The Effects of Repetitive Transcranial Magnetic Stimulation on Treatment Resistant Depression and Its Biological Underpinnings

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The effects of repetitive transcranial magnetic stimulation on treatment resistant depression and its biological underpinnings

Department of Medical and Clinical Psychology Tilburg University

Author: Loek van der Donk ANR: 830899 Supervisor: R. Hortensius MSc Date: 14-05-2013

Abstract

The objective of this review was to determine the effects of repetitive Transcranial Magnetic

Stimulation (rTMS) on Treatment Resistant Depression (TRD) and the associated biological underpinnings. In TRD, conventional therapies such as psychotherapy and pharmacotherapy tend to have little effect and a promising new therapy is rTMS. This therapy consists of several trials of magnetic stimulation of the brain through the skull. These magnetic pulses are thought to influence the underlying brain region. Many different parameters exist concerning rTMS treatment, such as intensity, duration, amount of sessions, frequency and location. All of these generate different treatment outcomes. In depression, the left dorsolateral prefrontal cortex

(LDLPFC) displays hypoactivity and is therefore frequently stimulated with high frequency rTMS to increase brain activity, possibly according to the mechanisms of Long Term

Potentiation (LTP). The right dorsolateral prefrontal cortex (RDLPFC) can be stimulated with low frequency and might follow the principle of Long Term Depression (LTD). The main conclusion is that rTMS is an effective way of treating TRD. In addition, the biological underpinnings in rTMS may be LTP and LTD-like effects. In the future, parameters of rTMS treatment deserve attention as well to obtain a golden standard concerning the most effective rTMS treatment for TRD. An emphasis should also be placed upon the possibility of combining different therapies or investigating bilateral stimulation for optimal rTMS treatment results. In addition, the stimulation of new brain regions requires further investigation as well.

Keywords:

Repetitive Transcranial Magnetic Stimulation, Treatment Resistant Depression, rTMS parameters, dorsolateral prefrontal cortex, Long Term Potentiation, Long Term Depression

Table of Contents

1. Introduction 4

a. Depression 5

b. TMS 9

2. The effects of rTMS on TRD 12

a. Parameters of rTMS 15

b. rTMS trends 17

c. Comparison with ECT 18

3. Biological underpinnings of TMS on depression 19

a. Biological underpinnings 21

4. Discussion 23

a. Summary 23

b. Limitations 23

c. Recommendations 26

5. References 28

6. Appendix 37

a. Figures 37

b. Tables 40

Introduction

Depression is a mental disorder which is characterized by a variety of symptoms concerning behavioral, affective, cognitive and somatic functioning. It is among the most widespread and debilitating forms of mental illnesses (Koenigs & Grafman, 2009). Typical symptoms are low mood and self-esteem and the loss in normally enjoyable activities that were formerly enjoyed such as hobbies or social interactions. Other factors concern changes in eating or sleeping behavior of the person. Besides that, depression most of the time also includes feelings of hopelessness or helplessness, loss of energy and difficulty concentrating on a certain task. Furthermore, depression has found to be the most common psychiatric disorder in people who die of suicide (Hawton, Casanas, Haw, & Saunders, 2013). Commonly used therapies for the treatment of depression are psychotherapy and medication. These therapies seem to reduce the risk of relapse or recurrence (DeRubeis, Siegle, & Hollon, 2008). Pharmacotherapy and cognitive therapy seem to be equally effective (Scott, 2001) and tend to be useful in more than half of the patients. Especially cognitive behavioral therapy is thought to be effective in the treatment of depression (Yoshimura et al., 2013). However, depression is still associated with high rates of recurrence and up to 50% - 60% of the patients may not respond to conventional pharmacotherapy (Kupfer & Charney, 2003). Moreover, a high risk of relapse or recurrence can be found in depression even after intensive psychiatric care (Koenigs & Grafman, 2009). In addition, between 20% and 30% of the patients who suffers from depression, are likely to have developed a treatment resistant depression (TRD) (Cusin & Darin, 2012). It causes a major concern in the management of health services and is associated with serious social morbidity. Therefore, there is an urgent need for an efficient treatment of TRD. The patients suffering from TRD are also highly demanding for their families and often require major involvement of health care services (Souery et al., 1999). Because of the lengthy hospitalization which has a great impact on the individual’s family and their social environment, research on treatment resistant depression is an urgent matter for science as well as society. For this reason, novel therapies need to be introduced in order to treat TRD. One of the promising new therapies in the treatment of TRD is Transcranial Magnetic Stimulation (TMS) (Kedzior, Rajput, Price, Lee, & Martin-Iverson, 2012; Kozel & George, 2002).

This study was conducted to analyze the effects of repetitive Transcranial Magnetic Stimulation (rTMS) on depression. Much research is available about this topic and it is suggested that TMS is an effective way of relieving mood symptoms in patients with Major Depressive Disorder. However, knowledge about the actual effects and underlying mechanisms of TMS on depression is scarce. This study tries to disclose these effects and the biological underpinnings of TMS on depression. It will focus on a) the effects of repetitive Transcranial Magnetic Stimulation (rTMS) on Treatment Resistant Depression (TRD) and b) its biological underpinnings.1 First, a general definition of depression is given according to the DSM-IV-TR (A.P.A., 2000). Next a specific form, namely treatment resistant depression is discussed. Subsequently, there is a focus on the therapy of TMS and its underlying principle. The effects of rTMS on TRD will be discussed thereafter and parameters determining the efficacy of rTMS treatment follow. Next, the biological underpinnings of rTMS on TRD are examined. Finally, a conclusion is given, followed by limitations of this study and recommendations for further investigation.

Depression Depression most commonly concerns Major Depressive Disorder (MDD), which is characterized by Major Depressive Episodes. See Table 1 for criteria of MDD. Due to the fact that depression has been investigated for more than half a century, much knowledge about the nature of this disorder has been unraveled. As a consequence, an abundance of research about depression arose and due to this amount of knowledge a broad, all-encompassing definition of depression was formed which is nowadays generally accepted. A commonly used definition for treatment resistant depression is the lack of an “adequate

1 The literature used in this study was found by the use of websites e.g. Pubmed, Google Scholar or Science Direct. After selection for recent and relevant articles, they were critically reviewed. For searching the right scientific articles, there was searched, using terms as ‘depression’, ‘treatment resistant depression’, ‘transcranial magnetic stimulation’, ‘repetitive transcranial magnetic stimulation’ and a combination of the terms above. Besides these terms, also more basic terms such as the definition of depression and TRD, the neuropathy of depression and the general effects of TMS were investigated. The primary information sources used in this study were checked on their conclusions based on the secondary sources and these were also attentively investigated. In other words: the original studies were used for conclusions. Moreover, in the library of Tilburg University (TiU) the DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders) was used for its definition of Major Depressive Episode.

Table 1: Criteria of Major Depressive Episode According to DSM-IV-TR Criterium Symptoms A. five (or more) of the following symptoms (1) Depressed mood most of the day, nearly have been present during the same 2-week every day, as indicated by either subjective period and represent a change from report (e.g. feels sad or empty) or previous functioning; at least one of the observation made by others (e.g.), appears symptoms is either (1) depressed mood or tearful). (2) loss of interest or pleasure (2) Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either

subjective account or observation made by

others)

(3) Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. (4) Insomnia or hypersomnia nearly every day (5) Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down) (6) Fatigue or loss of energy nearly every day (7) Feelings of worthlessness or excessive of inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick) (8) Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others) (9) Recurrent thoughts of death (not just fear

of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide B. The symptoms do not meet criteria for a Mixed Episode C. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g. hypothyroidism). E. The symptoms are not better accounted for by bereavement, i.e., after the loss of a loved one, the symptoms persist for longer than 2 months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation (American Psychiatric Association, 2000) . clinical response” to an appropriate dose of evidence-based treatment (Maalouf, Atwi, & Brent, 2011). This adequate response consists of a reduction of at least 50% of the symptoms of the depression or a global rating of improvement of “much” or “very much” improved during the treatment. If these terms cannot be met, the patient might suffer from treatment resistant depression. Thus, when the patient is not responding properly to the treatment or there isn’t enough progression in the decrease of the patient’s depressive symptoms (this progress is defined as being less than 50%) the patient tends to suffer from treatment resistant depression. In this case the patient remains depressed because conventional methods such as psychotherapy and

Table 2: A comparison of different therapies and their effect sizes and conclusion (Cuijpers,

Andersson, Donker, & van Straten, 2011)

Comparison of Therapies N* Effect size CI** Conclusion

Psychotherapy vs 37 d= -0,07 -0,15 to 0,01 The efﬁcacy of psychotherapy

Pharmacotherapy for mild to moderate depression is

about the same as the efﬁcacy of

pharmacotherapy

Psychotherapy vs 19 d= 0,35 0,24 to 0,45 Combined treatment is more

combined treatment effective than psychotherapy

alone

Pharmacotherapy vs 22 d= 0,30 0,17 to 0,43 Combined treatment is more

combined treatment effective than pharmacotherapy

alone

Note: * N = Sample size

** CI = Confidence Interval

antidepressants tend to have little to no effect (Lam, Wan, Cohen, & Kennedy, 2002; Vanneste, Ost, Langguth, & De Ridder, 2012). Subsequently, an alternative option is being sought-after, to treat the TRD of the patient. These options include augmentation of medication, combinations of medication, switching to other therapies or combinations of pharmacotherapy and psychotherapy (Keller, 2005). These combinations appear to be more effective than antidepressants of psychotherapy alone (Kornstein & Schneider, 2001). Still, there is only limited evidence of the efficacy of these combinations in the treatment of TRD (Lam, et al., 2002). In Table 2 a summary follows about the efficacy of psychotherapy compared to pharmacotherapy and to combined treatment. Also pharmacotherapy versus combined treatment is being compared. The data are obtained by a study (Cuijpers, et al., 2011) which analyzed the

Figure 1 A and B (top): Non-invasive neuromodulation techniques (Vanneste, et al., 2012)

results of a series of meta-analyses about treatments of depression. Derived from Table 2, the following conclusions can be made: combined treatment is more efficient than psychotherapy or pharmacotherapy for treating depression. In addition, only a small difference is found between psychotherapy and pharmacotherapy, in favor of psychotherapy. It is worth mentioning that effect sizes in this comparative study indicate differences between two treatments at post-tests, instead of differences between therapy and control group (Cuijpers, et al., 2011).

TMS A promising novel therapy which could provide a possible opportunity for treating TRD, is Transcranial Magnetic Stimulation (TMS) (Fitzgerald et al., 2003). TMS is a technique which uses magnetic stimulation to activate specific brain parts. Anthony Barker and colleagues were the first to successfully use TMS in their study (Barker, Jalinous, & Freeston, 1985). TMS is a noninvasive way of stimulating the cortex through the skull by sending strong magnetic fields (Martin et al., 2003; Teneback et al., 1999). See Figure 1 for images of TMS being applied on the scalp. There is a diversity of TMS implementation, depending on the purpose of stimulation. For stimulation with high focality, a figure-eight coil can be recommended (figure 1A), whereas double cone coil is preferred for stimulating deep brain parts (figure 1B) (Terao & Ugawa, 2002).

Figure 2 Visual illustration of the induction of electrical currents in the brain through the magnetic pulses applied by means of the coil positioned above the head (Ridding & Rothwell, 2007)

Note: The black arrow is the electrical current, the magnetic pulses are the red/pink lines and

the coil is the grey 8-shaped figure

In TMS, a coil will be placed on the patient’s scalp. Figure 2 displays an overall view of the mechanism of rTMS. This coil eradiates magnetic pulses and due to the changing magnetic field,

an electrical current is caused in the underlying brain tissue which penetrates the membranes of the neurons (Terao & Ugawa, 2002). Depending on several parameters, such as stimulation intensity, duration, amount of sessions and frequency, this may result in either activation or disruption of the specific brain parts (Herrmann & Ebmeier, 2009). Thus, this causes an excitation or an inhibition in the neurons. The underlying mechanism of TMS is based on Faraday’s law of electromagnetic induction. According to this law, a magnetic pulse which is situated near conductors will be transformed into an electric current (Bohning, 2000). As a result this current will depolarize or hyperpolarize the underlying nerve cells oriented to the magnetic field. In this way parts of the brain can be either stimulated or inhibited. Based on the technique of TMS, repetitive Transcranial Magnetic Stimulation (rTMS) was developed. This is a variant of TMS where the magnetic pulses are repeated at frequencies up to 50 Hz (Ji et al., 1998). It consists of several trials in which the patient receives these magnetic pulses. The time of the trial depends on many factors such as intensity, duration, frequency and location and is therefore variable. Unlike the electrical stimulation of the scalp, the magnetic pulses of rTMS eradiated by the coil enter the brain unimpeded (Padberg & George, 2009). In this way they cause a depolarization or hyperpolarization in the underlying neurons. Because of the interconnected nature of the cortical neurons, rTMS also exerts distant effects to surrounding areas of the site of stimulation, connected to the neural network (Lisanby & Belmaker, 2000). It not only influences the specific part of the brain which is stimulated, but also the surrounding brain parts. Depending on the site of stimulation, different effects of TMS treatment will be obtained. When the motor cortex is stimulated, a twitch in the hand or leg is caused as a result of a single stimulus (Barker, et al., 1985). TMS is also suggested to have effects on language (Epstein et al., 1996) and vision (Amassian et al., 1989) when applied. Some studies report no long-term cognitive side effects of TMS (Triggs et al., 1999). Memory processes such as encoding and retrieval, can be transiently disturbed when TMS is used on the dorsolateral prefrontal cortex (Rossi & Rossini, 2004). However, rTMS can also enhance rather than disturb cognitive performance. Effects were found such as shortening of picture naming and action naming, improving subjects speed at finding the solution to a reasoning puzzle and improving performance on a choice reaction task.

On the contrary, some studies (Gersner, Kravetz, Feil, Pell, & Zangen, 2011; Rossini & Rossi, 2007) found TMS to cause long-term effects, which may be beneficial for treatment with TMS. One study (Gersner, et al., 2011) suggests that neural activity during stimulation can affect the neurochemical outcomes. Furthermore, long-term changes in the levels of brain-derived neurotrophic factor (BDNF) can be found in the brain after stimulation (Zanardini et al., 2006). This study suggests a correlation between decreased levels of BDNF and depressive symptoms. rTMS might be capable of increasing these levels. This gives us more insight in the underlying processes and can therefore be beneficial for the treatment of depression. In the recent years, studies have suggested that rTMS might help in reducing depression. (Schutter, 2009). The antidepressant effect of rTMS has been found to improve symptoms of depression such as psychic anxiety, sleep disturbance and fatigue (Charnsil, Suttajit, Boonyanaruthee, & Leelarphat, 2012).

The effects of rTMS on TRD

An overview of meta-analyses concerning the effects of TMS on depression can be found in Table 3. Statistical information such as sample size (N), the amount of studies, stimulation site, effect size and the corresponding conclusion is given as well. The meta-analysis of Kozel and George (2002) found an effect of left prefrontal cortex rTMS to treat depression. The overall effect size was 0.53 and was found to be robust. Martin et al. (2003) found a significant result in their meta-analysis for sham versus active groups on the Hamilton Rating Scale for Depression (HRSD), but not on the Beck Depression Inventory (BDI). However, the quality of the included studies was low, especially because of the small sample size. Therefore the possibility of rTMS to be a beneficial intervention cannot be excluded, according to the authors. Another meta-analysis (Gross, Nakamura, Pascual-Leone, & Fregni, 2007) compared the meta-analyses about rTMS and depression in the past 12 months with the first rTMS clinical trials on depression. The results were significant and proved rTMS efficacy to have improved over time. The largest differences were found when studies of high-frequency left dorsolateral prefrontal cortex (LDLPFC) and low-frequency right dorsolateral prefrontal cortex (RDLPFC) were compared to earlier studies. However, it is worth mentioning that in this study the group ‘recent meta-analyses’ consisted out of only 5 studies. The meta-

Table 3: An overview of meta-analyses of TMS and depression

Meta-analysis N* Studies Stimulation Effect Conclusion

Site size**

(Kozel & George, 230 12 LPFC d=0,53 LPFC rTMS is an acute

2002) CI=0,24 antidepressant treatment with

to 0,82 significant effect sizes and

measurable clinical improvement

(Martin, et al., 362 19 Any SMD= Current trials are low of quality and

2003) location -0,35 and provide insufficient evidence to

-0,24*** support the use of rTMS in the

CI=-0,66 treatment of depression

to -0,04

(Gross, et al., 598 18 - SMD = Recent rTMS trials show larger

2007) -0,76 antidepressant effects compared

CI=-1,01 with earlier studies

to -0,51

(Lam, Chan, 1092 24 Any d=0,48 For patients with TRD, rTMS

Wilkins-Ho, & location CI=0,28 appears to provide significant

Yatham, 2008) to 0,69 benefits in short-term treatment

studies

Schutter (2009) 1164 30 LDLPFC d = 0.39 High Frequency rTMS over the

CI = 0,25 LDLPFC is superior to sham

to 0,54

Schutter (2010) 252 9 Frontal d=0,63 Slow-frequency rTMS to the frontal

cortex CI = 0,03 cortex is more effective than sham

to 1,24 treatment and may be equally

effective as fast-frequency rTMS in

the treatment of MDD

(Allan, 1531 31 LDLPFC, g=0,64 TMS appears to be an effective

Herrmann, & RDLPFC CI= 0,50 treatment in the management of

Ebmeier, 2011) and bilateral to 0,79 mood disorders

(Berlim, Van den 279 7 Bilateral CI=-1,95 Bileral rTMS is a promising

Eynde, & to 9,52 treatment for MD as it provides

Daskalakis, 2012) clinically meaningful benefits that

are comparable with those of

standard antidepressants and

unilateral rTMS

Note: * N = Total amount of subjects (sample size)

** Effect size: g =Hedges g, d = Cohen’s d, SMD = standardized mean difference, CI =

Confidence Interval

*** Measured for two different questionnaires: Hamilton Rating Scale for Depression

(-0,35) and Beck Depression Inventory (-0,24)

analysis of Lam et al. (2008) found significant results for rTMS in the treatment of depression, although these were accompanied by response and remission rates. Schutter, Laman, van Honk, Vergouwen, and Koerselman (2009) found also significant results which indicate LDLPFC

rTMS to be superior to sham in the treatment of depression. However, the lack of a proper control condition is a limitation of this study. Another meta-analysis (Schutter, 2010) found significant results and suggests low-frequency rTMS on the RDLPFC to be more effective than sham in the treatment of depression. Furthermore, due to the fact that both low and high frequency stimulations are suggested to be equally effective in this study, it favors slow- frequency on the RDLPFC compared to high-frequency on the LDLPFC because slow-frequency might be better tolerated and permits longer safe stimulation periods. The meta-analysis of Allan et al. (2011) found significant results for depression treatment, although these effects appeared not to last beyond 12 weeks. This is possibly caused by the variety of rTMS parameters and the authors presume the golden standard of rTMS treatment has yet to be discovered. The final meta- analysis (Berlim et al., 2012) suggests bilateral rTMS to be at least as effective as standard antidepressants and as unilateral rTMS. Possibly it can offer a solution for unilateral resistant patients. This review examines the effects of rTMS on TRD. Early studies already showed a link between the use of TMS and alleviation of depressive symptoms (George et al., 1995). In this study one of the initial rTMS trials for the treatment of depression is presented. The patients received HRSD before and after treatment. The scores decreased from 23.8 to 17.5 after treatment and this appeared to be a significant result (p=0.02). This study is one of the first to provide evidence for rTMS to be an effective way in reducing depressive symptoms. Accompanied by other evidence (Dell'osso et al., 2011; Jhanwar, Bishnoi, Singh, & Jhanwar, 2011), this implies TMS to be a promising new therapy in the treatment of depression.

Parameters Several factors appear to determine the effect of rTMS, namely stimulation intensity, duration, frequency and location (Herrmann & Ebmeier, 2009). All of these parameters have different influences on the specific part of the brain (Fuggetta & Noh, 2012).

A. Intensity The intensity of rTMS stimulation has great influences on the cortex. In specific, the cortex activation depends on the intensity of the stimulated brain part (Fitzgerald, Brown, Daskalakis, Chen, & Kulkarni, 2002). The intensity of rTMS is based on the patient’s individual motor

threshold (MT). This is the individual’s threshold to produce motor activity when the motor cortex is stimulated. In the procedure of TMS it is common to first stimulate the motor cortex to determine someone’s individual threshold. This motor cortex stimulation will cause a twitch in for example the hand. The stimulation intensity is decreased gradually until the MT is found. This threshold is the turning point where a movement because of stimulation can still be observed. This twitch is being measured by electromyography (EMG) and is referred to as a Motor Evoked Potential (MEP). The intensity of rTMS is based on the intensity needed to produce a MEP, depending on their individual MT (Moacyr, Marina, & Lisanby, 2010). One study divided patients into three groups and stimulated them at different intensities (Padberg et al., 2002). Best results were obtained with the group which was stimulated at 100% of their individual MT. These showed significant less depressive symptoms compared to the other groups after rTMS treatment. Another study suggests higher intensity TMS to cause more general activity both under the coil and contralaterally (Nahas et al., 2001). In this study there was stimulated at levels of 80%, 100% and 120% of the individual MT. Its results suggest that a higher intensity of TMS was found to cause more brain activity compared to a lower intensity. Stimulation at 80% of the MT of the individual for example, failed to produce significant prefrontal changes compared to the rest (Nahas, et al., 2001). In summary, stimulation intensity is a very important parameter of TMS treatment; there it differs among each individual, because of their individual MT.

B. Duration and sessions The duration of stimulation can vary greatly. Instead of single pulses which were being used in earlier studies, the trend started to develop to treat with repeated pulses (Gross, et al., 2007). The increase went from less than 1000 pulses in early studies to more than 2000 pulses afterwards and these alterations appeared to be more effective (Tice, 2009). Besides the number of pulses, the number of rTMS sessions in general has increased as well. First only a little amount of rTMS sessions were performed, but later on more sessions in general became the standard for treatment. This increase in sessions also appeared to be an improvement in rTMS treatment efficacy for the reduction of depression compared to earlier studies (Gross, et al., 2007).

C. Frequency A distinction can be made between low (or slow) and high frequencies. Low frequencies can be defined as frequencies containing up to 1 Hz. High frequencies on the other hand, start from 1 Hz and can reach levels up to 30 Hz or more (Rossi & Rossini, 2004). Whereas the low frequency might cause subtle changes in frontal alpha asymmetry, the high frequency triggers vast bioelectrical changes in the stimulated brain region (Valiulis et al., 2012). In addition, increases in delta power on the left hemisphere appear to correlate with positive clinical effects. Other studies found that low-frequency rTMS can inhibit brain parts and that these effects can last for minutes or sometimes hours (Wassermann & Lisanby, 2001). This effect however, differs for each individual. The inhibition of specific brain parts can be used for obtaining knowledge about brain mapping or for rehabilitative purposes (Rossi & Rossini, 2004) and therefore rTMS can be very helpful. In general, high frequency of the rTMS used on the stimulated brain regions was found to cause an activation of the specific part, whereas a relatively low frequency would have an inhibitory effect at the brain region (Rossi & Rossini, 2004).

D. Location Another important parameter of rTMS is location. Stimulation at different brain regions tends to cause different effects. Studies show the effects of TMS on depression to be the most effective when rTMS is being used on the LDLPFC (Eranti et al., 2007; George, et al., 1995; Rosenquist, Krystal, Heart, Demitrack, & Vaughn McCall, 2012). However, some studies suggest the stimulation of the RDLPFC to be effective as well for the treatment of depression (Januel et al., 2006; Schutter, 2010). In fact, there are also studies indicating bilateral stimulation of the cortex to be as efficient as unilateral stimulation (Berlim, et al., 2012). rTMS trends A large variety of different parameters is being used while conducting rTMS. Many studies tried to discover the golden standard concerning the most effective rTMS results by the use of different parameters (Padberg, et al., 2002; Zyss, Mamczarz, & Vetulani, 1999). Therefore, nowadays parameters are being used such as a higher frequency on the left dorsolateral prefrontal cortex, more numbers of pulses and more sessions in general for reducing depression (Tice, 2009). Research has shown that low intensity rTMS (beneath the MT) didn’t show any

significant improvement in mood (Padberg, et al., 2002), whereas high frequency rTMS being used on the LDLPFC however, caused an improvement of mood symptoms (Schrijvers, Baeken, De Raedt, & Sabbe, 2012). The stimulation of the DLPFC has currently proven to be an effective way of treating depression (Rosenquist, et al., 2012; Schrijvers, et al., 2012). TMS is a relatively new method for the treatment of depression, especially when the patient suffers from treatment resistant depression (TRD). The current literature suggests rTMS to be a good alternative for Electroconvulsive Therapy (ECT) (Dannon, Dolberg, Schreiber, & Grunhaus, 2002) and therefore the next section describes a comparison between both.

Comparison with ECT ECT was developed more than 70 years ago and has been an efficient but controversial way of treating a treatment resistant depression (Kellner et al., 2012). Possibly, ECT and rTMS create similar therapeutic effects, because of the overlapping responses. Although in both therapies in general anti-depressive effects are achieved, the underlying mechanisms may be activated in different ways. Whereas the current in rTMS is induced by electromagnetic induction, the current in ECT is induced by direct application of voltage (Ji, et al., 1998). The electrical current used in ECT, will cause a seizure in the brain and this will in turn cause convulsions which are thought to alter neurotransmitter systems in the brain (Merkl, Heuser, & Bajbouj, 2009). Some studies indicate rTMS to be as effective as ECT (Dannon, et al., 2002; Rosa et al., 2006) with less adverse effects. Moreover, ECT is nowadays perceived as being too aggressive, because of the risks and side effects, such as the ECT-related transient (and maybe long-term) cognitive impairment (Kozel & George, 2002; Myczkowski et al., 2012). Therefore, rTMS might be a more preferable alternative for the treatment of TRD, compared to ECT. A great advantage of rTMS compared to ECT is that anesthesia or sedation is not required for rTMS and no physical damage is dealt to the patient. Unlike ECT, in rTMS the patient remains conscious during treatment. Other advantages include the rTMS technique to be more localized than ECT and no muscle relaxants are needed. Furthermore, it’s easier to administer and there might be less stigma surrounding rTMS compared to ECT (Janicak et al., 2002). Unlike ECT, rTMS is not associated with any transient negative cognitive effects (Holtzheimer, Russo, Claypoole, Roy-Byrne, & Avery, 2004). One study in fact suggests that rTMS has some mild beneficial effects in some areas of cognition, such as verbal memory,

psychomotor speed and concentration (Hausmann et al., 2004). Besides the fact that studies showed no significant differences between the effects of rTMS and ECT (Dannon, et al., 2002), TMS offers an economic benefit as well, given the fact that the costs of ECT treatments are higher than the treatments of rTMS (Kozel, George, & Simpson, 2004). Because of these issues, rTMS may offer a solution for TRD as a milder, cheaper and effective way of treating TRD with less adverse effects (Schulze-Rauschenbach et al., 2005). Several studies already showed the antidepressant effect of rTMS on treatment resistant depression (Nemeroff, 2007) to be equally effective as ECT (Pridmore, Bruno, Turnier-Shea, Reid, & Rybak, 2000). In summary, TMS tends to be a good alternative for treating TRD (Berman et al., 2000; Kozel & George, 2002; Rosa, et al., 2006).

Biological underpinnings of TMS on depression

There are many studies indicating that rTMS significantly reduces depressive symptoms (Bortolomasi et al., 2007; Fitzgerald & Daskalakis, 2011; Rosenquist, et al., 2012). However, the underlying mechanisms through which this takes place are largely unknown. In this section biological underpinnings concerning the way TMS helps in reducing depression are discussed. In general, the prefrontal cortex is thought to be important for the mood regulation of the person (George, Ketter, & Post, 1994). The idea of the possible role of the dorsolateral prefrontal cortex in mood regulation was based upon former studies (Baxter et al., 1989). Earlier observations in depression have shown that depression as a consequence of a stroke was often associated with prefrontal cortex damage on the left side, but not on the right side. More evidence for the role of the left prefrontal cortex in depression can be found in neuro-imaging, which demonstrated a hypoactivity in the left anterior cortex in depressive patients (Baxter et al., 1989). Another study also revealed a reduced blood flow and metabolism in the left DLPFC in patients suffering from MDD (Grimm et al., 2008). These insights provide evidence for the role of the DLPFC in mood regulation. Whereas the left DLPFC in specific is thought to be responsible for the production and regulation of positive affect, the right DLPFC on the other hand, is possibly related to the production and regulation of negative affect (Tice, 2009).

Figure 3 Changes in rCBF measured by SPECT in brain areas associated with depression, after rTMS treatment (Kito, Fujita, & Koga, 2008)

Other studies confirm the involvement of the DLPFC in mood regulation (Baeken & De Raedt, 2011; Triggs et al., 1999). Kito et al. (2008) aimed in their study to evaluate changes in regional cerebral blood flow (rCBF) by using single photon emission computed tomography (SPECT) to reveal alteration in neuroanatomical function when rTMS was administered. The results (Figure 3) include a significantly increased rCBF in the LDLPFC after high-frequency rTMS. In addition, a negative correlation was observed between rCBF and depressive symptoms, indicating that the increase in rCBF resulted in a decrease of depressive symptoms. According to the mechanism of rTMS, a neuronal depolarization is caused in the brain while stimulated. Specific brain parts can be either activated or inhibited depending on the frequency of the stimulation. Studies suggest that stimulation with high frequency increases activity in the specific brain part, whereas stimulation with low frequency reduces the activity in this part (Speer et al., 2000). The electrical currents of rTMS are thought to influence the release

of several neurotransmitters in the brain such as serotonin, norepinephrine and dopamine (Baeken & De Raedt, 2011; Fuggetta & Noh, 2012). These neurotransmitters were found to play an important role in depression (Maas, 1979; Nutt, 2008). Although most rTMS research agrees about the involvement of neurotransmitters in the rTMS procedure for reducing depressive symptoms, the exact underlying mechanism is still unclear. It is suggested that the hypoactivity of the left DLPFC tends to cause depression. For this reason, the stimulation with high frequencies (which causes an excitatory effect in the stimulated brain part) is used for the left DLPFC (which concerns hypoactivity) for treatment (Schutter, 2009). As a consequence, more neurotransmitters may be released in the brain, which are suggested to improve the mood symptoms in patients with TRD (Tice, 2009). Some studies however, focus on the right DLPFC. Because the right DLPFC is suggested to be responsible for the negative affect, this brain part is stimulated with low frequencies, which cause an inhibitory effect (Isenberg et al., 2005; Klein et al., 1999). In other words, the negative affect of the RDLPFC is inhibited. Two studies (Isenberg, et al., 2005; Schutter, 2010) in fact suggested the stimulation of the RDLPFC with low-frequency to be equally effective compared to stimulation of the LDLPFC with high-frequency rTMS. In summary, rTMS is an intervention which may induce an alteration in the underlying neurons of patient when stimulated. In most rTMS studies the positive affect (the LDLPFC) is being stimulated, while others inhibit the negative affect (the RDLPFC). Both mechanisms tend to reduce depressive symptoms and are therefore a good way of treating treatment resistant depression. These mechanisms operate by means of their underlying biological underpinnings in reducing depressive symptoms.

Biological underpinnings Recent studies have placed an emphasis on the after-effects of rTMS (Gersner, et al., 2011). Some of these theories which are mainly based upon animal models, postulate long-term potentiation (LTP) and long-term depression (LTD) as potential underlying mechanisms of rTMS (Bliss & Cooke, 2011; Lisanby & Belmaker, 2000; Wang, Wang, & Scheich, 1996). Long-term potentiation concerns the long-lasting increase in strength of a synapse, whereas long- term depression describes the reduction in efficacy of the synapse (Massey & Bashir, 2007). Evidence for LTP and LTD to be involved in underlying mechanisms of rTMS, is based upon an

early animal study (Bliss & Lomo, 1973). This study stimulated granule cells in rabbits. After stimulation, potentiation in the granule cells was found for periods ranging from 30 minutes up to 10 hours. As a conclusion, the authors suggest that the effects last beyond the stimulation time and involve long-term potentiation. In addition, LTP may be caused by an increase in synaptic efficacy and an increase in the excitability of granule cells population. Based on this research, a LTP study in humans was conducted (Esser et al., 2006). In this study, the cortical responses to single TMS pulses were measured by EEG before and after applying rTMS. This study found that after high-frequency rTMS the motor responses were significantly increased (p < 0.05). These potentiated responses were found to last beyond the time of stimulation and this study therefore provides evidence for a direct relation of LTP induced by rTMS in humans. More evidence for LTP to be the underlying mechanism of high-frequency rTMS, is provided by Crupi (2007). In this study, mice first received rTMS and their brain was analyzed subsequently. Increases in brain plasticity and cell proliferation were observed and thence the main conclusion drafted from this study is that high-frequency rTMS enhances LTP. Evidence for LTD to be the underlying mechanism of low-frequency rTMS, can be found in a study of Chen et al. (1997). This study demonstrated in two experiments that low-frequency rTMS (0.9 Hz) for 15 minutes caused a significant decrease (p = 0.006) in motor cortex excitability. On the other hand, 0.1 Hz stimulation didn’t cause any significant change in MEP amplitudes. This can be explained because of the low rate of stimulation, which might be too weak to cause any significant change. Overall, evidence for a link between low-frequency rTMS and LTD was disclosed in this study. Another study (Fitzgerald & Daskalakis, 2011) also confirms this, by indicating that low-frequency rTMS which is thought to induce LTD-like effects, reduces depressive symptoms. A final example which provides evidence for LTP and LTD as being the underlying mechanism of rTMS, can be found in studies of Theta Burst Stimulation (Cardenas-Morales, Nowak, Kammer, Wolf, & Schonfeldt-Lecuona, 2010; Stagg et al., 2009). Theta Burst Stimulation (TBS) is a way of stimulation which is derived from rTMS and involves applying short trains of stimuli at high frequencies repeated at intervals of 200ms. Pulses are applied in bursts of three and delivered at frequencies of 50 Hz (Oberman, Edwards, Eldaief, & Pascual- Leone, 2011). It was based on animal studies which showed that bursts repeated at 5 Hz (theta rhythm) induced LTP (Larson, Wong, & Lynch, 1986). In TBS, a distinction is made between

continuous TBS (cTBS) and intermittent TBS (iTBS). The cTBS were found to inhibit MEPs, whereas the iTBS tends to have an excitatory effect on MEPs. Thus, TBS leads to after-effects that may reflect LTP/LTP-like synaptic effects (Stagg, et al., 2009). Whereas iTBS may induce LTP-like effects, cTBS are thought to cause LTD-like effects (Cardenas-Morales, et al., 2010). rTMS may cause long-lasting changes in the efficacy of the synaptic connections in the neurons. LTP and LTD effects were mainly found in animal studies and rTMS possibly mimics the effects of LTD and LTP (Huang, Edwards, Rounis, Bhatia, & Rothwell, 2005). LTP and LTD evoked by TMS may be caused by an upregulation or downregulation in the neurons. An upregulation involves an increase in the quantity of cellular components, whereas a downregulation concerns decrease in cellular components. (Ikeda, Kurosawa, Morimoto, Kitayama, & Nukina, 2013). These may arise through the magnetic radiation from rTMS. Thus, possibly by means of upregulation and downregulation, the LTP and LTD mechanisms of rTMS may reduce depressive symptoms in TRD. In conclusion, it is suggested that the underlying mechanism of rTMS possibly consists of LTP- and LTD-like effects on the cortex, which influence the cortex even after stimulation. In both mechanisms the underlying structure of the neurons has been modified. Whereas in high- frequency rTMS LTP-like effects are induced, low-frequency rTMS may cause LTD-like effects. Consequently, LTP and LTD may be the potential biological underpinnings of rTMS.

Discussion

This review confirmed the presumption that rTMS is an effective way of reducing depressive symptoms. The left dorsolateral prefrontal cortex tends to be related with positive affect and shows reduced activity in the LDLPFC in depressive patients. Stimulation with high frequency therefore activates the specific brain part, presumably through the mechanism of LTP, and is thought to increase the release of neurotransmitters related to depression such as serotonin, norepinephrine and dopamine. The right dorsolateral prefrontal cortex (RDLPFC) is thought to be responsible for the negative affect. Stimulation of this part with low frequencies therefore may lead to a suppression of the negative affect due to LTD-effects. The biological underpinnings of rTMS may consist of LTP and LTD-like effects. In general, rTMS seems to be a good alternative therapy for treating treatment resistant depression.

One limitation of this study is the absence of an adequate explanation for neural connectivity. In TMS, specific brain parts are being stimulated through the skull and cause primarily direct effects to the underlying brain tissue. However, the interconnected nature of the brain is not taken into account. The current which causes the direct effect in the brain is also connected to other brain parts and these are influenced as well. The changes induced by TMS can not only be observed in the direct underlying stimulation site, but also in regions presumably connected with this site (Paus et al., 1997). More attention should be given to indirect effects, because these tend to influence the cortex as well. Furthermore, when stimulating the left motor cortex, one study suggests a strong negative correlation (r = -0,86) with the contralateral hemisphere (Fox et al., 1997). This indicates an inhibitory connectivity between these brain parts. This example reflects the variety of effects rTMS can cause and should therefore be more investigated. The same current can have different effects in different brain parts. Not only the direct site of stimulation should be taken into account, but also the interconnected nature and thus the linked brain parts. With an overall picture of both direct effects and indirect effects of rTMS, the understanding of rTMS and the treatment of TRD can be improved. Some research (Davidson, 1983; Spielberg, Stewart, Levin, Miller, & Heller, 2008) suggests the current knowledge about the LDLPFC for being responsible for positive affect to be incomplete. The role of the RDLPFC for causing the negative affect is also suggested to be inaccurate. Those studies suggest that these brain regions are not for positive or negative affect, but are involved in processes of approach motivation and withdrawal motivation (Harmon-Jones, 2003). According to this theory, the LDLPFC is associated with approach behavior and the RDLPFC causes a withdrawal response. The fact that the true role of the LDLPFC and RDLPFC still isn’t clear indicates there is need for more research about this topic. There is also an urgent need for more knowledge about rTMS parameters. Although these were discussed in this review, no golden standard for parameters of rTMS was offered in this article. In fact, some research has suggested no standard parameters for the treatment of TMS can be found at all, possibly because TMS could have a nonspecific effect on depression (Herrmann & Ebmeier, 2006) Thus, no ideal set of parameters could be determined, due to the fact that the nature of the effect of TMS on depression might not be simplistic, but rather complicated. One study already showed the importance of a standardized set of parameters for rTMS (Herrmann & Ebmeier, 2006) and emphasizes the importance of investigating the complex

nature of rTMS for depression. Although significant results were found compared with sham (d = 0.71), this study failed to identify the optimal rTMS parameters and states that these are required for improving rTMS efficacy. Only with parameters standardized, meaningful comparisons concerning the efficacy of the treatment can be made between rTMS and other therapies. Moreover, with a golden standard for rTMS treatment, future rTMS research will increase in efficacy, because a basic set of parameters will be available which produces optimal rTMS results. The consensus among researchers also standardizes the treatment and this allows comparison with other therapies. Therefore a great urgency arises to closely examine these parameters and their influences on rTMS to define the exact meaning of treatment resistant depression. One of the parameters which requires further investigation is stimulation intensity. Many rTMS studies utilize the rTMS stimulation intensity based upon the individual motor threshold (MT). At this MT, a motor evoked potential (MEP) can be recorded using EMG. This simple metric however, might be inadequate because the distance between the coil and the cortex is not taken into account and this could influence the stimulation efficacy (McConnell et al., 2001). More specific, a positive correlation was found between the MT and the distance from the cortex (Kozel et al., 2000). Furthermore, this study also suggests a positive correlation between distance and age. As a consequence, the MT is not determined accurately. In conclusion, new ways of determining the ideal intensity of rTMS stimulation are needed, because measurements based upon MT appear to be inadequate. Aspects such as coil-cortex distance should be taken into account. An alternative for determining the stimulation intensity is provided by (Cai et al., 2012), however this method also requires further investigation. An emphasis should also be placed upon the different locations in the brain for rTMS locations. Currently, the dorsolateral prefrontal cortex is most under attention in rTMS treatment, because it is an effective way of treating depression. A study (Downar & Daskalakis, 2012) however, emphasizes the fact that little is known about the influence of rTMS on other brain parts. Furthermore, other brain parts are also involved in depression (Drevets, Price, & Furey, 2008; Ressler & Mayberg, 2007). Stimulating these could be as successful as stimulation of the DLPFC or perhaps even more effective. More evidence for the stimulation of other brain regions is provided by Schutter et al. (2009). This study suggests that stimulation of the right parietal cortex causes antidepressant effects and therefore is an efficient way of treating depression as

well. This assumption is based upon research indicating the right parietal cortex to be involved in the depression as well (Moratti, Rubio, Campo, Keil, & Ortiz, 2008; Uytdenhoef et al., 1983). Another study (Schutter & van Honk, 2005) also states a framework for investigating alternative brain regions. In this study, the focus is on slow rTMS to the parietal cortex and fast rTMS over the cerebellum. Evidence for the possible role of the parietal cortex was provided by Uytdenhoef et al. (1983). This study measured rCBF and found hypovascularization in the parietal cortex. The involvement of the cerebellum in depression was based upon a study (Schutter, van Honk, d'Alfonso, Peper, & Panksepp, 2003) which suggested a possible link between the cerebellum and prefrontal regions (which are associated with affect). Hence, in the future the influence of rTMS on new brain regions (e.g. dorsomedial prefrontal cortex, frontopolar cortex, ventromedial prefrontal cortex, ventrolateral prefrontal cortex, parietal cortex and cerebellum) should be examined. In summary, seeking alternative brain regions for stimulation could provide new opportunities for further improving rTMS treatment, because these may be equally or even more effective compared to currently investigated brain areas. Next to the focus on other brain regions, combinations of therapies deserve attention as well. Recommendations are given to broadening the knowledge of those therapies, because medication seems to be extra efficient combined with rTMS treatment (Schüle et al., 2003). In this study, patients were given medication after rTMS treatment. Results indicate the use of medication after treatment to further improve the mood. The depressive symptoms for combining rTMS and medication were significantly lower compared to rTMS treatment only and require therefore further investigation. In addition, the bilateral stimulation should be considered as an alternative. One study of simultaneously bilateral prefrontal rTMS (Loo et al., 2003) was conducted where both the cortices received high-frequency rTMS. However, this study didn’t show any significant results compared to sham. A possible explanation why no significant results were found, is because both cortices were stimulated with high frequency. The stimulation of the LDLPFC with high frequency and RDLPFC with low frequency however, might cause antidepressant effects. Namely, evidence shows the high-frequency stimulation of the LDLPFC as well as the low- frequency stimulation of the RDLPFC to produce antidepressant effects. As a consequence, a combination of these two strategies might be extra effective and should therefore be closely examined. Evidence for this is provided by Fitzgerald et al. (2006). In their study, they

stimulated left sided high-frequency and right sided low-frequency rTMS and found significant improvement after 2 weeks. However, all subjects used medication and therefore these data should be interpreted carefully. In general, bilateral stimulation with rTMS might prove useful for treating TRD and should be further investigated for future perspectives. To this date no clear definition of treatment resistant depression (TRD) has been used in the literature about TMS. The given definition in this review provided by Maalouf et al. (2011) is but one definition and there is no consensus about the definition of TRD so far. Therefore, the corresponding studies display a great variety of definitions and samples sizes of TRD. As a consequence, the supply of scientific evidence for the efficacy of rTMS in treating TRD, is impeded. First, a consensus should be gained about this definition, so all the research about the topic will be measured following the same standards. When this definition is standardized, more reliable evidence about the efficacy of rTMS treatment for TRD can be acquired. Therefore, an urgent need exists for unanimity about the TRD definition. In the current literature, most rTMS treatments involving depression are only administered in case of TRD. However, therapy resistant depression concerns severely depressed patients and these are presumably difficult to treat. The results obtained by rTMS are only applicable on samples of TRD, but patients with MDD tend to have a less severe depression compared to TRD patients. This indicates that the results of rTMS in TRD may be amplified when rTMS is applied upon MDD patients. Hence, recommendations are made for therapies in which not only TRD, but also patients suffering from Major Depressive Disorder receive rTMS for alleviation of depressive symptoms. Ultimately, repetitive Transcranial Magnetic Stimulation is a promising way of treating Treatment Resistant Depression which possibly operates through the mechanisms of long-term potentiation and long-term depression. It might offer a solution when conventional therapies such as psychotherapy and pharmacotherapy tend to have little effect.

References: Allan, C. L., Herrmann, L. L., & Ebmeier, K. P. (2011). Transcranial magnetic stimulation in the management of mood disorders. Neuropsychobiology, 64(3), 163-169. doi: 10.1159/000328951 Amassian, V. E., Cracco, R. Q., Maccabee, P. J., Cracco, J. B., Rudell, A., & Eberle, L. (1989). Suppression of visual perception by magnetic coil stimulation of human occipital cortex. Electroencephalogr Clin Neurophysiol, 74(6), 458-462. American Psychiatric Association, A. P. A. (2000). Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR Fourth Edition (Text Revision): Amer Psychiatric Pub. Baeken, C., & De Raedt, R. (2011). Neurobiological mechanisms of repetitive transcranial magnetic stimulation on the underlying neurocircuitry in unipolar depression. Dialogues Clin Neurosci, 13(1), 139-145. Barker, A. T., Jalinous, R., & Freeston, I. L. (1985). Non-invasive magnetic stimulation of human motor cortex. Lancet, 1(8437), 1106-1107. Baxter, L. R., Schwartz, J. M., Phelps, M. E., Mazziotta, J. C., Guze, B. H., & Selin, C. E. (1989). Reduction of prefrontal cortex glucose metabolism common to three types of depression. Archives of General Psychiatry 46, 243-250. Berlim, M. T., Van den Eynde, F., & Daskalakis, Z. J. (2012). A systematic review and meta- analysis on the efficacy and acceptability of bilateral repetitive transcranial magnetic stimulation (rTMS) for treating major depression. Psychological medicine, 1-10. doi: 10.1017/s0033291712002802 Berman, R. M., Narasimhan, M., Sanacora, G., Miano, A. P., Hoffman, R. E., Hu, X. S., . . . Boutros, N. N. (2000). A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression. Biol Psychiatry, 47(4), 332-337. Bliss, T. V., & Cooke, S. F. (2011). Long-term potentiation and long-term depression: a clinical perspective. Clinics (Sao Paulo), 66 Suppl 1, 3-17. Bliss, T. V., & Lomo, T. (1973). Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol, 232(2), 331-356. Bohning, D. (2000). Introduction and overview of TMS physics. Transcranial magnetic stimulation in neuropsychiatry, 13-44. Bortolomasi, M., Minelli, A., Fuggetta, G., Perini, M., Comencini, S., Fiaschi, A., & Manganotti, P. (2007). Long-lasting effects of high frequency repetitive transcranial magnetic stimulation in major depressed patients. Psychiatry research, 150(2), 181-186. doi: http://dx.doi.org/10.1016/j.psychres.2006.04.010 Cai, W., George, J. S., Chambers, C. D., Stokes, M. G., Verbruggen, F., & Aron, A. R. (2012). Stimulating deep cortical structures with the batwing coil: how to determine the intensity for transcranial magnetic stimulation using coil-cortex distance. J Neurosci Methods, 204(2), 238-241. doi: 10.1016/j.jneumeth.2011.11.020 Cardenas-Morales, L., Nowak, D. A., Kammer, T., Wolf, R. C., & Schonfeldt-Lecuona, C. (2010). Mechanisms and applications of theta-burst rTMS on the human motor cortex. Brain Topogr, 22(4), 294-306. doi: 10.1007/s10548-009-0084-7 Charnsil, C., Suttajit, S., Boonyanaruthee, V., & Leelarphat, S. (2012). Twelve-month, prospective, open-label study of repetitive transcranial magnetic stimulation for major depressive disorder in partial remission. Neuropsychiatric disease and treatment, 8, 393- 397. doi: 10.2147/NDT.S35253

Chen, R., Classen, J., Gerloff, C., Celnik, P., Wassermann, E. M., Hallett, M., & Cohen, L. G. (1997). Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology, 48(5), 1398-1403. Crupi, R. (2007). rTMS, antidepressant effect and synaptic plasticity in rodents. Working Paper, Columbia University, New York. Retrieved from http://hdl.handle.net/10022/AC:P:10067 Cuijpers, P., Andersson, G., Donker, T., & van Straten, A. (2011). Psychological treatment of depression: results of a series of meta-analyses. Nord J Psychiatry, 65(6), 354-364. doi: 10.3109/08039488.2011.596570 Cusin, C., & Darin, D. D. (2012). Somatic therapies for treatment-resistant depression ECT, TMS, VNS, DBS.pdf. Biology of Mood & Anxiety Disorders, 2(14). Dannon, P. N., Dolberg, O. T., Schreiber, S., & Grunhaus, L. (2002). Three and six-month outcome following courses of either ECT or rTMS in a population of severely depressed individuals--preliminary report. Biol Psychiatry, 51(8), 687-690. Davidson, R. J. (1983). Hemispheric specialization for cognition and affect. London: Academic Press. Dell'osso, B., Camuri, G., Castellano, F., Vecchi, V., Benedetti, M., Bortolussi, S., & Altamura, A. C. (2011). Meta-Review of Metanalytic Studies with Repetitive Transcranial Magnetic Stimulation (rTMS) for the Treatment of Major Depression. Clin Pract Epidemiol Ment Health, 7, 167-177. doi: 10.2174/1745017901107010167 DeRubeis, R. J., Siegle, G. J., & Hollon, S. D. (2008). Cognitive therapy versus medication for depression: treatment outcomes and neural mechanisms. Nat Rev Neurosci, 9(10), 788- 796. doi: http://dx.doi.org/10.1038/nrn2345 Downar, J., & Daskalakis, Z. J. (2012). New targets for rTMS in depression: A review of convergent evidence. Brain stimulation. doi: 10.1016/j.brs.2012.08.006 Drevets, W. C., Price, J. L., & Furey, M. L. (2008). Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct, 213(1-2), 93-118. doi: 10.1007/s00429-008-0189-x Epstein, C. M., Lah, J. J., Meador, K., Weissman, J. D., Gaitan, L. E., & Dihenia, B. (1996). Optimum stimulus parameters for lateralized suppression of speech with magnetic brain stimulation. Neurology, 47(6), 1590-1593. Eranti, S., Mogg, A., Pluck, G., Landau, S., Purvis, R., Brown, R. G., . . . McLoughlin, D. M. (2007). A randomized, controlled trial with 6-month follow-up of repetitive transcranial magnetic stimulation and electroconvulsive therapy for severe depression. Am J Psychiatry, 164(1), 73-81. doi: 10.1176/appi.ajp.164.1.73 Esser, S. K., Huber, R., Massimini, M., Peterson, M. J., Ferrarelli, F., & Tononi, G. (2006). A direct demonstration of cortical LTP in humans: a combined TMS/EEG study. Brain Res Bull, 69(1), 86-94. doi: 10.1016/j.brainresbull.2005.11.003 Fitzgerald, P. B., Benitez, J., de Castella, A., Daskalakis, Z. J., Brown, T. L., & Kulkarni, J. (2006). A randomized, controlled trial of sequential bilateral repetitive transcranial magnetic stimulation for treatment-resistant depression. Am J Psychiatry, 163(1), 88-94. doi: 10.1176/appi.ajp.163.1.88 Fitzgerald, P. B., Brown, T. L., Daskalakis, Z. J., Chen, R., & Kulkarni, J. (2002). Intensity- dependent effects of 1 Hz rTMS on human corticospinal excitability. Clinical Neurophysiology, 113(7), 1136-1141. doi: http://dx.doi.org/10.1016/S1388- 2457(02)00145-1

Fitzgerald, P. B., Brown, T. L., Marston, N. A., Daskalakis, Z. J., De Castella, A., & Kulkarni, J. (2003). Transcranial magnetic stimulation in the treatment of depression: a double-blind, placebo-controlled trial. Arch Gen Psychiatry, 60(10), 1002-1008. doi: 10.1001/archpsyc.60.9.1002 Fitzgerald, P. B., & Daskalakis, Z. J. (2011). The effects of repetitive transcranial magnetic stimulation in the treatment of depression. Expert Rev Med Devices, 8(1), 85-95. doi: 10.1586/erd.10.57 Fox, P., Ingham, R., George, M. S., Mayberg, H., Ingham, J., Roby, J., . . . Jerabek, P. (1997). Imaging human intra-cerebral connectivity by PET during TMS. Neuroreport, 8(12), 2787-2791. Fuggetta, G., & Noh, N. A. (2012). A neurophysiological insight into the potential link between transcranial magnetic stimulation, thalamocortical dysrhythmia and neuropsychiatric disorders. Experimental neurology. doi: 10.1016/j.expneurol.2012.10.010 George, M. S., Ketter, T. A., & Post, R. M. (1994). Prefrontal cortex dysfunction in clinical depression. Depression, 2(2), 59-72. doi: 10.1002/depr.3050020202 George, M. S., Wassermann, E. M., Williams, W. A., Callahan, A., Ketter, T. A., Basser, P., . . . Post, R. M. (1995). Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in depression. Neuroreport, 6(14), 1853-1856. Gersner, R., Kravetz, E., Feil, J., Pell, G., & Zangen, A. (2011). Long-term effects of repetitive transcranial magnetic stimulation on markers for neuroplasticity: differential outcomes in anesthetized and awake animals. J Neurosci, 31(20), 7521-7526. doi: 10.1523/jneurosci.6751-10.2011 Grimm, S., Beck, J., Schuepbach, D., Hell, D., Boesiger, P., Bermpohl, F., . . . Northoff, G. (2008). Imbalance between left and right dorsolateral prefrontal cortex in major depression is linked to negative emotional judgment: an fMRI study in severe major depressive disorder. Biol Psychiatry, 63(4), 369-376. doi: 10.1016/j.biopsych.2007.05.033 Gross, M., Nakamura, L., Pascual-Leone, A., & Fregni, F. (2007). Has repetitive transcranial magnetic stimulation (rTMS) treatment for depression improved? A systematic review and meta-analysis comparing the recent vs. the earlier rTMS studies. Acta Psychiatr Scand, 116(3), 165-173. doi: 10.1111/j.1600-0447.2007.01049.x Harmon-Jones, E. (2003). Early Career Award. Clarifying the emotive functions of asymmetrical frontal cortical activity. Psychophysiology, 40(6), 838-848. Hausmann, A., Pascual-Leone, A., Kemmler, G., Rupp, C. I., Lechner-Schoner, T., Kramer- Reinstadler, K., . . . Weiss, E. M. (2004). No deterioration of cognitive performance in an aggressive unilateral and bilateral antidepressant rTMS add-on trial. J Clin Psychiatry, 65(6), 772-782. Hawton, K., Casanas, I. C. C., Haw, C., & Saunders, K. (2013). Risk factors for suicide in individuals with depression: A systematic review. J Affect Disord. doi: 10.1016/j.jad.2013.01.004 Herrmann, L. L., & Ebmeier, K. P. (2006). Factors modifying the efficacy of transcranial magnetic stimulation in the treatment of depression: a review. J Clin Psychiatry, 67(12), 1870-1876. Herrmann, L. L., & Ebmeier, K. P. (2009). Transcranial magnetic stimulation. Psychiatry, 8(4), 130-134. doi: http://dx.doi.org/10.1016/j.mppsy.2009.01.008

Holtzheimer, P. E., 3rd, Russo, J., Claypoole, K. H., Roy-Byrne, P., & Avery, D. H. (2004). Shorter duration of depressive episode may predict response to repetitive transcranial magnetic stimulation. Depression and anxiety, 19(1), 24-30. doi: 10.1002/da.10147 Huang, Y. Z., Edwards, M. J., Rounis, E., Bhatia, K. P., & Rothwell, J. C. (2005). Theta burst stimulation of the human motor cortex. Neuron, 45(2), 201-206. doi: 10.1016/j.neuron.2004.12.033 Ikeda, T., Kurosawa, M., Morimoto, C., Kitayama, S., & Nukina, N. (2013). Multiple effects of repetitive transcranial magnetic stimulation on neuropsychiatric disorders. Biochem Biophys Res Commun. doi: 10.1016/j.bbrc.2013.03.017 Isenberg, K., Downs, D., Pierce, K., Svarakic, D., Garcia, K., Jarvis, M., . . . Kormos, T. C. (2005). Low frequency rTMS stimulation of the right frontal cortex is as effective as high frequency rTMS stimulation of the left frontal cortex for antidepressant-free, treatment- resistant depressed patients. Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists, 17(3), 153-159. Janicak, P. G., Dowd, S. M., Martis, B., Alam, D., Beedle, D., Krasuski, J., . . . Viana, M. (2002). Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression: preliminary results of a randomized trial. Biological Psychiatry, 51(8), 659- 667. doi: http://dx.doi.org/10.1016/S0006-3223(01)01354-3 Januel, D., Dumortier, G., Verdon, C. M., Stamatiadis, L., Saba, G., Cabaret, W., . . . Fermanian, J. (2006). A double-blind sham controlled study of right prefrontal repetitive transcranial magnetic stimulation (rTMS): therapeutic and cognitive effect in medication free unipolar depression during 4 weeks. Prog Neuropsychopharmacol Biol Psychiatry, 30(1), 126-130. doi: 10.1016/j.pnpbp.2005.08.016 Jhanwar, V. G., Bishnoi, R. J., Singh, L., & Jhanwar, M. R. (2011). Utility of repetitive transcranial magnetic stimulation as an augmenting treatment method in treatment- resistant depression. Indian J Psychiatry, 53(2), 145-148. doi: 10.4103/0019-5545.82543 Ji, R. R., Schlaepfer, T. E., Aizenman, C. D., Epstein, C. M., Qiu, D., Huang, J. C., & Rupp, F. (1998). Repetitive transcranial magnetic stimulation activates specific regions in rat brain. Proc Natl Acad Sci U S A, 95(26), 15635-15640. Kedzior, K. K., Rajput, V., Price, G., Lee, J., & Martin-Iverson, M. T. (2012). Cognitive correlates of repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant depression- a pilot study. BMC psychiatry, 12(1), 163. doi: 10.1186/1471-244X-12-163 Keller, M. B. (2005). Issues in treatment-resistant depression. The Journal of clinical psychiatry, 66 Suppl 8, 5-12. Kellner, C. H., Greenberg, R. M., Murrough, J. W., Bryson, E. O., Briggs, M. C., & Pasculli, R. M. (2012). ECT in treatment-resistant depression. Am J Psychiatry, 169(12), 1238-1244. doi: 10.1176/appi.ajp.2012.12050648 Kito, S., Fujita, K., & Koga, Y. (2008). Changes in regional cerebral blood flow after repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex in treatment- resistant depression. J Neuropsychiatry Clin Neurosci, 20(1), 74-80. doi: 10.1176/appi.neuropsych.20.1.74 Klein, E., Kreinin, I., Chistyakov, A., Koren, D., Mecz, L., Marmur, S., . . . Feinsod, M. (1999). Therapeutic efficacy of right prefrontal slow repetitive transcranial magnetic stimulation in major depression: a double-blind controlled study. Arch Gen Psychiatry, 56(4), 315- 320.

Koenigs, M., & Grafman, J. (2009). The functional neuroanatomy of depression: distinct roles for ventromedial and dorsolateral prefrontal cortex. [Research Support, N.I.H., Intramural Review]. Behavioural brain research, 201(2), 239-243. doi: 10.1016/j.bbr.2009.03.004 Kornstein, S. G., & Schneider, R. K. (2001). Clinical Features of Treatment-Resistant Depression. Journal of Clinical Psychiatry, 62, 18-25. Kozel, F. A., & George, M. S. (2002). Meta-analysis of left prefrontal repetitive transcranial magnetic stimulation (rTMS) to treat depression. J Psychiatr Pract, 8(5), 270-275. Kozel, F. A., George, M. S., & Simpson, K. N. (2004). Decision analysis of the cost- effectiveness of repetitive transcranial magnetic stimulation versus electroconvulsive therapy for treatment of nonpsychotic severe depression. CNS Spectr, 9(6), 476-482. Kozel, F. A., Nahas, Z., deBrux, C., Molloy, M., Lorberbaum, J. P., Bohning, D., . . . George, M. S. (2000). How coil-cortex distance relates to age, motor threshold, and antidepressant response to repetitive transcranial magnetic stimulation. J Neuropsychiatry Clin Neurosci, 12(3), 376-384. Kupfer, D. J., & Charney, D. S. (2003). “Difficult-to-treat depression”. Biological Psychiatry, 53(8), 633-634. doi: http://dx.doi.org/10.1016/S0006-3223(03)00188-4 Lam, R. W., Chan, P., Wilkins-Ho, M., & Yatham, L. N. (2008). Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and metaanalysis. Can J Psychiatry, 53(9), 621-631. Lam, R. W., Wan, D. D., Cohen, N. L., & Kennedy, S. H. (2002). Combining antidepressants for treatment-resistant depression: a review. J Clin Psychiatry, 63(8), 685-693. Larson, J., Wong, D., & Lynch, G. (1986). Patterned stimulation at the theta frequency is optimal for the induction of hippocampal long-term potentiation. Brain Research, 368(2), 347- 350. doi: http://dx.doi.org/10.1016/0006-8993(86)90579-2 Lisanby, S. H., & Belmaker, R. H. (2000). Animal models of the mechanisms of action of repetitive transcranial magnetic stimulation (RTMS): comparisons with electroconvulsive shock (ECS). Depression and anxiety, 12(3), 178-187. doi: 10.1002/1520- 6394(2000)12:3<178::aid-da10>3.0.co;2-n Loo, C. K., Mitchell, P. B., Croker, V. M., Malhi, G. S., Wen, W., Gandevia, S. C., & Sachdev, P. S. (2003). Double-blind controlled investigation of bilateral prefrontal transcranial magnetic stimulation for the treatment of resistant major depression. Psychological medicine, 33(1), 33-40. Maalouf, F. T., Atwi, M., & Brent, D. A. (2011). Treatment-resistant depression in adolescents: review and updates on clinical management. [Review]. Depression and anxiety, 28(11), 946-954. doi: 10.1002/da.20884 Maas, J. W. (1979). Neurotransmitters and depression Too much, too little, or too unstable? Trends in Neurosciences, 2(0), 306-308. doi: http://dx.doi.org/10.1016/0166- 2236(79)90118-8 Martin, J. L., Barbanoj, M. J., Schlaepfer, T. E., Thompson, E., Perez, V., & Kulisevsky, J. (2003). Repetitive transcranial magnetic stimulation for the treatment of depression. Systematic review and meta-analysis. Br J Psychiatry, 182, 480-491. Massey, P. V., & Bashir, Z. I. (2007). Long-term depression: multiple forms and implications for brain function. Trends Neurosci, 30(4), 176-184. doi: 10.1016/j.tins.2007.02.005 McConnell, K. A., Nahas, Z., Shastri, A., Lorberbaum, J. P., Kozel, F. A., Bohning, D. E., & George, M. S. (2001). The transcranial magnetic stimulation motor threshold depends on

the distance from coil to underlying cortex: a replication in healthy adults comparing two methods of assessing the distance to cortex. Biol Psychiatry, 49(5), 454-459. Merkl, A., Heuser, I., & Bajbouj, M. (2009). Antidepressant electroconvulsive therapy: mechanism of action, recent advances and limitations. Experimental neurology, 219(1), 20-26. doi: 10.1016/j.expneurol.2009.04.027 Moacyr, A. R., Marina, O. R., & Lisanby, S. H. (2010). The Black Book of Repetitive Transcranial Magnetic Stimulation: Determining Motor Threshold in rTMS, from http://www.psychweekly.com/aspx/article/articledetail.aspx?articleid=1207 Moratti, S., Rubio, G., Campo, P., Keil, A., & Ortiz, T. (2008). Hypofunction of right temporoparietal cortex during emotional arousal in depression. Arch Gen Psychiatry, 65(5), 532-541. doi: 10.1001/archpsyc.65.5.532 Myczkowski, M. L., Dias, A. M., Luvisotto, T., Arnaut, D., Bellini, B. B., Mansur, C. G., . . . Marcolin, M. A. (2012). Effects of repetitive transcranial magnetic stimulation on clinical, social, and cognitive performance in postpartum depression. Neuropsychiatric disease and treatment, 8, 491-500. doi: 10.2147/NDT.S33851 Nahas, Z., Lomarev, M., Roberts, D. R., Shastri, A., Lorberbaum, J. P., Teneback, C., . . . Bohning, D. E. (2001). Unilateral left prefrontal transcranial magnetic stimulation (TMS) produces intensity-dependent bilateral effects as measured by interleaved BOLD fMRI. Biol Psychiatry, 50(9), 712-720. Nemeroff, C. B. (2007). Prevalence and management of treatment-resistant depression. J Clin Psychiatry, 68 Suppl 8, 17-25. Nutt, D. J. (2008). Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry, 69 Suppl E1, 4-7. Oberman, L., Edwards, D., Eldaief, M., & Pascual-Leone, A. (2011). Safety of theta burst transcranial magnetic stimulation: a systematic review of the literature. J Clin Neurophysiol, 28(1), 67-74. doi: 10.1097/WNP.0b013e318205135f Padberg, & George, M. S. (2009). Repetitive transcranial magnetic stimulation of the prefrontal cortex in depression. Experimental neurology, 219(1), 2-13. doi: http://dx.doi.org/10.1016/j.expneurol.2009.04.020 Padberg, Zwanzger, P., Keck, M. E., Kathmann, N., Mikhaiel, P., Ella, R., . . . Moller, H. J. (2002). Repetitive transcranial magnetic stimulation (rTMS) in major depression: relation between efficacy and stimulation intensity. Neuropsychopharmacology, 27(4), 638-645. doi: 10.1016/s0893-133x(02)00338-x Paus, T., Jech, R., Thompson, C. J., Comeau, R., Peters, T., & Evans, A. C. (1997). Transcranial magnetic stimulation during positron emission tomography: a new method for studying connectivity of the human cerebral cortex. J Neurosci, 17(9), 3178-3184. Pridmore, S., Bruno, R., Turnier-Shea, Y., Reid, P., & Rybak, M. (2000). Comparison of unlimited numbers of rapid transcranial magnetic stimulation (rTMS) and ECT treatment sessions in major depressive episode. Int J Neuropsychopharmacol, 3(2), 129-134. doi: 10.1017/s1461145700001784 Ressler, K. J., & Mayberg, H. S. (2007). Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic. Nat Neurosci, 10(9), 1116-1124. doi: 10.1038/nn1944 Ridding, M. C., & Rothwell, J. C. (2007). Is there a future for therapeutic use of transcranial magnetic stimulation? Nat Rev Neurosci, 8(7), 559-567. doi: 10.1038/nrn2169

Rosa, M. A., Gattaz, W. F., Pascual-Leone, A., Fregni, F., Rosa, M. O., Rumi, D. O., . . . Marcolin, M. A. (2006). Comparison of repetitive transcranial magnetic stimulation and electroconvulsive therapy in unipolar non-psychotic refractory depression: a randomized, single-blind study. Int J Neuropsychopharmacol, 9(6), 667-676. doi: 10.1017/s1461145706007127 Rosenquist, P. B., Krystal, A., Heart, K. L., Demitrack, M. A., & Vaughn McCall, W. (2012). Left dorsolateral prefrontal transcranial magnetic stimulation (TMS): Sleep factor changes during treatment in patients with pharmacoresistant major depressive disorder. Psychiatry research. doi: 10.1016/j.psychres.2012.09.011 Rossi, S., & Rossini, P. M. (2004). TMS in cognitive plasticity and the potential for rehabilitation. Trends Cogn Sci, 8(6), 273-279. doi: 10.1016/j.tics.2004.04.012 Rossini, P. M., & Rossi, S. (2007). Transcranial magnetic stimulation: diagnostic, therapeutic, and research potential. Neurology, 68(7), 484-488. doi: 10.1212/01.wnl.0000250268.13789.b2 Schrijvers, D. L., Baeken, C., De Raedt, R., & Sabbe, B. G. (2012). The Impact of High- Frequency Repetitive Transcranial Magnetic Stimulation on Fine Motor Functions in Medication-Resistant Major Depression. Neuropsychobiology, 66(4), 252-258. doi: 10.1159/000341881 Schüle, C., Zwanzger, P., Baghai, T., Mikhaiel, P., Thoma, H., Möller, H.-J., . . . Padberg, F. (2003). Effects of antidepressant pharmacotherapy after repetitive transcranial magnetic stimulation in major depression: an open follow-up study. Journal of Psychiatric Research, 37(2), 145-153. doi: http://dx.doi.org/10.1016/S0022-3956(02)00101-2 Schulze-Rauschenbach, S. C., Harms, U., Schlaepfer, T. E., Maier, W., Falkai, P., & Wagner, M. (2005). Distinctive neurocognitive effects of repetitive transcranial magnetic stimulation and electroconvulsive therapy in major depression. Br J Psychiatry, 186, 410-416. doi: 10.1192/bjp.186.5.410 Schutter, D. J. (2009). Antidepressant efficacy of high-frequency transcranial magnetic stimulation over the left dorsolateral prefrontal cortex in double-blind sham-controlled designs: a meta-analysis. [Meta-Analysis Research Support, Non-U.S. Gov't]. Psychological medicine, 39(1), 65-75. doi: 10.1017/S0033291708003462 Schutter, D. J. (2010). Quantitative review of the efficacy of slow-frequency magnetic brain stimulation in major depressive disorder. [Research Support, Non-U.S. Gov't Review]. Psychological medicine, 40(11), 1789-1795. doi: 10.1017/S003329171000005X Schutter, D. J., Laman, D. M., van Honk, J., Vergouwen, A. C., & Koerselman, G. F. (2009). Partial clinical response to 2 weeks of 2 Hz repetitive transcranial magnetic stimulation to the right parietal cortex in depression. Int J Neuropsychopharmacol, 12(5), 643-650. doi: 10.1017/s1461145708009553 Schutter, D. J., & van Honk, J. (2005). A framework for targeting alternative brain regions with repetitive transcranial magnetic stimulation in the treatment of depression. J Psychiatry Neurosci, 30(2), 91-97. Schutter, D. J., van Honk, J., d'Alfonso, A. A., Peper, J. S., & Panksepp, J. (2003). High frequency repetitive transcranial magnetic over the medial cerebellum induces a shift in the prefrontal electroencephalography gamma spectrum: a pilot study in humans. Neurosci Lett, 336(2), 73-76.

Scott, J. (2001). Cognitive therapy for depression. British Medical Bulletin, 57(1), 101-113. doi: 10.1093/bmb/57.1.101 Souery, D., Amsterdam, J., de Montigny, C., Lecrubier, Y., Montgomery, S., Lipp, O., . . . Mendlewicz, J. (1999). Treatment resistant depression: methodological overview and operational criteria. Eur Neuropsychopharmacol, 9(1-2), 83-91. Speer, A. M., Kimbrell, T. A., Wassermann, E. M., J, D. R., Willis, M. W., Herscovitch, P., & Post, R. M. (2000). Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients. Biol Psychiatry, 48(12), 1133-1141. Spielberg, J. M., Stewart, J. L., Levin, R. L., Miller, G. A., & Heller, W. (2008). Prefrontal Cortex, Emotion, and Approach/Withdrawal Motivation. Soc Personal Psychol Compass, 2(1), 135-153. doi: 10.1111/j.1751-9004.2007.00064.x Stagg, C. J., Wylezinska, M., Matthews, P. M., Johansen-Berg, H., Jezzard, P., Rothwell, J. C., & Bestmann, S. (2009). Neurochemical effects of theta burst stimulation as assessed by magnetic resonance spectroscopy. J Neurophysiol, 101(6), 2872-2877. doi: 10.1152/jn.91060.2008 Teneback, C. C., Nahas, Z., Speer, A. M., Molloy, M., Stallings, L. E., Spicer, K. M., . . . George, M. S. (1999). Changes in prefrontal cortex and paralimbic activity in depression following two weeks of daily left prefrontal TMS. J Neuropsychiatry Clin Neurosci, 11(4), 426-435. Terao, Y., & Ugawa, Y. (2002). Basic mechanisms of TMS. J Clin Neurophysiol, 19(4), 322-343. Tice, J. A. M., M. D. (2009). Repetitive Transcranial Magnetic Stimulation for Treatment Resistant Depression. California Technology Assessment Forum. Triggs, W. J., McCoy, K. J., Greer, R., Rossi, F., Bowers, D., Kortenkamp, S., . . . Goodman, W. K. (1999). Effects of left frontal transcranial magnetic stimulation on depressed mood, cognition, and corticomotor threshold. Biol Psychiatry, 45(11), 1440-1446. Uytdenhoef, P., Portelange, P., Jacquy, J., Charles, G., Linkowski, P., & Mendlewicz, J. (1983). Regional cerebral blood flow and lateralized hemispheric dysfunction in depression. Br J Psychiatry, 143, 128-132. Valiulis, V., Gerulskis, G., Dapsys, K., Vistartaite, G., Siurkute, A., & Maciulis, V. (2012). Electrophysiological differences between high and low frequency rTMS protocols in depression treatment. Acta Neurobiol Exp (Wars), 72(3), 283-295. Vanneste, S., Ost, J., Langguth, B., & De Ridder, D. (2012). TMS by double-cone coil prefrontal stimulation for medication resistant chronic depression: A case report. Neurocase. doi: 10.1080/13554794.2012.732086 Wang, H., Wang, X., & Scheich, H. (1996). LTD and LTP induced by transcranial magnetic stimulation in auditory cortex. Neuroreport, 7(2), 521-525. Wassermann, E. M., & Lisanby, S. H. (2001). Therapeutic application of repetitive transcranial magnetic stimulation: a review. Clin Neurophysiol, 112(8), 1367-1377. Yoshimura, S., Okamoto, Y., Onoda, K., Matsunaga, M., Okada, G., Kunisato, Y., . . . Yamawaki, S. (2013). Cognitive behavioral therapy for depression changes medial prefrontal and ventral anterior cingulate cortex activity associated with self-referential processing. Soc Cogn Affect Neurosci. doi: 10.1093/scan/nst009 Zanardini, R., Gazzoli, A., Ventriglia, M., Perez, J., Bignotti, S., Maria Rossini, P., . . . Bocchio- Chiavetto, L. (2006). Effect of repetitive transcranial magnetic stimulation on serum brain derived neurotrophic factor in drug resistant depressed patients. J Affect Disord, 91(1), 83-86. doi: http://dx.doi.org/10.1016/j.jad.2005.12.029

Zyss, T., Mamczarz, J., & Vetulani, J. (1999). The influence of rapid-rate transcranial magnetic stimulation (rTMS) parameters on rTMS effects in Porsolt's forced swimming test. Int J Neuropsychopharmacol, 2(1), 31-34. doi: 10.1017/s1461145799001339

Appendix

Figure 1 A and B (top): Non-invasive neuromodulation techniques (Vanneste, et al., 2012)

Figure 2 Visual illustration of the induction of electrical currents in the brain through the magnetic pulses applied by means of the coil positioned above the head (Ridding & Rothwell, 2007)

Figure 3 Changes in rCBF measured by SPECT in brain areas associated with depression, after rTMS treatment (Kito, et al., 2008)

Table 1: Criteria of Major Depressive Episode According to DSM-IV-TR

Criterium Symptoms

A. five (or more) of the following symptoms (10) Depressed mood most of the day,

have been present during the same 2-week nearly every day, as indicated by either

period and represent a change from subjective report (e.g. feels sad or empty)

previous functioning; at least one of the or observation made by others (e.g.),

symptoms is either (1) depressed mood or appears tearful).

(2) loss of interest or pleasure (11) Markedly diminished interest or

pleasure in all, or almost all, activities most

of the day, nearly every day (as indicated

by either subjective account or observation

made by others)

(12) Significant weight loss when not

dieting or weight gain (e.g., a change of

more than 5% of body weight in a month),

or decrease or increase in appetite nearly

every day.

(13) Insomnia or hypersomnia nearly every

day

(14) Psychomotor agitation or retardation

nearly every day (observable by others, not

merely subjective feelings of restlessness

or being slowed down)

(15) Fatigue or loss of energy nearly every

day

(16) Feelings of worthlessness or excessive

of inappropriate guilt (which may be

delusional) nearly every day (not merely

self-reproach or guilt about being sick)

(17) Diminished ability to think or

concentrate, or indecisiveness, nearly every

day (either by subjective account or as

observed by others)

(18) Recurrent thoughts of death (not just

fear of dying), recurrent suicidal ideation

without a specific plan, or a suicide attempt

or a specific plan for committing suicide

B. The symptoms do not meet criteria for a

Mixed Episode

C. The symptoms cause clinically significant

distress or impairment in social,

occupational, or other important areas of

functioning.

D. The symptoms are not due to the direct

physiological effects of a substance (e.g., a

drug of abuse, a medication) or a general

medical condition (e.g. hypothyroidism).

E. The symptoms are not better accounted for

by Bereavement, i.e., after the loss of a

loved one, the symptoms persist for longer

than 2 months or are characterized by

marked functional impairment, morbid

preoccupation with worthlessness, suicidal

ideation, psychotic symptoms, or

psychomotor retardation (American

Psychiatric Association, 2000).

Table 2: A comparison of different therapies and their effect sizes and conclusion (Cuijpers, et al., 2011)

Comparison of Therapies N* Effect size CI** Conclusion

Psychotherapy vs 37 d=-0,07 -0,15 to 0,01 The efﬁcacy of psychotherapy

Pharmacotherapy for mild to moderate depression is

about the same as the efﬁcacy of

pharmacotherapy

Psychotherapy vs 19 d=0,35 0,24 to 0,45 Combined treatment is more combined treatment effective than psychotherapy

alone

Pharmacotherapy vs 22 d=0,30 0,17 to 0,43 Combined treatment is more combined treatment effective than pharmacotherapy

alone

Table 3: An overview of meta-analyzes of TMS and depression

Meta-analysis N* Studies Stimulation Effect Conclusion

site size**

(Kozel & George, 230 12 LPFC d=0,53 LPFC rTMS is an acute

2002) antidepressant treatment with

significant effect sizes and

measurable clinical improvement

(Martin, et al., 217 12 Any CI=-0,66 Current trials are low of quality and

2003) location to -0,04 provide insufficient evidence to

support the use of rTMS in the

treatment of depression

(Gross, et al., 598 18 - CI=-1,01 Recent rTMS trials show larger

2007) to -0,51 antidepressant effects compared with

earlier studies

(Lam, et al., 2008) 1092 24 Any d=0,48 For patients with TRD, rTMS

location appears to provide significant

benefits in short-term treatment

studies

Schutter (2009) 1164 30 LDLPFC d = 0.39 High Frequency rTMS over the

LDLPFC is superior to sham

Schutter (2010) 252 9 Frontal d=0,63 Slow-frequency rTMS to the frontal

cortex cortex is more effective than sham

treatment and may be equally

effective as fast-frequency rTMS in

the treatment of MDD

(Allan, et al., 1531 31 LDLPFC, g=0,64 TMS appears to be an effective

2011) RDLPFC treatment in the management of

and bilateral mood disorders

(Berlim, et al., 279 7 Bilateral CI=-1,95 Bileral rTMS is a promising

2012) to 9,52 treatment for MD as it provides

clinically meaningful benefits that are

comparable with those of standard

antidepressants and unilateral rTMS