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Dr. Bob is Robert Hsiung, MD,
[email protected]Shown: posts 1 to 25 of 26. This is the beginning of the thread.
Posted by linkadge on June 17, 2004, at 15:28:29
rTMS works wonders for me but I am afraid that it may be dammaging my brain somehow. Does anyone have studies on the safety of it ???
Linkadge
Posted by jrbecker on June 18, 2004, at 11:07:56
In reply to rTMS'rs out there ???, posted by linkadge on June 17, 2004, at 15:28:29
> rTMS works wonders for me but I am afraid that it may be dammaging my brain somehow. Does anyone have studies on the safety of it ???
>
>
> LinkadgeI am in an rTMS study right now. Based on my own extensive research and in discussing in much detail the parameters involved in this study and past ones, I am quite assured of its safety.
I have posted some of the past studies investigating safety below.However, if I recall correctly, you are administering TMS on yourself? After seeing the complexity with which the TMS is applied in my own study, there are so many factors that seem to go into assuring not only safety but efficacy as well. A few of these modalities are frequency, duration of stimulation, motor threshold, magnet location, magnet angle. I will not go into great detail, but suffice it to say, that it takes the treater at least 5-10 minutes just to set up the patient for the treatment by making sure all of the specific measurements and individualized customizations are in place. It's quite scientifically complex.
You might want to check out the national rTMS study that's going on right now. Maybe a site is near you and you qualify....
http://www.neuronetics.com
good luck.Transcranial Magnetic Stimulation in the Treatment of Depression
A Double-blind, Placebo-Controlled TrialPaul B. Fitzgerald, MBBS, MPM, FRANZCP; Timothy L. Brown, GradDipClinNurse (Psych); Natasha A. U. Marston, BA; Z. Jeff Daskalakis, MD, FRCP(C); Anthony de Castella, BA, DipAppSci; Jayashri Kulkarni, MBBS, MPM, FRANZCP, PhD
Arch Gen Psychiatry. 2003;60:1002-1008.ABSTRACT
Background High-frequency left-sided repetitive transcranial magnetic stimulation (HFL-TMS) has been shown to have antidepressant effects in double-blind trials. Low-frequency stimulation to the right prefrontal cortex (LFR-TMS) has also shown promise, although it has not been assessed in treatment-resistant depression and its effects have not been compared with those of HFL-TMS.
Objective To prospectively evaluate the efficacy of HFL-TMS and LFR-TMS in treatment-resistant depression and compared with a sham-treated control group.
Design A double-blind, randomized, sham-controlled trial.
Setting Two general psychiatric services.
Participants Sixty patients with treatment-resistant depression who had failed to respond to therapy with multiple antidepressant medications were divided into 3 groups of 20 that did not differ in age, sex, or any clinical variables. All patients completed the double-blind phase of the study.
Interventions Twenty 5-second HFL-TMS trains at 10 Hz and five 60-second LFR-TMS trains at 1 Hz were applied daily. Sham stimulation was applied with the coil angled at 45° from the scalp, resting on the side of one wing of the coil.
Main Outcome Measure Score on the Montgomery-Εsberg Depression Rating Scale.
Results There was a significant difference in response among the 3 groups (F56,2 = 6.2), with a significant difference between the HFL-TMS and sham groups and between the LFR-TMS and sham groups (P<.005 for all) but not between the 2 treatment groups. Baseline psychomotor agitation predicted successful response to treatment.
Conclusions Both HFL-TMS and LFR-TMS have treatment efficacy in patients with medication-resistant major depression. Treatment for at least 4 weeks is necessary for clinically meaningful benefits to be achieved. Treatment with LFR-TMS may prove to be an appropriate initial repetitive TMS strategy in depression taking into account safety, tolerability, and efficacy considerations.
INTRODUCTION
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SEVERAL STUDIES during recent years have evaluated the use of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depression. Most studies of depression have used high-frequency stimulation (5-20 Hz) and have targeted the left dorsolateral prefrontal cortex (eg, see George et al1 and Pascual-Leone et al2). A variety of sham-controlled double-blind studies of this sort have found significant differences between active treatment and placebo,3 although in some studies4-5 the differences between the groups have been of marginal clinical significance. An alternative paradigm has also shown promise: low-frequency stimulation (1 Hz) applied to the right dorsolateral prefrontal cortex. In the only double-blind evaluation of this type of stimulation, Klein et al6 randomized patients with major depression to either 1-Hz rTMS applied to the right dorsolateral prefrontal cortex or a sham condition. During 2 weeks, 17 of 35 patients in the active treatment group experienced a greater than 50% reduction in depression rating scores compared with 2 of 32 patients in the sham group. However, compared with studies of left-sided rTMS, the patients in this study were not "treatment resistant." No published research, to our knowledge, has directly compared high-frequency left-sided TMS (HFL-TMS) and low-frequency right-sided TMS (LFR-TMS).
The aim of this study was to prospectively evaluate the efficacy of HFL-TMS and LFR-TMS in treatment-resistant depression (TRD) under double-blind conditions and compared with a sham-treated control group. We hypothesized that both forms of treatment would show greater efficacy than a sham control but, based on studies in patients with TRD, that HFL-TMS would be more effective than LFR-TMS. We also aimed to establish whether differences could be found in tolerability and adverse effect profiles associated with the differing types of stimulation.
METHODS
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PATIENTS
Sixty patients with a DSM-IV diagnosis of major depression participated in the study (Table 1). There were no differences among the 3 groups in age, sex, or clinical variables. Patients were recruited from the outpatient departments of 2 public mental health services (Alfred Psychiatry, Melbourne, and Dandenong Area Mental Health Service, Dandenong, Australia) and by referral from a variety of private psychiatrists. Seventy-four patients were screened. Eight patients did not meet the diagnostic criteria, and in 6 patients, the depression was not of sufficient severity. All patients were outpatients during the trial. Recruitment for the trial occurred between October 1, 2000, and September 30, 2002.
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Table 1. Demographic and Baseline Clinical Characteristics of 60 Patients With Major Depression*
The treating psychiatrist and a study psychiatrist (P.B.F.) assigned a DSM-IV diagnosis. Fifty-four patients had a diagnosis of major depressive episode and 6 had a diagnosis of bipolar I disorder, depressive episode (1 in each active treatment group and 4 in the sham group; 2 = 3.3; P = .19). All patients scored greater than 20 on the Montgomery-Εsberg Depression Rating Scale (MADRS) (mean ± SD score, 36.5 ± 7.9) and had failed a minimum of 2 courses of antidepressant medications for at least 6 weeks (mean ± SD number of courses, 5.68 ± 3.40). Patients were not deliberately withdrawn from medication before the trial, but their doses were not allowed to have changed in the 4 weeks before commencement of or during the trial. Forty-six patients were taking medication during the trial: 13 were taking a selective serotonin reuptake inhibitor, 1 a tricyclic antidepressant, 8 a monoamine oxidase inhibitor, and 21 a serotonin-noradrenaline reuptake inhibitor or another class of medication (venlafaxine hydrochloride, mirtazapine, or reboxetine), and 3 patients were taking a combination of antidepressants. Eight patients were receiving lithium carbonate, 3 valproate sodium, 2 carbamazepine, 2 lamotrigine, and 1 combined lithium-carbamazepine. Fourteen patients were receiving antipsychotic medications (7 were taking olanzapine, 3 quetiapine, and 4 risperidone), although only 3 had symptoms rated mild or above (all mild) on the Brief Psychiatric Rating Scale7 psychosis symptom items (2 had hallucinations and 1 had suspiciousness). There were no differences in the proportions of patients taking any of the medication types among the 3 groups. Sixteen patients had previously received treatment with electroconvulsive therapy, 3 during the current episode. Patients with significant medical illnesses, neurologic disorders, or other Axis I psychiatric disorders were excluded. Five patients were left-handed (2 in the HFL-TMS group and 3 in the sham group; 2 = 2.2; P>.05).
Written informed consent was obtained from all patients on a form approved by the human research ethics committees of Southern Health, Dandenong Hospital, and The Alfred Hospital.
STUDY DESIGN
The design for the study is illustrated in Figure 1. Patients were randomized to 1 of 3 treatment arms (n = 20 each) via sealed envelopes opened immediately before commencement of the first treatment session by the clinician administering the rTMS. Patients and raters were blind to treatment, but the clinician administering rTMS was aware of the treatment group. All patients initially received 10 treatment sessions daily, 5 d/wk (phase 1). After the 10th session, a blinded assessment was made and the patients, but not the raters, were informed of their treatment group. Patients who had a reduction in MADRS score of greater than 20% in the active treatment arms could continue with the same TMS condition for another 10 sessions. Patients who did not achieve this improvement were offered the option of crossing over to the other active treatment. Patients initially randomized to the sham condition were randomized to 1 of the 2 active treatments after the initial review. During this second phase of study, the raters remained blind to treatment type. Patients were carefully and repeatedly instructed not to provide the raters with any information that would allow unblinding of group.
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Figure 1. Study design. HFL-TMS indicates high-frequency left-sided transcranial magnetic stimulation; LFR-TMS, low-frequency right-sided TMS; and MADRS, Montgomery-Εsberg Depression Rating Scale.
TMS TREATMENT
Repetitive TMS was administered using a Magstim Super Rapid magnetic stimulator (Magstim, Sheffield, England) and handheld 70-mm figure 8 coils, which were interchanged to allow cooling at times during treatment sessions. Patients sat in a reclining chair with a headrest for stabilization of the head, and there was limited interaction between the patient and the physician during the rTMS sessions. Prior to the commencement of the first rTMS treatment session, single-pulse TMS was used to measure the resting motor threshold (RMT) for the abductor pollicis brevis muscle in both hands using electromyographic recordings using the standard method of limits.2, 8 At all times, the coil was held tangential to the scalp, with the handle pointing back and away from the midline at 45°. The induced current flow was posterior to anterior in the cortex perpendicular to the central sulcus. The site of stimulation during the TMS sessions was defined by a point 5 cm anterior to that required for maximum stimulation of the abductor pollicis brevis.
In LFR-TMS, five 60-second trains were applied at 1 Hz and at 100% of RMT. There was a 1-minute intertrain interval (total of 300 stimuli per session). In HFL-TMS, twenty 5-second trains were applied at 10 Hz and at 100% of RMT. There was a 25-second intertrain interval (total of 1000 stimuli per session). Patients allocated to the sham condition were further randomized to receive sham stimulation on the left or right side. Sham stimulation was applied with stimulation parameters identical to those for active treatment on the side allocated but with the coil angled at 45° off the head. The medial wing of the coil was resting on the scalp. This produced some degree of scalp sensation in most participants but has been shown to produce a limited degree of intracortical activity.9-10 At the completion of each phase of treatment, patients were questioned about whether they thought they had received active or sham stimulation. As previous studies have shown minimal fluctuation of the RMT across treatment sessions,11 this was not adjusted on a daily basis.
CLINICAL RATINGS
The primary outcome measure for the study was the MADRS score.12 All patients were assessed at baseline and at each 10-session review via the MADRS, the Beck Depression Inventory,13 the Brief Psychiatric Rating Scale,7 and the CORE rating of psychomotor disturbance (CORE).14 Ratings at follow-up were also made using the Clinical Global Impressions scale.15 Handedness was recorded using the Edinburgh Handedness Inventory.16 In addition, a group of cognitive tasks were administered at baseline and at the end of the study. The cognitive measures were not administered at each review to minimize practice effects and because the primary reason for their inclusion was to assess the cognitive implication of the treatment sessions, including the accumulation of stimulation across study phases. The battery was designed to focus on memory effects and frontally mediated executive functions. The tasks included the Personal Semantic Memory Schedule, the Autobiographical Memory Schedule,17 the Wechsler Adult Intelligence ScaleRevised (Block Design test, verbal paired associates recall and recognition subscale, and digit span subscale),18 Tower of London,19 and the Controlled Oral Word Association Test.20
DATA ANALYSIS
One-way analysis of variance models and 2 tests were used to investigate differences among the 3 groups on demographic and baseline clinical variables. The primary outcome analysis was conducted on baseline to 2-week psychopathologic change scores, calculated by subtraction of the 2-week scores from the baseline scores. Differences between the groups were calculated using analysis of variance models for each psychopathologic variable. Post hoc tests (least squares difference) were only calculated where a significant effect was found in the analysis of variance model. Secondary analyses included calculation of differences in dichotomous outcome measures (percentage response criteria) using 2 tests. Repeated-measures general linear models were calculated to study the effects of rTMS over multiple times (baseline to 4 weeks). The primary analysis of change in MADRS score was also recalculated using medication treatments (use of antidepressants, mood stabilizers, and antipsychotics) as covariates.
Linear regression models were calculated to test for predictors of clinical response in the 40 patients receiving active treatment. The change in MADRS score in the double-blind phase was entered as the dependent variable. The following were entered into the models as independent variables: baseline depression severity (MADRS score), psychotic symptoms (Brief Psychiatric Rating Scale thought disturbance and hostile-suspiciousness subscale scores), measures of melancholia (CORE total score and noninteractiveness, retardation, and agitation subscale scores), demographic variables (age, sex, age at illness onset, and number of previous episodes), and medication treatment status (antidepressants, mood stabilizers, and antipsychotics).
The cognitive data were analyzed using paired t tests comparing the baseline and end study scores. Separate analyses were conducted for the group as a whole and for patients who received HFL-TMS only, LFR-TMS only, or both active treatment conditions. Pearson correlation coefficients were calculated between change in MADRS and Beck Depression Inventory scores and change in cognitive variables for the equivalent times.
All procedures were 2-tailed, and significance was set at = .05, except during the correlations in which the Bonferroni procedure was used to correct for multiple comparisons. All statistical analyses were conducted using statistical software (SPSS for Windows 10.0; SPSS Inc, Chicago, Ill).
RESULTS
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PATIENTS
Baseline clinical characteristics are summarized in Table 1. There were no statistically significant baseline differences among the groups. All patients who entered the study completed the double-blind randomized phase.
TREATMENT EFFICACY
Double-blind Phase: Baseline to Week 2
There was a reduction in mean ± SD MADRS scores in the 2 active treatment groups (HFL-TMS: 13.5% ± 16.7%; LFR-TMS: 15.0% ± 14.1%) and minimal change in the sham group (0.76% ± 16.2%) (Table 2 and Figure 2). There was an overall effect of group (F56,2 = 6.2; P = .004), with significant differences between the HFL-TMS and sham groups and between the LFR-TMS and sham groups (P<.005 for both). There was no significant difference between the 2 treatment groups (P = .91). There was also a significant difference among the groups for change in Beck Depression Inventory scores (F56,2 = 5.1; P = .03). On post hoc tests there was a trend toward a significant difference between the LFR-TMS and sham groups (P = .08) but not between the HFL-TMS and sham groups (P = .16). There was no significant difference between the 2 treatment groups (P = .61). There was an increase in Global Assessment of Functioning scale scores for the 2 active treatment groups but not for the sham group (overall: F56,2 = 2.6; P = .08; LFR-TMS vs sham: P = .03; and HFL-TMS vs sham: P = .09). There was no significant difference among the groups for changes in Brief Psychiatric Rating Scale and CORE rating measures. There was a significant overall difference among the 3 groups on the Clinical Global Impressions scale score at 2 weeks (F57,2 = 4.9; P = .01). Scores on the Clinical Global Impressions scale were significantly lower in the LFR-TMS group than in the sham group (P = .005) and in the HFL-TMS group than in the sham group (P = .01).
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Table 2. Baseline and Week 2 Scores for Each Outcome Measure in 60 Patients With Major Depression*
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Figure 2. Mean Montgomery-Εsberg Depression Rating Scale (MADRS) scores across all phases of the study. A significant difference in response is present between the 2 active treatment groups and the sham group in the double-blind phase. Patients in both active groups who continued with treatment continued to achieve significant therapeutic responses. There was limited improvement in most patients in the crossover phases. HFL-TMS indicates high-frequency left-sided transcranial magnetic stimulation; LFR-TMS, low-frequency right-sided TMS.
The primary efficacy analysis was repeated using models controlling for age, sex, diagnosis, baseline MADRS score, and treatment with any antidepressant, mood stabilizing, or antipsychotic medication as covariates. The effect of group remained significant (F2,56 = 4.8; P = .01), as did the post hoc differences between the HFL-TMS and sham groups (P = .02) and between the LFR-TMS and sham groups (P = .006). There were no other statistically significant effects. Concurrent use of antidepressant medication had a positive effect on outcome, but this was not significant (F = 1.49; P = .23). There was an effect of diagnosis (greater improvement for patients with a diagnosis of unipolar depression), but this did not reach significance (F = 2.8; P = .01).A separate analysis was conducted of the number of patients who met the initial response criteria of a greater than 20% reduction in MADRS score by 2 weeks. Eight patients in the HFL-TMS group, 7 in the LFR-TMS group, and 2 in the sham group met these criteria. This difference approached significance (2 = 5.1; P = .07). Of the 17 patients who met the response criteria, 7 were concurrently receiving a mood stabilizer. This proportion was not significantly different from the proportion not receiving a mood stabilizer (2 = 2.5; P = .11). Of the 3 patients reporting psychotic symptoms at baseline, 2 were randomized to LFR-TMS, and 1 met the response criteria. The third patient responded to LFR-TMS in the single-blind phase after initially receiving sham stimulation. Only 1 patient (LFR-TMS) achieved a 50% improvement in MADRS score during the initial 2 weeks.
Baseline to Week 4
All of the patients who met the initial response criteria continued to receive single-blind treatment for another 2 weeks. For the group as whole, after 4 weeks of treatment, the mean ± SD percentage change in the MADRS score from baseline was 48.0% ± 17.9% (range, 15.1%-87.5%) (Figure 2). There was a greater improvement in the LFR-TMS group compared with the HFL-TMS group from week 2 to week 4 (mean ± SD change in MADRS score: HFL-TMS, 14.1% ± 21.5%; LFR-TMS, 38.8% ± 19.7%; t13 = -2.12; P = .05). A repeated-measures general linear model was calculated using time (baseline, week 2, and week 4) as the repeated measure and group (HFL-TMS and LFR-TMS) as the between-patients factor. There was a significant overall effect of time (F12,2 = 68.9; P<.001; 2 = 0.92) but no time x group interaction (F12,2 = 0.29; P = .75). Seven of these patients had a reduction in the MADRS score of greater than 50% by the end of the 4 weeks (4 in the LFR-TMS group and 3 in the HFL-TMS group).
Sham Group
Eleven patients who received sham treatment initially were subsequently randomized to active treatment and received at least 10 sessions of TMS (7 received HFL-TMS and 4 received LFR-TMS) (Figure 2). Change scores from the commencement of active treatment until the end of treatment were calculated and compared among the groups. There was a mean ± SD improvement of 15.0 ± 10.4 points (45.3%) in MADRS scores in the LFR-TMS group and a change of 0.3 ± 4.1 points (1.3%) in the HFL-TMS group (t9 = -3.4; P<.005). Two patients in the LFR-TMS group achieved a greater than 50% reduction in the MADRS score.
Crossover After Failed Active Treatment
After the initial 2 weeks, 17 patients who initially received active treatment and were classified as nonre sponders progressed to receive the other active treatment condition (10 right-sided nonresponders and 7 left-sided nonresponders). For the second phase of treatment, analyzed using a repeated-measures general linear model, there was a significant effect of time (F1,15 = 4.4; P = .05) but no effect of group x time (F1,15 = 0.89; P = .36), with both groups showing a small but significant effect. However, significant improvement in this phase was limited to a few patients. Three patients in the HFL-TMS after LFR-TMS group and no patients in the LFR-TMS after HFL-TMS group achieved a greater than 50% reduction in the MADRS score.
PREDICTION OF RESPONSE
Several linear regression models were calculated using improvement in MADRS score in the double-blind phase as the dependent variable. The CORE agitation score was the only significant predictor (mean ± SE parameter estimate, 1.426 ± 0.46; P = .004), predicting 20% of the variance. A greater degree of baseline agitation was associated with better response. When these models were calculated separately for response to the 2 active treatments, the CORE agitation score predicted response for the LFR-TMS group (mean ± SE parameter estimate, 1.426 ± 0.53; P = .01; r2 = 0.29) but not for the HFL-TMS group.
ADVERSE EFFECTS
After phase 1, 7 (11%) of the 60 patients reported site discomfort or pain during rTMS and 6 (10%) reported a headache after rTMS. Although there was no difference in the incidence of these adverse effects (P = .08), patients in the HFL-TMS group seemed to report more discomfort during the procedure itself. Only 1 patient (in the HFL-TMS group) reported persistence of the headache for longer than 1 hour. Two patients (1 in each group) reported transient dizziness for a short time after treatment.
No patients withdrew because of adverse effects during the double-blind phase. One patient, originally randomized to the sham condition, withdrew after 1 session of HFL-TMS treatment in the single-blind phase of the study owing to site pain. One patient with bipolar disorder, who had a successful response to LFR-TMS treatment, experienced a manic episode 10 days after completion of the trial after ceasing treatment with valproate sodium at the end of the TMS trial independent of his treating clinicians. The episode resolved with reinstitution of the medication.
COGNITIVE ASSESSMENTS
No deterioration in performance was found in any cognitive measures in the group as a whole or in the analyses of patients who received HFL-TMS only, LFR-TMS only, or both active treatment conditions. Including all patients who underwent at least 1 type of active treatment, there was a significant improvement in performance on the verbal paired associates (t50 = -7.3; P<.001), verbal fluency (t48 = -3.8; P<.001), and digit span forwards (t48 = -1.8; P = .003) subscales; the Personal Semantic Memory Schedule (t50 = -2.4; P = .02); and the Autobiographical Memory Schedule (t50 = -1.9; P = .05). A similar pattern of improvements was seen for each of the treatment subgroups (HFL-TMS only, LFR-TMS only, or both active treatments). Changes in performance on the cognitive measures did not correlate with changes in MADRS and Beck Depression Inventory scores across the same times.
MAINTENANCE OF BLIND
Twenty-nine patients (48%) correctly guessed their type of treatment before disclosure, 17 (42%) of 40 in the active treatment group (2 = 0.90; P = .34) and 12 (60%) of 20 in the sham group (2 = 0.80; P = .37). The degree of response was the predominant reason given for the guess.
COMMENT
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The results of this study indicate that HFL-TMS and LFR-TMS have clinical efficacy in patients with TRD. There did not seem to be a significant difference in efficacy between the 2 active TMS treatments. The clinical improvements achieved with 2 weeks of rTMS are clinically modest and occur only in a subset of patients, although further improvement occurs in most patients with additional treatment. A higher score on the CORE agitation scale was the only variable associated with greater clinical improvement, specifically with response to LFR-TMS. Concurrent anticonvulsant therapy was not associated with clinical response. Repetitive TMS was generally well tolerated and was not associated with any major adverse events.
These results add to the evidence supporting the antidepressant efficacy of HFL-TMS in TRD. This efficacy has been established in a variety of sham-controlled clinical studies2, 5, 11 and has been supported by findings from several meta-analyses.21-24 Our analysis indicates that greater response accumulates with a longer period of stimulation than the frequently applied 2 weeks of treatment. It seems likely that this relates to the accumulated dose of TMS achieved over time. There is a trend in published studies for improved response rates when rTMS has been applied at a higher intensity or with a higher number of pulses per day.25 The number of stimuli applied in the HFL-TMS condition in this study (10 000 stimuli during 10 sessions) was significantly higher than that applied in several previous studies with results of limited clinical significance (1250 stimuli in the study by Padberg et al5 and 4000 stimuli in the study by Berman et al4) but less than that in the study by George et al11 (16 000 stimuli), in which the clinically relevant response rate was higher than we found. It is also possible, although it seems less likely, that improved responses during the 4-week period do not relate to accumulated "dose" but just to a longer duration of intervention. However, the differing time course of response in depression to medication and electroconvulsive therapy would suggest that the rapidity of clinical response is unlikely to be a property of the illness process itself.
To our knowledge, this study is the first to demonstrate the antidepressant efficacy of LFR-TMS in patients with TRD, although the overall response rate was lower than that seen where this treatment condition has been applied in medication-responsive patients despite the application of a greater number of pulses than in previous studies (300 vs 100-120 pulses).6, 26-27 As rTMS is most likely to be of clinical utility in medication-nonresponsive patients, demonstration of its clinical efficacy is crucial in this patient group. In addition to the clinical differences between the patients, it is possible that the smaller effect size compared with that in the study by Klein et al6 relates to differences in methods of administration. In that study, TMS was applied with a 9-cm-diameter round TMS coil, which produces a less focused area of stimulation compared with the coil used in the present study. This may be of benefit given recognized limitations in stimulation site localization,28 although the results of our study give more assurance that the antidepressant effects have been produced via right prefrontal cortex stimulation.
The antidepressant effects of LFR-TMS were of similar magnitude as those seen with HFL-TMS despite the LFR-TMS condition consisting of considerably fewer pulses per session (300 vs 1000 pulses). The number of 1-Hz pulses was chosen to equalize the treatment times and because there was limited information regarding the safety of a greater number of 1-Hz pulses at the time of inception of the study. It is possible that an equal number of pulses between conditions may have produced results in favor of the 1-Hz condition. Although the mechanism of action of rTMS is not clear, it has been suggested that it relates to synaptic changes such as long-term potentiation and long-term depression.29 Results of animal studies of electrically induced long-term potentiation/long-term depression and of human studies of motor cortical responses to rTMS indicate that these effects depend on the total number of pulses delivered in any conditioning regimen (eg, see Trepel and Racine30 and Maeda et al31).
The potential advantage of low-frequency stimulation has implications for the development of clinical rTMS protocols, as low-frequency stimulation has several advantages. First, as the potential for seizure induction is directly related to increasing frequency, LFR-TMS is associated with a significantly lower risk of seizure induction. In fact, 1-Hz stimulation may have some antiseizure properties.32-33 Therefore, low-frequency stimulation would be preferred in patients with any risk factors for seizure induction or with substantial medical comorbidity. Second, although not clearly illustrated by study data, our definite clinical impression was that patients better tolerate LFR-TMS than HFL-TMS, which produces a greater degree of local scalp discomfort during stimulation. Low-frequency stimulation may prove to be the best "universal" first choice if predictors of response to one or another therapy cannot be established. High-frequency left-sided TMS would be an option for patients who do not respond to LFR-TMS. Because there is some suggestion that slow left-sided stimulation may have antidepressant effects,5 a direct comparison of low-frequency left- and right-sided stimulation seems timely. The relationship of clinical variables, such as agitation, as seen in this study, to response to differing stimulation types also requires further assessment.
Several limitations of this study require consideration. First, although the sample size was large enough to distinguish between active and sham stimulation, it is possible that the lack of a difference between the 2 active conditions is a type II error. Although there was some variation in responses in the crossover phases, the equivalence of the effects in the double-blind phase of the study suggests that a very large sample size will be required to detect real differences between these 2 treatments if they exist. Second, although the clinical changes that occurred during the extension phase of the study in patients who continued active treatment were statistically significant and clinically meaningful, interpretation of this phase of the study is limited, as the patients were aware of their treatment type. Considerable efforts were made to ensure that the raters remained blind to the treatment condition during this period, but this does not exclude placebo effects. We also have limited capacity to draw conclusions about the value of swapping between treatments in patients who did not respond to one stimulation type. However, these data suggest that there is potential value in a trial of HFL-TMS after failed LFR-TMS, but perhaps less value in the opposite. This supports the idea of offering LFR-TMS as a first-line stimulation type with crossover to HFL-TMS in nonresponders.
Several medication issues are worthy of comment. First, most patients were receiving some form of antidepressant medication during the trial. However, we were careful to ensure that patients had been taking their current medication for several months and were taking a stable dose for at least 1 month before commencement of rTMS. We also excluded patients who seemed to be improving in clinical state in response to the medication, as judged by the patient or the treating clinician. Presumably, because of this careful screening, there was no effect of medication treatment on outcome. Second, the patient group as a whole had tried many antidepressant medications before the trial. This would indicate a high degree of treatment resistance and may explain the low sham response rate in the double-blind phase of the trial. Given the low rate of successful guessing, it is unlikely that the low sham response rate, and the overall results of this phase, were biased by unblinding of the patients.
In conclusion, our results support the efficacy of HFL-TMS and LFR-TMS in the treatment of TRD and suggest the equivalence of these treatments. Treatment for at least 4 weeks seems to be necessary for clinically meaningful benefits to be achieved with the parameters applied in this study. Further evaluation of whether alterations in stimulation parameters can increase the response rate or the rapidity of response to rTMS is required. Treatment with LFR-TMS may prove to be an appropriate initial rTMS strategy in depression taking into account safety, tolerability, and efficacy considerations.
AUTHOR INFORMATION
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Corresponding author and reprints: Paul B. Fitzgerald, MBBS, MPM, FRANZCP, Alfred Psychiatry Research Centre, Level 2, Old Baker Bldg, The Alfred Hospital, Commercial Rd, Melbourne, Victoria 3004, Australia (e-mail: [email protected]).
Submitted for publication January 21, 2003; final revision received March 5, 2003; accepted March 5, 2003.
This study was supported by grant 143651 from the National Health and Medical Research Council (Canberra, Australia) and by a grant from The Stanley Medical Research Institute (Bethesda, Md).
We thank the patients, whose participation was essential in the successful completion of this study. We also thank Marlies Largerberg, MBBS, and James Zurek, MBBS, who assisted with the provision of rTMS during the trial.
From the Alfred Psychiatry Research Centre, The Alfred Hospital, and the Department of Psychological Medicine, Monash University, Melbourne, Australia (Drs Fitzgerald and Kulkarni, Messrs Brown and de Castella, and Ms Marston); and the Clarke Division, Centre for Addiction and Mental Health, Toronto, Ontario (Dr Daskalakis).
REFERENCES
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References
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Neurocognitive effects of repetitive transcranial magnetic stimulation in severe major depressionBrian Martis, , a, Danesh Alama, Sheila M. Dowda, S. Kristian Hilla, Rajiv P. Sharmaa, Cherise Rosena, Neil Pliskina, Eileen Martinb, Valorie Carsonc and Philip G. Janicaka
a Department of Psychiatry, Psychiatric Clinical Research Center and Center for Cognitive Medicine, University of Illinois at Chicago, 912 South Wood Street Suite 137 MC 913, Chicago, IL 60612, USA
b Neurology and Psychiatry, University of Illinois at Chicago, 1601 West Taylor Street, Chicago, IL, USA
c University of Kansas, Lawrence, KS 66045, USAAccepted 5 February 2003. ; Available online 15 April 2003.
Abstract
Objective: Repetitive transcranial magnetic stimulation (rTMS) is being investigated as a potential treatment for depression. Few studies have addressed the neurocognitive effects of a course of rTMS in severely depressed patients. We evaluated neurocognitive effects of a 14 week course (mean 3 weeks) of rTMS using an aggressive set of parameters, in 15 severely depressed subjects.Methods: A battery of neurocognitive tests relevant to attention, working memory-executive function, objective memory and motor speed were administered to 15 subjects with treatment-resistant major depression (unipolar and bipolar), before and after a course of rTMS. Mean z scores were computed for each of 4 cognitive domains and analyzed using repeated measures multivariate analysis of covariance. Significant interactions were further clarified using univariate analysis of variance.
Results: There was no worsening of performance on any of the cognitive domains over the baseline-post rTMS period. On the contrary, evidence of modest but statistically significant improvement in performance was noted in working memory-executive function, objective memory and fine motor speed domains over the rTMS treatment period.
Conclusions: There was no evidence of adverse neurocognitive changes over the baseline-post rTMS period in 15 treatment-resistant depressed subjects undergoing a 3 week (mean) trial of rTMS. Significant improvements in several domains observed over the rTMS treatment period could not be explained by improved mood. Practice effects as well as other factors potentially contributing to these findings are discussed.
Significance: rTMS is being increasingly studied as a neurophysiological probe as well as for its potential antidepressive effects. The effects on neuronal function raise appropriate questions of safety of its use at varying stimulus parameters and durations. This study contributes to the small body of evidence of the cognitive effects of rTMS in severely depressed patients.
Author Keywords: Neurocognitive effects; Dorsolateral prefrontal cortex; Repetitive transcranial magnetic stimulation; Major depression
Article Outline
1. Introduction
2. Methods
2.1. Subjects
2.2. rTMS procedure
2.3. Neurocognitive tests
2.4. Statistical methods
3. Results
3.1. Interaction between time (baseline-post rTMS) and neuropsychological domain
3.2. Interaction between neuropsychological domain and response (responder versus non-responder)
4. Discussion
Acknowledgements
References
1. Introduction
Repetitive transcranial magnetic stimulation (rTMS) induces transient observable changes in brain functions subserved by the underlying cortical region being stimulated (George et al., 1999). The application of rTMS over areas of the scalp causes stimulus bound interruption of functions subserved by underlying cortical regions (a temporary lesion effect) such as, interference with free recall (frontal and temporal areas; Grafman et al., 1994), speech arrest (dominant fronto-temporal area; Pascual-Leone et al., 1991) and interference with letter identification (occipital area; Amassian et al., 1989). These effects are being increasingly utilized to test theories about specific regional cortical functions (for review see Jahanshahi and Rothwell, 2000). Evidence from animal studies at a cellular level and human neurophysiological and neuroimaging studies suggest that rTMS has local and remote effects on neural function ( Lisanby and Belmaker, 2000 and Fox et al., 1997). Early serendipitous observation of mood effects has also prompted investigation of rTMS as an experimental therapeutic strategy for depression over the last decade with some encouraging results ( George et al., 1999). These lines of evidence raise the possibility of cumulative adverse effects of rTMS on brain function ( Wassermann, 2000).Investigators addressing the potential lingering cognitive effects of TMS (single pulse) and rTMS (trains of pulses at different frequencies) in healthy volunteers have evaluated selected neuropsychological functions such as aspects of attention, memory, executive functions and motor processing. No significant major adverse cognitive effects were reported in these studies (Bridgers and Delaney, 1989; Hufnagel et al., 1993; Pascual-Leone et al., 1993; Wassermann, 1998 and Jahanshahi et al., 1997) though an episode of stimulus intensity related induction of focal seizures was reported in one subject ( Pascual-Leone et al., 1993).
The effects of long-term rTMS with more aggressive parameters in therapeutic trials with depressed patients are less clear and require systematic assessment. Patients with depression differ from healthy volunteers given the existence of state-dependent cognitive dysfunction (Austin et al., 2001). Additionally, optimal stimulation parameters for treatment of depression are still being investigated ( Martis and Janicak, 2000). Finally, more recent therapeutic studies involve longer exposure to rTMS, including its use as a maintenance strategy ( Li et al., 2002). Thus, ongoing investigation of potential rTMS related cognitive effects in depressed patients is essential to ensure their safety.
Given the preponderance of depression trials using left prefrontal cortical (L-PFC) stimulation, investigators have usually employed neurocognitive tests of frontal lobe functions, as well as some cognitive tests of functions affected by electroconvulsive therapy (ECT). Most studies have involved the assessment of rTMS effects in a small number of depressed patients. For example, Little et al. (2000) studied 10 patients with major depressive disorder (MDD) in a double-blind, sham controlled crossover study utilizing L-PFC stimulation (1 or 20 Hz, at 80% of motor threshold (MT); 8000 stimulations over 10 days). The test battery included the Busch Selective Reminding Test and the Verbal Fluency Test administered at baseline and at weeks 1 and 2. No adverse cognitive effects were reported. On the contrary, improvement in list recall from baseline was observed after 1 week of rTMS (P<0.05). In a more recent study reported by the same group (Speer et al., 2001), 18 patients with MDD randomized to a double-blind, crossover trial with 2 weeks of 1 Hz, 20 Hz or sham rTMS (L-PFC, increasing power to 100% of MT; 16,000 stimulations over 10 days) were studied. Again, the authors reported no decline in test scores, and a trend (P=0.09) toward improvement on the Verbal Fluency Task, which did not correlate with clinical improvement as measured by Hamilton Depression Rating Scale (HDRS) change scores.
It is known that drug-resistant patients comprise a small but significant proportion of the depressed population and rTMS has been studied as a potential treatment for this group. Avery et al. (1999) reported the lack of adverse cognitive effects in a small number (n=6) of treatment-resistant patients. In another study, Padberg et al. (1999), using a small number of stimulations per course (total 1250 over 5 days), reported similar findings in 18 medication-resistant depressed patients receiving fast (10 Hz), slow (0.3 Hz) or sham rTMS to L-PFC (at 90% MT for active treatments). Additionally, they found a statistically significant time by group interaction, indicating improvement in verbal memory scores for patients who received fast rTMS. Similarly, no significant worsening of cognitive performance was reported in 10 resistant MDD patients receiving L-PFC stimulation (20 Hz, 80% MT, 20,000 stimulations over 10 days) by Triggs et al. (1999). While performance on the Controlled Oral Word Association (COWA) and digit span forward tests at the end of 2 weeks improved, the absence of a control group precludes ruling out practice effects. In a more recent study, Loo et al. (2001) evaluated 18 medication-resistant, depressed patients before, during and after 2 and 4 weeks of rTMS in a parallel, double-blind sham controlled study (L-PFC, 10 Hz, 110% MT, 15,00030,000 stimulations over 24 weeks) and reported no adverse cognitive effects at 2 weeks (n=9) as well as 4 weeks (n=12). While there were improvements in scores for some test measures in unrelated cognitive domains, these did not survive correction for multiple comparisons. One patient however, had worsening of performance on the Rey Auditory Verbal Learning Test components after 2 weeks of real rTMS but reported no subjective memory complaints. Thirteen of these patients were continued on medications during this study, but this variable did not have a significant effect in the statistical analysis.
We report on the assessment of selected neurocognitive functions over a course of rTMS, in 15 treatment-resistant, severely depressed patients, who received a mean of 14,600 (±5400) stimulations over 14 weeks (mean 3 weeks) using a more aggressive profile of rTMS parameters.
2. Methods
2.1. Subjects
The present study was conducted in the context of an open, randomized, prospective comparison of rTMS versus ECT for treatment-resistant major depression. Details of the entire treatment study cohort as well as the design, methods and preliminary results of the comparative therapeutic trial (rTMS versus ECT) have been described elsewhere (Janicak et al., 2002). This paper includes data from additional subjects who were treated with rTMS. All subjects met DSM-IV criteria ( American Psychiatric Association, 1994) for a Major Depressive Episode (as part of unipolar or bipolar disorder) as determined by a Structured Clinical Interview for DSM-IV. Only those subjects randomized to the rTMS treatment arm qualified to participate in the cognitive study. Subjects who received ECT were not included in this study. ECT effects on cognition are well described and the presence of such adverse effects would limit meaningful comparison between the two groups.Subjects were screened carefully for significant neuromedical conditions, use of medications and contraindications to rTMS (e.g. pacemaker, ferromagnetic metallic implants, pregnancy). Due to the severity of their depression and the novelty of the procedure, all subjects were hospitalized for the entire rTMS course at the Psychiatric Clinical Research Center, University of Illinois at Chicago (UIC). All subjects underwent written informed consent procedures in accordance with the Institutional Review Board of the UIC.
All subjects were discontinued from psychotropic medications, although they were allowed rescue medications on an as needed basis, usually at night. Due to the severity of symptoms, most subjects received some rescue medications (specifically benzodiazepines and zolpidem) during the trial (Janicak et al., 2002).However, subjects were free of antidepressant and/or neuroleptics prior to the baseline cognitive evaluation (washout) till after the final cognitive evaluation. A baseline neurocognitive assessment battery was given to 19 subjects with major depression, who were randomized to receive a 24 week trial of rTMS. Three subjects received only a few stimulations before discontinuing the treatment study, and one subject was eliminated because she received a course of ECT just prior to rTMS ( Levy et al., 2000). Thus, the final analysis included 15 subjects whose sociodemographic and clinical characteristics are given in Table 1.
Table 1. Demographic, clinical and treatment characteristics of the study sample (N=15)a
2.2. rTMS procedure
MT was determined during the first session using the visual method with the right first dorsal interosseous (FDI) as the target muscle (Wassermann et al., 1996). The stimulator was set at 1 Hz, and starting from the vertex, was methodically moved across the left frontal-parietal region of the cranium, until the motor cortical region for the FDI was located. Up to 10 single pulses were given at each level of intensity. Beginning at 60%, intensity was increased in 2% increments and the procedure repeated until the FDI-MT was achieved. The motor threshold was defined as the stimulus intensity that reliably (at least 5 times out of 10 stimuli) produced visibly observable right FDI muscle contractions. The point of prefrontal magnetic stimulation was determined by moving the coil 5 cm anteriorly from the point of MT determination. The point of stimulation was then marked for reference with an indelible skin marker. Motor threshold was rechecked after the 10th treatment to assess if there were significant changes mid treatment. Results did not significantly differ from the original MT and neither coil placement nor intensity was readjusted for any patient.rTMS involved left prefrontal stimulation delivered daily (MondayFriday) using the following parameters per session: 20, 5-s trains of 10 Hz at 110% motor threshold (MT), with 30-s inter-train intervals, for 1020 sessions over 24 weeks. The Magstim Super-Rapid device (Magstim Co., Sheffield, UK) with a 70 mm figure eight coil was used to administer the rTMS treatments.
2.3. Neurocognitive tests
Subjects received a selected battery of neurocognitive tests either the day before or the morning prior to the first rTMS treatment (baseline) and approximately 3 days (mean 2.8±SD 1.1) following the last rTMS treatment. The tests were administered and scored by trained clinicians (BM, DA and VC). The training process included observing test administration as well as conducting supervised and unsupervised testing. The tests were selected based on the area stimulated (i.e. left prefrontal cortex) and incorporated recommendations from the International Workshop for Safety of Transcranial Stimulation held in Bethesda, MD, USA in 1996 (Wassermann, 1998).The following tests comprised the neurocognitive battery (1). Simple and Choice Reaction Time: computerized measures to test speed of information processing (2). Stroop test: a measure of response inhibition (3). Verbal Fluency (Letter): a measure of speeded word retrieval (4). Wechsler Adult Intelligence Scale-III (WAIS-III) Letter Number Span: a measure of working memory (5). Wechsler Memory Scale-Revised (WMS-R) Visual Reproduction and WMS-R Logical Memory: measures of anterograde memory for verbal and visual information (6). Mental Alternations: timed measure of mental control requiring the subject to recite an alternating letter number sequence (7). New Adult Reading Test: premorbid IQ estimate (8) Grooved Pegboard: speeded task to evaluate fine motor speed and dexterity (9). Squire Test: Subjects perception of attention, and memory, before and after treatment via a self rated inventory (Squire et al., 1979). Components of these tests were grouped into neurocognitive domains which included attention and mental speed (AMS), working memory-executive function (WMX), objective memory (MEM), and fine motor speed (FMS) (see Table 2). Thus, this battery involved a broad assessment of both cognitive functions as well as functions specifically attributed to the area of stimulation (left prefrontal cortex). Alternative forms of tests were not available for most tests and were not used in this study.
Table 2. Baseline and post rTMS neuropsychological battery results grouped by cognitive domainsa
2.4. Statistical methods
When possible, raw scores were converted into t-scores based on corrected norms (Heaton et al., 1992). Data were examined for skewness and kurtosis, and were normalized using log transformations when indicated. To provide a standard metric for comparison, z-scores (relative to baseline performance) were computed for all variables. A mean z-score composite was computed for each neuropsychological domain (AMS, WMX, MEM and FMS). A two by 4 repeated measures multivariate analysis of covariance (MANCOVA) was conducted to assess change over time [within subjects variables: the 4 neuropsychological domains (AMS, WMX, MEM and FMS), time (baseline-post rTMS) and between subjects variables (classification as rTMS responder or non-responder; responders: ≥50% reduction in HDRS and final HDRS score of ≤8)]. Clinical change (in HDRS score) over the treatment period and number of treatments were held constant in this model to control for change in HDRS scores over the treatment period [baseline: 32.7 (±7.8) and post rTMS: 14.3 (±11); percent CHANGE=56%] and length of treatment. When present, significant main effects or interactions were clarified using univariate analysis of variance (ANOVA).3. Results
A baseline and post rTMS neurocognitive assessment battery was given to 15 subjects (12 males, 3 females) (Table 1), and their performance at baseline and post rTMS (mean and SD of raw and corrected T-scores is tabulated in Table 2). Three subjects were left handed. Analysis of the data without and with these 3 subjects did not significantly change findings.Repeated MANCOVA revealed no significant main effects of time [F(1,11)=0.79; P=0.39], neuropsychological domain [F(3,33)=1.76; P=0.17] or response [F(1,11)=0.49; P=0.5]. Significant two-way interactions, however, were found between time (baseline-post rTMS) and neuropsychological domain [F(3,33)=5.03; P=<0.01], as well as neuropsychological domain and response [F(3,33)=8.44; P=<0.01]. There was no significant interaction between time and response [F(1,11)=4.03; P=0.07] or 3-way interaction between time by neuropsychological domain by response [F(3,33)=0.37; P=0.77].
3.1. Interaction between time (baseline-post rTMS) and neuropsychological domain
Clarification of the time by neuropsychological domain interaction was done using univariate comparisons for each domain. This revealed significant improvement in scores across 3 of the 4 domains over the baseline-post rTMS period: i.e. working memory-executive function (WMX) [F(1,14)=8.91; P=0.01], objective memory (MEM) [F(1,14)=23.05; P<0.01] and fine motor speed (FMS) [F(1,14)=10.63; P=<0.01], but not attention and mental speed (AMS) [F(1,14)=0.33; P=0.58] (see Fig. 1).
(5K)Fig. 1. Neurocognitive function in severely depressed treated with left prefrontal rTMS. Standardized z-scores of neurocognitive domains post-rTMS relative to baseline showing a modest (less than 1 SD) but statistically significant improvement in 3 out of the 4 domains (N=15). AMS, attention and mental speed; WMX, working memory-executive function; MEM, objective memory; and FMS, fine motor speed.
3.2. Interaction between neuropsychological domain and response (responder versus non-responder)
Clarification of the neuropsychological domain by response interaction was done using univariate ANOVA. There was a significant difference between responders versus non-responders on AMS [F(1,13)=11.7; P=<0.01] and FMS [F(1,13)=5.16; P=0.04], but not on WMX [F(1,13)=1.31; P=0.27] and MEM [F(1,13)=2.85; P=0.12] scores (collapsed across time).4. Discussion
The main finding of our study was the absence of gross adverse cognitive changes in 15 treatment-resistant, depressed subjects undergoing a 14 weeks (mean 3 weeks) rTMS course [treatment parameters: 10 Hz, 110% MT, 14,600 (mean), 5400 (SD) stimulations]. These results are consistent with earlier reports investigating the cognitive effects of an extended rTMS course in depressed subjects with varying rTMS parameters. Our study most closely resembles that of Loo et al. (2001) in terms of subject population and rTMS parameters [drug-resistant, 10 Hz, 110% MT, 15,00020,000 stimulations, 2 (n=9) to 4 (n=12) weeks].Thus, based on the few existing cognitive studies of daily left prefrontal stimulation in depression using a range of parameters (120 Hz, 80110% MT, 400020,000 stimulations), there appears to be no detectable worsening in group cognitive performance in depressed patients undergoing a 24 weeks trial. However, methodological issues in these studies, specifically, small sample sizes and (for some) the lack of a control group, advocate appropriate caution in interpreting these findings (discussed below).
Few preliminary studies have also reported performance improvement on several tests, such as verbal memory (Padberg et al., 1999), verbal fluency ( Triggs et al., 1999 and Speer et al., 2001) and improvement on list recall ( Little et al., 2000) after an rTMS course in depressed subjects. Others have reported trends towards performance improvement on several tests across various neuropsychological domains, which did not survive more stringent statistical control measures ( Loo et al., 2001). In this context, we found evidence of modest (less than one standard deviation) but statistically significant improvement in certain neurocognitive domain scores over the baseline-post testing period ( Fig. 1). Specifically, working memory-executive function, objective memory and fine motor speed domains improved after taking into consideration the effect of change in HDRS scores over the study period as well as the length of treatment.
Several issues must be considered in interpreting our findings. First, susceptibility of some tests in the battery to practice effects could have contributed to the improved test performance over the baseline-post rTMS period and potentially masked subtle adverse effects (Loo et al., 2001). Tests of fine motor speed and dexterity as well as tests of verbal learning and memory analogous to those used in the present study battery have been shown to be susceptible to practice effects ( Lezak, 1995) and alternative versions of most of these tests were not available or used in the present study. To partially address this issue, we aggregated subtests by cognitive domain and used standardized scores for analysis. In addition, number of treatments were included as a covariate to control for length of treatment in the main analysis (MANCOVA). Subjects in the current study served as their own controls, which limits interpretation of this improvement. However, administering rTMS with aggressive parameters to a healthy comparison group is not feasible from an ethical standpoint. On a related note, ECT effects on cognition are well described and include anterograde short term memory loss (retention of newly learned material) and retrograde amnesia (memory for past events: impersonal and autobiographical) ( Janicak et al., 1991; Sackeim et al., 1993 and Lisanby et al., 2000). The presence of such obvious deficits poses threats to valid comparison of the two groups.
Second, improving mood over the duration of the baseline-post rTMS testing could have resulted in the improved scores in several neurocognitive domains. State-dependent cognitive dysfunction in depressed patients improves following various therapeutic interventions (Austin et al., 2001). However, we observed these improvements while controlling for clinical improvement. Thus, consistent with previous studies ( Loo et al., 2001 and Speer et al., 2001), the observed improvement in cognitive performance in our study cannot be explained by factors related to clinical improvement in mood. The use of sham rTMS may have helped to separate effects associated with clinical improvement (assuming a difference between the active and sham condition on clinical response). Sham rTMS was not used because of the severity of illness in this population (i.e. all patients had to be appropriate for ECT, many had psychotic and suicidal symptoms and all were hospitalized).
A third albeit more remote possibility is that rTMS may independently enhance certain aspects of cognitive functions. Studies in healthy subjects have reported improvements in cognitive and motor performance (Siebner et al., 1999 and Mottaghy et al., 1999), as well as solution times in tests of analogic reasoning following rTMS ( Boroojerdi et al., 2001). Of more relevance to this study, Moser et al. (2002) reported on the cognitive function of 19 elderly, drug-resistant depressed subjects undergoing left prefrontal active (n=9) versus sham (n=10) rTMS. While both groups demonstrated a statistically significant reduction in HDRS scores, a significant improvement in a single test measure, the Trail Making Test-B (TMT-B) score was observed only in the active rTMS group (neither baseline or final TMT-B scores correlated with HDRS scores). This finding suggests mood-independent improvement in aspects of executive function and argues against practice effects contributing to this improvement in this study. While the study designs differed, and with the caveat of the limitations of the present study, we found similar improvement in measures of executive function. The authors (Moser et al., 2002) raise the intriguing possibility that rTMS-induced, mood-independent improvement in executive function may be linked to the area of stimulation (left PFC). However, methodological limitations in the few studies to date leaves this debate unresolved.
Finally, we also observed a significant difference in performance between responders and non-responders on two domains (responders did significantly worse on AMS but better on FMS compared to non-responders). This finding however involves domain scores collapsed across time (baseline+final) in a small sample size and this finding therefore is not open to meaningful interpretation. Larger sample sizes may help to clarify if certain neurocognitive profiles may be predictive of response.
Limitations of this preliminary trial include the small number of subjects; absence of a control group (e.g. sham group and/or healthy volunteers); an open design; and the susceptibility of some components of the neurocognitive battery to practice effects. Strengths of the present study include the use of a detailed neurocognitive battery; conservative statistical procedures; and inclusion of a unique clinical population exposed to more aggressive rTMS treatment parameters over an extended period. The primary purpose of this study was to monitor the safety of the subjects enrolled in an rTMS treatment study. Further studies are indicated involving larger sample sizes, specifically addressing confounds of practice effects and mood change in depressed subjects undergoing rTMS.
Acknowledgements
This work was supported in part by the Eleanor B. Pillsbury Fellowship for research (BM and DA); the Clinical Research Board (PGJ); the Department of Psychiatry (PGJ), and the NIH funded General Clinical Research Center (1MO1RR13987-01), all at UIC. Preliminary findings from this study have been presented as posters at the International Society for Transcranial Stimulation (ISTS) Satellite Meeting, Chicago, IL, USA, May 10, 2000; and at the Young Investigator New Research poster session, 153rd American Psychiatric Association (APA) Annual Meeting, May 15, 2000, Chicago, IL.USA (NR #81). We thank Dr Robin Reed and Ms Jennifer Taylor for advice on scoring.
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Bipolar Disord. 2003 Feb;5(1):40-7.Left prefrontal transcranial magnetic stimulation (TMS) treatment of depression in bipolar affective disorder: a pilot study of acute safety and efficacy.
Nahas Z, Kozel FA, Li X, Anderson B, George MS.
Brain Stimulation Laboratory, Department of Psychiatry, Medical University of South Carolina, Charleston 29425, USA.
OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) has been shown to improve depressive symptoms. We designed and carried out the following left prefrontal rTMS study to determine the safety, feasibility, and potential efficacy of using TMS to treat the depressive symptoms of bipolar affective disorder (BPAD). METHODS: We recruited and enrolled 23 depressed BPAD patients (12 BPI depressed state, nine BPII depressed state, two BPI mixed state). Patients were randomly assigned to receive either daily left prefrontal rTMS (5 Hz, 110% motor threshold, 8 sec on, 22 sec off, over 20 min) or placebo each weekday morning for 2 weeks. Motor threshold and subjective rating scales were obtained daily, and blinded Hamilton Rating Scale for Depression (HRSD) and Young Mania Rating Scales (YMRS) were obtained weekly. RESULTS: Stimulation was well tolerated with no significant adverse events and with no induction of mania. We failed to find a statistically significant difference between the two groups in the number of antidepressant responders (>50% decline in HRSD or HRSD <10 - 4 active and 4 sham) or the mean HRSD change from baseline over the 2 weeks (t = -0.22, p = 0.83). Active rTMS, compared with sham rTMS, produced a trend but not statistically significant greater improvement in daily subjective mood ratings post-treatment (t = 1.58, p = 0.13). The motor threshold did not significantly change after 2 weeks of active treatment (t = 1.11, p = 0.28). CONCLUSIONS: Daily left prefrontal rTMS appears safe in depressed BPAD subjects, and the risk of inducing mania in BPAD subjects on medications is small. We failed to find statistically significant TMS clinical antidepressant effects greater than sham. Further studies are needed to fully investigate the potential role, if any, of TMS in BPAD depression.
Publication Types:
Clinical Trial
Randomized Controlled Trial
Posted by linkadge on June 18, 2004, at 15:16:35
In reply to Re: rTMS'rs out there ???, posted by jrbecker on June 18, 2004, at 11:07:56
I'm not so much worried about things like seizures as I am about unknown things like
long term cellular dammage, unkown cancer risks things like that which they really don't know about yet.
Linkadge
Posted by Pfinstegg on June 18, 2004, at 21:19:11
In reply to rTMS'rs out there ???, posted by linkadge on June 17, 2004, at 15:28:29
It was good to hear that you are in an rTMS trial, and I hope you will let us know what you think of it. I have had it four times on "off-label" use, and feel it is extremely safe, both because of my own experience (I usually feel *smarter* for quite a while afterwards!), and from the reading I did before I started it. Like any new thing, it's impossible to know what the long-term effects might be, but we are discovering that that is also true of SSRI's which have been available for a long time.
I also wanted to join a study, but was not eligible because of being left-handed. I certainly agree that a lot of time and care is taken in finding exactly the right spot to apply it- it is only supposed to reach several centimeters into the brain- and the intensity, number of stimulations and secure placement on the scalp are very important. At the center I go to, an initial course of three week's daily treatment is given, followed by six sessions of twice daily treatments as maintenance. Some patients need to go every month for these "boosters"- others, like me go every few months. I would prefer to go every month, myself, but the travel distance is a limiting factor. I do think it's an excellent, side-effect free treatment.
I noticed that the vagus nerve stimulator received FDA approval. From what I know, this is a less effective treatment than TMS; I hope thatit won't be too long before rTMS receives approval also. I have read that it might be in 2005.
Linkadge, it's hard to know how to evaluate your treatments, as I believe you do them every day. I'm not sure what intensities, number of pulses and placements you are using. Do you have a specific reason for being concerned about brain damage- has anything happened to worry you?
Posted by poop'd-out on June 19, 2004, at 2:31:21
In reply to Re: rTMS'rs out there ???, posted by linkadge on June 18, 2004, at 15:16:35
Hi,
I tried to be involved in a study many years ago and was also turned down for being left-handed. I was soo disappointed...Was this current study at neuronetics the one that you were turned down for? If so, I won't get my hopes up. They are currently doing studies in my area.
So, being left-handed wasn't a problem with the treatment you have been getting now? If not, what side of the head did they put the coils on?
So sorry for all the questions, I just know this is something that would help me. I don't know how I know this, I guess I am just being hopeful.
Thanks in advance for answering my questions.
Beth
Posted by poop'd-out on June 19, 2004, at 2:33:19
In reply to Re: rTMS'rs out there ???, posted by poop'd-out on June 19, 2004, at 2:31:21
Posted by Pfinstegg on June 19, 2004, at 10:21:13
In reply to Re: rTMS'rs out there ???, posted by poop'd-out on June 19, 2004, at 2:31:21
I looked into all the studies being done in 2003, but the left-handedness precluded me from joining any of them. Through Emory University, which has been doing studies of its own, I was given the names of two psychiatrists who use it "off-label" They were Dr, Steven Best, just west of Chicago and Dr Mark Hutto of Atlanta. I go to him brcause he's the closest to where Iive, He's very experienced with it, having studied with Dr. Mark George at the University of South Carolina.Dr. Hutto informed me that he was having about a 65% success rate with it, that he did not consider it as powerful a treatment as ECT, but that the side effects were very minimal- at most some discomfort while it's being done and a slight headache afterwards- I don't even have those, and I can drive myself there, as no anesthesia or short-term memory loss is involved. It doesn't give you permanent relief from depression- you do need *boosters* usually, but I do think, for me, it's tremendously helpful. Not being FDA-approved, no insurance will cover it, but I was able to take it as a tax deduction, including travel, accomodations and the cost of the treatments themselves, which are roughly $170 per session.
Posted by Pfinstegg on June 19, 2004, at 10:32:02
In reply to Re: rTMS'rs out there ???, posted by poop'd-out on June 19, 2004, at 2:31:21
Sorry! I forgot to mention the details of how it was given. Dr. Hutto uses high frequency- 20 Herz, and each session consists of 400 pulses. He chooses the location very carefully- it's 5 cm. straight forward of the left motor area (which makes your thumb twitch. He gives it at 110% of the motor threshold. So, it's always to the left frontal lobe. He doesn't treat the right hemisphere, which some researchers are doing with lower frequencies. I think a number of studies have hown that treating the right hemisphere, while not completely ineffective, is much less so than treating the right one. This is really all I know about it, but I hope it's helpful to you in deciding what to do,
Posted by Pfinstegg on June 19, 2004, at 10:42:07
In reply to Re: rTMS'rs out there ??? » poop'd-out, posted by Pfinstegg on June 19, 2004, at 10:32:02
Sorry once more! Dr Hutto gives the treatments always to the LEFT hemisphere!
Posted by SLS on June 19, 2004, at 14:46:15
In reply to Re: rTMS'rs out there ??? » Pfinstegg, posted by Pfinstegg on June 19, 2004, at 10:42:07
Hi Pfinstegg.
Do you take medication?
What about using a MAOI continuously in conjunction with rTMS?
I once asked Dr. George if my failure to respond to ECT indicated a poor prognosis for treatment with rTMS. He was reluctant to offer an opinion without more data.
- Scott
Posted by Pfinstegg on June 19, 2004, at 15:30:21
In reply to Re: rTMS'rs out there ??? » Pfinstegg, posted by SLS on June 19, 2004, at 14:46:15
I do take medication: I'm trying to keep it low because of the side effects, which for me were anhedonia and loss of sexual interest, so I take 5 mg. of Lexapro and 37.5 mg of Wellbutrin- sort of a feeble version of an MAOI, since between them they target serotonin, nor-epinephrine and, to a lesser extent, dopamine. If you are given TMS by one of the *off-label* doctors, you just keep on taking whatever medication you are already taking. Most of the patients who go to Dr. Hutto come from all over the US, have failed a lot of other treatments, and are taking medication. He expects that, and I think he would never ask someone to discontinue what they are taking. If you go to him, he spends an hour or hour and a half taking a very careful history and making his decisions then, It's also possible to e-mail him and ask him that very question in advance.
The things TMS does- decreasing cortisol production and damping down the HPA axis, increasing BDNF and neuronal growth in the hippocampus, increasing the production of the three neurotransmitters, and enhancing blood flow- are just general, and temporary, things which help your brain back towards normal. I don't think the combination of TMS and an MAOI would be too much or toxic in any way.
Posted by Pfinstegg on June 19, 2004, at 16:24:53
In reply to Re: rTMS'rs out there ???, posted by poop'd-out on June 19, 2004, at 2:31:21
It seems to be taking me a while to respond to all your questions! Dr Hutto said that, even though I was left-handed, I had about only a 1-2% change of having an actual hemisphere reversal (with language and conscious cognition on the right side). Even though this chance is small, the people doing the studies do eliminate left-handed people, as it makes their data a bit more reliable. Critics would always ask about handedness, and might feel that the study was not as carefully done as it could have been if subjects had not been selected for handedness.
If you go to someone like Dr. Hutto, he will find out as much as he can about you, and will also tell you everything he knows about TMS. Because it's not an approved treatment, he will never recommend it- the choice is always up to you. The first time I went. I felt that I was almost begging him to give me a trial of it, but I'm so glad I did!
Posted by Pfinstegg on June 19, 2004, at 16:39:15
In reply to Re: rTMS'rs out there ??? » Pfinstegg, posted by SLS on June 19, 2004, at 14:46:15
I think you would get the same answer from Dr. Hutto as you did from Dr. George, because they simply do not know yet. You could be in the group of 64% who responds, or you might not be. They do feel that TMS is a less strong treatment than ECT in general; on the other hand, it is much more focal in nature, targetting the left frontal areas, and, by extension, the left limbic system. Even if you went to see him, you would be the one making the final decision about treatment, as they really do not know which people it will help, or whether it will help at all. It IS very low risk, however.
As an aside, Dr. Hutto, who does ECT also, as well as psychopharmacology, was named Georgia's "physician of the year" in 2003, so if you decided to consult him, you would be in the hands of a highly thought-of physician.
Posted by linkadge on June 19, 2004, at 17:26:52
In reply to Re: rTMS'rs out there ??? » SLS, posted by Pfinstegg on June 19, 2004, at 16:39:15
I have no specific reason to be freightened just little things that I have heard. For instance, a childrens elecetric blanket was recalled the other year because the electromagnetic feilds were shown to induce cancer growth in mice!.
I know the rTMS works but it seems a bit unnatural of a thing to be doing.
Also, I was looking for studies that showed rTMS boosed neurogenesis but could not find any. I have found a few studies that said it boosted BDNF but did not enhance neurogenesis. (I didn't know that was possible.)
Linkadge
Posted by Pfinstegg on June 19, 2004, at 17:46:32
In reply to Re: rTMS'rs out there ???, posted by linkadge on June 19, 2004, at 17:26:52
I think electric blankets are now considered a bad idea, and out-of-date, because of the question of whether they induced cancer. However, the type of electromagnetic current- the frequency, mainly)- is different in TMS, and I believe animal studies concluded that there was no increased risk of cancer. Like most things, we probably won't know for sure for quite a few years.
It's my understanding that under normal (non-depressed) conditions, our hippocampuses, and possibly other brain areas such as the medial orbito-frontal cortex. produce several thousand new neurons each day, and that this is vital to remain in a non-depressed (normal!) mood state. SSRI's are supposed to do this, at least initially, and I am assuming that returning to a non-depressed state, particularly with the added BDNF, allows regrowth of neurons to begin to occur naturally. I* had a discussion about this with Dr. Hutto, but cannot recall if I have seen it in a research paper.
It's wonderful that you feel that it is working so well! Can you tell us more about exactly where you place the coil, how many pulses you give, and at what intensity (amps) and frequency (Herz). How often do you do this? Do you take "holidays", or do you do it every day?
Posted by jrbecker on June 19, 2004, at 18:16:04
In reply to Re: rTMS'rs out there ??? jr becker, posted by Pfinstegg on June 18, 2004, at 21:19:11
I will be sure to give you guys a full report in a couple of weeks (3 weeks in).
Pfinstegg, it's too bad you were disqualified from the study b/c of your left-handedness. I don't even recall being asked the question about dominant hand usage when I was originally screened.
Scott, I would echo Pfinstegg's statement about rTMS being less effective than ECT. However, in one recent study rTMS was found to be effective in remitting 55% of patients vs. 64% in bilateral ECT. Secondly, they are still figuring out the optimal ways to enhance efficacy for rTMS. For this study, Neuronetics has manufactured brand new high-tech models to be used. And the procedural protocols such as angle of stimulation, location, frequency, treatment duration, etc; are becoming more and more fine-tuned to leverage the treatment outcome. For instance, this study is the first to increase the stimulation to 120% of one's motor threshold. In the past, 110% has been the typical limit. Lastly, in terms of comparing ECT to rTMS once again, it's apparent that ECT's advantage comes from its ability to cause a grand-mal seizure in the brain, thus affecting the deeper regions of the brain (e.g., the limbic system). rTMS, like Pfinstegg mentioned, is much more localized in its stimulation of the prefrontal cortex (and probably parts close to it like the anterior cingulate). I believe that this is in fact the benefit of rTMS over ECT for some individuals. It's been shown that individuals suffering from bipolar disorder [and probably atypical depression] show dysfunction in the PFC region in addition to deeper brain regions. Some studies have also shown that melancholic unipolars display PFC deficits, but probably to a much lesser degree. Anyways, this is why I hold a torch for the potential of rTMS. Newer ECT methods, such as nondominant right unilateral ECT or rapidpulse right unilateral ECT might also be beneficial for the same above reasons and have been reported to cause less side effects (e.g., ST memory loss) than other forms of ECT.
As for when it might be approved, the researchers and I have talked about this quite a bit. Because of the recent VNS approval it looks quite optimistic, especially since their data did not look as effective as past rTMS studies have. A potential obstacle to a speedy rTMS approval might be some political maneuvering from clinicians in the ECT camp who perhaps [falsely] see rTMS as a potential threat to it.Neuronetics, the maker of the newest magnetic stimulation devices, is the major backer of the current national rTMS study. The study includes 16 sites, and will be including 287 subjects in all. At this point, it seems that most of the sites have been very slow in being able to enroll subjects, mostly because the eligibility criteria is so stringent. Because of this, I have tended to be more conservative in predicting a possible approval by the FDA any time soon. If I had to guess, I would say 2-3 years.
But I could be wrong on this. For one thing, it seems that a few of the sites are finally beginning to enroll more and more subjects. Secondly, I've been told that the company might be approaching the FDA midway through the trial if the preliminary data analysis looks good. So perhaps an approval by the end of 2005 isn't completely out of the question. I will keep my ear to the ground on this one for you all and hope to give some frequent updates.
JRB
Posted by linkadge on June 19, 2004, at 19:14:52
In reply to Re: rTMS'rs out there ???, posted by jrbecker on June 19, 2004, at 18:16:04
I use two coils one on either side of the head. I am experimenting with frequency, I think that 10 hz works the best for me. I too am left handed, but have not taken this into consideration.
I am a little bit cautious because my last session put me in the hospital with something hightly resemblant of serotonin syndrome. I am also taking celexa 10-20mg.I find that it definately brightens up my vision. I have a tendancy for my vision to go very dark when I am depressed. rTMS seems to help this, it can be very alerting depending on what frequency is used. It sometimes makes my brain buzz, kind of like my whole body is vibrating slightly. I think it leaves me a little epileptogenic sometimes as limbs and such will be periodically twiching for the next week or so.
Linkadge
Posted by Pfinstegg on June 19, 2004, at 23:56:01
In reply to Re: rTMS'rs out there ???, posted by jrbecker on June 19, 2004, at 18:16:04
Thanks! Your post was so informative and optimistic- just the way I feel about the TMS I have had. I'm assuming that you don't yet know what you are receiving- I guess it could even be a *sham* arm of the study. I think they eventually tell you that, and offer you the real thing, if you have not been having it.
I like it very much that they are going to 120% of the motor threshold now. I believe that in the studies being done at Yale, they are actually going high enough to cause seizures- although they are not using anesthesia. Do please keep us informed as to all the details of the study you are in- especially whether it has truly been helpful. That would mean so much to me, and others like me, who have been doing it *off-label*, and have found it extremely helpful.
As to the "ECT lobby", I didn't think of that! Dr. Hutto uses ECT for a great many patients, but, if it works well enough for them to get somewhat better, he tries to switch them to TMS, as the risks are so much lower, and the quality of life so much better.
Posted by Cecilia on June 20, 2004, at 4:03:40
In reply to Re: rTMS'rs out there ??? » jrbecker, posted by Pfinstegg on June 19, 2004, at 23:56:01
Linkadge, I can`t imagine doing TMS on oneself-sounds a bit like performing surgery on oneself. Be careful! For those lookng into this, TMS is approved in Canada, and it`s perfectly legal for a non-Canadian to have it there. There are clinics in Vancouver and Toronto. I had 20 treatments (2 a day for 2 weeks in January). It`s definitely expensive $200 (U.S. dollars) per treatment. Unfortunately, it didn`t work for me. They claimed a 60 percent success rate. My doctor periodically suggests I try ECT, and the last time I saw him I asked what the success rate for ECT was for some one who had failed as many meds as I have. He said 60 percent. All I could think was "Yeah, sure, on paper maybe" He meant well, but knowing I failed TMS, how could he possibly think I had a 60 percent chance of success at ECT. Undoubtedly there are a few people who respond to one and not the other, but I think for the most part the 60 percent who respond to TMS are the same 60 perecent who would respond to ECT. I feel like the chance for me would be more like one percent and I`m just too terrified of the memory loss to consider it. Also, for those considering TMS, I want to say that my experience was excruciatingly painful. The brochure says it`s painless and even talks about reading a magazine while you`re having the treatments. I don`t think so, unless you`re in the habit of reading while someone hammers nails into your head. I read about studies talking about placebo "sham" treatments-believe me, if I had been in a study there was no way I wouldn`t have known if I were getting a real treatment. But apparently for many people it is painless-just don`t count on it. (And of course, if it had worked it would have been more than worth the pain and money.) Cecilia
Posted by Cecilia on June 20, 2004, at 4:51:27
In reply to Re: rTMS'rs out there ??? » poop'd-out, posted by Pfinstegg on June 19, 2004, at 10:32:02
P.S. Parameters for my treatment were 10 Hz. 50 stimuli per train, inter-train interval 25 seconds, 50 trains per session, (total of 50,000 stimuli in 2 weeks!) stimulus strength 100 to 120% of motor threshold. They normally do 120% but because I had so much pain, they started lower and gradually increased. Truthfully. I don`t know exactly what the Hz. means, anyone know? Cecilia
Posted by Pfinstegg on June 20, 2004, at 20:25:02
In reply to Re: rTMS'rs out there ???, posted by Cecilia on June 20, 2004, at 4:51:27
I think "Herz" refers to the the frequency of the pulses- how many are given in a certain time period. Two would be low- (usually given to the right hemisphere), 10 would be intermediate, and 20 is considered a rapid frequency. Sorry I don't know exactly what time period is used!
Posted by poop'd-out on June 21, 2004, at 14:21:05
In reply to Re: rTMS'rs out there ??? » poop'd-out, posted by Pfinstegg on June 19, 2004, at 16:24:53
Hi Pfinstegg,
Thank you so much for all your info. I was always wondering if the left-handedness thing had to do with the question as to where the emotion centers were truly located. I have always been more ambidexterous than just left-handed, the eating and writing have always been with the left hand.
Once again thanks for all the information. I don't think there is anyone in my area that is currently doing the trials(non-clinical) in my area at this time.
It almost makes me want to lie to get into a study. I just wasn't sure if that would be putting me at some kind of risk. Hopefully this will be available to all of us soon!
Beth
Posted by poop'd-out on June 21, 2004, at 14:33:26
In reply to Re: rTMS'rs out there ???, posted by jrbecker on June 19, 2004, at 18:16:04
Yes, please do keep us updated. Thanks for the site info!!
Posted by ravenstorm on June 24, 2004, at 10:50:22
In reply to Re: rTMS'rs out there ??? » jrbecker, posted by poop'd-out on June 21, 2004, at 14:33:26
Would rTMS work for both anxiety and depression, or just depression?
Posted by Pfinstegg on June 24, 2004, at 14:33:50
In reply to Re: rTMS'rs out there ???, posted by ravenstorm on June 24, 2004, at 10:50:22
For me, it helps both anxiety and depression a lot. But it is temporary, lasting between three and six weeks between booster sessions. I do have quite a bit of anxiety, and I am always amazed at how calm I feel in the few weeks after treatment.
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