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Neural correlates of clinical improvement after deep transcranial magnetic stimulation (DTMS) for treatment-resistant depression: a case report using functional magnetic resonance imaging ab
ab
c
Philippe-Olivier Harvey , Frederique Van den Eynde , Abraham Zangen & Marcelo T. ab
Berlim a
Department of Psychiatry, McGill University, Montreal, Quebec, Canada
b
Neuromodulation Research Clinic, Douglas Mental Health University Institute, Montreal, Quebec, Canada c
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Ben-Gurion University of the Negev, Beersheva, Israel Published online: 07 Dec 2013.
To cite this article: Philippe-Olivier Harvey, Frederique Van den Eynde, Abraham Zangen & Marcelo T. Berlim (2015) Neural correlates of clinical improvement after deep transcranial magnetic stimulation (DTMS) for treatment-resistant depression: a case report using functional magnetic resonance imaging, Neurocase: The Neural Basis of Cognition, 21:1, 16-22, DOI: 10.1080/13554794.2013.860173 To link to this article: http://dx.doi.org/10.1080/13554794.2013.860173
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Neurocase, 2015 Vol. 21, No. 1, 16–22, http://dx.doi.org/10.1080/13554794.2013.860173
Neural correlates of clinical improvement after deep transcranial magnetic stimulation (DTMS) for treatment-resistant depression: a case report using functional magnetic resonance imaging Philippe-Olivier Harveya,b, Frederique Van den Eyndea,b, Abraham Zangenc and Marcelo T. Berlima,b* a
Department of Psychiatry, McGill University, Montreal, Quebec, Canada; bNeuromodulation Research Clinic, Douglas Mental Health University Institute, Montreal, Quebec, Canada; cBen-Gurion University of the Negev, Beersheva, Israel
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(Received 7 June 2013; accepted 11 September 2013) We report the effects of a 4-week trial of deep transcranial magnetic stimulation (DTMS) on depressive and anxious symptoms and brain activity in a patient (Mrs A) with treatment-resistant depression (TRD). The protocol involved a preand a post-functional magnetic resonance imaging (fMRI) scan during which Mrs A had to perform a working memory task (i.e., n-back). Her baseline score on the 21-item Hamilton Depression Rating Scale (HAM-D21) was 24, indicating severe depressive symptoms. Immediately after 4 weeks of daily DTMS treatment applied over the left dorsolateral prefrontal cortex (DLPFC), her HAM-D21 score decreased to 13 (a 46% reduction), and 1 month later, it was 12 (a 50% reduction). Moreover, Mrs A’s accuracy scores on the n-back task (i.e., 2-back condition) improved from 79% (baseline) to 96% (after DTMS treatment). At the neural level, Mrs A showed significantly increased brain activity in the working memory network (e.g., DLPFC, parietal cortex) during the execution of the 2-back condition after DTMS treatment compared to baseline. Keywords: deep transcranial magnetic stimulation; functional magnetic resonance imaging; major depressive disorder; working memory; n-back task
Major depressive disorder (MDD) is highly prevalent, has a high incidence, and is associated with a substantial loss of quality of life, increased mortality rates, and enormous social and economic costs (Ebmeier, Donaghey, & Steele, 2006). MDD has been associated with abnormalities in several brain areas (e.g., prefrontal cortex, insula, hippocampus) (J. P. Hamilton et al., 2012) that have been shown to usually improve following clinical recovery (Krishnan & Nestler, 2010). Although the medical management of MDD has evolved substantially over the last decades, a significant number of patients still suffer from treatment-resistant depression (TRD) (Berlim & Turecki, 2007), a condition associated with very high levels of morbidity, chronicity, and societal costs (Dunner et al., 2006; Greden, 2001). Therefore, appropriate clinical management of TRD is of paramount clinical importance (Fava, 2003; Vieta & Colom, 2011). A promising therapeutic intervention for managing TRD is called standard repetitive transcranial magnetic stimulation (rTMS) (Loo & Mitchell, 2005; Padberg & Moller, 2003). This noninvasive procedure involves the safe induction of electrical currents within the brain produced by pulsating magnetic fields generated through a coil-of-wire near the scalp (Daskalakis, Levinson, & Fitzgerald, 2008). To date, several meta-analyses have shown that standard rTMS has clear antidepressant properties (Berlim, Van den Eynde, Perdomo, & Daskalakis, *Corresponding author. Email: [email protected] © 2013 Taylor & Francis
2013; Lam, Chan, Wilkins-Ho, & Yatham, 2008; Slotema, Blom, Hoek, & Sommer, 2010). However, treatment effects are variable, factors predictive of clinical response remain poorly understood, and a number of negative clinical trials have been published (Fitzgerald, 2010; George et al., 2009; Ridding & Rothwell, 2007). A possible explanation for these discrepant findings may be related to the fact that standard rTMS only enables direct modulation of more superficial and relatively limited cortical areas (George & Aston-Jones, 2010; Ridding & Rothwell, 2007), and thus cannot effectively and directly stimulate, for example, deeper layers of the prefrontal cortex that are intimately interconnected with several key mood- and reward-related neural sites (e.g., ventral striatum, ventral tegmentum area) (Levkovitz et al., 2007, 2009). This hypothesis has led to the development of the “H-coil”, a novel rTMS coil that putatively allows for the direct modulation of larger and deeper brain regions by significantly reducing the decay rate of the magnetic induced field, at the expense of reduced focality (Levkovitz et al., 2009). The H-coil maximizes the electrical field deep in the brain by summating separate fields projected into the skull from several points around its periphery, while minimizing the accumulation of electrical charge on the brain’s surface (Roth, Zangen, & Hallett, 2002). Indeed, “phantom brain” measurements have shown that the H-coil can produce an effective field at a depth of 3–4 cm beneath the skull, while the standard
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Neurocase figure-of-eight rTMS coil can only reach a depth of 1.50 cm or less (Roth, Amir, Levkovitz, & Zangen, 2007). This novel neuromodulation technique, called deep transcranial magnetic stimulation (DTMS), has been shown, in a recent 4-week randomized feasibility trial (20 daily sessions) in 65 medication-free patients with MDD, to be well tolerated and to be associated with response and remission rates of 47% and 42%, respectively (Levkovitz et al., 2009). Further studies have replicated these initial findings (Harel et al., 2012; Isserles et al., 2011; Rosenberg, Shoenfeld, Zangen, Kotler, & Dannon, 2010; Rosenberg, Zangen, Stryjer, Kotler, & Dannon, 2010; Rosenberg et al., 2011). Here, we report the effects of a 4-week trial of DTMS on depressive and anxious symptoms as well as on brain activity in an adult patient with TRD.
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also involved a pre- and a post-functional magnetic resonance imaging (fMRI) scan. The Ethics Review Board of the Douglas Mental Health University Institute (Montreal, Quebec, Canada) gave its approval and Mrs A gave us her informed consent.
Clinical assessments Depressive and anxious symptoms were measured by a clinical psychiatrist with the Hamilton Depression Rating Scale (HAM-D21) (M. Hamilton, 1960), and the Hamilton Anxiety Rating Scale (HAM-A) (M. Hamilton, 1959), respectively, at baseline and at weeks 5 and 9.
DTMS procedure Case report Mrs A is a 52-year-old female, separated, mother of a 31year-old daughter, and who has worked for over 20 years as a high school teacher. She has no previous psychiatric history, but reported that two of her brothers were treated in the past for “depressive episodes”. Her current mood disorder started around late 2009 and was related to a number of concomitant stressors, including her mother’s death, a divorce from her husband of several years, and conflicts at work. Her primary symptoms included depressed mood, anhedonia, hypersomnia (i.e., up to 20 hr of sleeping per day), pathological guilt (e.g., “I am very weak and incompetent”), weight loss (i.e., approximately 15 pounds in the first 3 months), low energy and concentration, and marked decision-making difficulties. Also, she reported passive suicidal ideation (e.g., “I wish I could sleep forever”), and significant levels of generalized anxiety on most days. She was diagnosed with a moderate to severe major depressive episode comorbid with a generalized anxiety disorder. Owing to her clinical condition, Mrs A was on a sick leave for over 2 years. Since starting her medical follow-up in late 2009, she was treated with a number of antidepressants (e.g., escitalopram 20 mg/d, venlafaxine up to 450 mg/d for 4 months, mirtazapine up to 45 mg/d for 4 months, and bupropion up to 450 mg/d for 5 months) and with weekly individual psychotherapy (13 months; cognitive–behavioral) but presented with no significant clinical improvement. At baseline, she was using venlafaxine 375 mg/d, bupropion 450 mg/d, and quetiapine 100 mg/d in stable dosages for the past 6 weeks, and her condition was classified as a stage II TRD according to Thase and Rush’s classification (Thase & Rush, 1997). As a consequence of her functional disability as well as the lack of meaningful clinical improvement despite the use of several therapeutic interventions, Mrs A accepted to participate in a 4-week trial of DTMS for MDD, which
DTMS was administered on an outpatient basis using a Magstim Rapid2® magnetic stimulator (Magstim Company Ltd., UK) connected to an H1-coil (that produces its most effective electric field in the anterior–posterior axis with a preference for the left brain hemisphere (Roth et al., 2007)). Prior to stimulation, Mrs A was instructed to insert earplugs. The resting motor threshold (rMT) was determined on a weekly basis over the left primary motor cortex using the visualization method (Pridmore, Fernandes Filho, Nahas, Liberatos, & George, 1998) and the maximum likelihood strategy (Mishory et al., 2004). The positioning of the H1-coil over the left dorsolateral prefrontal cortex (DLPFC) was performed by moving it 6 cm anteriorly to the rMT “hot-spot” (i.e., the point in the scalp in which a minimum magnetic field produced the largest motor twitch of the contralateral hand) parallel to the sagittal suture of the skull (Isserles et al., 2011; Levkovitz et al., 2009, 2011). To ensure placement reproducibility, spatial coordinates were marked on a cap placed on the patient’s head. Each DTMS session consisted of 84 trains (2 s, 20-s intertrain interval, and 3,024 pulses per session) delivered at a frequency of 18 Hz and an intensity of 120% of the measured rMT. Mrs A received 4 weeks of daily DTMS, totaling 20 sessions and 60,480 magnetic pulses, during which her pharmacological regimen remained unchanged.
fMRI procedure n-Back task (Owen, McMillan, Laird, & Bullmore, 2005) During each of the two scanning sessions, Mrs A performed a letter variant of the n-back task, according to which she was asked to indicate, using keypad buttons, whether a letter presented on the screen (the “target” stimulus) was similar to or different from a letter previously presented (the “cue stimulus”). Alternate versions of the task were administered at Time 1 and
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Time 2. The n-back task required Mrs A to maintain and permanently update the relevant pieces of information in working memory. Load and mental manipulation within working memory were incremented using two different levels of complexity: 1-back (maintenance of one piece of information in working memory within the interval between the cue and the target stimuli) and 2-back (interposition of one distractor between the cue and the target stimuli, the distractor becoming a cue for the next trial). Depending on which n-back condition (1- or 2back) was performed, the response was to match the current letter to the one seen 1 or 2 presentations backward. In addition, the patient performed a control task (virtually without working memory processes) called the 0-back task, which required her to identify a single prespecified letter (i.e., “X”). All trials consisted of an instruction (either “2-back”, “1-back”, or “0-back”) presented for 3 s followed by a pseudo-random sequence of 10 consonants varying in case. Each letter appeared on the screen for 1750 ms, followed by a blank screen presented for 750 ms. The total duration of a given trial, from instruction to the last letter was 28 s. Trials were separated one from another by a 10-s blank screen. Two runs of 12 trials each were presented to Mrs A (eight trials per condition). The total duration of a run was 466 s, which included a 10-s blank screen at the beginning of each run. The different condition trials were presented pseudo-randomly. Importantly, Mrs A had a practice/training session with the n-back task outside the scanner before each scanning session. This practice session was administered using a laptop computer. Trials administered during practice were different from the trials used in the scanner. The purpose of these practice sessions was to make sure that Mrs A was comfortable with the n-back task before performing it in the scanner. This helped reducing any potential learning effect during the scanning session. Image acquisition fMRI data were acquired at Time 1 (i.e., baseline) and Time 2 (i.e., in the week following DTMS treatment) at the Brain Imaging Centre at the Douglas Mental Health University Institute on a 3 Tesla Siemens Magnetom MRI scanner. A vacuum cushion was used to stabilize the patient’s head. Stimuli was generated by a PC computer running E-PRIME (Psychology Software Tools, Pittsburgh, PA, USA) and projected via an LCD projector and mirror system. A keypad connected to the computer recorded Mrs A’s responses. Functional T2*-weighted images were acquired with blood oxygenation leveldependent (BOLD) contrasts (two functional runs of 225 volumes, TR = 2090 ms, TE = 50 ms, flip angle = 90º, FOV = 256 mm, Matrix = 64 × 64), covering the entire brain (30 interleaved slices parallel to the anterior–
posterior commissural plane; in plane resolution: 4 × 4 mm; 4 mm thickness). Following the functional session, a 15-min high-resolution T1-weighted anatomical volume was acquired using a gradient echo pulse sequence (22 ms, TE = 9.2 ms, flip angle = 30º, voxel size 1 × 1 × 1 mm3). Each scanning session lasted approximately 1 hr, including set-up time.
Analyses Behavioral performance in the n-back task was defined as the percent response accuracy. For the purpose of this study, we directly compared percent accuracy at the 2back condition between Time 1 and Time 2. fMRI data was analyzed using Statistical Parametric Mapping (SPM8, Wellcome Department of Cognitive Neurology, London, UK). Images were realigned to the mean of the images to correct for inter-scan movement, spatially normalized to the MNI space (normalized voxel sixe 2 × 2 × 2), and smoothed with an 8-mm full-width half-maximum (FWHM) Gaussian kernel. Low-frequency temporal drifts were removed by applying a high-pass filter (cutoff: 128 s). An AR (1) model was used to estimate and correct for nonsphericity of the error covariance. Data from our block design were analyzed by the general linear model (GLM), in which blocks were modeled by a canonical HRF. Both scanning sessions were included in the same analysis. Each condition (2-back preDTMS, 1-back pre-DTMS, 0-back pre-DTMS, 2-back post-DTMS, 1-back post-DTMS, 0-back post-DTMS) was modeled separately. The contrast of interest for the current paper was 2-back post-DTMS minus 2-back preDTMS. This contrast allowed us to identify brain regions whose activity was significantly greater during the execution of the 2-back condition after DTMS treatment compared to before DTMS treatment. Resulting activation map was thresholded at p < 0.001, uncorrected for multiple comparisons, with a minimum cluster size of 30 contiguous voxels.
Results Clinical Mrs A’s baseline scores on HAM-D21 and on HAM-A were 24 and 22, respectively, indicating severe depressive and anxious symptoms. Immediately after 4 weeks of daily DTMS treatment, her scores on HAM-D21 and on HAM-A both decreased to 13 (i.e., a reduction of 46% and 41% in depressive and anxious symptoms, respectively). After 1 month, her scores remained significantly improved compared to baseline (i.e., HAM-D21 = 12, HAM-A = 14). DTMS was well tolerated overall and no significant side effects were reported by the patient.
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Behavioral and neuroimaging
Discussion
Mrs A’s accuracy scores at the 2-back condition improved from 79% at Time 1 to 96% at Time 2. At the neural level, Mrs A showed significantly increased brain activity in the working memory network (e.g., DLPFC, parietal cortex) during the execution of the 2-back condition after DTMS treatment compared to baseline (see Table 1 and Figure 1 for details).
We presented a case report of a patient with TRD that has significantly improved in terms of depressive and anxious symptoms after 4 weeks of daily DTMS. This overall clinical improvement, observed immediately after DTMS (week 5) and also 1 month later (week 9), was accompanied by a better cognitive performance in the n-back task at the 4-week follow-up compared to baseline, and by
Table 1. Brain regions showing increased activity during the execution of the n-back task (i.e., 2-back) after DTMS treatment (Time 2) compared to baseline (Time 1).
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MNI coordinates
Inferior frontal (BA 45/47) Cerebellum Supplementary motor area (BA 6) Precentral (BA 6) Superior parietal (BA 7) Middle occipital (BA 17/18) Middle occipital (BA 19) Middle frontal (BA 6/9) Middle temporal (BA 20) Middle frontal (BA 45/46) Middle frontal (BA 44/45)
H
x
y
z
t-Value
L R L L L L L R L R L
−56 32 −10 −52 −24 −10 −36 42 −54 46 −50
30 −74 6 4 −68 −94 −72 10 −38 40 26
−4 −22 76 46 60 0 38 60 −12 30 26
5.74 5.42 5.33 4.74 4.60 4.18 4.01 3.98 3.97 3.85 3.70
Cluster sizea 341 1,615 61 72 84 368 231 105 95 100 55
Abbreviations: L, Left; R, Right; H, Hemisphere; BA, Brodmann’s area. Notes: aThe cluster size represents the number of voxels. MNI coordinates represent the peak voxel of each cluster where x, y, and z indicate the distance measured in millimeters from the anterior commissure in the sagittal, coronal, and horizontal planes, respectively. All clusters of activation reported in Table 1 were significant at p < 0.001, uncorrected for multiple comparisons, with a minimum cluster size of 30 contiguous voxels. Mean performance accuracy for the 2-back condition was 79% at Time 1 and 96% at Time 2.
Inferior Frontal Gyrus z = –4
x = –56
Middle Frontal Gyrus z = 33
x = 46
Middle Occipital Gyrus z = 38
x = –36
Superior Parietal Gyrus z = 60
x = –24
Figure 1. Some of the brain regions that showed increased activity during the execution of the n-back task (i.e., 2-back) after DTMS treatment (Time 2) compared to baseline (Time 1). Statistical threshold set at p = 0.001, uncorrected for multiple comparisons. [To view this figure in color, please see the online version of this journal.]
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increased activity in brain regions typically linked to working memory and cognitive effort (Rajah & D’Esposito, 2005; Wager & Smith, 2003). The almost 50% reduction in depressive symptoms and the increased cognitive performance at the n-back task presented by Mrs A following DTMS treatment are encouraging. Our findings are consistent with those of recent studies that have showed that DTMS applied to the left DLPFC is efficacious for treating depressed patients and may also improve their performance on a number of cognitive domains (e.g., sustained attention, visuospatial memory, cognitive planning) (Harel et al., 2012; Isserles et al., 2011; Levkovitz et al., 2009, 2011; Rosenberg et al., 2011). More generally, according to the pathophysiological model of MDD, antidepressant treatments, irrespective of their mechanisms, are hypothesized to share the ability to normalize metabolic activity in both an underactive dorsal cortical (e.g., DLPFC) and an overactive ventral limbic circuit (e.g., subgenual cingulate gyrus [SCG]) involved in the regulation of emotion (Giacobbe, Mayberg, & Lozano, 2009). Our fMRI results are consistent with this hypothesis by showing a significant increase in the activity of the DLPFC after DTMS treatment compared to baseline. Thus, it is possible that DTMS treatment, through its putative action on deeper and more widespread brain structures, might have contributed to the normalization of dorsal cortical activity, allowing greater recruitment of cognitionrelated brain regions during the execution of the n-back task at Time 2. In this context, one important site of action for DTMS may be the SCG. Indeed, based on its anatomical position between the frontal cortex and the limbic system, the SCG may act as a fulcrum to modulate the activity of both the frontal cortex and the limbic system (Mayberg, 2002). Reduction of the hyperactivity in the SCG in TRD may thus represent a marker of antidepressant response and a necessary first step for the normalization of brain activity in remitted patients (Seminowicz et al., 2004). Consequently, patients with TRD may require treatments (perhaps such as DTMS) that are potentially capable of enlisting the cascade of adaptive neural processes necessary to compensate for a depressive mood state (Price & Drevets, 2010). Nevertheless, this is still speculative, and future studies are needed to better clarify the underlying neural basis of DTMS in MDD and its relationship with symptom improvement. Furthermore, head-to-head comparisons between DTMS and standard rTMS are of paramount importance to explore their differential neurobiological basis and clinical utility for MDD.
of mental health practitioners, researchers, and the patient alike may have impacted the results (Brunoni & Fregni, 2011). Also, it is possible that nonspecific factors (e.g., visiting the study center every day, regular contact with the investigators) might have played a role in the clinical improvement observed following DTMS treatment. However, as we did not employ a control (sham) intervention, we cannot estimate the potential impact of a placebo effect. There is, though, indirect evidence to suggest that the placebo response rates are much lower in subjects with TRD as compared to those with uncomplicated MDD (Dunner et al., 2006; Fekadu et al., 2009; Fournier et al., 2010). Second, we only examined the effectiveness of DTMS immediately after the treatment and 1 month later, and thus cannot estimate the stability of its medium- to long-term antidepressant effects. This is especially relevant considering the labor-intensive and time-consuming nature of DTMS. Although data remain somewhat limited in this regard, a recent small study has reported response and remission rates 3 months following a course of DTMS for MDD of 63% and 52%, respectively (n = 12) (Levkovitz et al., 2009). Moreover, a 3-month continuation trial (n = 29) has shown that the administration of DTMS following the acute treatment twice a week for 8 weeks and once a week for 10 more weeks was associated the probability of a sustained response and remission of 81.12% and 71.45%, respectively (Harel et al., 2012). Finally, as the ability of the H-coil to modulate deeper neuronal structures is obtained at the cost of less focality (Roth et al., 2007; Zangen, Roth, Voller, & Hallett, 2005), it is possible that the clinical improvement observed by Mrs A could have resulted from the larger brain volume receiving direct stimulation rather than from its depth. Thus, because of its more widespread effects, one hypothesis is that the H-coil might able to modulate the DLPFC more consistently/broadly as compared to the standard figure-of-eight coil, which, by being relatively focal, might instead preferentially target specific anatomical parts of the DLPFC in each individual. Nevertheless, additional studies are clearly needed to better explore this hypothesis. Declaration of interest Drs Van den Eynde and Harvey report no conflicts of interest. Dr Zangen is a consultant for and has financial interests in Brainsway, Inc. Funding This work was supported by a researcher-initiated grant received by Dr Berlim from Brainsway, Inc.
Limitations Our case report, despite its interesting findings, has a number of limitations. First, the clinical assessments were performed on an open label basis, and treatment expectations
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Ridding, M. C., & Rothwell, J. C. (2007). Is there a future for therapeutic use of transcranial magnetic stimulation? Nature Reviews Neuroscience, 8, 559–567. Rosenberg, O., Isserles, M., Levkovitz, Y., Kotler, M., Zangen, A., & Dannon, P. N. (2011). Effectiveness of a second deep TMS in depression: A brief report. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 35, 1041–1044. Rosenberg, O., Shoenfeld, N., Zangen, A., Kotler, M., & Dannon, P. N. (2010). Deep TMS in a resistant major depressive disorder: A brief report. Depress Anxiety, 27, 465–469. Rosenberg, O., Zangen, A., Stryjer, R., Kotler, M., & Dannon, P. N. (2010). Response to deep TMS in depressive patients with previous electroconvulsive treatment. Brain Stimulation, 3, 211–217. Roth, Y., Amir, A., Levkovitz, Y., & Zangen, A. (2007). Threedimensional distribution of the electric field induced in the brain by transcranial magnetic stimulation using figure-8 and deep H-coils. Journal of Clinical Neurophysiology, 24, 31–38. Roth, Y., Zangen, A., & Hallett, M. (2002). A coil design for transcranial magnetic stimulation of deep brain regions. Journal of Clinical Neurophysiology, 19, 361–370.
Seminowicz, D. A., Mayberg, H. S., McIntosh, A. R., Goldapple, K., Kennedy, S., Segal, Z., & Rafi-Tari, S. (2004). Limbicfrontal circuitry in major depression: A path modeling metaanalysis. NeuroImage, 22, 409–418. Slotema, C. W., Blom, J. D., Hoek, H. W., & Sommer, I. E. (2010). Should we expand the toolbox of psychiatric treatment methods to include repetitive transcranial magnetic stimulation (rTMS)? A meta-analysis of the efficacy of rTMS in psychiatric disorders. The Journal of Clinical Psychiatry, 71, 873–884. Thase, M. E., & Rush, A. J. (1997). When at first you don’t succeed: Sequential strategies for antidepressant nonresponders. The Journal of Clinical Psychiatry, 58, 23–29. Vieta, E., & Colom, F. (2011). Therapeutic options in treatment-resistant depression. Annals of Medicine, 43, 512–530. Wager, T. D., & Smith, E. E. (2003). Neuroimaging studies of working memory: A meta-analysis. Cognitive, Affective, & Behavioral Neuroscience, 3, 255–274. Zangen, A., Roth, Y., Voller, B., & Hallett, M. (2005). Transcranial magnetic stimulation of deep brain regions: Evidence for efficacy of the H-coil. Clinical Neurophysiology, 116, 775–779.
Neurocase: The Neural Basis of Cognition Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/nncs20
Neural correlates of clinical improvement after deep transcranial magnetic stimulation (DTMS) for treatment-resistant depression: a case report using functional magnetic resonance imaging ab
ab
c
Philippe-Olivier Harvey , Frederique Van den Eynde , Abraham Zangen & Marcelo T. ab
Berlim a
Department of Psychiatry, McGill University, Montreal, Quebec, Canada
b
Neuromodulation Research Clinic, Douglas Mental Health University Institute, Montreal, Quebec, Canada c
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Ben-Gurion University of the Negev, Beersheva, Israel Published online: 07 Dec 2013.
To cite this article: Philippe-Olivier Harvey, Frederique Van den Eynde, Abraham Zangen & Marcelo T. Berlim (2015) Neural correlates of clinical improvement after deep transcranial magnetic stimulation (DTMS) for treatment-resistant depression: a case report using functional magnetic resonance imaging, Neurocase: The Neural Basis of Cognition, 21:1, 16-22, DOI: 10.1080/13554794.2013.860173 To link to this article: http://dx.doi.org/10.1080/13554794.2013.860173
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Neurocase, 2015 Vol. 21, No. 1, 16–22, http://dx.doi.org/10.1080/13554794.2013.860173
Neural correlates of clinical improvement after deep transcranial magnetic stimulation (DTMS) for treatment-resistant depression: a case report using functional magnetic resonance imaging Philippe-Olivier Harveya,b, Frederique Van den Eyndea,b, Abraham Zangenc and Marcelo T. Berlima,b* a
Department of Psychiatry, McGill University, Montreal, Quebec, Canada; bNeuromodulation Research Clinic, Douglas Mental Health University Institute, Montreal, Quebec, Canada; cBen-Gurion University of the Negev, Beersheva, Israel
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(Received 7 June 2013; accepted 11 September 2013) We report the effects of a 4-week trial of deep transcranial magnetic stimulation (DTMS) on depressive and anxious symptoms and brain activity in a patient (Mrs A) with treatment-resistant depression (TRD). The protocol involved a preand a post-functional magnetic resonance imaging (fMRI) scan during which Mrs A had to perform a working memory task (i.e., n-back). Her baseline score on the 21-item Hamilton Depression Rating Scale (HAM-D21) was 24, indicating severe depressive symptoms. Immediately after 4 weeks of daily DTMS treatment applied over the left dorsolateral prefrontal cortex (DLPFC), her HAM-D21 score decreased to 13 (a 46% reduction), and 1 month later, it was 12 (a 50% reduction). Moreover, Mrs A’s accuracy scores on the n-back task (i.e., 2-back condition) improved from 79% (baseline) to 96% (after DTMS treatment). At the neural level, Mrs A showed significantly increased brain activity in the working memory network (e.g., DLPFC, parietal cortex) during the execution of the 2-back condition after DTMS treatment compared to baseline. Keywords: deep transcranial magnetic stimulation; functional magnetic resonance imaging; major depressive disorder; working memory; n-back task
Major depressive disorder (MDD) is highly prevalent, has a high incidence, and is associated with a substantial loss of quality of life, increased mortality rates, and enormous social and economic costs (Ebmeier, Donaghey, & Steele, 2006). MDD has been associated with abnormalities in several brain areas (e.g., prefrontal cortex, insula, hippocampus) (J. P. Hamilton et al., 2012) that have been shown to usually improve following clinical recovery (Krishnan & Nestler, 2010). Although the medical management of MDD has evolved substantially over the last decades, a significant number of patients still suffer from treatment-resistant depression (TRD) (Berlim & Turecki, 2007), a condition associated with very high levels of morbidity, chronicity, and societal costs (Dunner et al., 2006; Greden, 2001). Therefore, appropriate clinical management of TRD is of paramount clinical importance (Fava, 2003; Vieta & Colom, 2011). A promising therapeutic intervention for managing TRD is called standard repetitive transcranial magnetic stimulation (rTMS) (Loo & Mitchell, 2005; Padberg & Moller, 2003). This noninvasive procedure involves the safe induction of electrical currents within the brain produced by pulsating magnetic fields generated through a coil-of-wire near the scalp (Daskalakis, Levinson, & Fitzgerald, 2008). To date, several meta-analyses have shown that standard rTMS has clear antidepressant properties (Berlim, Van den Eynde, Perdomo, & Daskalakis, *Corresponding author. Email: [email protected] © 2013 Taylor & Francis
2013; Lam, Chan, Wilkins-Ho, & Yatham, 2008; Slotema, Blom, Hoek, & Sommer, 2010). However, treatment effects are variable, factors predictive of clinical response remain poorly understood, and a number of negative clinical trials have been published (Fitzgerald, 2010; George et al., 2009; Ridding & Rothwell, 2007). A possible explanation for these discrepant findings may be related to the fact that standard rTMS only enables direct modulation of more superficial and relatively limited cortical areas (George & Aston-Jones, 2010; Ridding & Rothwell, 2007), and thus cannot effectively and directly stimulate, for example, deeper layers of the prefrontal cortex that are intimately interconnected with several key mood- and reward-related neural sites (e.g., ventral striatum, ventral tegmentum area) (Levkovitz et al., 2007, 2009). This hypothesis has led to the development of the “H-coil”, a novel rTMS coil that putatively allows for the direct modulation of larger and deeper brain regions by significantly reducing the decay rate of the magnetic induced field, at the expense of reduced focality (Levkovitz et al., 2009). The H-coil maximizes the electrical field deep in the brain by summating separate fields projected into the skull from several points around its periphery, while minimizing the accumulation of electrical charge on the brain’s surface (Roth, Zangen, & Hallett, 2002). Indeed, “phantom brain” measurements have shown that the H-coil can produce an effective field at a depth of 3–4 cm beneath the skull, while the standard
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Neurocase figure-of-eight rTMS coil can only reach a depth of 1.50 cm or less (Roth, Amir, Levkovitz, & Zangen, 2007). This novel neuromodulation technique, called deep transcranial magnetic stimulation (DTMS), has been shown, in a recent 4-week randomized feasibility trial (20 daily sessions) in 65 medication-free patients with MDD, to be well tolerated and to be associated with response and remission rates of 47% and 42%, respectively (Levkovitz et al., 2009). Further studies have replicated these initial findings (Harel et al., 2012; Isserles et al., 2011; Rosenberg, Shoenfeld, Zangen, Kotler, & Dannon, 2010; Rosenberg, Zangen, Stryjer, Kotler, & Dannon, 2010; Rosenberg et al., 2011). Here, we report the effects of a 4-week trial of DTMS on depressive and anxious symptoms as well as on brain activity in an adult patient with TRD.
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also involved a pre- and a post-functional magnetic resonance imaging (fMRI) scan. The Ethics Review Board of the Douglas Mental Health University Institute (Montreal, Quebec, Canada) gave its approval and Mrs A gave us her informed consent.
Clinical assessments Depressive and anxious symptoms were measured by a clinical psychiatrist with the Hamilton Depression Rating Scale (HAM-D21) (M. Hamilton, 1960), and the Hamilton Anxiety Rating Scale (HAM-A) (M. Hamilton, 1959), respectively, at baseline and at weeks 5 and 9.
DTMS procedure Case report Mrs A is a 52-year-old female, separated, mother of a 31year-old daughter, and who has worked for over 20 years as a high school teacher. She has no previous psychiatric history, but reported that two of her brothers were treated in the past for “depressive episodes”. Her current mood disorder started around late 2009 and was related to a number of concomitant stressors, including her mother’s death, a divorce from her husband of several years, and conflicts at work. Her primary symptoms included depressed mood, anhedonia, hypersomnia (i.e., up to 20 hr of sleeping per day), pathological guilt (e.g., “I am very weak and incompetent”), weight loss (i.e., approximately 15 pounds in the first 3 months), low energy and concentration, and marked decision-making difficulties. Also, she reported passive suicidal ideation (e.g., “I wish I could sleep forever”), and significant levels of generalized anxiety on most days. She was diagnosed with a moderate to severe major depressive episode comorbid with a generalized anxiety disorder. Owing to her clinical condition, Mrs A was on a sick leave for over 2 years. Since starting her medical follow-up in late 2009, she was treated with a number of antidepressants (e.g., escitalopram 20 mg/d, venlafaxine up to 450 mg/d for 4 months, mirtazapine up to 45 mg/d for 4 months, and bupropion up to 450 mg/d for 5 months) and with weekly individual psychotherapy (13 months; cognitive–behavioral) but presented with no significant clinical improvement. At baseline, she was using venlafaxine 375 mg/d, bupropion 450 mg/d, and quetiapine 100 mg/d in stable dosages for the past 6 weeks, and her condition was classified as a stage II TRD according to Thase and Rush’s classification (Thase & Rush, 1997). As a consequence of her functional disability as well as the lack of meaningful clinical improvement despite the use of several therapeutic interventions, Mrs A accepted to participate in a 4-week trial of DTMS for MDD, which
DTMS was administered on an outpatient basis using a Magstim Rapid2® magnetic stimulator (Magstim Company Ltd., UK) connected to an H1-coil (that produces its most effective electric field in the anterior–posterior axis with a preference for the left brain hemisphere (Roth et al., 2007)). Prior to stimulation, Mrs A was instructed to insert earplugs. The resting motor threshold (rMT) was determined on a weekly basis over the left primary motor cortex using the visualization method (Pridmore, Fernandes Filho, Nahas, Liberatos, & George, 1998) and the maximum likelihood strategy (Mishory et al., 2004). The positioning of the H1-coil over the left dorsolateral prefrontal cortex (DLPFC) was performed by moving it 6 cm anteriorly to the rMT “hot-spot” (i.e., the point in the scalp in which a minimum magnetic field produced the largest motor twitch of the contralateral hand) parallel to the sagittal suture of the skull (Isserles et al., 2011; Levkovitz et al., 2009, 2011). To ensure placement reproducibility, spatial coordinates were marked on a cap placed on the patient’s head. Each DTMS session consisted of 84 trains (2 s, 20-s intertrain interval, and 3,024 pulses per session) delivered at a frequency of 18 Hz and an intensity of 120% of the measured rMT. Mrs A received 4 weeks of daily DTMS, totaling 20 sessions and 60,480 magnetic pulses, during which her pharmacological regimen remained unchanged.
fMRI procedure n-Back task (Owen, McMillan, Laird, & Bullmore, 2005) During each of the two scanning sessions, Mrs A performed a letter variant of the n-back task, according to which she was asked to indicate, using keypad buttons, whether a letter presented on the screen (the “target” stimulus) was similar to or different from a letter previously presented (the “cue stimulus”). Alternate versions of the task were administered at Time 1 and
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Time 2. The n-back task required Mrs A to maintain and permanently update the relevant pieces of information in working memory. Load and mental manipulation within working memory were incremented using two different levels of complexity: 1-back (maintenance of one piece of information in working memory within the interval between the cue and the target stimuli) and 2-back (interposition of one distractor between the cue and the target stimuli, the distractor becoming a cue for the next trial). Depending on which n-back condition (1- or 2back) was performed, the response was to match the current letter to the one seen 1 or 2 presentations backward. In addition, the patient performed a control task (virtually without working memory processes) called the 0-back task, which required her to identify a single prespecified letter (i.e., “X”). All trials consisted of an instruction (either “2-back”, “1-back”, or “0-back”) presented for 3 s followed by a pseudo-random sequence of 10 consonants varying in case. Each letter appeared on the screen for 1750 ms, followed by a blank screen presented for 750 ms. The total duration of a given trial, from instruction to the last letter was 28 s. Trials were separated one from another by a 10-s blank screen. Two runs of 12 trials each were presented to Mrs A (eight trials per condition). The total duration of a run was 466 s, which included a 10-s blank screen at the beginning of each run. The different condition trials were presented pseudo-randomly. Importantly, Mrs A had a practice/training session with the n-back task outside the scanner before each scanning session. This practice session was administered using a laptop computer. Trials administered during practice were different from the trials used in the scanner. The purpose of these practice sessions was to make sure that Mrs A was comfortable with the n-back task before performing it in the scanner. This helped reducing any potential learning effect during the scanning session. Image acquisition fMRI data were acquired at Time 1 (i.e., baseline) and Time 2 (i.e., in the week following DTMS treatment) at the Brain Imaging Centre at the Douglas Mental Health University Institute on a 3 Tesla Siemens Magnetom MRI scanner. A vacuum cushion was used to stabilize the patient’s head. Stimuli was generated by a PC computer running E-PRIME (Psychology Software Tools, Pittsburgh, PA, USA) and projected via an LCD projector and mirror system. A keypad connected to the computer recorded Mrs A’s responses. Functional T2*-weighted images were acquired with blood oxygenation leveldependent (BOLD) contrasts (two functional runs of 225 volumes, TR = 2090 ms, TE = 50 ms, flip angle = 90º, FOV = 256 mm, Matrix = 64 × 64), covering the entire brain (30 interleaved slices parallel to the anterior–
posterior commissural plane; in plane resolution: 4 × 4 mm; 4 mm thickness). Following the functional session, a 15-min high-resolution T1-weighted anatomical volume was acquired using a gradient echo pulse sequence (22 ms, TE = 9.2 ms, flip angle = 30º, voxel size 1 × 1 × 1 mm3). Each scanning session lasted approximately 1 hr, including set-up time.
Analyses Behavioral performance in the n-back task was defined as the percent response accuracy. For the purpose of this study, we directly compared percent accuracy at the 2back condition between Time 1 and Time 2. fMRI data was analyzed using Statistical Parametric Mapping (SPM8, Wellcome Department of Cognitive Neurology, London, UK). Images were realigned to the mean of the images to correct for inter-scan movement, spatially normalized to the MNI space (normalized voxel sixe 2 × 2 × 2), and smoothed with an 8-mm full-width half-maximum (FWHM) Gaussian kernel. Low-frequency temporal drifts were removed by applying a high-pass filter (cutoff: 128 s). An AR (1) model was used to estimate and correct for nonsphericity of the error covariance. Data from our block design were analyzed by the general linear model (GLM), in which blocks were modeled by a canonical HRF. Both scanning sessions were included in the same analysis. Each condition (2-back preDTMS, 1-back pre-DTMS, 0-back pre-DTMS, 2-back post-DTMS, 1-back post-DTMS, 0-back post-DTMS) was modeled separately. The contrast of interest for the current paper was 2-back post-DTMS minus 2-back preDTMS. This contrast allowed us to identify brain regions whose activity was significantly greater during the execution of the 2-back condition after DTMS treatment compared to before DTMS treatment. Resulting activation map was thresholded at p < 0.001, uncorrected for multiple comparisons, with a minimum cluster size of 30 contiguous voxels.
Results Clinical Mrs A’s baseline scores on HAM-D21 and on HAM-A were 24 and 22, respectively, indicating severe depressive and anxious symptoms. Immediately after 4 weeks of daily DTMS treatment, her scores on HAM-D21 and on HAM-A both decreased to 13 (i.e., a reduction of 46% and 41% in depressive and anxious symptoms, respectively). After 1 month, her scores remained significantly improved compared to baseline (i.e., HAM-D21 = 12, HAM-A = 14). DTMS was well tolerated overall and no significant side effects were reported by the patient.
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Discussion
Mrs A’s accuracy scores at the 2-back condition improved from 79% at Time 1 to 96% at Time 2. At the neural level, Mrs A showed significantly increased brain activity in the working memory network (e.g., DLPFC, parietal cortex) during the execution of the 2-back condition after DTMS treatment compared to baseline (see Table 1 and Figure 1 for details).
We presented a case report of a patient with TRD that has significantly improved in terms of depressive and anxious symptoms after 4 weeks of daily DTMS. This overall clinical improvement, observed immediately after DTMS (week 5) and also 1 month later (week 9), was accompanied by a better cognitive performance in the n-back task at the 4-week follow-up compared to baseline, and by
Table 1. Brain regions showing increased activity during the execution of the n-back task (i.e., 2-back) after DTMS treatment (Time 2) compared to baseline (Time 1).
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MNI coordinates
Inferior frontal (BA 45/47) Cerebellum Supplementary motor area (BA 6) Precentral (BA 6) Superior parietal (BA 7) Middle occipital (BA 17/18) Middle occipital (BA 19) Middle frontal (BA 6/9) Middle temporal (BA 20) Middle frontal (BA 45/46) Middle frontal (BA 44/45)
H
x
y
z
t-Value
L R L L L L L R L R L
−56 32 −10 −52 −24 −10 −36 42 −54 46 −50
30 −74 6 4 −68 −94 −72 10 −38 40 26
−4 −22 76 46 60 0 38 60 −12 30 26
5.74 5.42 5.33 4.74 4.60 4.18 4.01 3.98 3.97 3.85 3.70
Cluster sizea 341 1,615 61 72 84 368 231 105 95 100 55
Abbreviations: L, Left; R, Right; H, Hemisphere; BA, Brodmann’s area. Notes: aThe cluster size represents the number of voxels. MNI coordinates represent the peak voxel of each cluster where x, y, and z indicate the distance measured in millimeters from the anterior commissure in the sagittal, coronal, and horizontal planes, respectively. All clusters of activation reported in Table 1 were significant at p < 0.001, uncorrected for multiple comparisons, with a minimum cluster size of 30 contiguous voxels. Mean performance accuracy for the 2-back condition was 79% at Time 1 and 96% at Time 2.
Inferior Frontal Gyrus z = –4
x = –56
Middle Frontal Gyrus z = 33
x = 46
Middle Occipital Gyrus z = 38
x = –36
Superior Parietal Gyrus z = 60
x = –24
Figure 1. Some of the brain regions that showed increased activity during the execution of the n-back task (i.e., 2-back) after DTMS treatment (Time 2) compared to baseline (Time 1). Statistical threshold set at p = 0.001, uncorrected for multiple comparisons. [To view this figure in color, please see the online version of this journal.]
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increased activity in brain regions typically linked to working memory and cognitive effort (Rajah & D’Esposito, 2005; Wager & Smith, 2003). The almost 50% reduction in depressive symptoms and the increased cognitive performance at the n-back task presented by Mrs A following DTMS treatment are encouraging. Our findings are consistent with those of recent studies that have showed that DTMS applied to the left DLPFC is efficacious for treating depressed patients and may also improve their performance on a number of cognitive domains (e.g., sustained attention, visuospatial memory, cognitive planning) (Harel et al., 2012; Isserles et al., 2011; Levkovitz et al., 2009, 2011; Rosenberg et al., 2011). More generally, according to the pathophysiological model of MDD, antidepressant treatments, irrespective of their mechanisms, are hypothesized to share the ability to normalize metabolic activity in both an underactive dorsal cortical (e.g., DLPFC) and an overactive ventral limbic circuit (e.g., subgenual cingulate gyrus [SCG]) involved in the regulation of emotion (Giacobbe, Mayberg, & Lozano, 2009). Our fMRI results are consistent with this hypothesis by showing a significant increase in the activity of the DLPFC after DTMS treatment compared to baseline. Thus, it is possible that DTMS treatment, through its putative action on deeper and more widespread brain structures, might have contributed to the normalization of dorsal cortical activity, allowing greater recruitment of cognitionrelated brain regions during the execution of the n-back task at Time 2. In this context, one important site of action for DTMS may be the SCG. Indeed, based on its anatomical position between the frontal cortex and the limbic system, the SCG may act as a fulcrum to modulate the activity of both the frontal cortex and the limbic system (Mayberg, 2002). Reduction of the hyperactivity in the SCG in TRD may thus represent a marker of antidepressant response and a necessary first step for the normalization of brain activity in remitted patients (Seminowicz et al., 2004). Consequently, patients with TRD may require treatments (perhaps such as DTMS) that are potentially capable of enlisting the cascade of adaptive neural processes necessary to compensate for a depressive mood state (Price & Drevets, 2010). Nevertheless, this is still speculative, and future studies are needed to better clarify the underlying neural basis of DTMS in MDD and its relationship with symptom improvement. Furthermore, head-to-head comparisons between DTMS and standard rTMS are of paramount importance to explore their differential neurobiological basis and clinical utility for MDD.
of mental health practitioners, researchers, and the patient alike may have impacted the results (Brunoni & Fregni, 2011). Also, it is possible that nonspecific factors (e.g., visiting the study center every day, regular contact with the investigators) might have played a role in the clinical improvement observed following DTMS treatment. However, as we did not employ a control (sham) intervention, we cannot estimate the potential impact of a placebo effect. There is, though, indirect evidence to suggest that the placebo response rates are much lower in subjects with TRD as compared to those with uncomplicated MDD (Dunner et al., 2006; Fekadu et al., 2009; Fournier et al., 2010). Second, we only examined the effectiveness of DTMS immediately after the treatment and 1 month later, and thus cannot estimate the stability of its medium- to long-term antidepressant effects. This is especially relevant considering the labor-intensive and time-consuming nature of DTMS. Although data remain somewhat limited in this regard, a recent small study has reported response and remission rates 3 months following a course of DTMS for MDD of 63% and 52%, respectively (n = 12) (Levkovitz et al., 2009). Moreover, a 3-month continuation trial (n = 29) has shown that the administration of DTMS following the acute treatment twice a week for 8 weeks and once a week for 10 more weeks was associated the probability of a sustained response and remission of 81.12% and 71.45%, respectively (Harel et al., 2012). Finally, as the ability of the H-coil to modulate deeper neuronal structures is obtained at the cost of less focality (Roth et al., 2007; Zangen, Roth, Voller, & Hallett, 2005), it is possible that the clinical improvement observed by Mrs A could have resulted from the larger brain volume receiving direct stimulation rather than from its depth. Thus, because of its more widespread effects, one hypothesis is that the H-coil might able to modulate the DLPFC more consistently/broadly as compared to the standard figure-of-eight coil, which, by being relatively focal, might instead preferentially target specific anatomical parts of the DLPFC in each individual. Nevertheless, additional studies are clearly needed to better explore this hypothesis. Declaration of interest Drs Van den Eynde and Harvey report no conflicts of interest. Dr Zangen is a consultant for and has financial interests in Brainsway, Inc. Funding This work was supported by a researcher-initiated grant received by Dr Berlim from Brainsway, Inc.
Limitations Our case report, despite its interesting findings, has a number of limitations. First, the clinical assessments were performed on an open label basis, and treatment expectations
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