Paul Zarkowski

Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial.

CONTEXT Daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) has been studied as a potential treatment for depression, but previous work had mixed outcomes and did not adequately mask sham conditions. OBJECTIVE To test whether daily left prefrontal rTMS safely and effectively treats major depressive disorder. DESIGN Prospective, multisite, randomized, active sham-controlled (1:1 randomization), duration-adaptive design with 3 weeks of daily weekday treatment (fixed-dose phase) followed by continued blinded treatment for up to another 3 weeks in improvers. SETTING Four US university hospital clinics. PATIENTS Approximately 860 outpatients were screened, yielding 199 antidepressant drug-free patients with unipolar nonpsychotic major depressive disorder. INTERVENTION We delivered rTMS to the left prefrontal cortex at 120% motor threshold (10 Hz, 4-second train duration, and 26-second intertrain interval) for 37.5 minutes (3000 pulses per session) using a figure-eight solid-core coil. Sham rTMS used a similar coil with a metal insert blocking the magnetic field and scalp electrodes that delivered matched somatosensory sensations. MAIN OUTCOME MEASURE In the intention-to-treat sample (n = 190), remission rates were compared for the 2 treatment arms using logistic regression and controlling for site, treatment resistance, age, and duration of the current depressive episode. RESULTS Patients, treaters, and raters were effectively masked. Minimal adverse effects did not differ by treatment arm, with an 88% retention rate (90% sham and 86% active). Primary efficacy analysis revealed a significant effect of treatment on the proportion of remitters (14.1% active rTMS and 5.1% sham) (P = .02). The odds of attaining remission were 4.2 times greater with active rTMS than with sham (95% confidence interval, 1.32-13.24). The number needed to treat was 12. Most remitters had low antidepressant treatment resistance. Almost 30% of patients remitted in the open-label follow-up (30.2% originally active and 29.6% sham). CONCLUSION Daily left prefrontal rTMS as monotherapy produced statistically significant and clinically meaningful antidepressant therapeutic effects greater than sham. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00149838.

The Effect of Daily Prefrontal Repetitive Transcranial Magnetic Stimulation Over Several Weeks on Resting Motor Threshold

BACKGROUND The resting motor threshold (rMT) is an important factor in the selection of treatment intensity for patients receiving repetitive transcranial magnetic stimulation (rTMS). In many clinical studies to date, due to concerns about potential drift, the rMT has been routinely re-measured weekly or every fifth session. OBJECTIVE Our aim is to investigate whether ongoing treatment with rTMS affects the rMT, the degree of change, and whether frequent remeasurement is needed. METHODS Clinical data were drawn from 50 medication free patients receiving treatment for major depression with rTMS in a large U.S. NIH-sponsored multisite study. Four measurements of rMT were obtained including before and after the double blind phase, followed by weekly measurements during the open phase. Active treatment consisted of 75 four second trains of 10Hz stimulation applied over 37.5 minutes with the coil over the left DLPFC at 120% rMT. RESULTS For the group as a whole, there was no significant change in the rMT during a minimum of 2 weeks of treatment with prefrontal rTMS (p=0.911, one way ANOVA). The average within-subject coefficient of variation was 6.58%. On average the last rMT was 2.45% less than the baseline rMT (range 32.3% increase, 40.6% decrease). CONCLUSION Daily left prefrontal rTMS over several weeks as delivered in this trial does not cause systematic changes in rMT. While most subjects had <10% variance in rMT over time, 5 subjects had changes of approximately 20% from baseline, raising dosing and safety issues if undetected. We recommend that clinical trials of rTMS have periodic retesting of rMT, especially if the dose is at or near the edge of the TMS safety tables.

Baseline and treatment-emergent EEG biomarkers of antidepressant medication response do not predict response to repetitive transcranial magnetic stimulation.

There has been a surge of interest in biomarkers that can rapidly predict or assess response to psychiatric treatment, as the current standard practice of extended therapeutic trials is often dissatisfying to both clinicians and patients. Electroencephalographic (EEG) biomarkers in particular have been proposed as an inexpensive yet rapid way of determining whether a patient is responding to an intervention, usually before subjective mood improvement occurs. However, even the most well-reported EEG algorithms have not been subjected to independent replication, limiting their clinical generalizability. It is also unclear whether those biomarkers can generalize beyond their original study population, e.g. to patients undergoing somatic treatments for depression. We report here analysis of EEG data from the pivotal OPT-TMS study of transcranial magnetic stimulation (rTMS) for major depressive disorder. In this dataset, previously reported biomarkers of medication response showed no significant correlation with eventual response to rTMS treatment. Furthermore, EEG power in multiple bands measured at baseline and throughout the treatment course did not correlate with or predict either binary (response/nonresponse) or continuous (Hamilton Rating Scale for Depression) outcome measures. While somewhat limited by technical difficulties in data collection, these analyses are adequately powered to detect clinically relevant biomarkers. We believe this highlights a need for wider-scale independent replication of previous EEG biomarkers, both in pharmacotherapy and neuromodulation.

Hemispheric Asymmetry in Resting Motor Threshold in Major Depression

Previous studies of repetitive transcranial magnetic stimulation suggest a hemispheric imbalance in patients with major depression. These studies report an antidepressant effect by activation of the left prefrontal cortex or inhibition of the right prefrontal cortex. The aim of this study is to investigate interhemispheric differences in cortical excitability in a large sample of patients with major depression. Methods: The resting motor threshold (RMT) was measured on 91 patients with treatment-resistant major depression. We controlled for current medication use, gender, age, handedness, and study site. Results: There was no significant difference between the left RMT (55.96 [10.356]) and the right (57.74 [11.359]) (P = 0.131, Wilcoxon matched-pairs test). A multivariate analysis found no significant association between depression scores and right or left RMT. After adjusting for important cofactors, benzodiazepine use was found to be a significant predictor of left RMT (P = 0.017, linear regression) and right RMT (P = 0.007, linear regression). Conclusion: Our results do not support the existence of an interhemispheric imbalance of cortical excitability in depressed patients. Benzodiazepine use was found to raise both the left and right RMT.

Transcranial magnetic stimulation in the treatment of chronic widespread pain: a randomized controlled study.

Objective Our objective was to assess transcranial magnetic stimulation (TMS) in the treatment of chronic widespread pain. Methods Nineteen participants were randomized into 2 groups: one group receiving active TMS (n = 7) and another group receiving sham stimulation (n = 11) applied to the left dorsolateral prefrontal cortex. During sham stimulation, subjects heard a sound similar to the sound heard by those receiving the active treatment and received an active electrical stimulus to the scalp. The stimulation protocol consisted of 15 sessions completed within a 4-week period. Blind assessments were done at baseline and after each 5 sessions followed by blind assessments at 1 week, 1 month, and 3 months after the last TMS sessions. The primary outcome variable was a pain measure, the Gracely Box Intensity Scale (BIRS). Results The percentage of subjects who guessed that they were receiving TMS was similar in the 2 groups. Both the TMS group and the sham group showed a statistically significant reduction in the BIRS scores from baseline during the acute phase of treatment and the follow-up phase. However, the TMS and sham groups did not differ in the change in the BIRS scores. Discussion Although some previous clinical studies and basic science studies of TMS in treating pain are promising, this study found no difference in the analgesic effect of TMS and sham stimulation. Future studies should use a sham condition that attempts to simulate the sound and sensation of the TMS stimulation. Stimulus location and other stimulus parameters should be explored in future studies.

Validation of a rational malingering test using evoked potentials.

Summary: Malingering is easy to define, difficult to detect, and very costly for any health care system. The structured interview of reported symptoms (SIRS) was constructed using rational strategies to detect malingering in patients endorsing psychotic symptoms. This study validated the SIRS using evoked potentials. Nineteen patients meeting DSM-IV criteria for schizophrenia and 15 healthy controls completed an oddball and paired click protocol. Severity of psychotic symptoms was documented using the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms. The patient group was divided by probability of malingering according to the SIRS. Patients with a high probability of malingering had significantly greater P3 amplitude (P = 0.006, t-test) and more P50 suppression (P = 0.044, t-test) than patients with a low probability of malingering. No significant difference in P3 amplitude or P50 suppression was found between the patients with a high probability of malingering and the healthy controls. This study provides empirical support for the validity of the SIRS with evidence that is independent of patient report.

Replication of leaving Las Vegas in the #2 travel destination, Orlando, Florida. A commentary on Wray, Miller, Gurvey, Carroll and Kawachi (2008)

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Deblurring visual evoked potentials using commercially available software

e see front matter 2012 Elsevier Ltd. doi:10.1016/j.socscimed.2012.01.043 Shortly after the publication of “Leaving Las Vegas: Exposure to Las Vegas and risk of suicide” by Wray, Miller, Gurvey, Carroll and Kawachi (2008), a staff reporter from the Psychiatric News called to ask my opinion (see Levin, 2009). Contrary to Wray et al. who found an increased risk of suicide in travelers to Las Vegas, we found travel to Las Vegas to be protective against suicide in hotel room guests. After listing the possible confounding factors in the methodology, I suggested to the reporter that similar results could be obtained from any number of cities with a large tourist population. I summarized my review with a question that I hoped he would pass along to Wray et al. what if the study was replicated in Orlando Florida, one of the happiest places on earth? Wray et al. (2008) analyzed U.S. federal death records and found that visitors to Las Vegas, Clark County specifically, doubled their risk of suicide compared with those that stayed home after controlling for age, gender, marital status and calendar year. Travel to Las Vegas doubled the risk of suicide compared with travel to other destinations. Finally, Wray et al. verified the elevated suicide risk of Las Vegas residents and found the suicide risk to fall by 20% when residents of Las Vegas left the county. We foundWray et al.’s findings on travel to Las Vegas surprising as our studies on suicide in motel and hotel rooms have shown travel to be protective (Zarkowski & Avery, 2006). Hotel room guests from outside Las Vegas experienced a 72% decrease in their suicide risk compared to the national average (Gemar, Zarkowski, &

Daily Left Prefrontal Transcranial Magnetic Stimulation Therapy for Major Depressive Disorder

Visual evoked potentials are useful clinical tools to study visual pathways of the brain. Although the temporal resolution is unsurpassed by other brain imaging technologies, the spatial resolution is diminished or blurred by the low conductance of the electrical signals through the skull. Methods have been proposed to improve the spatial resolution by downwardly projecting the electrical signals measured on the scalp to the surface of the cerebral cortex through the inverse solution of the equations governing static current flow. We describe the adaptation and combination of commercially available engineering software programs to solve this inverse problem and report the results of a sample run of the system. Before deblurring, the visual evoked potentials appeared to be diffusely localized over the posterior scalp. After deblurring, the visual evoked potentials were only found at the electrodes closest to the visual cortex, as would be predicted by our current knowledge of neuroanatomy.