The Efficacy of Transcranial Magnetic Stimulation in the Treatment of Non-epileptic Seizures
Phase: NA
Conditions: Nonepileptic Seizures
Sponsor: University of Manitoba

 
 
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Cover Page 
 
 
Study Title:  
The efficacy of Transcranial Magnetic Stimulation in the treatment 
of non-epileptic seizures. 
 
 
NCT Number:  
NCT02796924 
 
 
Document Date:  
6 May 2016 
 
 

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Introduction: 
 
Psychogenic non-epileptic seizures (PNES) is a severely distressing condition that 
commonly presents in fields of psychiatry and neurology. In the Diagnostic and 
Statistical Manual of Mental Disorders, fifth edition (DSM-5) PNES is classified as a 
Functional Neurological Symptom Disorder (1). This disorder has been defined as 
seizure-like activity, including abrupt recurrent changes in behavior, or consciousness 
with no epileptiform abnormalities on EEG (2). Functional Neurological Symptom 
Disorder, also known as Conversion Disorder, is listed under Somatic Symptom and 
Related Disorders. The DSM-5 describes this group of disorders as symptoms of altered 
voluntary movement (1). However, patients presenting with PNES indicate no sense of 
voluntary control. It is estimated that about 5%-20% of patients admitted to epilepsy units 
for monitoring are diagnoses with PNES, and a further 20-30% of patients whose seizure 
activity is considered to be intractable epilepsy are also eventually diagnosed with PNES 
(2). Currently there is no effective treatment for PNES. Although functional 
neuroimaging data increasingly support specific neurobiological dysfunction, the 
pathophysiology of the disorder remains poorly understood. 
 
Prevalence rates of psychiatric comorbidities among PNES patients have been noted 
throughout the literature to be high (3). Patients with PNES often present with multiple 
psychiatric conditions including mood and anxiety disorders. Problems involving 
emotional dysregulation, dissociation, psychological trauma, and reports of previous 
abuse are common (3). However, the exact nature of the relationship between PNES and 
other psychiatric symptoms, whether present or absent altogether, is unclear. 
 
Resting cortical positron emission tomography (PET) studies and functional connectivity 
analysis on resting state functional magnetic resonance imaging (rsfMRI) have both 
identified abnormalities in the parietal cortex in patients with PNES. Two recent fMRI 
studies by van der Kruijs et al. (4 & 5) assessing abnormal connectivity strength in four 
global networks show support for the role of the temporoparietal junction (TPJ) in the 
pathophysiology of PNES. Higher functional connectivity in 11 patients with PNES was 
found in a global network involving emotion (the insula), movement (the precentral 
sulcus), and executive control (the inferior frontal gyrus and parietal cortex) (5). The 
authors were further able to correlate these connectivity differences to elevated 
dissociation scores within their patient sample (4). Whether these finding were a result of 
dissociative comorbidity, or a direct result of PNES remains unclear. 
 
Additional neuroimaging evidence presented in a study by Arthuis et al. (2) showed 
abnormal glucose metabolism in sixteen patients with PNES. Arthuis et al. assessed 
interictal (resting state) cerebral metabolism on sixteen PNES patients originally thought 
to have intractable epilepsy. Positron Emission tomography (PET) scans using 2-deoxy-
2-fluoro-D-glucose (18FDG-PET) showed hypometabolism within the right inferior 
parietal and central region, and within the anterior cingulate cortex (ACC). The authors 
of this study further noted the possible significance of these regions contributing to two 
pathological mechanisms of the disorder; that of emotion dysregulation (ACC 
hypometabolism) and a compromise of processes responsible for the consciousness of the 

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self and the environment (right parietal hypometabolism). 
 
Despite growing awareness of the neurobiological networks involved in PNES, there are 
currently no effective treatments for the disorder. Given the findings of TPJ 
hypometabolism in patients with PNES, and the contribution of the TPJ to consciousness 
of self and the environment, this region may very well serve as a major contributor to the 
pathophysiology of the disorder (2). A decrease in motor intentional awareness, and self-
agency may result in an inability to take authorship of ones’ movements, thus perceiving 
them as involuntary. In light of the recent work implicating the TPJ in the 
pathophysiology of PNES, increasing cortical excitability in this region could provide a 
novel starting point for the treatment of this disorder. High frequency (20 Hz) repetitive 
Transcranial Magnetic Stimulation (rTMS), a non-invasive method of brain stimulation, 
is known to increase focal cortical activity. Applied over the TPJ, it may then serve to 
correct the TPJ hypoactivity observed in patients with PNES. 
 
A recent systematic review of transcranial magnetic stimulation in the treatment of 
functional neurological symptoms by Pollak et al. (6) has highlighted the results of a 
study conducted in 2011 by Dafotakis M et al. (7). This pilot study demonstrated 
symptom improvement in 7 out of 11 patients with psychogenic tremors using inhibitory 
rTMS. As such, we propose a pilot study of rTMS using a sample size of 15 patients with 
PNES to demonstrate significant effect.  
 
Objective: 
 
To conduct an open label pilot study in order to investigate the feasibility of repetitive 
Transcranial Magnetic Stimulation (rTMS) over the right TPJ, in decreasing the 
frequency of PNES episodes.   
 
Hypothesis: 
 
We hypothesize that 30 sessions of rTMS on 15 patients with PNES will decrease the 
frequency of non-epileptic seizures. 
 
Methods: 
 
This study is an open label pilot study that aims to investigate the feasibility of repetitive 
Transcranial Magnetic Stimulation (rTMS) in decreasing the frequency of PNES 
episodes. A psychiatric profile including patient’s mood, anxiety, dissociative states, 
psychological trauma, impulsivity, and functional disability will be taken on all 15 
patients using Research Electronic Data Capture (REDCap). Subsequently, patients will 
receive high frequency brain stimulation (20 Hz) over the right TPJ using TMS. Two 
sessions of TMS will be administered each weekday for 15 days, with a total 3000 pulses 
each session. Since there is no current data on the expected effect size of rTMS in this 
population of individuals, this study is an open label pilot study to assess the feasibility of 
rTMS as a treatment for PNES. As such, results of the questionnaires including patients’ 
symptom severity and scores on REDCap scales will be analyzed using linear regression 

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analysis to determine the effect of the treatment condition on PNES episodes and 
functional impairment. The significance level for this test will be set to 0.05.  
 
As this is a pilot study, we will also be evaluating the effect size and the feasibility of a 
more definitive project in the future. We will be observing patient response and 
tolerability to rTMS.   
 
Eligibility and Screening: Eligible participants will be adults who have been officially 
diagnosed with PNES. Additionally, participants will have to have been previously 
monitored with video-EEG to confirm that seizures are non-epileptic in origin. The 
participating study psychiatrist will assess all referrals to the Neuromodulation and 
Neuropsychiatry Unit for eligibility criteria. This diagnostic assessment will include a full 
medical history review, a semi-structured neurological 
examination, and a 
neuropsychological evaluation. This assessment will be performed as part of the regular 
standard of care for these patients and is not unique to this study. 
 
Inclusion criteria:  
i) 
Adults with confirmed PNES 
 
Exclusion criteria:  
i) 
Evidence of previous or comorbid epileptic seizures (as shown by video-EEG 
monitoring) 
ii) 
Any other major comorbid neurological diseases 
iii) 
Currently taking medications that are known to reduce seizure-threshold 
iv) 
Currently pregnant 
 
Patient Recruitment: Patients will be recruited from the pool of referrals to the 
Neuromodulation and Neuropsychiatry Unit, St Boniface Hospital. Eligible candidates 
will be identified by the participating psychiatrist. They will be informed about the 
voluntary nature of the study and will be asked for permission for a research assistant to 
approach them regarding potential participation in the study. All consents will be 
voluntary and the participants will be free to withdraw from the study at any time. 
Patients will be reassured that their care will not be affected as a result of withdrawal 
from or deciding not to participate in the study. If a patient wishes to participate in the 
study, a research assistant will review the study consent form with that individual. The 
participant will then sign the consent form and be given a copy of the form for their 
records. 
 
Sample Size: This is a study is an open label pilot study that aims to investigate the 
feasibility of high-frequency repetitive Transcranial Magnetic Stimulation (rTMS) in 
decreasing the frequency of PNES episodes. Since there is no current data on the 
expected effect size of rTMS in this population of individuals with PNES, we have based 
our pilot sample size on current literature describing a confidence interval approach to 
pilot study sample size calculations by Cocks et al. (14). In this study, we have estimated 
a minimum effect size of 0.5 for the use of rTMS in the treatment of PNES. Using an 
80% one-sided CI with an effect size of 0.5, Cocks et al. suggest a pilot sample size of at 

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least 9% of the main planned trial. Assuming a 5% significance level, and 80% power, 
we anticipate a main trial with a sample size of 128 participants. This allows for a pilot 
study sample of 12 participants to show effect, as described by Cocks et al. (14). We have 
included a sample size of 15 patients with PNES for this study. Our goal is to estimate the 
effect size for future definitive studies. 
 
Questionnaires: Prior to the first session of rTMS, patients will complete a series of 
questionnaires to assess mood, anxiety, dissociative states, psychological trauma, 
impulsivity, and functional disability. The majority of these questions will be answered 
through REDCap software. REDCap (Research Electronic Data Capture) is a secure, 
web-based application designed to support data capture for research studies. Two 
REDCap questionnaires will be completed by each participant within one week prior to 
their first session of rTMS: 
1) 
FND I Questionnaire 
2) 
FND II Questionnaire 
Additionally, two paper-and-pencil questionnaires will be administered by a research 
assistant prior to the first session of rTMS:  
3) 
Montreal Cognitive Assessment (MoCA)  
4) 
Wide Range Achievement Test–3 (WRAT–3) 
A follow-up REDCap questionnaire will be completed by each participant one week 
following the last session of rTMS: 
5) 
FND Follow-Up Questionnaire 
 
The FND questionnaires were designed to assess the following symptoms/topics and 
contain elements of the listed tests: 
 
Mood/Anxiety: 
Beck Depression Inventory-II 
Spielberger State-Trait Anxiety Inventory 
Dissociation: 
Dissociative Experience Scale 
Somatoform Dissociation Questionnaire-20 
PTSD/Trauma: 
PTSD Checklist-5 
Childhood Trauma Questionnaire 
Connor-Davidson Resilience Scale 
Somatization and Related Topics: 
Screening for Somatoform Symptoms (SOMS-7) – Conversion Subscale 
Patient Health Questionnaire 15 Somatic Symptom Severity Scale 
Pain Catastrophizing Scale 
Other Measures of Interest: 
Barratt Impulsivity Scale (Version 11) 
Relationship Scales Questionnaire (Attachment Scale) 
Toronto Alexithymia Scale 20 
Ways of Coping Scale – Revised Version 
Laboratory Designed Participant Questionnaires: 

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Educational Background Assessment 
Edinburgh Handedness Inventory 
SF-36v1 Health Survey 
 
MRI localizer: Prior to rTMS treatment, patients will undergo a structural MRI scan. 
Images from this scan will be used in the neuronavigation software used in conjunction 
with the rTMS machine, to allow for the precise localization of target cortical structures 
in each participant’s brain. Scans will be acquired using a T1-weighted fast spin-echo 
sequence. The image resolution will be about 1x1x1 mm. Each scan typically takes about 
15 minutes. 
 
rTMS: Participants will then begin rTMS therapy. Treatment will consist of 30 sessions 
of rTMS treatment. Each session will take roughly 20 minutes. We will perform two 
sessions per day with a 15 minute break in between sessions. As such, the entire 
treatment length will be three weeks (15 weekdays, with two session/days). Stimulation 
will be applied to the right TPJ using a 70mm figure eight coil attached to a MagStim 
Rapid-2 rTMS machine (MagStim Ltd., UK).  Motor threshold will be defined as the 
minimum stimulator output that elicits a contraction of the abductor pollicis brevis 
muscle on 5 out of 10 consecutive pulses. For the active stimulation condition, rTMS will 
be applied to the target location at 110% motor threshold. Sessions will last 20 mins and 
will comprise consecutive trains of two-second 20 Hz pulses followed by 28 seconds of 
no stimulation. The target location will be identified using a Brainsight Neuronavigator 
system (Rogue Research, QC) loaded with each patient’s structural MRI scans. 
 
Analysis: This is a study is an open label pilot design in which all participants will be 
exposed to active stimulation. Results from questionnaires; including patients’ symptom 
severity and scores on REDCap scales will be analyzed using linear regression analysis to 
determine the effect of the treatment condition (rTMS) on PNES episodes and functional 
impairment. The significance level for this test will be set to 0.05.  
 
As this is a pilot study, we will also be evaluating the effect size and the feasibility of a 
more definitive project in the future, while observing patient response and tolerability to 
rTMS.   
 
Anticipated risk: The primary major adverse side-effect associated with rTMS is the rare 
occurrence of induced seizure. For this reason, a history of seizures is normally 
considered a contraindication for rTMS treatment. However, participants recruited to this 
study will be diagnosed with PNES confirmed by video-EEG monitoring. This means 
that our participants will not have a history of epileptic-seizures. For this reason, our 
study participants should be at no greater risk of experiencing an rTMS-induced 
electrogenic seizure than the general population. Furthermore, seizure-induced events 
associated with rTMS are thought to mainly occur when protocols are used that fall 
outside of generally accepted safety guidelines proposed by Rossi et al. (16). Our 
protocol falls within these guidelines, and the proposed study procedures and materials 
have been used without incident with several different psychiatric populations.  
 

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Minor side-effects sometimes associated with rTMS treatment include headache and 
fatigue. These side-effects are transient and are not known to persist following the end of 
therapy. Headaches can usually be ameliorated through the use of over-the-counter pain 
relief medications. The neuropsychological questionnaires do not pose any physical risks 
to participants. 
 
Expected Results: 
 
The expected results of this study are that trials of high frequency rTMS over the right 
TPJ will decrease the frequency of non-epileptic seizures and contribute to a greater 
understanding of this regions’ contribution to the pathophysiology of PNES. 
 
Expected Conclusion: 
 
Significant functional impairment in the lives of patients suffering with PNES 
necessitates the development of effective treatments for this disorder, and further 
investigation into its pathophysiological mechanisms. An increase in comorbid 
psychiatric symptoms within this population suggests that patients with PNES are at 
greater risk of psychiatric aliments, which further impact on their psychological and 
social wellbeing. The decrease in frequency of non-epileptic seizures, as a result of high 
frequency rTMS over the right TPJ, shows that rTMS may be a novel and efficient 
treatment for this disorder. Greater understanding of the biological components of this 
disorder, in conjunction with their associated psychiatric symptoms, will aid in reducing 
stigma, and help in the development of effective methods for identification, treatment, 
and prognosis of this condition. 
 
References: 
 
[1] American Psychiatric Association. Diagnostic and Statistical Manual of Mental 
Disorders. 5th ed. Arlington, Virginia: American Psychiatric Publishing; 2013. Found at: 
http://dsm.psychiatryonline.org.uml.idm.oclc.org 
 
[2] Arthuis M, Micoulaud-Franchi JA, Bartolomei F, McGonigal A, Guedj E. Resting 
cortical PET metabolic changes in psychogenic non-epileptic seizures. J Neurol 
Neurosurg Psychiatry. 2015 Oct 86(10): 1106-12. 
 
[3] Perez DL, Dworetzky BA, Dickerson BC, Leung L, Cohn R, Baslet G, Silbersweig 
DA. An Integrative Neurocircuit Perspective on Psychogenic Nonepileptic 
Seizures and Functional Movement Disorders: Neural Functional Unawareness. Clinical 
EEG and Neuroscience. 2015; 46(1): 4-15. 
 
[4] van der Kruijs SJM, Jagannathan SR, Bodde NMG, Besseling RMH, LAzeron RHC, 
Vonck KEL, et al. Resting-state networks and dissociation in psychogenic non- 
epileptic seizures. J Psych Research. 2014 Jul 54:126-133. 
 
[5] van der Kruijs SJM, Bodde NMG, Lazeron RHC, Vonck k, Boon P, Hofman PAM, et 

Version 2 – May 6, 2016 
 
8/7 
 
al. Functional connectivity of dissociation in patients with psychogenic nono-epileptic 
seizures. J Neurol Neurosurg Psychiatry. 2012; 83:239-247. 
 
[6] Pollak TA, Nicholson TR, Edwards MJ, David AS. A systematic review of 
transcranial magnetic stimulation in the treatment of functional (conversion) neurological 
symptoms. J Neurol Neurosurg Psychiatry. 2014; 85:191-197. 
 
[7] Dafotakis M, Ameli M, Vitinius, F et al. Transcranial magnetic stimulation for 
psychogenic tremor- a pilot study. Fortschr Neurol Psychiatr. 2011; 79:226-233. 
 
[8] Ding j, An D, Liao W, Wu G, Xu Q, Zhou D, Vhen H. Abnormal functional 
connectivity density in psychogenic non-epileptic seizures. Epilepsy Research. 2014; 
108: 1184-1194 
 
[9] Ding j, An d, Liao W, Jinmei L, Wu G, Xu Q, et al. Altered Functional and Structural 
Connectivity Networks in Psychogenic Non-Epileptic Seizures. PLOS One. 2013; (8)5. 
Pub Med PMCID: PMC3661726. 
 
[10] Voon V, Gallea C, Hattori N, Bruno M, Ekanayake V, Hallett M. The involuntary 
nature of conversion disorder. Neurology. 2012 Jan 19;74(3):223-8. 
 
[11] Voon V, Brezing C, Gallea C, Hallett M. Aberrant supplementary motor complex 
and limbic activity during motor preparation in motor conversion disorder. 
Mov Disord 2011; 26:2396-403. 
 
[12] Christopeit M, Simeon D, Urban N, Gowatsky J, Lisanby S, Mantovani A. Effects of 
Repetitive Transcranial Magnetic Stimulation (rTMS) on Specific Symptom Clusters in 
Depersonalization Disorder (DPD). Brain Stimulation. 2014; 7(1): 141-150. 
 
[13] Mantovani A, Simeon D, Urban N, Bulow P, Allart A, Lisanby S. Temporo-parietal 
junction stmulation in the treatment of depersonalization disorder. Psychiatry Research. 
2011; 168(1): 138-140. 
 
[14] Cocks K, and Torgerson D.  Sample size calculations for pilot randomized trials: a 
confidence interval approach. J Clinical Epidemiology. 2013; 99: 197-201. 
 
[15] Levkovitz Y, Isserles M, Padberg F, Lisanby S. World Psychiatry. Efficacy and 
safety of deep transcranial magnetic stimulation for major depression: a prospective 
multicenter randomized controlled trial. 2015; 14(1): 64-73. 
 
[16] Rossi S, Hallett M, Rossini PM, Pascual-Leone A. Safety, ethical considerations, 
and application guidelines for the use of transcranial magnetic stimulation in clinical 
practice and research. Clin Neurophysiol. 2009; 120(12):2008-39.