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Repetitive transcranial magnetic stimulation of thedorsolateral prefrontal cortex affects divided attentionimmediately after cessation of stimulation
Michael Wagner
c
, Tonia A. Rihs
b
, Urs P. Mosimann
a
,Hans U. Fisch
a
, Thomas E. Schlaepfer
a,c,*
a
Psychiatric Neuroimaging Group, Department of Psychiatry, University Hospital Bern, Switzerland 
b
Functional Brain Mapping Laboratory, Neurology Clinic, University Hospital of Geneva, Switzerland 
c
Brain Stimulation Group, Department of Psychiatry, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany
Received 2 February 2005; received in revised form 22 May 2005; accepted 9 June 2005
Abstract
Transcranial magnetic stimulation has evolved into a powerful neuroscientific tool allowing to interfere transiently with specificbrain functions. In addition, repetitive TMS (rTMS) has long-term effects (e.g. on mood), probably mediated by neurochemicalalterations. While long-term safety of rTMS with regard to cognitive functioning is well established from trials exploring its ther-apeutic efficacy, little is known on whether rTMS can induce changes in cognitive functioning in a time window ranging from min-utes to hours, a time in which neurochemical effects correlated with stimulation have been demonstrated.This study examined effects of rTMS on three measures of executive function in healthy subjects who received one single rTMSsession (40 trains of 2 s duration 20 Hz stimuli) at the left dorsolateral prefrontal cortex (DLPFC). Compared to a sham conditionone week apart, divided attention performance was significantly impaired about 30–60 min after rTMS, while Stroop-interferenceand performance in the Wisconsin Card Sorting Test was unaffected after rTMS.Repetitive TMS of the left DLPFC, at stimulation parameters used in therapeutic studies, does not lead to a clinically relevantimpairment of executive function after stimulation. However, the significant effect on divided attention suggests that cognitive effectsof rTMS are not limited to the of acute stimulation, and may possibly reflect known neurochemical alterations induced by rTMS.Sensitive cognitive measures may be useful to trace those short-term effects of rTMS non-invasively in humans.
Ó
2005 Elsevier Ltd. All rights reserved.
Keywords:
rTMS; DLPFC; Wisconsin card sorting test; Stroop test; Visual attention
1. Introduction
Transcranial magnetic stimulation (TMS) is a power-ful tool to investigate the human brain non-invasively.By inducing an intracranial electrical current flow,TMS pulses lead to neuronal depolarization, andresearchers can thus interfere with cortical processes inthe stimulated region with high temporal and regionalprecision (George et al., 1999). Repetitive TMS withlower (up to 1 Hz) frequencies reduces, while rTMS withhigher frequencies increases cortical excitability for upto some minutes. TMS thus provides a unique possibil-ity to make reversible ‘‘lesions’’ in humans (Robertsonet al., 2003).Repetitive TMS has also been extensively studied forits use in the treatment of neuropsychiatric conditions,including mood disorders. While a recent meta-analysisconcluded that the evidence to support the use of rTMS
0022-3956/$ - see front matter
Ó
2005 Elsevier Ltd. All rights reserved.doi:10.1016/j.jpsychires.2005.06.001
*
Corresponding author. Tel.: +49 228 287 4715; fax: +49 228 2875025.
E-mail address:
schlaepf@jhmi.edu(T.E. Schlaepfer).
www.elsevier.com/locate/jpsychires
Journal of Psychiatric Research 40 (2006) 315–321
 J
OURNALOF
P
SYCHIATRIC
R
ESEARCH
 
in the clinical treatment of major depression is insuffi-cient yet (Martin et al., 2003), numerous studies pursuethe refinement and clinical evaluation of this non-phar-macological treatment.In light of the demonstrated statistically significantsustained antidepressant effects of rTMS (Gershonet al., 2003; Holtzheimer et al., 2001, 2004; Schlaepferet al., 2003), it is important to establish potential mech-anisms for those effects. Repetitive TMS of frontal brainregions has modulatory effects on several neurotransmit-ter systems. For instance, rTMS at 20 Hz has beenfound to increase the release of several monoamines inthe hippocampus in rats (Keck et al., 2002), and to in-crease levels of dopamine by 50–100% both in the mes-olimbic and the mesostriatal dopamine system for up to2 h after cessation of stimulation (Keck et al., 2002).Completely line with this finding, Strafella et al. foundthat rTMS of the motor cortex increased striatal dopa-mine release, as detected by raclopride PET (Strafellaet al., 2001). The antidepressant effect of rTMS foundin some clinical studies is probably related to such neu-rochemical rTMS effects, which are similar to thosebrought about by other effective antidepressants likeelectroconvulsive therapy (Zyss et al., 1997), but othermechanisms including altered gene expression are alsoposited (Muller et al., 2000;Wassermann and Lisanby, 2001). These preclinical and PET data suggest thatrTMS may affect neurotransmission for hours, whichin turn could alter cognitive and emotional processes.Surprisingly little research has been done on cognitiveeffects of rTMS immediately
after
cessation of stimula-tion, possibly because
cognitive neuroscientists
are focus-sing on the immediate effects of TMS on cognition – which allows them to make
Ô
reversible lesions
Õ
and thestudy of information processing with high temporal pre-cision – while
clinical researchers
understandably ex-plore longer term effects of rTMS on affect with afocus on therapeutic applications, with cognitive effectsbeing only a treatment safety aspect.Direct disruptive effects on cognitive functions weredemonstrated for speech generation at high frequency(20 Hz) rTMS (Pascual-Leone et al., 1991) and for ran-dom number generation (Jahanshahi and Dirnberger,1999). Safety studies convincingly suggest that rTMSdoes not result in long term cognitive impairments (Lit-tle et al., 2000;Schulze-Rauschenbach et al., 2005;Was- sermann et al., 1996b). However, there are only fewstudies, which examined cognitive changes hours afterthe cessation of rTMS, in the very time window whereneurochemical effects of rTMS, e.g. effects on dopaminerelease, have been reported. One study found that sub- jects stimulated at high intensity and at short interstim-ulus intervals showed impaired performance in theWechsler memory test after cessation of the stimulation(Flitman et al., 1998). Some studies reported on acutemood effects of left prefrontal high-frequency rTMS,but the results remain inconclusive (Mosimann et al.,2000). Better knowledge about the effects of rTMS aftercessation of the stimulation could also contribute to elu-cidate mechanisms of rTMS effects on affect.We attempted to further explore this crucial time win-dow of subacute rTMS effects on cognition by studyingthe impact of rTMS on executive functions. The timewindow of 20 min to 1 h has shown to be significant inprevious studies measuring summation effects of manytrains of pulses within one stimulation session (Dearinget al., 1997). We investigated executive and attentionalfunctions after a single session of high frequency repet-itive transcranial magnetic stimulation, with parameterstypically used in clinical studies of rTMS in refractorymajor depression. The site of stimulation was the leftdorsolateral prefrontal cortex, the region consistentlychosen in depression treatment with rTMS (Georgeet al., 1999) and in studies of induction of mood changesin healthy subjects (Mosimann et al., 2000). Clinical andneuroimaging studies identified the left dorsolateral pre-frontal cortex as being involved in executive functions(categorizing, higher order functions, and dealing withinterference) and attention (Berman et al., 1995).In order to trace possible functional effects of rTMSlasting beyond the end of stimulation, we chose threewell-established cognitive tasks tapping into frontalbrain function, as evidenced by neuroimaging studies.The divided attention task used here has been foundto activate the left prefrontal cortex (Loose et al.,2003). In contrast, the Stroop interference conditionhas frequently been found to activate the anterior cingu-late gyrus (Pardo et al., 1990). The Wisconsin Card Sort-ing Task (WCST), activates a network of several frontal(including the DLPFC) as well as other brain regions(Berman et al., 1995).
2. Methods
 2.1. Subjects/samples
Seventeen male students gave their written informedconsent for the study, after the approval of the protocolby the local Ethical Committee.Their mean age was 22.3 years (SD = 2.1, range: 19– 26). All subjects were right-handed and were carefullyscreened for history of mental illness, substance abuse,head injury or physical illness. All subjects werescreened for medical contra-indications to participatingin an rTMS study according to safety guidelines forrTMS (Wassermann, 1998). Subjects familiar with theStroop Test, the WCST and the Divided Attention Taskwere excluded as well as persons with red–green colourblindness. All subjects were non-smokers and nativeGerman speakers. In addition to the psychiatric inter-view, the Prime MD instrument was administered for
316
M. Wagner et al. / Journal of Psychiatric Research 40 (2006) 315–321
 
its properties as a standardized screening instrument(Spitzer et al., 1999). Subjects were paid the equivalentof 50 US$ in local currency (75 CHF) in addition to tra-vel expenses.
 2.2. Design
The study was conducted as a randomized within-subject crossover design, where each participant wastested after sham stimulation as well as after stimulationof the left DLPF cortex (this condition is henceforthcalled
real stimulation
) on two different days. The orderof the stimulus conditions sham-real (
N 
= 8) versus real-sham (
N 
= 9) was randomised. Tests started 20 minafter terminating the rTMS session.Direct comparisons between sham and real stimula-tion were made for the Stroop Test (Ba¨umler, 1985)and for the Divided Attention Task (Zimmermann andFimm, 1994). Since the WCST is not designed for re-peated administrations, the WCST was only presentedafter real stimulation, and performance was comparedto test norms adjusted for age and education (Tienet al., 1996).
 2.3. Procedure
According to randomization, subjects received eitherrTMS at the first visit, followed by the sham stimulationat the second visit (
N 
= 9), or vice versa (
N 
= 8). Stimu-lation threshold was determined according to the proce-dure of Wassermann et al. (1999), by measuring theminimum stimulus intensity necessary for an evokedmotor potential to occur on the right abductor pollicisbrevis muscle after stimulation of the corresponding siteof the primary motor cortex. The stimulus location onthe left dorsolateral prefrontal cortex was obtained bycentering the coil 5 cm anterior to the midline of thestimulation site for the right abductor pollicis brevismuscle (Mosimann et al., 2002). Stimulation was appliedat 100% of individual motor threshold with a MagstimRapid stimulator (Magstim Inc. Sheffield, UK) and a70 mm figure of eight coil. Subjects were stimulated with40 trains of 2 s during each 20-min stimulation session;frequency of stimulation was 20 Hz. In order to mini-mize the risk of seizure the interstimulus interval lasted28 s (Wassermann et al., 1996a).In the sham stimulus condition, the motor evoked po-tential was determined exactly the same way as in thereal condition, but the coil was placed at a 90
°
angleto the skull (Graf et al., 2001). Subjects were not in-formed in which condition they were stimulated. Theywere only told that two different stimulation intensitieswere compared. The other parameters of the stimulationwere applied in the same manner as for real stimulation.During stimulation sessions, subjects were seated andkept verbal contact with the examiner. After the stimu-lation, subjects were asked to retreat to a quiet room for20 min. After this break, the following tests were ap-plied. In the case of subjects having had real stimulationat the first session, the series started with a computerizedversion of the WCST (Tien et al., 1996), followed by theStroop Test (Ba¨umler, 1985) and the Divided AttentionTask (Zimmermann and Fimm, 1994). If subjects hadsham stimulation at their first appointment, testing ser-ies started immediately with the Stroop Test, followedby the Divided Attention Task. Subjects had not beentested before with any of the procedures.
 2.4. Computerized Wisconsin Card Sorting Test
The Computerized WCST (Tien et al., 1996) is anadaptation of the Heaton Standard Version (Heatonet al., 1993) for computer testing. The task of the subjectconsisted in matching new cards appearing on the rightcorner of the screen to one of the stimulus cards bypushing on a specially designed button board, depictingthe four stimulus cards. Test parameters were categoriesachieved, perseverative errors and non-perseverativeerrors.
 2.5. Stroop test
The Stroop Test is a common test for the assessmentof executive and attentional functions. Stroop interfer-ence occurs when subjects are requested to name theprint colour of a word with a different meaning (e.g.the word, ‘‘red’’ printed in green colour). The Germanversion of Ba¨umler (1985)consists of three subtests:reading of black ink colour words, naming colour barsand naming the print colour of colour words (the inter-ference condition proper). The difference between thetwo latter conditions was taken to reflect Stroopinterference.
 2.6. Divided attention
The Divided Attention Task is a part of the AttentionTest Battery byZimmermann and Fimm (1994). Thetest is based on a dual-task principle where reactiontimes and error rates to presentation of stimuli of theacoustic and visual modality are measured. The acousticstimuli consist of a sequence of high and low pitchedtones. The subject has to react when two sounds of thesame pitch follow each other, which happens 16 timesduring 200 auditory stimulus presentations. The visualtask consists of a 4
·
4 matrix where 8 crosses occuron pseudo-randomly chosen locations for each stimulus.The subject has to react, when four adjacent crossesform a square, which happens 17 times during 100 visualstimulus presentations. To ensure that the instructionwas understood, a short pre-test was conducted beforestarting the test phase. Test parameters were reaction
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