Inter-hemispheric asymmetry of motor corticospinal excitability in major depression studied by transcranial magnetic stimulation

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JOURNAL OF PSYCHIATRIC RESEARCH

Journal of Psychiatric Research 42 (2008) 389–398

www.elsevier.com/locate/jpsychires

Inter-hemispheric asymmetry of motor corticospinal excitability in major depression studied by transcranial magnetic stimulation J.P. Lefaucheur a,*, B. Lucas a,b, F. Andraud a,c, J.Y. Hogrel d, F. Bellivier e, A. Del Cul a,f, A. Rousseva e, M. Leboyer e,f, M.L. Paille`re-Martinot f a

e

Service de Physiologie – Explorations Fonctionnelles, Hoˆpital Henri Mondor, Assistance Publique-Hoˆpitaux de Paris, 51 avenue du Mare´chal de Lattre de Tassigny, 94010 Creteil, France b Service de Psychiatrie, Hoˆpital Fontan, Centre Hospitalier Re´gional et Universitaire de Lille, boulevard Professeur Laguesse, 59037 Lille, France c Service de Psychiatrie, Hoˆpital de Biceˆtre, Assistance Publique-Hoˆpitaux de Paris, 78 rue du Ge´ne´ral Leclerc, 94270 Le Kremlin-Biceˆtre, France d Institut de Myologie, Groupe Hospitalier Pitie´-Salpeˆtrie`re, 47/83 boulevard de l’Hopital, 75013 Paris, France Service de Psychiatrie, Hoˆpital Henri Mondor, Assistance Publique-Hoˆpitaux de Paris, 51 avenue du Mare´chal de Lattre de Tassigny, 94010 Creteil, France f Service de Psychiatrie, Hoˆpital Albert Chenevier, Assistance Publique-Hoˆpitaux de Paris, 40 rue de Mesly, 94000 Cre´teil, France Received 16 November 2005; received in revised form 29 January 2007; accepted 5 March 2007

Abstract Background: Imaging and electroencephalographic studies have reported inter-hemispheric asymmetries in frontal cortical regions associated with depression. This study aimed at comparing motor corticospinal excitability assessed by methods of transcranial magnetic stimulation (TMS) between the right and left hemispheres in patients with major depression and healthy controls. Method: Patients with major depression (n = 35) and healthy controls (n = 35) underwent a bilateral study of various motor corticospinal excitability parameters, including rest motor threshold (RMT), corticospinal silent period (CSP) duration and intra-cortical inhibition (ICI) and facilitation (ICF). Indexes of asymmetry were calculated, and the relationships between excitability parameters and clinical scores of depression were statistically analyzed. Results: Depressed patients showed a reduced excitability of both excitatory (RMT, ICF) and inhibitory (CSP, ICI) processes in the left hemisphere, compared to the right hemisphere and to healthy controls. Conclusion: The present results confirmed the existence of inter-hemispheric asymmetries in frontal cortex activities of depressed patients in favor of a left-sided reduced excitability. This neurophysiological approach may help to guide repetitive TMS procedures in the treatment of depressive disorders.  2007 Elsevier Ltd. All rights reserved. Keywords: Corticospinal silent period; Intra-cortical facilitation; Intra-cortical inhibition; Major depression; Motor evoked potentials; Rest motor threshold

1. Introduction Repetitive transcranial magnetic stimulation (rTMS) of the prefrontal cortex was reported to induce antidepressant effects, which might have therapeutic potential in major depression. These effects were observed after activation of *

Corresponding author. Tel.: +33 1 4981 2694; fax: +33 1 4981 4660. E-mail address: [email protected] (J.P. Lefaucheur). 0022-3956/$ - see front matter  2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2007.03.001

the left prefrontal cortex by rTMS applied at 10–20 Hz (George et al., 1997) or inhibition of the right prefrontal cortex by rTMS applied at 0.2–1 Hz (Klein et al., 1999). This is consistent with the existence of functional asymmetries between the right and left prefrontal cortices associated with depression. In fact, several imaging studies of patients with major depressive disorder have disclosed inter-hemispheric asymmetries in prefrontal cortical regions, with a relative reduction of glucose metabolism or cerebral blood flow on the left side (Baxter et al.,

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1989; Martinot et al., 1990; Kocmur et al., 1998). A number of electroencephalographic studies also revealed interhemispheric asymmetry of frontal activation and the rate of asymmetry correlated with clinical scores of depression (Schaffer et al., 1983; Koek et al., 1999; Diego et al., 2001; Knott et al., 2001). Since a few years, the excitability of the frontal motor cortex can be studied using various TMS methods (Abbruzzese and Trompetto, 2002). These methods include the determination of motor threshold in a muscle at rest (RMT), the calculation of motor evoked potential (MEP) amplitude ratio at increasing stimulus intensities and the measurement of corticospinal silent period (CSP) duration. These tests are performed with single TMS pulses, while intra-cortical inhibition (ICI) and facilitation (ICF) phenomena are assessed with paired TMS pulses. The physiological significance of these parameters of corticospinal excitability have been quite well defined: RMT and MEP size reflect the overall corticospinal input–output balance (Ziemann et al., 1996; Devanne et al., 1997); excitatory inputs from high-threshold glutamatergic pathways to the motor cortex lead to ICF (Liepert et al., 1997; Ilic et al., 2002), whereas inhibitory inputs from low-threshold GABA-A-mediated pathways lead to ICI (Kujirai et al., 1993; Ilic et al., 2002); finally, CSP is produced through activation of both spinal and cortical circuits (Cantello et al., 1992), at least partly mediated by GABA-B receptors (Werhahn et al., 1999). In the present study, we assessed corticospinal excitability parameters bilaterally in a series of 35 patients with major depressive disorder and 35 healthy volunteers, looking for side-to-side and patients-to-controls differences. Correlations between electrophysiological parameters and various clinical scores of depression were analyzed. 2. Methods 2.1. Subjects The study included 35 right-handed patients (21 women, 14 men, aged from 18 to 90 years, with a mean (±SEM) age of 56.0 (±2.8) years), who met the criteria for major depression according to the DSM-IV, as established by a trained psychiatrist. The local ethical committee approved this study as ancillary to a core project aimed at assessing the treatment of major depression by applying rTMS. All these patients were receiving medication at the time of the study, including selective serotonin reuptake inhibitor (n = 9), mixed serotonin-noradrenaline reuptake inhibitor (n = 15), tricyclic antidepressant (n = 5), lithium (n = 5), anticonvulsant drugs or benzodiazepins (n = 17), antihistaminic drugs or antipsychotic medication (n = 25). The demographic data of the patients, including the medications and their dosage are presented in Table 1. The study also included 35 healthy right-handed volunteers (18 women, 17 men, aged from 24 to 72 years, with a mean age of 43 years), who did not present any sign or

medical history of psychiatric disorders and did not receive any medication. 2.2. TMS procedure Subjects were seated in a comfortable reclining chair with a tightly fitting Lycra swimming cap being placed on the head. They were instructed to keep their hands still and as relaxed as possible. The TMS was performed with a Magstim 200 stimulator (Magstim Company, Carmarthenshire, UK) and a figure-of-eight double 70 mm coil (#992500, Magstim). Two Magstim 200 stimulators connected through a Bistim module served to deliver paired pulses. The optimal sites for evoking responses from the right and left abductor pollicis brevis (APB) muscles (when stimulating the left and right hemispheres, respectively) were determined over the scalp and marked on the cap. The MEPs were recorded at 10 kHz from the APB muscle through a 20–1000 Hz bandpass filter using a standard electromyograph (Phasis II, EsaOte, Florence, Italy) and pre-gelled self-adhesive disposable surface electrodes (#9013S0241, Medtronic Functional Diagnostics, Skovlunde, Denmark), which were placed on the belly and tendon of APB muscles. A Velcro bracelet was strapped around the forearm as ground electrode (#9013S0711, Medtronic). The coil was positioned tangentially to the surface of the head, and the handle of the coil was placed along a sagittal axis pointing occipitally. In this position, the induced current in the brain predominantly activates corticospinal neurons transsynaptically. Motor corticospinal excitability testing included the determination of five parameters for each hemisphere. The RMT was defined as the minimal intensity of stimulation required to elicit MEPs of more than 50 lV in amplitude in at least five out of 10 trials performed during complete muscle relaxation (Rossini et al., 1994). The relationship between stimulus intensity and MEP amplitude was assessed by studying the most variable part of the stimulus–response curve, which was previously found to correspond to TMS intensities ranging between 120% and 140% of RMT (Davey et al., 1999; Han et al., 2001). We calculated, therefore, the amplitude ratio of the MEP obtained at 140% of RMT to that obtained at 120% of RMT (140/ 120r) (Lefaucheur et al., 2006). The CSP was determined as the duration of the post-MEP interruption of the electromyographic activity induced by single TMS pulses delivered at 140% of RMT during a tonic voluntary contraction. Four rectified traces, each consisting of a block of three averaged trials, were superimposed. The minimal CSP duration was measured from the end of the MEP until the first re-occurrence of electromyographic activity. Finally, paired pulses were delivered with the intensity of the conditioning stimulus set at 80% of RMT and the intensity of the test stimulus at 120% of RMT, while the APB muscle was at rest (Kujirai et al., 1993). Interstimuli intervals (ISIs) of 2 and 4 ms (to determine intra-cortical inhibition, ICI) and ISIs of 10 and 15 ms

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391

Table 1 Demographic and clinical characteristics of the 35 patients with major depression enrolled in the study, including depression scale scores and medication with daily dosages

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

Sex

Age (years)

HRSD

MADRS

CGI

ERD

Medication (daily dosage in mg)

M M M F F F M F M F M F F F M F M M M F F F F F F F F M M F M F F M F

50 61 50 51 51 62 53 60 38 90 54 77 79 79 50 47 52 65 53 80 62 44 48 55 55 55 35 19 36 50 70 80 80 52 18

19 18 29 13 20 22 26 26 16 44 26 15 23 26 17 28 23 24 11 19 31 20 22 26 20 20 27 19 14 14 18 14 14 22 17

34 26 35 24 33 39 35 38 28 54 33 19 38 46 25 46 42 27 19 34 47 32 37 35 32 32 38 23 24 20 30 27 23 23 25

5 4 5 4 5 6 5 6 5 6 6 5 6 7 6 5 6 5 5 6 5 4 4 6 5 5 6 4 4 4 5 4 4 5 5

20 25 29 25 22 28 29 31 27 52 22 28 25 45 34 33 38 26 26 39 37 18 29 30 32 30 27 22 25 21 29 42 33 26 21

Lithium (1500), hydroxyzine (250) Lithium (500), venlafaxine (150), clonazepam (4) Fluvoxamine (100), clonazepam (2), alimemazine (30) Clomipramine (150), clonazepam (2) Venlafaxine (300), clonazepam (1) Clomipramine (150), oxazepam (50) Venlafaxine (300), carbamazepine (600), loxapine (15), risperidone (2) Venlafaxine (250), loxapine (25), clonazepam (4) Clomipramine (150), loxapine (25), clonazepam (1.5) Venlafaxine (250), thioridazine (12) Valpromide (1200), clonazepam (2.5), alimemazine (75) Venlafaxine (200), oxazepam (50), alimemazine (30), hydroxyzine (50) Paroxetine (40), valpromide (600), loxapine (8) Venlafaxine (100), valpromide (900) Fluvoxamine (100), hydroxyzine (100) Fluoxetine (20), chlorpromazine (100), hydroxyzine (300) Paroxetine (40), alimemazine (50), hydroxyzine (100) Carbamazepine (600) Venlafaxine (250), hydroxyzine (100) Venlafaxine (100), valpromide (900) Lithium (750), hydroxyzine (150), alimemazine (30) Fluoxetine (20), alimemazine (50) Venlafaxine (250), hydroxyzine (100) Venlafaxine (200), valpromide (600) Lithium (1000), hydroxyzine (100) Paroxetine (40), alimemazine (30) Clomipramine (150), alimemazine (30) Venlafaxine (150), loxapine (25) Clomipramine (150), clonazepam (2) Lithium (750), hydroxyzine (150) Venlafaxine (200), clonazepam (10), cyamemazine (25) Venlafaxine (100), risperidone (4) Venlafaxine (50) Fluoxetine (40), hydroxyzine (100) Sertraline (50), hydroxyzine (100), alimemazine (20)

HRSD: Hamilton Rating Scale for Depression; MADRS: Montgomery-Asberg Depression Rating Scale; CGI: Clinical Global Impression scale; ERD: Echelle du Ralentissement Depressif.

(to determine intra-cortical facilitation, ICF) were randomly applied and intermixed with control trials (test stimulus alone). On the whole, four trials were recorded and averaged for the test pulse alone and for each ISI. Results were expressed as the percentage below (for ICI) or above (for ICF) 100% of test MEP amplitude, i.e. the amounts of inhibition or facilitation. The maximal ICI and ICF values observed at any ISI were retained for analysis (Chen et al., 1998). In addition, indexes of asymmetry were calculated for each TMS parameter as the percentage difference between values obtained from the right and left stimulated hemispheres. 2.3. Clinical assessment Severity of depression was assessed with the Hamilton Rating Scale for Depression (HRSD-21 items) (Hamilton, 1960), the Montgomery-Asberg Depression Rating Scale (MADRS) (Montgomery and Asberg, 1979) and the Clinical Global Impression (CGI) scale (Guy, 1976). Psycho-

motor retardation was assessed with the Echelle du Ralentissement Depressif (ERD) (Jouvent et al., 1980), also known as the Salpeˆtrie`re Retardation Rating Scale (Dantchev and Widlo¨cher, 1998). All these tests were administered by a trained psychiatrist. 2.4. Data analysis Nonparametric tests have been applied, because various data did not pass the normality test, as shown by the method of Kolmogorov–Smirnov. Firstly, side-to-side differences were assessed in both patient and control groups using the Wilcoxon matched-pairs signed-ranks test. Secondly, values (including indexes of asymmetry) were compared between controls and patients using the Mann– Whitney test. Thirdly, a principle component factor analysis was performed to determine how the indexes of asymmetry of the different variables related to each others and whether these variables were able to differentiate patients from healthy subjects. Finally, correlations between TMS

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data (including indexes of asymmetry) and clinical scores were studied in patients using the Spearman correlation test. In all cases, a p value of less than 0.05 was considered as significant. In second-step analyses, Bonferroni’s correction for multiple comparisons was applied, i.e. setting the alpha level at 0.05 divided by the number of comparisons performed. 3. Results The distributions of the right and left values of corticospinal excitability and of their indexes of asymmetry are presented for healthy controls and patients in Figs. 1 and 2. The statistical significances of side-to-side and patientsto-controls differences have been separately analyzed. 3.1. Side-to-side differences

For the right hemisphere, the only significant difference between patients and controls was a reduced ICI in patients (Table 2). Regarding the left hemisphere, patients showed increased RMT, shorter CSP, and reduced ICF and ICI (Table 2). After Bonferroni correction of the significance level, only CSP and ICI changes remained significant in patients compared to controls. Regarding the indexes of asymmetry, significant differences between patients and controls were observed for RMT, CSP, and ICF (Table 3). The difference tended to be significant for ICI but not for 140/120r. 3.3. Principle component factor analysis (PCA) A PCA was performed in order to investigate possible dependence among asymmetry of the different variables. Fig. 3 shows that the five variables were not correlated since their directions in the PCA plan are largely distributed. Three variables presented nearly the same weight for the first component: CSP, 140/120r and ICF. For the second component, the weight of ICI was slightly higher than the weight of the other variables. Therefore, the PCA failed to demonstrate that some measurements were redundant and that the amount of data could be reduced. The PCA also revealed that the variance of the patient pop-

100

10.0

75

7.5

50

140/120r

RMT (%)

In healthy controls, no significant differences were found between the right and left values of motor corticospinal excitability (Table 2). There was only a trend towards RMT reduction in the left vs. the right hemisphere. In patients, RMT was increased, CSP was shorter, and both ICI and ICF were reduced in the left vs. the right hemisphere (Table 2). After correcting the statistics for multiple comparisons (level for p significance set at 0.01), only ICI and ICF asymmetries remained significant.

3.2. Patients-to-controls differences

25

2.5

0

0.0

200

100 50

100 50

ICI (%)

150

CSP (ms)

5.0

0 -50 -100 -150

0 700

ICF (%)

500

Healthy controls

right

left

Patients

right

left

300 100 -100

Fig. 1. Distribution of right and left corticospinal excitability values in healthy controls (squares) and in patients with major depression (triangles). The mean values are indicated as a thin horizontal line. RMT: rest motor threshold (RMT); 140/120r: motor evoked potential amplitude ratio at increasing stimulus intensity from 140% to 120%; CSP: corticospinal silent period duration; ICI: intra-cortical inhibition; ICF: intra-cortical facilitation.

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25

RMT

100

393

140/120r

50

0

0

-25 -50

-50

-100 -150

-75

100

300

CSP

ICI

250

0

200 -100

150

-200

100 50

-300

0 -50

-400 2500

ICF

2000 1500 1000 500

Healthy controls

0

Patients

-500 -1000 -1500

Fig. 2. Distribution of the indexes of asymmetry of corticospinal excitability in healthy controls (squares) and in patients with major depression (triangles). The mean values are indicated as a thin horizontal line. RMT: rest motor threshold (RMT); 140/120r: motor evoked potential amplitude ratio at increasing stimulus intensity from 140% to 120%; CSP: corticospinal silent period duration; ICI: intra-cortical inhibition; ICF: intra-cortical facilitation.

ulation was noticeably greater than the variance of the healthy control population for the second component in general and for ICI in particular. 3.4. Correlation between excitability parameters and clinical scores The mean (SEM) clinical scores were 21.2 (1.1) for HRSD, 32.1 (1.4) for MADRS, 5.1 (0.1) for CGI, and

29.3 (1.2) for ERD. Spearman test revealed significant correlations between various excitability parameters and clinical scores, at least before correction for multiple comparisons (p values ranging between 0.01 and 0.05): correlations were found between left CSP duration and CGI; between index of asymmetry of CSP duration and HDRS, MADRS, or CGI; between right ICI values and ERD; between left ICF values and MADRS. Fig. 4 illustrates these correlations and pro-

Table 2 Mean (SEM) of the right and left corticospinal excitability values in healthy controls and in patients with major depression Healthy subjects (n = 35) Right hemisphere

Rest motor threshold (%) 140/120 Amplitude ratio Silent period duration (ms) Intra-cortical inhibition (%) Intra-cortical facilitation (%)

Left hemisphere

Patients with major depression (n = 35)

Subjects vs. patients

Right vs. left

Right hemisphere

Right hemisphere

Mean (SEM)

Left hemisphere

Right vs. left

Left hemisphere

Mean (SEM)

Mean (SEM)

p

Mean (SEM)

p

p

p

71.37 (1.75)

69.69 (1.64)

0.062

71.34 (2.06)

75.97 (2.20)

0.032

0.995

0.016

2.58 (0.22) 77.49 (4.59)

2.30 (0.13) 76.09 (4.67)

0.546 0.952

3.43 (0.52) 73.89 (7.29)

2.29 (0.30) 56.06 (6.46)

0.176 0.015

0.482 0.324

0.237 0.005

79.64 (1.66)

77.36 (2.18)

0.136

57.43 (5.91)

36.00 (9.99)

0.006

0.0006

0.0001

65.00 (20.42)

69.29 (19.96)

0.528

118.40 (30.52)

13.34 (12.60)

0.008

0.310

0.047

Side-to-side and patients-to-controls statistical comparisons are presented for the both groups and the both sides.

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Table 3 Mean (SEM) of the indexes of asymmetry of corticospinal excitability in healthy controls and in patients with major depression Index of asymmetry [100 · (right

left)/right]

Rest motor threshold 140/120 Amplitude ratio Silent period duration Intra-cortical inhibition Intra-cortical facilitation

Healthy subjects

Depressed patients

Mean (SEM)

Mean (SEM)

p

7.98 0.43 2.40 40.09 222.01

0.008 0.310 0.018 0.063 0.043

2.01 0.85 2.35 2.44 63.79

(1.14) (7.43) (5.32) (2.52) (58.75)

(3.15) (18.35) (17.47) (26.25) (120.25)

healthy controls patients

ICI

5

Subjects vs. patients

140/120r

4 3

CSP

component 2

2 1 0 -1 -2

ICF

-3

RMT

-4 -5 -5

-4

-3

-2

-1

0

1

2

3

4

5

component 1

Fig. 3. Projection of subjects and variables on the plan of the principle-components factor analysis of the indexes of asymmetry of corticospinal excitability. The part of the explained variance by the first two components was 51.4% of the total variance. Note the homogeneous localization of the projected population of healthy controls compared to the projected population of patients with major depression.

vides correlation coefficient and p significance. Other correlation analyses were negative. 4. Discussion This study showed a significant reduction in the overall excitability (increased RMT) and in the amount of both inhibitory (shortened CSP and reduced ICI) and facilitatory (reduced ICF) inputs regarding the left frontal cortex of patients with major depressive disorder compared to the right homologous region in the same patients, and also compared to the left frontal cortex of healthy controls. Regarding the right frontal cortex, patients and controls only differed for ICI. The analysis of the indexes of asymmetry revealed significant inter-hemispheric asymmetry in patients for RMT, CSP and ICF, in favor of a reduced excitability of both excitatory and inhibitory pathways in the left hemisphere. 4.1. Asymmetry of motor corticospinal excitability in depression Three studies previously assessed inter-hemispheric asymmetry of TMS parameters of motor corticospinal excitability in depressive patients. The first study, per-

formed by Maeda et al. (2000), included only eight patients and eight controls. The second study, performed by Fitzgerald et al. (2004), included 60 patients, but no controls. The third study, performed by Bajbouj et al. (2006b) included 20 patients and 20 controls. Maeda et al. (2000) reported a significant RMT increase in the left vs. the right hemisphere in patients compared to controls, as in the present study. Bajbouj et al. (2006b) found a significant RMT decrease in the right vs. the left hemisphere in patients compared to controls. In contrast, RMT tended to be higher for the right vs. the left hemisphere in the study of Fitzgerald et al. (2004). Compared to controls, CSP duration was reduced bilaterally in the series reported by Bajbouj et al. (2006b). The study of Fitzgerald et al. (2004) was also suggestive of bilateral CSP shortening, in the light of the rather short values that were reported, even if the lack of controls did not allow firm conclusions. In contrast, CSP was shortened only for the left side in the present study. Conflicting results also exist for ICI. In patients with major depressive disorder, the amount of cortical inhibition was significantly reduced in the left hemisphere at an ISI of 1 ms in the study of Fitzgerald et al. (2004), while ICI was replaced by a paradoxical facilitation in the right hemisphere at an ISI of 6 ms in the

J.P. Lefaucheur et al. / Journal of Psychiatric Research 42 (2008) 389–398

395

7 7

6

6 5

5

CGI

CGI

4 3 2

4 3 2

1

1

r = -0.33 p = 0.05

r = 0.36 p = 0.03 0 -400 -350 -300 -250 -200 -150 -100 -50

0 0

50

100

150

200

left CSP (ms)

50

40

40

30 20

150

0

50

100

150

0

50

100

150

30

10 r = -0.33 p = 0.05

0 -100

0

-50

50

100

r = 0.37 p = 0.03 0 -400 -350 -300 -250 -200 -150 -100 -50

150

right ICI (%)

CSP - IA

60

60

50

50

40

40

MADRS

MADRS

100

20

10

30 20

-100

-50

30 20 10

r = -0.41 p = 0.01

0 -150

50

60

50

HRSD

ERD

60

10

0

CSP - IA

0

50

100

150

200

250

300

left ICF (%)

r = 0.36 p = 0.03

0 -400 -350 -300 -250 -200 -150 -100 -50

CSP - IA

Fig. 4. Significant correlations (Spearman tests) between various corticospinal excitability parameters and clinical scores of depression. CGI: Clinical Global Impression scale; ERD: Echelle du Ralentissement Depressif; HRSD: Hamilton Rating Scale for Depression; MADRS: Montgomery-Asberg Depression Rating Scale; CSP: corticospinal silent period duration; ICI: intra-cortical inhibition; ICF: intra-cortical facilitation; IA: index of asymmetry.

study of Maeda et al. (2000). However, these ISIs were not perfectly relevant to study ICI: an ISI of 1 ms corresponds to the refractory period of the corticospinal axons but not to the active recruitment of inhibitory interneurons, while an ISI of 6 ms corresponds to the frontier between ICI and ICF (Abbruzzese and Trompetto, 2002). In the present study, ICI was found bilaterally reduced in patients with major depression compared to controls, but predominantly in the left hemisphere for usual ISIs (2–4 ms). At these ISIs, Bajbouj et al. (2006b) also found bilateral ICI reduction in patients compared to controls, but at similar level for the both hemispheres. Stimulus intensities applied for the paired-pulse testing differed between these studies. The conditioning pulse intensity was set at 60–65% of RMT in the study of Fitzgerald et al. (2004), but at 80% of RMT in the present study and those of Maeda et al. (2000) and Bajbouj et al. (2006b). The test stimulus was set at 120% of RMT in the present study, but adjusted to evoke MEPs of 0.6– 1.0 mV in amplitude in the study of Maeda et al. (2000), 0.5–1.5 mV in the study of Fitzgerald et al. (2004), and 0.8–1.2 mV in the study of Bajbouj et al. (2006b).

The discrepancies between the results provided by all these studies may be due to the methods that were employed but also to differences in clinical presentation, disease severity, or medication status between the patients who have been included. In particular, clinical presentation and drugs are known to greatly influence motor corticospinal excitability parameters. This was emphasized, for instance, in studies of patients with Parkinson’s disease (Lefaucheur, 2005). Medications were withdrawn for the patients included by Maeda et al. (2000) and Bajbouj et al. (2006b), with a 2–4-week washout period prior to inclusion. On the contrary, 46 of the 60 patients evaluated in the study of Fitzgerald et al. (2004) were on medication at the time of TMS testing, as all the patients recruited in the present study. A statistical analysis (using Fisher’s exact test) revealed that these two latter studies significantly differed for the use of tricyclics and anticonvulsant drugs. We must keep in mind that controversial corticospinal excitability results can reflect various pharmacological influences or the multi-faceted aspect of a disease. For instance, the heterogeneity in the population of depressive patients included in the present study was illustrated by the principle component analysis that revealed a strong heter-

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ogeneous behaviour for the patient population compared to the healthy population. The present results support the hypothesis that patients with major depressive disorder present inter-hemispheric asymmetry of frontal motor cortex activity. This does not imply the existence of similar functional asymmetries in prefrontal regions. The motor cortex is not thought to play a key role in the pathophysiology of depression, but major depression has clearly an impact on motor function. For instance, motor retardation is clinically and neurophysiologically very similar between depression and parkinsonism, suggesting common mechanisms (Sachdev and Aniss, 1994; Caligiuri and Ellwanger, 2000). In addition, a functional coupling between prefrontal and motor cortices was demonstrated during various action tasks (Rowe et al., 2002, 2005). The prefrontal cortex may exert control on selection of neuronal representations in the motor system related to working memory and attention. In particular, attention to action increased the effective connectivity between prefrontal and motor cortical regions (Rowe et al., 2002, 2005). Therefore, motor cortex excitability alterations may be associated with functional changes in prefrontal regions in the context of major depression. However, it remains difficult to infer functional asymmetry between the left and right prefrontal cortices only by examining differences in motor responses to motor cortex stimulation. Whatever their precise anatomical correspondence, the present results suggest that both glutamatergic and GABAergic pathways may be defective in the left hemisphere of patients with major depressive disorder. This is consistent with the fact that both glutamate and GABA synaptic transmissions are potential targets for antidepressant treatments (Krystal et al., 2002). In particular, the role of a defective GABA transmission in mood disorders was supported by the reduced levels of GABA in the cerebrospinal fluid of patients with depression (Gold et al., 1980; Kasa et al., 1982; Gerner et al., 1984). Reduced GABA or glutamate levels were also shown in vivo in occipital or cingulate brain regions of patients with major depression using magnetic resonance spectroscopy (Sanacora et al., 1999; Auer et al., 2000). Finally, successful antidepressant treatment based on medication, electroconvulsive therapy (ECT) or rTMS were found to be associated with the normalization of GABA or glutamate levels in various cortical regions (Sanacora et al., 2002, 2003; Michael et al., 2003; Pfleiderer et al., 2003; Luborzewski et al., 2007). 4.2. Clinical correlation In this study, depression severity correlated with left CSP shortening, and also with left ICF reduction, as previously observed by Maeda et al. (2000). Bajbouj et al. (2006b) reported predominant correlation of depression severity and ICI reduction in the left hemisphere. This seems to confirm that major depression is related to an overall hypoexcitability of the left frontal region, including

both inhibitory and excitatory pathways. In contrast, Fitzgerald et al. (2004) found that various psychopathological scores correlated with the right but not the left ICF. In the present study, only ICI reduction in the right hemisphere had significant clinical correlate, namely a more severe psychomotor retardation. 4.3. Asymmetry of corticospinal excitability as a predictive factor for rTMS Several imaging studies support the idea that rTMS could exert antidepressant effects through the activation of hypoactive cerebral regions when applied at high frequency or through the inhibition of hyperactive cerebral regions when applied at low frequency (Speer et al., 2000; Catafau et al., 2001; Kimbrell et al., 2002; Loo et al., 2003). Mottaghy et al. (2002) found a significant interhemispheric asymmetry of cerebral blood flow within the prefrontal cortices favoring the right hemisphere, which was no longer detectable after treatment by rTMS. Such a result was also observed under effective drug treatment of depression (Baxter et al., 1989; Martinot et al., 1990; Kocmur et al., 1998; Ogura et al., 1998). Kimbrell et al. (1999) suggested that the level of brain metabolism could predict rTMS outcome: clinical response to high-frequency rTMS correlated with baseline cerebral glucose hypometabolism, whereas hypermetabolism correlated with the efficacy of low-frequency rTMS. It remains to ascertain that high-frequency rTMS is more efficacious when it is applied over a cortical area with reduced excitability and that low-frequency rTMS works when it is applied over a cortical area with increased excitability, as assessed by TMS testing. First, RMT was not found to be predictive for clinical response to high-frequency rTMS (Dolberg et al., 2002). On the contrary, Fitzgerald et al. (2004) reported a negative correlation between left CSP duration and antidepressant effects of rTMS: as shorter was left CSP duration, as better was rTMS efficacy. In the future, specific patterns of inhibitory and excitatory TMS parameters should be used to predict rTMS outcome or to determine the type of rTMS procedure. Motor cortex excitability can be influenced by prefrontal cortex rTMS in patients with depression. Bajbouj et al. (2005a) reported that 10 sessions of high-frequency rTMS over the left prefrontal cortex lead to increase CSP duration and ICI bilaterally. These changes correlated to clinical improvement as assessed by HRSD and Beck Depression Inventory scores. Similar results were observed after electroconvulsive therapy (ECT) (Bajbouj et al., 2005b, 2006a), associated with ICF decrease in some patients (Bajbouj et al., 2003). However, opposite results were found by Chistyakov et al. (2005a,b), including increased MEP size and reduced ICI or CSP duration following rTMS or ECT. In any case, motor corticospinal excitability is able to change with effective antidepressant therapy and inter-hemispheric asymmetry appears to depend on mood state, and thereby cannot be considered

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as a marker trait (endophenotype) for depression. The assessment of motor corticospinal excitability is a simple and possibly useful tool for monitoring brain effects of different antidepressant techniques. 5. Conclusion The present study showed an asymmetry of excitability affecting motor corticospinal pathways in patients with major depressive disorder, in favor of a reduced activation of both excitatory and inhibitory circuits on the left side. This result was consistent with various functional imaging results, even if asymmetries observed in cerebral blood flow are difficult to extrapolate to changes in TMS parameters of corticospinal excitability. The relationship between baseline or rTMS-induced changes in motor corticospinal excitability and rTMS efficacy in the treatment of depression. Conflict of interest None. References Abbruzzese G, Trompetto C. Clinical and research methods for evaluating cortical excitability. Journal of Clinical Neurophysiology 2002;19: 307–21. Auer DP, Putz B, Kraft E, Lipinski B, Schill J, Holsboer F. Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study. Biological Psychiatry 2000;47:305–13. Bajbouj M, Gallinat J, Lang UE, Neu P, Niehaus L. Motorcortical excitability after electroconvulsive therapy in patients with major depressive disorder. Supplements to Clinical Neurophysiology 2003;56:433–40. Bajbouj M, Brakemeier EL, Schubert F, Lang UE, Neu P, Schindowski C, et al. Repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex and cortical excitability in patients with major depressive disorder. Experimental Neurology 2005a;196:332–8. Bajbouj M, Luborzewski A, Danker-Hopfe H, Lang UE. Motor cortical excitability in depressive patients after electroconvulsive therapy and repetitive transcranial magnetic stimulation. Journal of ECT 2005b;21: 243–5. Bajbouj M, Lang UE, Niehaus L, Hellen FE, Heuser I, Neu P. Effects of right unilateral electroconvulsive therapy on motor cortical excitability in depressive patients. Journal of Psychiatry Research 2006a;40: 322–7. Bajbouj M, Lisanby SH, Lang UE, Danker-Hopfe H, Heuser I, Neu P. Evidence for impaired cortical inhibition in patients with unipolar major depression. Biological Psychiatry 2006b;59:395–400. Baxter LR, Schwartz JM, Phelps ME, Mazziotta JC, Guze BH, Selin CE, et al. Reduction of prefrontal cortex glucose metabolism common to three types of depression. Archives of General Psychiatry 1989;46: 243–50. Caligiuri MP, Ellwanger J. Motor and cognitive aspects of motor retardation in depression. Journal of Affective Disorders 2000;57: 83–93. Cantello R, Gianelli M, Civardi C, Mutani R. Magnetic brain stimulation: the silent period after the motor evoked potential. Neurology 1992;42:1951–9. Catafau AM, Perez V, Gironell A, Martin JC, Kulisevsky J, Estorch M, et al. SPECT mapping of cerebral activity changes induced by

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