Previous studies have claimed that weak transcranial direct current stimulation (tDCS) induces persisting excitability changes in the human motor cortex that can be more pronounced than cortical modulation induced by transcranial magnetic stimulation, but there are no studies that have evaluated the effects of tDCS on working memory. Our aim was to determine whether anodal transcranial direct current stimulation, which enhances brain cortical excitability and activity, would modify performance in a sequential-letter working memory task when administered to the dorsolateral prefrontal cortex (DLPFC). Fifteen subjects underwent a three-back working memory task based on letters. This task was performed during sham and anodal stimulation applied over the left DLPFC. Moreover seven of these subjects performed the same task, but with inverse polarity (cathodal stimulation of the left DLPFC) and anodal stimulation of the primary motor cortex (M1). Our results indicate that only anodal stimulation of the left prefrontal cortex, but not cathodal stimulation of left DLPFC or anodal stimulation of M1, increases the accuracy of the task performance when compared to sham stimulation of the same area. This accuracy enhancement during active stimulation cannot be accounted for by slowed responses, as response times were not changed by stimulation. Our results indicate that left prefrontal anodal stimulation leads to an enhancement of working memory performance. Furthermore, this effect depends on the stimulation polarity and is specific to the site of stimulation. This result may be helpful to develop future interventions aiming at clinical benefits.

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Dorsolateral prefrontal cortex (DLPFC) is recruited during visual working memory (WM) when relevant information must be maintained in the presence of distracting information. The mechanism by which DLPFC might ensure successful maintenance of the contents of WM is, however, unclear; it might enhance neural maintenance of memory targets or suppress processing of distracters. To adjudicate between these possibilities, we applied time-locked transcranial magnetic stimulation (TMS) during functional MRI, an approach that permits causal assessment of a stimulated brain region's influence on connected brain regions, and evaluated how this influence may change under different task conditions. Participants performed a visual WM task requiring retention of visual stimuli (faces or houses) across a delay during which visual distracters could be present or absent. When distracters were present, they were always from the opposite stimulus category, so that targets and distracters were represented in distinct posterior cortical areas. We then measured whether DLPFC-TMS, administered in the delay at the time point when distracters could appear, would modulate posterior regions representing memory targets or distracters. We found that DLPFC-TMS influenced posterior areas only when distracters were present and, critically, that this influence consisted of increased activity in regions representing the current memory targets. DLPFC-TMS did not affect regions representing current distracters. These results provide a new line of causal evidence for a top-down DLPFC-based control mechanism that promotes successful maintenance of relevant information in WM in the presence of distraction.external interference | top-down control D orsolateral prefrontal cortex (DLPFC) has long been associated with visual working memory (WM) function, with current models suggesting that it is a source of top-down control over posterior regions maintaining information across the short term (1, 2). One such control process is that of resistance to external distraction, when the appearance of irrelevant information in the visual scene could potentially interfere with maintenance of visual memoranda (3). Moreover, recent studies suggest that filtering of irrelevant information is one important determinant of WM capacity (4, 5), as irrelevant information may occupy limited storage resources that could otherwise be devoted to maintaining relevant information (4). Human lesion (6) and functional magnetic resonance imaging (fMRI) studies (7-9) indicate a specific role for the DLPFC when external distraction must be overcome during the maintenance phase of WM. However, little causal, temporally specific evidence exists on whether DLPFC acts during delays to suppress further processing of distracters (6,8,9) or whether it instead enhances neural representations of the maintained targets to protect them (7,10,11). One striking aspect of DLPFC responses is that they typically concern relevant stimuli (targets) but not irrelevant information (distracters) (11), inc...

Abstract& Understanding the contributions of the prefrontal cortex (PFC) to working memory is central to understanding the neural bases of high-level cognition. One question that remains controversial is whether the same areas of the dorsolateral PFC (dlPFC) that participate in the manipulation of information in working memory also contribute to its short-term retention (STR). We evaluated this question by first identifying, with functional magnetic resonance imaging (fMRI), brain areas involved in manipulation. Next, these areas were targeted with repetitive transcranial magnetic stimulation (rTMS) while subjects performed tasks requiring only the STR or the STR plus manipulation of information in working memory. fMRI indicated that manipulation-related activity was independent of retention-related activity in both the PFC and superior parietal lobule (SPL). rTMS, however, yielded a different pattern of results. Although rTMS of the dlPFC selectively disrupted manipulation, rTMS of the SPL disrupted manipulation and STR to the same extent. rTMS of the postcentral gyrus (a control region) had no effect on performance. The implications of these results are twofold. In the PFC, they are consistent with the view that this region contributes more importantly to the control of information in working memory than to its STR. In the SPL, they illustrate the importance of supplementing the fundamentally correlational data from neuroimaging with a disruptive method, which affords stronger inference about structure-function relations. &

Emerging evidence suggests that items held in working memory (WM) might not all be in the same representational state. One item might be privileged over others, making it more accessible and thereby recalled with greater precision. Here, using transcranial magnetic stimulation (TMS), we provide causal evidence in human participants that items in WM are differentially susceptible to disruptive TMS, depending on their state, determined either by task relevance or serial position. Across two experiments, we applied TMS to area MTϩ during the WM retention of two motion directions. In Experiment 1, we used an "incidental cue" to bring one of the two targets into a privileged state. In Experiment 2, we presented the targets sequentially so that the last item was in a privileged state by virtue of recency. In both experiments, recall precision of motion direction was differentially affected by TMS, depending on the state of the memory target at the time of disruption. Privileged items were recalled with less precision, whereas nonprivileged items were recalled with higher precision. Thus, only the privileged item was susceptible to disruptive TMS over MTϩ. By contrast, precision of the nonprivileged item improved either directly because of facilitation by TMS or indirectly through reduced interference from the privileged item. Our results provide a unique line of evidence, as revealed by TMS over a posterior sensory brain region, for at least two different states of item representation in WM.

Modern neurostimulation approaches in humans provide controlled inputs into the operations of cortical regions, with highly specific behavioral consequences. This enables causal structure–function inferences, and in combination with neuroimaging, has provided novel insights into the basic mechanisms of action of neurostimulation on distributed networks. For example, more recent work has established the capacity of transcranial magnetic stimulation (TMS) to probe causal interregional influences, and their interaction with cognitive state changes. Combinations of neurostimulation and neuroimaging now face the challenge of integrating the known physiological effects of neurostimulation with theoretical and biological models of cognition, for example, when theoretical stalemates between opposing cognitive theories need to be resolved. This will be driven by novel developments, including biologically informed computational network analyses for predicting the impact of neurostimulation on brain networks, as well as novel neuroimaging and neurostimulation techniques. Such future developments may offer an expanded set of tools with which to investigate structure–function relationships, and to formulate and reconceptualize testable hypotheses about complex neural network interactions and their causal roles in cognition.

Constrained principal component analysis (CPCA) with a finite impulse response (FIR) basis set was used to reveal functionally connected networks and their temporal progression over a multistage verbal working memory trial in which memory load was varied. Four components were extracted, and all showed statistically significant sensitivity to the memory load manipulation. Additionally, two of the four components sustained this peak activity, both for approximately 3 s (Components 1 and 4). The functional networks that showed sustained activity were characterized by increased activations in the dorsal anterior cingulate cortex, right dorsolateral prefrontal cortex, and left supramarginal gyrus, and decreased activations in the primary auditory cortex and "default network" regions. The functional networks that did not show sustained activity were instead dominated by increased activation in occipital cortex, dorsal anterior cingulate cortex, sensori-motor cortical regions, and superior parietal cortex. The response shapes suggest that although all four components appear to be invoked at encoding, the two sustained-peak components are likely to be additionally involved in the delay period. Our investigation provides a unique view of the contributions made by a network of brain regions over the course of a multiple-stage working memory trial.

Controlling the effects of proactive interference (PI), the deleterious effect of prior mental activity on current memory representations, is believed to be a key function of the prefrontal cortex. This view is supported by neuroimaging evidence for a correlation between the longer reaction times caused by high PI conditions of a working memory task and increased activity in left inferior frontal gyrus (IFG) of the prefrontal cortex. An alternative that has never been ruled out, however, is that this left IFG effect may merely reflect sensitivity to such nonspecific factors as difficulty and/or time on task. To resolve this confound, we applied the interference methodology of repetitive transcranial magnetic stimulation (rTMS) to the left IFG and two control regions while subjects performed delayed letter recognition. rTMS was guided with high-resolution magnetic resonance images and was timelocked to the onset of the memory probe. The effect of rTMS, a disruption of accuracy restricted to high-PI probes, was specific to the left IFG. These results demonstrate that unpredictable, phasic disruption of the left IFG selectively disrupts control of responses to high-conflict verbal working memory probes, and they conclusively reject nonspecific alternative accounts.cognitive control ͉ inferior frontal gyrus ͉ transcranial magnetic stimulation T he left inferior frontal gyrus (IFG) of the prefrontal cortex is central to many theoretical accounts of cognitive control, including retrieval of semantic knowledge (1), selection among competing alternatives (2), reactive control (3), and the control of the effects of proactive interference (PI) in working memory (4). PI, the deleterious effect of previously remembered information on current memory representations, is widely seen as a critical factor in forgetting, and therefore capacity, in working memory (5-7). Thus, understanding the control of PI in working memory has implications for understanding the cognitive and neural bases of a remarkable breadth of cognitive functions and ''real-world'' outcome measures, from general fluid intelligence, to reading ability, to standardized test performance, to income and socioeconomic status, to personality traits, that are predicted by working memory capacity (8-10).One influential experimental paradigm for the investigation of PI is the ''recent probes'' variant of the classic item-recognition task (Fig. 1), which controls the level of PI by varying whether or not an invalid memory probe matches an item from the preceding trial. The PI produced by such ''recent negative'' (RN) probes manifests as costs in reaction time (RT), and, less reliably, in accuracy. This PI derives from the presumed conflict of processing the probe's high level of familiarity vs. its absence from the current trial's memory set. The neuroimaging correlate of these effects is an increase of signal in the left IFG that is time-locked to the onset of the memory probe. It has been interpreted as evidence for prefrontal cortex-based control of PI (reviewed in ...