Transcranial magnetic stimulation of left prefrontal cortex impairs working memory Brendan R. Mull, Masud Seyal * Department of Neurology, Section of Clinical Neurophysiology, University of California, Davis, 2315 Stockton Boulevard, Room 5308, Sacramento, CA 95817, USA Accepted 18 May 2001 Abstract Objectives: Several lines of evidence suggest that the prefrontal cortex is involved in working memory. Our goal was to determine whether transient functional disruption of the dorsolateral prefrontal cortex (DLPFC) would impair performance in a sequential-letter working memory task. Methods: Subjects were shown sequences of letters and asked to state whether the letter just displayed was the same as the one presented 3-back. Single-pulse transcranial magnetic stimulation (TMS) was applied over the DLPFC between letter presentations. Results: TMS applied over the left DLPFC resulted in increased errors relative to no TMS controls. TMS over the right DLPFC did not alter working memory performance. Conclusion: Our results indicate that the left prefrontal cortex has a crucial role in at least one type of working memory. q 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Working memory; Dorsolateral prefrontal cortex; Functional disruption; Transcranial magnetic stimulation 1. Introduction Working memory refers to temporary storage and manip- ulation of the information necessary for complex tasks such as language comprehension, learning, and reasoning (Baddeley, 1992). Fuster et al. (1982) found that some neurons of the prefrontal cortex increase their ®ring when a cue is presented and continue to ®re during a delay period after the cue disappears. Functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) studies indicate that the frontal cortex plays a crucial role during working memory tasks (e.g. Roland, 1984; Paulesu et al., 1993; Jonides et al., 1993; Petrides et al., 1993a,b; Cohen et al., 1994). PET and fMRI studies have shown increased metabolic activity in the frontal lobes during working memory tasks, with other cortical areas also acti- vated depending on the task involved (e.g. Berman et al., 1995; Smith et al., 1996; Salmon et al., 1996; D'Esposito et al., 1995). The activation of frontal cortex appears to be proportional to working memory demands and not `mental effort' more generally (Barch et al., 1997). Using EEG tech- niques with high spatial resolution, Gevins et al. (1996) identi®ed several frontally localized waveforms modulated by working memory task manipulations. A left-lateralized slow frontal positivity with a mean peak latency of 450 ms (P450) was larger in both spatial and verbal memory tasks than in the respective controls. Single-pulse transcranial magnetic stimulation (TMS) can transiently disrupt the function of restricted regions of cortex. For example, TMS over sensory cortex can decrease perception of cutaneous stimuli delivered to the ®ngers of the contralateral hand (Cohen et al., 1991; Seyal et al., 1992) for up to 500 ms after the TMS pulse (Seyal et al., 1997). Repetitive TMS (rTMS) of the frontal cortex has been shown to increase errors in a visuospatial delayed-recall task when stimulation was applied throughout the entire delay period, but not with a shorter duration of stimulus (Pascual-Leone and Hallett, 1994). TMS of human cortex causes brief disruption of cortical activity and can therefore provide information on dynamic cortical processes with sub-second temporal resolution. Single-pulse TMS can be safely used in normal human subjects without the risks inherent with rTMS (Wassermann, 1998). We proposed that under certain conditions single-pulse TMS should be effective in disrupting verbal working memory. First, we targeted the pulse to an approximate time and location where Gevins et al. (1996) found EEG Clinical Neurophysiology 112 (2001) 1672±1675 1388-2457/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S1388-2457(01)00606-X www.elsevier.com/locate/clinph CLINPH 2001036 * Corresponding author. Tel.: 11-916-734-2636; fax: 11-916-736-2976. E-mail address: mseyal@ucdavis.edu (M. Seyal).