Effects of Transcranial Magnetic Stimulation on Motor Symptoms of Patients With Psychiatric Disorders
Phase: NA
Conditions: Psychomotor Retardation, Psychomotor Slowing, Schizophrenia and Related Disorders, Major Depressive Disorder
Sponsor: University of Bern

Effects of Transcranial Magnetic Stimulation on motor symptoms of 
patients with psychiatric disorders 
 
Study Protocol/ Version 4 
 
Trial Registration (Art. 64, KlinV) in Swiss National Clinical Trial Portal (KOFAM): SNCTP610 
Ref.-Nr KEK-BE: 060/2014 
20.05.15 
 
Principle Investigator: 
PD Dr. med. S. Walther 
Universitätsklinik für Psychiatrie und Psychotherapie 
Bolligenstrasse 111 
3000 Bern 60 
Tel.: +41 31 930 9404 
Email: walther@puk.unibe.ch 
 
Further investigators: 
Georgios Schoretsanitis, Katharina Stegmayer 
 
 
 
 
 
 
 
 
 

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Signatures  
Date: 
 
Signature: 
 
 
 
 
 
PD Dr. med. Sebastian Walther 
Universitätsklinik für Psychiatrie und Psychotherapie 
Bern 
 
Date: 
 
Signature: 
 
 
 
Georgios Schoretsanitis 
Universitätsklinik für Psychiatrie und Psychotherapie 
Bern 
 
Date: 
 
Signature:  
Katharina Stegmayer 
 
Universitätsklinik für Psychiatrie und Psychotherapie 
Bern 
 
 
 
 
 
 

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Structure and content of the study protocol 
1 
Title of study 
2 
Background information of Transcranial Magnetic Stimulation (TMS) 
2.1 
Description and indication of TMS 
2.2 
Reason for the dosage and dosage plan and the length of TMS trial 
 3 
Objectives and purpose  
3.1 
Background, reason for the study and objective of the study 
3.2 
Research Questions, study population 
3.3 
Study Hypothesis  
4 
Study Design 
4.1 
Targeted primary end point and secondary end points (effectiveness and safety parameters) 
4.2 
Specification of the parameter that is of primary interest and other parameters that will be assessed 
as additional, secondary end points 
4.3 
Study design, tabular overview, course of the study, study duration (for each participant), break-
off criteria and procedure for unblinding 
4.4. 
Measures to minimize bias risk 
5 
Selection of participants 
5.1 
Subject Recruitment 
5.2 
Inclusion criteria 
5.3 
Exclusion criteria 
6 
Assessment of effectiveness 
6.1 
Effectiveness parameters: measuring methods and reference dates 
7 
Assessment of safety 
7.1 
Safety parameters: measuring methods and times 
7.2 
Guarantee of follow-up examination of patients in case of adverse reactions 
8 
Statistics 
8.1 
Definition of the primary end point and secondary end points  
8.2 
Planned number of trial subjects with clearly stated justification (power analysis) 
8.3 
Description of the statistical methods foreseen and the planned intermediate assessments 
8.4 
Planned significance level  
8.5 
Handling of missing data, dropout cases  

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Study-specific safety precautions and responsibilities 
9.1 
Safety precautions  
9.2 
If appropriate: exit examination in case of dropout 
10.  
Duties of the investigator 
10.1 
Confirmation that the conduct of the study will be in accordance with the GCP protocol, the 
current legal regulations and rights 
10.2 
Adverse reactions, protocol changes, other changes, progress report and final report 
10.3 
Statement of arrangements to cover damages  
11 
11.1 
11.2 
Ethical considerations 
Potential risks/ benefits balance  
Benefits for the participants 
12. 
Quality control and quality assurance: description of measures 
12.1 
Warranty to access to original data, permission of audits and monitoring by authorities, Ethic 
Committee and quality control 
 
12.2 
12.3 
Handling of data and samples, archiving and destruction  
Data collected specifically for the study 
 
References 
 
1. Title of the study: Effects of Transcranial Magnetic Stimulation on motor 
symptoms of patients with psychiatric disorders 
2. Background information of Transcranial Magnetic Stimulation (TMS) 
2.1. Description and indication of TMS 
Transcranial magnetic stimulation (TMS) was introduced as a non-invasive tool for 
the investigation of the motor cortex allowing the modulation of human cortical 
excitability. Furthermore TMS was used as a brain mapping tool, mostly combined 
with other brain mapping techniques and as a probe of neuronal networks. Its 
repetitive application (rTMS), with longer lasting effects, was used to study the 
influence on a variety of cerebral functions and tested as an add-on therapy for 
psychiatric disorders. Initially applied in patients suffering from major depressive 
disorder (MDD), it was soon tested for patients in treating auditory verbal 
hallucinations, negative symptoms of schizophrenia, obsessive-compulsive disorder, 
post-traumatic stress disorder and other mental health disorders (Slotema et al., 2011). 
In the last decade researchers proceeded assessing the effects of TMS on particular 
symptoms, e.g. cognitive disturbances or auditory verbal hallucinations (Guse et al., 
2010; Slotema et al., 2011). 

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Although TMS triggers action potentials in cortical neurons, especially in 
superficial parts of the cerebral cortex using a rapidly changing magnetic field to 
induce brief electric current pulses (Siebner et al., 2009), its efficacy may not be 
restricted to the effects under the directly stimulated area, but also due to the 
secondary affection of subcortical areas. The various effects include the modification 
of cerebral blood flow, glucose metabolism and neuronal excitability in the stimulated 
area as well as in interconnected brain regions (Fox et al., 1997; Conca et al., 2002). 
Moreover, studies reported changes of synaptic potentiation and rapid dynamic 
alterations in gray matter density are reported (Esser et al., 2006; May et al., 2007).  
A variety of methods has been used to measure the neurobiological effects of 
TMS on the brain. Several studies employed single photon emission computerized 
tomography (SPECT) to quantify changes in brain perfusion during and after TMS. 
The combination of TMS and positron emission tomography (PET) allowed the study 
of connectivity of the human cerebral cortex. Electroencephalogram (EEG) is yet 
another variable that can be recorded before, during or/and after TMS sessions 
offering unique insights into the speed of neuronal conduction within and between the 
two hemispheres (Paus, 1999). 
Stimulation frequencies range from ‘low frequency’ (1 Hz) to ‘high 
frequency’ (5- 20 Hz). The application of repeated pulses at low frequencies leads to 
suppression of the underlying cortical activity, while high-frequency is thought to 
have a stimulating effect (Gershon et al., 2003; Fox et al., 2012). Although several 
studies failed to demonstrate statistical differences between lower and higher 
frequency simulation groups (Loo & Mitchell, 2005). Another critical TMS parameter 
is the stimulation intensity, the calculation of which is based on the motor threshold 
(the lowest stimulation intensity demanded to induce muscle contractions, most 
usually abductor pollicis brevis twitches in at least 5 of 10 consecutive trials). The 
effects of subthreshold rTMS appear to be more local, in contrast to suprathreshold 
rTMS, which results in more distant transsynaptic effects (Schutter & van Honk, 
2005). The design of many TMS efficacy studies includes a sham condition, which is 
supposed to produce a negligible cortical stimulation. However, an important number 
of various sham conditions have been found to have a substantially stimulating effect 
on motor and premotor cortices (Loo et al., 2000; Lisanby et al., 2001). This may 
explain the considerable variability in effect sizes across sham controlled studies.  
The implementation of TMS in human brain mapping opened up new 
possibilities to probe causality at the systems level of sensory, cognitive, and motor 
brain networks enabling its application as a reliable diagnostic tool. Quite common is 
the use of TMS in creating temporary, virtual brain “lesions” by reversibly disrupting 
the normal functioning of the targeted cortical area. The application of TMS during 
various experimental tasks (online TMS) enables causal inferences regarding the 
functional contribution of the stimulated cortex to a specific brain function to be made 
(Walsh et al., 1998; Robertson et al., 2000). Due to the high temporal resolution of 
single-pulse TMS, the latter can be moreover exploited to identify critical time 
intervals during which the targeted area and interconnected brain regions contribute to 
the experimental task (Pascual-Leone et al., 2000). Especially the contribution of 
combinations of TMS with neuroimaging approaches in tracing the temporospatial 
dynamics of causal interactions within functional brain networks has been 
fundamental (Siebner et al., 2009).  
 
2.2. Reason for the dosage and dosage plan and the length of TMS trial  
 

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The effect of TMS varies and depends on the applied protocol. Stimulation studies in 
healthy subjects indicated the particular specificity of the dorsolateral prefrontal 
cortex (DLPFC), SMA and preSMA. The left DLPFC has been highlighted for its 
involvement in the regulation of positive and negative emotion as well as executive 
function. The importance of this area in cognitive functions and modulation of limbic 
activity may be attributed to its extensive connectivity to cortical and subcortical 
circuits (Schutter & van Honk, 2005; Fox et al., 2012). Alternative brain regions to 
stimulate include Supplementary Motor Area (SMA) and Presupplementary Motor 
Area (pre-)SMA (Rochas et al., 2012; Obeso et al., 2013). These brain areas are 
centrally involved in motor planning and processing (Goldberg, 1985; Tanji, 1994; 
Boylan et al., 2001) and belong to motor pathways, the alteration of which was 
correlated with decreased levels of motor activity in schizophrenia and MDD (Bracht 
et al., 2012; Bracht et al., 2013). However, the two areas are not densely 
interconnected and get activated during different tasks. The decidedly differentiated 
subcortical projections to the two areas led Akkal et al. (2007) to hypothesize that the 
two areas are nodes in distinct neural systems. SMA projects predominantly to 
primary motor cortex (Arai et al., 2012) and is more activated in movement 
generation and control, while pre-SMA, which is densely interconnected with regions 
of prefrontal cortex, is pronouncedly activated during nonmotor, cognitive tasks 
(Akkal et al., 2007; Lawrence et al., 2009).  
 
TMS in Major Depressive Disorder (MDD)/Schizophrenia  
The consistent findings of meta-analyses detected a significant antidepressant effect 
of high frequency repetitive transcranial stimulation of dorsolateral prefrontal cortex 
(DLPFC) (Slotema et al., 2011; Berlim et al., 2013). In schizophrenia, low frequency 
TMS over left temporoparietal cortex showed moderate effect in treating auditory 
verbal hallucinations, while left dorsolateral prefrontal cortex stimulation was used in 
the treatment of negative symptoms (Slotema et al., 2011). 
 
The effect of TMS on psychomotor retardation (PR) 
Previous high frequency TMS trials at DLPFC displayed significant positive effects 
on psychomotor performance in patients with MDD or schizophrenia. In the study of 
Huber et al. (2003), women with schizophrenia demonstrated a significant 
improvement in the Number Connecting Test performance. Hausmann et al. (2004) 
detected a significant effect of TMS on psychomotor performance assessed by the 
Trail Making Test, a dot connecting test, in patients with MDD. Furthermore, Martis 
et al. (2003) demonstrated that patients with MDD treated with TMS displayed a 
significant improvement in fine motor activity, while Baeken et al. (2010) detected a 
significant improvement of the psychomotor symptoms assessed by a validated rating 
instrument, the Depression Retardation Rating Scales (DRRS) in patients with MDD. 
However, there is conflicting evidence from numerous high-frequency rTMS 
studies on the left DLPFC, which failed to detect effects on psychomotor function 
(Rollnik et al., 2000; Loo, 2001; Speer et al., 2001; Moser et al., 2002; Hoeppner et 
al., 2003; Fabre et al., 2004; Sachdev et al., 2005; Schulze-Rauschenbach et al., 2005; 
Avery et al., 2006; Ulrich et al., 2012; Schrjivers et al., 2012). The heterogeneity of 
findings is probably due to heterogeneous assessment methods and study samples. 
Next, studies are required to disentangle pathophysiologic mechanisms of 
psychomotor retardation in schizophrenia and MDD. Furthermore, potentially 
effective TMS stimulation protocols need to be tested. Thus, we aim to test the short-

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term effects of three different active TMS protocols and one sham protocol on 
psychomotor retardation applying different TMS locations and stimulation modes. 
 
TMS Protocol 
Patients with psychomotor retardation will be randomly assigned to four groups 
receiving sessions of TMS of different stimulation parameters in order to test 
pathophysiologic mechanisms underlying psychomotor retardation. The choice of 
stimulation parameters is based on protocols of previous studies with highly 
beneficial findings. The accurate definition of the location of the stimulation sites will 
follow the 10/20 System (Jasper, 1958), an international method serving primarily the 
application of Electroencephalography (EEG). The use of the 10/20 system for the 
placement of TMS electrodes is common among TMS studies (Herwig et al., 2003; 
Schutter & van Honk, 2006; Griskova et al., 2007). In all cases stimulation will be 
delivered using a figure eight coil, except sham condition where a placebo coil, 
identical to the normal coil will be used. The four different stimulation conditions 
include:  
1) 15 Hz left dorsolateral prefrontal Cortex (DLPFC) repetitive TMS. Twenty 5-s 
trains with a 60-s interval between, giving 1500 TMS pulses per session at intensity 
100%  of the active motor threshold (AMT). TMS will be delivered using a figure-
eight coil. As mentioned above, there is a considerable number of previous high 
frequency TMS trials at this site with significant effects on the psychomotor 
performance (Huber et al., 2003; Hausmann et al., 2004; Martis et al., 2003; Baeken 
et al., 2010). The rTMS protocol that will be used derives from the study of 
Hernández-Ribas et al. (2013), which detected a significant antidepressant effect of 
high frequency TMS over DLPFC.  
2) 1 Hz SMA/ pre- SMA rTMS. A single continuous session with 1,000 pulses was 
performed at intensity 110% of the AMT using a circular coil (approximate duration 
17 minutes). Low frequency rTMS has been demonstrated to decrease motor cortex 
excitability, the motor consequences of which are still to be unraveled. Moreover, low 
frequency rTMS has shown a highly beneficial effect on motor symptoms in patients 
with Parkinson Disease (PD) (Shirota et al., 2013). We will use the stimulation 
protocol of the study of Shirota et al. (2013).  
3) Supplementary Motor Area (SMA)/ Presupplementary Motor Area (pre-)SMA 
intermittent Thetaburst Stimulation (iTBS). Three pulses of stimulation are given at 
50 Hz, 80% of AMT, repeated every 200 ms. 2 s trains are repeated every 10 s for a 
total of 190 s (600 pulses, 200 seconds). iTBS is a modality of stimulation eliciting an 
excitatory effect on cortical excitability, applied primarily in patients with multiple 
sclerosis or post-stroke implications with beneficial findings. The findings of studies 
assessing the effect of iTBS over SMA on psychomotor performance in healthy 
individuals and patients with Parkinson Disease have been encouraging (Dusek et al., 
2011; Ilic et al., 2012). We will apply the widely used protocol of the study of Huang 
et al. (2005).  
4) Sham stimulation over occipital cortex. In this group a placebo coil, similar to the 
real one will be used. According to the review of Loo et al. (2000) sham conditions 
including various coil positions have displayed a significant effect in many cases. 
Based on these findings, we chose to use a placebo coil over a different stimulation 
area expecting a negligible stimulation effect.  

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The MagVenture TMS device that will be used is CE-marked for use in 
patients (CE 0543). Regardless of the type and the frequency of TMS, the stimulation 
protocol will consist of 15 daily sessions during a 3 week period. 
 
3. Objectives and purpose 
Summary of the project 
Background Motor symptoms are common among schizophrenia and affective 
disorders and may have significant clinical and therapeutic implications. Transcranial 
magnetic stimulation (TMS) was introduced as a non-invasive tool for the 
investigation of the motor cortex allowing the modulation of human cortical 
excitability, as it triggers action potentials in cortical neurons using a rapidly changing 
magnetic field to induce brief electric current pulses (Siebner et al., 2009). Its 
secondary effects include modification of cerebral blood flow and glucose metabolism 
in the stimulated area as well as in interconnected brain regions (Fox et al., 1997; 
Conca et al., 2002). Despite the widely accepted inclusion of TMS in the toolbox of 
psychiatric treatment methods, little is known about the effect of TMS sessions on 
motor abnormalities. 
Aim The aim of the study is to investigate the effect of TMS at different brain areas 
on motor functioning in patients with schizophrenia or major depressive disorder 
(MDD) displaying motor abnormalities. The areas we chose to stimulate, based on an 
extensive body of research, include Dorsolateral Prefrontal Cortex (DLPFC) and 
Supplementary Motor Area (SMA)/ Presupplementary Motor Area (pre-) SMA.  
Hypothesis We hypothesize that patients with motor abnormalities receiving different 
configurations of TMS will demonstrate an improvement of motor performance. 
Across diagnoses, patients with motor retardation will benefit from inhibitory 
stimulation over SMA/preSMA. 
Methods The study design is a single site four arm randomized, sham-controlled trial 
to unravel the pathophysiology of psychomotor retardation. 80 patients with reduced 
psychomotor performance will be randomly assigned to four groups (20 patients per 
group) receiving sessions of TMS of different stimulation parameters. One of the 
groups will receive sham stimulation. Regardless of the type and the frequency of 
TMS, the stimulation protocol will consist of 15 daily sessions during a 3 week 
period. 
The four different stimulation conditions include: 1) 15 Hz left dorsolateral 
prefrontal Cortex (DLPFC) repetitive TMS. 2) 1 Hz SMA/ pre- SMA rTMS. Low 
frequency TMS has been demonstrated to decrease motor cortex excitability, the 
motor consequences of which are still to be unraveled. 3) Supplementary Motor Area 
(SMA)/ Presupplementary Motor Area (pre-)SMA intermittent Thetaburst Stimulation 
(iTBS). iTBS is a modality of stimulation eliciting an excitatory effect on cortical 
excitability. 4) Sham stimulation over occipital cortex using a placebo coil, similar to 
the real one will be used. 
Outcome will be evaluated as improvement in gross motor behavior 
(actigraphy, SRRS), fine motor function (finger tapping test), and hand gesture 

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performance (TULIA). In addition, patients will be assessed with the Hamilton Rating 
Scale for Depression (HAMD) (Hamilton, 1960), Montgomery Åsberg Depression 
Rating Scale (MADRS) (Montgomery and Asberg, 1979) Beck Depression Inventory 
(BDI) (Beck et al., 1961), Positive and Negative Syndrome Scales (PANSS) (Kay et 
al., 1987) and Scales for the Assessment of Negative Symptoms (SANS) (Andreasen, 
1983), Clinical Assessment Interview for Negative Symptoms (CAINS) (Kring et al., 
2013) and Bush Francis Catatonia Rating Scales (Bush et al.,1996). Clinical ratings 
will be assessed at baseline and after the last TMS stimulation by a rater blinded to 
stimulation protocol. Statistical analysis will comprise ANOVAs of motor variables 
and stimulation mode as between subject variable. 
 
3.1. Background, reason for the study and objective of the study  
Psychomotor retardation (PR) is according to the Diagnostic and Statistical Manual 
for Mental Disorders, 5th edition (DSM-5), defined as an ‘a visible generalized 
slowing of movements and speech’. 
The occurrence of PR is in psychiatry appears to be of central significance 
across a spectrum of mental disorders such as schizophrenia and depression subtypes, 
in which the planning and the execution of movements is affected, resulting to 
disturbances in main psychomotor domains such as fine and gross motor activity and 
speech (Morrens et al. 2007; Schrijvers et al., 2008).  
Psychomotor symptoms have also been reported in patients with chronic abuse 
of cannabis (King et al., 2011), chronic fatigue syndrome (Eede et al., 2011), PTSD 
(Peleikis et al., 2012), while they may also be elicited by psychopharmacological 
agents (Casey, 2006). The occurrence of PR seems to affect the everyday life of 
patients since it is strongly associated with poorer quality of life (Muslimovic et al., 
2008) and it may have a restraining effect on common physical activities of patients 
as walking (Putzhammer et al., 2005; Schrijvers et al., 2008). 
 
Psychomotor retardation (PR) in patients diagnosed with major depressive 
disorder (MDD) 
PR is considered to be a primary behavioral disturbance in all affective disorders 
(Widlocher, 1983; Parker et al., 1994). Schrijvers et al. (2008) concluded that PR is a 
strong diagnostic marker for melancholic depression. According to the same review, 
PR may have a diagnostic role in the discrimination between unipolar and bipolar 
depression. In fact, PR is consistently more frequent in patients diagnosed with a 
bipolar depression compared to unipolar depression (Akiskal, 2000; Bowden, 2005; 
Benazzi & Akiskal, 2008; Mitchell et al., 2008; Calugi et al., 2011; Faurholt-Jepsen et 
al., 2012).  
The higher occurrence of PR in patients diagnosed with affective disorders 
with melancholic features, although disputed (Schrijvers et al., 2008), may be 
explained by the association of the degree of severity of the illness with both the 
frequency of the melancholic subtype and the occurrence of PR (Knapen et al., 2012; 
Terziivanova & Haralanov, 2012; Caldieraro et al., 2013,); patients with severe forms 
of depression report more often motor abnormalities (Cagligiuri & Ellwanger, 2000; 
Callugi, 2011).  
Despite the great number of studies assessing the prognostic role of the PR 
regarding treatment response, results have been contradictory. The effect of different 
antidepressive drugs differs between studies. Preliminary evidence suggests TCAs to 
have a beneficial short-term effect on psychomotor performance in depressed patients 

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reporting PR (Schrijvers et al., 2008). Regarding the use of SSRIs, the same review 
(2008) demonstrated a significant improvement of psychomotor symptoms, with 
sertraline being more effective than fluoxetine (Sechter et al., 1999). The prognostic 
value of PR regarding the response to electroconvulsive therapy (ECT) has to be 
further evaluated, as the findings are inconsistent (Sobin & Sackheim, 1997).  
Concerning the course of the psychomotor symptoms improvement of PR is 
usually accompanied by clinical response (Sabbe et al., 1996; Schrijvers et al., 2008; 
Douglas et al., 2011; Lee et al., 2012). 
 
Neurophysiological substrates of PR in major depressive disorder (MDD) 
Psychomotor retardation in patients with MDD has been attributed to 
hypodopaminergic states, particularly in the basal ganglia (Hickie et al., 1999; 
Videbech, 2000; Martinot et al., 2001; Schrijvers et al., 2008; Walther et al., 2012). 
The central role of basal ganglia in psychomotor symptoms in MDD remains a 
consistent finding also among neuroimaging studies (Sobin & Sackheim, 1997; Lohr 
& Caligiuri, 2006; Loo et al., 2008; Buyukdura et al., 2011). Apart from the decreased 
dopamine turnover, another very common finding in these patients is the dysfunction 
of prefrontal subcortical circuits and hippocampus (Hickie et al., 1999; Videbech, 
2000; Martinot et al., 2001; Cheng et al., 2010; Halvorsen et al., 2012).  
Studies investigating regional cerebral blood flood (CBF) in depressive 
patients with PR detected reduced CBF in dorsolateral and left prefrontal cortex, 
angular gyrus, and the anterior cingulate (Mayberg et al., 1994; Narita et al., 2004; 
Videbech et al, 2002; Buyukdura et al., 2011). Walther et al. (2012a) demonstrated a 
positive association of motor activity with perfusion in resting state in the right 
orbitofrontal and an inverse one in the left supplementary motor area in patients with 
MDD. Findings differed in healthy controls with associations detected in left caudal 
cingulated zone and in the right external globus pallidus. 
Walther et al. (2012b) were the first to study the motor activity levels in 
patients with MDD with regard to white matter integrity. Findings indicated that 
white matter integrity in patients was not related to motor activity underneath the right 
dorsal premotor cortex in contrast to controls. In patients, significant associations 
were detected in the posterior cingulum, underneath the left primary motor cortex and 
the left parahippocampus gyrus. In a similar study, Bracht et al. (2013) found an 
association across the pathway between right rostral anterior cingulate cortex and the 
pre-supplementary motor area.  
 
PR in patients with schizophrenia 
A wide range of various psychomotor symptoms have been studied in patients with 
schizophrenia spectrum disorders. However, a commonly accepted symptom 
definition is still not available (Walther & Strik, 2012). Among studies, motor 
symptoms have been described as parkinsonian symptoms, catatonic symptoms, 
reduced motor drive, neurological soft signs and various dyskinesias (Walther & 
Strik, 2012).  
The correlation of motor abnormalities, negative symptomatology and 
cognitive deficits in schizophrenia is a consistent finding among studies (Wolff & O’ 
Driscoll, 1999; Farrow et al., 2005; Morrens et al., 2007; Walther et al., 2009; 
Bervoets et al., 2013). However, Wolff & O’ Driscoll (1999) mentioned that the 
methods assessing these symptoms need to be more sensitive as a reduction of 
psychomotor activity levels is sometimes recognized as negative symptoms (Morrens 
et al., 2007).  

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PR may antecede the appearance of psychotic symptoms according to 
Gschwandtner et al. (2006), who demonstrated as well that psychomotor function in 
individuals at high risk for schizophrenia was significantly worse in comparison to 
risk-free controls, a finding that replicated the findings of a study of the neuromotor 
development during the childhood of adults diagnosed with schizophrenia (Walker et 
al., 1996).  
Regarding the effect of medication on PR, typical neuroleptics do not present 
an improvement according to the review of Morrens et al. (2007), while Hoothoofd et 
al. (2008) demonstrated no differences between Risperidone and Haloperidol. Walther 
et al (2010) noticed that patients treated with olanzapine had higher motor activity 
during the day compared to patients treated with risperidone, which may be connected 
to the frequent occurrence of extrapyramidal side effects in patients treated with 
risperidone (Leucht et al., 2009). 
 
Neurophysiological Substrates of PR in Schizophrenia 
Reduced blood flow in various brain regions and specifically in prefrontal cortex of 
patients with schizophrenia is a consistent finding in literature. Walther el al. (2011) 
detected a linear association between CBF in the right ventral anterior nucleus of the 
thalamus in healthy subjects that was missing in schizophrenia patients. In patients 
but not in controls, motor activity was correlated with CBF in the SMA, the cingulate 
motor area and the DLPFC. It was hypothesized that in schizophrenia cortical motor 
areas may compensate for insufficient basal ganglia motor output. 
Motor activity levels were associated with the volumes of anterior cingulate 
cortex (ACC) (Farrow et al., 2005). 
Walther et al. (2011) were furthermore the first to demonstrate a significant 
correlation between reduced motor activity and white matter ultrastructure underneath 
the primary and secondary motor cortex but only in schizophrenia patients. These 
findings were corroborated by structural connectivity analyses. Bracht et al. (2013) 
found that motor activity in controls was related to connection probability in 
thalamocortical (primary motor cortex) and striato-cortical (pre-SMA-pallidum) 
connections. In schizophrenia patients instead, motor activity was associated with the 
connection probability of preSMA-SMA connections. Thus, impaired subcortico-
cortical interaction was suggested to contribute to psychomotor retardation in 
schizophrenia. 
To sum up the findings, basal ganglia output and interaction with the cortical 
motor areas seems critical for motor functioning in MDD and schizophrenia. Cortical 
areas of interest that may easily targeted by TMS are the preSMA, SMA proper and 
the DLPFC. Results of imaging studies suggest these areas to have aberrant function 
and connectivity in MDD and schizophrenia, particularly in those patients with 
psychomotor retardation. It thus appears plausible that stimulation of these areas 
might alter the motor loop function.  
 
Assessment methods of PR  
The study of the psychomotor function has focused on a cluster of symptoms 
regarding domains such as gross or fine motor activity, body movements, speech, 
motor response time and gesture performance.  
Gross motor performance One of the commonly used rating scales for the 
assessment of psychomotor function Salpêtrière Retardation Rating Scales (SRRS) 
evaluates gait, gross and facial motorics, speech and cognitive elements (Widlöcher & 

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Ghozlan, 1989). The gross motor activity will be furthermore assessed by actigraphs. 
Actigraphy is a method of quantitative assessment of motor behavior. Patients wear 
continuously a wrist actigraph, which records the gross motor activity in naturalistic 
settings. The baseline screening of patients for motor abnormalities will be based on 
ratings of Bern Psychopathology Scales (BPS), a validated quantitative and 
qualitative scales for the assessment of system-specific psychotic symptoms of three 
main domains: motor behavior, language and affectivity. 
Fine motor performance The assessment of fine motor performance is based on a 
finger tapping test, during which, participants are asked to tap their index finger 
against their thumb as fast as possible in ten seconds. After a short period of practice, 
three periods will be measured and videotaped. An analysis of the tapping is 
additionally conducted in slow motion (Barkemeyer et al., 1998).    
Gesture Performance The Test of upper limb apraxia (TULIA) (Vanbellingen et al., 
2010) is a standardized examination of gesture performance that covers both 
pantomime and imitation domains and multiple semantic features.  
Rationale and aim of the study 
Psychomotor retardation is often reported by patients diagnosed with schizophrenia or 
MDD. Various brain regions may contribute to psychomotor slowing, but the 
pathophysiology still remains unclear. The effect of TMS of various stimulation 
parameters at different stimulation sites may lead to improved motor performance. 
Across diagnoses, patients with motor retardation will benefit from inhibitory 
stimulation over SMA. Taking into account findings of previous studies, the aims of 
the study are 
a. To assess the effects of the 3 weeks of daily TMS sessions on motor 
performance in patients with schizophrenia or MDD (fine motor activity, gross 
motor activity and gesture performance). 
b. To compare the psychomotor symptoms improvement between different TMS 
protocols 
c. To assess the effect of daily TMS in different configurations on other non-
motor symptoms e.g. depressive symptoms, negative symptoms. 
 
3.2. Research Questions, study population 
Research Questions 
 
We aim to investigate the effect of TMS in various configurations on psychomotor 
retardation in patients diagnosed with MDD or schizophrenia. Diagnoses will be 
given following application of Mini-International Neuropsychiatric Interview 
(MINI)(Sheehan et al., 1998) and review of the complete cases files The study 
consists of a single site four arm randomized, sham-controlled trial. In total, 80 
patients will be randomly assigned to four groups (20 patients per group) receiving 
sessions of TMS of different stimulation parameters. Sham stimulation will be 
administered in one group. Regardless of the type and the frequency of TMS, the 

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stimulation protocol will consist of 15 daily sessions during a 3 week period. The four 
different stimulation conditions have been described above. 
Outcome will be evaluated as improvement in gross motor behavior 
(actigraphy, SRRS), fine motor function (finger tapping test), and hand gesture 
performance (TULIA). In addition, changes may be demonstrated by the Hamilton 
Rating Scale for Depression (HAMD) (Hamilton, 1960), Montgomery Åsberg 
Depression Rating Scale (MADRS) (Montgomery and Asberg, 1979) Beck 
Depression Inventory (BDI) (Beck et al., 1961), Positive and Negative Syndrome 
Scales (PANSS) (Kay et al., 1987) and Scales for the Assessment of Negative 
Symptoms (SANS) (Andreasen, 1983), Clinical Assessment Interview for Negative 
Symptoms (CAINS) (Kring et al., 2013) and Bush Francis Catatonia Rating Scales 
(Bush et al.,1996). Clinical ratings will be assessed at baseline and after the last TMS 
session by a rater blinded to stimulation protocol. Statistical analysis will comprise 
ANOVAs of motor variables and stimulation mode as between subject variable. 
Clinical response will be defined as a 30% reduction of the SRRS scores. Frequency 
of response will be compared between groups using Chi2-Tests. 
 
Study Population 
80 in- and outpatients with schizophrenia or major depressive disorder according to 
DSM-5 displaying reduced levels of motor activity. Diagnoses will be given 
following application of MINI and review of the complete cases files. 
Age: 18-65 
Right-handed 
Races: all ethnic groups 
Gender: male and female. Pregnant patients will be eliminated. 
Patients must have normal or corrected-to-normal vision and hearing. 
 
3.3. Study Hypothesis 
Psychomotor symptoms are frequent in schizophrenia and MDD. Various brain 
regions may contribute to psychomotor slowing, but the precise pathophysiology 
remains unclear. Patients will be randomly assigned to four groups receiving sessions 
of TMS in different configurations. After TMS sessions, patients are expected to 
display an improvement of fine and gross motor activity as well as gesture 
performance. Across diagnoses, patients with motor retardation will benefit from 
inhibitory stimulation over SMA. Furthermore, TMS of various stimulation 
parameters is expected to affect disorder specific symptoms e.g. depressive symptoms 
and negative symptoms, which will be rated before and after TMS.  
 
4. Study design 

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4.1. Targeted primary end point and secondary end points (effectiveness and 
safety parameters) 
Main objective is the effect of TMS on psychomotor retardation (PR) in 
patients with major depressive disorder or schizophrenia. Primary outcome marker 
will be the change in psychomotor performance as assessed by Salpêtrière Retardation 
Rating Scales (SRRS). Clinical response will be defined as a 30% reduction of the 
SRRS baseline scores. 
Secondary targets will be the effect of TMS on other motor parameters and on 
specific symptoms e.g. depressive or negative symptoms. 
Efficacy parameters: TMS parameters may be of critical role determining the effect of 
the applied TMS on motor symptoms. 
Safety parameters: As specific safety factors in relation to TMS, patients with 1. past 
history of epilepsy, or 2. other increased neuronal activity in Electroencephalography 
(EEG), 3. MRI contraindications and 4. substance misuse will be excluded. EEG 
recordings will be held for all patients before the beginning of TMS. Patients will be 
screened every 5 sessions with SRRS and actigraphy. In case of moderate 
deterioration of motor performance (30% change of initial ratings of SRRS or/and 
actigraphy) or adverse reactions during the TMS protocol, patients will be excluded 
from further participation in the study. .  
 
4.2. Specification of the parameter that is of primary interest and other 
parameters that will be assessed as additional, secondary end points. 
Primary outcome of the study will be efficacy as defined by >30% improvement from 
the baseline score of the Salpêtrière Retardation Rating Scales (SRRS). Outcome will 
be further evaluated as improvement in gross motor behavior (actigraphy), fine motor 
function (finger tapping test), and hand gesture performance (TULIA). In addition, we 
will investigate the effect of TMS on the disorder specific symptoms. Patients will be 
assessed with the Hamilton Rating Scale for Depression (HAMD) (Hamilton, 1960), 
Montgomery Åsberg Depression Rating Scale (MADRS) (Montgomery and Asberg, 
1979) Beck Depression Inventory (BDI) (Beck et al., 1961), Positive and Negative 
Syndrome Scales (PANSS) (Kay et al., 1987) and Scales for the Assessment of 
Negative Symptoms (SANS) (Andreasen, 1983),  Clinical Assessment Interview for 
Negative Symptoms (CAINS) (Kring et al., 2013) and Bush Francis Catatonia Rating 
Scales (Bush et al.,1996). Clinical ratings will be assessed at baseline  and after the 
last TMS session by a rater blinded to stimulation protocol. Statistical analysis will 
comprise ANOVAs of motor variables and stimulation mode as between subject 
variable. Clinical response will be defined as a 30% reduction of the SRRS scores. 
Frequency of response will be compared between groups using Chi2-Tests. 
 
4.3 Study design, tabular overview, course of the study, study duration (for each 
participant), break-off criteria and procedure for unblinding 
Study Design 
Single site four arm randomized, sham-controlled trial to disentangle the 
pathophysiology of psychomotor retardation. We will investigate 80 in- and 
outpatients, aged between 18 and 65, diagnosed with MDD or schizophrenia, 

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displaying reduced levels of motor activity. Diagnoses will be given through 
application of MINI and review of the complete cases files. Only patients displaying 
reduced levels of motor activity assessed with Bern Psychopathology Scales (BPS) 
will be included and will be randomly assigned to four equal groups. Patients will be 
informed about the stimulation procedure and the goals of the study. Written informed 
consent will be obtained. Female patients will take a urine pregnancy test before the 
beginning of the TMS sessions and they will be required to use contraceptive methods 
during the TMS protocol in order to enroll in the study. In case of a suspicion of a 
pregnancy during the study despite the use of contraceptives a urine test will be taken. 
Subjects will undergo a series of diagnostic tests assessing primarily different 
psychomotor domains and secondarily disorder specific symptoms. Questions 
concerning demographic data (age, gender, education, occupational status) as well as 
substance use and medication will also be included. Each group will receive sessions 
of TMS of different stimulation parameters. Regardless of the type and the frequency 
of TMS, the stimulation protocol will consist of 15 daily sessions during a 3 week 
period. The four different stimulation conditions have been described above. Subjects 
will be reassessed after TMS. 
Following assessments will be performed:  
- 
Mini-International Neuropsychiatric Interview (MINI) – A validated 
structured diagnostic psychiatric interview. 
- 
Bern Psychopathology Scales (BPS) – A validated quantitative and qualitative 
scales for the assessment of system-specific psychotic symptoms 
- 
Actigraphy – gross motor activity levels will be recorded by wrist actigraphs 
- 
Salpêtrière Retardation Rating Scales (SRRS) – A validated scales allowing 
the assessment various domains of psychomotor performance including gait, 
gross and facial motorics, speech and cognitive elements 
- 
Finger tapping test – video-taped assessments of fine motor performance 
- 
Test of Upper Limp Apraxia (TULIA) –video-taped, blinded ratings of gesture 
performance 
- 
Patients with Major Depressive Disorder (MDD): Hamilton Rating Scale for 
Depression (HAMD), Montgomery Åsberg Depression Rating Scale 
(MADRS), Beck Depression Inventory (BDI) (Beck et al., 1961),  
- 
Patients with Schizophrenia: Positive and Negative Syndrome Scales 
(PANSS), Scales for the Assessment of Negative Symptoms (SANS), Clinical 
Assessment Interview for Negative Symptoms (CAINS) and Bush Francis 
Catatonia Rating Scales (Bush et al.,1996). 
Transcranial Magnetic Stimulation sessions 
The first group will receive 15 Hz TMS over dorsolateral prefrontal cortex (DLPFC) 
repetitive TMS. As mentioned above, there is a considerable number of previous high 
frequency TMS trials at this site with significant effects on the psychomotor 
performance (Huber et al., 2003; Hausmann et al., 2004; Martis et al., 2003; Baeken 
et al., 2010). The rTMS protocol that will be used derives from the study of 

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Hernández-Ribas et al. (2013), which detected a significant antidepressant effect of 
high frequency TMS over DLPFC. 
 
The second group will be tested with transcranial magnetic stimulation of 1 Hz rTMS 
over SMA/ pre- SMA. Low frequency TMS has been demonstrated to decrease motor 
cortex excitability, the motor consequences of which are still to be unraveled. 
Moreover, low frequency rTMS has shown a highly beneficial effect on motor 
symptoms in patients with Parkinson Disease (PD) (Shirota et al., 2013). We will use 
the stimulation protocol of the study of Shirota et al. (2013). 
The third group will receive intermittent Thetaburst Stimulation (iTBS) 50 Hz over 
Supplementary Motor Area (SMA)/ Presupplementary Motor Area (pre-)SMA. iTBS 
is a modality of stimulation eliciting an excitatory effect on cortical excitability, 
applied primarily in patients with multiple sclerosis or post-stroke implications with 
beneficial findings. The findings of studies assessing the effect of iTBS over SMA on 
psychomotor performance in healthy individuals and patients with Parkinson Disease 
have been encouraging (Dusek et al., 2011; Ilic et al., 2012). We will apply the widely 
used protocol of the study of Huang et al. (2005). 
The fourth group (control group) will receive sham stimulation over occipital cortex. 
In this group a placebo coil, similar to the real one will be used. According to the 
review of Loo et al. (2000) sham conditions including various coil positions have 
displayed a significant effect in many cases. Based on these findings, we chose to use 
a placebo coil over a different stimulation area expecting a negligible stimulation 
effect.  
The complete stimulation details are given in section TMS Protocol. Regardless of the 
type and the frequency of TMS, the stimulation protocol will consist of 15 daily 
sessions during a 3 week period. The ratings mentioned above will be repeated after 
the end of the TMS.  
Tabular overview 
Selection of participants 
Information about the procedure and the goals 
of the study 
 
Written informed consent is obtained 
 
Specific safety parameters for TMS sessions 
will be assessed 
 
EEG Recordings  
 
Bern Psychopathology Scales (BPS) for the 
assessment of motor activity levels 
 
Mini-International Neuropsychiatric Interview 
(MINI) 
Assessment before TMS  
Actigraphy 
 
Salpêtrière Retardation Rating Scales (SRRS) 
 
Finger tapping test 
 
Test of Upper Limp Apraxia (TULIA) 
Specific assessment: patients with 
Major Depressive Disorder 
Hamilton Rating Scale for Depression 
(HAMD) 

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Montgomery Åsberg Depression Rating Scale 
(MADRS) 
 
Beck Depression Inventory (BDI) 
Specific assessment: patients with 
schizophrenia 
Positive and Negative Syndrome Scales 
(PANSS) 
 
Scales for the Assessment of Negative 
Symptoms (SANS) 
 
Clinical Assessment Interview for Negative 
Symptoms (CAINS) 
 
Bush Francis Catatonia Rating Scales 
(BFCRS) 
Transcranial magnetic stimulation Randomized allocation to four equal groups 
 
15 daily sessions (3 week period) 
Assessment after TMS  
Repetition of the assessments taken place 
before TMS 
 
Course of the study 
The study will be started immediately after ethical approval. Subject recruitment, 
testing and data analysis will last approximately 36 months.  
The study will encompass the following periods:  
Preparation (2 months) 
At this period, the rater will be trained using the rating scales and the assessment 
methods. Additionally, the various departments of the clinic will receive detailed 
information on the study, while the function of all technical equipment and its’ 
response to the design of the study will be tested. Modifications, if necessary, will be 
made. 
Subject recruitment, ratings, TMS sessions and repetition of ratings (24 months) 
During this phase, patients will be motivated to participate in the study. As the 
recruitment and screening of individuals will be taking place, TMS will be performed 
continuously during this period. Patients will be reassessed after every 5 sessions and 
in the end of the TMS. Contemporaneously, the data of the rating scales and methods 
will be digitalised and prepared for statistical analyses. 
Analyses and publication (10 months) 
After collecting all data, the final analyses will follow and manuscripts will be 
written. 
Settings 
Recruitment, screening and selection of patients will take place at the University 
Hospital of Psychiatry in Bern. The assessments and the TMS sessions will be carried 

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out at the Lab of the Department of Psychiatric Neurophysiology, University Hospital 
of Psychiatry in Bern. 
Study duration for each participant  
In total the duration for each participant will be as following 
Duration of assessments 
A) Pre TMS clinical ratings & tests  
 
210 min 
B) TMS sessions  
 
 
30 min x 15 sessions=450 min 
C) Post- TMS clinical ratings & tests 
 
210 min 
Procedure of unblinding 
Reassessments after TMS sessions will be carried out by a rater, blinded to the 
stimulation allocation. The data of patients such as the TMS configuration delivered 
will be concealed in a sealed and opaque envelope and kept by the main investigator. 
The envelope will be opened only in case of adverse reactions, leading to 
discontinuation of the rTMS sessions and exclusion from the study. 
 
4.4. Measures to minimize bias risk 
After recruitment patients will be randomly allocated to four groups. Groups will be 
matched for age, gender, education and diagnose. Rater is blinded, patient is semi-
blinded (has no knowledge of TMS, but could however find out where stimulation 
occurs). 
5. Selection of the participants 
5.1. Subject Recruitment 
Patients with schizophrenia or major depressive disorder (MDD) according to DSM-5 
criteria, displaying reduced levels of motor activity, will be recruited from the 
inpatient and outpatient departments of the University Hospital of Psychiatry in Bern.  
 
5.2. Inclusion criteria 
Right handed patients with MDD or schizophrenia according to DSM 5, ages 18-65 
years old displaying reduced motor activity screened with the Bern Psychopathology 
Scale (BPS) (Strik et al., 2010). BPS is a validated, quantitative and qualitative scales 
for the assessment of system-specific psychotic symptoms. Diagnoses will be given 
through application of MINI and review of complete cases records. Patients must 
have normal or corrected-to-normal vision and hearing.  
 
5.3. Exclusion criteria 
History of head trauma 
Substance misuse other than nicotine. 

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Pregnancy. Female patients will take a urine pregnancy test before the beginning of 
the TMS sessions and they will be required to use contraceptive methods during the 
study in order to enroll in the study. In case of a suspicion of a pregnancy during the 
study despite the use of contraceptives a urine test will be taken. 
 
TMS specific criteria (exclusion criteria) 
Past history of epilepsy  
Other increased neuronal activity in Electroencephalography (EEG). EEGs of all 
patients will be recorded before the beginning of TMS. Patients displaying abnormal 
EEG findings will be excluded. 
MRI contraindications, since such an examination maybe necessary in case of adverse 
reactions. 
 
6. Assessment of effectiveness 
6.1. Effectiveness parameters: measuring methods and reference dates  
The efficacy of TMS sessions will be evaluated primarily as improvement in SRRS 
baseline score after treament. Furthermore, we investigate the effect of TMS on gross 
motor behavior (SRRS, actigraphy), fine motor function (finger tapping test), and 
hand gesture performance (TULIA). To this purpose, clinical ratings will be assessed 
twice, at baseline and after the last TMS session. Furthermore, changes may be 
demonstrated by the scales assessing the disorder specific symptoms; in patients with 
major depressive disorder, HAMD, MADRS and BDI, in patients with schizophrenia 
PANSS, SANS, CAINS and the Bush Francis Catatonia Rating Scales. Statistical 
analysis will comprise repeated measures ANOVAs of motor variables and 
stimulation mode as between subject variable. Clinical response will be defined as a 
30% reduction of the SRRS scores. 
 
7. Assessment of safety 
7.1. Safety parameters: measuring methods and times 
Specific safety parameters for TMS include: past history of epilepsy, pregnancy, 
other increased neuronal activity in Electroencephalography (EEG), MRI 
contraindications and substance misuse other than nicotine. Female patients will take 
a urine pregnancy test before the beginning of the TMS sessions and they will be 
required to use contraceptive methods during the study in order to enroll in the study. 
In case of a suspicion of a pregnancy during the study despite the use of 
contraceptives a urine test will be taken. These parameters will be observed and are 
explicit exclusion criteria. EEGs of all patients will be recorded before the beginning 
of TMS. Patients displaying abnormal EEG findings will be excluded. The rest of 
above mentioned parameters will be as well observed and are explicit exclusion 
criteria. After every 5 sessions, assessments of gross motor behaviour (SRRS, 

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actigraphy) will be repeated. In case of moderate deterioration of motor performance 
(30% change of initial ratings) patients will be excluded from the study. 
7.2. Guarantee of follow-up examination of patients in case of adverse reactions. 
The study will be carried out according to the protocol. In case of serious adverse 
events, which may be connected to the TMS stimulation or any relevant assessments 
(Art.42, KlinV), the Ethics Committee will be as soon as possible informed by the 
sponsor. Serious adverse events may include seizures or exacerbation of psychiatric 
symptoms. In such cases the TMS sessions will be immediately stopped and the 
patient will excluded from the study. A MRI examination will be held and any 
necessary additional medical consultations will be arranged.  
8. Statistics 
8.1. Definition of the primary end point and secondary end points 
Primary outcome of the study will be clinical response as defined by >30% 
improvement from the baseline score of the Salpêtrière Retardation Rating Scales 
(SRRS). Moreover, gross motor behavior (actigraphy), fine motor function (finger 
tapping test), and hand gesture performance (TULIA) will be assessed at baseline and 
after the last TMS. Furthermore, we will investigate the efficacy of TMS on disorder 
specific symptoms; in patients with major depressive disorder, HAMD, MADRS and 
BDI, in patients with schizophrenia PANSS, SANS, CAINS and the Bush Francis 
Catatonia Rating Scales will be carried out before and after TMS. Statistical analysis 
will comprise ANOVAs of motor variables and stimulation mode as between subject 
variable. Clinical response will be defined as a 30% reduction of the SRRS scores. 
Frequency of response will be compared between groups using Chi2-Tests. 
 
8.2. Planned number of trial subjects with clearly stated justification (power 
analysis) 
When we simulate a distribution of responders, in which two groups get 25% of the 
responders, the more effective group third group gets 40% and the most ineffective 
group only 10%, and compare this distribution to an equal distribution of 25% in each 
group, then the df is 3, noncentrality critical and the effect 
sizeThus, we could expect a medium to large effect.  
Applying a Chi2-Test with this effect size of a significance level of  = 
0.05, a power of 1- = 0.90 and a df = 3, then the total required sample size would be 
79 subjects. Therefore, each group has to contain at least 20 subjects. 
 
8.3. Description of the statistical methods foreseen and the planned intermediate 
assessments  
 
Descriptive data analyses will be performed using Statistical Package for Social 
Sciences SPSS 17.0® (SPSS Inc., Chicago, IL, USA). In order to compare efficacy of 
the intervention arms, the primary outcome will be the frequency of patients 

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achieving response to psychomotor retardation (i.e. >30% improvement from SRRS 
baseline scores). This group statistic will be calculated using Chi2-Tests. 
In order to investigate the effect of rTMS on the psychomotor performance of 
participants, we will analyze changes in motor variables within and between groups 
using repeated measures-ANOVAs. This way, we will test for time effects and effects 
of stimulation protocol. In case of unequal distribution of descriptive parameters 
between groups, these parameters will be entered as covariates to the repeated 
measures ANCOVA. Before performing ANOVAs, a normalizing transformation will 
be carried out if necessary.  
The same procedure will be followed in case of the diagnose specific symptoms 
ratings (BDI, MADRS, Hamilton, PANSS, SANS, CAINS).  
To control if a possible improvement of psychomotor performance after rTMS may be 
attributed to a general clinical response, we will use the analysis of covariance 
(ANCOVA) with psychomotor performance ratings (before and after TMS) as within 
subjects factor and changes in ratings of diagnose specific symptoms ratings as 
covariate.  
At three major recruitment steps (25% of total sample, 50% and 75% respectively) we 
will calculate the primary analysis. If one group proves to have significantly poorer 
outcome than the others, we will stop this study arm. 
 
8.4. Planned significance level  
Planned level of significance will be held as p<0.05. 
8.5. Handling of missing data, dropout cases 
Only complete data records with assessments at two time points will be entered in the 
analyses. In case of dropout we will perform an intention-to treat (ITT) analysis 
applying the last-observation-carried-forward method (LOCF). In case of revocation 
of patients (KlinV, Art.9), data will be anonymized. 
9. Study-specific safety precautions and responsibilities 
9.1. Safety precautions 
The specific risks for TMS include past history of epilepsy, pregnancy, other 
increased neuronal activity in Electroencephalography (EEG), MRI contraindications 
and substance misuse other than nicotine. EEGs of all patients will be recorded before 
the beginning of TMS. Patients displaying abnormal EEG findings will be excluded. 
Female patients will take a urine pregnancy test before the beginning of the TMS 
sessions and they will be required to use contraceptive methods during the study in 
order to enroll in the study. In case of a suspicion of a pregnancy during the study 
despite the use of contraceptives a urine test will be taken. The rest of above 
mentioned parameters will be as well observed and are explicit exclusion criteria. 

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After every 5 sessions, assessments of gross motor behaviour (SRRS, actigraphy) will 
be repeated. In case of moderate deterioration of motor performance (30% change of 
initial ratings) during the study, patients will be excluded from the TMS. The 
investigators are responsible for the observation of the above mentioned criteria and 
the screening of patients. Patients will have to provide written informed consent, 
which will include explicit questions referring to the exclusion criteria. The safety 
criteria will be asked again before the beginning of TMS sessions and participants 
will have to warrant that none of the exclusion criteria is fulfilled.  
9.2. If appropriate: exit examination in case of dropout 
At the end of every week of the TMS stimulation, assessments of gross motor 
behaviour (SRRS, actigraphy) will be repeated. In case of moderate deterioration of 
motor performance (30% change of initial ratings), patients will be excluded from the 
study. In case of seizures or persisting headaches a Magnetic Resonance Imaging 
Examination will be held for diagnostic purposes.  
10. Duties of the investigator 
10.1. Confirmation that the conduct of the study will be in accordance with the 
GCP protocol, the current legal regulations and rights. 
Hereby investigators confirm that they have knowledge of the GCP protocol, 
according to which the study will be carried out. All current legal regulations and 
rights will be additionally taken into account. 
10.2. Adverse reactions, protocol changes, other changes, progress report and 
final report 
Serious adverse events (SAE) may include seizures or exacerbation of psychiatric 
symptoms, which may be connected to the TMS or any relevant assessments (Art.42, 
KlinV). In such cases the TMS sessions will be immediately stopped and the patient 
will excluded from the study. Hereby the investigators guarantee that in case of any 
adverse events, as well as protocol changes or other changes, the Ethics Committee 
will receive a progress report and final report. Additionally, investigators confirm the 
knowledge of the AKEK safety reporting procedures (Arbeitsgemeinschaft der 
Schweizerischen Forschungs- Ethikkomissionen für klinische Versuche). 
10.3. Statement of arrangements to cover damages 
An insurance policy will be taken out and insurance form according to the 
requirements of the “schweizerische Ethikkomission” (“Versicherungszertifikat zu 
Handen der schweizerischen Ethikkomissionen”) is appended in order to assure that 
any possible damage will be covered. 
11. Ethical considerations 
11.1. Potential risks/ benefits balance 

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Clinical ratings & questionnaires: 
The clinical tests and the questionnaires are non-invasive methods, used mainly in 
route examinations with no reported side effects.  
TMS sessions:  
TMS is a well known, clinical, diagnostic and therapeutic, non-invasive tool, widely 
used with seldom reported adverse reactions, as supported by an extensive body of 
studies and meta-analyses (Padberg & George, 2009). In rare single cases, seizures 
and mild headaches have been reported, while in very few cases negative effects on 
cognition, mood and various hormone levels were elicited (Wasserman, 1998; Burt et 
al., 2002). The TMS-induced seizures were in most cases self-limiting, and did not 
seem to have permanent squeal. Once again, it is important to point out that the risk of 
adverse reactions is noticeably low, below 1/1000 investigations (Information 
Brochure on rTMS, rTMS committee of the International Federation of Clinical 
Neurophysiology). TMS parameters (intensity, frequency, number of stimulations) of 
the presented study will be in accordance to international safety guidelines (e.g. 
Wasserman , 1998). 
TMS potential adverse effects will be minimized and the risk/benefit ratio will be 
supportable by following the TMS safety parameters, as they were above described. 
Any severe adverse effect will lead to discontinuation of the rTMS protocol in the 
respective patient. TMS exclusion criteria are past history of epilepsy, other increased 
neuronal activity in Electroencephalography (EEG), MRI contraindications and 
substance misuse. EEG recordings of all patients will be conducted before the 
beginning of rTMS sessions. 
11.2. Benefits for the participants 
Patients with motor abnormalities are expected to display an improvement of motor 
performance after receiving different configurations of TMS. A potential beneficial 
effect of TMS on the disorder specific symptoms may be also detected. Additional 
benefit will be the gained knowledge, possibly helpful for future patients with the 
same problems. 
Importance of the trial 
Psychomotor retardation appears to be of central significance across a spectrum of 
mental disorders such as schizophrenia and depression subtypes, in which the 
planning and the execution of movements is affected, resulting in disturbances in 
main psychomotor domains (Morrens et al., 2007; Schrijvers et al., 2008). The 
occurrence of PR is strongly associated with poorer quality of life (Muslimovic et al., 
2008) and it may have a restraining effect on common physical activities of patients 
(Putzhammer et al., 2005; Schrijvers et al., 2008). Our study of the efficacy of 
different TMS protocols on PR will significantly extend the knowledge on the 
pathophysiology of PR. Moreover, the study will inform on potential mechanisms for 
noninvasive therapeutic brain stimulation to target psychomotor retardation.  
 

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12. Quality control and quality assurance: description of measures 
The study conforms to the declaration of Helsinki. Participants will provide written 
informed consent and will be informed about the option to drop out of the study at any 
moment.  
12.1. Warranty to access to original data, permission of audits and monitoring by 
authorities, Ethic Committee and quality control  
Direct access to original data and inspection by pertinent authorities and Ethic 
committee will be provided if required.  
12.2. Handling of data and samples, archiving and destruction 
The data will be encoded (subjects’ initials and date of birth will be used to code their 
data), digitalised and processed exclusively on the local computer of the principal 
investigator, while a copy of them will be kept on server of the Department of 
Psychiatric Neurophysiology, University Hospital of Psychiatry in Bern, following 
the strict security rules of the Department. Only the principal investigator will be 
aware of the decoded data, while the other investigators will use the encoded data. 
The encryption key as well as the list of the participants will be kept by the main 
investigator. The encryption code and the list guarantee the traceability of the 
patients’ data (KlinV, Art.18). In case of revocation (KlinV, Art.9), data will be 
anonymized. Paper records will be archived in the archive of the University Hospital 
of Psychiatry in Bern for 10 years and they will be destructed according to the 
security rules of the archive. Digital data will be as well preserved for 10 years and 
afterwards will be deleted. In the meantime they may be used in upcoming studies. No 
genetic examinations/transfers of samples are planned.  
12.3. Data collected specifically for the study 
Pre- and post-TMS assessments and tests will be registered. No data will be included 
in the patient files. 
 
 

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