Neural mechanisms of spatial working memory: Contributions of the dorsolateral prefrontal cortex and the thalamic mediodorsal nucleus

The dorsolateral prefrontal cortex (DLPFC) has been known to play an important role in working memory. Neurophysiological studies have revealed that delay period activity observed in the DLPFC is a neural correlate of the temporary storage mechanism for information and that this activity represents either retrospective or prospective information, although the majority represents retrospective information. However, the DLPFC is not the only brain area related to working memory. The analysis of neural activity in the thalamic mediodorsal (MD) nucleus reveals that the MD also participates in working memory. Although similar task-related activities were observed in the MD, the directional bias of these activities and the proportion of presaccadic activity are different between the MD and the DLPFC. These results indicate that, although the MD participates in working memory, the way it participates in this process is different between these two areas, in that the MD participates more in motor control aspects than the DLPFC does.     

右侧背外侧前额叶在视觉工作记忆中的因果性作用

以往的影像学研究表明右侧背外侧前额叶皮层(DLPFC)在视觉工作记忆中发挥重要作用, 然而缺乏因果性的证据。本研究旨在考察右侧DLPFC的激活与视觉工作记忆容量的因果关系, 并探讨这一关系受到记忆负荷的调节及其神经机制。被试接受经颅直流电刺激之后完成视觉工作记忆变化检测任务, 根据被试在虚假刺激情况下从负荷4到负荷6任务记忆容量的增量将被试分为低记忆增长潜力组(简称低潜力组)和高记忆增长潜力组(简称高潜力组), 结果发现正性电刺激右侧DLPFC相对于虚假电刺激显著提升了高潜力组被试在低记忆负荷(负荷4)下的记忆容量及其对应的提取阶段的脑电指标SPCN成分。表明右侧DLPFC在视觉工作记忆的提取阶段发挥重要的因果性作用; 正性经颅直流电刺激右侧DLPFC可使工作记忆容量高潜力被试获得更多的脑活动增益, 并导致更好的行为提升效果。     

右侧背外侧前额叶皮质在时间知觉中的作用:基于经颅磁刺激的研究

将10 Hz的重复经颅磁刺激(r TMS)施加于右背外侧前额叶皮质(r DLPFC),探讨该区域在时间加工模型中的作用。实验一采用时间复制任务,通过比较基线和后测条件下时间估计行为的差异,探究高频r TMS离线施加于r DLPFC之后对时间知觉的影响。实验二采用毫秒和秒两种范围的时距,探究r DLPFC在不同范围的时间知觉中的作用。结果发现r TMS施加于r DLPFC导致对1.5 s高估,对600 ms的估计无显著影响,提示r DLPFC在涉及工作记忆加工过程的秒范围的时间知觉中有重要作用。     

Developmental differences in prefrontal activation during working memory maintenance and manipulation for different memory loads

The ability to keep information active in working memory is one of the cornerstones of cognitive development. Prior studies have demonstrated that regions which are important for working memory performance in adults, such as dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex (VLPFC), and superior parietal cortex, become increasingly engaged across school-aged development. The primary goal of the present functional MRI study was to investigate the involvement of these regions in the development of working memory manipulation relative to maintenance functions under different loads. We measured activation in DLPFC, VLPFC, and superior parietal cortex during the delay period of a verbal working memory task in 11-13-year-old children and young adults. We found evidence for age-related behavioral improvements in working memory and functional changes within DLPFC and VLPFC activation patterns. Although activation profiles of DLPFC and VLPFC were similar, group differences were most pronounced for right DLPFC. Consistent with prior studies, right DLPFC showed an interaction between age and condition (i.e. manipulation versus maintenance), specifically at the lower loads. This interaction was characterized by increased activation for manipulation relative to maintenance trials in adults compared to children. In contrast, we did not observe a significant age-dependent load sensitivity. These results suggest that age-related differences in the right DLPFC are specific to working memory manipulation and are not related to task difficulty and/or differences in short-term memory capacity.     

Integrating rewards and cognition in the frontal cortex

Research indicates that the dorsolateral prefrontal cortex (DLPFC) contributes to working memory and executive control, whereas the ventral frontal cortex (VFC) contributes to affective and motivational processing. Few studies have examined both the functional specificity and the integration of these regions. We did so using fMRI and a verbal working memory task in which visual cues indicated whether recall performance on an upcoming trial would be linked to a monetary reward. On the basis of prior findings obtained in delayed response tasks performed by nonhuman primates, we hypothesized that (1) VFC would show an increase only in response to a cue indicating potential for a monetary reward; (2) DLPFC would show sustained activity across a delay interval for all trials, though activity in rewarded trials would be enhanced; and (3) regions engaged in speech-based rehearsal would be relatively insensitive to monetary incentive. Our hypotheses about DLPFC and rehearsal-related regions were confirmed. In VFC regions, we failed to observe statistically significant effects of reward when the cue or delay epochs of the task were examined in isolation. However, an unexpected and significant deactivation was observed in VFC during the delay epoch; furthermore, a post hoc voxelwise analysis indicated a complex interaction between (1) the cue and delay epochs of the task and (2) the reward value of the trials. The pattern of activation and deactivation across trial types suggests that VFC is sensitive to reward cues, and that portions of DLPFC and VFC may work in opposition during the delay epoch of a working memory task in order to facilitate task performance.     

Working memory load reduces the late positive potential and this effect is attenuated with increasing anxiety

Emotion regulation decreases the processing of arousing stimuli, as indexed by the late positive potential (LPP), an electrocortical component that varies in amplitude with emotional arousal. Emotion regulation increases activity in the prefrontal areas associated with cognitive control, including the dosolateral prefrontal cortex (DLPFC). The present study manipulated working memory load, known to activate the DLPFC, and recorded the LPP elicited by aversive and neutral IAPS pictures presented during the retention interval. The LPP was larger on low-load compared to high-load trials, and on trials with aversive compared to neutral pictures. These LPP data suggest that emotional content and working memory load have opposing effects on attention to distracting stimuli. State anxiety was associated with reduced modulation of the LPP by working memory load. Results are discussed in terms of competition for attention between emotion and cognition and suggest a relationship between DLPFC activation and the allocation of attentional resources to distracting visual stimuli–a relationship that may be disrupted with increasing anxiety.     

Recognition memory and prefrontal cortex: dissociating recollection and familiarity processes using rTMS

Recognition memory can be supported by both the assessment of the familiarity of an item and by the recollection of the context in which an item was encountered. The neural substrates of these memory processes are controversial. To address these issues we applied repetitive transcranial magnetic stimulation (rTMS) over the right and left dorsolateral prefrontal cortex (DLPFC) of healthy subjects performing a remember/know task. rTMS disrupted familiarity judgments when applied before encoding of stimuli over both right and left DLPFC. rTMS disrupted recollection when applied before encoding of stimuli over the right DLPFC. These findings suggest that the DLPFC plays a critical role in recognition memory based on familiarity as well as recollection.     

The effect of motivation on working memory: an fMRI and SEM study

This study investigated the effective connectivity between prefrontal regions of human brain supporting motivational influence on working memory. Functional magnetic resonance imaging (fMRI) and structural equation modeling (SEM) were used to examine the interaction between the lateral orbitofrontal (OFC), medial OFC, and dorsolateral prefrontal (DLPFC) regions in the left and right hemisphere during performance of the verbal 2-back working memory task under two reinforcement conditions. The "low-motivation" condition was not associated with monetary reinforcement, while the "high-motivation" condition involved the probability of winning a certain amount of money. In the "low-motivation" condition, the OFC regions in both hemispheres positively influenced the left DLPFC activity. In the "high-motivation" condition, the connectivity in the network including the right OFC regions and left DLPFC changed from positive to negative, whereas the positive connectivity in the network composed of the left OFC and left DLPFC became slightly enhanced compared with the "low-motivation" condition. However, only the connection between the right lateral OFC and left DLPFC showed a significant condition-dependent change in the strength of influence conveyed through the pathway. This change appears to be the functional correlate of motivational influence on verbal working memory.     

工作记忆刷新及其训练效应——经颅直流电刺激的作用

工作记忆刷新是执行功能的重要成分之一。以往研究结合n-back任务和经颅直流电刺激（transcranial direct current stimulation ,tDCS）技术探究刷新能力,发现tDCS技术能够一定程度上增强刷新训练效果并引起大脑神经元相关活动的变化,其增强效果能够维持一定的时间,且能够迁移到其他认知任务之中。但tDCS的干预效果在各项研究中存在一定的差异性。其作用效果会受到训练任务与训练方式、电流强度、电极布局和训练时间间隔等因素的影响。未来研究可以探索tDCS结合刷新训练的最佳刺激参数,以获得最优化的干预效果。     

Anxiety and cognitive efficiency: Differential modulation of transient and sustained neural activity during a working memory task

According to the processing-efficiency hypothesis (Eysenck, Derakshan, Santos, & Calvo, 2007), anxious individuals are thought to require greater activation of brain systems supporting cognitive control (e.g.,dorsolateral prefrontal cortex; DLPFC) in order to maintain equivalent performance to nonanxious subjects. A recent theory of cognitive control (Braver, Gray, & Burgess, 2007) has proposed that reduced cognitive efficiency might occur as a result of changes in the temporal dynamics of DLPFC recruitment. In this study, we used a mixed blocked/ event-related fMRI design to track transient and sustained activity in DLPFC while high- and low-anxious participants performed a working memory task. The task was performed after the participants viewed videos designed to induce neutral or anxiety-related moods. After the neutral video, the high-anxious participants had reduced sustained but increased transient activation in working memory areas, in comparison with low-anxious participants. The high-anxious group also showed extensive reductions in sustained activation of "default-network" areas (possible deactivation). After the negative video,the low-anxiety group shifted their activation dynamics in cognitive control regions to resemble those of the high-anxious group. These results suggest that reduced cognitive control in anxiety might be due to a transient, rather than sustained, pattern of working memory recruitment. Supplementary information for this study may be found at www.psychonomic.org/archive.     

Trait anxiety and the neural efficiency of manipulation in working memory

The present study investigates the effects of trait anxiety on the neural efficiency of working memory component functions (manipulation vs. maintenance) in the absence of threat-related stimuli. For the manipulation of affectively neutral verbal information held in working memory, high- and low-anxious individuals (N = 46) did not differ in their behavioral performance, yet trait anxiety was positively related to the neural effort expended on task processing, as measured by BOLD signal changes in fMRI. Higher levels of anxiety were associated with stronger activation in two regions implicated in the goal-directed control of attention--that is, right dorsolateral prefrontal cortex (DLPFC) and left inferior frontal sulcus--and with stronger deactivation in a region assigned to the brain's default-mode network--that is, rostral-ventral anterior cingulate cortex. Furthermore, anxiety was associated with a stronger functional coupling of right DLPFC with ventrolateral prefrontal cortex. We interpret our findings as reflecting reduced processing efficiency in high-anxious individuals and point out the need to consider measures of functional integration in addition to measures of regional activation strength when investigating individual differences in neural efficiency. With respect to the functions of working memory, we conclude that anxiety specifically impairs the processing efficiency of (control-demanding) manipulation processes (as opposed to mere maintenance). Notably, this study contributes to an accumulating body of evidence showing that anxiety also affects cognitive processing in the absence of threat-related stimuli.     

Short theta burst stimulation to left frontal cortex prior to encoding enhances subsequent recognition memory

Deep semantic encoding of verbal stimuli can aid in later successful retrieval of those stimuli from long-term episodic memory. Evidence from numerous neuropsychological and neuroimaging experiments demonstrate regions in left prefrontal cortex, including left dorsolateral prefrontal cortex (DLPFC), are important for processes related to encoding. Here, we investigated the relationship between left DLPFC activity during encoding and successful subsequent memory with transcranial magnetic stimulation (TMS). In a pair of experiments using a 2-session within-subjects design, we stimulated either left DLPFC or a control region (Vertex) with a single 2-s train of short theta burst stimulation (sTBS) during a semantic encoding task and then gave participants a recognition memory test. We found that subsequent memory was enhanced on the day left DLPFC was stimulated, relative to the day Vertex was stimulated, and that DLPFC stimulation also increased participants’ confidence in their decisions during the recognition task. We also explored the time course of how long the effects of sTBS persisted. Our data suggest 2 s of sTBS to left DLPFC is capable of enhancing subsequent memory for items encoded up to 15 s following stimulation. Collectively, these data demonstrate sTBS is capable of enhancing long-term memory and provide evidence that TBS protocols are a potentially powerful tool for modulating cognitive function.     

Dorsolateral prefrontal cortex mediates working memory processes in motor skill learning

Neuroimaging studies have shown that the dorsolateral prefrontal cortex (DLPFC) is recruited during motor skill learning, which suggests the involvement of the DLPFC in working memory (WM) processes, such as selection and integration of motor representations temporarily stored in WM. However, direct evidence linking activation of the DLPFC to WM storage and manipulation during motor skill learning in real-time is rare. In this study, we conducted two experiments to investigate the causal role of DLPFC activity in WM storage and manipulation during motor skill learning under low and high WM-demand conditions. Participants received continuous theta burst stimulation (cTBS) and sham stimulation (crossover design) over the left DLPFC (experiment 1) or right DLPFC (experiment 2). Before and after stimulation, participants in both experiments performed a sequential finger-tapping (SFT) task containing repeated sequence (low-WM demand) and non-repeated sequence (high-WM demand) conditions which are used to study WM processes. The number of correct sequences (NoCS) and reproduction error rate were analyzed. Learning gains in NoCS improved significantly with the practice for both sequence types in the presence of either stimulation type. Compared to sham stimulation, cTBS over the left DLPFC resulted in significantly reduced learning gains in NoCS for non-repeated sequences. These results suggest that the left DLPFC contributes to WM manipulation during motor skill learning.     

Subliminal food images compromise superior working memory performance in women with restricting anorexia nervosa

Prefrontal cortex (PFC) is dysregulated in women with restricting anorexia nervosa (RAN). It is not known whether appetitive non-conscious stimuli bias cognitive responses in those with RAN. Thirteen women with RAN and 20 healthy controls (HC) completed a dorsolateral PFC (DLPFC) working memory task and an anterior cingulate cortex (ACC) conflict task, while masked subliminal food, aversive and neutral images were presented. During the DLPFC task, accuracy was higher in the RAN compared to the HC group, but superior performance was compromised when subliminal food stimuli were presented: errors positively correlated with self-reported trait anxiety in the RAN group. These effects were not observed in the ACC task. Appetitive activation is intact and anxiogenic in women with RAN, and non-consciously interacts with working memory processes associated with the DLPFC. This interaction mechanism may underlie cognitive inhibition of appetitive processes that are anxiety inducing, in people with AN.     

rTMS stimulation on left DLPFC increases the correct recognition of memories for emotional target and distractor words

According to a recent hypothesis, the prefrontal cortex has been proposed as the site of emotional memory integration, because it is sensitive to the recognition of emotional contents. In the present research, we explored the role of the dorsolateral prefrontal cortex (DLPFC) in memory recognition processes for positive versus negative emotional stimuli when old (target) and new (distractor, either semantically related or unrelated to the target) stimuli were presented. The role of the DLPFC was analysed using an rTMS (repeated transcranial magnetic stimulation) paradigm that induced increased cortical activation of the left DLPFC. The subjects were required to perform a task that consisted of two experimental phases (i.e., an encoding and a recognition phase) in which the targets and the distractors were presented and recognition performance was measured. rTMS stimulation was provided over the left DLPFC during the recognition phase. We found that the rTMS stimulation affected the memory recognition of positive emotional material. Moreover, related and unrelated distractors were discarded better when they were positively valenced, and a more significant effect (i.e., increased performance) was produced in response to related distractors. This result suggests that the activation of the left DLPFC favours the memory recognition of positive emotional information, and that such activation is able to induce a more appropriate selective process to distinguish target from distractor stimuli in the presence of more complex processes (related distractors). The valence model of emotional cue processing may explain this increased performance by demonstrating the distinct role of the left hemisphere in the retrieval of positive emotional information.     

Working memory improvement with non-invasive brain stimulation of the dorsolateral prefrontal cortex: A systematic review and meta-analysis

Recent studies have used non-invasive brain stimulation (NIBS) techniques, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), to increase dorsolateral prefrontal cortex (DLPFC) activity and, consequently, working memory (WM) performance. However, such experiments have yielded mixed results, possibly due to small sample sizes and heterogeneity of outcomes. Therefore, our aim was to perform a systematic review and meta-analyses on NIBS studies assessing the n-back task, which is a reliable index for WM. From the first data available to February 2013, we looked for sham-controlled, randomized studies that used NIBS over the DLPFC using the n-back task in PubMed/MEDLINE and other databases. Twelve studies (describing 33 experiments) matched our eligibility criteria. Active vs. sham NIBS was significantly associated with faster response times (RTs), higher percentage of correct responses and lower percentage of error responses. However, meta-regressions showed that tDCS (vs. rTMS) presented only an improvement in RT, and not in accuracy. This could have occurred in part because almost all tDCS studies employed a crossover design, possibly due to the reliable tDCS blinding. Study design was also associated with no improvement in correct responses in the active vs. sham groups. To conclude, rTMS of the DLPFC significantly improved all measures of WM performance whereas tDCS significantly improved RT, but not the percentage of correct and error responses. Mechanistic insights on the role of DLPFC in WM are further discussed, as well as how NIBS techniques could be used in neuropsychiatric samples presenting WM deficits, such as major depression, dementia and schizophrenia.     

Some surprising findings on the involvement of the parietal lobe in human memory

The posterior parietal lobe is known to play some role in a far-flung list of mental processes: linking vision to action (saccadic eye movements, reaching, grasping), attending to visual space, numerical calculation, and mental rotation. Here, we review findings from humans and monkeys that illuminate an untraditional function of this region: memory. Our review draws on neuroimaging findings that have repeatedly identified parietal lobe activations associated with short-term or working memory and episodic memory. We also discuss recent neuropsychological findings showing that individuals with parietal lobe damage exhibit both working memory and long-term memory deficits. These deficits are not ubiquitous; they are only evident under certain retrieval demands. Our review elaborates on these findings and evaluates various theories about the mechanistic role of the posterior parietal lobe in memory. The available data point towards the conclusion that the posterior parietal lobe plays an important role in memory retrieval irrespective of elapsed time. However, the available data do not support simple dichotomies such as recall versus recognition, working versus long-term memory. We conclude by formalizing several open questions that are intended to encourage future research in this rapidly developing area of memory research.     

背外侧前额叶对主动遗忘负性社会反馈的作用：针对抑郁症的TMS研究

抑郁症患者的负性心境可能源于其抑制功能障碍。患者在主动遗忘负性材料时无法有效调用背外侧前额叶(the dorsolateral prefrontal cortex, DLPFC)等负责抑制控制的额叶脑网络。同时, 患者对社会信息的加工比对非社会信息的加工存在更明显的认知神经障碍, 很难主动遗忘对自己不利的社会反馈信息。为了提高抑郁症患者对负性社会反馈的主动遗忘能力, 本研究采用经颅磁刺激技术(transcranial magnetic stimulation, TMS), 考察抑郁症患者在左侧(n = 32)或右侧DLPFC (n = 30)被激活后其记忆控制能力的改变。结果表明, 当患者的DLPFC被TMS激活时, 他们对社会拒绝的回忆正确率与健康对照组(n = 31)无差异, 且TMS激活右侧DLPFC还改善了患者对他人的社会态度。本研究是采用TMS提高抑郁症患者主动遗忘能力的首次尝试, 研究结果不但支持了DLPFC与记忆控制功能的因果关系, 还为临床治疗抑郁症、创伤后应激障碍、药物成瘾等患者的记忆控制缺陷提供了明确的神经靶点。     

Effects of 1 mA and 2 mA transcranial direct current stimulation on working memory performance in healthy participants

Anodal transcranial current stimulation (tDCS) to the left dorsolateral prefrontal cortex (DLPFC) has been shown to enhance working memory (WM) in neuropsychiatric patients. In healthy populations, however, tDCS obtains inconclusive results, mostly due to heterogeneous study and stimulation protocols. Here, we approached these issues by investigating effects of tDCS intensity on simultaneous WM performance with three cognitive loads by directly comparing findings of two double-blind, cross-over, sham-controlled experiments. TDCS was administrated to the left DLPFC at intensity of 1 mA (Experiment 1) or 2 mA (Experiment 2), while participants completed a verbal n-back paradigm (1-, 2-, 3-back). Analysis showed no overall effects of tDCS on WM, but a significant interaction with cognitive load. The present study suggests that cognitive load rather than tDCS intensity could be a decisive factor for effects on WM. Moreover, it emphasizes the need of thorough investigation on study parameters to develop more efficient stimulation protocols.     

Gender-moderated dorsolateral prefrontal reductions in 22q11.2 Deletion Syndrome: implications for risk for schizophrenia.

To investigate the impact of the microdeletion on morphology of the prefrontal cortex in 22q11.2 Deletion Syndrome (22q11.2 DS), high-resolution, anatomic magnetic resonance imaging was performed on 19 children and adolescents with 22q11.2 DS (11 females, 8 males) and 18 unaffected controls (10 females, 8 males). Tissue volumes of the dorsolateral, dorsomedial, orbitolateral, and orbitomedial prefrontal cortex were measured. Tasks of executive function and working memory were administered to investigate the association between anatomy and function. Whole brain volume and frontal lobe tissue volume were preserved in girls but reduced in boys with 22q11.2 DS relative to age-matched controls. Dorsolateral prefrontal cortex (DLPFC) volumes were reduced in participants with 22q11.2 DS, although the gender-by-diagnosis effect found for frontal lobe was not as robust for DLPFC. DLPFC volumes were associated with performance on tasks of planning and emotional facial recognition. Longitudinal studies are needed to clarify whether gender differences in frontal lobe and DLPFC persist with development, and whether the volumes of the DLPFC are associated with eventual deterioration in adaptive/psychosocial function that may presage the onset of schizophrenia, for which individuals with 22q11.2 DS are at a disproportionately high risk.