforeversus after mean difference ) beforeand after rTMS treatment on the test group, whereas no sig-nificant difference was found on FAB (

; before versus aftermean difference ). In the control group, wefound a significant decrease in HDRS (

; before versus aftermean difference ), MADRS (

; before versus aftermean difference ), STROOP T (

; before versus aftermean difference ) before and after sham rTMS, althoughthe decrease was less than the one achieved on the test group.No significant difference was identified on FAB for the controlgroup ( ; beforeversus after mean difference ). Table IIIsummarizes the above results on the neuropsychological testscores both for the control group and for the test group.

B. Neurophysiological Outcome

The two-way ANOVA conducted to examine the effects ofhemisphere (right versus left) and group (control versus test)on motor threshold (rMT) at baseline showed that: there wasno significant interaction between the effects of group andhemisphere ; there was no sig-nificant effect of group, ,whereas there was a significant effect of hemisphere

. There was homogeneityof variance between groups as assessed by Levene’s test forequality of error variances. Simple main effects analysis showedthat the rMT at left hemisphere was significantly higher than theright hemisphere both in the control group (right: ,left: ) and in the test group (right:

, left: ). A no significantmain effect of group , of hemi-sphere and interaction grouphemisphere was also iden-

tified for cSP. When comparing the MEP amplitudes betweenthe two groups at baseline, it resulted that the interactions ofeffects group ISI , grouphemisphere and group

ISI hemisphere were notstatistically significant. Simple main effects analysis showed asignificant increase of MEP facilitation from right hemispherecompared to left hemisphere at ISI 10 ms and at ISI 15 ms bothfor the control group (ISI 10: right versus left:

, ISI 15: right versusleft: ) and the test group (ISI 10: right

versus left: , ISI 15:right versus left: ),whereas no significant interhemispheric asymmetry was ob-served in the ICI tract for both groups.To test the effects of rTMS on neurophysiological parame-

ters in both groups the two way ANOVA with repeated mea-sures was performed. On rMT for the test group, we found asignificant main effect of hemisphere

, whereas no significant main effect of treatment wasidentified . A significant inter-action of treatment and hemisphere

was found. Post hoc tests using the Bonferroni correc-tion revealed that rTMS treatment elicited a reduction of thegap of rMT between left and right hemispheres (mean differ-ence: 1.41, left: versus. right:

) compared to the baseline (mean difference: 8.00,left: versus right: ). Nomain effects of hemisphere andtreatment and no interactioneffect hemisphere treatment wereidentified on CSP.For rMT in the control group, we found a significant main ef-

fect of hemisphere and of treat-ment , whereas no significantinteraction of treatment hemisphere

was found. Post hoc tests using the Bonferroni correctionindicated that at baseline there was a significant difference ofrMT between left hemisphere and right hemisphere (mean dif-ference: 8.50, left versus right:

) which remained after the treatment (mean difference:6.20, left versus right ).No main effects of hemisphereand treatment and no interactioneffect hemisphere treatmentwere observed on CSP for the control group. Data regardingrMT values before and after treatment in both control and testgroup are summarized in Table IV.


TABLE IIINEUROPSYCHOLOGICAL TEST MEAN SCORES ( SD) IN BOTH CONTROL AND TEST GROUP AT BASELINE AND AFTER TREATMENT

TABLE IVRESTING MOTOR THRESHOLD VALUES (%, SD) IN BOTH CONTROL

AND TEST GROUP AT BASELINE AND AFTER TREATMENT

For MEP amplitude at ISI 2, 3, 10, and 15 the ANOVAwith repeated measures test with a Greenhouse–Geissercorrection on the test group identified a significant inter-action treatment ISI ,whereas no significant interactions treatment hemisphere

and treatment ISIhemisphere were detected.However, simple main effects analysis showed that at base-line a significant increase of MEP facilitation from righthemisphere was observed at ISI 10 (right:versus left: ) and at ISI 15 (right:

versus left: ),whereas after treatment, the two paired-pulse curves tended tooverlap, without any significant interhemispheric asymmetry inboth ICI and ICF. For MEP amplitude in the control group, wefound a significant main effects interaction of ISI hemisphere

, whereas no significant interac-tions treatment ISI ,treatment hemisphere , andtreatment ISI hemispherewere detected. However, simple main effects analysis showedthat at baseline a significant increase of MEP facilitation fromright hemisphere was observed at ISI 10 (right:versus left: ), whereas at ISI 15the difference between right and left hemisphere was notsignificant although a trend towards an increase of MEP fromright hemisphere was noticed (right: versusleft: ). The differences betweenright hemisphere and left hemisphere remained also after thesham rTMS both for ISI 10 (right: versus left:

) which was statistically significantand for ISI 15 (right: versus left:

) which revealed a trend of increased MEP amplitudein the right hemisphere. Fig. 4 shows the conditioned MEPamplitude at different ISIs obtained from the two hemispheresbefore and after rTMS both for the test group and the controlgroup.We also performed a two-way ANOVA with the fac-

tors group (control versus test), time (before treatment andafter treatment), and hemisphere (right versus left) for theneurophysiological parameters rMT and MEP amplitudes(at different ISIs). For rMT, we found a significant maineffect of hemisphere ,whereas no significant interaction of treatment hemispheregroup and treatmentgroup was found, al-

though a trend towards the significance of the treatmentgroup interaction appears evident. For MEP amplitudes wefound a significant interaction of group treatment ISI

and a trend towards thesignificance of interaction group hemisphere treatment

.Finally, univariate analysis was carried out and the results

are shown in Table V. The difference of rMT between hemi-spheres was significantly positively correlated with HDRS andMADRS. The interhemispheric difference of MEP amplitudeat ISI 10 was significantly positively correlated with HDRS,MADRS, and STROOP T, whereas the difference of MEP am-plitude at ISI 15 between the two hemisphere was positivelycorrelated with HDRS, MADRS, and STROOP T, although thisresults was not significant.

IV. DISCUSSION

This study investigated how TMS parameters of cortical ex-citability before and after rTMS treatment might be used asa practical measure to support clinical assessment of depres-sive disorders and treatment outcome. The main finding of ourstudy is the interhemispheric difference in motor threshold MTand in the paired-pulse response of patients with drug resis-tant major depression at baseline that was then reduced aftertreatment with active rTMS. This interhemispheric differencewas still evident in the control group after sham rTMS. Thisdata is consistent with the theories regarding hemispheric lat-eralization in the regulation of mood [48] and confirm the pre-vious data about the presence of hemispheric asymmetry in pa-tients with major depression [11]. In fact, previous TMS studiesof patients with major depression have shown a reduced ex-citability of both inhibitory (CSP, ICI) and facilitatory (rMT,


Fig. 4. Mean intracortical excitability obtained by the paired conditioning-test stimulus paradigm in the two hemispheres for the test group before (a) and afteractive rTMS (c) and for the control group before (b) and after the sham rTMS (d). Bars indicate standard errors and MEPs are expressed as the percentage ofthe MEP amplitude produced by paired stimulation over that evoked by a test stimulation alone. Interstimulus intervals (ISIs); motor evoked potential (MEP);repetitive transcranial magnetic stimulation (rTMS); * .

TABLE VSPEARMAN RHO VALUES FOR CORRELATION OF NEUROPSYCHOLOGICAL

PARAMETERS AND NEUROPSYCOLOGICAL TEST SCORES

ICF) inputs of the left frontal cortex compared to the contralat-eral hemisphere [22]–[24]. These results are consistent with thehypothesis of GABAergic involvement in the pathophysiologyof depression, as previously suggested by animal, neurochem-ical and neuroimaging studies [49], [50]. Fitzgerald et al. [22]explored the motor cortex excitability measuring resting and ac-tive MT, MEP size, CSP, ICI, and ICF before rTMS, in 60 pa-tients with drug-resistant depression, who were receiving dif-

ferent types of medication. They did not find differences inhemispheric activity, although there was a relationship betweenthe degree of psychopathology and cortical excitability of theright hemisphere and an inverse relationship between inhibitoryactivity in the left hemisphere and clinical response. Bajboujet al. [23] found a significant interhemispheric asymmetry inmotor threshold and a reduction of CSP and ICI, consistentwith a reduction of GABAergic tone, on 20 medication-free de-pressed patients. Lefaucheur et al. [24] examined rMT, CSP,ICI, and ICF on 35 depressedmedicated patients. They observedthat patients with major depressive disorder exhibited a reducedexcitability of both excitatory and inhibitory mechanisms in theleft hemisphere compared to the contralateral.In our study, at baseline, we found a significant interhemi-

spheric difference for the facilitatory circuits (ICF, rMT).However, the meaning of the enhanced ICF that normalizedafter treatment remains rather complex. Compared to the in-hibitory intracortical network, the physiology underlying ICF isless clear. The leading hypothesis is that ICF reflects the state of


excitability of distinct excitatory interneuronal circuits withinthe motor cortex [44], [51]. Several neuropharmacologicalTMS studies pointed out the role of excitatory glutamatergicinterneurons within the motor cortex and N-methyl-d-aspartate(NMDA) receptors in the regulation of facilitation within themotor cortex [14]. However, ICF seems to be a more complexneurophysiological phenomenon, likely to be mediated byglutamatergic facilitation, tempered by persisting GABAergicinhibition and influenced by the cholinergic, dopaminergic,adrenergic, and serotonergic systems [14]. A growing body ofevidence indicates that the glutamatergic neurotransmission,which is known to play a major role in neuronal plasticity, isdisrupted in major depressive disorder, and that drugs targetingthe NMDA receptor have shown antidepressant properties[52]. Reduction in glutamate/glutamine levels in the anteriorcingulate cortex [53] and in the left cingulum [54] have beendocumented in adult depressed patients. In this view, theobserved reduction in motor cortex facilitation before rTMSmight be the expression of the disruption of plasticity-relatedprocesses mediated by NMDA receptor. A trend towards anincrease of ICF without changes in other TMS measures wasobserved in a recent study [55] on a sample of patients withvascular depression, clinically presenting as a “depression-ex-ecutive dysfunction of late life” [56]. Although the pattern ofmotor cortex excitability in vascular depression differs fromthat previously reported in major depression and is similar tothat of patients with subcortical vascular disease [57], the clin-ical presentation of these patients were comparable with ours:i.e., psychomotor retardation, difficulties at work, apathy, lackof insight and executive dysfunction. This finding suggestedthat, probably in vascular depressed patients, enhancement ofICF might play a compensatory glutamate-mediated role inresponse to vascular damage of the frontal cortical–subcorticalcircuits implicated in mood regulation and cognition [58].In our patients, rTMS improved performance at the Stroop

Color Word Test interference and restored ICF at the same levelof the contralateral hemisphere, suggesting that ICF behaviormight probably correlate to executive functions, both before andafter treatment. The therapeutic effects of high-frequency rTMSare probably mediated by increased cortical excitability andneurochemical transmission. The mechanisms of these changesare not clear, but seem to be related to synaptic long-term po-tentiation (LTP) and long-term depression (LTD) in the centralnervous system. In an experimental model of cortical plasticityin humans, Ziemann et al. in [59] argued that plasticity involvesrapid downregulation of GABA-related inhibitory circuits andshort-term changes in synaptic efficacy dependent on Na andCa channels. The rTMS induced long-lasting ( min)reduction in ICI involved NMDA receptor activation and wasprobably related to an LTP-like mechanism. LTD is also pre-dominantly mediated by activation of synaptic NMDA receptoror by metabotropic glutamate receptors (mGluR) at the level ofthe hippocampal CA3:CA1 synapses [60].Finally, it is common knowledge that the administration of

CNS active drugs with a well-defined mode of action on aneurotransmitter or neuromodulator system may have effectson TMS measures of cortical excitability [14]. Taking intoaccount these possible interactions, we have therefore selected

patients assuming Quetiapine and Olanzapine as augmentationpharmacotherapy because of their antidepressant propertiesand no significant effect on motor cortex excitability [61]–[63].All patients were taking mood stabilizers (Lithium, Valproate)because of their efficacy for the potentiatory effect on antide-pressant drugs [64]. Other TMS studies conducted in patientswith epilepsy have shown that chronic treatment with Valproateincreases motor threshold [65], probably because of its effectson voltage-dependent Na channels. Moreover, Valproateaffects the silent period curve and the motor-evoked potentialrecruitment curve, likely due to its effect on the activation ofGABA A receptors [66]. However, a recent work on healthyvolunteers showed that a single 800 mg Valproate dose doesnot modify intracortical excitability measures, namely, rMT,CSP, SICI, ICF, and motor evoked potential recruitment [67].To our knowledge, the influence of tricyclic antidepressantnortriptyline and SNRI Venlafaxine on brain excitability isunexplored. Among SSRI, although Paroxetine and Sertralineintake induces an increase of MEPs amplitude and a decrease ofICF, their modulation on cortical excitability is less pronouncedwith respect to other SSRI like citalopram [63]. However, theserotoninergic reinforcement may enhance facilitatory after-effects and thereby modulate neuroplasticity and increase theefficacy of therapeutic brain stimulation [68].Some limitations should be taken into account when inter-

preting the findings of this study. First of all, as usual in mostTMS studies, the small sample-size; however it should be notedthat the control and test groups were homogeneous in terms ofclinical profiles and pharmacological treatment. The statisticalanalysis showed a clear difference between the two groups be-fore and after the rTMS treatment. Secondly, the influence ofa drug-induced effect on the TMS parameters can not be ex-cluded; several classes of psychotropic medications have indeeddemonstrated to influence motor cortex excitability [14]. How-ever, this aspect does not seem to affect significantly the findingsof this study since both groups were treated with the same stan-dardized pharmacological treatment for resistant MDD. On theother hand, according to standardized treatment protocols, mostof the patients with drug-resistant major depression are often onmedications not different from the ones used in this study.

V. CONCLUSION

The application of rTMS in restoring mood disorders mightlead to the development of stimulation protocols as a possiblerehabilitation method in patients with drug resistant major de-pression. In this study we observed that the interhemisphericdifference of cortical excitability in the test group patients wasreduced by a rehabilitative treatment with rTMS, which resultedalso in a clinical benefit demonstrated by the improvement in theneuropsychological test scores. However, the main limitation ofthis study seems to be the relatively small number of patientsin the test group, although they were very homogeneous in de-mographics, clinical and neurophysiological features as well aspharmacological treatment and age-matched with controls andthe minimum sample size was reached according to Tabachnickand Fidell [69]. In order to investigate if a larger sample sizewould have led to different results, a sample size calculationwas performed using the difference of rMT and MEP amplitude


at ISI 10 between hemispheres, after rTMS, for the test group asprobe. The idea is to determine which difference between rMTof the two hemispheres would have yielded a significant resultwith a significant level of 0.05 and a power of 80%. Based on theresults observed when we used a coefficient of 0.5, we wouldhave needed 660 subjects in the test group to reach a significantdifference, at , between right and left hemisphere. Thesame procedure was performed on the difference of MEP am-plitude at ISI 10 between the two hemisphere and we obtainedthat we would have needed 211 patients in the test group to geta significant difference between the two hemispheres. Thus, inspite of the small sample size, the balancing of rMT and ICFbetween the two hemispheres in patients with major depressiontreated with active rTMS appears to be clear, although it needsto be further verified and confirmed by independent investiga-tions with larger group sizes. Nevertheless, the proposed studyis the first attempt in quantitatively assessing the neurophysio-logical effects of rTMS and a trend of differences in intracorticalexcitability before and after the treatment with rTMS has beendetected. A follow-up stage on the same set of patients, hereindescribed, is already in progress to quantitatively evaluate thelong-term effects of rTMS.In conclusion, TMS is a comprehensive valuable tool to

support assessment and follow the clinical course of patientswith major depression. In detail, the study of parameters ofcortical excitability and underlying neurochemical mechanismsbefore and after rTMS provides a potentially new window intothe pathophysiological mechanisms behind depression. More-over, the combination of TMS with other measures of brainactivity (electroencephalography, evoked potentials, functionalneuroimaging), might be promising for understanding neu-ropsychiatric disorders.

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C. Spampinato (M’12) received the Laurea (grade110/110 cum laude) degree in computer engineeringand the Ph.D. degree from the University of Catania,Catania, Italy, in 2004 and 2008, respectively, wherehe is currently Research Assistant.His research interests include mainly image and

video analysis, medical image analysis, and medicalinformatics. He has particular interest in ecologicaldata analysis, being involved in the EU projectFish4Knowledge. He has coauthored more than 90publications in international refereed journals and

conference proceedings. As further research activities, he have organizedand chaired dedicated workshops and several special sessions at mainstreamconferences and guest-edited four special issues of international journals withimpact factor.

E. Aguglia was born in Catania, Italy, in 1952.From November 1986 to February 2008 he was FullProfessor of Psychiatry at the School of Medicineof the University of Trieste. From 1987 to 2008 hedirected the School of Specialization in Psychiatryand the Social Services Unit. In March 2008 he be-came Full Professor and Director of the PsychiatricUnit at the School of Medicine of Catania. He is theauthor of 468 scientific works on psychiatric clinic,psychopharmacology, psychiatry epidemiology,suicide, eating disorders, and Alzheimer’s disease,

published in international journals.Prof. Aguglia was President of the Italian Society of Psychiatry from 2003

to 2006 and from 2009 to 2012. From 2006 to 2009 he was President of theProfessors College of Psychiatry. He is Vice President of the Italian Society ofNeuropsychopharmacology andVice President of the Italian Society of ForensicPsychiatry.

C. Concerto is Resident in Psychiatry at the Uni-versity of Catania, Italy. Her main clinical interestsare psychiatric clinic, management of drug-resistantmajor depression and repetitive transcranial magneticstimulation (rTMS). Her recent scientific activity fo-cused on the application of rTMS in the treatment ofmood disorders.Dr. Concerto has been a member of the Italian As-

sociation of Psychiatry since 2010. She is member ofthe European College of Neuropsychopharmacology.

M. Pennisi graduated with honors in medicine fromthe University of Catania, in 2004. She is currentlyworking toward the Ph.D. degree in neurobiology atthe University of Catania.She is a Neurologist at the Spinal Unit of

“Ospedale Cannizzaro,” Catania, Italy. Her mainresearch interests are on clinical neurophysi-ology, neuromuscular disorders and neuromotorrehabilitation. She is also involved in researchprojects on redox proteomics, thiol homeostasisand neurophysiological correlations in aging and

neurodegeneration. She has published over 20 papers in referred journals andinternational conferences.

G. Lanza is a Neurologist Researcher at the Univer-sity of Catania, Italy, and Visiting Clinical ResearchFellow at the Newcastle University, U.K. He trainedat the School of Neurology based at the University ofCatania. His main clinical interests are cerebrovas-cular diseases, vascular-related cognitive disorders,clinical neurophysiology, transcranial magnetic stim-ulation and related techniques and applications. Hisrecent scientific activity focuses on the neurophysio-logical evaluation of cortical excitability and neuro-chemical basis of the cognitive and mood-behavioral

characteristics of different neurological and psychiatric diseases, such as vas-cular cognitive impairment and major depression.

R. Bella received the medical degree from the Uni-versity of Catania, in 1983, with a specialization inneurology, in 1988. She received the master’s degreein “cerebrovascular diseases” from the RomeUniver-sity “La Sapienza,” in 2007.In 1992 she began her career as a Clinical Assis-

tant at the First Neurological Clinic of the UniversityHospital of Catania. In 2002 she became a Researcherat the Department of Neurosciences of the Universityof Catania. Her main research activity was carried outin the field of cognitive and psychiatric symptoms of

cerebrovascular diseases by means of transcranial magnetic stimulation. Thisactivity is reflected in scientific publications in international journals and bycommunications and poster presentations in national and internationalmeetings.

M. Cantone graduated with honors in medicine, in2005, from the University of Catania, where she hasbeen working toward the Ph.D. degree since 2010.She is a Neurologist at the Department of Neu-

rology I.C., Oasi Institute for Research on MentalRetardation and Brain Aging, Troina, Italy. Hermain clinical interests are cerebrovascular diseases,dementias, neuromotor rehabilitation. Her currentresearch projects focus on noninvasive functionalevaluation of glutamatergic, gabaergic and cholin-ergic circuits of the human brain in cerebrovascular,

neurodegenerative and sleep disorders and on the clinical applications oftranscranial magnetic stimulation to promote recovery in neuropsychiatricdisorders such as depression and stroke.


G. Pennisi received themedical degree from the Uni-versity of Catania, in 1974, with a specialization inneurology, in 1978, and in forensicmedicine, in 1981.He worked at the Neurological Department of the

University of Torino, in 1977–1978, and at the Neu-rological Clinic of the University of Liege, Belgium,in 1988. He began his career as a Clinical Assistantat the Clinic of Neurological and Mental diseases, in1977, and worked as a Researcher at the NeurologicalClinic, in 1981. He became an Associate Professorat the Department of Neurosciences of the Univer-

sity of Catania, in 1985. His research activities include the prognostic value oftranscranial magnetic stimulation in motor recovery after stroke, motor cortexexcitability in dementia and behavior disorders, and oxidative stress in neurode-generative diseases. This activity is reflected in several scientific publicationsin international journals and by communications and poster presentations in na-tional and international meetings.

I. Kavasidis received the Laurea degree in computerengineering, in 2009, from the University of Catania,where he is currently working toward the Ph.D.degree.His main research interests include image and

video processing, medical informatics and semanticweb technologies in medicine. He has publishedover 20 papers in referred journals and internationalconferences.

D. Giordano (M’12) received the Laurea degree inelectronic engineering (grade 110/110 cum laude)from the University of Catania, Italy, in 1990, andthe Ph.D. degree in educational technology fromConcordia University, Montreal, Canada, in 1998.She is Associate Professor of Information Sys-

tems at the Engineering Faculty of the Universityof Catania since 2001. Her research has beenpublished in international refereed journals andconference proceedings and has dealt with topicssuch as advanced learning technology, knowledge

discovery, image processing, and information technology in medicine. Hercurrent research interests include cognitive systems, multimodal interactionand semantic technologies. She has published over 150 articles in referredjournals and international conferences.

Documents

Transcranial Magnetic Stimulation in the Assessment of Motor Cortex Excitability and Treatment of Drug-Resistant Major Depression