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Motor cortical excitability and clinical response to rTMS in depression
Journal of Affective Disorders 82 (2004) 71 – 76 www.elsevier.com/locate/jad
Research report
Motor cortical excitability and clinical response to rTMS in depression Paul B. Fitzgerald a,*, Timothy L. Brown a, Natasha A.U. Marston a, Z. Jeff Daskalakis b, Anthony de Castella a, John L. Bradshaw c, Jayashri Kulkarni a a
Alfred Psychiatry Research Center, The Alfred and Monash University, Department of Psychological Medicine, Level 2, Old Baker Building, Commercial Road, Melbourne, Vic. 3004, Australia b Center for Addiction and Mental Health, Clarke Division, Toronto, Ontario, Canada c Department of Psychology, Neuropsychology Research Group, Monash University, Australia Received 9 May 2003; received in revised form 29 September 2003; accepted 29 September 2003
Abstract Background: The relationship between frontal lobe activity in the left and right hemispheres and the pathophysiology of depression remains unclear. In addition, it is uncertain whether levels of frontal or motor cortical excitability relate to clinical response to treatment modalities. We aimed to explore whether motor cortical excitability as assessed with single and paired pulse transcranial magnetic stimulation (TMS) could be used to predict the response to treatment with repetitive TMS (rTMS) applied to the left or right prefrontal cortex. Methods: Motor thresholds, cortical excitability and cortical inhibition (CI) were assessed prior to a trial of rTMS in patients with treatment resistant depression. Results: There was no consistent pattern of differences in hemispheric activity, although there was a relationship between the degree of psychopathology and cortical excitability (right hemisphere) and an inverse relationship between inhibitory activity and clinical response (left hemisphere). Conclusions: The study does not support a simple model of laterality in motor cortical excitability in depression. The TMS measures used in this study appear to be of limited use in the prediction of clinical response to rTMS. D 2003 Elsevier B.V. All rights reserved. Keywords: Repetitive transcranial magnetic stimulation; Depression; Prefrontal cortex; Cortical excitability; Cortical inhibition
1. Introduction Changes in activity levels in frontal cortical regions have been widely implicated in the pathophysiology of depression. It has been suggested that depression is accompanied by a relative reduction in * Corresponding author. Tel.: +61-3-9276-6552; fax: +61-39276-6556. E-mail address: [email protected] (P.B. Fitzgerald). 0165-0327/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2003.09.014
left prefrontal cortical (PFC) activity compared to activity in the contralateral hemisphere. This has been supported by imaging studies indicating left frontal hypoactivity (Baxter et al., 1989) and right sided hyperactivity (Abou-Saleh et al., 1999) and EEG studies that show left –right prefrontal alpha EEG asymmetry (Davidson and Meltzer-Brody, 1999). Differences in cortical activity in depressed subjects have also been demonstrated in transcranial magnetic stimulation (TMS) studies of the motor cortex. For example, Meada et al. assessed bilateral
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motor cortical excitability in a small group of depressed subjects and a group of normal controls (Maeda et al., 2000). They found a greater resting motor threshold (RMT) on the left in the patient group and differences in paired pulse curves suggesting lowered left and greater right sided excitability in the patients compared to the control group. Paired pulse TMS (ppTMS) has been extensively used over recent years to assess motor cortical excitability in various neuropsychiatric disorders (for example Daskalakis et al., 2002; Fitzgerald et al., 2002). In ppTMS a supra-threshold stimulus is paired with a preceding sub-threshold stimulus and the response to the paired stimuli may be increased (facilitation) or decreased (inhibition) depending on the interstimulus interval (ISI) (Kujirai et al., 1993). Inhibitory cortical activity can also be measured through the recording of the cortical silent period (CSP) which is a period of suppression of tonic motor activity produced following the induction of a descending motor evoked potential (MEP). The objective of this study was to assess cortical excitability in a sample of patients involved in a treatment trial with repetitive TMS (rTMS) for major depression. We aimed to investigate differences between the left and right motor cortex and whether cortical excitability levels would predict clinical response to rTMS.
2. Methods 2.1. Subjects Patients were included in this study who participated in a clinical trial of rTMS. The design of the trial and outcome data have been reported separately (Fitzgerald et al., 2003). In brief, 60 patients with treatment resistant depression (54 patients—major depressive episode, 6—bipolar I disorder) were enrolled and randomized to either a sham condition, high frequency left prefrontal active rTMS (LA) or low frequency right prefrontal active rTMS (RA). All patients received 10 daily sessions of treatment under double-blind conditions. After the 10 sessions, patients who met criteria for response could continue for a further 10 sessions. Non-responders and the
sham group were able to cross over to alternative conditions and were treated under single blind conditions (raters remained blind to group). All the patients had received treatment with at least two courses of antidepressant medication at standard doses for at least 6 weeks and scored ˚ sberg Depresgreater than 20 on the Montgomery –A sion Rating Scale (MADRS) (Montgomery and Asberg, 1979). Forty six of the patients were on medication during assessment and the trial. Thirteen patients were taking a selective serotonin reuptake inhibitor, one a tricyclic antidepressant, eight a monoamine oxidase inhibitor, 21 patients a serotonin –noradrenaline reuptake inhibitor or other class of medication (venlafaxine, mirtazipine, reboxetine) and three patients were on a combination of antidepressants. In addition, eight patients were receiving lithium, three patients Na Valproate, two patients Carbamazepine, two patients Lamotrigine and one patient the combination of Lithium and Carbamazepine. Fourteen patients were receiving antipsychotic medication (seven Olanzapine, three Quetiapine and four Risperidone). Written informed consent was obtained from all patients on a form approved by the Human Research Ethics committees of Southern Health, Dandenong Hospital and The Alfred Hospital. 2.2. Testing procedures EMG was recorded from the right abductor pollicis brevis (APB) muscle using techniques that we have previously described (Fitzgerald et al., 2002). In all subjects, cortical excitability was assessed once, immediately prior to the commencement of the first session of treatment in the clinical trial. The TMS methods have been described in detail previously (Fitzgerald et al., 2002). In brief, focal TMS was administered with a figure-of-8 coil (70 mm coil diameter) using two Magstim 200 magnetic stimulators (Magstim, Sheffield, UK) and a Bistim module (Magstim). Initially, the site that produced the largest MEP in the APB muscle for each hand was located. The operator during the TMS procedure and the person performing offline data scoring were blind to the treatment group the patients would enter in the clinical trial. All subjects were tested with the following protocol.
P.B. Fitzgerald et al. / Journal of Affective Disorders 82 (2004) 71–76
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2.2.1. Resting and active motor threshold The RMT was determined as the minimum stimulator intensity that evoked a peak-to-peak MEP of >50 AV in at least five out of 10 consecutive trials during 1% reductions in intensity from above threshold. Active motor threshold (AMT) was measured during a sustained low intensity contraction (5 – 10% of maximal) with visual monitoring and feedback. The AMT was determined as the lowest intensity producing at least 1 MEP of 100 AV in five consecutive trials.
Depression Inventory (BDI) (Beck et al., 1961), the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962) and the CORE rating of psychomotor disturbance (Parker et al., 1990). The CORE rating consists of 18 signs which are summed into three dimensions, non-interactiveness, retardation and agitation. Handedness was rated with the Oldfield handedness questionnaire (Oldfield, 1971).
2.2.2. Measurement of MEP size and cortical silent period MEP size was recorded at rest with visual monitoring and feedback. Ten sweeps of data were recorded during stimulation at 125% of the RMT. CSP duration was measured during a sustained contraction of 5% of maximum. Ten sweeps of data were recorded with stimulation at 125% of the AMT. The CSP duration was defined as the time from stimulation until return of voluntary tonic motor activity and was measured on averaged rectified sweeps.
Log transformation was required to adjust the CSP, MEP, CI and CF data to meet the assumptions of normality. To test for differences in the TMS measures between the hemispheres, a multivariate general linear model was calculated with hemisphere as the within subjects measure and the TMS measures as the dependent variables. Pair-wise t-tests were subsequently calculated for each dependent variable with Bonferroni adjustment for multiple comparisons. Separate models were calculated to test for differences between the two hemispheres on the various dependent measures for the group excluding patients receiving treatment with antipsychotic, anticonvulsant and all medications. Separate multivariate models were also calculated for patients with high (>7) and low ( < 8) CORE scores excluding patients receiving treatment with anticonvulsant medication. Pearson’s correlation coefficients were calculated to explore the relationship between TMS measures and psychopathology. Supplementary analyses were also conducted excluding patients receiving anticonvulsant medication. Correlation coefficients were also used to investigate relationships between TMS measures and clinical response. Correlations were calculated between TMS measures and response (total MADRS score at baseline minus MADRS total at week 2) across the double-blind phase of the trial (initial 10 sessions). Correlations were also calculated with MADRS change scores (baseline minus end trial) for the patients who received a total of 4 weeks of treatment. All statistical procedures were calculated in SPSS 11.5 and all tests were two-tailed. A significance level of < 0.05 was used except during correlations where a level of < 0.01 was considered significant to control for multiple comparisons.
2.2.3. Cortical inhibition and facilitation The procedure for measuring cortical inhibition (CI) and cortical facilitation (CF) followed that described in the literature (Kujirai et al., 1993; Ziemann et al., 1996a,b). All measurements were conducted at rest with continual EMG monitoring. The second stimulus (test stimulus) was of a consistent intensity that would produce a moderate MEP response (0.5 – 1.5 mV). The initial or conditioning stimulus was set at 5% below the AMT and did not produce a MEP response (Ziemann et al., 1996a,b). The ISI was varied through the procedure in a pseudo-random allocation. Ten trials of data were recorded for four conditions; a control single stimulus and at 1, 3, and 15 ms intervals. CI and CF were calculated as percentages of the mean control condition based on the average peak-to-peak MEP size for each ISI and the control condition. 2.3. Clinical assessments All patients were assessed at baseline and at each 10-session review with the MADRS, the Beck
2.4. Statistical analysis
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3. Results
3.2. Relationship of TMS measures to psychopathology
All subjects tolerated the procedures without difficulty. Measurements were not able to be performed in a number of subjects due to technical difficulties with the ppTMS equipment. The complete data set was available for 55 subjects enrolled in the clinical trial.
A number of significant correlations were seen between psychopathology measures and right sided CF. These included positive correlations with BDI score (r = 0.35, P < 0.01), BPRS total score (r = 0.43, P = 0.001) and CORE total score (r = 0.44, P = 0.001). No significant correlations were seen with other measures. These relationships remained significant excluding patients taking anticonvulsant medication.
3.1. Laterality TMS data for all subjects is presented in Table 1. In the multivariate model there was a significant effect of hemisphere ( F(7,45) = 2.4, P < 0.05). There was significantly less CI on the right side which was significant for the 1 ms ISI ( P < 0.05) but not the 3 ms ISI. The difference between RMT levels was significant at a trend level ( P = 0.09). When the model was re-calculated excluding the subjects taking antipsychotic and mood stabilizing medication, the overall effect of hemisphere and the difference in CI at 1 ms did not remain significant. The difference in RMT was significant when these medication groups were excluded ( P < 0.05). There was also no differences between hemispheres in the subjects receiving no medication treatment (n = 12). Separate multivariate models were also calculated for subjects with or without high CORE total scores. There was a significant difference in CI scores (1 ms ISI) between hemispheres for the subjects with a high CORE score ( P < 0.05) but no differences for those with low CORE scores.
Table 1 TMS measures for each hemisphere Measure
RMT (%) AMT (%) MEP size (AV) CSP (ms) CI-1 (%) CI-3 (%) CF
Left
Right
Sign
Mean
S.D.
Mean
S.D.
46.8 35.2 724.9 61.7 39.7 55.0 147.2
9.2 7.3 529.9 22.0 32.3 44.9 90.6
48.2 35.0 673.7 64.5 29.7 46.7 128.4
9.0 7.2 617.6 28.8 24.0 33.4 45.5
0.09 0.93 0.30 0.47 0.04 0.28 0.14
The dependent variable values for all subjects (RMT, resting motor threshold; AMT, active motor threshold; MEP, motor evoked potential; CSP, cortical silent period; CI, cortical inhibition; CF, cortical facilitation).
3.3. Relationship of TMS measures to clinical response The only relationship found between TMS variables and clinical response (change in MADRS scores in the double blind phase of the trial), was with the left sided CSP duration (r = 0.37, P < 0.005). Longer CSP (greater inhibition) was associated with poorer clinical response. This relationship was significant when calculated for the high CORE score group (r = 0.43, P < 0.05) but not the low CORE score group and remained significant excluding patients on anticonvulsant medication. As well as the double blind phase, correlations were calculated between TMS measures and clinical response across the entire trial (baseline minus treatment end scores). In this analysis, longer CSP duration was associated with poorer clinical response at a trend level (r = 0.23, P = 0.08) as was right sided MEP size (r = 0.37, P < 0.005). These remained significant excluding patients receiving anticonvulsants. For the patients who received high frequency left sided TMS treatment for 4 weeks, increased CI was associated with poorer clinical response at marginally significant levels (CI at 1 ms: r = 0.82, P = 0.01, CI at 3 ms: r = 0.83, P = 0.01). There were no relationships between response and TMS measures for the patients receiving 4 weeks of RA treatment.
4. Discussion Our study found an indication of reduced motor cortical excitability in the left hemisphere of subjects with depression (increased CI, lower RMT levels)
P.B. Fitzgerald et al. / Journal of Affective Disorders 82 (2004) 71–76
especially in subjects rated with higher CORE scores of melancholia although we did not find a clear and consistent pattern of altered excitability over several TMS measures. We also found a relationship between excitability in the right hemisphere and the severity of psychopathology. In addition, the study’s findings suggested a relationship between increased inhibition in the left motor cortex (reduced excitability) and poorer response to rTMS in the clinical trial, especially in the subjects with a greater degree of melancholic symptoms. The finding of reduced left sided excitability in this patient group is consistent with one previous report of a relative reduction in left sided activity (Maeda et al., 2000). The major difficulty with interpretation of these results lies in the heterogeneous nature of our sample as several classes of psychotropic medications, especially anticonvulsants, have been shown to influence motor cortical excitability (Manganotti et al., 2001; Ziemann et al., 1996a,b, 1997). This issue is of limited concern, however, when questioning whether these TMS measures can be used to predict therapeutic response to treatment, as in ‘real world’ clinical settings patients are likely to be receiving treatment with a variety of medication types and any predictive tool would need to have validity in that environment. However, even though there was a relationship found between the left sided CSP duration and clinical response, this was relatively weak and it seems unlikely that measures of CSP duration could be applied in a way that would have predictive value. This result is consistent with the results of Dolberg et al. who failed to find a predictive relationship between RMT levels and clinical response to high frequency left sided rTMS (Dolberg et al., 2002). The meaning of the relationship between greater left sided inhibition (reduced excitability) and poor response is not clear. On the surface this would appear to contradict previous imaging research which found that lower left frontal activity greater was associated with enhanced, not poorer, clinical response to high frequency left sided rTMS (Kimbrell et al., 1999). However, a comparison of these TMS and imaging studies is problematic as it is not clear how inhibition (for example GABAergic activity) relates to metabolism or blood flow. Activa-
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tion in some functional imaging paradigms seems much more highly linked to excitation than inhibition (Waldvogel et al., 2000). It is possible that increased GABAergic activity may result in increased blood flow through the disinhibition of activity in excitatory neurons. The relationship between right sided CF and psychopathology was of interest, especially as it was seen across all of the rating scales used in the study and it presents some support for the notion of right sided ‘hyper-excitability’ in depression. The role of altered frontal activity in depression remains unclear. Some imaging studies have suggested that depression relates to a reduction in left frontal activity, (for example Baxter et al., 1989; Teneback et al., 1999) although these studies have not specifically focused on treatment resistant depression. Alternative models include the possibility that there is a relative imbalance between the two hemispheres (Davidson and Meltzer-Brody, 1999) or that there are differences in the pathogenic hemisphere between illness subtypes or between individuals. To date, there is limited direct evidence to support either of these alternative hypotheses although further research is clearly required to explore the relationship between activity levels and mood alteration. In conclusion, our study provides supporting evidence for alterations in motor cortical excitability in depression and an indication that these findings are more clearly related to the degree of melancholic symptoms. We also found a relationship between cortical activity and response to rTMS in the clinical trial. However, the strength of this association indicates that these TMS measures of motor cortical excitability are unlikely to be of utility in the prediction of antidepressant response to rTMS.
Acknowledgements The study was supported by a National Health and Medical Research Council grant (143651) and a grant from The Stanley Medical Research Institute. We would like to thank the patients whose participation was essential in the successful completion of the study. We would also like to thank Dr. Marlies Largerberg and Dr. James Zurek who assisted with the provision of rTMS during the clinical trial.
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References Abou-Saleh, M.T., Al Suhaili, A.R., Karim, L., Prais, V., Hamdi, E., 1999. Single photon emission tomography with 99 m TcHMPAO in Arab patients with depression. J. Affect. Disord. 55, 115 – 123. Baxter Jr., 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 common to three types of depression. Arch. Gen. Psychiatry 46, 243 – 250. Beck, A., Ward, C., Mendelson, M., Mock, J., Erbaugh, J., 1961. An inventory for measuring depression. Arch. Gen. Psychiatry 4, 561 – 571. Daskalakis, Z.J., Christensen, B.K., Chen, R., Fitzgerald, P.B., Zipursky, R., Kapur, S., 2002. Evidence for impaired cortical inhibition in schizophrenia using transcranial magnetic stimulation. Arch. Gen. Psychiatry 59, 347 – 354. Davidson, J.R., Meltzer-Brody, S.E., 1999. The underrecognition and undertreatment of depression: what is the breadth and depth of the problem? J. Clin. Psychiatry 60 (Suppl. 7), 4 – 9 (discussion 10-1). Dolberg, O.T., Dannon, P.N., Schreiber, S., Grunhaus, L., 2002. Magnetic motor threshold and response to TMS in major depressive disorder. Acta Psychiatr. Scand. 106, 220 – 223. Fitzgerald, P.B., Brown, T., Daskalakis, Z.J., Kulkarni, J., 2002. A transcranial magnetic stimulation study of inhibitory deficits in the motor cortex in patients with schizophrenia. Psychiatry Res. Neuroimaging 114, 11 – 22. Fitzgerald, P.B., Brown, T., Marston, N.A.U., Daskalakis, Z.J., de Castella, A., Kulkarni, J., 2003. A double-blind placebo controlled trial of transcranial magnetic stimulation in the treatment of depression. Arch. Gen. Psychiatry 60, 1002 – 1008. 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 antidepressant response to left prefrontal repetitive transcranial magnetic stimulation (rTMS) as a function of baseline cerebral glucose metabolism. Biol. Psychiatry 46, 1603 – 1613.
Kujirai, T., Caramia, M.D., Rothwell, J.C., Day, B.L., Thompson, P.D., Ferbert, A., Wroe, S., Asselman, P., Marsden, C.D., 1993. Corticocortical inhibition in human motor cortex. J. Physiol. (London) 471, 501 – 519. Maeda, F., Keenan, J.P., Pascual-Leone, A., 2000. Interhemispheric asymmetry of motor cortical excitability in major depression as measured by transcranial magnetic stimulation. Br. J. Psychiatry 177, 169 – 173. Manganotti, P., Bortolomasi, M., Zanette, G., Pawelzik, T., Giacopuzzi, M., Fiaschi, A., 2001. Intravenous clomipramine decreases excitability of human motor cortex. A study with paired magnetic stimulation. J. Neurol. Sci. 184, 27 – 32. Montgomery, S.A., Asberg, M., 1979. A new depression scale designed to be sensitive to change. Br. J. Psychiatry 134, 382 – 389. Oldfield, R.C., 1971. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9, 97 – 113. Overall, J.E., Gorham, D., 1962. The Brief Psychiatric Rating Scale. Psychol. Rep. 10, 799 – 812. Parker, G., Hadzi-Pavlovic, D., Boyce, P., Wilhelm, K., Brodaty, H., Mitchell, P., Hickie, I., Eyers, K., 1990. Classifying depression by mental state signs. Br. J. Psychiatry 157, 55 – 65. Teneback, C.C., Nahas, Z., Speer, A.M., Molloy, M., Stallings, L.E., Spicer, K.M., Risch, S.C., George, M.S., 1999. Changes in prefrontal cortex and paralimbic activity in depression following 2 weeks of daily left prefrontal TMS. J. Neuropsychiatry Clin. Neurosci. 11, 426 – 435. Waldvogel, D., van Gelderen, P., Muellbacher, W., Ziemann, U., Immisch, I., Hallett, M., 2000. The relative metabolic demand of inhibition and excitation. Nature 406, 995 – 998. Ziemann, U., Rothwell, J.C., Ridding, M.C., 1996a. Interaction between intracortical inhibition and facilitation in human motor cortex. J. Physiol. (London) 493, 873 – 881. Ziemann, U., Lonnecker, S., Steinhoff, B.J. et al., 1996b. Effects of antiepileptic drugs on motor cortex excitability in humans: a transcranial stimulation study. Ann. Neurol. 40, 367 – 378. Ziemann, U., Tergau, F., Bruns, D., Baudewig, J., Paulus, W., 1997. Changes in human motor cortex excitability induced by dopaminergic and anti-dopaminergic drugs. Electroencephalogr. Clin. Neurophysiol. 105, 430 – 437.
Research report
Motor cortical excitability and clinical response to rTMS in depression Paul B. Fitzgerald a,*, Timothy L. Brown a, Natasha A.U. Marston a, Z. Jeff Daskalakis b, Anthony de Castella a, John L. Bradshaw c, Jayashri Kulkarni a a
Alfred Psychiatry Research Center, The Alfred and Monash University, Department of Psychological Medicine, Level 2, Old Baker Building, Commercial Road, Melbourne, Vic. 3004, Australia b Center for Addiction and Mental Health, Clarke Division, Toronto, Ontario, Canada c Department of Psychology, Neuropsychology Research Group, Monash University, Australia Received 9 May 2003; received in revised form 29 September 2003; accepted 29 September 2003
Abstract Background: The relationship between frontal lobe activity in the left and right hemispheres and the pathophysiology of depression remains unclear. In addition, it is uncertain whether levels of frontal or motor cortical excitability relate to clinical response to treatment modalities. We aimed to explore whether motor cortical excitability as assessed with single and paired pulse transcranial magnetic stimulation (TMS) could be used to predict the response to treatment with repetitive TMS (rTMS) applied to the left or right prefrontal cortex. Methods: Motor thresholds, cortical excitability and cortical inhibition (CI) were assessed prior to a trial of rTMS in patients with treatment resistant depression. Results: There was no consistent pattern of differences in hemispheric activity, although there was a relationship between the degree of psychopathology and cortical excitability (right hemisphere) and an inverse relationship between inhibitory activity and clinical response (left hemisphere). Conclusions: The study does not support a simple model of laterality in motor cortical excitability in depression. The TMS measures used in this study appear to be of limited use in the prediction of clinical response to rTMS. D 2003 Elsevier B.V. All rights reserved. Keywords: Repetitive transcranial magnetic stimulation; Depression; Prefrontal cortex; Cortical excitability; Cortical inhibition
1. Introduction Changes in activity levels in frontal cortical regions have been widely implicated in the pathophysiology of depression. It has been suggested that depression is accompanied by a relative reduction in * Corresponding author. Tel.: +61-3-9276-6552; fax: +61-39276-6556. E-mail address: [email protected] (P.B. Fitzgerald). 0165-0327/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2003.09.014
left prefrontal cortical (PFC) activity compared to activity in the contralateral hemisphere. This has been supported by imaging studies indicating left frontal hypoactivity (Baxter et al., 1989) and right sided hyperactivity (Abou-Saleh et al., 1999) and EEG studies that show left –right prefrontal alpha EEG asymmetry (Davidson and Meltzer-Brody, 1999). Differences in cortical activity in depressed subjects have also been demonstrated in transcranial magnetic stimulation (TMS) studies of the motor cortex. For example, Meada et al. assessed bilateral
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motor cortical excitability in a small group of depressed subjects and a group of normal controls (Maeda et al., 2000). They found a greater resting motor threshold (RMT) on the left in the patient group and differences in paired pulse curves suggesting lowered left and greater right sided excitability in the patients compared to the control group. Paired pulse TMS (ppTMS) has been extensively used over recent years to assess motor cortical excitability in various neuropsychiatric disorders (for example Daskalakis et al., 2002; Fitzgerald et al., 2002). In ppTMS a supra-threshold stimulus is paired with a preceding sub-threshold stimulus and the response to the paired stimuli may be increased (facilitation) or decreased (inhibition) depending on the interstimulus interval (ISI) (Kujirai et al., 1993). Inhibitory cortical activity can also be measured through the recording of the cortical silent period (CSP) which is a period of suppression of tonic motor activity produced following the induction of a descending motor evoked potential (MEP). The objective of this study was to assess cortical excitability in a sample of patients involved in a treatment trial with repetitive TMS (rTMS) for major depression. We aimed to investigate differences between the left and right motor cortex and whether cortical excitability levels would predict clinical response to rTMS.
2. Methods 2.1. Subjects Patients were included in this study who participated in a clinical trial of rTMS. The design of the trial and outcome data have been reported separately (Fitzgerald et al., 2003). In brief, 60 patients with treatment resistant depression (54 patients—major depressive episode, 6—bipolar I disorder) were enrolled and randomized to either a sham condition, high frequency left prefrontal active rTMS (LA) or low frequency right prefrontal active rTMS (RA). All patients received 10 daily sessions of treatment under double-blind conditions. After the 10 sessions, patients who met criteria for response could continue for a further 10 sessions. Non-responders and the
sham group were able to cross over to alternative conditions and were treated under single blind conditions (raters remained blind to group). All the patients had received treatment with at least two courses of antidepressant medication at standard doses for at least 6 weeks and scored ˚ sberg Depresgreater than 20 on the Montgomery –A sion Rating Scale (MADRS) (Montgomery and Asberg, 1979). Forty six of the patients were on medication during assessment and the trial. Thirteen patients were taking a selective serotonin reuptake inhibitor, one a tricyclic antidepressant, eight a monoamine oxidase inhibitor, 21 patients a serotonin –noradrenaline reuptake inhibitor or other class of medication (venlafaxine, mirtazipine, reboxetine) and three patients were on a combination of antidepressants. In addition, eight patients were receiving lithium, three patients Na Valproate, two patients Carbamazepine, two patients Lamotrigine and one patient the combination of Lithium and Carbamazepine. Fourteen patients were receiving antipsychotic medication (seven Olanzapine, three Quetiapine and four Risperidone). Written informed consent was obtained from all patients on a form approved by the Human Research Ethics committees of Southern Health, Dandenong Hospital and The Alfred Hospital. 2.2. Testing procedures EMG was recorded from the right abductor pollicis brevis (APB) muscle using techniques that we have previously described (Fitzgerald et al., 2002). In all subjects, cortical excitability was assessed once, immediately prior to the commencement of the first session of treatment in the clinical trial. The TMS methods have been described in detail previously (Fitzgerald et al., 2002). In brief, focal TMS was administered with a figure-of-8 coil (70 mm coil diameter) using two Magstim 200 magnetic stimulators (Magstim, Sheffield, UK) and a Bistim module (Magstim). Initially, the site that produced the largest MEP in the APB muscle for each hand was located. The operator during the TMS procedure and the person performing offline data scoring were blind to the treatment group the patients would enter in the clinical trial. All subjects were tested with the following protocol.
P.B. Fitzgerald et al. / Journal of Affective Disorders 82 (2004) 71–76
73
2.2.1. Resting and active motor threshold The RMT was determined as the minimum stimulator intensity that evoked a peak-to-peak MEP of >50 AV in at least five out of 10 consecutive trials during 1% reductions in intensity from above threshold. Active motor threshold (AMT) was measured during a sustained low intensity contraction (5 – 10% of maximal) with visual monitoring and feedback. The AMT was determined as the lowest intensity producing at least 1 MEP of 100 AV in five consecutive trials.
Depression Inventory (BDI) (Beck et al., 1961), the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962) and the CORE rating of psychomotor disturbance (Parker et al., 1990). The CORE rating consists of 18 signs which are summed into three dimensions, non-interactiveness, retardation and agitation. Handedness was rated with the Oldfield handedness questionnaire (Oldfield, 1971).
2.2.2. Measurement of MEP size and cortical silent period MEP size was recorded at rest with visual monitoring and feedback. Ten sweeps of data were recorded during stimulation at 125% of the RMT. CSP duration was measured during a sustained contraction of 5% of maximum. Ten sweeps of data were recorded with stimulation at 125% of the AMT. The CSP duration was defined as the time from stimulation until return of voluntary tonic motor activity and was measured on averaged rectified sweeps.
Log transformation was required to adjust the CSP, MEP, CI and CF data to meet the assumptions of normality. To test for differences in the TMS measures between the hemispheres, a multivariate general linear model was calculated with hemisphere as the within subjects measure and the TMS measures as the dependent variables. Pair-wise t-tests were subsequently calculated for each dependent variable with Bonferroni adjustment for multiple comparisons. Separate models were calculated to test for differences between the two hemispheres on the various dependent measures for the group excluding patients receiving treatment with antipsychotic, anticonvulsant and all medications. Separate multivariate models were also calculated for patients with high (>7) and low ( < 8) CORE scores excluding patients receiving treatment with anticonvulsant medication. Pearson’s correlation coefficients were calculated to explore the relationship between TMS measures and psychopathology. Supplementary analyses were also conducted excluding patients receiving anticonvulsant medication. Correlation coefficients were also used to investigate relationships between TMS measures and clinical response. Correlations were calculated between TMS measures and response (total MADRS score at baseline minus MADRS total at week 2) across the double-blind phase of the trial (initial 10 sessions). Correlations were also calculated with MADRS change scores (baseline minus end trial) for the patients who received a total of 4 weeks of treatment. All statistical procedures were calculated in SPSS 11.5 and all tests were two-tailed. A significance level of < 0.05 was used except during correlations where a level of < 0.01 was considered significant to control for multiple comparisons.
2.2.3. Cortical inhibition and facilitation The procedure for measuring cortical inhibition (CI) and cortical facilitation (CF) followed that described in the literature (Kujirai et al., 1993; Ziemann et al., 1996a,b). All measurements were conducted at rest with continual EMG monitoring. The second stimulus (test stimulus) was of a consistent intensity that would produce a moderate MEP response (0.5 – 1.5 mV). The initial or conditioning stimulus was set at 5% below the AMT and did not produce a MEP response (Ziemann et al., 1996a,b). The ISI was varied through the procedure in a pseudo-random allocation. Ten trials of data were recorded for four conditions; a control single stimulus and at 1, 3, and 15 ms intervals. CI and CF were calculated as percentages of the mean control condition based on the average peak-to-peak MEP size for each ISI and the control condition. 2.3. Clinical assessments All patients were assessed at baseline and at each 10-session review with the MADRS, the Beck
2.4. Statistical analysis
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3. Results
3.2. Relationship of TMS measures to psychopathology
All subjects tolerated the procedures without difficulty. Measurements were not able to be performed in a number of subjects due to technical difficulties with the ppTMS equipment. The complete data set was available for 55 subjects enrolled in the clinical trial.
A number of significant correlations were seen between psychopathology measures and right sided CF. These included positive correlations with BDI score (r = 0.35, P < 0.01), BPRS total score (r = 0.43, P = 0.001) and CORE total score (r = 0.44, P = 0.001). No significant correlations were seen with other measures. These relationships remained significant excluding patients taking anticonvulsant medication.
3.1. Laterality TMS data for all subjects is presented in Table 1. In the multivariate model there was a significant effect of hemisphere ( F(7,45) = 2.4, P < 0.05). There was significantly less CI on the right side which was significant for the 1 ms ISI ( P < 0.05) but not the 3 ms ISI. The difference between RMT levels was significant at a trend level ( P = 0.09). When the model was re-calculated excluding the subjects taking antipsychotic and mood stabilizing medication, the overall effect of hemisphere and the difference in CI at 1 ms did not remain significant. The difference in RMT was significant when these medication groups were excluded ( P < 0.05). There was also no differences between hemispheres in the subjects receiving no medication treatment (n = 12). Separate multivariate models were also calculated for subjects with or without high CORE total scores. There was a significant difference in CI scores (1 ms ISI) between hemispheres for the subjects with a high CORE score ( P < 0.05) but no differences for those with low CORE scores.
Table 1 TMS measures for each hemisphere Measure
RMT (%) AMT (%) MEP size (AV) CSP (ms) CI-1 (%) CI-3 (%) CF
Left
Right
Sign
Mean
S.D.
Mean
S.D.
46.8 35.2 724.9 61.7 39.7 55.0 147.2
9.2 7.3 529.9 22.0 32.3 44.9 90.6
48.2 35.0 673.7 64.5 29.7 46.7 128.4
9.0 7.2 617.6 28.8 24.0 33.4 45.5
0.09 0.93 0.30 0.47 0.04 0.28 0.14
The dependent variable values for all subjects (RMT, resting motor threshold; AMT, active motor threshold; MEP, motor evoked potential; CSP, cortical silent period; CI, cortical inhibition; CF, cortical facilitation).
3.3. Relationship of TMS measures to clinical response The only relationship found between TMS variables and clinical response (change in MADRS scores in the double blind phase of the trial), was with the left sided CSP duration (r = 0.37, P < 0.005). Longer CSP (greater inhibition) was associated with poorer clinical response. This relationship was significant when calculated for the high CORE score group (r = 0.43, P < 0.05) but not the low CORE score group and remained significant excluding patients on anticonvulsant medication. As well as the double blind phase, correlations were calculated between TMS measures and clinical response across the entire trial (baseline minus treatment end scores). In this analysis, longer CSP duration was associated with poorer clinical response at a trend level (r = 0.23, P = 0.08) as was right sided MEP size (r = 0.37, P < 0.005). These remained significant excluding patients receiving anticonvulsants. For the patients who received high frequency left sided TMS treatment for 4 weeks, increased CI was associated with poorer clinical response at marginally significant levels (CI at 1 ms: r = 0.82, P = 0.01, CI at 3 ms: r = 0.83, P = 0.01). There were no relationships between response and TMS measures for the patients receiving 4 weeks of RA treatment.
4. Discussion Our study found an indication of reduced motor cortical excitability in the left hemisphere of subjects with depression (increased CI, lower RMT levels)
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especially in subjects rated with higher CORE scores of melancholia although we did not find a clear and consistent pattern of altered excitability over several TMS measures. We also found a relationship between excitability in the right hemisphere and the severity of psychopathology. In addition, the study’s findings suggested a relationship between increased inhibition in the left motor cortex (reduced excitability) and poorer response to rTMS in the clinical trial, especially in the subjects with a greater degree of melancholic symptoms. The finding of reduced left sided excitability in this patient group is consistent with one previous report of a relative reduction in left sided activity (Maeda et al., 2000). The major difficulty with interpretation of these results lies in the heterogeneous nature of our sample as several classes of psychotropic medications, especially anticonvulsants, have been shown to influence motor cortical excitability (Manganotti et al., 2001; Ziemann et al., 1996a,b, 1997). This issue is of limited concern, however, when questioning whether these TMS measures can be used to predict therapeutic response to treatment, as in ‘real world’ clinical settings patients are likely to be receiving treatment with a variety of medication types and any predictive tool would need to have validity in that environment. However, even though there was a relationship found between the left sided CSP duration and clinical response, this was relatively weak and it seems unlikely that measures of CSP duration could be applied in a way that would have predictive value. This result is consistent with the results of Dolberg et al. who failed to find a predictive relationship between RMT levels and clinical response to high frequency left sided rTMS (Dolberg et al., 2002). The meaning of the relationship between greater left sided inhibition (reduced excitability) and poor response is not clear. On the surface this would appear to contradict previous imaging research which found that lower left frontal activity greater was associated with enhanced, not poorer, clinical response to high frequency left sided rTMS (Kimbrell et al., 1999). However, a comparison of these TMS and imaging studies is problematic as it is not clear how inhibition (for example GABAergic activity) relates to metabolism or blood flow. Activa-
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tion in some functional imaging paradigms seems much more highly linked to excitation than inhibition (Waldvogel et al., 2000). It is possible that increased GABAergic activity may result in increased blood flow through the disinhibition of activity in excitatory neurons. The relationship between right sided CF and psychopathology was of interest, especially as it was seen across all of the rating scales used in the study and it presents some support for the notion of right sided ‘hyper-excitability’ in depression. The role of altered frontal activity in depression remains unclear. Some imaging studies have suggested that depression relates to a reduction in left frontal activity, (for example Baxter et al., 1989; Teneback et al., 1999) although these studies have not specifically focused on treatment resistant depression. Alternative models include the possibility that there is a relative imbalance between the two hemispheres (Davidson and Meltzer-Brody, 1999) or that there are differences in the pathogenic hemisphere between illness subtypes or between individuals. To date, there is limited direct evidence to support either of these alternative hypotheses although further research is clearly required to explore the relationship between activity levels and mood alteration. In conclusion, our study provides supporting evidence for alterations in motor cortical excitability in depression and an indication that these findings are more clearly related to the degree of melancholic symptoms. We also found a relationship between cortical activity and response to rTMS in the clinical trial. However, the strength of this association indicates that these TMS measures of motor cortical excitability are unlikely to be of utility in the prediction of antidepressant response to rTMS.
Acknowledgements The study was supported by a National Health and Medical Research Council grant (143651) and a grant from The Stanley Medical Research Institute. We would like to thank the patients whose participation was essential in the successful completion of the study. We would also like to thank Dr. Marlies Largerberg and Dr. James Zurek who assisted with the provision of rTMS during the clinical trial.
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