Neural mechanisms for response selection: comparing selection of responses and items from working memory

Recent functional imaging studies of working memory (WM) have suggested a relationship between the requirement for response selection and activity in dorsolateral prefrontal (DLPFC) and parietal regions. Although a number of WM operations are likely to occur during response selection, the current study was particularly interested in the contribution of this neural network to WM-based response selection when compared to the selection of an item from a list being maintained in memory, during a verbal learning task. The design manipulated stimulus-response mappings so that selecting an item from memory was not always accompanied with selecting a motor response. Functional activation during selection supported previous findings of fronto-parietal involvement, although in contrast to previous findings left, rather than right, DLPFC activity was significantly more active for selecting a memory-guided motor response, when compared to selecting an item currently maintained in memory or executing a memory-guided response. Our results contribute to the debate over the role of fronto-parietal activity during WM tasks, suggesting that this activity appears particularly related to response selection, potentially supporting the hypothesized role of prefrontal activity in biasing attention toward task-relevant material in more posterior regions.     

Effects of transcranial direct current stimulation on pain perception and working memory

Previous studies have shown that non‐invasive stimulation of the dorsolateral prefrontal cortex (DLPFC) could modulate experimentally induced pain and working memory (WM) in healthy subjects. However, the two aspects have never been assessed concomitantly. The present study was set up to investigate the effects of transcranial direct current stimulation (tDCS) of the DLPFC on thermal pain and WM in the same population of healthy volunteers. In a randomized and balanced order of different sessions separated by 1 week, 20 min of 2 mA anodal, cathodal or sham tDCS were applied to the left or right DLPFC in two separate experiments. Twelve healthy volunteers were enrolled for each stimulated hemisphere. Warm and cold detection thresholds, heat and cold pain thresholds as well as heat pain tolerance thresholds were measured before, during and following tDCS. WM was assessed by a 2‐back task applied once during cortical stimulation. Anodal tDCS of the right DLPFC led to an increase of tolerance to heat pain. The 2‐back task revealed fewer outliers during cathodal tDCS of the left DLPFC. The present data show an involvement of the DLPFC in the processing of pain and WM. There was no correlation between these findings, suggesting that the analgesic effects of cortical stimulation are not associated with cognitive processing. However, this conclusion is difficult to affirm because of some limitations of the study regarding the parameters of stimulation or a ceiling effect of the 2‐back task for instance.     

Common neural substrates for visual working memory and attention

Humans are severely limited in their ability to memorize visual information over short periods of time. Selective attention has been implicated as a limiting factor. Here we used functional magnetic resonance imaging to test the hypothesis that this limitation is due to common neural resources shared by visual working memory (WM) and selective attention. We combined visual search and delayed discrimination of complex objects and independently modulated the demands on selective attention and WM encoding. Participants were presented with a search array and performed easy or difficult visual search in order to encode one or three complex objects into visual WM. Overlapping activation for attention-demanding visual search and WM encoding was observed in distributed posterior and frontal regions. In the right prefrontal cortex and bilateral insula blood oxygen-level-dependent activation additively increased with increased WM load and attentional demand. Conversely, several visual, parietal and premotor areas showed overlapping activation for the two task components and were severely reduced in their WM load response under the condition with high attentional demand. Regions in the left prefrontal cortex were selectively responsive to WM load. Areas selectively responsive to high attentional demand were found within the right prefrontal and bilateral occipital cortex. These results indicate that encoding into visual WM and visual selective attention require to a high degree access to common neural resources. We propose that competition for resources shared by visual attention and WM encoding can limit processing capabilities in distributed posterior brain regions.     

rTMS evidence of different delay and decision processes in a fronto-parietal neuronal network activated during spatial working memory

The existence of a specific and widely distributed network for spatial working memory (WM) in humans, involving the posterior parietal cortex and the prefrontal cortex, is supported by a number of neuroimaging studies. We used a repetitive transcranial magnetic stimulation (rTMS) approach to investigate the temporal dynamics and the reciprocal interactions of the different areas of the parieto-frontal network in normal subjects performing a spatial WM task, with the aim to compare neural activity of the different areas in the delay and decision phases of the task. Trains of rTMS at 25 Hz were delivered over the posterior parietal cortex (PPC), the premotor cortex (SFG) and the dorsolateral prefrontal cortex (DLPFC) of the right hemisphere alternatively during the two phases. We found a pattern of interference of TMS during the delay phase for both parietal and DLPFC sites of stimulation, with no effect observed for the SFG site. When rTMS trains were applied during the decision phase, an interference was observed selectively for DLPFC. The present study shows the existence of a parallel processing in the parieto-frontal network of spatial WM during the delay phase. Furthermore, it provides new evidence of the critical role of the DLPFC during both the delay and the decision phases. We suggest that in DLPFC, two different networks coexist: A local neural network subserving the decisional processes and a second neural population functionally interconnected with the PPC and activated when a certain spatial information has to be kept in memory, available to use.     

Neural correlates of relational and item-specific encoding during working and long-term memory in schizophrenia

Successful long-term memory (LTM) depends upon effective control of information in working memory (WM), and there is evidence that both WM and LTM are impaired by schizophrenia. This study tests the hypothesis that LTM deficits in schizophrenia may result from impaired control of relational processing in WM due to dorsolateral prefrontal cortex (DLPFC) dysfunction. fMRI was performed on 19 healthy controls and 20 patients with schizophrenia during WM tasks emphasizing relational (reorder trials) versus item-specific (rehearse trials) processing. WM activity was also examined with respect to LTM recognition on a task administered outside the scanner. Receiver operator characteristic analysis assessed familiarity and recollection components of LTM. Patients showed a disproportionate familiarity deficit for reorder versus rehearse trials against a background of generalized LTM impairments. Relational processing during WM led to DLPFC activation in both groups. However, this activation was less focal in patients than in controls, and patients with more severe negative symptoms showed less of a DLPFC increase. fMRI analysis of subsequent recognition performance revealed a group by condition interaction. High LTM for reorder versus rehearse trials was associated with bilateral DLPFC activation in controls, but not in patients who activated the left middle temporal and inferior occipital gyrus. Results indicate that although patients can activate the DLPFC on a structured relational WM task, this activation is less focal and does not translate to high retrieval success, suggesting a disruption in the interaction between WM and LTM processes in schizophrenia.     

Collaborative activity between parietal and dorso-lateral prefrontal cortex in dynamic spatial working memory revealed by fMRI

Functional MRI was used to determine how the constituents of the cortical network subserving dynamic spatial working memory respond to two types of increases in task complexity. Participants mentally maintained the most recent location of either one or three objects as the three objects moved discretely in either a two- or three-dimensional array. Cortical activation in the dorsolateral prefrontal (DLPFC) and the parietal cortex increased as a function of the number of object locations to be maintained and the dimensionality of the display. An analysis of the response characteristics of the individual voxels showed that a large proportion were activated only when both the variables imposed the higher level of demand. A smaller proportion were activated specifically in response to increases in task demand associated with each of the independent variables. A second experiment revealed the same effect of dimensionality in the parietal cortex when the movement of objects was signaled auditorily rather than visually, indicating that the additional representational demands induced by 3-D space are independent of input modality. The comodulation of activation in the prefrontal and parietal areas by the amount of computational demand suggests that the collaboration between areas is a basic feature underlying much of the functionality of spatial working memory.     

Left posterior parietal cortex participates in both task preparation and episodic retrieval

Optimal memory retrieval depends not only on the fidelity of stored information, but also on the attentional state of the subject. Factors such as mental preparedness to engage in stimulus processing can facilitate or hinder memory retrieval. The current study used functional magnetic resonance imaging (fMRI) to distinguish preparatory brain activity before episodic and semantic retrieval tasks from activity associated with retrieval itself. A catch-trial imaging paradigm permitted separation of neural responses to preparatory task cues and memory probes. Episodic and semantic task preparation engaged a common set of brain regions, including the bilateral intraparietal sulcus (IPS), left fusiform gyrus (FG), and the pre-supplementary motor area (pre-SMA). In the subsequent retrieval phase, the left IPS was among a set of frontoparietal regions that responded differently to old and new stimuli. In contrast, the right IPS responded to preparatory cues with little modulation during memory retrieval. The findings support a strong left-lateralization of retrieval success effects in left parietal cortex, and further indicate that left IPS performs operations that are common to both task preparation and memory retrieval. Such operations may be related to attentional control, monitoring of stimulus relevance, or retrieval.     

Differentiation between external and internal cuing: an fMRI study comparing tracing with drawing

Externally cued movement is thought to preferentially involve cerebellar and premotor circuits whereas internally generated movement recruits basal ganglia, pre-supplementary motor cortex (pre-SMA) and dorsolateral prefrontal cortex (DLPFC). Tracing and drawing are exemplar externally and internally guided actions and Parkinson's patients and cerebellar patients show deficits in tracking and drawing, respectively. In this study we aimed to examine this external/internal distinction in healthy subjects using functional imaging. Ten healthy subjects performed tracing and drawing of simple geometric shapes using pencil and paper while in a 3-T fMRI scanner. Results indicated that compared to tracing, drawing generated greater activation in the right cerebellar crus I, bilateral pre-SMA, right dorsal premotor cortex and right frontal eye field. Tracing did not recruit any additional activation compared to drawing except in striate and extrastriate visual areas. Therefore, drawing recruited areas more frequently associated with cognitively challenging tasks, attention and memory, but basal ganglia and cerebellar activity did not differentiate tracing from drawing in the hypothesised manner. As our paradigm was of a simple, repetitive and static design, these results suggest that the task familiarity and the temporal nature of visual feedback in tracking tasks, compared to tracing, may be important contributing factors towards the degree of cerebellar involvement. Future studies comparing dynamic with static external cues and visual feedback may clarify the role of the cerebellum and basal ganglia in the visual guidance of drawing actions.     

Individual differences in neural activity during a facial expression vs. identity working memory task

Facial expressions of emotion constitute a critical portion of our non-verbal social interactions. In addition, the identity of the individual displaying this expression is critical to these interactions as they embody the context in which these expressions will be interpreted. To identify any overlapping and/or unique brain circuitry involved in the processing of these two information streams in a laboratory setting, participants performed a working memory (WM) task (i.e., n-back) in which they were instructed to monitor either the expression (EMO) or the identity (ID) of the same set of face stimuli. Consistent with previous work, during both the EMO and ID tasks, we found a significant increase in activity in dorsolateral prefrontal cortex (DLPFC) supporting its generalized role in WM. Further, individuals that showed greater DLPFC activity during both tasks also showed increased amygdala activity during the EMO task and increased lateral fusiform gyrus activity during the ID task. Importantly, the level of activity in these regions significantly correlated with performance on the respective tasks. These findings provide support for two separate neural circuitries, both involving the DLPFC, supporting working memory for the faces and expressions of others.     

Visual search and memory search engage extensive overlapping cerebral cortices: an fMRI study

Previous studies have investigated neural correlates of visual search and memory search independently, but none of those studies examined whether cortical regions involved in these searches are overlapping or segregated by directly comparing the two types of search. In this study, we compared the cortical regions involved in visual search and memory search in the same functional magnetic resonance imaging (fMRI) experiment run on the same subjects, using identical stimuli and time courses of stimulus presentation. The right dorsolateral prefrontal cortex (DLPFC), the left frontal eye field (FEF), the right precuneus and cuneus, and the left cerebellum were activated by both visual search and memory search. We suggest that the right DLPFC is associated with the process of monitoring and manipulating multiple elements, while the left FEF is involved in cognitive planning. We also propose that the right precuneus and cuneus as well as the left cerebellum are responsible for both spatial and nonspatial shifts of attention, including attentional shifts in long-term memory, although each of these regions has a slightly different role.     

Functional neuroanatomy of auditory working memory in schizophrenia: relation to positive and negative symptoms

Functional brain imaging studies of working memory (WM) in schizophrenia have yielded inconsistent results regarding deficits in the dorsolateral prefrontal (DLPFC) and parietal cortices. In spite of its potential importance in schizophrenia, there have been few investigations of WM deficits using auditory stimuli and no functional imaging studies have attempted to relate brain activation during auditory WM to positive and negative symptoms of schizophrenia. We used a two-back auditory WM paradigm in a functional MRI study of men with schizophrenia (N = 11) and controls (N = 13). Region of interest analysis was used to investigate group differences in activation as well as correlations with symptom scores from the Brief Psychiatric Rating Scale. Patients with schizophrenia performed significantly worse and were slower than control subjects in the WM task. Patients also showed decreased lateralization of activation and significant WM related activation deficits in the left and right DLPFC, frontal operculum, inferior parietal, and superior parietal cortex but not in the anterior cingulate or superior temporal gyrus. These results indicate that in addition to the prefrontal cortex, parietal cortex function is also disrupted during WM in schizophrenia. Withdrawal-retardation symptom scores were inversely correlated with frontal operculum activation. Thinking disturbance symptom scores were inversely correlated with right DLPFC activation. Our findings suggest an association between thinking disturbance symptoms, particularly unusual thought content, and disrupted WM processing in schizophrenia.     

The functional neuroanatomy of visual conjunction search: a parametric fMRI study

Visual conjunction search is proposed to be a multicomponent process which involves scaling and successive shifts of attention in space as well as object identification. Here, we first mapped brain areas sustaining the proposed attentional subprocesses and then tested whether their activity was modulated by search load, i.e., the number of shifts, as predicted by serial search models. Search load was manipulated indirectly by precueing a varying number of locations at which relevant objects were shown. Multiple subregions within the intraparietal sulcus (IPS) and the prefrontal cortex were activated after cueing. Activity in the right posterior IPS was modulated by the distance of attention shifts and in the left posterior IPS by "zooming out" to cover a large region of the visual field. More anterior subregions of the left IPS responded to object identification irrespective of the need for serial scanning. Corresponding regions in the right IPS were modulated parametrically with respect to search load, along with the right temporoparietal junction. These results support a functional segregation of subregions of the IPS. The posterior regions participate in large-scale shifts and scaling of the attentional focus and the anterior regions in object identification and rapid serial shifts during search. The sustained activation in the frontal eye fields after cueing suggests a role in maintaining attention in the periphery. Together with the findings in early visual areas from this experiment (Müller et al., 2003) the current observations are best accounted for by hybrid models of visual conjunction search, where parallel processing in visual and temporoparietal regions and serial scanning controlled by the right IPS cooperate.     

缺陷型及非缺陷型精神分裂症执行功能障碍的fMRI初步研究

目的比较缺陷型、非缺陷型精神分裂症患者与执行控制功能有关的脑区激活情况,探讨精神分裂症执行功能障碍的表现规律与相应脑机制。方法缺陷型、非缺陷型精神分裂症患者各6名及与之匹配的正常对照组,在执行参量设计的倒数n项实验时进行全脑BOLD-fMRI扫描。数据处理时采用单因素方差分析进行差异检测,分离出激活强度随记忆负荷增加而增强的脑区（执行加工相关脑区）。结果正常组执行加工相关脑区主要为左侧前额叶及顶叶后部皮层,两精神分裂症组前额叶激活体积相对较小,而且涉及更多皮层下结构。其中非缺陷型组双侧前额皮层均显著激活,且背外侧前额叶（BA9/46区）激活数目较正常组明显增多。而缺陷型组无论是前额皮层激活的脑区分布范围还是体积均显著减少于其他两组。结论精神分裂症患者存在以前额叶功能失调为基础的执行功能障碍。不同亚型的患者前额叶功能失调的机制不同：缺陷型患者前额叶可能存在特异性损伤,而非缺陷型患者主要表现为前额叶的生理低效能。     

Diffusion tensor studies dissociated two fronto-temporal pathways in the human memory system

Recent functional neuroimaging studies have shown that multiple cortical areas are involved in memory encoding and retrieval. However, the underlying anatomical connections among these memory-related areas in humans remain elusive due to methodological limitations. Diffusion tensor imaging (DTI) is a technique based on detecting the diffusion of water molecules from magnetic resonance images. DTI allows non-invasive mapping of anatomical connections and gives a comprehensive picture of connectivity throughout the entire brain. By combining functional magnetic resonance imaging (fMRI) and DTI, we show that memory-related areas in the left dorsolateral prefrontal cortex (DLPFC) and the left ventrolateral prefrontal cortex (VLPFC) each connect with memory-related areas in the left temporal cortex. This result suggests there are two pathways between prefrontal cortex and temporal cortex related to the human memory system.     

The cognitive control network: Integrated cortical regions with dissociable functions

Consensus across hundreds of published studies indicates that the same cortical regions are involved in many forms of cognitive control. Using functional magnetic resonance imaging (fMRI), we found that these coactive regions form a functionally connected cognitive control network (CCN). Network status was identified by convergent methods, including: high inter-regional correlations during rest and task performance, consistently higher correlations within the CCN than the rest of cortex, co-activation in a visual search task, and mutual sensitivity to decision difficulty. Regions within the CCN include anterior cingulate cortex/pre-supplementary motor area (ACC/pSMA), dorsolateral prefrontal cortex (DLPFC), inferior frontal junction (IFJ), anterior insular cortex (AIC), dorsal pre-motor cortex (dPMC), and posterior parietal cortex (PPC). We used a novel visual line search task which included periods when the probe stimuli were occluded but subjects had to maintain and update working memory in preparation for the sudden appearance of a probe stimulus. The six CCN regions operated as a tightly coupled network during the 'non-occluded' portions of this task, with all regions responding to probe events. In contrast, the network was differentiated during occluded search. DLPFC, not ACC/pSMA, was involved in target memory maintenance when probes were absent, while both regions became active in preparation for difficult probes at the end of each occluded period. This approach illustrates one way in which a neuronal network can be identified, its high functional connectivity established, and its components dissociated in order to better understand the interactive and specialized internal mechanisms of that network.     

Dynamic interactions in the fronto-parietal network during a manual stimulus-response compatibility task

Attentional orienting can be modulated by stimulus-driven bottom-up as well as task-dependent top-down processes. In a recent study we investigated the interaction of both processes in a manual stimulus-response compatibility task. Whereas the intraparietal sulcus (IPS) and the dorsal premotor cortex (dPMC) were involved in orienting towards the stimulus side facilitating congruent motor responses, the right temporoparietal junction (TPJ), right dorsolateral prefrontal cortex (DLPFC) as well as the preSMA sustained top-down control processes involved in voluntary reorienting. Here we used dynamic causal modelling to investigate the contributions and task-dependent interactions between these regions. Thirty-six models were tested, all of which included bilateral IPS, dPMC and primary motor cortex (M1) as a network transforming visual input into motor output as well as the right TPJ, right DLPFC and the preSMA as task-dependent top-down regions influencing the coupling within the dorsal network. Our data showed the right temporoparietal junction to play a mediating role during attentional reorienting processes by modulating the inter-hemispheric balance between both IPS. Analysis of connection strength supported the proposed role of the preSMA in controlling motor responses promoting or suppressing activity in primary motor cortex. As the results did not show a clear tendency towards a role of the right DLPFC, we propose this region, against the usual interpretation of an inhibitory influence in stimulus-response compatibility tasks, to subserve generic monitoring processes. Our DCM study hence provides evidence for context-dependent top-down control of right TPJ and DLPFC as well as the preSMA in stimulus-response compatibility.     

Working memory effects on semantic processing: priming differences in pars orbitalis

Both working memory (WM) and controlled (attention-mediated) semantic processing functions have been thought to operate as limited capacity systems, but the possible link between these processes has not been investigated. We found that increased WM load attenuated semantic priming (i.e., reduced the response time advantage for semantically primed relative to unprimed items) and changed fMRI signal intensities in brain regions usually associated with both WM (dorsolateral prefrontal cortex) and controlled semantic retrieval (inferior frontal gyrus [IFG], pars orbitalis). fMRI signal changes in dorsolateral prefrontal cortex were negatively correlated with signal changes in pars orbitalis. The findings suggest that controlled semantic processing and working memory share neural system resources.     

Preparatory allocation of attention and adjustments in conflict processing

Attentional control involves the ability to allocate preparatory attention to improve subsequent stimulus processing and response selection. There is behavioral evidence to support the hypothesis that increased expectancy of stimulus and response conflict may decrease the subsequent experience of conflict during task performance. We used a cued flanker and event-related fMRI design to separate processes involved in preparation from those involved in resolving conflict and to identify the brain systems involved in these processes as well as the association between preparatory activity levels and activity related to subsequent conflict processing. Our results demonstrate that preparatory attentional allocation following a cue to the upcoming level of conflict is mediated by a network involving Dorsolateral Prefrontal Cortex (DLPFC) and the Intraparietal Sulcus (IPS). Informed preparation for conflict processing was associated with decreased Anterior Cingulate Cortex/pre-Supplementary Motor Area (ACC/pre-SMA) and IPS activity during the flanker target presentation, supporting their roles in conflict processing and visuospatial attention during the flanker task. Ventrolateral Prefrontal Cortex/Orbitofrontal Cortex (VLPFC/OFC) was active when specific strategic task rule and outcome information was available.     

An fMRI Investigation of Cortical Contributions to Spatial and Nonspatial Visual Working Memory

The experiments presented in this report were designed to test the hypothesis that visual working memory for spatial stimuli and for object stimuli recruits separate neuronal networks in prefrontal cortex. We acquired BOLD fMRI data from subjects while they compared each serially presented stimulus to the one that had appeared two or three stimuli previously. Three experiments failed to reject the null hypothesis that prefrontal cortical activity associated with spatial working memory performance cannot be dissociated from prefrontal cortical activity associated with nonspatial working memory performance. Polymodal regions of parietal cortex (inferior and superior parietal lobules), as well as cortex surrounding the superior frontal sulcus (and encompassing the frontal eye fields), also demonstrated equivalent levels of activation in the spatial and object conditions. Posterior cortical regions associated with the ventral visual processing stream (portions of lingual, fusiform, and inferior temporal gyri), however, demonstrated greater object than spatial working memory-related activity, particularly when stimuli varied only along spatial or featural dimensions. These experiments, representing fMRI studies of spatial and object working memory in which the testing procedure and the stimuli were identical in the two conditions, suggest that domain-specific visual working memory processing may be mediated by posterior regions associated with domain-specific sensory processing.     

Load response functions in the human spatial working memory circuit during location memory updating

Previous studies have emphasized that the dorsolateral prefrontal cortex is important for manipulating information in working memory, although activations in other frontal and parietal areas are commonly observed under the same conditions. We conducted an fMRI experiment to examine brain responses as a parametric function of memory updating, which is considered as an elemental process in working memory. In a variant spatial delayed-response task, human subjects performed updating operations over a 9-second delay period, during which they mentally transform the location of a memorized target in a 4 by 4 grid according to 3 to 12 instruction cues. Activity increased monotonically with increasing updating load in numerous cortical and subcortical regions including the rostrodorsal premotor (rdPM), lateral precentral sulcus, lateral prefrontal, posterior associative, striatal and cerebellar areas. The rdPM and superior parietal were particularly sensitive to the updating manipulation. There were several main findings. First, updating spatial working memory involved mostly the same cortical and subcortical regions that were activated during maintenance of spatial information. Second, the updating load response functions of regions in the spatial working memory circuit showed a strong linear component. However, none shows significant increases in activity from 9 to 12 updating operations. Third, activity in the right rdPM and anterior inferior frontal gyrus correlated positively with working memory performance in the high updating load condition. Our findings suggest that updating and maintenance of spatial information may share similar processes and that the rostrodorsal premotor cortex and anterior inferior frontal gyrus may be important for the success of tracking spatial information in working memory.