Repetitive transcranial magnetic stimulation dissociates working memory manipulation from retention functions in the prefrontal, but not posterior parietal, cortex

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

Functional asymmetries in human working memory

Thesis (Ph.D.)--Boston UniversityWorking memory is the cognitive ability to maintain and manipulate information in mind to guide behavior. This relies on the coordinated activity of a bilateral brain network, which has been modeled as a central executive in control of separate storage systems for verbal and spatial information. Evidence from human and nonhuman primate research demonstrates that the dorsolateral prefrontal cortex (dlPFC) is critical for manipulating information in working memory. However, whether the dlPFC is dissociable by the domain of information remains unsettled. Recent human studies using repetitive transcranial magnetic stimulation (rTMS) suggest the left and right dlPFC may play separable roles in manipulating verbal and spatial information. In the present study, this theory was investigated further with two experiments on healthy right-handed adults. Both experiments utilized the 3-back task of visual working memory with letters and locations serving as verbal and spatial stimuli, respectively. In Experiment 1, tasks were administered during functional neuroimaging in two formats: one using centrally-presented single letters as verbal stimuli, and dots in different locations as spatial stimuli; and another using single letters in different locations for both verbal and spatial tasks. At the whole-brain group-level, letter- and location-specific contrasts did not differ between formats, indicating verbal/spatial differences reflected discrete subsystems in working memory and not simply separate perceptual processing. Nevertheless, in the dlPFC, bilateral activity was observed across versions, suggesting its contributions to working memory are domain-independent. Experiment 2 tested whether this relationship was causal by assessing 3-back performance after applying low-frequency rTMS to the dlPFC. Following rTMS of the right dlPFC, accuracy improved on the letter task, but worsened on the location task, while the opposite was observed after left rTMS. These double-dissociations suggest left and right dlPFC operate as competing subsystems for manipulating verbal and spatial information, respectively. Thus, the observation of equivalent bilateral dlPFC activity during the letter and location tasks might reflect a left-lateralized system for verbally-encoded information and a right-lateralized system for nonverbal representations operating in parallel on all stimuli. Such a functional asymmetry would have implications for therapies aimed at ameliorating working memory impairments in disease and even normal aging

The Role of Working Memory Load in Distractor Suppression

The well-established Load Theory of Attention and Cognitive Control (Load Theory) has sparked research over two decades. There are two integral components of Load Theory, i.e. ‘cognitive load’ and ‘perceptual load’ with the former concept receiving less attention in the literature. The core assumptions of Load Theory, with an emphasis on ‘cognitive load’,have been systematically investigated in this thesis using electroencephalography (EEG) and transcranial magnetic stimulation(TMS). The current research uncovered robust working memory (WM) effects in the healthy youngeradult populationwhich partially supported Load Theory. Experiment 1 revealed that the WM load effect on distractor processing increases when more items were held in WM but can plateau at a certain set-size(i.e.,3 items). In Experiment 2, the direction of distractor interference was inconsistent across the behavioural measures of reaction times and error rates, with the latter in support of Load Theory. In contrast, therewas strong electrophysiological evidence (i.e.,the N2pc and Pd components) for increased susceptibility to peripheral distractors under low WM load conditions (remembering one item). The behavioural effects of Experiments1and 2 which partially supported Load Theory, were not replicated with a TMS protocol (Experiment 3). There were significant effects, partially supporting Load Theory, when the spatial position of distractor and a subsequent target item was considered. Altogether, the findings have contributed to a clearer understanding of WM load effects, especially in terms of the attentional processes involved in distractor processing within a single-task setting. The results have provided recommendations of factors which were omitted in Load Theory such as the distinction of functions (updating and shifting) rather than positing a general executive load. This understanding can inform future research specifically targeting visual processing, WM and selective attention processes which can be extrapolated to everyday situations where attention to detail is crucial

Repetitive Transcranial Magnetic Stimulation Affects behavior by Biasing Endogenous Cortical Oscillations

A governing assumption about repetitive transcranial magnetic stimulation (rTMS) has been that it interferes with task-related neuronal activity – in effect, by “injecting noise” into the brain – and thereby disrupts behavior. Recent reports of rTMS-produced behavioral enhancement, however, call this assumption into question. We investigated the neurophysiological effects of rTMS delivered during the delay period of a visual working memory task by simultaneously recording brain activity with electroencephalography (EEG). Subjects performed visual working memory for locations or for shapes, and in half the trials a 10-Hz train of rTMS was delivered to the superior parietal lobule (SPL) or a control brain area. The wide range of individual differences in the effects of rTMS on task accuracy, from improvement to impairment, was predicted by individual differences in the effect of rTMS on power in the alpha-band of the EEG (∼10 Hz): a decrease in alpha-band power corresponded to improved performance, whereas an increase in alpha-band power corresponded to the opposite. The EEG effect was localized to cortical sources encompassing the frontal eye fields and the intraparietal sulcus, and was specific to task (location, but not object memory) and to rTMS target (SPL, not control area). Furthermore, for the same task condition, rTMS-induced changes in cross-frequency phase synchrony between alpha- and gamma-band (>40 Hz) oscillations predicted changes in behavior. These results suggest that alpha-band oscillations play an active role cognitive processes and do not simply reflect absence of processing. Furthermore, this study shows that the complex effects of rTMS on behavior can result from biasing endogenous patterns of network-level oscillations

The effect of high-frequency rTMS over left DLPFC and fluid abilities on goal neglect

Goal neglect refers to when an aspect of task instructions is not utilised due to increased competition between goal representations, an attentional limit theoretically linked to working memory. In an attempt to alleviate goal neglect and to investigate the association between dorsolateral prefrontal cortex (DLPFC)-supported working memory and goal neglect, we used high-frequency repetitive transcranial magnetic stimulation to the left DLPFC whilst participants completed the letter-monitoring task, a measure of goal neglect, and an N3-back task, a working memory task known to be affected by rTMS of the left DLPFC, following 20 min of active and sham stimulation (run on separate days). We found increased accuracy on the N3-back task in addition to decreased goal neglect in the active compared to sham condition when controlling for age and fluid abilities (as assessed by matrix reasoning performance). Furthermore, analysis showed that active stimulation improvements on both the N3-back and letter-monitoring tasks were greater for those with higher fluid abilities. These findings provide support for the link between the DLPFC-support working memory and goal neglect. Increased performance on the N3-back task also supports the literature reporting a link between left DLPFC and verbal working memory. Results are evaluated in the context of potential use to alleviate symptoms of disorders related to goal neglect

rTMS evidence for a dissociation in short-term memory for spoken words and nonwords

Differing patterns of verbal short-term memory (STM) impairment have provided unique insights into the relationship between STM and broader language function. Lexicality effects (i.e., better recall for words than nonwords) are larger in patients with phonological deficits following left temporoparietal lesions, and smaller in patients with semantic impairment and anterior temporal damage, supporting linguistic accounts of STM. However, interpretation of these patient dissociations are complicated by (i) non-focal damage and (ii) confounding factors and secondary impairments. This study addressed these issues by examining the impact of inhibitory transcranial magnetic stimulation (TMS) on auditory-verbal STM performance in healthy individuals. We compared the effects of TMS to left anterior supramarginal gyrus (SMG) and left anterior middle temporal gyrus (ATL) on STM for lists of nonwords and random words. SMG stimulation disrupted nonword recall, in a pattern analogous to that observed in patients, compatible with a role for this site in processing speech sounds without support from long-term lexical-semantic representations. Stimulation of ATL, a semantic site, disrupted the recall of words but not nonwords. A visual pattern memory task indicated that these effects of TMS were restricted to the verbal domain. These data provide convergent evidence for the conclusions of neuropsychological studies that support linguistic accounts of verbal STM

Short-term memory of temporal aspects of noxious and innocuous thermal sensation : psychophysical and fMRI studies

La douleur peut être considérée comme un système de protection qui signale une menace et qui nous avertit des dégâts imminents aux tissus. En tant que mécanisme de défense, il nécessite l'apprentissage et la mémoire des expériences du passé pour la survie et les comportements liés à la douleur. Par conséquent, notre expérience de la douleur actuelle est fortement influencée par les expériences antérieures et l'apprentissage. Cependant, malgré son importance, notre compréhension actuelle de l'interaction entre le système de la douleur et le système de mémoire est très limitée. La mémoire de la douleur est un sujet de recherche très vaste. Il nécessite une compréhension des mécanismes impliqués à chaque étape du système de mémoire (mémoire immédiate, à court terme et à long terme) et l'interaction entre eux. Parmi les étapes multiples de la mémoire, la mémoire à court terme de la douleur est une zone qui est moins recherchée, alors qu'il existe une énorme quantité de recherche neuroscientifique dans la mémoire à court terme sur d'autres modalités, en particulier la vision. L'étude de la mémoire à court terme de la douleur est particulièrement importante car cette trace de la mémoire à court terme de la douleur est ensuite convertie en mémoire à long terme et affecte ensuite les expériences futures de la douleur. Cette thèse est largement axée sur la mémoire à court terme de la douleur. La complexité et la multi dimensionnalité de la douleur ajoutent encore un autre élément à la recherche sur la mémoire de la douleur. Par exemple, la trace de la mémoire de la douleur peut contenir des traces de mémoire de diverses composantes de la douleur telles que la réponse sensorielle affective, cognitive et motrice et l'interaction entre elles. Par conséquent, une première étape dans l'exploration neuroscientifique de la mémoire de la douleur nécessite la réduction de l'expérience de la douleur tout en englobant tous ces différents composants à un seul composant. Dans la recherche présentée ici, nous avons généralement examiné cela par des instructions d'attention ‘ top-down’ pour assister à la dimension sensorielle de la douleur. La recherche précédente sur la mémoire à court terme de la douleur a également porté principalement sur la dimension sensorielle de la douleur. Cependant, parmi les dimensions sensorielles de la douleur, la mémoire à court terme de l'intensité et de la dimension spatiale de la douleur a fait l'objet de recherches antérieures. Malgré son importance, la dimension temporelle de la douleur est restée complètement inexplorée dans la recherche sur la mémoire de la douleur. La recherche menée dans cette thèse est consacrée à l'exploration de la mémoire à court terme de la durée de la douleur. La durée de la douleur peut être suivie de manière indépendante, mais peut également être suivie conjointement avec la dimension d'intensité telle que le suivi dynamique de l'intensité de la douleur dans le temps. Les études menées dans cette thèse traitent spécifiquement du traitement isolé de la durée de la douleur ainsi que du traitement conjoint de la dimension durée / intensité de la douleur. La première étude psychophysique a exploré la nature de la représentation mentale du modèle de mémoire de la douleur thermique dynamique et a également été conçue pour aborder les différences de la dimension sensorielle et affective de la douleur thermique dans la mémoire à court terme. La deuxième étude psychophysique portait sur les propriétés de la mémoire à court terme de la sensation thermique non douloureux en comparant le suivi dynamique de la sensation et le suivi isolé de la durée d'un événement thermique non douloureux. La troisième étude poursuit l'exploration du traitement dynamique de la durée conjointement avec l'intensité par rapport au traitement isolé de la durée dans la mémoire à court terme en utilisant des stimuli thermiques douloureuse une résonance magnétique fonctionnelle (IRMF). Dans l'ensemble, les résultats des études psychophysiques ont montré une transformation significative de la durée et de la dynamique de la sensation thermique douloureux et non-douloureux dans la mémoire à court terme; comme la perte d'informations somatosensorielles temporelles en mémoire. Nous avons en outre montré une amélioration du rappel de la durée dans le suivi dynamique de la durée, en comparaison avec le suivi de la durée isolée. Nous avons également montré des différences dans les corrélats neuronaux de la mémoire à court terme de la durée de douleur par rapport à la dynamique de douleur. L'étude de l'IRMF a montré des similitudes frappantes dans les corrélats neuronaux sous-jacents à la mémoire à court terme de douleur et d'autres modalités telles que la contribution des coticés fronto-pariétales ainsi que les corticaux sensoriels impliqués dans le traitement perceptuel.Pain can be viewed as a protective system that signals threat and alerts us to impending tissue damage. As a defense mechanism, it necessitates the learning and memory of past painful experiences for survival and pain-related behavior. Therefore our current pain experience is heavily influenced by previous experiences and learning. However, despite its importance, our current understanding of the interaction between the pain system and the memory system is very limited. Pain memory is a very broad topic of research on its own. It requires an understanding of the mechanisms involved at each stage of the memory system (immediate, short-term, and long-term memory), and the interaction among them. Among the multiple stages of memory, the short-term memory of pain is an area that is less researched, while there are enormous amount of neuroscientific research in short-term memory of other modalities, particularly vision. Investigation of the short-term memory of pain is especially important as the short-term memory trace of pain is converted to long-term memory and subsequently affects future pain experiences. This thesis is broadly focused on the short-term memory of pain. The complexity and multi-dimensionality of pain adds yet another element to the research on pain memory. For example, the memory trace of pain may contain memory traces of various components of pain such as sensory, affective, cognitive, and motoric responses, and the interactions among them. Therefore, an initial step in the neuroscientific exploration of pain memory requires narrowing down the pain experience, which encompasses all of these various components, to one single component. In the research presented here, we achieved this using top-down attentional instructions to attend to the sensory component of pain. The previous research on short-term memory of pain also focused mainly on the sensory component of pain. However, within the sensory component of pain the short-term memory of intensity and spatial dimension of pain has been the focus of previous research. Despite its importance, the temporal dimension of pain remained completely unexplored in pain memory research. Thus, the research conducted in this thesis is devoted to the exploration of short-term memory of the duration of pain. Pain duration can be tracked independently, but it can also be tracked conjointly with intensity, such as in dynamic tracking of pain intensity over time. The studies addressed in this thesis examined the isolated processing of pain duration as well as conjoint processing of the duration and intensity of pain. The first psychophysical study explored the nature of the mental representation of the memory template of dynamic thermal pain sensation and, additionally, addressed the differences between the sensory versus affective dimensions of thermal pain sensation in short-term memory. The second psychophysical study focused on properties of the short-term memory of innocuous thermal sensation by comparing dynamic tracking of sensation versus isolated tracking of duration of an innocuous thermal event. The third study explored the dynamic processing of duration conjointly with intensity, versus the isolated processing of duration in short-term memory, using noxious thermal stimuli and functional magnetic resonance imaging (fMRI). Overall, the results of the psychophysical studies showed significant transformation of duration and dynamics information of noxious and innocuous thermal sensation in short-term memory, such as loss of temporal somatosensory information. Additionally, we showed improvement in duration recall during dynamic tracking versus isolated tracking of duration. The fMRI study revealed differences in neural correlates of short-term memory of pain duration versus pain dynamics. Importantly, it also showed striking similarities between neural correlates underlying the short-term memory of pain and those underlying other modalities, such as a contribution of fronto-parietal cortices as well as sensory cortices involved in perceptual processing

Concurrent neuroimaging and neurostimulation reveals a causal role for dlPFC in coding of task-relevant information.

Dorsolateral prefrontal cortex (dlPFC) is proposed to drive brain-wide focus by biasing processing in favour of task-relevant information. A longstanding debate concerns whether this is achieved through enhancing processing of relevant information and/or by inhibiting irrelevant information. To address this, we applied transcranial magnetic stimulation (TMS) during fMRI, and tested for causal changes in information coding. Participants attended to one feature, whilst ignoring another feature, of a visual object. If dlPFC is necessary for facilitation, disruptive TMS should decrease coding of attended features. Conversely, if dlPFC is crucial for inhibition, TMS should increase coding of ignored features. Here, we show that TMS decreases coding of relevant information across frontoparietal cortex, and the impact is significantly stronger than any effect on irrelevant information, which is not statistically detectable. This provides causal evidence for a specific role of dlPFC in enhancing task-relevant representations and demonstrates the cognitive-neural insights possible with concurrent TMS-fMRI-MVPA

Tes and its Effects on Cognitive FUnctions: Feasibility and Limitations for a Broader Clinical Application

Trascranial electrical stimulation (tES) is a neuromodulation technique which applies a mild current to modulate a wide variety of cognitive functions. It was shown that depending on the protocol applied, tES is effective in enhancing or interfering with cortical excitation, even if further research is needed in order to better understand its effects. In our studies, we focused on the online or offline effects of various tES protocols and on disparate tasks, in order to evaluate potential future application on clinical population. To date, few studies investigated offline, transfer effects of tES, both after single or multiple sessions administration. Similarly, evidence assessing tES offline and long-term effects on cortical excitability is still lacking. This doctoral thesis contributed to shed light on different aspects concerning tES. Firstly, we demonstrated that cathodal tDCS applied over right inferior frontal gyrus (rIFG) is effective in modulating selectively incongruent trials in a dots comparison task. Moreover, the effect was specific for offline measures, but not online, suggesting possible short-term after-effects of this protocol. Secondly, we showed that bilateral tRNS is more effective than anodal tDCS in inducing after-stimulation changes in attention both on behavioral performance and cortical excitation. Our studies confirmed that the two protocols are differentially effective, consistently with literature showing that different neural mechanisms underlie tDCS and tRNS neural after-effects. Finally, we demonstrated that despite the absence of online effects, coupling bilateral tRNS with cognitive training is effective to induce long-term changes, as assessed by behavioral measures and cortical plasticity investigations. Interestingly, the effects were still present a month after the end of the training. Taken together, our studies contributed to better understand the after-effects of tES and suggests that bilateral tRNS is best suited for clinical applications, even if further research is needed