Disrupted functional connectivity for controlled visual processing as a basis for impaired spatial working memory in schizophrenia

Although regional brain abnormalities underlying spatial working memory (SWM) deficits in schizophrenia have been identified, little is known about which brain circuits are functionally disrupted in the SWM network in schizophrenia. We investigated SWM-related interregional functional connectivity in schizophrenia using functional magnetic resonance imaging (fMRI) data collected during a memory task that required analysis of spatial information in object structure. Twelve schizophrenia patients and 11 normal control subjects participated. Patients had SWM performance deficits and deficient neural activation in various brain areas, especially in the high SWM load condition. Examination of the covariation of regional brain activations elicited by the SWM task revealed evidence of functional disconnection between prefrontal and posterior visual association areas in schizophrenia. Under low SMW load, we found reduced functional associations between dorsolateral prefrontal cortex (DLPFC) and inferior temporal cortex (ITC) in the right hemisphere in patients. Under high SWM load, we found evidence for further functional disconnection in patients, including additional reduced functional associations between left DLPFC and right visual areas, including the posterior parietal cortex (PPC), fusiform gyrus, and V1, as well as between right inferior frontal cortex and right PPC. Greater prefrontal-posterior cortical functional connectivity was associated with better SWM performance in controls, but not in patients. These results suggest that prefrontal-posterior functional connectivity associated with the maintenance and control of visual information is central to SWM, and that disruption of this functional network underlies SWM deficits in schizophrenia.     

Seeking the neural substrates of visual working memory storage

It is widely assumed that the prefrontal cortex (PFC) is a critical site of working memory storage in monkeys and humans. Recent reviews of the human lesion literature and recent neuroimaging results, however, challenge this view. To test these alternatives, we used event-related fMRI to trace the retention of working memory representation of target faces across three delay periods that were interposed between the presentation of each of four stimuli. Across subjects, only posterior fusiform gyrus demonstrated reliable retention of target-specific activity across all delay periods. Our results suggest that no part of frontal cortex, including PFC, stores mnemonic representation of faces reliably across distracted delay periods. Rather, working memory storage of faces is mediated by a domain- specific network in posterior cortex.     

Modulation of steady state functional connectivity in the default mode and working memory networks by cognitive load

Interregional correlations between blood oxygen level dependent (BOLD) magnetic resonance imaging (fMRI) signals in the resting state have been interpreted as measures of connectivity across the brain. Here we investigate whether such connectivity in the working memory and default mode networks is modulated by changes in cognitive load. Functional connectivity was measured in a steady-state verbal identity N-back task for three different conditions (N = 1, 2, and 3) as well as in the resting state. We found that as cognitive load increases, the functional connectivity within both the working memory the default mode network increases. To test whether functional connectivity between the working memory and the default mode networks changed, we constructed maps of functional connectivity to the working memory network as a whole and found that increasingly negative correlations emerged in a dorsal region of the posterior cingulate cortex. These results provide further evidence that low frequency fluctuations in BOLD signals reflect variations in neural activity and suggests interaction between the default mode network and other cognitive networks.     

The role of the pulvinar in resolving competition between memory and visual selection: a functional connectivity study

Memory and attention interact. Information held in working memory (WM) can bias visual selection toward matching stimuli in a subsequent search display, while a search target that is different from the memory stimulus can interfere with its subsequent recognition. In recent fMRI studies, the pulvinar has been consistently shown to have an enhanced response when an item in WM matches a search target and a reduced response when the WM item matches a distracter in search. Here we used Granger causality analysis to help understand the role of the pulvinar in resolving competition between memory and selection processes. Across three experiments the results showed increased coupling between the pulvinar and the ipsilateral superior frontal gyrus, contralateral temporal-parietal junction (TPJ) and calcarine sulcus when a visual search distracter matched the item held in memory. This connection pattern suggests that the pulvinar suppresses visual responses to the target when a contralateral distracter contains information held in working memory. We propose that this suppression acts to protect the memory item from interference arising from information associated with the search target. Consistent with this proposal we showed that the strength of the thalamus-to-visual connection predicted performance on a subsequent memory test. The data therefore suggest that the thalamus modulates bottom up processing in sensory cortex to minimize interference to WM content.     

Anterior cingulate cortex differently modulates frontoparietal functional connectivity between resting‐state and working memory tasks

The brain frontoparietal regions and the functional communications between them are critical in supporting working memory and other executive functions. The functional connectivity between frontoparietal regions are modulated by working memory loads, and are shown to be modulated by a third brain region in resting‐state. However, it is largely unknown whether the third‐region modulations remain the same during working memory tasks or were largely modulated by task demands. In the current study, we collected functional MRI (fMRI) data when the subjects were performing n‐back tasks and in resting‐state. We first used a block‐designed localizer to define the frontoparietal regions that showed higher activations in the 2‐back than the 1‐back condition. Next, we performed physiophysiological interaction (PPI) analysis using left and right middle frontal gyrus (MFG) and superior parietal lobule (SPL) regions, respectively, in three continuous‐designed runs of resting‐state, 1‐back, and 2‐back conditions. No regions showed consistent modulatory interactions with the seed pairs in the three conditions. Instead, the anterior cingulate cortex (ACC) showed different modulatory interactions with the right MFG and SPL among the three conditions. While the increased activity of the ACC was associated with decreased functional coupling between the right MFG and SPL in resting‐state, it was associated with increased functional coupling in the 2‐back condition. The observed task modulations support the functional significance of the modulations of the ACC on frontoparietal connectivity.     

Dissociable frontal controls during visible and memory‐guided eye‐tracking of moving targets

When tracking visible or occluded moving targets, several frontal regions including the frontal eye fields (FEF), dorsal‐lateral prefrontal cortex (DLPFC), and anterior cingulate cortex (ACC) are involved in smooth pursuit eye movements (SPEM). To investigate how these areas play different roles in predicting future locations of moving targets, 12 healthy college students participated in a smooth pursuit task of visual and occluded targets. Their eye movements and brain responses measured by event‐related functional MRI were simultaneously recorded. Our results show that different visual cues resulted in time discrepancies between physical and estimated pursuit time only when the moving dot was occluded. Visible phase velocity gain was higher that that of occlusion phase. We found bilateral FEF association with eye‐movement whether moving targets are visible or occluded. However, the DLPFC and ACC showed increased activity when tracking and predicting locations of occluded moving targets, and were suppressed during smooth pursuit of visible targets. When visual cues were increasingly available, less activation in the DLPFC and the ACC was observed. In addition, there was a significant hemisphere effect in DLPFC, where right DLPFC showed significantly increased responses over left when pursuing occluded moving targets. Correlation results revealed that DLPFC, the right DLPFC in particular, communicates more with FEF during tracking of occluded moving targets (from memory). The ACC modulates FEF more during tracking of visible targets (likely related to visual attention). Our results suggest that DLPFC and ACC modulate FEF and cortical networks differentially during visible and memory‐guided eye tracking of moving targets. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Fronto-temporal interactions during overt verbal initiation and suppression

The Hayling Sentence Completion Task (HSCT) is known to activate left hemisphere frontal and temporal language regions. However, the effective connectivity between frontal and temporal language regions associated with the task has yet to be examined. The aims of the study were to examine activation and effective connectivity during the HSCT using a functional magnetic resonance imaging (fMRI) paradigm in which participants made overt verbal responses. We predicted that producing an incongruent response (response suppression), compared to a congruent one (response initiation), would be associated with greater activation in the left prefrontal cortex and an increase in the effective connectivity between temporal and frontal regions. Fifteen participants were scanned while completing 80 sentence stems. The congruency and constraint of sentences varied across trials. Dynamic Causal Modeling (DCM) and Bayesian Model Selection (BMS) were used to compare a set of alternative DCMs of fronto-temporal connectivity. The HSCT activated regions in the left temporal and prefrontal cortices, and the cuneus. Response suppression was associated with greater activation in the left middle and orbital frontal gyri and the bilateral precuneus than response initiation. Left middle temporal and frontal regions identified by the conventional fMRI analyses were entered into the DCM analysis. Using a systematic BMS procedure, the optimal DCM showed that the connection from the left middle temporal gyrus, which was driven by verbal stimuli per se, was significantly increased in strength during response suppression compared to initiation. Greater effective connectivity between left temporal and prefrontal regions during response suppression may reflect the transfer of information from posterior temporal regions where semantic and lexical information is stored to prefrontal regions where it is manipulated in preparation for an appropriate response.     

Representation of UV-B-induced thermal and mechanical hyperalgesia in the human brain: a functional MRI study

Surrogate models of pain and hyperalgesia allow the investigation of underlying mechanisms in healthy volunteers. Here, we investigated brain activation patterns during mechanical and heat hyperalgesia in an inflammatory human pain model using functional magnetic resonance imaging. Heat and mechanical hyperalgesia were induced on the right forearm by UV-B application in 14 healthy subjects. All four conditions (nonsensitized heat and nonsensitized mechanical pain, sensitized heat and sensitized mechanical pain) were perceptually matched. A 2 x 2 factorial analysis was performed. Areas with main effect of sensitization were insula, anterior cingulate cortex (ACC), prefrontal cortices (PFC), parietal association cortices (PA), thalamus, and basal ganglia. A main effect of modality with more activation during heat hyperalgesia was found in primary somatosensory cortex (S1), ACC, PFC, and PA. A main effect of modality with more activation during mechanical hyperalgesia was found in secondary somatosensory cortices, posterior insula, and contralateral inferior frontal cortex (IFC). An interaction of sensitization and modality was found bilaterally in IFC. Areas with similar effects of sensitization in both stimulus modalities were ACC, bilateral anterior insula and bilateral IFC. We conclude that different types of hyperalgesia in a human surrogate model of inflammatory pain produce different brain activation patterns. This is partly due to a differential processing of thermal and mechanical pain and an interaction of sensitization and modality in the caudal portion of the IFC. Finally, the data provide evidence for the existence of a common "sensitization network" consisting of ACC, bilateral anterior insula, and parts of the IFC.     

fMRI及DTI技术在成人工作记忆研究的初步探索

目的：联合应用脑功能磁共振成像（BOLD—fMRI）和弥散张量成像（DTI）两种磁共振技术,探索工作记忆功能激活部位与叶间白质纤维束的关系。方法：健康志愿者16名,以步进式视觉累加试验作为刺激模式,扫描获得fMRI激活图及各向异性（FA）图。将两者叠加,选取双侧额顶叶白质兴趣区测量其部分FA值。结果：①额顶叶皮质为工作记忆功能最主要的激活区;②脑的激活像素几乎均位于FA程度低的区域（P〈0．01）;③左额顶间白质FA值较对侧高（P〈0．02）。结论：联合应用fMRI和DTI技术提示成人工作记忆功能与额顶叶白质纤维髓鞘化程度密切相关。     

Default network connectivity during a working memory task

The default network exhibits correlated activity at rest and has shown decreased activation during performance of cognitive tasks. There has been little investigation of changes in connectivity of this network during task performance. In this study, we examined task‐related modulation of connectivity between two seed regions from the default network posterior cingulated cortex (PCC) and medial prefrontal cortex (mPFC) and the rest of the brain in 12 healthy adults. The purpose was to determine (1) whether connectivity within the default network differs between a resting state and performance of a cognitive (working memory) task and (2) whether connectivity differs between these nodes of the default network and other brain regions, particularly those implicated in cognitive tasks. There was little change in connectivity with the other main areas of the default network for either seed region, but moderate task‐related changes in connectivity occurred between seed regions and regions outside the default network. For example, connectivity of the mPFC with the right insula and the right superior frontal gyrus decreased during task performance. Increased connectivity during the working memory task occurred between the PCC and bilateral inferior frontal gyri, and between the mPFC and the left inferior frontal gyrus, cuneus, superior parietal lobule, middle temporal gyrus and cerebellum. Overall, the areas showing greater correlation with the default network seed regions during task than at rest have been previously implicated in working memory tasks. These changes may reflect a decrease in the negative correlations occurring between the default and task‐positive networks at rest. Hum Brain Mapp, 2011. © 2010 Wiley‐Liss, Inc.     

Abnormal distraction and load‐specific connectivity during working memory in cognitively normal Parkinson's disease

Visuospatial working memory impairments are common in Parkinson's disease (PD), yet the underlying neural mechanisms are poorly understood. The present study investigated abnormalities in context‐dependent functional connectivity of working memory hubs in PD. Cognitively normal PD and control participants underwent fMRI while performing a visuospatial working memory task. To identify sources of dysfunction, distraction, and load‐modulated connectivity were disentangled for encoding and retrieval phases of the task. Despite normal working memory performance in PD, two features of abnormal connectivity were observed, one due to a loss in normal context‐related connectivity and another related to upregulated connectivity of hubs for which the controls did not exhibit context‐dependent connectivity. During encoding, striatal‐prefrontal coupling was lost in PD, both during distraction and high memory loads. However, long‐range connectivity of prefrontal, medial temporal and occipital hubs was upregulated in a context‐specific manner. Memory retrieval was characterized by different aberrant connectivity patterns, wherein precuneus connectivity was upregulated during distraction, whereas prefrontal couplings were lost as memory load approached capacity limits. Features of abnormal functional connectivity in PD had pathological and compensatory influences as they correlated with poorer working memory or better visuospatial skills. The results offer new insights into working memory‐related signatures of aberrant cortico–cortical and corticostriatal functional connections, which may portend future declines in different facets of working memory.     

Regional brain activation changes and abnormal functional connectivity of the ventrolateral prefrontal cortex during working memory processing in adults with attention‐deficit/hyperactivity disorder

Previous studies on working memory (WM) function in adults with attention‐deficit/hyperactivity disorder (ADHD) suggested aberrant activation of the prefrontal cortex and the cerebellum. Although it has been hypothesized that activation differences in these regions most likely reflect aberrant frontocerebellar circuits, the functional coupling of these brain networks during cognitive performance has not been investigated so far. In this study, functional magnetic resonance imaging (fMRI) and both univariate and multivariate analytic techniques were used to investigate regional activation changes and functional connectivity differences during cognitive processing in healthy controls (n = 12) and ADHD adults (n = 12). Behavioral performance during a parametric verbal WM paradigm did not significantly differ between adults with ADHD and healthy controls. During the delay period of the activation task, however, ADHD patients showed significantly less activation in the left ventrolateral prefrontal cortex (VLPFC), as well as in cerebellar and occipital regions compared with healthy control subjects. In both groups, independent component analyses revealed a functional network comprising bilateral lateral prefrontal, striatal, and cingulate regions. ADHD adults had significantly lower connectivity in the bilateral VLPFC, the anterior cingulate cortex, the superior parietal lobule, and the cerebellum compared with healthy controls. Increased connectivity in ADHD adults was found in right prefrontal regions, the left dorsal cingulate cortex and the left cuneus. These findings suggest both regional brain activation deficits and functional connectivity changes of the VLPFC and the cerebellum as well as functional connectivity abnormalities of the anterior cingulate and the parietal cortex in ADHD adults during WM processing. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.     

Verbal Working Memory Dysfunction in Schizophrenia: An fMRI Investigation

Impaired processing of working memory information is one of the cognitive deficits seen in patients with schizophrenia. This study aims at corroborating the differences in the brain activities involved in the process of working memory between patients with schizophrenia and the controls. Twelve patients with schizophrenia and 11 controls participated in the study. Functional magnetic resonance imaging (fMRI) was used to assess cortical activities during the performance of a two-back verbal working memory paradigm using the Korean alphabet as mnemonic content. Group analysis revealed that inferior fontal, middle frontal, and superior temporal region showed decreased cortical activities in the patient group compared to those of the controls. This study showed a decreased activation in inferior fontal (BA 47), middle frontal (BA 6), and superior temporal (BA 22/38) neural networks from the patient group and confirmed the earlier findings on the impaired working memory of schizophrenic patients in the fMRI investigation.     

Interference of working memory load with long-term memory formation

Traditionally, it has been assumed that the medial temporal lobe (MTL) is indispensable for long-term memory (LTM) encoding, but only plays a minor role for working memory (WM) maintenance. Recently, however, an increasing number of studies questioned this seemingly clear distinction by showing that the MTL does participate in some WM processes, especially if multiple items are being maintained. This would predict that WM maintenance of multiple items interferes with simultaneous LTM encoding. Here, we tested this idea in a functional magnetic resonance imaging paradigm that required subjects to encode stimuli into LTM during simultaneous WM maintenance of either single or multiple items. Indeed, we found that maintenance of multiple items deteriorates simultaneous LTM encoding as compared with maintenance of single items. WM-related activation of the hippocampus was more pronounced in the condition with high WM load; in contrast, hippocampal activation related to LTM encoding was stronger in the low WM load condition. Successful LTM encoding was associated with a high level of activity in the adjacent parahippocampal cortex (PHC), leading to pronounced parahippocampal subsequent memory effects in the high load condition. This suggests that the PHC is a locus of WM–LTM interaction. Functional connectivity analysis with a seed in the PHC confirmed this result by revealing strong connectivity with the medial frontal cortex, which was only active in the high WM load condition. Taken together, these findings suggest that high WM demands interfere with LTM encoding and thus support the idea that WM and LTM processes interact in the MTL.     

Ventromedial Prefrontal Cortex Drives the Prioritization of Self-Associated Stimuli in Working Memory

Humans show a pervasive bias for processing self- over other-related information, including in working memory (WM), where people prioritize the maintenance of self- (over other-) associated cues. To elucidate the neural mechanisms underlying this self-bias, we paired a self- versus other-associated spatial WM task with fMRI and transcranial direct current stimulation (tDCS) of human participants of both sexes. Maintaining self- (over other-) associated cues resulted in enhanced activity in classic WM regions (frontoparietal cortex), and in superior multivoxel pattern decoding of the cue locations from visual cortex. Moreover, ventromedial PFC (VMPFC) displayed enhanced functional connectivity with WM regions during maintenance of self-associated cues, which predicted individuals'' behavioral self-prioritization effects. In a follow-up tDCS experiment, we targeted VMPFC with excitatory (anodal), inhibitory (cathodal), or sham tDCS. Cathodal tDCS eliminated the self-prioritization effect. These findings provide strong converging evidence for a causal role of VMPFC in driving self-prioritization effects in WM and provide a unique window into the interaction between social, self-referential processing and high-level cognitive control processes.SIGNIFICANCE STATEMENT People have a strong tendency to attend to self-related stimuli, such as their names. This self-bias extends to the automatic prioritization of arbitrarily self-associated stimuli held in working memory. Since working memory is central to high-level cognition, this bias could influence how we make decisions. It is therefore important to understand the underlying brain mechanisms. Here, we used neuroimaging and noninvasive neurostimulation techniques to show that the source of self-bias in working memory is the ventromedial PFC, which modulates activity in frontoparietal brain regions to produce prioritized representations of self-associated stimuli in sensory cortex. This work thus reveals a brain circuit underlying the socially motivated (self-referential) biasing of high-level cognitive processing.     

Angular default mode network connectivity across working memory load

Initially identified during no‐task, baseline conditions, it has now been suggested that the default mode network (DMN) engages during a variety of working memory paradigms through its flexible interactions with other large‐scale brain networks. Nevertheless, its contribution to whole‐brain connectivity dynamics across increasing working memory load has not been explicitly assessed. The aim of our study was to determine which DMN hubs relate to working memory task performance during an fMRI‐based n‐back paradigm with parametric increases in difficulty. Using a voxel‐wise metric, termed the intrinsic connectivity contrast (ICC), we found that the bilateral angular gyri (core DMN hubs) displayed the greatest change in global connectivity across three levels of n‐back task load. Subsequent seed‐based functional connectivity analysis revealed that the angular DMN regions robustly interact with other large‐scale brain networks, suggesting a potential involvement in the global integration of information. Further support for this hypothesis comes from the significant correlations we found between angular gyri connectivity and reaction times to correct responses. The implication from our study is that the DMN is actively involved during the n‐back task and thus plays an important role related to working memory, with its core angular regions contributing to the changes in global brain connectivity in response to increasing environmental demands. Hum Brain Mapp 38:41–52, 2017. © 2016 Wiley Periodicals, Inc.     

Functional connectivity of the frontotemporal network in preattentive detection of abstract changes: Perturbs and observes with transcranial magnetic stimulation and event‐related optical signal

Current theories of automatic or preattentive change detection suggest a regularity or prediction violation mechanism involving functional connectivity between the inferior frontal cortex (IFC) and the superior temporal cortex (STC). By disrupting the IFC function with transcranial magnetic stimulation (TMS) and recording the later STC mismatch response with event‐related optical signal (EROS), previous study demonstrated a causal IFC‐to‐STC functional connection in detecting a pitch or physical change. However, physical change detection can be achieved by memory comparison of the physical features and may not necessarily involve regularity/rule extraction and prediction. The current study investigated the IFC–STC functional connectivity in detecting rule violation (i.e., an abstract change). Frequent standard tone pairs with a constant relative pitch difference, but varying pitches, were presented to establish a pitch interval rule. This abstract rule was violated by deviants with reduced relative pitch intervals. The EROS STC mismatch response to the deviants was abolished by the TMS applied at the IFC 80 ms after deviance onset, but preserved in the spatial (TMS on vertex), auditory (TMS sound), and temporal (200 ms after deviance onset) control conditions. These results demonstrate the IFC–STC connection in preattentive abstract change detection and support the regularity or prediction violation account.     

Aberrant visual circuitry associated with normal spatial match-to-sample accuracy in schizophrenia

A goal of this study was to evaluate the function of the anterior cingulate cortex (ACC) and of the dorsolateral prefrontal cortex (DLPFC) in medicated patients with schizophrenia (SZ), a small group of first-degree relatives, and healthy controls using a visual delayed match-to-sample task in conjunction with functional magnetic resonance imaging (fMRI). To mitigate performance differences between SZ and healthy controls, we used a novel task that allows for individualized adjustment of task difficulty to match ability level. We also trained participants on the task prior to scanning. Using an event-related design, we modeled three components of the match-to-sample trial: visual encoding, delay, and discrimination. We did not find significant differences in ACC/medial frontal cortex activation between the groups. However, compared to healthy controls, SZ showed decreased activation in visual processing areas during the encoding and discrimination phases of the task and in the ventrolateral prefrontal cortex during the delay. These findings emphasize the tendency of schizophrenia subjects to solve perceptual memory problems by engaging diverse regions.     

FUNCTIONAL NEUROANATOMY OF SUBCOMPONENT COGNITIVE PROCESSES INVOLVED IN VERBAL WORKING MEMORY

Recent research has used functional magnetic resonance imaging (fMRI) to examine brain regions related to specific subcomponent cognitive processes of verbal working memory, which include initial encoding of material, maintenance of the information over a brief delay interval, and later retrieval of the information. The present study examined each of these subcomponents in 14 healthy adults using a Sternberg verbal working memory task and fMRI. Group analysis revealed several brain regions active during all subcomponent processes, which included dorsolateral and ventrolateral prefrontal, parietal, hippocampal, and premotor cortex. Several other brain regions showed activation limited to specific subcomponent processes.     

Effect of working memory on evaluation-related frontocentral negativity

Recent results suggest that a negative ERP potential emerges not only on error trials, but is also found after correct responses. There is broad evidence that this component is generated in the anterior cingulate cortex (ACC). The present study aimed to explore the influence of working memory demands on the evaluation process probably reflected by the negative potential. To this purpose, a modified continuous performance task (CPT) was used, with variations of the delay between cues and imperative stimuli. Data were analyzed using conventional averaging techniques as well as source localization with LORETA (low resolution brain electromagnetic tomography). Results suggest a significant effect of working memory delay on the amplitude of the post-response negative ERP component. Its source was located in the anterior cingulate cortex, with the exact location being dependent upon working memory demands. The results support the notion of a general response evaluation system reflected by a post-response negative component. The findings of a working memory dependent modification of this potential suggest a functional link between the medial frontal cortex and the lateral frontal regions primarily involved in working memory processing.