Repetitive Transcranial Magnetic Stimulation for Negative Symptoms of Schizophrenia: Review and Meta-Analysis
Background: Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a treatment for the negative symptoms of schizophrenia. During the past decade, several trials have reported on the efficacy of rTMS treatment; however, the results were inconsistent.
Objective: To assess the efficacy of prefrontal rTMS for treating negative symptoms of schizophrenia.
Data Sources: A literature search was performed in PubMed, ISI Web of Science, and EMBASE for the years 1985 through July 2008. The search terms used (language not specified) were “transcranial magnetic stimulation,” “negative symptoms,” and “schizophrenia.” A cross-reference search of eligible articles was performed to identify studies not found in the computerized search.
Study Selection: Studies selected were randomized controlled trials assessing the therapeutic efficacy of prefrontal rTMS for negative symptoms in schizophrenia.
Data Extraction: Effect sizes (Cohen d) of each study were calculated. The overall standardized mean difference was calculated under a random effects model with 95% confidence intervals.
Data Synthesis: Nine trials, involving 213 patients, were included in the meta-analysis. The overall mean weighted effect size for rTMS versus sham was in the small-to-medium range and statistically significant (d = 0.43; 95% CI, 0.05–0.80). When including only the studies using a frequency of stimulation of 10 Hz, the mean effect size increased to 0.63 (95% CI, 0.11–1.15). When including only the studies requiring participants to be on a stable drug regimen before and during the study, the mean weighted effect size decreased to 0.34 (95% CI, 0.01–0.67). Studies with a longer duration of treatment (≥ 3 weeks) had a larger mean effect size when compared to studies with a shorter treatment duration: d = 0.58 (95% CI, 0.19–0.97) and d = 0.32 (95% CI, −0.3 to 0.95), respectively.
Conclusions: The results of this meta-analysis warrant further study of rTMS as a potential treatment of negative symptoms of schizophrenia.
J Clin Psychiatry 2010;71(4):411–418
© Copyright 2010 Physicians Postgraduate Press, Inc.
Submitted: October 17, 2008; accepted January 2, 2009.
Online ahead of print: February 23, 2010 (doi:10.4088/JCP.08r04808yel).
Corresponding author: Jozarni J. Dlabač-de Lange, MD, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands (firstname.lastname@example.org).
Negative symptoms of schizophrenia include blunted affect, apathy, poverty of speech, and social withdrawal. These symptoms predict an unfavorable clinical outcome and are often indicative of poorer social, occupational, and global outcomes.1–4 Currently, treatment options to improve negative symptoms yield disappointing results. Antipsychotic medication has limited efficacy to improve negative symptoms.5,6
Activation of the prefrontal cortex is impaired in people with schizophrenia.7–12 Negative symptoms appear to be associated with this hypoactivity of the frontal cortex; in particular, the dorsolateral prefrontal cortex (DLPFC) seems to be affected.13,14 High-frequency repetitive transcranial magnetic stimulation (rTMS) (≥ 5 Hz) can increase cortical excitability.15,16 Thus, increasing brain activity in the DLPFC by using high frequency rTMS might prove to be an effective treatment of negative symptoms in schizophrenia. In addition, there is evidence that decreased dopamine release in the prefrontal cortex results in negative symptoms.17–20 Several studies in animals and humans found that prefrontal rTMS can induce mesolimbic and mesostriatal dopamine release via excitatory corticostriatal projections.21–27 The mesolimbic pathway and the ventral striatal pathway are involved in feelings of reward (motivation) and reinforcement. The negative symptoms of schizophrenia include lack of motivation. Thus, in addition to high-frequency prefrontal rTMS increasing prefrontal cortical excitability, prefrontal rTMS may also modulate the dopaminergic regulation in the brain of schizophrenic patients, which may prove to be effective in the treatment of negative symptoms in schizophrenia. In the past decade, several studies have focused on finding a possible treatment for negative symptoms of schizophrenia by using prefrontal rTMS. Some studies reported a significant improvement,28–36 but others failed to prove a therapeutic effect of rTMS.37–41 Given the importance of negative symptoms for the outcome of schizophrenia, and given the fact that current treatment strategies have not yielded substantial improvement, it is of interest to examine the efficacy of novel treatment options. This meta-analysis aims to provide a quantitative review of studies on the efficacy of rTMS treatment of negative symptoms in schizophrenia.
Literature Search and Study Selection
Studies were found by performing a literature search in PubMed, ISI Web of Science, and EMBASE for the years 1985 through July 2008 and by conducting a cross-reference search of the eligible articles to identify additional studies not found in the electronic search. The search terms used (language not specified) were “transcranial magnetic stimulation,” “negative symptoms,” and “schizophrenia.” The main outcome measure was reduction of negative symptoms as measured with the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), or the negative symptom subscale of the Positive and Negative Syndrome Scale (PANSS). Criteria for inclusion in the meta-analysis were a parallel or crossover design with sham control in patients with schizophrenia, schizophreniform disorder, or schizoaffective disorder. However, in 2 studies, statistically significant improvement of negative symptoms after rTMS was maintained at 4-week follow-up.27,28 Therefore, crossover trials with a wash-out phase of less than 4 weeks were excluded. Only studies using rTMS of the prefrontal cortex were included. If there was insufficient information in the article to calculate the effect size, the corresponding author was contacted. Cohort studies without sham control and studies that did not provide sufficient data to permit calculation of effect sizes were excluded from the meta-analysis.
Individual effect sizes (Cohen d) of each study were calculated with reported significance values using the effect size program developed by Wilson.42 When data on different scales rating the same effect were available, the data were summarized, calculating a standardized mean difference. If no standard deviations were reported, we used the mean standard deviation of all the other studies as an estimate (this procedure was necessary for only 1 study33). A random effects model was used, and the mean weighted effect size was calculated by using Review Manager 5.0, developed by The Cochrane Collaboration.43 Individual effect sizes were weighted by the standard error of the estimate. Heterogeneity refers to variability among studies in a systematic review, which may be caused by clinical and methodological diversity. Significant heterogeneity limits a reliable interpretation of the results. Heterogeneity was assessed by using τ2, χ2, and I2 tests. Potential publication bias was assessed by using a funnel plot.
Sixteen studies were found that reported empirical data regarding prefrontal rTMS treatment of schizophrenia.28–41,44,45 Nine studies fulfilled the inclusion criteria and were included in the treatment effect analysis.29,30,33,34,37–41 The study by Langguth et al31 was excluded because it reported on the same sample as Hajak et al,30 the latter including the largest sample size. The study by Rollnik et al45 was excluded because, although information was given concerning changes of the total BPRS after prefrontal rTMS, specific data about changes of the negative symptom cluster of the BPRS were not available. The study by Jin et al36 was excluded because the wash-out phase was 2 weeks.
The included studies all had a parallel design and used the PANSS negative subscale or the SANS, or both, to measure pretreatment and posttreatment change. Information regarding the included studies is given in Table 1, and information regarding the excluded studies is given in Table 2. The studies included in the meta-analysis involved 213 patients, of whom 198 were diagnosed with schizophrenia and 15 with schizoaffective disorder. The mean weighted effect size for rTMS compared to sham treatment was 0.43 (95% CI, 0.05–0.80) (Figure 1). There was, however, significant heterogeneity among individual effect sizes (χ29 = 16.69, P = .05). Visual assessment of the funnel plot showed asymmetry. The study by Goyal et al29 had a different research method compared to the other studies. This small study conducted among 10 patients found a large treatment effect after rTMS. Patients entering the study were drug-free or drug-naive. After entering the study, patients were started on antipsychotic medication. The other studies included in the analyses required participants taking antipsychotic medication to be on a stable drug regimen before entering the study and for the duration of the study. When excluding the study by Goyal et al29 from the analyses, the mean weighted effect size decreased to 0.34 (95% CI, 0.01–0.67) but remained significant. Furthermore, the heterogeneity disappeared and the funnel plot was symmetrical.
Click figure to enlarge
Click figure to enlarge
Click figure to enlarge
Click figure to enlarge
In order to discover whether the frequency of stimulation had influence on the effect size, we calculated the mean effect size of the 7 studies that used a frequency of stimulation of 10 Hz. The mean effect size increased to 0.63 (95% CI, 0.11–1.15), but the heterogeneity was significant (χ26 = 12.96, P = .04) (Figure 2). When excluding the study by Goyal et al29 from the analyses, the mean weighted effect size was 0.5 (95% CI, 0.03–0.96), and, again, the heterogeneity disappeared. We also compared studies with a duration of treatment of less than 3 weeks (6 studies) to those applying treatment for 3 weeks or longer (3 studies). The mean effect sizes were 0.32 (95% CI, −0.3 to 0.95) and 0.58 (95% CI, 0.19–0.97), respectively.
To assess the influence of the rating scale used, we calculated the mean weighted effect size as measured by the negative subscale of the PANSS and the SANS separately. The mean weighted effect size as measured by the negative subscale of the PANSS was 0.35 (95% CI, −0.12 to 0.82; K = 8, N = 172). When excluding the study by Goyal et al29 from the analyses, the mean weighted effect size was 0.22 (95% CI, −0.17 to 0.61; K = 7, N = 162). The mean weighted effect size as measured by the SANS was 0.73 (95% CI, 0.26–1.19; K = 3, N = 93).
The results of this meta-analysis provide evidence that high-frequency rTMS of the DLPFC may be beneficial in the treatment of negative symptoms in schizophrenia. Although the overall treatment effect size of 0.43 was small, it did approach the medium range according to the nomenclature of Cohen,46 in which d = 0.2 is considered a small effect size and d = 0.5 is considered a medium effect size. The effect size was smaller than that reported for a meta-analysis of 10 studies regarding 1 Hz rTMS over the left temporoparietal cortex for reducing auditory hallucinations in schizophrenia, which was 0.76.47 In general, other treatments, such as antipsychotics, have also been more successful in targeting positive than negative symptoms of schizophrenia. There was significant heterogeneity, and the funnel plot was asymmetric. When excluding the study applying a research method different from the other studies, the overall treatment effect decreased to 0.34 and the heterogeneity disappeared. The funnel plot was then symmetrical. An important question is how the mean effect size for TMS compares to the effect of antipsychotics. A meta-analysis on the treatment of negative symptoms with antipsychotic medication found antipsychotics to be more effective than placebo. However, all the effect sizes found were small, the mean effect sizes as measured by the Pearson correlation coefficients ranging between 0.17 and 0.21.48 When considering the working mechanism of TMS, this differs from antipsychotics. Specifically, rTMS might address neurobiologic mechanisms relevant for negative symptoms that have not been targeted by antipsychotics. High-frequency rTMS (≥ 5 Hz) can increase cortical excitability and thereby increase brain activity in the DLPFC and, in addition, may induce mesolimbic and mesostriatal dopamine release.15 It is important to note that an advantage of rTMS above antipsychotic medication might be the mild side effects of rTMS. Adverse effects of rTMS are mainly limited to discomfort due to twitches of scalp muscles during stimulation in some people and headache up to several hours after stimulation (which can be treated with acetaminophen). This suggests that rTMS might be more effective than current antipsychotic medication. However, caution is needed when interpreting these results as the evidence base (number of published studies) for antipsychotics is large, but the evidence base for rTMS still rather limited.
Interestingly, the mean effect size increased to 0.63 when including only those studies using a frequency of 10 Hz. The study included in the meta-analyses that used a higher-frequency stimulation of 20 Hz showed a better treatment effect in the placebo group than in the verum group.41 This difference, however, did not reach significance. The study using lower-frequency stimulation of 1 Hz also found no significant treatment effect.33,39 Although the study by Jin et al36 could not be included in the analyses because the wash-out phase was less than 4 weeks, the findings are of interest. Jin et al36 performed a crossover trial and found that rTMS stimulation set at each patient’s peak α frequency EEG, which varies between 8 and 13 Hz, produced a significantly larger therapeutic effect on negative symptoms in schizophrenia when compared to sham rTMS, 3-Hz rTMS, or 20-Hz rTMS. Considering that a frequency of 10 Hz lies within the peak α frequency band, this may explain the larger treatment effect found in the 10-Hz group in comparison with the 1-Hz and 20-Hz groups.
The larger mean effect size found in the group receiving a longer duration of rTMS treatment suggests a possible dose-response relationship. A meta-analysis comparing the recent versus the earlier prefrontal rTMS studies on depression found that the more recent rTMS clinical trials showed larger antidepressant effects than the earlier trials.49 The recent studies used more rTMS sessions.
Finally, hypoactivity and hypometabolism in the prefrontal cortex have been suggested to underlie cognitive dysfunction in schizophrenia.13,14 In 5 studies, cognitive assessments were administered before and after rTMS.28,33,37,40,41 One study found a significant improvement in a delayed visual memory task, and another study found better delayed recall on a test of verbal learning at 2-week follow-up in the rTMS group.28,40 Three studies did not find any significant improvement in cognitive functioning.33,37,41 Thus, although the putative beneficial effect of rTMS on cognition remains unclear, it is at least apparent that no adverse effects on cognition were observed.
The underlying working mechanism of rTMS remains unclear. The 2 studies that combined rTMS treatment with Single Photon Emission Computed Tomography (SPECT) scans did not detect any changes in regional cerebral blood flow.28,30 However, 1 EEG study50 found a significant cortical activation upon the improvement of negative symptoms. SPECT scanning is not as accurate as positron emission tomography (PET) scanning and functional magnetic resonance imaging (fMRI). The latter offers the best approach to analyze brain activity and to detect changes in brain activity; it has better spatial and temporal resolutions. Considering the above, functional imaging studies using fMRI or PET scanning to assess possible changes in brain activity are needed. Finally, rTMS of the prefrontal cortex has been found to decrease depressive symptoms in patients diagnosed with a depression. Yet, the improvement of negative symptoms could not be accounted for by an antidepressant action of the rTMS.29,30,33
The most effective combination of rTMS parameters has not yet been determined. The studies in this meta-analysis differed in rTMS stimulation site (right prefrontal cortex, left prefrontal cortex, and bilateral stimulation), frequency, stimulation intensity, number of trains per session, duration of each train and duration of treatment. Seven studies applied stimulation to the left dorsolateral prefrontal cortex (DLPFC), 1 study stimulated the left and right DLPFC, and 1 study stimulated the right prefrontal cortex. The DLPFC was defined as 5 cm anterior and in a parasagittal plane from the point of maximal stimulation of the abductor pollicis breves. Herwig et al51 found that this method for locating the DLPFC was not precise anatomically—only in 7 of 22 subjects (12 healthy subjects and 10 depressed patients) was the DLPFC targeted correctly in this manner.51 Functional targeting by applying navigating procedures to locate the DLPFC takes individual anatomic differences into account and may increase treatment effect. In addition, further research is required to determine the optimal rTMS stimulation site—right, left, or bilateral prefrontal rTMS.52 Neuroimaging studies have found hypoactivity in both the right and left DLPFC. Most studies applied rTMS to the left DLPFC. One study37 included in our meta-analysis studied the effect of bilateral rTMS. This study found a trend for a treatment effect in the rTMS group as compared to the placebo group based on SANS data, but this difference did not reach statistical significance. Yet, in an exploratory analysis, a greater reduction in scores on the autistic preoccupation scale of the PANSS in the rTMS group was noted.37 Finally, it is important to mention that the studies differed in the total number of pulses administered. We suggest that future studies should control for the number of pulses administered.
For measurement of the treatment effect, studies applied the PANSS and/or the SANS, both of which are semistructured interviews. Both instruments have adequate construct and concurrent validity, good internal consistency reliability, moderate test-retest reliability, and interrater reliability coefficients ranging from moderate to high.53–60 However, the rating scales may differ in the amount of information obtained for the negative syndrome and the extent to which cognitive functioning is estimated. For example, the “attentional impairment,” “inappropriate affect,” and “poverty of content of speech” items of the SANS may be more closely related to cognitive dysfunction than negative symptoms.61 The National Institute of Mental Health- Measurement and Treatment Research to Improve Cognition in Schizophrenia (NIMH-MATRICS) consensus statement62 on negative symptoms agreed that the SANS is preferred to the PANSS in research focusing on negative symptoms because the SANS covers multiple domains and multiple items in each domain.62 The 6 earliest studies included in our analysis used the negative subscale of the PANSS, 2 more recent studies used both rating scales, and the latest study used the SANS. The mean weighted effect size as measured by the SANS was larger in comparison with the negative subscale of the PANSS. The more recent studies had a better study design and longer treatment duration, partially explaining the difference found. Two studies34,37 included in the analyses used both rating scales. In both studies the treatment effect as measured by the negative subscale of the PANSS was smaller in comparison with the treatment effect as measured by the SANS. Indeed, it has been suggested that the SANS is more sensitive to change than is the negative subscale of the PANSS.63
Another important issue to address is that, in all studies, all or at least a substantial proportion of the patients enrolled were using psychoactive drugs. The study by Holi et al,38 which had a negative effect size, was carried out on chronically severely ill and hospitalized patients, often using high dosages of medication, including benzodiazepines and anticonvulsant drugs. Anticonvulsant drugs reduce the intracortical excitability and raise the motor threshold.64,65 This activity may decrease the effect of rTMS treatment in patients using anticonvulsant drugs, corresponding with the results published by Hoffman et al.66 Antipsychotics block dopamine and may thus interfere with the putative mechanisms of rTMS, ie, to increase mesolimbic and mesostriatal dopamine release.21–27 Combining prefrontal rTMS with a third-generation antipsychotic such as aripiprazole would be interesting in this regard, as third-generation antipsychotics are partial dopamine agonists. However, one should note that each study titrated the dose according to each individual motor threshold, which may compensate for medically induced changes in cortical excitability.
An important and potentially confounding variable to address is the sham condition. An ideal sham condition in rTMS studies would mimic the clicking sound of the real rTMS coil and cause the same scalp or facial sensation caused by the real rTMS coil but induce no therapeutic effect. The studies in our analysis applied different methods for sham stimulation. In most of the studies, the coil was tilted off the scalp by 45° or 90°, with 1 or 2 wings of the coil touching the scalp. This method may produce similar tactile sensations and the same clicking sounds as the real rTMS treatment. However, this method can stimulate the cortex and, as a consequence, may induce a therapeutic effect.67,68 Some of the studies used a sham coil system that imitates the clicking sound of the real rTMS coil but does not induce a magnetic field, or it blocks the magnetic field so that it does not pass through the skull. The latter system, however, does not cause scalp or facial sensation, in contrast to the real rTMS coil.
Finally, an important limitation of this meta-analysis is the small number of included studies (9) and total number of subjects (213). Larger randomized controlled trials are needed to further establish the clinical significance of this treatment and to systematically vary the TMS parameters.
In conclusion, this meta-analysis suggests that prefrontal rTMS might be a beneficial treatment for negative symptoms of schizophrenia. A frequency of stimulation of 10 Hz and a duration of treatment of at least 3 weeks enhances the treatment effect. Randomized clinical trials with larger samples are needed to further establish clinical efficacy and to determine the most effective combination of rTMS parameters. In addition, it is important to further optimize the TMS technique by, for example, developing more valid sham conditions and by controlling the coil-to-cortex distance.69,70 Finally, neuroimaging studies using fMRI or PET scans before and after rTMS treatment may be informative to elucidate underlying mechanisms of action of rTMS treatment.
Author affiliations: Department of Psychiatry (Drs Dlabač-de Lange and Knegtering) and BCN Neuroimaging Center (Dr Aleman), University Medical Center Groningen, University of Groningen, The Netherlands.
Potential conflicts of interest: None reported.
Funding/support: None reported.
Previous presentation: Preliminary results of this meta-analysis were presented at the 1st Schizophrenia International Research Society Conference; June 21–25, 2008; Venice, Italy.
Acknowledgment: The authors thank Huib Burger, MD, PhD, and Marjolijn Hoekert, PhD, for their help during data analysis and Elly S. M. de Lange-de Klerk, MD, PhD, for reviewing the article.
1. Buchanan RW, Gold JM. Negative symptoms: diagnosis, treatment and prognosis. Int Clin Psychopharmacol. 1996;11(suppl 2):3–11. doi:10.1097/00004850-199605002-00002 PubMed
2. Gasquet I, Haro JM, Novick D, et al. Pharmacological treatment and other predictors of treatment outcomes in previously untreated patients with schizophrenia: results from the European Schizophrenia Outpatient Health Outcomes (SOHO) study. Int Clin Psychopharmacol. 2005;20(4):199–205. doi:10.1097/00004850-200507000-00002 PubMed
3. Kurtz MM, Moberg PJ, Ragland JD, et al. Symptoms versus neurocognitive test performance as predictors of psychosocial status in schizophrenia: a 1- and 4-year prospective study. Schizophr Bull. 2005; 31(1)167–174. doi:10.1093/schbul/sbi004 PubMed
4. Sergi MJ, Kern RS, Mintz J, et al. Learning potential and the prediction of work skill acquisition in schizophrenia. Schizophr Bull. 2005;31(1): 67–72. doi:10.1093/schbul/sbi007 PubMed
5. Harvey PD, McClure MM. Pharmacological approaches to the management of cognitive dysfunction in schizophrenia. Drugs. 2006; 66(11):1465–1473. doi:10.2165/00003495-200666110-00004 PubMed
6. Murphy BP, Chung YC, Park TW, et al. Pharmacological treatment of primary negative symptoms in schizophrenia: a systematic review. Schizophr Res. 2006;88(1-3):5–25. doi:10.1016/j.schres.2006.07.002 PubMed
7. Barch DM, Carter CS, Braver TS, et al. Selective deficits in prefrontal cortex function in medication-naive patients with schizophrenia. Arch Gen Psychiatry. 2001;58(3):280–288. doi:10.1001/archpsyc.58.3.280 PubMed
8. Perlstein WM, Carter CS, Noll DC, et al. Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia. Am J Psychiatry. 2001;158(7):1105–1113. doi:10.1176/appi.ajp.158.7.1105 PubMed
9. Potkin SG, Alva G, Fleming K, et al. A PET study of the pathophysiology of negative symptoms in schizophrenia. Positron emission tomography. Am J Psychiatry. 2002;159(2):227–237. doi:10.1176/appi.ajp.159.2.227 PubMed
10. Siever LJ, Davis KL. The pathophysiology of schizophrenia disorders: perspectives from the spectrum. Am J Psychiatry. 2004;161(3):398–413. doi:10.1176/appi.ajp.161.3.398 PubMed
11. Tan HY, Callicott JH, Weinberger DR. Dysfunctional and compensatory prefrontal cortical systems, genes and the pathogenesis of schizophrenia. Cereb Cortex. 2007;17(suppl 1):i171–i181. doi:10.1093/cercor/bhm069 PubMed
12. Weinberger DR, Berman KF. Prefrontal function in schizophrenia: confounds and controversies. Philos Trans R Soc Lond B Biol Sci. 1996;351(1346):1495–1503. doi:10.1098/rstb.1996.0135 PubMed
13. Wolkin A, Sanfilipo M, Wolf AP, et al. Negative symptoms and hypofrontality in chronic schizophrenia. Arch Gen Psychiatry. 1992;49(12):959–965. PubMed
14. Hill K, Mann L, Laws KR, et al. Hypofrontality in schizophrenia: a meta-analysis of functional imaging studies. Acta Psychiatr Scand. 2004;110(4):243–256. doi:10.1111/j.1600-0447.2004.00376.x PubMed
15. Peinemann A, Reimer B, Loer C, et al. Long-lasting increase in corticospinal excitability after 1800 pulses of subthreshold 5 Hz repetitive TMS to the primary motor cortex. Clin Neurophysiol. 2004;115(7): 1519–1526. doi:10.1016/j.clinph.2004.02.005 PubMed
16. Shajahan PM, Glabus MF, Steele JD, et al. Left dorso-lateral repetitive transcranial magnetic stimulation affects cortical excitability and functional connectivity, but does not impair cognition in major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26(5):945–954. doi:10.1016/S0278-5846(02)00210-5 PubMed
17. Goldman-Rakic PS. The physiological approach: functional architecture of working memory and disordered cognition in schizophrenia. Biol Psychiatry. 1999;46(5):650–661. doi:10.1016/S0006-3223(99)00130-4 PubMed
18. Goldman-Rakic PS, Muly EC III, Williams GV. D(1) receptors in prefrontal cells and circuits. Brain Res Brain Res Rev. 2000;31(2-3):295–301. doi:10.1016/S0165-0173(99)00045-4 PubMed
19. Goldman-Rakic PS, Castner SA, Svensson TH, et al. Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology (Berl). 2004;174(1):3–16. doi:10.1007/s00213-004-1793-y PubMed
20. Castner SA, Goldman-Rakic PS, Williams GV. Animal models of working memory: insights for targeting cognitive dysfunction in schizophrenia. Psychopharmacology (Berl). 2004;174(1):111–125. doi:10.1007/s00213-003-1710-9 PubMed
21. Pogarell O, Koch W, Popperl G, et al. Acute prefrontal rTMS increases striatal dopamine to a similar degree as D-amphetamine. Psychiatry Res. 2007;156(3):251–255. doi:10.1016/j.pscychresns.2007.05.002 PubMed
22. Pogarell O, Koch W, Popperl G, et al. Striatal dopamine release after prefrontal repetitive transcranial magnetic stimulation in major depression: preliminary results of a dynamic [123I] IBZM SPECT study. J Psychiatr Res. 2006;40(4):307–314. doi:10.1016/j.jpsychires.2005.09.001 PubMed
23. Strafella AP, Paus T, Barrett J, et al. Repetitive transcranial magnetic stimulation of the human prefrontal cortex induces dopamine release in the caudate nucleus. J Neurosci. 2001;21(15):RC157. PubMed
24. Strafella AP, Paus T, Fraraccio M, et al. Striatal dopamine release induced by repetitive transcranial magnetic stimulation of the human motor cortex. Brain. 2003;126(Pt 12):2609–2615. doi:10.1093/brain/awg268 PubMed
25. Funamizu H, Ogiue-Ikeda M, Mukai H, et al. Acute repetitive transcranial magnetic stimulation reactivates dopaminergic system in lesion rats. Neurosci Lett. 2005;383(1-2):77–81. doi:10.1016/j.neulet.2005.04.018 PubMed
26. Kanno M, Matsumoto M, Togashi H, et al. Effects of acute repetitive transcranial magnetic stimulation on dopamine release in the rat dorsolateral striatum. J Neurol Sci. 2004;217(1):73–81. doi:10.1016/j.jns.2003.08.013 PubMed
27. Zangen A, Hyodo K. Transcranial magnetic stimulation induces increases in extracellular levels of dopamine and glutamate in the nucleus accumbens. Neuroreport. 2002;13(18):2401–2405. doi:10.1097/00001756-200212200-00005 PubMed
28. Cohen E, Bernardo M, Masana J, et al. Repetitive transcranial magnetic stimulation in the treatment of chronic negative schizophrenia: a pilot study. J Neurol Neurosurg Psychiatry. 1999;67(1):129–130. doi:10.1136/jnnp.67.1.129 PubMed
29. Goyal N, Nizamie SH, Desarkar P. Efficacy of adjuvant high frequency repetitive transcranial magnetic stimulation on negative and positive symptoms of schizophrenia: preliminary results of a double-blind sham-controlled study. J Neuropsychiatry Clin Neurosci. 2007;19(4):464–467. PubMed
30. Hajak G, Marienhagen J, Langguth B, et al. High-frequency repetitive transcranial magnetic stimulation in schizophrenia: a combined treatment and neuroimaging study. Psychol Med. 2004;34(7):1157–1163. doi:10.1017/S0033291704002338 PubMed
31. Langguth B, Eichhammer P, Kharraz A, et al. Repetitive transcranial magnetic stimulation in schizophrenia (preliminary results). Nervenheilkunde. 2003;22:350.
32. Sachdev P, Loo C, Mitchell P, et al. Transcranial magnetic stimulation for the deficit syndrome of schizophrenia: a pilot investigation. Psychiatry Clin Neurosci. 2005;59(3):354–357. doi:10.1111/j.1440-1819.2005.01382.x PubMed
33. Schneider AL, Schneider TL, Stark H. Repetitive transcranial magnetic stimulation (rTMS) as an augmentation treatment for the negative symptoms of schizophrenia: a 4-week randomized placebo controlled study. Brain Stimulation. 2008;1(2):106–111. doi:10.1016/j.brs.2008.01.001
34. Prikryl R, Kasparek T, Skotakova S, et al. Treatment of negative symptoms of schizophrenia using repetitive transcranial magnetic stimulation in a double-blind, randomized controlled study. Schizophr Res. 2007; 95(1-3)151–157. doi:10.1016/j.schres.2007.06.019 PubMed
35. Jandl M, Bittner R, Sack A, et al. Changes in negative symptoms and EEG in schizophrenic patients after repetitive transcranial magnetic stimulation (rTMS): an open-label pilot study. J Neural Transm. 2005;112(7):955–967. doi:10.1007/s00702-004-0229-5 PubMed
36. Jin Y, Potkin SG, Kemp AS, et al. Therapeutic effects of individualized alpha frequency transcranial magnetic stimulation (alphaTMS) on the negative symptoms of schizophrenia. Schizophr Bull. 2005;32(3): 556–561. doi:10.1093/schbul/sbj020 PubMed
37. Fitzgerald PB, Herring S, Hoy K, et al. A study of the effectiveness of bilateral transcranial magnetic stimulation in the treatment of the negative symptoms of schizophrenia. Brain Stimulation. 2008;1(1)27–32. doi:10.1016/j.brs.2007.08.001
38. Holi MM, Eronen M, Toivonen K, et al. Left prefrontal repetitive transcranial magnetic stimulation in schizophrenia. Schizophr Bull. 2004;30(2):429–434. PubMed
39. Klein E, Kolsky Y, Puyerovsky M, et al. Right prefrontal slow repetitive transcranial magnetic stimulation in schizophrenia: a double-blind sham-controlled pilot study. Biol Psychiatry. 1999;46(10):1451–1454. doi:10.1016/S0006-3223(99)00182-1 PubMed
40. Mogg A, Purvis R, Eranti S, et al. Repetitive transcranial magnetic stimulation for negative symptoms of schizophrenia: a randomized controlled pilot study. Schizophr Res. 2007;93(1-3):221–228. doi:10.1016/j.schres.2007.03.016 PubMed
41. Novak T, Horacek J, Mohr P, et al. The double-blind sham-controlled study of high-frequency rTMS (20 Hz) for negative symptoms in schizophrenia: negative results. Neuroendocrinol Lett. 2006;27(1-2):209–213. PubMed
42. Wilson DB. Professional Development Course on Meta-Analysis. http://mason.gmu.edu/~dwilsonb/ma.html. Access verified January 4, 2010.
43. Manager R. RevMan [computer program]. Copenhagen, Denmark: The Nordic Cochrane Centre, The Cochrane Collaboration; 2008
44. Stanford AD, Corcoran C, Buloh P, et al. A pilot study of high frequency prefrontal rTMS for the treatment of the negative symptoms of schizophrenia. Biol Psychiatry. 2006;59:77S.
45. Rollnik JD, Huber TJ, Mogk H, et al. High frequency repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex in schizophrenic patients. Neuroreport. 2000;11(18):4013–4015. doi:10.1097/00001756-200012180-00022 PubMed
46. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Hillsdale, NJ: Erlbaum; 1988.
47. Aleman A, Sommer IE, Kahn RS. Efficacy of slow repetitive transcranial magnetic stimulation in the treatment of resistant auditory hallucinations in schizophrenia: a meta-analysis. J Clin Psychiatry. 2007;68(3):416–421. PubMed
48. Leucht S, Pitschel-Walz G, Abraham D, et al. Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo: a meta-analysis of randomized controlled trials. Schizophr Res. 1999;35(1):51–68. doi:10.1016/S0920-9964(98)00105-4 PubMed
49. Gross M, Nakamura L, Pascual-Leone A, et al. Has repetitive transcranial magnetic stimulation (rTMS) treatment for depression improved? a systematic review and meta-analysis comparing the recent vs the earlier rTMS studies. Acta Psychiatr Scand. 2007;116(3):165–173. doi:10.1111/j.1600-0447.2007.01049.x PubMed
50. Cordes J, Arends M, Mobascher A, et al. Potential clinical targets of repetitive transcranial magnetic stimulation treatment in schizophrenia. Neuropsychobiology. 2006;54(2)87–99. doi:10.1159/000096990 PubMed
51. Herwig U, Padberg F, Unger J, et al. Transcranial magnetic stimulation in therapy studies: examination of the reliability of “standard” coil positioning by neuronavigation. Biol Psychiatry. 2001;50(1)58–61. doi:10.1016/S0006-3223(01)01153-2 PubMed
52. Fitzgerald PB, Daskalakis ZJ. A review of repetitive transcranial magnetic stimulation use in the treatment of schizophrenia. Can J Psychiatry. 2008;53(9):567–576. PubMed
53. Burlingame GM, Dunn TW, Chen S, et al. Selection of outcome assessment instruments for inpatients with severe and persistent mental illness. Psychiatr Serv. 2005;56(4):444–451. doi:10.1176/appi.ps.56.4.444 PubMed
54. Norman RM, Malla AK, Cortese L, et al. A study of the interrelationship between and comparative interrater reliability of the SAPS, SANS and PANSS. Schizophr Res. 1996;19(1):73–85. doi:10.1016/0920-9964(95)00055-0 PubMed
55. Andreasen NC. Negative symptoms in schizophrenia. Definition and reliability. Arch Gen Psychiatry. 1982;39(7):784–788. PubMed
56. Thiemann S, Csernansky JG, Berger PA. Rating scales in research: the case of negative symptoms. Psychiatry Res. 1987;20(1):47–55. doi:10.1016/0165-1781(87)90122-3 PubMed
57. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2)261–276. PubMed
58. Bell M, Milstein R, Beam-Goulet J, et al. The Positive and Negative Syndrome Scale and the Brief Psychiatric Rating Scale. Reliability, comparability, and predictive validity. J Nerv Ment Dis. 1992;180(11):723–728. PubMed
59. Eckert SL, Diamond PM, Miller AL, et al. A comparison of instrument sensitivity to negative symptom change. Psychiatry Res. 1996;63(1): 67–75. doi:10.1016/0165-1781(96)02870-3 PubMed
60. Peralta V, Cuesta MJ. Psychometric properties of the positive and negative syndrome scale (PANSS) in schizophrenia. Psychiatry Res. 1994;53(1):31–40. doi:10.1016/0165-1781(94)90093-0 PubMed
61. Buchanan RW. Persistent negative symptoms in schizophrenia: an overview. Schizophr Bull. 2007;33(4):1013–1022. doi:10.1093/schbul/sbl057 PubMed
62. Kirkpatrick B, Fenton WS, Carpenter WT Jr, et al. The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull. 2006;32(2):214–219. doi:10.1093/schbul/sbj053 PubMed
63. Lane HY, Chang YC, Liu YC, et al. Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study. Arch Gen Psychiatry. 2005;62(11):1196–1204. doi:10.1001/archpsyc.62.11.1196 PubMed
64. Ziemann U, Lonnecker S, Steinhoff BJ, et al. Effects of antiepileptic drugs on motor cortex excitability in humans: a transcranial magnetic stimulation study. Ann Neurol. 1996;40(3):367–378. doi:10.1002/ana.410400306 PubMed
65. Michelucci R, Passarelli D, Riguzzi P, et al. Transcranial magnetic stimulation in partial epilepsy: drug-induced changes of motor excitability. Acta Neurol Scand. 1996;94(1):24–30. doi:10.1111/j.1600-0404.1996.tb00034.x PubMed
66. Hoffman RE, Boutros NN, Hu S, et al. Transcranial magnetic stimulation and auditory hallucinations in schizophrenia. Lancet. 2000;355(9209):1073–1075. doi:10.1016/S0140-6736(00)02043-2 PubMed
67. Loo CK, Taylor JL, Gandevia SC, et al. Transcranial magnetic stimulation (TMS) in controlled treatment studies: are some “sham” forms active? Biol Psychiatry. 2000;47(4):325–331. doi:10.1016/S0006-3223(99)00285-1 PubMed
68. Lisanby SH, Gutman D, Luber B, et al. Sham TMS: intracerebral measurement of the induced electrical field and the induction of motor-evoked potentials. Biol Psychiatry. 2001;49(5)460–463. doi:10.1016/S0006-3223(00)01110-0 PubMed
69. Stanford AD, Sharif Z, Corcoran C, et al. rTMS strategies for the study and treatment of schizophrenia: a review. Int J Neuropsychopharmacol. 2008;11(4):563–576. doi:10.1017/S1461145707008309 PubMed
70. Hoeft F, Wu DA, Hernandez A, et al. Electronically switchable sham transcranial magnetic stimulation (TMS) system. PLoS One. 2008;3(4)e1923. doi:10.1371/journal.pone.0001923 PubMed