Repetitive Noninvasive Brain Stimulation to Modulate Cognitive Functions in Schizophrenia: A Systematic Review of Primary and Secondary Outcomes

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1 Schizophrenia Bulletin vol. 42 suppl. no. 1 pp. S95 S109, 2016 doi: /schbul/sbv158 Repetitive Noninvasive Brain Stimulation to Modulate Cognitive Functions in Schizophrenia: A Systematic Review of Primary and Secondary Outcomes Alkomiet Hasan*,1, Wolfgang Strube 1, Ulrich Palm 1, and Thomas Wobrock 2,3 1 Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich, Germany; 2 County Hospitals Darmstadt- Dieburg, Groß-Umstadt, Germany; 3 Department of Psychiatry and Psychotherapy, Georg-August-University, Göttingen, Germany *To whom correspondence should be addressed; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Nussbaumstr. 7, D Munich, Germany; tel: +49-(0) , fax: +49-(0) , alkomiet.hasan@med.uni-muenchen.de Despite many years of research, there is still an urgent need for new therapeutic options for the treatment of cognitive deficits in schizophrenia. Noninvasive brain stimulation (NIBS) has been proposed to be such a novel add-on treatment option. The main objective of this review was to systematically evaluate the cognitive effects of repetitive NIBS in schizophrenia. As most studies have not been specifically designed to investigate cognition as primary outcome, we have focused on both, primary and. The PubMed/MEDLINE database ( ) was systematically searched for interventional studies investigating the effects of repetitive NIBS on schizophrenia symptoms. All interventional clinical trials using repetitive transcranial stimulation, transcranial theta burst stimulation, and transcranial direct current stimulation for the treatment of schizophrenia were extracted and analyzed with regard to cognitive measures as primary or secondary. Seventy-six full-text articles were assessed for eligibility of which 33 studies were included in the qualitative synthesis. Of these 33 studies, only 4 studies included cognition as primary outcome, whereas 29 studies included cognitive measures as. A beneficial effect of frontal NIBS could not be clearly established. No evidence for a cognitive disruptive effect of NIBS (temporal lobe) in schizophrenia could be detected. Finally, a large heterogeneity between studies in terms of inclusion criteria, stimulation parameters, applied cognitive measures, and follow-up intervals was observed. This review provides the first systematic overview regarding cognitive effects of repetitive NIBS in schizophrenia. Key words: schizophrenia/cognition/noninvasive brain stimulation/rtms/tdcs/neuroplasticity Introduction Cognitive impairments are core symptoms of schizophrenia, stable over time, they contribute to the debilitating effects, and are one of the main contributor to longterm impairments in social and vocational functioning. 1,2 Several separable cognitive factors have been identified to characterize the global cognitive deficit in schizophrenia: processing speed, attention and vigilance, working memory, verbal learning and memory, visual learning and memory, reasoning and problem solving, and verbal and social cognition. 3 Despite the enormous importance of cognitive symptoms, there are still no satisfying treatment options in clinical practice. 2 The initial hope that secondgeneration antipsychotics would prove effective for the treatment of cognitive deficits was not fulfilled satisfactorily, 2 whereas recently one meta-analysis suggests at least a moderate effect. 4 Especially in recent years, noninvasive brain stimulation (NIBS) techniques have been proposed as new treatment options for cognitive deficits. The term NIBS summarizes various techniques, including repetitive transcranial magnetic stimulation (rtms) and its variants such as theta burst stimulation (TBS), and transcranial electric stimulation including transcranial direct current stimulation (tdcs), transcranial random noise stimulation, and transcranial alternating current stimulation. More specifically, magnetic and electric stimulation have fundamentally different physiological modes of action. TMS induces neuronal action potentials, whereas the static electric field induced by tdcs does not result in such a rapid depolarization but modulates spontaneous neuronal activity by a tonic depolarization or hyperpolarization. 5 Common to all is the possibility to induce longlasting changes in brain excitability, to modulate cortical connectivity and network plasticity. 6,7 One consensus paper 8 provides evidence for a moderate clinical efficacy of rtms for the treatment of persistent auditory hallucinations (temporal lobe stimulation) and predominant negative symptoms (frontal lobe stimulation), although recent studies with relevant sample sizes 9,10 are questioning these statements. One tdcs pilot study showed that The Author Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please journals.permissions@oup.com S95

2 A. Hasan et al tdcs can improve both auditory hallucinations as well as negative symptoms in severely affected schizophrenia patients. 11 Especially, the improvement of negative symptoms following tdcs deserves particular attention as negative symptoms and cognitive impairments are considered to be correlated. 12 Negative symptoms and cognitive impairments have separable but related etiologies, whereas alternative models describing common or independent etiologies are also deemed as possible. 12 However, a clear dividing line between both concepts cannot be easily drawn challenging the differentiation between both. 12 In this context, the treatment of schizophrenia-associated cognitive deficits in patients suffering from predominant negative symptoms came early into the focus of interest. In 1999, one of the very first proof-of-concept trials in the field (open-label, N = 6) showed that 2 weeks of 20 Hz rtms applied to the left dorsolateral prefrontal cortex (DLPFC) improved negative symptoms. 13 Moreover, the authors also investigated a broad cognitive battery and showed a numeric improvement in various cognitive measures, whereas delayed visual memory achieved significance. 13 From a principle point of view, 2 effects of NIBS on cognition in schizophrenia are possible. Firstly, a disruptive effect on cognitive functions 14,15 (mainly following temporal lobe stimulation) as a side-effect or, secondly, an improvement of cognitive function as a positive effect 6,16 were discussed. The latter beneficial effects have been linked to impaired DLPFC function and connectivity in schizophrenia 17 and the overall idea is that neurostimulation techniques have the capacity to enhance neuroplasticity and to remodel connectivity. 6 However, no systematic evaluation of the cognitive effects of the whole range of NIBS techniques in schizophrenia is yet available. One meta-analysis provided by the Cochrane group summarized for the comparison of active and sham rtms that the cognitive state was reported in 3 studies using 39 different measures, but that the results were equivocal for all measures. 18 However, as only few repetitive NIBS studies used cognitive measures as primary, but since many studies included cognitive measures as secondary outcome, systematic qualitative analyses are needed. The main objective was to gain a detailed overview on potential positive and negative effects of NIBS. Therefore, we performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 19 requirements and analyzed all cognitive measures reported in the extracted trials. As most available trials focused on persistent positive or negative symptoms, we hypothesized that despite the clinical importance and the clear pathophysiological rational, only few trials will be available that specifically investigate the efficacy of NIBS for the treatment of cognitive impairments. Furthermore, based on the possibility to modulate various stimulation parameters and outcome measures, we hypothesized that a large heterogeneity between studies will limit the generalizability of findings. Methods This systematic review was conducted via the internet database PubMed/MEDLINE taking into account recommendations for the standardized reporting of systematic reviews (PRISMA). 19 The data source contained studies published from January 1, 1985 to August 15, 2015 (ENDNOTE X7 filter entered between [1985/01/01:2015/12/31], with the last search conducted on August 15, 2015). We have started in 1985 as TMS was introduced to the field in Literature was searched manually and via the ENDNOTE X7 search tools using the following terms: brain stimulation and schizophrenia ; brain stimulation and schizophrenia and cognition ; repetitive transcranial magnetic stimulation and schizophrenia ; repetitive transcranial magnetic stimulation and schizophrenia and cognition ; repetitive transcranial magnetic stimulation and schizophrenia and negative symptoms ; repetitive transcranial magnetic stimulation and schizophrenia and auditory hallucinations ; rtms and schizophrenia ; rtms and schizophrenia and cognition ; rtms and schizophrenia and negative symptoms ; rtms and schizophrenia and auditory hallucinations ; transcranial direct current stimulation and schizophrenia ; transcranial direct current stimulation and schizophrenia and cognition ; transcranial direct current stimulation and schizophrenia and negative symptoms ; transcranial direct current stimulation and schizophrenia and auditory hallucinations ; tdcs and schizophrenia ; tdcs and schizophrenia and cognition ; tdcs and schizophrenia and negative symptoms ; tdcs and schizophrenia and auditory hallucinations ; Theta Burst Stimulation and schizophrenia ; Theta Burst Stimulation and schizophrenia and cognition ; Theta Burst Stimulation and schizophrenia and negative symptoms ; Theta Burst Stimulation and schizophrenia and auditory hallucinations ; TBS and schizophrenia ; TBS and schizophrenia and cognition ; TBS and schizophrenia and negative symptoms ; TBS and schizophrenia and auditory hallucinations. Results from all search terms were combined and duplicate records were removed using the ENDNOTE X7 deduplication feature. The titles and, if relevant, the abstracts of each citation were screened and the full text of each potentially relevant citation was retrieved and reviewed in detail. Only clinical trials with repetitive stimulation sessions and longitudinal design (controlled, uncontrolled, blinded, open-label) reported in English language were included. Case reports and case series, single-session studies, abstracts of congress presentations, reviews, and meta-analyses were S96

3 NIBS for the Treatment of Cognitive Symptoms in Schizophrenia excluded. Furthermore, the recent meta-analyses on persistent auditory hallucinations and negative symptoms, 20,21 as well the latest large-scale clinical trials in the field, 9,10 were also screened for citations not revealed by the systematic literature search. Full-text articles were then analyzed with respect to the presentation of cognitive measures as primary or secondary outcome parameters. This data item search was not restricted to any cognitive measure. Fulltext articles from the same research groups were compared regarding the risk of duplicate populations. We further analyzed 2 databases (first: and second: to detect ongoing or planned trials with any cognitive parameters as primary outcome measure. For both databases, we used the terms rtms and schizophrenia, repetitive transcranial magnetic stimulation and schizophrenia, tdcs and schizophrenia, and transcranial direct current stimulation and schizophrenia. Results Study Selection On the basis of our search strategy, 2231 unique records could be identified. A total of 2155 records were excluded after screening of titles, abstracts, and article format reviews, resulting in 76 full texts that could then be retrieved. Of these 76 full texts, 5 were not detected through our search strategy and included via other sources and targeted manual search. These 76 full-text articles were then analyzed regarding the presentation of any cognitive measures before and after NIBS intervention. In total, 33 primary studies published between 1999 and ,13 15,22,23,26 52 were included for further analyses in this systematic review. All other full texts (N = 43) were excluded due to the lacking presentation of cognitive measures. Of these 43 studies not reporting cognitive measures, 28 focused on persistent auditory hallucinations, 10 on predominant negative symptoms, and 5 on other primary outcome measures (clinical global impression, affective symptoms, global symptoms). Please see figure 1 for the PRISMA 19 flow diagram. Study Characteristics Among the 33 studies included in this systematic review, 4 studies reported cognitive measures as primary outcome. 40,44,47,52 Out of these 4 studies, one used the Cambridge Neuropsychological Test Automated Battery (CANTAB), 40 one focused on working memory using a silent phonemic Verbal Fluency Task, 44 one focused also on working memory using a verbal n-back task, 47 and one used the MATRICS Consensus Cognitive Battery (MCCB). 52 The remaining 29 studies had global symptoms (N = 12), 13,27 30,38,39,41 43,48,49 negative symptoms (N = 11), 9,22,26,32,34 37,45,50,51 or persistent auditory hallucinations (N = 6) 14,15,23,31,33,46 as primary. All studies had a pre/post design and participants were at rest during the stimulation. Apart from 3, 9,26,50 all publications reported single-centre results. The mean sample size across all publications (inclusion of all 33 studies regardless of a possible overlap of sample across publications [see table 1]) was (SD: 28.03) with a minimum of N = 4 and a maximum of N = 157. Twenty-seven studies had a double-blind sham-controlled parallel group design and 6 studies were open-label studies. Thirty studies used rtms (including deep TMS and TBS) and 3 studies used tdcs as noninvasive stimulation techniques. No studies were found using other transcranial electric stimulation methods. Identification 3998 records identified through database searching 5 additional records identified through other sources Screening Eligibility 2231 records after duplicates removed 2231 of records screened 76 of full-text articles assessed for eligibility 2155 records excludedat title / abstract / article format review (case reports, meta-analysis, reviews) 43 full-text articles excluded (these full-text articles did not describe cognitive measures as primary or secondayry ) Included 33 studies included in qualitative synthesis Fig. 1. PRISMA diagram summarizing the flow of information through all phases of this systematic review. S97

4 A. Hasan et al Regarding the localization of the respective stimulation sites, 17 studies used the electroencephalogram (EEG) 10/20 method, 12 studies used the 5-cm-anterior method (for DLPFC localization), 4 studies used neuronavigation based on individual structural MRI, and 1 study did not report the applied procedure. Regarding rtms sham procedures, 10 trials tilted the coil away from the scalp at an angle of 45, 9,14,15,23,26,27,29,31,45,46 7 trials tilted the coil at an angle of 90, 30,34,36,43,47,50,51 6 trials used a specific sham coil, 33,35,37,38,44,49 and 1 study did not describe the sham procedure. 22 However, as the latter study used the Brainsway H1 deep-tms coil, 22 one could speculate that the built-in sham mode has been used. For tdcs, 3 trials used different variations of the ramp-up/ramp-down procedure, 41,48,52 but no study used the built-in study-mode. The stimulation parameters varied across studies dependent on the target symptoms resulting in a high interstudy heterogeneity for this parameter. Most studies investigated cognitive functioning immediately after the respective stimulation intervention (1 4 wk). Only few studies included follow-up measures after the end of intervention. The longest followup periods were 8 12 weeks (for details, see table 1). Most studies required a stable medication regime during the intervention 9,13 15,26 32,34 45,49 51 and 6 studies did not include this information. 22,23,33,47,48,52 With respect to the use and abuse of legal and illegal drugs, a large heterogeneity across studies could be observed. Ten studies did not describe whether legal or illegal drugs were permitted or not. 23,27 30,32,33,37,41,52 All other studies 9,13 15,22,26,31,34,36,38,40,42 46,50,51 described drug abuse or drug dependency as exclusion criterion. In more detail, legal and illegal drug dependency within 2 years, 38,49 5 years, 13 or in general 14,22,31,36,40,44,46,48 was an exclusion criterion in many studies. Other studies excluded the abuse/dependency 4 weeks, 15 3 months, 34 and 6 months prior to study inclusion. 11,15,19,23,24,30 Finally, some studies 9,26,42,45 excluded a current drug abuse/dependency at the time of study start. Regarding new trials, our database search revealed 3 trials investigating the efficacy of rtms/tbs for the treatment of working memory deficit (NCT , CTRI/2015/01/005448, and ChiCTR-TRC ), 2 trials focusing on social cognition (NCT and NCT ), and 1 trial focusing on overall cognition according to BACS (Brief Assessment of Cognition in Schizophrenia) (NCT ). For tdcs, 3 trials are focusing on overall cognition measured by the MCCB (NCT , NCT , and NCT ), 2 trials are aiming to improve general cognition without further specification (NCT and NCT ), and 1 has working memory as primary outcome (ACTRN ). Risk of Bias Within and Across Studies The main bias within and across studies was that almost all studies did not access cognitive performance as primary outcome. Therefore, most studies were not designed and powered to detect differences between active and sham intervention for these parameters. Furthermore, the limited sample sizes and the monocentric design of most studies question the generalizability of the presented positive and negative findings regards cognition. A possible additional bias could be the procedures used to localize the target areas for NIBS. Various different methods, including the application of different stimulation parameters, were used across studies resulting in a high interstudy heterogeneity and hampering comparability. Results of Individual Studies (Outcomes) The cognitive measures used in the different studies were dependent on various factors including theoretical deliberations and/or pathophysiological hypotheses as well as safety questions. Studies with a stimulation focus on the frontal lobe followed the idea of improving cognition through neurostimulation (cognition as outcome parameter). As most studies did not investigate cognition as primary outcome and as the applied cognitive measures are subject to a high interstudy variability, no clear pattern across studies could be observed. Studies with a double-blind design that had cognitive measures as could principally not overserve a beneficial effect of active stimulation compared to sham stimulation. 9,22,26,27,30,34,36,41,45 Other studies 33,35,37,50 indicate a potential benefit of active neurostimulation applied to the DLPFC on verbal memory, source monitoring, cognitive flexibility, or verbal fluency, whereas the aforementioned negative studies failed to show a benefit in the same or related domains. Interestingly, one study using high-frequency rtms applied to the left DLPFC focused on the safety effect of frontal neurostimulation and did not reveal any potential harmful effect on cognition. 38 The largest study investigated the efficacy of 10 Hz rtms applied to the left DLPFC (EEG 10/20 F3) on various cognitive domains in schizophrenia patients with predominant negative symptoms and did not show a superiority of active compared to sham rtms. However, the reported effect sizes point towards a numeric, but nonsignificant superiority of the active intervention (positive effect sizes favoring active rtms: global composite z score [0.28], Trail Making Test [TMT] domain z score [0.27], Verbal Learning and Memory Test [VLMT] domain z score [0.24], Wisconsin Card Sorting Test [WCST] domain z score [0.24]). 26 Studies focusing on cognition as primary outcome revealed a slightly different pattern. Three of the 4 studies 27,31,34,39 had a doubleblind sham control and parallel group design and of these 3 studies, 2 used rtms and 1 used tdcs. Barr et al 47 applied 20 Hz rtms with 1500 stimuli to the left and right DLPFC (neuronavigated rtms) for a treatment duration of 4 weeks. The DLPFC was targeted by individual structural MRI scans, 27 patients were randomized and the S98

5 NIBS for the Treatment of Cognitive Symptoms in Schizophrenia Table 1. Cognitive Effects of Repetitive NIBS in Schizophrenia Reference Study Design; Total Sample Size; Follow-up Period; Study Population NIBS Parameters; NIBS Device and Stimulation Site; Sham Parameters Cognitive Outcome Measures; Primary Outcome Yes/No Cohen et al 13 Open-label pilot study (N = 6); before and immediately after 2 wk; chronic schizophrenia patients Rollnik et al 27 Double blind; sham-controlled crossover study (N = 12); before and after 1 and 2 wk; chronic schizophrenia patients D Alfonso et al 28 Open-label trial (N = 8); before and after 1 and 2 wk; medication-resistant schizophrenia patients Hoffman et al 15 Double blind; sham-controlled parallel group study (N = 24); before and after 9 d; medication-resistant AH patients Huber et al 29 Re-evaluation of Rollnik et al 24 ; chronic schizophrenia patients 20 Hz rtms for 2 s; once per minute for 20 min at 80% MT for 2 wk (5 d/wk); MagPro magnetic stimulator with figureof-eight coil; EEG 10/20; coil was placed tangential to the orbital area on the C3 and C4 point 20 2 s; 20 Hz stimulations with 80% of MT intensity over 20 min for 2 wk (800 pulses/session; 10 sessions at 10 working days); Magstim Rapid stimulator with figure-of-eight-coil; coil over the DLPFC of the dominant hemisphere (5 cm anterior M1); for sham rtms, the coil was tilted at an angle of 45 1 Hz rtms for 20 min for 2 wk (10 sessions at 10 working days) with 80% MT; Neopulse magnetic stimulator; EEG 10/20; coil was placed approximately 2 cm above T3 (no coil specifications described) 1 Hz rtms for 16 min for day 3 9 (day 1: 8 min; day 2: 12 min) with 90% MT; Magstim Super Rapid System with figureof-eight coil; EEG 10/20 halfway between T3 and P3; for sham rtms, the coil was tilted at an angle of 45 Wechsler Adult Intelligence Scale, TMT A and B, the FAS Verbal Fluency Test, and 2 subtests of the WMS (the visual memory reproduction and the verbal paired associates subtests); cognitive measures were NCT; cognitive measures were Auditory Imagery Test, Rey Auditory Verbal Learning Test, Token Test (short form), verbal fluency and phoneme detection, Judgment of Line Orientation, Line Bisection Test, Benton Visual Retention Test, and the Test for Facial Recognition; short form; cognitive measures were California Verbal Learning Test, Controlled Oral Word Association Test, Semantic Fluency, Digit Distraction Task, WRAT-R, TMT A and B, Grooved Pegboard, Digit Symbol Task, Temporal Orientation, HVLT, Letters- Number Span Test (the latter 2 were administered serially during the trial); cognitive measures were See Rollnik et al 26 NCT; cognitive measures were McIntosh et al 23 Double blind; sham-controlled crossover study (N = 16); before and after 1 wk; medication-resistant AH patients 1 Hz rtms for 4 min at day 1, 8 min at day 2, 12 min at day 3, and 16 min until the end of 2 wk with 80% MT; each minute of stimulation was followed by 15 s of rest; Dantec magnetic stimulator with figure-ofeight coil; EEG 10/20 halfway between T3 and P3; for sham rtms, the coil was tilted at an angle of 45 AVLT; cognitive measures were Summary of Results (Cognitive Measures) Numeric improvement in all cognitive measures, whereas only delayed visual reproduction achieved significance NCT tended to improve during active rtms and to worsen during sham stimulation without reaching significance Only the auditory imagery tests revealed a significant improvement over time, whereas only 6 patients had a complete dataset for this test. All other cognitive measures did not show a significant difference before and after intervention No differences in cognitive measures over time apart from a marginal significant time treatment effect for the HVLT Women (N = 4) improved in the NCT performance, whereas men (N = 8) did not improve during active rtms No differences in AVLT S99

6 A. Hasan et al Table 1. Continued Reference Study Design; Total Sample Size; Follow-up Period; Study Population Holi et al 30 Double blind; sham-controlled parallel group study (N = 22); before and after 2 wk; chronic patients Fitzgerald et al 31 Double blind; sham-controlled parallel group study (N = 33); before and after 2 wk; medication-resistant AH patients Sachdev et al 32 Open-pilot study (N = 4); before and after 4 wk; predominant negative symptoms (deficit syndrome) Hoffman et al 14 Double blind; sham-controlled parallel group study (N = 50; 27 active rtms); before and after 9 working days; medication-resistant AH patients Brunelin et al 33 Double blind; sham-controlled parallel group study (N = 24; 14 active rtms); before and after 5 working days; medication-resistant AH patients Novák et al 34 Double blind; sham-controlled parallel group study (N = 16); before and after 8 wk; predominant negative symptoms NIBS Parameters; NIBS Device and Stimulation Site; Sham Parameters 10 Hz rtms with 20 trains (each of 5 s; 30 s apart) with 100% MT; Magstim stimulator with figure-of-eight coil; left DLPFC (5 cm anterior left M1); for sham rtms, the coil was tilted at an angle of 90 1 Hz rtms for 15 min for 10 working days with 90% MT; Magstim Super Rapid System with figure-of-eight coil; EEG 10/20 T3; for sham rtms, the coil was tilted at an angle of Hz rtms with 24 trains (each of 5 s; 25 s apart) with 90% MT; Magstim Super Rapid System with figure-of-eight coil; coil over the DLPFC of the left hemisphere (5 cm anterior M1) 1 Hz rtms for 16 min for day 3 9 (day 1: 8 min; day 2: 12 min) with 90% MT; Magstim Super Rapid System with figureof-eight coil; EEG 10/20 halfway between T3 and P3; for sham rtms, the coil was tilted at an angle of 45 1 Hz rtms for 17 min twice/d for 5 working days with 90% MT; Medtronic MagPro with figure-of-eight coil; EEG 10/20 halfway between T3 and P3; for sham rtms, a specific sham coil was used 20 Hz rtms with 40 trains (each of 2.5 s; 30 s apart; 2000 stimuli) with 90% MT; Magstim Super Rapid System with figureof-eight coil; coil over the DLPFC of the left hemisphere (5 cm anterior M1); for sham rtms, the coil was tilted at an angle of 90 Cognitive Outcome Measures; Primary Outcome Yes/No MMSE; cognitive measures were HVLT (also assessed after the first session), Visuospatial Digit Span; cognitive measures were secondary MMSE, Digit Forward and Backward, TMT A and B Symbol Digit Coding, Verbal Fluency for letter and category, and WCST; cognitive measures were secondary California Verbal Learning Test, Controlled Oral Word Association Test, Animal Naming, Digit Recall Task (nondistraction and distraction conditions), WRAT-R Reading Test, TMT A and B, Grooved Pegboard (dominant and nondominant), Digit Symbol Task, Temporal Orientation, HVLT, Letters-Number Span Test (the latter 2 were administered serially during the trial); cognitive measures were Source Memory Tasks (discrimination between silent- and overt-reading words); cognitive measures were AVLT, TMT A and B, Rey- Osterrieth Complex Figure, CPT; cognitive measures were secondary Summary of Results (Cognitive Measures) No change in the MMSE scores within either group No changes in cognitive functions across time and groups. For the HVLT, a small but significant deterioration in performance was reported in both study groups No changes in any of the cognitive measures over time No differences between active and sham rtms could be detected for the full neuropsychological battery before and after intervention. One patient receiving active rtms and one receiving sham rtms were removed from the trial due to drops in the Hopkins Verbal Learning Task Active rtms resulted in improvements in source monitoring. Reduction of AHs showed a trend-wise correlation with the improvement in the number of total confusion during source monitoring tasks Between-group comparisons did not show any differences for any of cognitive measures after a follow-up of 8 wk S100

7 NIBS for the Treatment of Cognitive Symptoms in Schizophrenia Table 1. Continued Reference Study Design; Total Sample Size; Follow-up Period; Study Population Mogg et al 35 Double blind; sham-controlled parallel group study (N = 17; 8 active rtms); before and after 2 and 4 wk; predominant negative symptoms Fitzgerald et al 36 Double blind; sham-controlled parallel group study (N = 20); before and after 3 wk; treatment-resistant negative symptoms Schneider et al 37 Double blind; sham-controlled parallel group study (N = 51; 34 active rtms); before and after 2, 4, and 8 wk; predominant negative symptoms Mittrach et al 38 Double blind; sham-controlled parallel group study (N = 32; 18 active rtms); before and after 2 wk; chronic schizophrenia patients Demirtas- Open-label pilot study (N = 8); before Tatlidede et al 39 and immediately after 5 d; treatmentresistant schizophrenia patients NIBS Parameters; NIBS Device and Stimulation Site; Sham Parameters 10 Hz rtms with 20 trains (each of 10 s; 50 s apart; 2000 stimuli) with 110% MT; Magstim Super Rapid System with figureof-eight coil; coil over the DLPFC of the left hemisphere (5 cm anterior M1); for sham rtms, a specific sham coil was used 10 Hz rtms with 20 trains (each of 5 s; 25 s apart; 1000 stimuli) with 110% MT; 20 trains were applied to each hemisphere at every session; Medtronic MagPro 30 magnetic stimulators with figure-of-eight coils; coils over the left and right DLPFC (5 cm anterior M1); for sham rtms, the coils were tilted at an angle of Hz rtms or 1 Hz rtms with 20 trains (each of 5 s; 15 s apart; 1000 stimuli) with 110% MT; 20 trains were applied for 4 consecutive weeks; Neotonus 1000 magnetic stimulator; coil not specified; coil over the left DLPFC (5 cm anterior M1); for sham rtms, one of 2 head covers on the magnet was fitted by a person not involved in the stimulation 10 Hz rtms with 20 trains (each of 5 s; 55 s apart; 1000 stimuli) with 110% MT; 20 trains were applied to each hemisphere at every session; Medtronic MagPro X100 magnetic stimulators with figure-of-eight coils; coil over the left DLPFC (5 cm anterior M1); for sham rtms, a specific sham coil was used Intermittent TBS (3 pulses at 50-Hz repeated at a rate of 5 Hz; 20 trains of 10 bursts given with 8-s intervals; 600 pulses) with 100% active MT were applied twice a day to the cerebellar vermis; Medtronic MagPro X100 magnetic stimulators with figure-of-eight coil; MR navigation based on individual MRI Cognitive Outcome Measures; Primary Outcome Yes/No Controlled Oral Word Association Test, Stroop interference task, HVLT, Grooved Pegboard Test; cognitive measures were secondary Stroop Test, Controlled Oral Word Association Test, TMT A and B; cognitive measures were secondary WCST; cognitive measures were Kurztest für Allgemeine Intelligenz (German version of a short test of general intelligence), the Mehrfach- Wortwahl-Test (German verbal intelligence test), D2 attention task, TMT A and B, WCST; cognitive measures were Auditory CPT, Letter-Number Span, WMS, 3rd Edition (WMS- III)-Spatial Span, Phonemic/Letter Fluency, Category Fluency, BACS- Symbol Coding, TMT A and B, WCST, Delis-Kaplan Executive Function System, California Verbal Learning Test, Rey-Osterrieth Complex Figure Test, Grooved Pegboard; cognitive measures were Summary of Results (Cognitive Measures) For the HVLT-delayed recall, there was a significant difference between groups in favor of active rtms at 2-wk follow-up. For the Stroop Test, there was a trend towards a group effect in favor of active rtms There were no significant overall or between-group effects of rtms on any of the cognitive measures The 10 Hz group showed significant improvement at weeks 4 and 8 on the failure to maintain set and perseverative response errors; but betweengroup differences did not reach significance. The 1 Hz group demonstrated significant improvement on WCST only at week 2. The results of this cognitive measure were biased by a high noncompletion rate in all study groups No significant effect of rtms on cognitive measures could be observed A significant improvement over time could be detected for the CPT (memory and interference condition), for the spatial span forward performance, and for the organization score of the Rey-Osterrieth Complex figure. No negative effects of the intervention were shown S101

8 A. Hasan et al Table 1. Continued Reference Study Design; Total Sample Size; Follow-up Period; Study Population Levkovitz et al 40 Open-label pilot study (N = 15); before and after 2 and 4 wk; predominant negative symptoms Mattai et al 41 Double blind; sham-controlled pilot study (N = 12); before and after 2 wk; childhood-onset schizophrenia Oh et al 42 Open-label study (N = 10); before and after 1 and 4 wk; treatment-resistant schizophrenia patients Blumberger et al 43 Double blind; sham-controlled parallel group study (N = 51; 34 active rtms); before and after 4 wk; medication-resistant AH patients Prikryl et al 44 Double blind; sham-controlled parallel group study (N = 30; 19 active rtms); before and after 3 wk; predominant negative symptoms NIBS Parameters; NIBS Device and Stimulation Site; Sham Parameters 20 Hz Deep-TMS (42 trains of 2 s; 40 pulses each; with 20-s intertrain interval) with 120% MT was applied once a day for 20 d; Magstim Super Rapid stimulator connected to an H1 coil; coil over the left DLPFC (5 cm anterior M1) Bilateral anodal DLPFC stimulation (n = 8) or bilateral cathodal STG stimulation (n = 5); 20-min stimulation once a day for 10 working days; Phoresor II Auto Model PM850 with 25 cm 2 sponge electrodes; EEG 10/20 FP1 and FP2 for left and right DLPFC and T3 for STG reference electrode at nondominant forearm; for sham tdcs; the current was turned on for 1 min and then ramped down 10 Hz rtms with 20 trains (each of 3 s; 30 s apart) to the left DLPFC and 1 Hz rtms with 20 trains (each of 30 s; 30 s apart) to the left TPC with 80% 100% MT; Magstim Rapid stimulator with figure-of-eight coil; EEG 10/20 F3 for left DLPFC and P3-T3 midpoint for TPC 1 Hz rtms for 20 min with 115% MR; primed 1 Hz rtms was administered by 10 min of 6 Hz rtms (20 trains; 5 s each; 25 s apart) with 90% MT followed by 10-min 1 Hz rtms with 115% rtms; Medtronic Repetitive Magnetic Stimulator with figure-of-eight coil; MR navigation based on individual MRI; for sham rtms, the coil were tilted at an angle of Hz rtms with 15 trains (each of 10 s; 30 s apart; 1500 stimuli) with 110% MT; Magstim Super Rapid stimulator with figure-of-eight coil; left DLPFC localization was not described; for sham rtms, a specific sham coil was used Cognitive Outcome Measures; Primary Outcome Yes/No CANTAB with 4 domains: psychomotor speed (RTI), visuospatial memory (spatial recognition memory), sustained attention (RVP), and executive functions (SOC, SWM, spatial span, and intra-/extradimensional shift); cognitive measures were together with the SANS scale primary MMSE, California Verbal Learning Test, WMS; cognitive measures were RKMT (K-AVLT), Complex Figure Test, Stroop Test, WCST; cognitive measures were secondary RBANS; cognitive measures were Silent Phonemic VFT during fmri; cognitive measures were primary Summary of Results (Cognitive Measures) A significant improvement in RVP and SOC (problems solved), SWM (between errors), SWM (strategy), and spatial span length could be observed No changes in cognitive measures in favor of any stimulation condition could be observed Short-term auditory verbal memory improved over time. All other cognitive measures did not show a significant change over time No difference in RBANS change could be observed across groups and between responders and nonresponders No differences in the VFT performance could be observed between active and sham rtms S102

9 NIBS for the Treatment of Cognitive Symptoms in Schizophrenia Table 1. Continued Reference Study Design; Total Sample Size; Follow-up Period; Study Population Guse et al 45 Double blind; sham-controlled parallel group study (N = 25; 13 active rtms); before and after 3 wk; predominant negative symptoms; subgroup of Wobrock et al 7 Hoffman et al 46 Double blind; sham-controlled parallel group study (N = 83; 55 active rtms); before and after 3 wk (third stimulation block); medicationresistant AH patients Barr et al 47 Double blind; sham-controlled parallel group study (N = 27; 13 active rtms); before and after 4 wk; chronic schizophrenia patients Fitzgerald et al 48 Double blind; sham-controlled parallel group pilot studies (2 pilot studies in 1 publication) (total N = 24); before and after 3 wk; medication-resistant AH patients and nonresponsive negative symptoms Wölwer et al 49 Double blind; sham-controlled parallel group study (N = 32; 18 active rtms); before and after 2 wk; chronic schizophrenia patients (overlap to Mittrach et al 35 ) NIBS Parameters; NIBS Device and Stimulation Site; Sham Parameters 10 Hz rtms with 20 trains (each 30 s apart; 1000 stimuli) with 110% MT; 20 trains were applied to each hemisphere at every session; Medtronic MagPro X100 magnetic stimulators with figureof-eight coil; EEG 10/20 F3 for DLPFC localization; for sham rtms, the coil was tilted at an angle of 45 1 Hz rtms for 16 min with 90% MT; Magstim Rapid-2 System with figureof-eight coil; MR navigation based on individual MRI; Wernicke s area and the right homologue; for sham rtms, the coil was tilted at an angle of Hz rtms with 25 trains (each 30 s apart; 1500 stimuli [750 pulses/ hemisphere]) with 90% MT; 20 trains were applied to each hemisphere at every session; Medtronic MagPro magnetic stimulators with figure-of-eight coil; MR navigation based on individual MRI; for sham rtms, the coil was tilted at an angle of 90 tdcs (2 ma; 20 min; ramp up of 120 s and ramp down of 15 s); 15 daily sessions over 3 consecutive weeks; neuroconn Eldith Stimulator Plus; EEG 10/20; unimodal tdcs: anode F3 and cathode TP3; bimodal tdcs: anode F3 and F4 and cathode TP3 and TP4; sham stimulation: ramp up of stimulation and 30 s of stimulation prior to stimulation off set 10 Hz rtms with 20 trains (each of 5 s; 55 s apart; 1000 stimuli) with 110% MT; Medtronic MagPro X100 magnetic stimulators with figure-of-eight coil; coil over the left DLPFC (5 cm anterior M1); for sham rtms, a specific sham coil was used Cognitive Outcome Measures; Primary Outcome Yes/No Verbal n-back WM task with parametrically varied WM load among 0, 1, and 2 items during fmri; TMT A and B; divided attention (TAP); WCST; cognitive measures were of the initially randomized population of schizophrenia patients 7 Hopkins verbal memory and letternumbers working tasks (baseline and after the 3rd, 8 th, and 13th session), full Neuropsychological Test Battery (baseline and during the third stimulation block), 2 laterality tasks at baseline: dichotic listening task and right-left pegboard difference; cognitive measures were n-back WM task at 1- and 3-back conditions; cognitive measures were primary outcome Forwards and backwards digit span, block spatial span tests, N-back task, Tower of London planning task, FAS VFT, TMT A and B; cognitive measures were Facial affect recognition task during fmri, Mehrfach- Wortwahl-Test (German verbal intelligence test), D2 attention task, TMT A and B, WCST; cognitive measures were Summary of Results (Cognitive Measures) No changes in cognitive performance in favor of any stimulation condition could be observed As outlined in the Results section of the respective publication, aggregate neuropsychological data did not reveal any significant alterations, either improvements or declines when contrasting rtms with sham stimulation Active rtms improved 3-back accuracy to targets compared with sham. Active rtms normalized the performance in this condition to the level of a healthy control group. No effect on 1- and 2-back as well on correct responses to nontargets and on RTI in responses to both targets and nontargets could be observed No changes in cognitive measures in favor of any stimulation condition could be observed Active rtms was superior to sham rtms in improving the facial affect recognition performance. No changes in the other cognitive measures could be observed S103

10 A. Hasan et al Table 1. Continued Reference Study Design; Total Sample Size; Follow-up Period; Study Population Rabany et al 22 Double blind; sham-controlled parallel group study (total N = 30; 20 active deep TMS); before and after 4 and 5 wk; predominant negative symptoms Dlabac-de Lange 50 Double blind; sham-controlled parallel group study (total N = 32); before and after 3 wk and at 4-wk follow-up; predominant negative symptoms Dlabac-de Lange 51 Double blind; sham-controlled parallel group study (total N = 24); before and after end of intervention; predominant negative symptoms (overlap to Dlabac-de Lange et al 46 ) Wobrock et al 9 Double blind; sham-controlled parallel group study (N = 157; 76 active rtms); before and after 3, 6, and 12 wk; predominant negative symptoms Smith et al 52 Double blind; sham-controlled parallel group study (N = 33; 17 active tdcs); before and after 5 d or 1 wk, 6 wk, and 12 wk; chronic patients NIBS Parameters; NIBS Device and Stimulation Site; Sham Parameters 20 Hz Deep-TMS (42 trains of 2 s; 40 pulses each; with 20-s intertrain interval) with 120% MT was applied once a day for 20 d; Magstim Super Rapid stimulator connected to an H1 coil; coil over the left DLPFC (5.5 cm anterior M1); the technique of sham stimulation was not described 10 Hz rtms with 20 trains (each of 10 s; 50 s apart; 2000 stimuli) with 90% MT; 20 trains were applied to each hemisphere at every session; Medtronic MagPro X100 magnetic stimulators with figure-of-eight coils; EEG 10/20; coils over the left (F3) and right (F4) DLPFC; for sham rtms, the coil was tilted at an angle of Hz rtms with 20 trains (each of 10 s; 50 s apart; 2000 stimuli) with 90% MT; 20 trains were applied to each hemisphere at every session; Medtronic MagPro X100 magnetic stimulators with figure-of-eight coils; EEG 10/20; coils over the left (F3) and right (F4) DLPFC; for sham rtms, the coil was tilted at an angle of Hz rtms with 20 trains (each 30 s apart; 1000 stimuli) with 110% MT; 20 trains were applied to each hemisphere at every session; Medtronic MagPro X100 magnetic stimulators with figureof-eight coil; EEG 10/20 F3 for DLPFC localization; for sham rtms, the coil was tilted at an angle of 45 tdcs (2 ma; 20 min; ramp up/ramp down not described); 5 sessions over 5 consecutive work days); tdcs device manufacturer not described; EEG 10/20; anode F3 and cathode FP2 (contralateral supraorbital ridge); sham stimulation: 40 s with 2 ma Cognitive Outcome Measures; Primary Outcome Yes/No CANTAB: psychomotor speed: MOT and RTI, visuospatial memory: PRM, sustained attention: RVP, executive functions: SOC and SWM; cognitive measures were Verbal Learning Test, Digit Symbol Substitution Test, TMT A and B, Dutch version of the Rey AVLT, Verbal Fluency Test, WCST; cognitive measures were secondary Tower of London task during fmri; cognitive measures were TMT A and B; cognitive measures were MCCB: composite score and the following domains MCCB domains: WM, attentionvigilance, reasoning/problems, verbal learning, visual learning, processing speed, social cognition; cognitive measures were primary Summary of Results (Cognitive Measures) Apart from one SOC measure (subsequent times for 5 move problems at week 4), no changes in cognitive measures in favor of any stimulation condition could be observed Semantic verbal fluency improved significantly in the active group (n = 10) compared with the sham group (n = 9) up to 4-wk follow-up. No changes in the other cognitive measures could be observed Brain activity in the active group increased in the right DLPFC and the right medial frontal gyrus. Further analyses revealed decreased activation in the active and increased activation in the sham group in the left posterior cingulate. Behavioral data did not show a change over time between groups No differences in cognitive measures in favor of any stimulation condition could be observed Active tdcs was superior to sham tdcs in improving MCCB with the greatest improvement in the composite score and the domain scores for WM and attention-vigilance S104

11 NIBS for the Treatment of Cognitive Symptoms in Schizophrenia Table 1. Continued Summary of Results (Cognitive Measures) Cognitive Outcome Measures; Primary Outcome Yes/No NIBS Parameters; NIBS Device and Stimulation Site; Sham Parameters Study Design; Total Sample Size; Follow-up Period; Study Population Reference No differences in cognitive measures in favor of any stimulation condition could be observed. However, effect sizes indicate a numeric but nonsignificant superiority of active rtms in certain cognitive tests See Wobrock et al 7 Rey AVLT, TMT A and B, WCST, Digit Span Test, Regensburg Word Fluency Test, neuropsychological composite score; cognitive measures were Hasan et al 26 Double blind; sham-controlled parallel group study (N = 156; 77 active rtms); before and after 3, 6, and 12 wk; predominant negative symptoms (overlap to Wobrock et al 7 ) Note: AH, auditory hallucinations; AVLT, Auditory Verbal Learning Test; BACS, Brief Assessment of Cognition in Schizophrenia; CANTAB, Cambridge Neuropsychological Test Automated Battery; CPT, Continuous Performance Test; DLPFC, dorsolateral prefrontal cortex; EEG, electroencephalogram; FAS, Verbal Fluency Test (uses the letters F, A, and S); fmri, functional magnetic resonance imaging; HVLT, Hopkins Verbal Learning Test; K-AVLT, Korean versions of the Auditory Verbal Learning Test; MCCB, MATRICS Consensus Cognitive Battery; MMSE, Mini-Mental State Examination; MOT, Motor Screening Task; MT, motor threshold; NCT, Number Connection Test; NIBS, noninvasive brain stimulation; PRM, pattern recognition memory; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; RKMT, Rey-Kim Memory Test; RTI, reaction time; rtms, repetitive transcranial magnetic stimulation; RVP, rapid visual information processing; SANS, Scale for the Assessment of Negative Symptoms; SOC, Stockings of Cambridge; STG, superior temporal gyrus; SWM, spatial working memory; TAP, Test of Attentional Performance; TBS, theta burst stimulation; tdcs, transcranial direct current stimulation; TMT, Trail Making Test, version A or B; TPC, temporoparietal cortex; VFT, Verbal Fluency Task; WCST, Wisconsin Card Sorting Test; WM, working memory; WMS, Wechsler Memory Scale; WRAT-R, Wide Range Achievement Test-Revised. primary outcome was the mean magnitude of change in the n-back accuracy for target responses (verbal working memory). Active rtms improved 3-back target accuracy to a level comparable with the performance of a healthy control group in contrast to sham rtms (performance correct target responses: active rtms: pre: 40.06% ± 18.57%, post: 49.86% ± 23.50%; sham rtms: pre: 36.02% ± 24.34%, post: 33.33% ± 20.34%). However, no effect on 1- and 2-back, as well on correct responses to nontargets and on reaction time in responses to both targets and nontargets was observed. 47 Prikryl et al 44 applied 10 Hz rtms with 1500 stimuli to the left DLPFC for a treatment duration of 3 weeks. The authors did not describe the procedure to detect the left DLPFC and analyses did neither show differences in the performance of the silent phonemic Verbal Fluency Task (working memory) nor in fmri activation between groups. Smith et al 52 applied tdcs with 2 ma (EEG 10/20: anode F3, cathode FP2) for 5 days and used the MCCB performance as primary outcome. Active tdcs was superior to sham tdcs with regard to the overall MCCB performance (composite score, effect size: 1.03) and with regard to the domain scores for working memory (effect size: 1.25) and attention vigilance (effect size: 0.84). Finally, Levkovitz et al showed in an open-label pilot study of 15 schizophrenia patients with predominant negative symptoms that 20 Hz Deep-TMS (target region left DLPFC, 5 cm anterior left M1) improved rapid visual information processing, problem solving, spatial working memory, and spatial span length 40 (see table 1). Cognition as safety parameter was accessed in studies with a stimulation focus on the temporal lobe of the dominant hemisphere. Various cognitive measures were evaluated before and after intervention following possible concerns that temporal stimulation might disrupt cognitive functioning. In this context, no evidence was actually revealed that temporal stimulation disrupts cognitive functioning. 14,15,23,28,31,43,46 Discussion This is the first systematic review to investigate the impact of repetitive NIBS on different cognitive domains in schizophrenia patients. Following a standardized literature search and analysis, 76 full-text articles were assessed for eligibility and of these article, 33 studies were included in the qualitative synthesis. Remarkably, only 4 studies had different cognitive measures as primary making clear that the available evidence is very limited and that previous studies focused on the improvement of clinical symptoms. Different reviews are discussing possibilities and hypotheses to treat neurocognitive deficits in schizophrenia with NIBS (eg, Lett et al 6, Demirtas- Tatlidede et al 16 ), but until today the data basis for clear conclusions is still sparse. In principle, 2 different areas of interest need to be distinguished: (1) the possibility to S105