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Brief report Acute prefrontal cortex transcranial magnetic stimulation in healthy volunteers: No effects on brain-derived neurotrophic factor (BDNF) concentrations in serum Undine E. Lang a, ,1 , Rainer Hellweg b,1 , Juergen Gallinat a , Malek Bajbouj b a Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany b Department of Psychiatry, Charité - University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany Received 26 March 2007; received in revised form 13 August 2007; accepted 13 August 2007 Available online 7 September 2007 Abstract Background: Transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex is a brain stimulation technique widely used to treat depression. BDNF serum concentrations have been shown to be decreased in patients with major depressive disorder and can be upregulated by several antidepressive treatment strategies including repetitive TMS. Methods: In this study we were interested whether acute TMS evolves effects on serum BDNF concentrations in 42 healthy volunteers. Results: Mean BDNF serum concentration in 19 male and 23 female volunteers was 10.70 ± 3.6 ng/ml (n = 42) at baseline, and 10.76 ± 3.9 ng/ml (n = 42) after TMS treatment. BDNF serum levels did not change after acute TMS (n = 42, Z = - 0.44, p = 0.965). BDNF serum concentrations at baseline did not differ between male (n = 19, 10.05 ± 2.6 ng/ml) and female (n = 23, 11.25 ± 4.27 ng/ml) participants of the study (n = 42, Z = - 0.91, p = 0.363). Conclusions: Our result suggests that TMS does not change BDNF serum concentrations immediately in healthy human volunteers. Published by Elsevier B.V. Keywords: Brain-derived neurotrophic factor (BDNF); Transcranial magnetic stimulation (rTMS); TMS; depression 1. Introduction Recent evidence suggests that expression of brain- derived neurotrophic factor (BDNF) might be a target of antidepressant treatment as BDNF serum concentrations have been described to be decreased in depressive patients (Lee et al., 2007, Lang et al., 2004) and to increase after different antidepressant medications (Russo-Neustadt and Chen, 2005, Karege et al., 2005a,b, Gervasoni et al., 2005), exercise (Ferris et al., 2007) and electroconvulsive therapy (Marano et al., 2007). Transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex is a therapeutic and diagnostic brain stimulation intervention, which is non- invasive, safe and generally well-tolerated and which has been extensively used over recent years to investigate antidepressant efficacy (Siebner and Rothwell, 2003). Repetitive TMS had recently been investigated as a putative antidepressant intervention, with response rates ranging from 1746% (Brakemeier et al., 2007, McLough- lin et al., 2007, Eranti et al., 2007); however, there is little Journal of Affective Disorders 107 (2008) 255 258 www.elsevier.com/locate/jad Corresponding author. Tel.: +49 1786241689. E-mail address: [email protected] (U.E. Lang). 1 Both authors contributed equally to this paper. 0165-0327/$ - see front matter. Published by Elsevier B.V. doi:10.1016/j.jad.2007.08.008

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Page 1: Acute prefrontal cortex transcranial magnetic stimulation in healthy volunteers: No effects on brain-derived neurotrophic factor (BDNF) concentrations in serum

Journal of Affective Disorders 107 (2008) 255–258www.elsevier.com/locate/jad

Brief report

Acute prefrontal cortex transcranial magnetic stimulation in healthyvolunteers: No effects on brain-derived neurotrophic factor

(BDNF) concentrations in serum

Undine E. Lang a,⁎,1, Rainer Hellweg b,1, Juergen Gallinat a, Malek Bajbouj b

a Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germanyb Department of Psychiatry, Charité - University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany

Received 26 March 2007; received in revised form 13 August 2007; accepted 13 August 2007Available online 7 September 2007

Abstract

Background: Transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex is a brain stimulation technique widelyused to treat depression. BDNF serum concentrations have been shown to be decreased in patients with major depressive disorderand can be upregulated by several antidepressive treatment strategies including repetitive TMS.Methods: In this study we were interested whether acute TMS evolves effects on serum BDNF concentrations in 42 healthyvolunteers.Results:Mean BDNF serum concentration in 19male and 23 female volunteers was 10.70±3.6 ng/ml (n=42) at baseline, and 10.76±3.9 ng/ml (n=42) after TMS treatment. BDNF serum levels did not change after acute TMS (n=42, Z=−0.44, p=0.965). BDNFserum concentrations at baseline did not differ between male (n=19, 10.05±2.6 ng/ml) and female (n=23, 11.25±4.27 ng/ml)participants of the study (n=42, Z=−0.91, p=0.363).Conclusions: Our result suggests that TMS does not change BDNF serum concentrations immediately in healthy human volunteers.Published by Elsevier B.V.

Keywords: Brain-derived neurotrophic factor (BDNF); Transcranial magnetic stimulation (rTMS); TMS; depression

1. Introduction

Recent evidence suggests that expression of brain-derived neurotrophic factor (BDNF) might be a target ofantidepressant treatment as BDNF serum concentrationshave been described to be decreased in depressive patients(Lee et al., 2007, Lang et al., 2004) and to increase afterdifferent antidepressant medications (Russo-Neustadt and

⁎ Corresponding author. Tel.: +49 1786241689.E-mail address: [email protected] (U.E. Lang).

1 Both authors contributed equally to this paper.

0165-0327/$ - see front matter. Published by Elsevier B.V.doi:10.1016/j.jad.2007.08.008

Chen, 2005, Karege et al., 2005a,b, Gervasoni et al.,2005), exercise (Ferris et al., 2007) and electroconvulsivetherapy (Marano et al., 2007).

Transcranial magnetic stimulation (TMS) of the leftdorsolateral prefrontal cortex is a therapeutic anddiagnostic brain stimulation intervention, which is non-invasive, safe and generally well-tolerated andwhich hasbeen extensively used over recent years to investigateantidepressant efficacy (Siebner and Rothwell, 2003).Repetitive TMS had recently been investigated as aputative antidepressant intervention, with response ratesranging from17–46% (Brakemeier et al., 2007,McLough-lin et al., 2007, Eranti et al., 2007); however, there is little

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256 U.E. Lang et al. / Journal of Affective Disorders 107 (2008) 255–258

agreement about clinically useful predictors of rTMSoutcome and the neurochemical basis of this treatmentremains poorly understood.

It has been shown in a recent study that acute TMS ofprefrontal cortical areas modulates aspects of tryptophan/5-HT metabolism in limbic areas in healthy subjects(Sibon et al., 2006), and several findings point to a distinctrelationship between BDNF and the serotonergic system(Kim et al., 2007; Guiard et al., 2007; Lang et al., 2005).Furthermore it had been shown that during tryptophandepletion, BDNF levels increased in healthy volunteersbut did not show a similar response in patients with re-mitted major depressive disorder, where BDNF levelsremained low (Neumeister et al., 2005).

As also acute TMS has been hypothesized to exertcertain antidepressive properties (Conca et al., 2000) theinfluence of acute TMS on BDNF serum concentrationshas been measured in healthy volunteers in this study.Acute changes of BDNF serum concentrations inhealthy volunteers after acute TMS might explain themechanism of antidepressive properties in repetitiveTMS treatment and could possibly be established asearly response parameter in depressed patients.

2. Materials and methods

42 healthy volunteers (19male, 23 female; age: 31.50±11.3) from the Department of Psychiatry, CharitéUniversity Medicine Berlin, Campus Benjamin Franklinparticipated consecutively in a TMS study.After the studyhad been explained in detail full written consent wasobtained from all subjects in accordance to the Declara-tion of Helsinki. The study was approved by the JointEthics Committee of the Charité (Campus BenjaminFranklin). This study was part of a larger study, whichaimed to investigate biological effects of acute TMS inhealthy volunteers, however, other results of this studyhave not been published yet. The participants, who wereof German descent, were interviewed by a researchpsychiatrist with structured clinical interviews (Mini-International Neuropsychiatric Interview, Sheehan et al.,1998). Exclusion criteria were axis-I or axis-II disorders,alcohol or illegal drug abuse, significant cardiovascular,hepatic, renal, gastrointestinal, metabolic, or othersystemic disease, concurrent psychiatric or neurologicalillness, organic mental disorder, seizure disorder, mentalretardation, Parkinson's disease, toxic central nervoussystem depression or any clinically relevant abnormali-ties. A healthy medical condition was determined by aclinical interview, physical examination and laboratorydata. Participants received a single session of transcranialmagnetic stimulation at the left and right motor cortex

with a total number of 1000 stimuli and stimulationintensities between 70 and 130% related to resting motorthreshold. BDNF was measured at baseline and within5 min after termination of the session.

3. Measurement of BDNF levels

Endogenous levels of BDNF were measured in there-thawed serum samples using commercial ELISA kitsin principle according to the manufacturer's instructions(Promega Inc., Mannheim, Germany) but adapted to thefluorometric technique used also for nerve growth factordetermination (Hellweg et al., 2003; Ziegenhorn et al.,2007).

4. Data analysis

Kolmogorov–Smirnov test was employed to evaluatewhether BDNF level is a normally distributed trait.BDNF changes were measured usingWilcoxon's test forpaired matches. Results are presented as means±onestandard deviation. Analyses were computed using sta-tistical software (SPSS 12.0®). A p value of pb0.05 wasconsidered significant while pb0.10 was accepted inorder to detect trends.

5. Results

5.1. Participants had no adverse effects of acute TMS

Kolmogorov–Smirnov test (Z=0.717, p=0.683)showed that BDNF serum concentrations in our samplewere normally distributed.

BDNF serum levels in healthy volunteerswere 10.70±3.6 ng/ml (n=42) at baseline, after TMS treatment theywere 10.76±3.9 ng/ml (n=42). BDNF (n=42, Z=−0.44,p=0.965) serum levels did not change over the rTMStreatment period. No correlation between BDNF concen-trations and age has been detected in the same sample(n=42, corr.: 0.080, p=0.614).

BDNF serum concentrations at baseline did not differbetween male (n=19, 10.05±2.6 ng/ml) and female(n=23, 11.25±4.27 ng/ml) participants of the study(n=42, Z=−0.91, p=0.363). Also after TMS BDNFlevels did not differ between male (n=19, 10.01±3.68 ng/ml) and female (n=23, 11.38±4.16 ng/ml)participants of the study (Z=−0.872, p=0.383).

6. Discussion

In the present investigation we studied the acute ef-fect of TMS on BDNF serum concentrations in healthy

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257U.E. Lang et al. / Journal of Affective Disorders 107 (2008) 255–258

human volunteers but found no significant changesduring the procedure.

Our data are in line with an own study, where wefound no changes of BDNF serum concentrations and noassociation of BDNF in serum with clinical parametersin depressed patients during repetitive TMS treatment(Lang et al., 2006). In this study we hypothesized BDNFserum changes during antidepressive treatment rather aneffect of antidepressive medications on platelet activitythan a specific therapeutic downstream target (Langet al., 2006; Karege et al., 2002).

An influence of TMS on anxiety has been describedearlier (Isogawa et al., 2003). However, a significantincrease of serum BDNF after repetitive TMS treatmentin depressed patients has been observed in another study,where BDNF levels were also associated with clinicalparameters (Zanardini et al., 2006). Moreover plasmalevels of BDNF have been shown to be increased by 23%in depressed patients after repetitive TMS treatment(Yukimasa et al., 2006). In this context of two positivefindings our negative finding could possibly be due to along term expression effect of repetitive TMS rather thanan acute change of this neurotrophin. This would be inline with an animal study, where it has further beenshown that long-term repetitive transcranial magneticstimulation increases the expression of BDNF mRNA inspecific areas of rat brain (Muller et al., 2000).

Another explanation would be, that changes ofBDNF serum concentrations do not occur in healthybut only in depressed subjects. Correspondingly, inlow frequency 1 Hz repetitive TMS in healthy subjectsBDNF plasma levels were progressively decreased andthere was no effect reported of 1 Hz repetitive TMS onBDNF plasma levels in ALS patients (Angelucci et al.,2004).

We suggest that changes of BDNF in serum arepossibly not directly altered by TMS treatment althoughrepetitive treatment could influence BDNF serum levels,which we did not measure yet.

Role of funding sourceFunding for this study was provided by the Sonnenfeldstiftung,

who sponsored the transcranial magnetic apparatus but has nofurther role in study design; in the collection, analysis andinterpretation of data; in the writing of the report; and in thedecision to submit the paper for publication.

Conflict of interestAcute prefrontal cortex transcranial magnetic stimulation in

healthy volunteers: No effects on brain-derived neurotrophicfactor (BDNF) concentrations in serum.

ALL authors (Malek Bajbouj, Jürgen Gallinat, RainerHellweg, Undine Lang) have no actual or potential conflicts of

interest including any financial, personal or other relationshipswith other people or organizations within three years of beginningthe work submitted that could inappropriately influence, or beperceived to influence, their work.

An original signatured form will be send to the Journal's officeper mail.

Undine E. LangI have no actual or potential conflicts of interest including any

financial, personal or other relationships with other people ororganizations within three years of beginning the work submittedthat could inappropriately influence, or be perceived to influence,the work.

Malek BajboujI have no actual or potential conflicts of interest including any

financial, personal or other relationships with other people or orga-nizations within 3 years of beginning the work submitted that couldinappropriately influence, or be perceived to influence, the work.

Juergen GallinatI have no actual or potential conflicts of interest including any

financial, personal or other relationships with other people ororganizations within three years of beginning the work submittedthat could inappropriately influence, or be perceived to influence,the work.

Rainer Hellweg

Acknowledgements

The project was supported by a Grant of the Son-nenfeldstiftung in Germany.

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