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Acute high-frequency rTMS of the left dorsolateral prefrontal cortex and attentional control in healthy young men
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Acute high-frequency rTMS of the left dorsolateral prefrontal cortex and attentional control in healthy young men Ji Hee Hwang a , Sang Hee Kim b,⁎, Chang Soo Park a , Seong Ae Bang a , Sang Eun Kim a,⁎ a
Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea Department of Brain and Cognitive Engineering, Korea University, Seoul, Korea
b
A R T I C LE I N FO
AB S T R A C T
Article history:
Previous studies have shown that high-frequency repetitive transcranial magnetic
Accepted 4 March 2010
stimulation (rTMS) over the dorsolateral prefrontal cortex induces neuromodulation in
Available online 11 March 2010
prefrontal and striatal regions. We hypothesized that high-frequency rTMS over the dorsolateral prefrontal cortex would influence attentional control, which has been
Keywords:
associated with neural activity in the same region. Seventeen healthy young men
rTMS
volunteered to participate in a sham-controlled rTMS study. Participants received both
Dorsolateral prefrontal cortex
rTMS and sham stimulation on separate days and the Conners' continuous performance
Attentional control
test was used to assess response inhibition and attentional vigilance. Results indicated that
Conners' CPT
participants showed fewer commission errors during trials after rTMS as compared with sham stimulation, at longer interstimulus intervals (ISIs), which suggests that highfrequency rTMS may have the potential to improve response inhibition. This finding contributes to the understanding of the relationship between the dorsolateral prefrontal cortex and attentional control and suggests possible therapeutic applications for highfrequency rTMS. © 2010 Elsevier B.V. All rights reserved.
1.
Introduction
High-frequency repetitive transcranial magnetic stimulation (rTMS) has received increasing attention recently due to its potential therapeutic effects in several neuropsychiatric disorders, which include depression, schizophrenia, and Parkinson's disease (Gross et al., 2007; Mally and Stone, 1999; PascualLeone et al., 1996; Sedlackova et al., 2009; Siebner et al., 2000; Sommer and Paulus, 2003; Vanderhasselt et al., 2009b; Wassermann and Lisanby, 2001). The underlying neurobiological mechanisms of these effects have not been determined;
however, a general agreement has emerged that the therapeutic effect of high-frequency rTMS is probably mediated by increased cortical excitability and neurochemical transmission (Paus and Barrett, 2004). For example, 2 Hz rTMS applied over the frontal cortex in healthy volunteers increased glucose metabolism in the stimulation site and in remote connected areas (Siebner et al., 1998, 2001). Furthermore, a series of receptor binding studies in humans and animals suggest that dopaminergic neurotransmission is modulated by prefrontal rTMS. Strafella and colleagues, using C-11 raclopride PET techniques, found that 10 Hz rTMS applied to the left prefrontal cortex
⁎ Corresponding authors. S.H. Kim, Department of Brain and Cognitive Engineering, Korea University, Anam-dong 5-ga, Seongbuk-gu, Seoul 136-713, Korea. S.E. Kim, Department of Nuclear Medicine, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam 463-707, South Korea. Fax: +82 31 787 4018. E-mail addresses: [email protected] (S.H. Kim), [email protected] (S.E. Kim). 0006-8993/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2010.03.013
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induced endogenous dopamine release from the healthy human striatum (Strafella et al., 2001, 2003), and this also occurs in Parkinson's disease (Strafella et al., 2005) and depression (Pogarell et al., 2007). Changes in striatal dopaminergic levels have also been observed in rodent (Keck et al., 2002) and monkey studies (Ohnishi et al., 2004). Because an increasing number of human and animal studies have documented evidence of rTMS-induced neuromodulation in the prefrontal and associated regions, several studies have been undertaken to determine whether HF-rTMS can modulate cognitive functions in various domains, and one of the most relevant areas of study considered was the domain of attentional control (Acosta and Leon-Sarmiento, 2003). The vast majority of rTMS studies that have addressed attention have investigated the role of the right frontoparietal network during the orientation and maintenance of visuospatial attention using a virtual lesion paradigm, according to which low-frequency rTMS is applied to the cortical region to induce a temporary functional deficit in the brain (Hilgetag et al., 2001; Rounis et al., 2006). Recently, more research attention has been directed at the role of the left lateral prefrontal regions in the attentional control of target responses (MacDonald et al., 2000; Rounis et al., 2007), and studies have shown that high-frequency rTMS over the left prefrontal region improves behavioral performance in the depressed during attentional control tasks (Vanderhasselt et al., 2009a). For example, Vanderhasselt et al. (2009a) stimulated the left dorsolateral prefrontal cortex (DLPFC) in depressed patients and had them perform a switching task that required the control of attention between visual and auditory cues. It was found patients that received active stimulation had improved reaction times, whereas those that received sham stimulation showed no improvement. However, it remains largely unknown whether high-frequency rTMS of the left DLPFC enhances attentional control in healthy individuals. Based on previous evidence, which suggests that attentional control relies on a network of brain regions including the left dorsolateral prefrontal and striatal regions (MacDonald et al., 2000; Rounis et al., 2007), in which the modulatory effects of high-frequency rTMS have been observed (Pogarell et al., 2007; Siebner et al., 1998, 2001; Strafella et al., 2001, 2003, 2005), we hypothesized that high-frequency rTMS over the left DLPFC would alter attentional control performance. To test this hypothesis, we recruited 17 healthy male volunteers in a sham-controlled rTMS study. Participants were administered high-frequency rTMS or sham stimulation in two separate sessions. Changes in attentional control following rTMS stimulation were assessed using the Conners' Continuous Performance Test (CPT) (Conners et al., 2003). In the task, English alphabet letters were presented sequentially and participants were instructed to press a button as quickly as possible when the letter presented is other than the letter “X.” The interstimulus interval (ISI) varied between 1-s, 2-s and 4-s. We also assessed participants' moods before and after stimulation in order to control for the possibly confounding effects of mood on task performance. We hypothesized that ability to control response to letters would improve after rTMS. We additionally predicted that the effect of rTMS would be increased in larger ISI trials because previous studies showed that lower letter presentation rates more sensitively detected changes in attentional control (Chee et al., 1989; Epstein et al., 2006; Hervey et al., 2006).
2.
Results
All analyses were conducted using SPSS version 13.0. Statistical significance was accepted for p values of <.05, and effect sizes were assessed using partial eta squared (η2P).
2.1.
Mood effects
To examine whether rTMS had any effect on positive or negative affect, a 2 × 2 within-subject repeated measures analysis of variance (ANOVA) was conducted on positive and negative affect scores separately, with stimulation condition (rTMS vs. sham) and time (pre- vs. post-stimulation) as withinfactors. Time was found to have a main effect on positive affect, (F(1, 16) = 8.59, p < .01, η2P = .35). Participants reported an overall reduced positive affect after stimulation as compared with baseline (Table 1). No other main or no interaction effects were obtained (F's < .367, η2P's < .02). In terms of negative affect, stimulation was found to have a main effect (F(1, 16) = 6.56, p < .02, η2P = .29). As compared with sham stimulation, rTMS increased the overall negative affect (Table 1). No other main or interaction effects were obtained (F's < 2.97, η2P's = <.16).
2.2.
Changes in Conners' CPT
A series of 2 × 3 × 2 repeated measures analysis of variance (ANOVA) were conducted with stimulation (rTMS vs. sham) and interstimulus interval (ISI) (1 vs. 2 vs. 4) as within-subject factors and order of stimulation as between-subject factor. The dependent variables were mean reaction time for hits, the standard error of reaction time for hits, and the number of commission errors. Planned comparisons were conducted using the paired t-test at each ISI level to test our hypothesis that the effect of stimulation would be more prominent at longer ISIs.
2.2.1.
Hit reaction times (Hit RTs)
Repeated measures ANOVA revealed that ISI had a significant main effect F(2,30) = 40.40, p < .000, η2P = .73 (Fig. 1a). No other main or interaction effect was significant (all F's < 1.91 , all η2P's < .113 ). Follow-up contrast analyses indicated that overall hit reaction time at an ISI of 1 s was less than that at an ISI of 2 s (F(1,15) = 17.15, p < .000, η2P = .57) and of 4 s (F(1,15) = 60.37, p < .000, η2P = .80). Overall hit reaction time at an ISI of 2 s was
Table 1 – Means and standard deviations of the positive and negative affect schedule (PANAS) across stimulation conditions. Stimulation Sham Positive Time Pre 17.18 (5.75) Affect Post 14.59 (5.28) Negative Time Pre 13.76 (4.01) Affect Post 14.35 (4.47)
Statistics
rTMS 17.82 15.47 14.18 16.18
(7.75) (5.14) (3.36) (6.02)
Time (F(1, 16) = 8.59, p < .01) Stimulation (F(1, 16) = 6.56, p < .02)
Positive affect was overall reduced after stimulation compared to the baseline, p < .01. Negative affect was increased in the rTMS session compared to the sham stimulation session, p < .02.
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Fig. 1 – Illustrations of the means and standard deviations of (a) hit reaction time, (b) standard error of hit reaction time, and (c) commission errors as functions of ISI and stimulation conditions. Error bars indicate the standard errors of means.
less than that at an ISI of 4 s (F(1,15) = 27.58, p < .000, η2P = .65). Based on our prediction that the effect of stimulation would be more evident for greater ISI conditions, we performed paired t-tests at each ISI level. However, no differences in hit RTs were observed between rTMS and sham stimulation at any ISI (all t's < 1.47 ).
2.2.2.
The standard error of hit reaction time
Repeated measures ANOVA revealed that ISI had a significant main effect on the standard error of hit reaction time, F(2,30) = 8.480, p < .001, η2P = .361 (Fig. 1b). No other main or interaction effect was found (all F's < 2.572, all η2P's < .146). Follow-up contrast analyses indicated that the standard error of hit RT at an ISI of 1 s was less than that at an ISI of 2 s (F(1,15) = 8.94, p < .01, η2 P = .37) or of 4 s (F(1,15) = 10.89, p < .005, η2 P = .42). The standard error of hit RTs at an ISI of 2 s was less than that at an ISI of 4 s (F(1,15)= 4.77, p < .05, η2P = .24). We conducted paired t-tests comparing rTMS and sham stimulation effect at each ISI level. No differences were found between at any ISI (all t's < 1.33).
2.2.3.
Commission errors
Repeated measures ANOVA revealed no main or interaction effects for stimulation, ISI, or order of stimulation (all F's < 2.678, all η2P's < .152). Paired t-tests conducted at each ISI level revealed that at an ISI of 4 s, commission errors were lower after rTMS than after sham stimulation, t(16)= 2.120, p < .05 (Fig. 1c). However, no differences were observed at other ISI values (all t's < 1.04).
2.2.4.
(negative affect shampost − negative affect shampre)]. These rTMS-specific affect change scores were then correlated with the change scores of hit RTs, the standard errors of hit RTs, and commission errors between stimulation conditions (rTMS − sham). The results obtained indicated no statistically significant correlation between affect changes and any of the CPT performance measures, all r's < .38.
Correlations between mood and the effects of rTMS
Because our participants reported an increased negative affect after rTMS sessions compared to sham stimulation sessions, we investigated whether the observed differential change in CPT performance after rTMS versus sham stimulation was associated with the negative mood change. For this assessment, we conducted Pearson's correlation coefficient analyses between individuals' differential negative affect scores and corresponding differential scores in performance. We limited this analysis to negative affect because rTMS effect was only observed for negative affect but not for positive affect. We extracted negative affect change scores specific to rTMS stimulation by numerically subtracting negative affect changes due to sham stimulation from the negative affect change due to rTMS [(negative affect rTMSpost − negative affect rTMSpre) −
3.
Discussion
In the present study, we investigated the effect of highfrequency rTMS over the left dorsolateral prefrontal cortex on attentional control using the Continuous Performance Test. It was found that rTMS decreased commission errors during trials at an ISI of 4 s as compared with sham stimulation. Negative mood was found to increase after rTMS versus sham stimulation, but no systematic association was observed between changes in mood and behavioral performance. These results suggest that high-frequency rTMS may have potential to influence attentional control. Our results show that high-frequency rTMS over the dorsolateral prefrontal cortex improved performance on the CPT task by decreasing the number of commission errors during trials at the longest ISI (i.e., 4 s) are in-line with the results obtained during a medication study, in which patients with attention deficit hyperactivity disorder were tested using the CPT task. In a study undertaken to examine how medication improves attentional control, Epstein et al. (2006) found that the medicated group had fewer commission and omission errors, and shorter and less variable reaction times while performing the CPT task than the non-medicated group. Interestingly, these medication effects increased linearly with ISI, which appeared to be related to poorer performance during longer ISI trials. According to the cognitive-energetic model (Sergeant, 2000), longer ISIs induce a low energetic state, which results in slower and more inaccurate responses, and treatment enhances energetic state to an optimal level, and thus, normalizes performance (Epstein et al., 2006). Consistent with this model, our participants performed poorer in trials with the longest ISIs, and rTMS exerted its beneficial effect only at these ISI levels. In addition, we also expected to see an improvement in reaction time, but unlike the previously mentioned medication study (Epstein et al., 2006), in which reaction time measures improved after medication, we found only a non-significant decrease in mean reaction time and lesser
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variability in reaction time following rTMS. This disagreement may have resulted from differences between study populations, i.e., typical adults on the one hand and children with ADHD on the other. That is, ceiling effects may have affected reaction time measures in our participants, who were all college students. Furthermore, children and adults may perform the CPT task differently. Alternatively, the neurobiology of methylphenidate administered in the above-mentioned study may differ from that of rTMS, although they are both believed to influence frontostriatal pathways. Reaction times assess vigilance and response speed, which may tap relatively more neural resources in the parietal cortex and striatum than commission error rate, which assesses the ability to inhibit prepotent responses that may tap more prefrontal resources (Ballard, 2001). Further studies are warranted to investigate the mechanisms whereby rTMS influences attention. Our study adds to a growing body of literature regarding the effect of high-frequency rTMS over the dorsolateral prefrontal cortex on attentional control. In a series of high-frequency rTMS studies, Vanderhasselt et al. found, using the Stroop task and a task-switching task, that stimulation over the dorsolateral prefrontal regions of healthy female subjects improved the preparation and maintenance of a task-relevant attentional set (Vanderhasselt et al., 2006a,b, 2007). However, in studies that used the Stroop task to investigate changes in attentional control following high-frequency rTMS, no evidence of the modulation of inhibitory control was obtained. That is, healthy female participants showed no difference in the Stroop interference effect (i.e., reaction time differences between incongruent and congruent trials) across rTMS and sham stimulation conditions (Vanderhasselt et al., 2006a). Typical performance on the Stroop task involves not only response inhibition but also conflict monitoring between two different response sets (i.e., word reading vs. naming the color of a word) which have dissociable cognitive and neural mechanisms (Braver et al., 2001; MacDonald et al., 2000; Miyake et al., 2000). Therefore, our findings add to previous knowledge by suggesting that high-frequency rTMS may exert its role via simple response inhibition rather than via monitoring or resolving response conflicts. We also found that a single session of rTMS had an effect on negative affect than sham stimulation. This increased negative affect associated with active rTMS could be related to the physical sensation experienced during rTMS but not during sham stimulation, although no participant explicitly reported that either active or sham stimulation caused any discomfort. This result is not consistent with previous findings, which found no differences in mood after a single session of high-frequency rTMS (Mosimann et al., 2000; Vanderhasselt et al., 2007, 2009a), or alternatively, an increase in positive mood after repeated rTMS treatment, especially in patients with depression (Pascual-Leone et al., 1996; Vanderhasselt et al., 2009b), as compared to sham stimulation. This inconsistency could be related to sex differences because our participants were all men and previous studies have included either women or both sexes. Further studies are warranted to critically assess potential sex differences on the effects of rTMS. Because of the close relationship between affect and cognition, one could argue that the observed effect of reduced commission errors after rTMS stimulation might be related to changes in
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affect rather than the effect of rTMS per se. However, we found no statistical association between changes in affect and changes in performance, which indicates that rTMSinduced changes in affect and cognitive performance were not directly associated. In fact, dissociations between the affective and cognitive consequences of rTMS have been more frequently observed in previous studies (Moser et al., 2002; Vanderhasselt et al., 2007, 2009b; Wagner et al., 2006). For example, Vanderhasselt and colleagues found in a series of studies that a single session of high-frequency rTMS improves cognitive performance (such as attentional control) but not mood (Vanderhasselt et al., 2007, 2009b). The present study has several limitations that need to be considered. We only included male participants in order to control for possible sex effects (Huber et al., 2003). The inclusion of women in a larger study would allow a more comprehensive understanding of the effects of high-frequency rTMS on cognitive functions. Another possible study limitation concerns the control conditions where the sham stimulation was performed at the active stimulation site by tilting the coil at 90° off the scalp. Although this sham treatment provides an acoustic sensation similar to that of active rTMS, the scalp sensation is lacking. Furthermore, it is possible that the tilted coil may still deliver stimulation to the cortex, although a previous study found that 90° sham produced no measurable biological effect (Lisanby et al., 2001). It is unclear as to whether the increased negative affect observed for the active rTMS condition is related to physical sensation in the scalp caused by real stimulation. However, because we found no relation between an increased negative affect and task performance, we believe that the sensation of physical contact in the scalp during active stimulation did not influence performance. In future studies, the inclusion of active stimulation sites as an additional control would be preferred. In summary, we show that high-frequency rTMS over the left dorsolateral prefrontal cortex enhances attentional control as compared to sham stimulation in healthy young men. These findings may increase our understanding of the effects of high-frequency rTMS and contribute to the development of a treatment for attentional dysfunctions.
4.
Experimental procedures
4.1.
Participants
Study participants were recruited by advertizing in a university campus. All participants were monetarily compensated (∼US $10/h). Volunteers were first interviewed to verify eligibility for this study. No participant had a personal or a family history of a psychiatric or neurological disorder, and all were mediation free at the time of participation. No one had contraindications to rTMS (Wassermann, 1998). Seventeen healthy, right-handed young men (mean age: 23.53 years, SD= 2.12) participated in this study and all were naïve to TMS. Handedness was assessed with using the Edinburgh Handedness Inventory (Oldfield, 1971). All participants provided written informed consent prior to participation, after the nature of the procedure and its possible risks and side effects had been fully explained. Participants were
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informed that they could stop participating in the study at any time and were encouraged to report if they experienced any discomfort associated with stimulation. However, no participant reported discomfort and no adverse event occurred. Participants' personal and health information were treated confidentially and data were coded with numeric IDs. The study was performed in accordance with the Declaration of Helsinki and the protocol used was approved by the local ethics committee of Seoul National University Bundang Hospital.
4.2.
Repetitive transcranial magnetic stimulation (rTMS)
A Magstim 200 magnetic stimulator (Magstim Company, Whitland, UK) connected to a figure-of-eight-shaped coil was used to apply rTMS and sham stimulation. Before stimulation, each subject underwent a mapping session during which single magnetic pulses were delivered to locate the hand area of each primary motor cortex and to determine the motor threshold (MT) of the right abductor pollicis brevis (APB) muscle, as described previously (Rossini et al., 1999). The left DLPFC stimulation site was defined as the region 6 cm rostral and 1 cm lateral in the parasagital plane from the site of maximal APB stimulation (Brandt et al., 1998). Stimulation intensity was 90% of motor threshold to the right APB muscle, and the stimulation frequency was 10 Hz. These parameters were adopted and modified from previous studies on high-frequency rTMS, which reliably demonstrated neuromodulation of prefrontal and striatal regions (Barrett et al., 2004; Sibon et al., 2007; Strafella et al., 2001, 2003). For active stimulation, participants received three consecutive blocks of stimulation; each stimulation block consisted of 15 trains of 2-s duration, separated by an intertrain interval of 10 s (900 pulses were administered per session). The interval between stimulation blocks was 10 min, during which participants were instructed to close their eyes and rest. A graphical illustration of the timeline is presented in Fig. 3. Sham stimulation was conducted in the same manner except that the coil was held at an angle of 90° and only one edge of it rested on the scalp. During rTMS all participants wore earplugs and safety guidelines were followed (Wassermann, 1998).
4.3.
Conners' continuous performance test (Conners' CPT)
Attentional inhibition was assessed using the Conners' CPT (Conners et al., 2003). Participants were instructed to press the keyboard spacebar as quickly as possible in response to any letter except the letter “X.” The probability of the occurrence of “X” was 10%. Each letter was displayed for 250 ms and 20 letters were displayed per block. The ISI rate in each block was either 1, 2 or 4 s, and each rate of block repeated six times throughout the task. The total number of blocks was 18. The block order was pseudorandomized. The CPT took approximately 14 min to complete. The outcome measures of this task included hit reaction time, the standard error of hit reaction time (a measure of response speed consistency across blocks), and commission errors (as a measure of inhibitory control). The omission errors were not analyzed because participants rarely made these errors (Mrtms = .60%, SD = 1.06%; Msham = .45%, SD = 1.15%).
4.4.
Study design and procedure
The study had a randomized within-subject crossover design, which involved both real rTMS and sham stimulation over the left DLPFC on two different days, separated by an interval of a week (except for three participants that underwent second sessions after 5 days). The order of stimulation was randomized across subjects. In order to investigate whether any mood changes would be induced by stimulation, and if so, whether rTMS-induced mood changes influenced task performance, participants completed a Korean translation of the positive affect and negative affect scale (PANAS) (Watson et al., 1988) before and after stimulation sessions and reported using a 5-point Likert scale (“not at all,” “a little,” “moderately,” “quite a bit,” and “extremely”) their responses to 20 emotional adjectives (e.g., interested, enthusiastic, distressed, nervous). Participants performed the CPT task immediately after completing PANAS. Fig. 2 illustrated the timeline of the procedure. At the end of each session, participants were instructed to report any adverse effects that they might have experienced during participation.
Fig. 2 – Illustration of the experimental design. Each participant underwent rTMS and sham stimulation on two different days. Stimulation sessions consist of three separate blocks of treatment with a resting interval. The stimulation frequency used was 10 Hz and the stimulation intensity was 90% of motor threshold.
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Acknowledgments This work was supported by grants from the National Research Foundation of Korea (M2008-03915, 20090093889) funded by the Ministry of Education, Science and Technology of Republic of Korea and the Seoul National University Bundang Hospital Research Fund (02-2007-002).
REFERENCES
Acosta, M.T., Leon-Sarmiento, F.E., 2003. Repetitive transcranial magnetic stimulation (rTMS): new tool, new therapy and new hope for ADHD. Curr. Med. Res. Opin. 19, 125–130. Ballard, J.C., 2001. Assessing attention: comparison of response-inhibition and traditional continuous performance tests. J. Clin. Exp. Neuropsychol. 23, 331–350. Barrett, J., Della-Maggiore, V., Chouinard, P.A., Paus, T., 2004. Mechanisms of action underlying the effect of repetitive transcranial magnetic stimulation on mood: behavioral and brain imaging studies. Neuropsychopharmacology 29, 1172–1189. Brandt, S.A., Ploner, C.J., Meyer, B.U., Leistner, S., Villringer, A., 1998. Effects of repetitive transcranial magnetic stimulation over dorsolateral prefrontal and posterior parietal cortex on memory-guided saccades. Exp. Brain Res. 118, 197–204. Braver, T.S., Barch, D.M., Gray, J.R., Molfese, D.L., Snyder, A., 2001. Anterior cingulate cortex and response conflict: effects of frequency, inhibition and errors. Cereb. Cortex 11, 825–836. Chee, P., Logan, G., Schachar, R.J., Lindsay, P., Wachsmuth, R., 1989. Effects of event rate and display time on sustained attention in hyperactive, normal, and control children. J. Abnorm. Child Psychol. 17, 371–391. Conners, C.K., Epstein, J.N., Anogold, A., Klaric, J., 2003. Continuous performance test performance in a normative epidemiological sample. J. Abnorm. Child Psychol. 31, 555–562. Epstein, J.N., Conners, C.K., Hervey, A.S., Tonev, S.T., Arnold, L.E., Abikoff, H.B., Elliott, G., Greenhill, L.L., Hechtman, L., Hoagwood, K., Hinshaw, S.P., Hoza, B., Jensen, P.S., March, J.S., Newcorn, J.H., Pelham, W.E., Severe, J.B., Swanson, J.M., Wells, K., Vitiello, B.T.W., 2006. Assessing medication effects in the MTA study using neuropsychological outcomes. J. Child Psychol. Psychiatry 47, 446–456. Gross, M., Nakamura, L., Pascual-Leone, A., Fregni, F., 2007. Has repetitive transcranial magnetic stimulation (rTMS) treatment for depression improved? A systematic review and metaanalysis comparing the recent vs. the earlier rTMS studies. Acta Psychiatr. Scand. 116, 165–173. Hervey, A.S., Epstein, J.N., Curry, J.F., Tonev, S., Arnold, L.E., Conners, C.K., Hinshaw, S.P., Swanson, J.M., Hechtman, L., 2006. Reaction time distribution analysis of neuropsychological performance in an ADHD sample. Child Neuropsychol. 12, 125–140. Hilgetag, C.C., Théoret, H., Pascual-Leone, A., 2001. Enhanced visual spatial attention ipsilateral to rTMS-induced 'virtual lesions' of human parietal cortex. Nat. Neurosci. 4, 953–957. Huber, T.J., Schneider, U., Rollinik, J., 2003. Gender differences in the effect of repetitive transcranial magnetic stimulation in schizophrenia. Psychiat. Res. 120 (1), 103–105. Keck, M.E., Welt, T., Müller, M.B., Erhardt, A., Ohl, F., Toschi, N., Holsboer, F., Sillaber, I., 2002. Repetitive transcranial magnetic stimulation increases the release of dopamine in the mesolimbic and mesostriatal system. Neuropharmacology 43, 101–109.
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Lisanby, S.H., Gutman, D., Luber, B., Schroeder, C., Sackeim, H.A., 2001. Sham TMS: intracerebral measurement of the induced electrical field and the induction of motor-evoked potentials. Biol. Psychiatry 49, 460–463. MacDonald III, A.W., Cohen, J.D., Stenger, V.A., Carter, C.M., 2000. Dissociating the role of the dorsolateral prefrontal and anterior cingulate cortex in cognitive control. Science 288, 1835–1838. Mally, J., Stone, T.W., 1999. Therapeutic and dose-dependent effect of repetitive microelectroshock induced by transcranial magnetic stimulation in Parkinson's disease. J. Neurosci. Res. 57, 935–940. Miyake, A., Friedman, N.P., Emerson, M.J., Witzki, A.H., Howerter, A., 2000. The unity and diversity of executive functions and their contributions to complex “frontal lobe” tasks: A latent variable analysis. Cogn. Psychol. 41, 49–100. Moser, D.J., Jorge, R.E., Manes, F., Paradiso, S., Benjamin, M.L., Robinson, R.G., 2002. Improved executive functioning following repetitive transcranial magnetic stimulation. Neurology 58, 1288–1290. Mosimann, U.P., Rihs, T.A., Engeler, J., Fisch, H.-U., Schlaepfer, T.E., 2000. Mood effects of repetitive transcranial magnetic stimulation of left prefrontal cortex in healthy volunteers. Psychiatr. Res. 94, 251–256. Ohnishi, T., Hayashi, T., Okabe, S., Nonaka, I., Matsuda, H., Iida, H., Imabayashi, E., Watabe, H., Miyake, Y., Ogawa, M., Teramoto, N., Ohta, Y., Ejima, N., Sawada, T., Ugawa, Y., 2004. Endogenous dopamine release induced by repetitive transcranial magnetic stimulation over the primary motor cortex: an [11C]raclopride positron emission tomography study in anesthetized macaque monkeys. Biol. Psychiatry 55, 484–489. Oldfield, R.C., 1971. The assessment and analysis of handedness: The Edinburgh Inventory. Neuropsychologia 9, 97–113. Pascual-Leone, A., Rubio, B., Pallard, F., Catala, M.D., 1996. Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression. Lancet 348, 233–237. Paus, T., Barrett, J., 2004. Transcranial magnetic stimulation (TMS) of the human frontal cortex: implications for repetitive TMS treatment of depression. J. Psychiatry Neurosci. 29, 268–279. Pogarell, O., Koch, W., Pöpperl, G., Tatsch, K., Jakob, F., Mulert, C., Grossheinrich, N., Rupprecht, R., Möller, H.-J., Hegerl, U., Padberg, F., 2007. Acute prefrontal rTMS increases striatal dopamine to a similar degree as d-amphetamine. Psychiatry Res: Neuroimaging 156, 251–255. Rossini, P.M., Berardelli, A., Deuschl, G., Hallett, M., MaertensdeNoordhout, A.M., Paulus, W., Pauri, F., 1999. Applications of magnetic cortical stimulation. The International Federation of Clinical Neurophysiology. Electroencephalogr Clin Neurophysiol 52, 171–185 (suppl). Rounis, E., Stephan, K.E., Lee, L., Siebner, H.R., Friston, K.J., Rothwell, J.C., Frackowiak, R.S.J., 2006. Acute changes in fronto-parietal activity following rTMS over the dorsolateral prefrontal cortex in a cued reaction time task. J. Neurosci. 26, 9629–9638. Rounis, E., Yarrow, K., Rothwell, J.C., 2007. Effects of rTMS conditioning over the fronto-parietal network on motor versus visual attention. J. Cogn. Neurosci. 19 (3), 513–524. Sedlackova, S., Rektorova, I., Srovnalova, H., Rektor, I., 2009. Effect of high frequency repetitive transcranial magnetic stimulation on reaction time, clinical features and cognitive functions in patients with Parkinson's disease. J. Neural Transm. 116, 1093–1101. Sergeant, J., 2000. The cognitive-energetic model: an empirical approach to Attention-Deficit Hyperactivity Disorder. Neurosci. Biobehav. Rev. 24, 7–12. Sibon, I., Strafella, A.P., Gravel, P., Ko, J.H., Booji, L., Soucy, J.P., Leyton, M., Diksic, M., Benkelfat, C., 2007. Acute prefrontal cortex TMS in healthy volunteers: Effects on brain 11C-αMtrp trapping. NeuroImage 34, 1658–1664.
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Siebner, H.R., Willoch, F., Peller, M., Auer, C., Boekcer, H., Conrad, B., Bartenstein, P., 1998. Imaging brain activation induced by long trains of repetitive transcranial magnetic stimulation. NeuroReport 9, 943–948. Siebner, H.R., Rossmeier, C., Mentschel, C., Peinemann, A., Conrad, B., 2000. Short-term motor improvement after sub-threshold 5-Hz repetitive transcranial magnetic stimulation of the primary motor hand area in Parkinson's disease. J. Neurol. Sci. 178, 91–94. Siebner, H.R., Peller, M., Bartenstein, P., Willoch, F., Rossmeier, C., Schwaiger, M., Conrad, B., 2001. Activation of frontal premotor areas during suprathreshold transcranial magnetic stimulation of the left primary sensorimotor cortex: A glucose metabolic PET study. Hum. Brain Mapp. 12, 157–167. Sommer, M., Paulus, W., 2003. Pulse configuration and rTMS efficacy: a review of clinical studies. Suppl. Clin. Neurophysiol. 56, 33–41. Strafella, A.P., Paus, T., Jennifer, B., Dagher, A., 2001. Repetitive transcranial magnetic stimulation of the human prefrontal cortex induces dopamine release in the caudate nucleus. J. Neurosci. 21, 1–4. Strafella, A.P., Paus, T., Fraraccio, M., Dagher, A., 2003. Striatal dopamine release induced by repetitive transcranial magnetic stimulation of the human motor cortex. Brain 126, 2609–2615. Strafella, A.P., Ko, J.H., Grant, J., Fraraccio, M., Monchi, O., 2005. Corticostriatal functional interactions in Parkinson's disease: a rTMS⁄[11C]raclopride PET study. Eur. J. NeuroSci. 22, 2946–2952. Vanderhasselt, M.-A., de Raedt, R., Baeken, C., Leyman, L., D'haenen, H., 2006a. The influence of rTMS over the left dorsolateral prefrontal cortex on stroop task performance. Exp. Brain Res. 169, 279–282. Vanderhasselt, M.-A., de Raedt, R., Baeken, C., Leyman, L., D'haenen, H., 2006b. The influence of rTMS over the right
dorsolateral prefrontal cortex on intentional set switching. Exp. Brain Res. 172, 561–565. Vanderhasselt, M.-A., de Raedt, R., Baeken, C., Leyman, L., Clerinx, P., D'haenen, H., 2007. The influence of rTMS over the right dorsolateral prefrontal cortex on top-down attentional processes. Brain Res. 1137, 111–116. Vanderhasselt, M.-A., de Raedt, R., Baeken, C., Leyman, L., D'haenen, H., 2009a. A single session of rTMS over the left dorsolateral prefrontal cortex influences attentional control in depressed patients. World J. Biol. Psychiatry 10, 34–42. Vanderhasselt, M.-A., De Raedt, R., Leyman, L., Baeken, C., 2009b. Acute effects of repetitive transcranial magnetic stimulation on attentional control are related to antidepressant outcomes. J. Psychiatr. Neurosci. 34, 119–126. Wagner, M., Rihs, T.A., Mosimann, U.P., Fisch, H.U., Schlaepfer, T.E., 2006. Repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex affects divided attention immediately after cessation of stimulation. J. Psychiatr. Res. 40, 315–321. Wassermann, E.M., 1998. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5–7, 1996. Electroencephalogr. Clin. Neurophysiol. 108, 1–16. Wassermann, E.M., Lisanby, S.H., 2001. Therapeutic application of repetitive transcranial magnetic stimulation: a review. Clin. Neurophysiol. 112, 1367–1377. Watson, D., Clark, L.A., Tellegen, A., 1988. Development and validation of brief measures of positive and negative affect: the PANAS scales. J. Pers. Soc. Psychol. 54, 1063–1070.
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Research Report
Acute high-frequency rTMS of the left dorsolateral prefrontal cortex and attentional control in healthy young men Ji Hee Hwang a , Sang Hee Kim b,⁎, Chang Soo Park a , Seong Ae Bang a , Sang Eun Kim a,⁎ a
Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea Department of Brain and Cognitive Engineering, Korea University, Seoul, Korea
b
A R T I C LE I N FO
AB S T R A C T
Article history:
Previous studies have shown that high-frequency repetitive transcranial magnetic
Accepted 4 March 2010
stimulation (rTMS) over the dorsolateral prefrontal cortex induces neuromodulation in
Available online 11 March 2010
prefrontal and striatal regions. We hypothesized that high-frequency rTMS over the dorsolateral prefrontal cortex would influence attentional control, which has been
Keywords:
associated with neural activity in the same region. Seventeen healthy young men
rTMS
volunteered to participate in a sham-controlled rTMS study. Participants received both
Dorsolateral prefrontal cortex
rTMS and sham stimulation on separate days and the Conners' continuous performance
Attentional control
test was used to assess response inhibition and attentional vigilance. Results indicated that
Conners' CPT
participants showed fewer commission errors during trials after rTMS as compared with sham stimulation, at longer interstimulus intervals (ISIs), which suggests that highfrequency rTMS may have the potential to improve response inhibition. This finding contributes to the understanding of the relationship between the dorsolateral prefrontal cortex and attentional control and suggests possible therapeutic applications for highfrequency rTMS. © 2010 Elsevier B.V. All rights reserved.
1.
Introduction
High-frequency repetitive transcranial magnetic stimulation (rTMS) has received increasing attention recently due to its potential therapeutic effects in several neuropsychiatric disorders, which include depression, schizophrenia, and Parkinson's disease (Gross et al., 2007; Mally and Stone, 1999; PascualLeone et al., 1996; Sedlackova et al., 2009; Siebner et al., 2000; Sommer and Paulus, 2003; Vanderhasselt et al., 2009b; Wassermann and Lisanby, 2001). The underlying neurobiological mechanisms of these effects have not been determined;
however, a general agreement has emerged that the therapeutic effect of high-frequency rTMS is probably mediated by increased cortical excitability and neurochemical transmission (Paus and Barrett, 2004). For example, 2 Hz rTMS applied over the frontal cortex in healthy volunteers increased glucose metabolism in the stimulation site and in remote connected areas (Siebner et al., 1998, 2001). Furthermore, a series of receptor binding studies in humans and animals suggest that dopaminergic neurotransmission is modulated by prefrontal rTMS. Strafella and colleagues, using C-11 raclopride PET techniques, found that 10 Hz rTMS applied to the left prefrontal cortex
⁎ Corresponding authors. S.H. Kim, Department of Brain and Cognitive Engineering, Korea University, Anam-dong 5-ga, Seongbuk-gu, Seoul 136-713, Korea. S.E. Kim, Department of Nuclear Medicine, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam 463-707, South Korea. Fax: +82 31 787 4018. E-mail addresses: [email protected] (S.H. Kim), [email protected] (S.E. Kim). 0006-8993/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2010.03.013
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induced endogenous dopamine release from the healthy human striatum (Strafella et al., 2001, 2003), and this also occurs in Parkinson's disease (Strafella et al., 2005) and depression (Pogarell et al., 2007). Changes in striatal dopaminergic levels have also been observed in rodent (Keck et al., 2002) and monkey studies (Ohnishi et al., 2004). Because an increasing number of human and animal studies have documented evidence of rTMS-induced neuromodulation in the prefrontal and associated regions, several studies have been undertaken to determine whether HF-rTMS can modulate cognitive functions in various domains, and one of the most relevant areas of study considered was the domain of attentional control (Acosta and Leon-Sarmiento, 2003). The vast majority of rTMS studies that have addressed attention have investigated the role of the right frontoparietal network during the orientation and maintenance of visuospatial attention using a virtual lesion paradigm, according to which low-frequency rTMS is applied to the cortical region to induce a temporary functional deficit in the brain (Hilgetag et al., 2001; Rounis et al., 2006). Recently, more research attention has been directed at the role of the left lateral prefrontal regions in the attentional control of target responses (MacDonald et al., 2000; Rounis et al., 2007), and studies have shown that high-frequency rTMS over the left prefrontal region improves behavioral performance in the depressed during attentional control tasks (Vanderhasselt et al., 2009a). For example, Vanderhasselt et al. (2009a) stimulated the left dorsolateral prefrontal cortex (DLPFC) in depressed patients and had them perform a switching task that required the control of attention between visual and auditory cues. It was found patients that received active stimulation had improved reaction times, whereas those that received sham stimulation showed no improvement. However, it remains largely unknown whether high-frequency rTMS of the left DLPFC enhances attentional control in healthy individuals. Based on previous evidence, which suggests that attentional control relies on a network of brain regions including the left dorsolateral prefrontal and striatal regions (MacDonald et al., 2000; Rounis et al., 2007), in which the modulatory effects of high-frequency rTMS have been observed (Pogarell et al., 2007; Siebner et al., 1998, 2001; Strafella et al., 2001, 2003, 2005), we hypothesized that high-frequency rTMS over the left DLPFC would alter attentional control performance. To test this hypothesis, we recruited 17 healthy male volunteers in a sham-controlled rTMS study. Participants were administered high-frequency rTMS or sham stimulation in two separate sessions. Changes in attentional control following rTMS stimulation were assessed using the Conners' Continuous Performance Test (CPT) (Conners et al., 2003). In the task, English alphabet letters were presented sequentially and participants were instructed to press a button as quickly as possible when the letter presented is other than the letter “X.” The interstimulus interval (ISI) varied between 1-s, 2-s and 4-s. We also assessed participants' moods before and after stimulation in order to control for the possibly confounding effects of mood on task performance. We hypothesized that ability to control response to letters would improve after rTMS. We additionally predicted that the effect of rTMS would be increased in larger ISI trials because previous studies showed that lower letter presentation rates more sensitively detected changes in attentional control (Chee et al., 1989; Epstein et al., 2006; Hervey et al., 2006).
2.
Results
All analyses were conducted using SPSS version 13.0. Statistical significance was accepted for p values of <.05, and effect sizes were assessed using partial eta squared (η2P).
2.1.
Mood effects
To examine whether rTMS had any effect on positive or negative affect, a 2 × 2 within-subject repeated measures analysis of variance (ANOVA) was conducted on positive and negative affect scores separately, with stimulation condition (rTMS vs. sham) and time (pre- vs. post-stimulation) as withinfactors. Time was found to have a main effect on positive affect, (F(1, 16) = 8.59, p < .01, η2P = .35). Participants reported an overall reduced positive affect after stimulation as compared with baseline (Table 1). No other main or no interaction effects were obtained (F's < .367, η2P's < .02). In terms of negative affect, stimulation was found to have a main effect (F(1, 16) = 6.56, p < .02, η2P = .29). As compared with sham stimulation, rTMS increased the overall negative affect (Table 1). No other main or interaction effects were obtained (F's < 2.97, η2P's = <.16).
2.2.
Changes in Conners' CPT
A series of 2 × 3 × 2 repeated measures analysis of variance (ANOVA) were conducted with stimulation (rTMS vs. sham) and interstimulus interval (ISI) (1 vs. 2 vs. 4) as within-subject factors and order of stimulation as between-subject factor. The dependent variables were mean reaction time for hits, the standard error of reaction time for hits, and the number of commission errors. Planned comparisons were conducted using the paired t-test at each ISI level to test our hypothesis that the effect of stimulation would be more prominent at longer ISIs.
2.2.1.
Hit reaction times (Hit RTs)
Repeated measures ANOVA revealed that ISI had a significant main effect F(2,30) = 40.40, p < .000, η2P = .73 (Fig. 1a). No other main or interaction effect was significant (all F's < 1.91 , all η2P's < .113 ). Follow-up contrast analyses indicated that overall hit reaction time at an ISI of 1 s was less than that at an ISI of 2 s (F(1,15) = 17.15, p < .000, η2P = .57) and of 4 s (F(1,15) = 60.37, p < .000, η2P = .80). Overall hit reaction time at an ISI of 2 s was
Table 1 – Means and standard deviations of the positive and negative affect schedule (PANAS) across stimulation conditions. Stimulation Sham Positive Time Pre 17.18 (5.75) Affect Post 14.59 (5.28) Negative Time Pre 13.76 (4.01) Affect Post 14.35 (4.47)
Statistics
rTMS 17.82 15.47 14.18 16.18
(7.75) (5.14) (3.36) (6.02)
Time (F(1, 16) = 8.59, p < .01) Stimulation (F(1, 16) = 6.56, p < .02)
Positive affect was overall reduced after stimulation compared to the baseline, p < .01. Negative affect was increased in the rTMS session compared to the sham stimulation session, p < .02.
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Fig. 1 – Illustrations of the means and standard deviations of (a) hit reaction time, (b) standard error of hit reaction time, and (c) commission errors as functions of ISI and stimulation conditions. Error bars indicate the standard errors of means.
less than that at an ISI of 4 s (F(1,15) = 27.58, p < .000, η2P = .65). Based on our prediction that the effect of stimulation would be more evident for greater ISI conditions, we performed paired t-tests at each ISI level. However, no differences in hit RTs were observed between rTMS and sham stimulation at any ISI (all t's < 1.47 ).
2.2.2.
The standard error of hit reaction time
Repeated measures ANOVA revealed that ISI had a significant main effect on the standard error of hit reaction time, F(2,30) = 8.480, p < .001, η2P = .361 (Fig. 1b). No other main or interaction effect was found (all F's < 2.572, all η2P's < .146). Follow-up contrast analyses indicated that the standard error of hit RT at an ISI of 1 s was less than that at an ISI of 2 s (F(1,15) = 8.94, p < .01, η2 P = .37) or of 4 s (F(1,15) = 10.89, p < .005, η2 P = .42). The standard error of hit RTs at an ISI of 2 s was less than that at an ISI of 4 s (F(1,15)= 4.77, p < .05, η2P = .24). We conducted paired t-tests comparing rTMS and sham stimulation effect at each ISI level. No differences were found between at any ISI (all t's < 1.33).
2.2.3.
Commission errors
Repeated measures ANOVA revealed no main or interaction effects for stimulation, ISI, or order of stimulation (all F's < 2.678, all η2P's < .152). Paired t-tests conducted at each ISI level revealed that at an ISI of 4 s, commission errors were lower after rTMS than after sham stimulation, t(16)= 2.120, p < .05 (Fig. 1c). However, no differences were observed at other ISI values (all t's < 1.04).
2.2.4.
(negative affect shampost − negative affect shampre)]. These rTMS-specific affect change scores were then correlated with the change scores of hit RTs, the standard errors of hit RTs, and commission errors between stimulation conditions (rTMS − sham). The results obtained indicated no statistically significant correlation between affect changes and any of the CPT performance measures, all r's < .38.
Correlations between mood and the effects of rTMS
Because our participants reported an increased negative affect after rTMS sessions compared to sham stimulation sessions, we investigated whether the observed differential change in CPT performance after rTMS versus sham stimulation was associated with the negative mood change. For this assessment, we conducted Pearson's correlation coefficient analyses between individuals' differential negative affect scores and corresponding differential scores in performance. We limited this analysis to negative affect because rTMS effect was only observed for negative affect but not for positive affect. We extracted negative affect change scores specific to rTMS stimulation by numerically subtracting negative affect changes due to sham stimulation from the negative affect change due to rTMS [(negative affect rTMSpost − negative affect rTMSpre) −
3.
Discussion
In the present study, we investigated the effect of highfrequency rTMS over the left dorsolateral prefrontal cortex on attentional control using the Continuous Performance Test. It was found that rTMS decreased commission errors during trials at an ISI of 4 s as compared with sham stimulation. Negative mood was found to increase after rTMS versus sham stimulation, but no systematic association was observed between changes in mood and behavioral performance. These results suggest that high-frequency rTMS may have potential to influence attentional control. Our results show that high-frequency rTMS over the dorsolateral prefrontal cortex improved performance on the CPT task by decreasing the number of commission errors during trials at the longest ISI (i.e., 4 s) are in-line with the results obtained during a medication study, in which patients with attention deficit hyperactivity disorder were tested using the CPT task. In a study undertaken to examine how medication improves attentional control, Epstein et al. (2006) found that the medicated group had fewer commission and omission errors, and shorter and less variable reaction times while performing the CPT task than the non-medicated group. Interestingly, these medication effects increased linearly with ISI, which appeared to be related to poorer performance during longer ISI trials. According to the cognitive-energetic model (Sergeant, 2000), longer ISIs induce a low energetic state, which results in slower and more inaccurate responses, and treatment enhances energetic state to an optimal level, and thus, normalizes performance (Epstein et al., 2006). Consistent with this model, our participants performed poorer in trials with the longest ISIs, and rTMS exerted its beneficial effect only at these ISI levels. In addition, we also expected to see an improvement in reaction time, but unlike the previously mentioned medication study (Epstein et al., 2006), in which reaction time measures improved after medication, we found only a non-significant decrease in mean reaction time and lesser
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variability in reaction time following rTMS. This disagreement may have resulted from differences between study populations, i.e., typical adults on the one hand and children with ADHD on the other. That is, ceiling effects may have affected reaction time measures in our participants, who were all college students. Furthermore, children and adults may perform the CPT task differently. Alternatively, the neurobiology of methylphenidate administered in the above-mentioned study may differ from that of rTMS, although they are both believed to influence frontostriatal pathways. Reaction times assess vigilance and response speed, which may tap relatively more neural resources in the parietal cortex and striatum than commission error rate, which assesses the ability to inhibit prepotent responses that may tap more prefrontal resources (Ballard, 2001). Further studies are warranted to investigate the mechanisms whereby rTMS influences attention. Our study adds to a growing body of literature regarding the effect of high-frequency rTMS over the dorsolateral prefrontal cortex on attentional control. In a series of high-frequency rTMS studies, Vanderhasselt et al. found, using the Stroop task and a task-switching task, that stimulation over the dorsolateral prefrontal regions of healthy female subjects improved the preparation and maintenance of a task-relevant attentional set (Vanderhasselt et al., 2006a,b, 2007). However, in studies that used the Stroop task to investigate changes in attentional control following high-frequency rTMS, no evidence of the modulation of inhibitory control was obtained. That is, healthy female participants showed no difference in the Stroop interference effect (i.e., reaction time differences between incongruent and congruent trials) across rTMS and sham stimulation conditions (Vanderhasselt et al., 2006a). Typical performance on the Stroop task involves not only response inhibition but also conflict monitoring between two different response sets (i.e., word reading vs. naming the color of a word) which have dissociable cognitive and neural mechanisms (Braver et al., 2001; MacDonald et al., 2000; Miyake et al., 2000). Therefore, our findings add to previous knowledge by suggesting that high-frequency rTMS may exert its role via simple response inhibition rather than via monitoring or resolving response conflicts. We also found that a single session of rTMS had an effect on negative affect than sham stimulation. This increased negative affect associated with active rTMS could be related to the physical sensation experienced during rTMS but not during sham stimulation, although no participant explicitly reported that either active or sham stimulation caused any discomfort. This result is not consistent with previous findings, which found no differences in mood after a single session of high-frequency rTMS (Mosimann et al., 2000; Vanderhasselt et al., 2007, 2009a), or alternatively, an increase in positive mood after repeated rTMS treatment, especially in patients with depression (Pascual-Leone et al., 1996; Vanderhasselt et al., 2009b), as compared to sham stimulation. This inconsistency could be related to sex differences because our participants were all men and previous studies have included either women or both sexes. Further studies are warranted to critically assess potential sex differences on the effects of rTMS. Because of the close relationship between affect and cognition, one could argue that the observed effect of reduced commission errors after rTMS stimulation might be related to changes in
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affect rather than the effect of rTMS per se. However, we found no statistical association between changes in affect and changes in performance, which indicates that rTMSinduced changes in affect and cognitive performance were not directly associated. In fact, dissociations between the affective and cognitive consequences of rTMS have been more frequently observed in previous studies (Moser et al., 2002; Vanderhasselt et al., 2007, 2009b; Wagner et al., 2006). For example, Vanderhasselt and colleagues found in a series of studies that a single session of high-frequency rTMS improves cognitive performance (such as attentional control) but not mood (Vanderhasselt et al., 2007, 2009b). The present study has several limitations that need to be considered. We only included male participants in order to control for possible sex effects (Huber et al., 2003). The inclusion of women in a larger study would allow a more comprehensive understanding of the effects of high-frequency rTMS on cognitive functions. Another possible study limitation concerns the control conditions where the sham stimulation was performed at the active stimulation site by tilting the coil at 90° off the scalp. Although this sham treatment provides an acoustic sensation similar to that of active rTMS, the scalp sensation is lacking. Furthermore, it is possible that the tilted coil may still deliver stimulation to the cortex, although a previous study found that 90° sham produced no measurable biological effect (Lisanby et al., 2001). It is unclear as to whether the increased negative affect observed for the active rTMS condition is related to physical sensation in the scalp caused by real stimulation. However, because we found no relation between an increased negative affect and task performance, we believe that the sensation of physical contact in the scalp during active stimulation did not influence performance. In future studies, the inclusion of active stimulation sites as an additional control would be preferred. In summary, we show that high-frequency rTMS over the left dorsolateral prefrontal cortex enhances attentional control as compared to sham stimulation in healthy young men. These findings may increase our understanding of the effects of high-frequency rTMS and contribute to the development of a treatment for attentional dysfunctions.
4.
Experimental procedures
4.1.
Participants
Study participants were recruited by advertizing in a university campus. All participants were monetarily compensated (∼US $10/h). Volunteers were first interviewed to verify eligibility for this study. No participant had a personal or a family history of a psychiatric or neurological disorder, and all were mediation free at the time of participation. No one had contraindications to rTMS (Wassermann, 1998). Seventeen healthy, right-handed young men (mean age: 23.53 years, SD= 2.12) participated in this study and all were naïve to TMS. Handedness was assessed with using the Edinburgh Handedness Inventory (Oldfield, 1971). All participants provided written informed consent prior to participation, after the nature of the procedure and its possible risks and side effects had been fully explained. Participants were
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informed that they could stop participating in the study at any time and were encouraged to report if they experienced any discomfort associated with stimulation. However, no participant reported discomfort and no adverse event occurred. Participants' personal and health information were treated confidentially and data were coded with numeric IDs. The study was performed in accordance with the Declaration of Helsinki and the protocol used was approved by the local ethics committee of Seoul National University Bundang Hospital.
4.2.
Repetitive transcranial magnetic stimulation (rTMS)
A Magstim 200 magnetic stimulator (Magstim Company, Whitland, UK) connected to a figure-of-eight-shaped coil was used to apply rTMS and sham stimulation. Before stimulation, each subject underwent a mapping session during which single magnetic pulses were delivered to locate the hand area of each primary motor cortex and to determine the motor threshold (MT) of the right abductor pollicis brevis (APB) muscle, as described previously (Rossini et al., 1999). The left DLPFC stimulation site was defined as the region 6 cm rostral and 1 cm lateral in the parasagital plane from the site of maximal APB stimulation (Brandt et al., 1998). Stimulation intensity was 90% of motor threshold to the right APB muscle, and the stimulation frequency was 10 Hz. These parameters were adopted and modified from previous studies on high-frequency rTMS, which reliably demonstrated neuromodulation of prefrontal and striatal regions (Barrett et al., 2004; Sibon et al., 2007; Strafella et al., 2001, 2003). For active stimulation, participants received three consecutive blocks of stimulation; each stimulation block consisted of 15 trains of 2-s duration, separated by an intertrain interval of 10 s (900 pulses were administered per session). The interval between stimulation blocks was 10 min, during which participants were instructed to close their eyes and rest. A graphical illustration of the timeline is presented in Fig. 3. Sham stimulation was conducted in the same manner except that the coil was held at an angle of 90° and only one edge of it rested on the scalp. During rTMS all participants wore earplugs and safety guidelines were followed (Wassermann, 1998).
4.3.
Conners' continuous performance test (Conners' CPT)
Attentional inhibition was assessed using the Conners' CPT (Conners et al., 2003). Participants were instructed to press the keyboard spacebar as quickly as possible in response to any letter except the letter “X.” The probability of the occurrence of “X” was 10%. Each letter was displayed for 250 ms and 20 letters were displayed per block. The ISI rate in each block was either 1, 2 or 4 s, and each rate of block repeated six times throughout the task. The total number of blocks was 18. The block order was pseudorandomized. The CPT took approximately 14 min to complete. The outcome measures of this task included hit reaction time, the standard error of hit reaction time (a measure of response speed consistency across blocks), and commission errors (as a measure of inhibitory control). The omission errors were not analyzed because participants rarely made these errors (Mrtms = .60%, SD = 1.06%; Msham = .45%, SD = 1.15%).
4.4.
Study design and procedure
The study had a randomized within-subject crossover design, which involved both real rTMS and sham stimulation over the left DLPFC on two different days, separated by an interval of a week (except for three participants that underwent second sessions after 5 days). The order of stimulation was randomized across subjects. In order to investigate whether any mood changes would be induced by stimulation, and if so, whether rTMS-induced mood changes influenced task performance, participants completed a Korean translation of the positive affect and negative affect scale (PANAS) (Watson et al., 1988) before and after stimulation sessions and reported using a 5-point Likert scale (“not at all,” “a little,” “moderately,” “quite a bit,” and “extremely”) their responses to 20 emotional adjectives (e.g., interested, enthusiastic, distressed, nervous). Participants performed the CPT task immediately after completing PANAS. Fig. 2 illustrated the timeline of the procedure. At the end of each session, participants were instructed to report any adverse effects that they might have experienced during participation.
Fig. 2 – Illustration of the experimental design. Each participant underwent rTMS and sham stimulation on two different days. Stimulation sessions consist of three separate blocks of treatment with a resting interval. The stimulation frequency used was 10 Hz and the stimulation intensity was 90% of motor threshold.
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Acknowledgments This work was supported by grants from the National Research Foundation of Korea (M2008-03915, 20090093889) funded by the Ministry of Education, Science and Technology of Republic of Korea and the Seoul National University Bundang Hospital Research Fund (02-2007-002).
REFERENCES
Acosta, M.T., Leon-Sarmiento, F.E., 2003. Repetitive transcranial magnetic stimulation (rTMS): new tool, new therapy and new hope for ADHD. Curr. Med. Res. Opin. 19, 125–130. Ballard, J.C., 2001. Assessing attention: comparison of response-inhibition and traditional continuous performance tests. J. Clin. Exp. Neuropsychol. 23, 331–350. Barrett, J., Della-Maggiore, V., Chouinard, P.A., Paus, T., 2004. Mechanisms of action underlying the effect of repetitive transcranial magnetic stimulation on mood: behavioral and brain imaging studies. Neuropsychopharmacology 29, 1172–1189. Brandt, S.A., Ploner, C.J., Meyer, B.U., Leistner, S., Villringer, A., 1998. Effects of repetitive transcranial magnetic stimulation over dorsolateral prefrontal and posterior parietal cortex on memory-guided saccades. Exp. Brain Res. 118, 197–204. Braver, T.S., Barch, D.M., Gray, J.R., Molfese, D.L., Snyder, A., 2001. Anterior cingulate cortex and response conflict: effects of frequency, inhibition and errors. Cereb. Cortex 11, 825–836. Chee, P., Logan, G., Schachar, R.J., Lindsay, P., Wachsmuth, R., 1989. Effects of event rate and display time on sustained attention in hyperactive, normal, and control children. J. Abnorm. Child Psychol. 17, 371–391. Conners, C.K., Epstein, J.N., Anogold, A., Klaric, J., 2003. Continuous performance test performance in a normative epidemiological sample. J. Abnorm. Child Psychol. 31, 555–562. Epstein, J.N., Conners, C.K., Hervey, A.S., Tonev, S.T., Arnold, L.E., Abikoff, H.B., Elliott, G., Greenhill, L.L., Hechtman, L., Hoagwood, K., Hinshaw, S.P., Hoza, B., Jensen, P.S., March, J.S., Newcorn, J.H., Pelham, W.E., Severe, J.B., Swanson, J.M., Wells, K., Vitiello, B.T.W., 2006. Assessing medication effects in the MTA study using neuropsychological outcomes. J. Child Psychol. Psychiatry 47, 446–456. Gross, M., Nakamura, L., Pascual-Leone, A., Fregni, F., 2007. Has repetitive transcranial magnetic stimulation (rTMS) treatment for depression improved? A systematic review and metaanalysis comparing the recent vs. the earlier rTMS studies. Acta Psychiatr. Scand. 116, 165–173. Hervey, A.S., Epstein, J.N., Curry, J.F., Tonev, S., Arnold, L.E., Conners, C.K., Hinshaw, S.P., Swanson, J.M., Hechtman, L., 2006. Reaction time distribution analysis of neuropsychological performance in an ADHD sample. Child Neuropsychol. 12, 125–140. Hilgetag, C.C., Théoret, H., Pascual-Leone, A., 2001. Enhanced visual spatial attention ipsilateral to rTMS-induced 'virtual lesions' of human parietal cortex. Nat. Neurosci. 4, 953–957. Huber, T.J., Schneider, U., Rollinik, J., 2003. Gender differences in the effect of repetitive transcranial magnetic stimulation in schizophrenia. Psychiat. Res. 120 (1), 103–105. Keck, M.E., Welt, T., Müller, M.B., Erhardt, A., Ohl, F., Toschi, N., Holsboer, F., Sillaber, I., 2002. Repetitive transcranial magnetic stimulation increases the release of dopamine in the mesolimbic and mesostriatal system. Neuropharmacology 43, 101–109.
157
Lisanby, S.H., Gutman, D., Luber, B., Schroeder, C., Sackeim, H.A., 2001. Sham TMS: intracerebral measurement of the induced electrical field and the induction of motor-evoked potentials. Biol. Psychiatry 49, 460–463. MacDonald III, A.W., Cohen, J.D., Stenger, V.A., Carter, C.M., 2000. Dissociating the role of the dorsolateral prefrontal and anterior cingulate cortex in cognitive control. Science 288, 1835–1838. Mally, J., Stone, T.W., 1999. Therapeutic and dose-dependent effect of repetitive microelectroshock induced by transcranial magnetic stimulation in Parkinson's disease. J. Neurosci. Res. 57, 935–940. Miyake, A., Friedman, N.P., Emerson, M.J., Witzki, A.H., Howerter, A., 2000. The unity and diversity of executive functions and their contributions to complex “frontal lobe” tasks: A latent variable analysis. Cogn. Psychol. 41, 49–100. Moser, D.J., Jorge, R.E., Manes, F., Paradiso, S., Benjamin, M.L., Robinson, R.G., 2002. Improved executive functioning following repetitive transcranial magnetic stimulation. Neurology 58, 1288–1290. Mosimann, U.P., Rihs, T.A., Engeler, J., Fisch, H.-U., Schlaepfer, T.E., 2000. Mood effects of repetitive transcranial magnetic stimulation of left prefrontal cortex in healthy volunteers. Psychiatr. Res. 94, 251–256. Ohnishi, T., Hayashi, T., Okabe, S., Nonaka, I., Matsuda, H., Iida, H., Imabayashi, E., Watabe, H., Miyake, Y., Ogawa, M., Teramoto, N., Ohta, Y., Ejima, N., Sawada, T., Ugawa, Y., 2004. Endogenous dopamine release induced by repetitive transcranial magnetic stimulation over the primary motor cortex: an [11C]raclopride positron emission tomography study in anesthetized macaque monkeys. Biol. Psychiatry 55, 484–489. Oldfield, R.C., 1971. The assessment and analysis of handedness: The Edinburgh Inventory. Neuropsychologia 9, 97–113. Pascual-Leone, A., Rubio, B., Pallard, F., Catala, M.D., 1996. Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression. Lancet 348, 233–237. Paus, T., Barrett, J., 2004. Transcranial magnetic stimulation (TMS) of the human frontal cortex: implications for repetitive TMS treatment of depression. J. Psychiatry Neurosci. 29, 268–279. Pogarell, O., Koch, W., Pöpperl, G., Tatsch, K., Jakob, F., Mulert, C., Grossheinrich, N., Rupprecht, R., Möller, H.-J., Hegerl, U., Padberg, F., 2007. Acute prefrontal rTMS increases striatal dopamine to a similar degree as d-amphetamine. Psychiatry Res: Neuroimaging 156, 251–255. Rossini, P.M., Berardelli, A., Deuschl, G., Hallett, M., MaertensdeNoordhout, A.M., Paulus, W., Pauri, F., 1999. Applications of magnetic cortical stimulation. The International Federation of Clinical Neurophysiology. Electroencephalogr Clin Neurophysiol 52, 171–185 (suppl). Rounis, E., Stephan, K.E., Lee, L., Siebner, H.R., Friston, K.J., Rothwell, J.C., Frackowiak, R.S.J., 2006. Acute changes in fronto-parietal activity following rTMS over the dorsolateral prefrontal cortex in a cued reaction time task. J. Neurosci. 26, 9629–9638. Rounis, E., Yarrow, K., Rothwell, J.C., 2007. Effects of rTMS conditioning over the fronto-parietal network on motor versus visual attention. J. Cogn. Neurosci. 19 (3), 513–524. Sedlackova, S., Rektorova, I., Srovnalova, H., Rektor, I., 2009. Effect of high frequency repetitive transcranial magnetic stimulation on reaction time, clinical features and cognitive functions in patients with Parkinson's disease. J. Neural Transm. 116, 1093–1101. Sergeant, J., 2000. The cognitive-energetic model: an empirical approach to Attention-Deficit Hyperactivity Disorder. Neurosci. Biobehav. Rev. 24, 7–12. Sibon, I., Strafella, A.P., Gravel, P., Ko, J.H., Booji, L., Soucy, J.P., Leyton, M., Diksic, M., Benkelfat, C., 2007. Acute prefrontal cortex TMS in healthy volunteers: Effects on brain 11C-αMtrp trapping. NeuroImage 34, 1658–1664.
158
BR A I N R ES E A RC H 1 3 2 9 ( 2 01 0 ) 1 5 2 –15 8
Siebner, H.R., Willoch, F., Peller, M., Auer, C., Boekcer, H., Conrad, B., Bartenstein, P., 1998. Imaging brain activation induced by long trains of repetitive transcranial magnetic stimulation. NeuroReport 9, 943–948. Siebner, H.R., Rossmeier, C., Mentschel, C., Peinemann, A., Conrad, B., 2000. Short-term motor improvement after sub-threshold 5-Hz repetitive transcranial magnetic stimulation of the primary motor hand area in Parkinson's disease. J. Neurol. Sci. 178, 91–94. Siebner, H.R., Peller, M., Bartenstein, P., Willoch, F., Rossmeier, C., Schwaiger, M., Conrad, B., 2001. Activation of frontal premotor areas during suprathreshold transcranial magnetic stimulation of the left primary sensorimotor cortex: A glucose metabolic PET study. Hum. Brain Mapp. 12, 157–167. Sommer, M., Paulus, W., 2003. Pulse configuration and rTMS efficacy: a review of clinical studies. Suppl. Clin. Neurophysiol. 56, 33–41. Strafella, A.P., Paus, T., Jennifer, B., Dagher, A., 2001. Repetitive transcranial magnetic stimulation of the human prefrontal cortex induces dopamine release in the caudate nucleus. J. Neurosci. 21, 1–4. Strafella, A.P., Paus, T., Fraraccio, M., Dagher, A., 2003. Striatal dopamine release induced by repetitive transcranial magnetic stimulation of the human motor cortex. Brain 126, 2609–2615. Strafella, A.P., Ko, J.H., Grant, J., Fraraccio, M., Monchi, O., 2005. Corticostriatal functional interactions in Parkinson's disease: a rTMS⁄[11C]raclopride PET study. Eur. J. NeuroSci. 22, 2946–2952. Vanderhasselt, M.-A., de Raedt, R., Baeken, C., Leyman, L., D'haenen, H., 2006a. The influence of rTMS over the left dorsolateral prefrontal cortex on stroop task performance. Exp. Brain Res. 169, 279–282. Vanderhasselt, M.-A., de Raedt, R., Baeken, C., Leyman, L., D'haenen, H., 2006b. The influence of rTMS over the right
dorsolateral prefrontal cortex on intentional set switching. Exp. Brain Res. 172, 561–565. Vanderhasselt, M.-A., de Raedt, R., Baeken, C., Leyman, L., Clerinx, P., D'haenen, H., 2007. The influence of rTMS over the right dorsolateral prefrontal cortex on top-down attentional processes. Brain Res. 1137, 111–116. Vanderhasselt, M.-A., de Raedt, R., Baeken, C., Leyman, L., D'haenen, H., 2009a. A single session of rTMS over the left dorsolateral prefrontal cortex influences attentional control in depressed patients. World J. Biol. Psychiatry 10, 34–42. Vanderhasselt, M.-A., De Raedt, R., Leyman, L., Baeken, C., 2009b. Acute effects of repetitive transcranial magnetic stimulation on attentional control are related to antidepressant outcomes. J. Psychiatr. Neurosci. 34, 119–126. Wagner, M., Rihs, T.A., Mosimann, U.P., Fisch, H.U., Schlaepfer, T.E., 2006. Repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex affects divided attention immediately after cessation of stimulation. J. Psychiatr. Res. 40, 315–321. Wassermann, E.M., 1998. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5–7, 1996. Electroencephalogr. Clin. Neurophysiol. 108, 1–16. Wassermann, E.M., Lisanby, S.H., 2001. Therapeutic application of repetitive transcranial magnetic stimulation: a review. Clin. Neurophysiol. 112, 1367–1377. Watson, D., Clark, L.A., Tellegen, A., 1988. Development and validation of brief measures of positive and negative affect: the PANAS scales. J. Pers. Soc. Psychol. 54, 1063–1070.