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Analysis of Brain Functional Changes in High-Frequency Repetitive Transcranial Magnetic Stimulation in Treatment-Resistant Depression Serhat Ozekes, Turker Erguzel, Gokben Hizli Sayar and Nevzat Tarhan Clin EEG Neurosci 2014 45: 257 originally published online 14 April 2014 DOI: 10.1177/1550059413515656 The online version of this article can be found at: http://eeg.sagepub.com/content/45/4/257
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515656 research-article2014
EEGXXX10.1177/1550059413515656Ozekes et alClinical EEG and Neuroscience
Article
Analysis of Brain Functional Changes in High-Frequency Repetitive Transcranial Magnetic Stimulation in Treatment-Resistant Depression
Clinical EEG and Neuroscience 2014, Vol. 45(4) 257–261 © EEG and Clinical Neuroscience Society (ECNS) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1550059413515656 eeg.sagepub.com
Serhat Ozekes1, Turker Erguzel1, Gokben Hizli Sayar2,3, and Nevzat Tarhan2,3
Abstract Repetitive transcranial magnetic stimulation (rTMS) is a treatment procedure that uses magnetic fields to stimulate nerve cells in the brain, and is associated with significant improvements in clinical symptoms of major depressive disorder (MDD). The effect of rTMS treatment on the brain can be evaluated by cordance, a quantitative electroencephalography (QEEG) method that extracts information from absolute and relative power of EEG spectra. In this study, to analyze brain functional changes, preand post-rTMS, QEEG data were collected from 6 frontal electrodes (Fp1, Fp2, F3, F4, F7, and F8) in 2 slow bands (delta and theta) for 55 MDD subjects. To examine brain changes, cordance scores were determined, using repeated-measures analysis of variance (ANOVA). High-frequency rTMS was associated with cordance decrease in left frontal and right prefrontal regions in both delta and theta for nonresponders; it was associated with cordance increase in all right and left frontal electrodes, except F8, for responders. Keywords repetitive transcranial magnetic stimulation, QEEG cordance, repeated-measures analysis of variance, major depressive disorder, analysis of brain functional changes Received August 15, 2013; revised October 11, 2013; accepted November 10, 2013.
Introduction The treatment of MDD with rTMS, investigated intensively in recent years as an alternative to antidepressants, is associated with significant improvements in clinical symptoms. Around 40% of patients fail to respond to an initial course of antidepressant treatment.1 Since a large number fail to respond to antidepressants, there is a clear need for methods that determine the right treatment for the right patient.2 Compared with electroconvulsive therapy (ECT), rTMS is less invasive and painful.3,4 The establishment of the efficacy of rTMS has increased interest in finding potential predictors of clinical response. Studies have been primarily with neurophysiological EEG5,6 and functional neuroimaging biomarkers.7,8 These studies demonstrated the predictive capability of change of frontal QEEG cordance in theta and delta frequency bands. QEEG cordance is one of the auspicious biomarkers, used to predict the treatment response, which has generated research interest. Cordance is related to absolute and relative spectral powers, derived from the resting EEG. The reason for using absolute and relative power, is that brain areas with abnormal function may have low absolute but high relative spectral power.9
When treatment responses of MDD subjects were analyzed, neurophysiologic changes were observed early in antidepressant treatment.10-12 rTMS delivered over the motor cortex has different effects on cortical excitability, depending on the pulse frequency.13 Frequencies in the range of 5 to 20 Hz enhance cortical response (facilitation), which is demonstrated by decreased motor-evoked potential (MEP) threshold.14,15 Repeated stimulation at frequencies of about 1 Hz inhibits cortical response.16 According to Speer et al,13 flow in frontal, and related subcortical circuits, increases in high-frequency (10-20 Hz) and decreases in low-frequency (1-5Hz) rTMS. Valiulis et al17 concluded that delta power increases on the left hemisphere, and alpha power on the right, in high-frequency (10 Hz) rTMS. 1
Department of Computer Engineering, Faculty of Engineering and Natural Sciences, Uskudar University, Istanbul, Turkey 2 Department of Psychiatry, NPIstanbul Hospital, Istanbul, Turkey 3 Department of Psychology, Faculty of Humanities and Social Sciences, Uskudar University, Istanbul, Turkey Corresponding Author: Serhat Ozekes, Department of Computer Engineering, Faculty of Engineering and Natural Sciences, Uskudar University, Istanbul, Turkey. Email: [email protected] Full-color figures are available online at http://eeg.sagepub.com
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Another study18 showed that all 9 responders’, and 6 out of 16 nonresponders’, prefrontal cordance value decreased after the first week of 1-Hz rTMS. High- is more effective than low-frequency rTMS in MDD, according to rando mized clinical trials that compare high and low stimulation frequencies.19-21 This study analyzed brain functional changes in treatment of depression using high-frequency (25 Hz) rTMS. The cordance values of frontal electrodes in delta and theta before and after rTMS were analyzed using ANOVA for responders and nonresponders.
Materials and Methods Subjects The research, conducted in the Neuropsychiatry Istanbul Hospital, was approved by the local Medical Research Ethics Committee. Patients met inclusion criteria as determined by their psychiatrist. All were free of psychotropic medication for at least 2 weeks prior to enrollment. Subjects who met the Structured Clinical Interview for DSM-IV criteria for depression, and scored higher than 14 on the 17-item Hamilton Depression Rating Scale (HAMD), were eligible. A total of 55 MDD subjects, resistant to medication treatment, completed the protocols for the study. Responder and nonresponder groups did not differ with respect to the psychopharmacological treatment process. To minimize potential confusing outcomes of pharmacological withdrawal symptoms, all subjects were on a monotherapy regimen and received concurrent selective serotonin reuptake inhibitor (SSRI) antidepressant medication during 20 sessions of rTMS therapy. No patients were receiving lithium, mood stabilizers or benzodiazepines. A baseline assessment was conducted on the day prior to rTMS treatment by a psychiatrist using the 17-item HAMD scale. Twice during the study patients had clinical, neuropsychological, and QEEG assessments. Complete blood count, chemistry, thyroid stimulating hormone, urine toxicology, and electrocardiogram were performed at screening, and subjects were required to be medically stable before entry. Patients with organic brain disorders, pacemakers, psychotic symptoms, dementia, delirium, substance-related disorders, cluster A or B axis II disorders, ECT in the prior 6 months, history of craniotomy, skull fracture, seizures, neurological illness, suicidal intent, plan, or attempt were ineligible.
Quantitative EEG Techniques and Cordance Calculations Cordance, introduced by Leuchter et al,22 combines complementary information from absolute and relative power of EEG spectra, to yield values that correlate with regional cerebral perfusion better than either measure alone.23 Pre- and posttreatment QEEG data were collected in the eyes-closed, maximally alert state, in a quiet room with subdued lighting. The researchers monitored QEEG data and alerted the subjects
every minute as needed to avoid drowsiness. Three minutes of eye-closed EEG at rest were acquired, using Scan LT EEG amplifier and electrode cap (Compumedics/Neuroscan, Charlotte, NC), with a sampling rate of 250 Hz. Nineteen sintered Ag/AgCl electrodes were positioned according to the 10/20 International System with binaural reference. The data from 6 frontal electrodes (Fp1, Fp2, F3, F4, F7, and F8) in delta and theta were used. Raw EEG signal was filtered through a band-pass of 0.15-30 Hz before artifact elimination. Manually selected (minimum 2 minutes) artifact-free EEG data, with minimal split-half reliability ratio of 0.95 and test–retest reliability ratio of 0.09 were used for cordance calculations. Prior to calculation of absolute and relative power, electrode referencing was to bipolar electrode pairs for cordance.24 Fast Fourier Transform was used to calculate absolute and relative power in each of 2 nonoverlapping frequency bands: delta (1-4 Hz) and theta (4-8 Hz) by using NeuroGuide Deluxe 2.5.1 software (Applied Neuroscience; St Petersburg, FL). Cordance values were calculated using MATLAB, and was based on 3 consecutive steps in the processing of power values. The steps are: reattribution of power from bipolar pairs of electrodes to individual electrodes, spatial normalization of absolute and relative power across brain areas, and characterization of the association between normalized absolute and relative power measures.25
Repetitive Transcranial Magnetic Stimulation Session Procedures and Ratings rTMS was applied using the Magstim Super Rapid2 stimulator (Magstim Company, Whitland, UK) with figure-of-eight shaped air film coil in all patients in an open-label manner. The rTMS intensity was set at 100% of the motor threshold, which was determined by visual inspection. Stimulations were given to the left prefrontal cortex, deemed to be located anterior to the cortical motor area of the abductor pollicis brevis of which the motor threshold was determined. The treatment schedule was 6 days in a week, from Monday to Saturday for 3 weeks. Twenty-five Hz stimulation, duration of 2 seconds, was delivered 20 times with 30-second intervals.26 A full course comprised 1000 magnetic pulses. Depressive symptom changes were measured by the HAMD scale.27 The primary outcome parameter, the 17-item HAMD (HAMD-17) score, constitutes a valid and reliable measure of the severity of depressive symptoms.28 Scores were obtained at baseline and 1 week after completing rTMS. For research purposes, the HAMD percentage change value is divided into responder (R), larger than or equal to 50%, and nonresponder (NR) otherwise.29
Statistical Analysis Analysis of brain function measures was by SPSS version 20. Subjects were categorized, according to changes in HAMD scores, as responders and nonresponders. Changes in the cordance scores of 6 frontal electrodes in delta and theta were
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Figure 1. Effect of period of treatment on cordance values in delta frequency band for electrodes: (A) Fp1, (B) Fp2, (C) F7, (D) F8, (E) F3, and (F) F4. *Significant difference in pretreatment and posttreatment mean cordance values in responder (R) and nonresponder (NR) groups, P < .05.
tested using ANOVA. Analysis tested the hypothesis that there was no change in cordance over the treatment duration. The minimum significance level (P) was set at 5%.
Results Thirty of the 55 subjects (54.5%) met criteria for responder after rTMS. For the responder group, ANOVA analysis did not detect any significant differences between pre- and post-treatment cordance in delta for frontal electrodes: Fp1 (F(1, 29) = 1.506, P = .23), Fp2 (F(1, 29) = 0.455, P = .505), F7 (F(1, 29) = 0.143, P = .708), F8 (F(1, 29) = 0.564, P = .459), F3 (F(1, 29) = 2.237, P = .146), F4 (F(1, 29) = 0.756, P = .392). In theta, all electrodes, except F8, had significant differences between pre- and posttreatment cordance values: Fp1 (F(1, 29) = 10.262, P = .003), Fp2 (F(1, 29) = 5.302, P = .029), F7 (F(1, 29) = 6.101, P = .02), F8 (F(1, 29) = 1.989, P = .169), F3 (F(1, 29) = 13.826, P = .001), F4 (F(1, 29) = 5.449, P = .027). For nonresponders, significant differences were detected between pre- and post-treatment cordance values in delta for all left frontal electrodes: Fp1 (F(1, 24) = 12.084, P = .002), F7 (F(1, 24) = 4.312, P = .049), F3 (F(1, 24) = 6.332, P = .019). In delta for right frontal electrodes, only Fp2 had significantly different pre- and post-treatment cordance: Fp2 (F(1, 24) = 11.914, P = .002), F8 (F(1, 24) = 3.248, P = .084), F4 (F(1, 24) = 2.847, P = .105). In theta, all electrodes in the left frontal region had significantly different pre- and post-treatment cordance: Fp1 (F(1, 24) = 23.25, P = .000), F7 (F(1, 24) = 27.052, P = .000), F3 (F(1, 24) = 4.951, P = .036). For right frontal electrodes in theta, only Fp2 had
Figure 2. Effect of period of treatment on cordance values in theta frequency band for electrodes: (A) Fp1, (B) Fp2, (C) F7, (D) F8, (E) F3, and (F) F4. *Significant difference in pretreatment and posttreatment mean cordance values in responder (R) and nonresponder (NR) groups, P < .05.
significantly different pre- and post-treatment cordance: Fp2 (F(1, 24) = 4.991, P = .035), F8 (F(1, 24) = 0.206, P = .654), F4 (F(1, 24) = 0.052, P = .822). As seen in Figure 1, for nonresponders, mean cordance of electrodes Fp1, Fp2, F7, and F3 show a significant decrease in delta. For responders, although increases in cordance values are observed after rTMS in all electrodes, these are not statistically significant. In Figure 2, it is observed that in theta, mean cordance values decrease significantly after rTMS in electrodes Fp1, Fp2, F7, and F3 in nonresponders. For responders, significant increases are observed after treatment in Fp1, Fp2, F7, F3, and F4 electrodes in theta.
Discussion and Conclusions The aim of this article is to examine the relationship between changes in brain function after high-frequency (25 Hz) rTMS on frontal region of 55 depressed subjects. QEEG cordance measures at baseline and at the end of rTMS were obtained. A significant decrease was observed in left frontal cordance in delta and theta for nonresponders. Also for both the slow bands, nonresponders’ right prefrontal cordances were decreased significantly after stimulation. There was no significant change in delta for responders. But, except for F8, all right and left frontal electrodes’ cordance values increased significantly in theta after 25-Hz stimulation. The results replicate previous literature. Both the EEG frequency and the cerebral blood flow are known to be closely related to the cerebral metabolic rate.30 The effects of rTMS frequency on absolute cerebral blood flow
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in depressed patients was studied13 and opposite effects of high- and low-frequency rTMS on local and distant regional brain activity, which may have important implications for clinical therapeutics in various neuropsychiatric disorders, was underlined. According to various studies, the frequencydependent changes of excitability in the stimulated brain area are produced by stimulation with rTMS. Effects of highfrequency rTMS are predominantly excitatory.14,15 and those of low-frequency rTMS are inhibitory.16 Thus, high-frequency stimulation over frontal cortex leads to cordance increase in theta for responders contrary to low-frequency responders.10 Teneback et al31 have found that responders to highfrequency rTMS are characterized by increased metabolic activity in frontal regions. One of the baseline neurophysiological biomarkers for poor treatment outcome for depression is decreased metabolic activity in frontal regions. In our nonresponder group, decreased frontal and prefrontal cordance in delta and theta may be indicative of a less concordant EEG. This may reflect the lower relative perfusion in the underlying cortex. We can speculate that the higher perfusion in the frontal cortex in the responder group is represented as increased in cordance in frontal electrodes. This study was retrospective and did not use a double-blind placebo-controlled design. All the patients were on SSRI medications. Hence, it cannot be ruled out that the results are partly explained by SSRI effects. Although this is a limitation of the study, the nonresponders did not respond to both the rTMS and SSRI. Therefore, using a combination treatment may be useful to obtain the generic predictors of nonresponse in clinical practice. More studies are required to replicate these findings and to investigate what treatment modalities might be useful for the nonresponder group. Acknowledgments The authors would like to express their thanks for the support of NPIstanbul Hospital in providing the required EEG data.
Declaration of Conflicting Interests The author(s) declared no conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Trivedi MH, Morris DW, Grannemann BD, Mahadi S. Symptom clusters as predictors of late response to antidepressant treatment. J Clin Psychiatry. 2005;66:1064-1070. 2. Bares M, Brunovsky M, Novak T, et al. The change of prefrontal QEEG theta cordance as a predictor of response to bupropion treatment in patients who had failed to respond to previous antidepressant treatments. Eur Neuropsychopharmacol. 2010;20: 459-466. 3. O’Reardon J, Solvason HB, Janicak PG, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of
major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007;62:1208-1216. 4. Im C, Lee C. Computer-aided performance evaluation of a multichannel transcranial magnetic stimulation system. IEEE Trans Magn. 2006;42:3803-3808. 5. Price G, Lee JW, Garvey C, Gibson N. Appraisal of sessional EEG features as a correlate of clinical changes in an rTMS treatment of depression. Clin EEG Neurosci. 2008;39:131-138. 6. Micoulaud J, Micoulaud-Franchi JA, Richieri R, et al. Parietotemporal alpha EEG band power at baseline as a predictor of antidepressant treatment response with repetitive transcranial magnetic stimulation: a preliminary study. J Affect Disord. 2012;137:156-160. 7. Kito S, Hasegawa T, Koga Y. Cerebral blood flow ratio of the dorsolateral prefrontal cortex to the ventromedial prefrontal cortex as a potential predictor of treatment response to transcranial magnetic stimulation in depression. Brain Stimul. 2012;5: 547-553. 8. Richieri R, Boyer L, Farisse J, et al. Predictive value of brain perfusion SPECT for rTMS response in pharmacoresistant depression. Eur J Nucl Med Mol Imaging. 2011;38:1715-1722. 9. Schachter SC, Holmes GL, Kasteleijn-Nolst Trenite DGA. Behavioral Aspects of Epilepsy: Principles and Practice. New York, NY: Demos Medical; 2007: 268-269 10. Sackeim HA, Prohovnik I. Brain imaging studies of depressive disorders. In: Mann JJ, Kupfer DJ, eds. The Biology of Depressive Disorders, Part A: A Systems Perspective. New York, NY: Plenum; 1993:205-258. 11. Drevets WC, Bogers W, Raichle ME. Functional anatomi cal correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism. Eur Neuropsychopharmacol. 2002;12:527-544. 12. Hunter AM, Cook IA, Leuchter AF. The promise of the quantitative electroencephalogram as a predictor of antidepressant treatment outcomes in major depressive disorder. Psychiatr Clin North Am. 2007;30:105-124. 13. Speer MA, Kimbrell TA, Wassermann EM, et al. Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients. Biol Psychiatry. 2000;48:1133-1141. 14. Berardelli A, Inghilleri M, Rothwell JC, et al. Facilitation of muscle evoked responses after repetitive cortical stimulation in man. Exp Brain Res. 1998;122:79-84. 15. Pascual-Leone A, Valls-Sole J, Wassermann EM, Hallett M. Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain. 1994;117:847-858. 16. Chen R, Classen J, Gerloff C, et al. Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology. 1997;48:1398-1403. 17. Valiulis V, Gerulskis G, Dapsys K, Vistartaite G, Siurkute A, Maciulis V. Electrophysiological differences between high and low frequency rTMS protocols in depression treatment. Acta Neurobiol Exp (Wars). 2012;72:283-295. 18. Bares M, Novak T. Prefrontal cordance in the outcome prediction of 1-Hz, right-sided, prefrontal rTMS in patients with depression. Paper presented at: 12th International Forum on Mood and Anxiety Disorders; November 7-9, 2012; Barcelona, Spain. 19. Bystritsky A, Kaplan JT, Feusner JD, et al. A preliminary study of fMRI-guided rTMS in the treatment of generalized anxiety disorder. J Clin Psychiatry. 2008;69:1092-1098. 20. Cohen H, Kaplan Z, Kotler M, Kouperman I, Moisa R, Grisaru N. Repetitive transcranial magnetic stimulation of the right
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Ozekes et al dorsolateral prefrontal cortex in posttraumatic stress disorder: a double-blind, placebo-controlled study. Am J Psychiatry. 2004;161:515-524. 21. Loo CK, Sachdev PS, Haindl W, et al. High (15 Hz) and low (1 Hz) frequency transcranial magnetic stimulation have different acute effects on regional cerebral blood flow in depressed patients. Psychol Med. 2003;33:997-1006. 22. Leuchter AF, Cook IA, Lufkin RB, et al. Cordance: a new method for assessment of cerebral perfusion and metabolism using quantitative electroencephalography. Neuroimage. 1994;1:208-219. 23. Bares M, Brunovsky M, Kopecek M, et al. Changes in QEEG prefrontal cordance as a predictor of response to antidepressants in patients with treatment resistant depressive disorder: a pilot study. J Psychiatr Res. 2007;41:319-325. 24. Siuly S, Li Y. Improving the separability of motor imagery EEG signals using a cross correlation-based least square support vector machine for brain-computer interface. IEEE Trans Neural Syst Rehabil Eng. 2012;20:526-538. 25. Leuchter AF, Uijtdehaage SH, Cook IA, O’Hara R, Mandelkern M. Relationship between brain electrical activity and cortical perfusion in normal subjects. Psychiatry Res. 1999;90:125-140.
26. Tarhan N, Sayar GH, Tan O, Kağan G. Efficacy of high-frequency repetitive transcranial magnetic stimulation in treatment-resistant depression. Clin EEG Neurosci. 2012;43:279-284. 27. Hamilton M. A rating scale for depression, J Neurol Neurosurg Psychiatry. 19760;23:56-62. 28. Hizli Sayar G, Ozten E, Tan O, Tarhan N. Transcranial magnetic stimulation for treating depression in elderly patients, Neuropsychiatr Dis Treat. 2013;9:501-504. 29. Khodayari A, Reilly J, Hasey G, DeBruin H, MacCrimmon D. Using pre-treatment electroencephalography data to predict response to transcranial magnetic stimulation therapy for major depression. Paper presented at: 33rd Annual International Conference of the IEEE Engineering in Medicine and Biology Society; August 30–September 3, 2011; Boston, MA. 30. Melamed E, Lavy S, Portnoy Z, Sadan S, Carmon A. Correlation between regional cerebral blood flow and EEG frequency in the contralateral hemisphere in acute cerebral infarction. J Neurol Sci. 1975;26:21-27. 31. Teneback CC, Nahas Z, Speer AM, et al. Changes in prefrontal cortex and paralimbic activity in depression following two weeks of daily left prefrontal TMS. J Neuropsychiatry Clin Neurosci. 1999;11:426-435.
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Analysis of Brain Functional Changes in High-Frequency Repetitive Transcranial Magnetic Stimulation in Treatment-Resistant Depression Serhat Ozekes, Turker Erguzel, Gokben Hizli Sayar and Nevzat Tarhan Clin EEG Neurosci 2014 45: 257 originally published online 14 April 2014 DOI: 10.1177/1550059413515656 The online version of this article can be found at: http://eeg.sagepub.com/content/45/4/257
Published by: http://www.sagepublications.com
On behalf of:
EEG and Clinical Neuroscience Society
Additional services and information for Clinical EEG and Neuroscience can be found at: Email Alerts: http://eeg.sagepub.com/cgi/alerts Subscriptions: http://eeg.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> Version of Record - Sep 1, 2014 OnlineFirst Version of Record - Apr 14, 2014 What is This?
Downloaded from eeg.sagepub.com at UNIV OF UTAH SALT LAKE CITY on November 29, 2014
515656 research-article2014
EEGXXX10.1177/1550059413515656Ozekes et alClinical EEG and Neuroscience
Article
Analysis of Brain Functional Changes in High-Frequency Repetitive Transcranial Magnetic Stimulation in Treatment-Resistant Depression
Clinical EEG and Neuroscience 2014, Vol. 45(4) 257–261 © EEG and Clinical Neuroscience Society (ECNS) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1550059413515656 eeg.sagepub.com
Serhat Ozekes1, Turker Erguzel1, Gokben Hizli Sayar2,3, and Nevzat Tarhan2,3
Abstract Repetitive transcranial magnetic stimulation (rTMS) is a treatment procedure that uses magnetic fields to stimulate nerve cells in the brain, and is associated with significant improvements in clinical symptoms of major depressive disorder (MDD). The effect of rTMS treatment on the brain can be evaluated by cordance, a quantitative electroencephalography (QEEG) method that extracts information from absolute and relative power of EEG spectra. In this study, to analyze brain functional changes, preand post-rTMS, QEEG data were collected from 6 frontal electrodes (Fp1, Fp2, F3, F4, F7, and F8) in 2 slow bands (delta and theta) for 55 MDD subjects. To examine brain changes, cordance scores were determined, using repeated-measures analysis of variance (ANOVA). High-frequency rTMS was associated with cordance decrease in left frontal and right prefrontal regions in both delta and theta for nonresponders; it was associated with cordance increase in all right and left frontal electrodes, except F8, for responders. Keywords repetitive transcranial magnetic stimulation, QEEG cordance, repeated-measures analysis of variance, major depressive disorder, analysis of brain functional changes Received August 15, 2013; revised October 11, 2013; accepted November 10, 2013.
Introduction The treatment of MDD with rTMS, investigated intensively in recent years as an alternative to antidepressants, is associated with significant improvements in clinical symptoms. Around 40% of patients fail to respond to an initial course of antidepressant treatment.1 Since a large number fail to respond to antidepressants, there is a clear need for methods that determine the right treatment for the right patient.2 Compared with electroconvulsive therapy (ECT), rTMS is less invasive and painful.3,4 The establishment of the efficacy of rTMS has increased interest in finding potential predictors of clinical response. Studies have been primarily with neurophysiological EEG5,6 and functional neuroimaging biomarkers.7,8 These studies demonstrated the predictive capability of change of frontal QEEG cordance in theta and delta frequency bands. QEEG cordance is one of the auspicious biomarkers, used to predict the treatment response, which has generated research interest. Cordance is related to absolute and relative spectral powers, derived from the resting EEG. The reason for using absolute and relative power, is that brain areas with abnormal function may have low absolute but high relative spectral power.9
When treatment responses of MDD subjects were analyzed, neurophysiologic changes were observed early in antidepressant treatment.10-12 rTMS delivered over the motor cortex has different effects on cortical excitability, depending on the pulse frequency.13 Frequencies in the range of 5 to 20 Hz enhance cortical response (facilitation), which is demonstrated by decreased motor-evoked potential (MEP) threshold.14,15 Repeated stimulation at frequencies of about 1 Hz inhibits cortical response.16 According to Speer et al,13 flow in frontal, and related subcortical circuits, increases in high-frequency (10-20 Hz) and decreases in low-frequency (1-5Hz) rTMS. Valiulis et al17 concluded that delta power increases on the left hemisphere, and alpha power on the right, in high-frequency (10 Hz) rTMS. 1
Department of Computer Engineering, Faculty of Engineering and Natural Sciences, Uskudar University, Istanbul, Turkey 2 Department of Psychiatry, NPIstanbul Hospital, Istanbul, Turkey 3 Department of Psychology, Faculty of Humanities and Social Sciences, Uskudar University, Istanbul, Turkey Corresponding Author: Serhat Ozekes, Department of Computer Engineering, Faculty of Engineering and Natural Sciences, Uskudar University, Istanbul, Turkey. Email: [email protected] Full-color figures are available online at http://eeg.sagepub.com
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Another study18 showed that all 9 responders’, and 6 out of 16 nonresponders’, prefrontal cordance value decreased after the first week of 1-Hz rTMS. High- is more effective than low-frequency rTMS in MDD, according to rando mized clinical trials that compare high and low stimulation frequencies.19-21 This study analyzed brain functional changes in treatment of depression using high-frequency (25 Hz) rTMS. The cordance values of frontal electrodes in delta and theta before and after rTMS were analyzed using ANOVA for responders and nonresponders.
Materials and Methods Subjects The research, conducted in the Neuropsychiatry Istanbul Hospital, was approved by the local Medical Research Ethics Committee. Patients met inclusion criteria as determined by their psychiatrist. All were free of psychotropic medication for at least 2 weeks prior to enrollment. Subjects who met the Structured Clinical Interview for DSM-IV criteria for depression, and scored higher than 14 on the 17-item Hamilton Depression Rating Scale (HAMD), were eligible. A total of 55 MDD subjects, resistant to medication treatment, completed the protocols for the study. Responder and nonresponder groups did not differ with respect to the psychopharmacological treatment process. To minimize potential confusing outcomes of pharmacological withdrawal symptoms, all subjects were on a monotherapy regimen and received concurrent selective serotonin reuptake inhibitor (SSRI) antidepressant medication during 20 sessions of rTMS therapy. No patients were receiving lithium, mood stabilizers or benzodiazepines. A baseline assessment was conducted on the day prior to rTMS treatment by a psychiatrist using the 17-item HAMD scale. Twice during the study patients had clinical, neuropsychological, and QEEG assessments. Complete blood count, chemistry, thyroid stimulating hormone, urine toxicology, and electrocardiogram were performed at screening, and subjects were required to be medically stable before entry. Patients with organic brain disorders, pacemakers, psychotic symptoms, dementia, delirium, substance-related disorders, cluster A or B axis II disorders, ECT in the prior 6 months, history of craniotomy, skull fracture, seizures, neurological illness, suicidal intent, plan, or attempt were ineligible.
Quantitative EEG Techniques and Cordance Calculations Cordance, introduced by Leuchter et al,22 combines complementary information from absolute and relative power of EEG spectra, to yield values that correlate with regional cerebral perfusion better than either measure alone.23 Pre- and posttreatment QEEG data were collected in the eyes-closed, maximally alert state, in a quiet room with subdued lighting. The researchers monitored QEEG data and alerted the subjects
every minute as needed to avoid drowsiness. Three minutes of eye-closed EEG at rest were acquired, using Scan LT EEG amplifier and electrode cap (Compumedics/Neuroscan, Charlotte, NC), with a sampling rate of 250 Hz. Nineteen sintered Ag/AgCl electrodes were positioned according to the 10/20 International System with binaural reference. The data from 6 frontal electrodes (Fp1, Fp2, F3, F4, F7, and F8) in delta and theta were used. Raw EEG signal was filtered through a band-pass of 0.15-30 Hz before artifact elimination. Manually selected (minimum 2 minutes) artifact-free EEG data, with minimal split-half reliability ratio of 0.95 and test–retest reliability ratio of 0.09 were used for cordance calculations. Prior to calculation of absolute and relative power, electrode referencing was to bipolar electrode pairs for cordance.24 Fast Fourier Transform was used to calculate absolute and relative power in each of 2 nonoverlapping frequency bands: delta (1-4 Hz) and theta (4-8 Hz) by using NeuroGuide Deluxe 2.5.1 software (Applied Neuroscience; St Petersburg, FL). Cordance values were calculated using MATLAB, and was based on 3 consecutive steps in the processing of power values. The steps are: reattribution of power from bipolar pairs of electrodes to individual electrodes, spatial normalization of absolute and relative power across brain areas, and characterization of the association between normalized absolute and relative power measures.25
Repetitive Transcranial Magnetic Stimulation Session Procedures and Ratings rTMS was applied using the Magstim Super Rapid2 stimulator (Magstim Company, Whitland, UK) with figure-of-eight shaped air film coil in all patients in an open-label manner. The rTMS intensity was set at 100% of the motor threshold, which was determined by visual inspection. Stimulations were given to the left prefrontal cortex, deemed to be located anterior to the cortical motor area of the abductor pollicis brevis of which the motor threshold was determined. The treatment schedule was 6 days in a week, from Monday to Saturday for 3 weeks. Twenty-five Hz stimulation, duration of 2 seconds, was delivered 20 times with 30-second intervals.26 A full course comprised 1000 magnetic pulses. Depressive symptom changes were measured by the HAMD scale.27 The primary outcome parameter, the 17-item HAMD (HAMD-17) score, constitutes a valid and reliable measure of the severity of depressive symptoms.28 Scores were obtained at baseline and 1 week after completing rTMS. For research purposes, the HAMD percentage change value is divided into responder (R), larger than or equal to 50%, and nonresponder (NR) otherwise.29
Statistical Analysis Analysis of brain function measures was by SPSS version 20. Subjects were categorized, according to changes in HAMD scores, as responders and nonresponders. Changes in the cordance scores of 6 frontal electrodes in delta and theta were
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Figure 1. Effect of period of treatment on cordance values in delta frequency band for electrodes: (A) Fp1, (B) Fp2, (C) F7, (D) F8, (E) F3, and (F) F4. *Significant difference in pretreatment and posttreatment mean cordance values in responder (R) and nonresponder (NR) groups, P < .05.
tested using ANOVA. Analysis tested the hypothesis that there was no change in cordance over the treatment duration. The minimum significance level (P) was set at 5%.
Results Thirty of the 55 subjects (54.5%) met criteria for responder after rTMS. For the responder group, ANOVA analysis did not detect any significant differences between pre- and post-treatment cordance in delta for frontal electrodes: Fp1 (F(1, 29) = 1.506, P = .23), Fp2 (F(1, 29) = 0.455, P = .505), F7 (F(1, 29) = 0.143, P = .708), F8 (F(1, 29) = 0.564, P = .459), F3 (F(1, 29) = 2.237, P = .146), F4 (F(1, 29) = 0.756, P = .392). In theta, all electrodes, except F8, had significant differences between pre- and posttreatment cordance values: Fp1 (F(1, 29) = 10.262, P = .003), Fp2 (F(1, 29) = 5.302, P = .029), F7 (F(1, 29) = 6.101, P = .02), F8 (F(1, 29) = 1.989, P = .169), F3 (F(1, 29) = 13.826, P = .001), F4 (F(1, 29) = 5.449, P = .027). For nonresponders, significant differences were detected between pre- and post-treatment cordance values in delta for all left frontal electrodes: Fp1 (F(1, 24) = 12.084, P = .002), F7 (F(1, 24) = 4.312, P = .049), F3 (F(1, 24) = 6.332, P = .019). In delta for right frontal electrodes, only Fp2 had significantly different pre- and post-treatment cordance: Fp2 (F(1, 24) = 11.914, P = .002), F8 (F(1, 24) = 3.248, P = .084), F4 (F(1, 24) = 2.847, P = .105). In theta, all electrodes in the left frontal region had significantly different pre- and post-treatment cordance: Fp1 (F(1, 24) = 23.25, P = .000), F7 (F(1, 24) = 27.052, P = .000), F3 (F(1, 24) = 4.951, P = .036). For right frontal electrodes in theta, only Fp2 had
Figure 2. Effect of period of treatment on cordance values in theta frequency band for electrodes: (A) Fp1, (B) Fp2, (C) F7, (D) F8, (E) F3, and (F) F4. *Significant difference in pretreatment and posttreatment mean cordance values in responder (R) and nonresponder (NR) groups, P < .05.
significantly different pre- and post-treatment cordance: Fp2 (F(1, 24) = 4.991, P = .035), F8 (F(1, 24) = 0.206, P = .654), F4 (F(1, 24) = 0.052, P = .822). As seen in Figure 1, for nonresponders, mean cordance of electrodes Fp1, Fp2, F7, and F3 show a significant decrease in delta. For responders, although increases in cordance values are observed after rTMS in all electrodes, these are not statistically significant. In Figure 2, it is observed that in theta, mean cordance values decrease significantly after rTMS in electrodes Fp1, Fp2, F7, and F3 in nonresponders. For responders, significant increases are observed after treatment in Fp1, Fp2, F7, F3, and F4 electrodes in theta.
Discussion and Conclusions The aim of this article is to examine the relationship between changes in brain function after high-frequency (25 Hz) rTMS on frontal region of 55 depressed subjects. QEEG cordance measures at baseline and at the end of rTMS were obtained. A significant decrease was observed in left frontal cordance in delta and theta for nonresponders. Also for both the slow bands, nonresponders’ right prefrontal cordances were decreased significantly after stimulation. There was no significant change in delta for responders. But, except for F8, all right and left frontal electrodes’ cordance values increased significantly in theta after 25-Hz stimulation. The results replicate previous literature. Both the EEG frequency and the cerebral blood flow are known to be closely related to the cerebral metabolic rate.30 The effects of rTMS frequency on absolute cerebral blood flow
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in depressed patients was studied13 and opposite effects of high- and low-frequency rTMS on local and distant regional brain activity, which may have important implications for clinical therapeutics in various neuropsychiatric disorders, was underlined. According to various studies, the frequencydependent changes of excitability in the stimulated brain area are produced by stimulation with rTMS. Effects of highfrequency rTMS are predominantly excitatory.14,15 and those of low-frequency rTMS are inhibitory.16 Thus, high-frequency stimulation over frontal cortex leads to cordance increase in theta for responders contrary to low-frequency responders.10 Teneback et al31 have found that responders to highfrequency rTMS are characterized by increased metabolic activity in frontal regions. One of the baseline neurophysiological biomarkers for poor treatment outcome for depression is decreased metabolic activity in frontal regions. In our nonresponder group, decreased frontal and prefrontal cordance in delta and theta may be indicative of a less concordant EEG. This may reflect the lower relative perfusion in the underlying cortex. We can speculate that the higher perfusion in the frontal cortex in the responder group is represented as increased in cordance in frontal electrodes. This study was retrospective and did not use a double-blind placebo-controlled design. All the patients were on SSRI medications. Hence, it cannot be ruled out that the results are partly explained by SSRI effects. Although this is a limitation of the study, the nonresponders did not respond to both the rTMS and SSRI. Therefore, using a combination treatment may be useful to obtain the generic predictors of nonresponse in clinical practice. More studies are required to replicate these findings and to investigate what treatment modalities might be useful for the nonresponder group. Acknowledgments The authors would like to express their thanks for the support of NPIstanbul Hospital in providing the required EEG data.
Declaration of Conflicting Interests The author(s) declared no conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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