Transcranial magnetic stimulation of left prefrontal cortex impairs working memory
Introduction
Working memory refers to temporary storage and manipulation 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 firing when a cue is presented and continue to fire 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, Petrides et al., 1993b, 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 activated 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 techniques with high spatial resolution, Gevins et al. (1996) identified 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 fingers 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 evidence of dorsolateral prefrontal cortex (DLPFC) activity in a verbal working memory task. Second, we ensured that subjects were engaged in a task with a high working memory load by having them participate in a relatively difficult ‘3-back’ working memory task. This ‘3-back’ sequential letter matching task activates the DLPFC (Cohen et al., 1997) Third, we explored a number of regions on the left frontal scalp of each subject to find the location where TMS appeared to have the greatest effect on task performance.
Section snippets
Methods
Nine healthy human subjects were tested. The age range was 23–59 years (mean 34 years). Eight were strongly right-handed; one was strongly left-handed. Subjects gave informed consent, and the local Human Subjects Review Committee approved the study.
Subjects were presented with a pseudo-random set of 33 letters (A–J). Letters were displayed serially on a backlit LCD screen for 30 ms every 2 s. Subjects were required to state if the letter just presented was the same as the letter presented
Results
Seven subjects completed the entire experiment; two completed 6 of 8 sets. In all, there were 34 sets of data following TMS (1020 responses) and the same number of no TMS controls for each hemisphere. Fig. 1 shows the errors made by each subject during the TMS condition and the corresponding control condition.
With left frontal scalp stimulation, significantly more errors were made following TMS than in the corresponding controls (P=0.008). There were 183 (17.9%) incorrect responses in the left
Discussion
In this study, there was a significant increase in task errors related to TMS applied over the left DLPFC relative to the control condition. This degradation in task performance is likely related to transient functional inactivation of the left DLPFC by TMS. Right prefrontal cortex stimulation resulted in no significant change in working memory performance relative to the control condition.
The effect of single pulse TMS on working memory in this study is less pronounced than that reported with
Conclusion
The results of this study indicate that working memory performance, in a sequential-letter-matching task, is impaired by TMS-induced functional inactivation of left prefrontal cortex. This effect occurs during the period when EEG evidence suggests that this region of cortex is engaged in a working memory task. PET and fMRI provide localizing information but have relatively poor temporal resolution as these techniques are dependent on hemodynamic changes that are delayed and temporally dispersed
Acknowledgements
This project was supported by the Predoctoral Research and Enrichment Fellowship, University of California, Davis, School of Medicine (Dr Mull).
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