Cognitive functioning and deep transcranial magnetic stimulation (DTMS) in major psychiatric disorders: A systematic review

Accepted Manuscript Cognitive functioning and deep transcranial magnetic stimulation (DTMS) in major psychiatric disorders: a systematic review Karina Karolina Kedzior, Prof., Lioba Gierke, Helena Marie Gellersen, Marcelo T. Berlim PII:

S0022-3956(15)30033-9

DOI:

10.1016/j.jpsychires.2015.12.019

Reference:

PIAT 2790

To appear in:

Journal of Psychiatric Research

Received Date: 9 October 2015 Revised Date:

18 December 2015

Accepted Date: 18 December 2015

Please cite this article as: Kedzior KK, Gierke L, Gellersen HM, Berlim MT, Cognitive functioning and deep transcranial magnetic stimulation (DTMS) in major psychiatric disorders: a systematic review, Journal of Psychiatric Research (2016), doi: 10.1016/j.jpsychires.2015.12.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Cognitive functioning and deep transcranial magnetic stimulation (DTMS) in major psychiatric disorders: a systematic review Authors and affiliations: Karina Karolina Kedzior1*, Lioba Gierke1, Helena Marie Gellersen2, Marcelo T. Berlim3 Institute of Psychology and Transfer, University of Bremen, Bremen, Germany; 2School of

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Engineering and Science, Jacobs University Bremen, Bremen, Germany; 3Department of Psychiatry, McGill University, and Neuromodulation Research Clinic, Douglas Institute,

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Montreal, Canada *Corresponding author:

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Prof. Karina Kedzior De Santis, University of Bremen, Institute of Psychology and Transfer, Grazer Str. 2c, 28359 Bremen, Germany; Tel: +49-421-218-68720, E-mail: [email protected] Manuscript content:

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Word count: 218 abstract, 3124 (main text without abstract, references, tables, and figure) Figures and Tables: 1 figure, 3 tables

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Short title/running head: Cognition and DTMS

ACCEPTED MANUSCRIPT Abstract Deep transcranial magnetic stimulation (DTMS) is a non-invasive brain stimulation method mostly utilised in the treatment of major depression. The aim of the current study was to systematically review the literature on the cognitive effects of DTMS applied with the H-

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coil system in major psychiatric disorders. Following a literature search in PsycInfo and PubMed (any time to December 2015), 13 out of 32 studies on DTMS and cognitive functioning were included in the current review. Three studies included 38 healthy

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participants, eight studies included 158 unipolar or bipolar depression patients and two studies included 45 schizophrenia patients. Low-frequency DTMS (1-3 sessions) had little effect on

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cognitive functioning in healthy participants. The most consistent cognitive and clinical improvements were reported in the short-term (after 20 daily sessions of high-frequency DTMS with H1-coil) in studies with major depression patients. There was also a trend towards a short-term cognitive and clinical improvement in studies with schizophrenia

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patients. High-frequency DTMS might improve cognitive functioning and alleviate clinical symptoms in the short-term, particularly in major depression. However, this conclusion is based on data from mostly uncontrolled, open-label studies with patients receiving concurrent

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antidepressants or antipsychotics. Randomised, sham-controlled trials are needed to investigate the magnitude of the cognitive outcomes of DTMS in the short-term and beyond

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the daily stimulation phase in major psychiatric disorders.

ACCEPTED MANUSCRIPT Cognitive functioning and deep transcranial magnetic stimulation (DTMS) in major psychiatric disorders: a systematic review Abstract Deep transcranial magnetic stimulation (DTMS) is a non-invasive brain stimulation

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method mostly utilised in the treatment of major depression. The aim of the current study was to systematically review the literature on the cognitive effects of DTMS applied with the Hcoil system in major psychiatric disorders. Following a literature search in PsycInfo and

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PubMed (any time to December 2015), 13 out of 32 studies on DTMS and cognitive functioning were included in the current review. Three studies included 38 healthy

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participants, eight studies included 158 unipolar or bipolar depression patients and two studies included 45 schizophrenia patients. Low-frequency DTMS (1-3 sessions) had little effect on cognitive functioning in healthy participants. The most consistent cognitive and clinical improvements were reported in the short-term (after 20 daily sessions of high-

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frequency DTMS with H1-coil) in studies with major depression patients. There was also a trend towards a short-term cognitive and clinical improvement in studies with schizophrenia patients. High-frequency DTMS might improve cognitive functioning and alleviate clinical

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symptoms in the short-term, particularly in major depression. However, this conclusion is

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based on data from mostly uncontrolled, open-label studies with patients receiving concurrent antidepressants or antipsychotics. Randomised, sham-controlled trials are needed to investigate the magnitude of the cognitive outcomes of DTMS in the short-term and beyond the daily stimulation phase in major psychiatric disorders. Key Words: deep transcranial magnetic stimulation (DTMS); H-coil; cognition; major depressive disorder; schizophrenia; systematic review Introduction

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ACCEPTED MANUSCRIPT Brain stimulation methods have gained popularity and acceptance as promising nonpharmacological interventions to treat various psychiatric disorders. One example of such a method is a non-invasive, repetitive transcranial magnetic stimulation (rTMS), which has consistent antidepressant properties during and beyond the daily treatment phase (Berlim et

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al., 2014b; Kedzior et al., 2014; Kedzior et al., 2015c). RTMS is typically administered using figure-of-eight coils, which can stimulate selective, but relatively superficial, cortical regions (Zangen et al., 2005). A novel alternative to rTMS is a non-invasive, deep transcranial

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magnetic stimulation (DTMS), which is delivered using the H-coil system (Roth et al., 2002). Unlike the figure-of-eight coil, the H-coil stimulates wider, and presumably deeper, brain

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regions (Roth et al., 2014; Zangen et al., 2005). According to a randomised-controlled trial (RCT) (Levkovitz et al., 2015) and two meta-analyses (Kedzior et al., 2015a; Kedzior et al., 2015b), high-frequency DTMS appears to have short-term antidepressant and anxiolytic properties in the treatment of major depression. However, it remains unclear if this

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therapeutic intervention is also able to improve the cognitive impairments associated with major depression (Rock et al., 2014) and other psychiatric disorders. To date, only one systematic review (Minichino et al., 2012) addressed this issue. According to this review,

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high-frequency DTMS is associated with small, short-term improvements in sustained

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attention and cognitive planning as well as larger improvements in spatial and visuospatial memory based on data from two open-label studies including patients with treatmentresistant, medication-free, unipolar depression (Minichino et al., 2012). Similar conclusions regarding the putative cognitive effects of the conventional, high-frequency rTMS have been drawn in two other systematic reviews (Guse et al., 2010; Serafini et al., 2015). Indeed, both reviews reported consistent trends towards improvement in some cognitive functions, such as visuospatial memory and verbal memory, especially in studies including patients with major depression (Guse et al., 2010; Serafini et al., 2015). Given the growing interest in the

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ACCEPTED MANUSCRIPT application of DTMS in psychiatry and the increasing number of published studies, it is important to assess the magnitude of its cognitive effects. Therefore, the aim of the current study was to systematically review the literature on the cognitive effects of DTMS applied with the H-coil system in major psychiatric disorders.

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Material and methods

A systematic literature search was conducted in PsycInfo and PubMed databases from any date until December 7, 2015 (Table S1 in the online supplementary materials). A total of

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32 relevant studies (with terms “deep transcranial magnetic stimulation”, DTMS, or H-coil in titles and “cognitive” or “cognition” in text) were identified from the electronic search and

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the hand search of bibliographies of these relevant studies. Study selection

The detailed study selection procedure is summarised on the PRISMA flowchart (Moher et al., 2009) (Figure 1). Studies were excluded if they did not include patients with major

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psychiatric disorders (k=4), did not assess cognitive functioning (k=12), or did not report primary data (k=3 review articles). Thirteen studies (Berlim et al., 2014a; Bersani et al., 2013a; Harel et al., 2014; Harel et al., 2011; Harvey et al., 2015; Isserles et al., 2011; Krause

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et al., 2012; Levkovitz et al., 2009; Levkovitz et al., 2011; Levkovitz et al., 2007; Rabany et

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al., 2014; Rapinesi et al., 2015; Zangen et al., 2005) meeting the following criteria were included in the current review: • •

DTMS treatment applied using any parameters and any H-coil type; any cognitive function assessed at baseline and at the end of DTMS intervention and/or at follow-up;

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inclusion of clinical samples with major psychiatric disorders according to DSM-IV or ICD-10 and/or healthy controls. Insert Figure 1 about here

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ACCEPTED MANUSCRIPT Data coding The following data were extracted from each study: stimulation parameters, demographic data, clinical characteristics of patients and clinical outcomes (Table 1), cognitive assessment

Insert Table 1 about here Insert Table 2 about here Results

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Study and participant characteristics

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methods (cognitive functions tested and scales), and cognitive outcomes (Table 2).

The majority of the 13 studies were performed in Israel (k=7), where the DTMS system

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was developed, followed by Canada and Italy (k=2 each), and the USA and Australia (k=1 each; Table 1). Most studies with clinical samples have used open-label or single-blind designs and did not include sham-control groups (Table 1) except for one RCT with schizophrenia patients (Rabany et al., 2014). Three studies were case reports with one patient

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each (Table 1).

Of the 13 studies, 10 included clinical samples (eight studies with 158 unipolar or bipolar depression patients and two studies with 45 schizophrenia patients; Table 3). The remaining

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three studies included 38 healthy participants who received DTMS (other healthy control

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groups in studies with clinical samples did not receive DTMS). Participants in all studies were mostly middle aged (on average about 40-50 years old) and about half of them were female (Table 3). The majority of unipolar or bipolar depression patients (59%) received concurrent antidepressants and 88% were classified as treatment-resistant (Table 3). The overall dropout rate due to adverse effects was 5%. A total of 11 clinical patients (out of 241 participants in 13 studies) dropped out due to discomfort or intolerance, although seizures and suicidal ideation also occurred in seven out of 11 patients (Table 3). Insert Table 3 about here

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ACCEPTED MANUSCRIPT Stimulation parameters DTMS was delivered using various types of H-coils (with multiple coils being compared in some studies; Tables 1 and 3). The left prefrontal cortex was targeted using H1- or H1Lcoils in 11 studies. Bilateral stimulation of the prefrontal cortex (H2-coil) or the medial

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prefrontal cortex (Haut-coil) was performed in three studies. The motor cortex was stimulated using H-coil in one study. DTMS was most often applied as a high-frequency (18-20 Hz), high-intensity (110-120% of the resting motor threshold) paradigm with 20 daily sessions in

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studies with major depression or schizophrenia patients (Table 1). In contrast, healthy

participants received between 1-3 sessions of mostly low-frequency DTMS (Table 1).

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Cognitive outcomes

The cognitive outcomes in 13 studies are shown in Table 2. Several cognitive functions were investigated in these studies, including visuospatial and working memory, attention, executive functioning, psychomotor coordination, and cognitive speed. One study (Berlim et

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al., 2014a) assessed psychological quality of life (Table 2). Although different standardised scales were used to assess cognitive functioning, the most commonly used scale was the Cambridge Neuropsychological Test Automated Battery (CANTAB) (Table 2).

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Cognitive outcomes in studies with healthy participants

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Low-frequency DTMS treatment with 1-3 sessions had little effects on cognitive functioning in studies with healthy participants (Table 2). Specifically, cognitive abilities remained unchanged between baseline and immediately after the last DTMS in three studies with 38 healthy participants (Krause et al., 2012; Levkovitz et al., 2007; Zangen et al., 2005). Cognitive outcomes in studies with major depression and healthy control groups Compared to healthy controls, cognitive functioning tended to improve after 20 sessions of DTMS in studies with major depression patients (Table 2). Two studies reported that all cognitive domains were impaired in major depression patients compared to healthy controls

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ACCEPTED MANUSCRIPT at baseline (Harel et al., 2011; Levkovitz et al., 2009). Of these domains, visuospatial and working memory improved in major depression patients after DTMS (Harel et al., 2011; Levkovitz et al., 2009). The cognitive improvement was particularly evident in the study with 19 bipolar patients on concurrent antidepressants who were no longer cognitively impaired

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compared to 20 healthy controls (Harel et al., 2011). The second study showed that cognitive functioning improved particularly in groups stimulated with H1- and H1L coils targeting the left prefrontal cortex (Levkovitz et al., 2009).

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Cognitive outcomes in studies with major depression without healthy control groups Compared to baseline, several cognitive domains, including visuospatial and working

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memory, information processing speed, and orientation, as well as psychological quality of life, improved after 20 sessions of DTMS in five studies with 46 major depression patients without healthy control groups (Berlim et al., 2014a; Bersani et al., 2013a; Harvey et al., 2015; Isserles et al., 2011; Rapinesi et al., 2015). In contrast, one study reported no changes

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in cognitive functioning after 20 sessions of DTMS in 10 unipolar patients on concurrent antidepressants (Harel et al., 2014).

Cognitive outcomes in studies with schizophrenia patients

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Compared to baseline, executive functions, visuospatial memory, and sustained attention

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improved after 20 sessions of DTMS in one open-label study with 15 schizophrenia patients receiving concurrent antipsychotics (Levkovitz et al., 2011). Similarly, executive functioning also improved after 20 sessions of DTMS in one sham-controlled RCT (Rabany et al., 2014). However, this cognitive improvement was not related to DTMS alone because it was observed in the active DTMS and sham groups. Durability of cognitive outcomes Only limited follow-up data were reported to speculate about the durability (the length of persistence) of the cognitive effects of DTMS beyond the daily stimulation phase.

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ACCEPTED MANUSCRIPT Improvements in cognitive functioning tended to be maintained after daily DTMS for 1-2 weeks in both schizophrenia studies (Levkovitz et al., 2011; Rabany et al., 2014) and for one or three months after daily DTMS in two patients with unipolar or bipolar depression (Bersani et al., 2013a; Harvey et al., 2015).

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Clinical outcomes

Short-term antidepressant and anxiolytic effects of 20 sessions of DTMS were reported in all eight studies with unipolar or bipolar depression patients (Table 1). The majority of these

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patients were treated with concurrent antidepressants and were treatment-resistant (Table 3). Furthermore, negative symptoms also tended to be reduced after 20 sessions of DTMS in two

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studies with schizophrenia patients receiving concurrent antipsychotics (Levkovitz et al., 2011; Rabany et al., 2014). Although negative symptoms were reduced in the sham group in the RCT, the magnitude of reduction was larger in the active DTMS group which had a higher severity of negative symptoms at baseline (Rabany et al., 2014).

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Follow-up assessments were conducted at one to 18 weeks after daily DTMS in seven studies and data regarding the longer-term clinical outcomes were reported in four studies (including two case studies; Table 1). Reduction in negative symptoms in schizophrenia

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tended to be maintained for 2-4 weeks after daily DTMS (Levkovitz et al., 2011; Rabany et

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al., 2014), while antidepressant and anxiolytic effects were maintained in one bipolar depression patient three months after daily DTMS (Bersani et al., 2013a). In contrast, worsening in anxiety was observed in one patient with comorbid unipolar depression and mitochondrial myopathy one week after daily DTMS (Rapinesi et al., 2015). Discussion Results of the current study suggest that 20 sessions of high-frequency DTMS might improve cognitive deficits associated with major depression and, possibly, schizophrenia. In contrast, DTMS does not seem to affect cognitive functioning in healthy adults. Although

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ACCEPTED MANUSCRIPT these results are based on a qualitative synthesis of outcomes in mostly uncontrolled studies with relatively small samples, a consistent worsening of cognitive functioning was not observed after DTMS in any of the 13 studies included in the current review. Cognitive dysfunctions in domains of memory, attention, language, and executive

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functioning are chronic components of psychiatric disorders (Bersani et al., 2013b).

Therefore, effective therapies are required to simultaneously act on the cognitive and the psychopathological domains (Bersani et al., 2013b). Based on the current review, DTMS

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appears to be a promising candidate in this regard, especially in the treatment of major

depression. Compared to baseline or to healthy controls DTMS tended to improve a number

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of cognitive domains, including visuospatial and working memory, executive functions, information processing speed, orientation, as well as psychological quality of life in the shortterm (after 20 sessions) in patients with major depression. In addition to the cognitive improvements, short-term clinical effects (reduction in depression and anxiety symptom

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severity) of DTMS have also been demonstrated in studies with major depression patients (Kedzior et al., 2015a; Kedzior et al., 2015b). Similarly to DTMS, the conventional highfrequency rTMS also tended to improve several cognitive domains, including selective and

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sustained attention, working memory, verbal fluency, and executive functioning, in studies

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with major depression patients (Guse et al., 2010; Minichino et al., 2012; Serafini et al., 2015). In contrast, ECT tended to have transient detrimental effects on memory during shortterm treatment (Minichino et al., 2012) and during the subacute phase up to three days after treatment (Semkovska and McLoughlin, 2010). However, two weeks after ECT most cognitive functions either recovered to pretreatment levels or improved beyond baseline (Semkovska and McLoughlin, 2010) together with favourable clinical outcomes (Bersani et al., 2013b). Head-to-head RCTs with sham control groups are necessary to compare the cognitive and clinical effectiveness, safety and acceptability of ECT, rTMS, and DTMS in

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ACCEPTED MANUSCRIPT major depression. In contrast to depression studies, the cognitive and clinical outcomes of DTMS in schizophrenia are less consistent according to data from only two studies published to date (Levkovitz et al., 2011; Rabany et al., 2014). The current review shows that improvements in executive functioning and reduction in negative symptoms might not be

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attributable to DTMS alone because comparable effects were also evident in the inactive sham stimulation group (Rabany et al., 2014). Further research is required to test the clinical utility of DTMS with regards to other symptoms or subtypes of schizophrenia patients, such

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as those with positive symptoms.

It can be speculated that there is a causal relationship between the clinical and the

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cognitive improvements after brain stimulation. The improvement in both outcomes could be due to stimulation of putatively more widespread and deeper neural regions with DTMS compared to the conventional rTMS coils (Roth et al., 2014). However, the neural mechanisms of DTMS and rTMS are still largely unknown. It is also unclear which outcome

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drives the improvement in the other outcome. On the one hand, brain stimulation (such as DTMS) might improve cognitive functioning which subsequently leads to alleviation of clinical symptoms (Kedzior et al., 2012). Thus, the clinical effects could be secondary to

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improvements in various cognitive domains induced by direct modulation of frontostriatal

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pathways by DTMS (Levkovitz et al., 2009). An improvement in cognitive functioning could be associated with better quality of life, including improved personal relationships, social support, and sex life (Berlim et al., 2014a), which in turn could contribute to the alleviation of clinical symptoms. On the other hand, the alleviation of clinical symptoms with DTMS could drive the cognitive improvements in major depression (Levkovitz et al., 2009). Finally, the clinical and cognitive effects of brain stimulation could be independent from one another and mediated by different neural pathways (Kedzior et al., 2012). Indeed, it has been shown that some patients with major depression in clinical remission still exhibit cognitive impairments

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ACCEPTED MANUSCRIPT (Rock et al., 2014). Similarly, higher severity of depression symptoms was only moderately associated with diminished executive functioning (McDermott and Ebmeier, 2009). The clinical and cognitive improvements observed after high-frequency DTMS were also not correlated in the largest study (with 65 medication-free patients with unipolar depression)

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included in this review (Levkovitz et al., 2009). Similarly to DTMS research, studies with conventional rTMS coils show that the association between cognitive and clinical

improvement is ambiguous in major depression. Specifically, some studies show significant

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associations based on correlation and regression analyses while others report no difference in cognitive performance between responders and non-responders to rTMS (Serafini et al.,

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2015). Neural mechanisms of DTMS need to be investigated to better understand the direction of association (and putative causality) between clinical and cognitive improvements after DTMS in major psychiatric disorders.

Cognitive outcomes of brain stimulation might depend on the appropriate combination of

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coils and stimulation parameters according to the conventional rTMS research (Guse et al., 2010). A similar conclusion can be tentatively drawn based on results from DTMS studies included in the current review. Specifically, most consistent cognitive improvements were

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observed after 20 daily sessions of high-frequency (18-20 Hz) and high-intensity (120% of

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the resting motor threshold) DTMS with H1-coil in studies with major depression patients. Therefore, H1-coil, which produces an anterior-posterior electric field and induces stimulation mostly in the left prefrontal cortex (Levkovitz et al., 2007), might facilitate the cognitive improvement in major depression. In contrast, H1-coil with the same stimulation parameters as those used in major depression studies, might be less effective at improving cognitive functioning in schizophrenia patients with negative symptoms (Rabany et al., 2014).

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ACCEPTED MANUSCRIPT Due to the novelty of DTMS there are still insufficient data on the longer-term clinical and cognitive outcomes of this method beyond the daily stimulation phase. Preliminary data suggest that maintenance (continuation) treatment might prolong the short-term antidepressant effects of DTMS in major depression (Gellersen and Kedzior, 2015).

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Similarly, a maintenance protocol might also prolong the cognitive enhancement beyond the daily stimulation phase. More research is required to investigate the durability of the cognitive and clinical effects of DTMS with or without maintenance treatment.

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There were a number of limitations in this review. First, we did not perform a meta-

analysis because most studies did not report sufficient quantitative data. Instead of focusing

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on effect sizes, the current review summarises several cognitive outcomes tested using different instruments in underpowered studies with mostly low sample sizes. Quantitative data are necessary to compare DTMS outcomes in terms of effect sizes for individual cognitive functions. Second, most studies included in the current review were not blinded and

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did not include sham control groups. Therefore, some of the apparent cognitive improvements might have been secondary to increased expectations or other placebo effects. Although these effects cannot be eliminated in open-label designs, they might be comparable

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in magnitude to the effects observed in ‘real world’ patients who are aware of the treatment

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received. RCTs with sham control groups are required to quantify the cognitive effects of DTMS beyond the placebo effect. Third, since concurrent antidepressants or antipsychotics were used in most studies with clinical samples, the cognitive improvement could have been due to the combination of DTMS and pharmacotherapy. However, instead of improvement, some psychotropic medications could also impair cognitive functioning, such as attention (Serafini et al., 2015). Studies with medication-free patients are required to investigate the cognitive effects of DTMS as a monotherapy. Fourth, publication bias might have affected the current results. It cannot be ruled out that studies showing detrimental effects of DTMS

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ACCEPTED MANUSCRIPT on cognition were not published in peer-reviewed journals and, thus, were not included in the current review. Fifth, the improvement in cognitive functioning might have been partially due to practice (learning) effects. In general, it is difficult to eliminate practice effects in cognitive testing (Kedzior et al., 2011). It can only be assumed that, even if present, the impact of

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practice effects was relatively low due to the long time-lag between baseline and final

cognitive assessments in studies with DTMS administered for 20 daily sessions over the course of one month.

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Conclusions

High-frequency DTMS tends to improve cognitive performance particularly in studies

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with major depression patients. RCTs with sham control groups are required to assess the magnitude of cognitive effects of DTMS compared to placebo in major psychiatric disorders. Furthermore, durability of the cognitive effects needs to be investigated beyond the daily stimulation phase.

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function. J. Affect. Disord. 119, 1-8. Minichino, A., Bersani, F.S., Capra, E., Pannese, R., Bonanno, C., Salviati, M., Delle Chiaie, R., Biondi, M., 2012. ECT, rTMS, and deepTMS in pharmacoresistant drug-free patients with unipolar depression: a comparative review. Neuropsychiatr. Dis. Treat. 8, 55-64. Moher, D., Liberati, A., Tetzlaff, J., Altman, D., 2009. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. B. M. J. 339, b2535.

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ACCEPTED MANUSCRIPT Rabany, L., Deutsch, L., Levkovitz, Y., 2014. Double-blind, randomized sham controlled study of deep-TMS add-on treatment for negative symptoms and cognitive deficits in schizophrenia. J. Psychopharm. 28, 686-690. Rapinesi, C., Janiri, D., Kotzalidis, G.D., Serata, D., Del Casale, A., Scatena, P., Dacquino,

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C., Gentile, G., Manfredi, G., Danese, E., Raccah, R.N., Brugnoli, R., Callovini, G., Ferri, V.R., Ferracuti, S., Zangen, A., Simmaco, M., Angeletti, G., Girardi, P., 2015.

Mitochondrial myopathy and comorbid major depressive disorder: Effectiveness of dtms

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on gait and mood symptoms. Gen. Hosp. Psychiat. 37, 274.e277-279.

Rock, P.L., Roiser, J.P., Riedel, W.J., Blackwell, A.D., 2014. Cognitive impairment in

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depression: a systematic review and meta-analysis. Psychol. Med. 44, 2029-2040. Roth, Y., Pell, G.S., Chistyakov, A.V., Sinai, A., Zangen, A., Zaaroor, M., 2014. Motor cortex activation by H-coil and figure-8 coil at different depths. Combined motor threshold and electric field distribution study. Clin. Neurophysiol. 125, 336-343.

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Roth, Y., Zangen, A., Hallett, M., 2002. A coil design for transcranial magnetic stimulation of deep brain regions. J. Clin. Neurophysiol. 19, 361-370. Semkovska, M., McLoughlin, D.M., 2010. Objective cognitive performance associated with

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electroconvulsive therapy for depression: a systematic review and meta-analysis. Biol.

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Psychiatry 68, 568-577.

Serafini, G., Pompili, M., Belvederi Murri, M., Respino, M., Ghio, L., Girardi, P., Fitzgerald, P.B., Amore, M., 2015. The effects of repetitive transcranial magnetic stimulation on cognitive performance in treatment-resistant depression. A systematic review. Neuropsychobiology 71, 125-139. Zangen, A., Roth, Y., Voller, B., Hallett, M., 2005. Transcranial magnetic stimulation of deep brain regions: evidence for efficacy of the H-coil. Clin. Neurophysiol. 116, 775-779.

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Healthy (N=6)

No adverse-effects

27

56

Healthy (N=16)

No adverse-effects

27

62

Healthy (N=16)

No adverse effects

Single-blind, placebo-controlled, crossover study

46

53

MDD (N=64) Antidepressant-free TRD

No adverse-effects; Short-term antidepressant and axiolytic effects

58

BPD I or II (N=19) On antidepressants

No adverse-effects; Short-term antidepressant and axiolytic effects

Open-label study, randomised study with 4 groups with different treatment configurations (stimulation intensity, laterality); healthy controls (N=20; no DTMS) Open-label study (short-term assessment one week after the last DTMS); healthy controls (N=20; no DTMS)

Dropouts: 1 seizure, 5 suicidal ideation, 2 discomfort/ intolerance; Short-term antidepressant and axiolytic effects No adverse effects; Short-term antidepressant and axiolytic effects maintained at follow-up Dropouts: 2 scalp discomfort; Short-term antidepressant and axiolytic effects No adverse effects; Short-term antidepressant and axiolytic effects

3

1

-

1

42

20

20

1680

42

Studies with major depression patients without healthy controls (k=6) Isserles et al., 2011; H1 20 120 33600 1680 Israel

42

20

20

45

20

20

44

47

MDD (N=45) On antidepressants TRD

H1

18

120

Berlim et al., 2014a; Canada

H1

20

120

Harel et al., 2014; Israel

H1

20

120

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Bersani et al., 2013a; Italy

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42

20

60000

3000

75

20

20

47

76

33600

1680

42

20

20

41

48

55

20

46

0

BPD I (N=1) Antidepressant-free TRD MDD (N=17) On antidepressants TRD MDD (N=29) On antidepressants TRD

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Dropouts due to adverse effects of DTMS Clinical outcomes

Study design

Participant type Diagnosis (DSM-IV, ICD-10) Medication Treatment resistance (TRD)

33

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% female at baseline

33600

Mean age at baseline

120

No. of sessions

20

36

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H1

1

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Studies with healthy participants (k=3) Zangen et al., 2005; H 1 pulse USA Levkovitz et al., H1, 1 pulse/day 1; 110 2007; Israel H2a 10 Hz/day 3; 20Hz/day 5 Krause et al., 2012; Haut 1 100 900 900 Australia Studies with major depression patients compared to healthy controls (k=2) Levkovitz et al., H1, 20 110 33600 1680 2009; Israel H2, 120 H1L

Harel et al., 2011; Israel

Inter-train interval (s)

Trains/session

Stimuli/session

Total stimuli

Intensity (% MT)

Frequency (Hz)

Coil type

Study (by year and first author); country

Table 1. Stimulation parameters, demographic and clinical characteristics of participants in k=13 studies

Open-label study (measured motor threshold with H-coil and F8 coil) Randomised study with 4 groups: H1, H2, F8, sham-coils

Open-label study, 3 groups (positive, negative, no emotional priming), N=26/45 completed cognitive assessments after 20 DTMS sessions Case study

Open-label study

Open-label study; cognitive functioning assessed in N=10 patients

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120

Rapinesi et al., 2015; Italy

H1

18

120

Studies with schizophrenia patients (k=2) Levkovitz et al., H1 20 2011; Israel

H1

20

120

33600

3024

1680

MDD, Anxiety disorder (N=1) On antidepressants TRD MM, MDD, Anxiety (N=1) On antidepressants TRD

No adverse effects; Short-term antidepressant and axiolytic effects

Case study

No adverse effects; Short-term antidepressant and axiolytic effects (although worsening of anxiety 1 week after DTMS)

Case study

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Schizophrenia (N=15) On antipsychotics

30

Schizophrenia (N=20 active DTMS, N=10 sham) On antipsychotics

Dropout: 1 seizure; Short-term negative symptom reduction maintained at 2-week post-DTMS follow-up Reasons for dropouts unclear; Short-term reduction in negative symptoms in active DTMS group but no difference from sham (active group more severe negative symptoms than sham at baseline and 4-week follow-up)

84

20

20

52

100

55

20

20

67

100

42

20

20

33

42

20

20

34

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Rabany et al., 2014; Israel

120

60480

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H1

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Harvey et al., 2015; Canada

Open-label study

Double-blind, randomised, sham controlled study

Notes. Magstim Super Rapid stimulator and Brainsway H-coils were used in all studies. Abbreviations: BPD, bipolar disorder; DTMS, deep

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transcranial magnetic stimulation; F8, conventional figure-of-eight coil; H, H-coil types (H, H1, H1L, H2, or Haut coils); k, number of studies; MDD, major depressive disorder or episode; MM, mitochondrial myopathy; MT, resting motor threshold (stimulation intensity); N, number of

Data from the F8 coil and the sham H-coil groups are not included in the current study.

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participants; TRD, treatment resistance (failed or intolerant to two antidepressants or antidepressant trials in current episode).

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Table 2. Cognitive effects of DTMS in k=13 studies Cognitive outcomes (short-term) -/0/+a Conclusions from individual studies

Follow-up length

Cognitive outcomes (follow-up)

CalCap

0

No change in cognitive abilities

N/A

N/A

CANTAB

-/0/+

No deterioration in cognitive functions, except for a transient reduction in short-term effect on spatial recognition memory (1st day of DTMS) in H1 coil group; SWM significantly improved in H2 coil group

N/A

N/A

Yoni Task

0

No difference in cognitive performance on the Yoni Task (accuracy or reaction times) between sham and active DTMS conditions

N/A

N/A

+

Baseline: significant deficits in sustained attention, visuospatial and working memory, psychomotor speed (patients vs. controls). After 20 DTMS sessions vs. baseline (patients only): significant improvement in sustained attention, visuospatial and working memory, and executive functioning (SOC), although some functions still significantly reduced compared to controls Best cognitive outcomes observed in H1- and H1L-120% groups Baseline: significant deficits in all functions (patients vs. healthy). After 20 DTMS sessions: visuospatial and working memory and psychomotor speed no longer reduced (patients vs. healthy)

3 months

N/A

N/A

N/A

Memory and information processing speed significantly improved after 20 sessions of DTMS compared to baseline (other cognitive functions did not change compared to baseline) MMSE scores progressively increased, mainly due to improved orientation

1 month

N/A

3 months

Significant improvement in psychological quality of life after 20 sessions of DTMS vs. baseline No significant differences were found between baseline and end of daily stimulation phase

N/A

No difference in MMSE scores between last and last follow-up sessions N/A

18 weeks maintenance

N/A

Improved accuracy on the task (from 79% at baseline to 96% after 20 sessions of DTMS), increased activity in the working memory network according to fMRI

1 month

Better cognitive performance compared to baseline

Psychomotor speed (RTI) Visuospatial memory (SWM, PAL) Sustained attention (RVP) Executive functions (SOC)

Berlim et al., 2014a Harel et al., 2014

MDD (N=17) MDD (N=10)

Harvey et al., 2015

MDD, Anxiety (N=1)

Psychological quality of life

Psychomotor speed (RTI) Problem solving (SOC) Sustained attention (RVP) Memory (PRM, SWM, SSP, SRM) Working memory

0/+

Mindstreams Cognitive Battery

0/+

MMSE

+

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Studies with major depression patients without healthy controls (k=6) Isserles et al., MDD Memory; Executive, visuo-spatial, 2011 (N=26) verbal functions; Attention; Information processing speed; Psychomotor speed Bersani et al., BPD Type I Cognitive effects 2013a (N=1)

CANTAB

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BPD (N=19) vs. healthy (N=20; no DTMS)

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Harel et al., 2011

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Studies with major depression patients compared to healthy controls (k=2) Levkovitz et al., MDD (N=64) Psychomotor speed (RTI) CANTAB Visuospatial memory (SWM, PAL) 2009 vs. healthy (N=20; no Sustained attention (RVP) DTMS) Executive functions (SOC, SSP)

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Scales

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Study (by year, Participants Functions assessed first author) (diagnosis) Studies with healthy participants (k=3) Zangen et al., Healthy Immediate and delayed memory 2005 (N=6) Levkovitz et al., Healthy Psychomotor speed (RTI) 2007 (N=16) Visuospatial memory (SRM, SWM, PRM) Sustained attention (RVP) Executive functions (SOC, SSP) Krause et al., Healthy Cognitive Theory of Mind 2012 (N=16)

WHOQOLBREF CANTAB

+

n-back task

+

0

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Studies with schizophrenia patients (k=2) Levkovitz et al., Schizophrenia Visuospatial memory (SRM, 2011 (N=15) SWM) Sustained attention (RVP) Executive functions (SOC, SSP)

Rabany et al., 2014; Israel

Schizophrenia (N=30)

Visuospatial memory (PRM, SWM) Sustained attention (RVP) Executive functions (SOC)

+

Executive functions tests, Wisconsin Card Sorting Test CANTAB

+

CANTAB

0/+

Baseline: deficits in the long-term visuospatial memory, cognitive processing speed, and flexibility deficits on the Wisconsin Card Sorting Test After 20 DTMS sessions: no deficits in cognitive functions, improvements on executive function tests and on cognitive speed

N/A

N/A

Improvement in cognitive deficits in frontal and frontoparietal-related tasks- executive functions (SOC, SSP, SWM) and sustained attention (RVP). No improvement in cognitive functions associated with striatal and parietal areas (intra-/extra-dimensional set shift, spatial recognition memory) No differences between active DTMS and sham groups from baseline to session 20. SOC significantly improved in both groups from baseline to session 20

2 weeks

Cognitive improvement in rapid visual processing was maintained at follow-up

1 and 4 weeks

Cognitive data reported at 1week follow-up only; Improvement in SOC maintained in both groups

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Verbal memory, language motor-planning, long-term visuospatial memory, cognitive processing speed, executive functioning

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MM, MDD, Anxiety (N=1)

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Rapinesi et al., 2015

Note. Abbreviations: DTMS, deep transcranial magnetic stimulation; CANTAB, Cambridge Neuropsychological Test Automated Battery; fMRI, functional magnetic resonance imaging; k, number of studies; MM, mitochondrial myopathy; MMSE, Mini Mental State Evaluation; N, number

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of participants; N/A, not assessed or not reported; PAL, paired associative learning (total errors); PRM, pattern recognition memory; RTI, reaction time (psychomotor speed: five choice reaction time or movement time or latency); RVP, rapid visual information processing (test A);

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SOC, Stockings of Cambridge Test (cognitive planning: problems solved in minimum moves); SRM, spatial recognition memory; SSP, spatial

Version. a

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memory span; SWM, spatial working memory (between errors); WHOQOL-BREF, World Health Organization’s Quality of Life Measure- Brief

Cognitive outcomes after the last daily session of DTMS: +, improvement; -, worsening; 0, no effect on cognition.

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ACCEPTED MANUSCRIPT Table 3. Synthesis of stimulation parameters and participant characteristics in k=13 studies Stimulation parameters/demographics

k=13 studies Mode H1 20 Hz 120% 1680 33600 42 20 s 20 46 47-58% k studies (% of 13)

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Coil type Frequency (Hz) Intensity (% resting motor threshold) Stimuli/session Total stimuli Trains/session Inter-train interval (s) Number of sessions Mean age Gender (% female) Participant characteristics

Range H1, H1L, H2, H, Haut 1-20 Hz 100-120% 900-3024 900-60480 1-84 20 s 1-20 27-67 0-100% N participants (% of 241)

Total participants all studies at baseline Healthy Unipolar/bipolar depression Schizophrenia Dropout rate due to adverse effects Reasons for dropouts: Seizure Suicidal ideation Discomfort/intolerance Clinical characteristics in depression studies

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k=3 (23%) k=8 (62%) k=2 (15%)

k studies (% of 8)

N=241 N=38 (16%) N=158 (66%) N=45 (19%) N=11 (5%)

N=2 N=5 N=4 N patients (% of 158)

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Unipolar/bipolar depression patients N=158 On concurrent antidepressants k=6 (75%) N=93 (59%) Antidepressant-free k=2 (25%) N=65 (41%) Treatment-resistant k=7 (88%) N=139 (88%) Note. Abbreviations: DTMS, deep transcranial magnetic stimulation; k, number of studies; N,

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number of participants

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ACCEPTED MANUSCRIPT Figure 1. PRISMA flowchart

SCREENING

k=32 studies (duplicates excluded)

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IDENTIFICATION

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k=1 published studies from hand search

k=44 published studies from electronic database search

k=7 studies excluded: • k=4: other primary diagnosis (aphasia, Tourette’s syndrome, Parkinson’s disease) • k=3: review (no new data)

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k=32 studies (titles/abstracts) screened

k=25 full-text studies assessed

INCLUDED

k=13 included in the qualitative synthesis

k=12 studies excluded: • k=12: cognitive functioning not assessed

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ELIGIBILITY

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Note. Abbreviations: DTMS, deep transcranial magnetic stimulation; k, number of studies.

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ACCEPTED MANUSCRIPT Highlights DTMS improved cognitive functioning particularly in major depression.

•

Cognition improved after 20 high-frequency DTMS sessions with H1-coil.

•

Cognitive functioning was not affected by DTMS in healthy participants.

•

These results are based on data from 13 studies with 241 participants.

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•

ACCEPTED MANUSCRIPT Conflict of Interest Dr. Kedzior, Ms. Gierke, and Ms. Gellersen have nothing to disclose. Dr Berlim has received a researcher-initiated grant from Brainsway, Inc., to study the neural basis of DTMS in MDD

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using neuroimaging.

ACCEPTED MANUSCRIPT Authors’ contributions KKK and HMG conceptualised the study; LG and KKK performed the search; KKK, LG, HMG assessed the studies and extracted data; all authors contributed to writing of the

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manuscript.

ACCEPTED MANUSCRIPT Role of funding source

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There was no external funding for this study.

ACCEPTED MANUSCRIPT Acknowledgements

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None.