A systematic fMRI investigation of the brain systems subserving different working memory components in schizophrenia

Working memory impairment is one of the cardinal cognitive disturbances in schizophrenia and considerable evidence suggests that it can be traced to functional alterations in the brain. The exact allocation of specific deficits to regional specific dysfunctions, however, remains elusive. The aim of this study was to examine the functional integrity of three distinguishable brain systems underlying maintenance-related subprocesses of working memory (articulatory rehearsal, non-articulatory maintenance of phonological information, maintenance of visuospatial information) in patients with schizophrenia. Using an experimental paradigm, which had been designed to selectively activate these different brain systems, we assessed the brain activation of patients and controls with functional magnetic resonance imaging. Compared with controls, patients showed reduced activation of the fronto-opercular, intraparietal and anterior cingulate cortex during the non-articulatory maintenance of phonological information, as well as attenuated deactivation of the hippocampus. Additionally, we found prefrontal activation to depend critically on the patients' current symptom status. During visuospatial maintenance, patients showed impaired activation of the superior parietal, temporal and occipital cortex, combined with enhanced activation of the frontal eye field and the inferior parietal cortex. No abnormal activations were observed during the articulatory rehearsal task. All activation differences were independent of group differences in task performance. Our fine-grained analysis of dysfunctions in particular aspects of working memory circuitry provides evidence for a differential impairment of the brain systems supporting working memory subcomponents in schizophrenia and extends knowledge of the relationship between cognitive deficits, brain activation abnormalities and symptoms in schizophrenia.     

Evidence for quantitative domain dominance for verbal and spatial working memory in frontal and parietal cortex

Neuroimaging studies in humans have shown that different working memory (WM) tasks recruit a common bilateral fronto-parietal cortical network. Animal studies as well as neuroimaging studies in humans have suggested that this network, in particular the prefrontal cortex, is preferentially recruited when material from different domains (e.g. spatial information or verbal/object information) has to be memorized. Early imaging studies have suggested qualitative dissociations in the prefrontal cortex for spatial and object/verbal WM, either in a left-right or a ventral-dorsal dimension. However, results from different studies are inconsistent. Moreover, recent fMRI studies have failed to find evidence for domain dependent dissociations of WM-related activity in prefrontal cortex. Here we present evidence from two independent fMRI studies using physically identical stimuli in a verbal and spatial WM task showing that domain dominance for WM does indeed exist, although only in the form of quantitative differences in activation and not in the form of a dissociation with different prefrontal regions showing mutually exclusive activation in different domains. Our results support a mixed dimension model of domain dominance for WM within the prefrontal cortex, with left ventral prefrontal cortex (PFC) supporting preferentially verbal WM and right dorsal PFC supporting preferentially spatial WM. The concept of domain dominance is discussed in the light of recent theories of prefrontal cortex function.     

Age-dependent and -independent changes in attention-deficit/hyperactivity disorder (ADHD) during spatial working memory performance

Objectives: Attention-deficit/hyperactivity disorder (ADHD) has been associated with spatial working memory as well as frontostriatal core deficits. However, it is still unclear how the link between these frontostriatal deficits and working memory function in ADHD differs in children and adults. This study examined spatial working memory in adults and children with ADHD, focussing on identifying regions demonstrating age-invariant or age-dependent abnormalities. Methods: We used functional magnetic resonance imaging to examine a group of 26 children and 35 adults to study load manipulated spatial working memory in patients and controls. Results: In comparison to healthy controls, patients demonstrated reduced positive parietal and frontostriatal load effects, i.e., less increase in brain activity from low to high load, despite similar task performance. In addition, younger patients showed negative load effects, i.e., a decrease in brain activity from low to high load, in medial prefrontal regions. Load effect differences between ADHD and controls that differed between age groups were found predominantly in prefrontal regions. Age-invariant load effect differences occurred predominantly in frontostriatal regions. Conclusions: The age-dependent deviations support the role of prefrontal maturation and compensation in ADHD, while the age-invariant alterations observed in frontostriatal regions provide further evidence that these regions reflect a core pathophysiology in ADHD.     

Load effects on spatial working memory performance are linked to distributed alpha and beta oscillations

Increasing spatial working memory (SWM) load is generally associated with declines in behavioral performance, but the neural correlates of load‐related behavioral effects remain poorly understood. Herein, we examine the alterations in oscillatory activity that accompany such performance changes in 22 healthy adults who performed a two‐ and four‐load SWM task during magnetoencephalography (MEG). All MEG data were transformed into the time‐frequency domain and significant oscillatory responses were imaged separately per load using a beamformer. Whole‐brain correlation maps were computed using the load‐related beamformer difference images and load‐related accuracy effects on the SWM task. The results indicated that load‐related differences in left inferior frontal alpha activity during encoding and maintenance were negatively correlated with load‐related accuracy differences on the SWM task. That is, individuals who had more substantial decreases in prefrontal alpha during high‐relative to low‐load SWM trials tended to have smaller performance decrements on the high‐load condition (i.e., they performed more accurately). The same pattern of neurobehavioral correlations was observed during the maintenance period for right superior temporal alpha activity and right superior parietal beta activity. Importantly, this is the first study to employ a voxel‐wise whole‐brain approach to significantly link load‐related oscillatory differences and load‐related SWM performance differences.     

Relationship between prefrontal task-related activity and information flow during spatial working memory performance

While monkeys performed spatial working memory tasks, cue- (C), delay- (D), and response-period (R) activities or their combinations (CD, CR, DR, CDR) were observed in prefrontal neurons. In the present study, we tried to understand information flow during spatial working memory performances and how each task-related neuron contributed to this process. We first characterized each neuron based on which task-related activity was exhibited and which information (cue location or saccade direction) each task-related activity represented, then classified these neurons into 9 groups (C, Dcue, Dsac, CDcue, DcueRcue, DsacRsac, DcueRsac, CDcueRcue and CDcueRsac). Preferred directions were similar between cue- and delay-period activities in CDcue, CDcueRcue, and CDcueRsac, indicating that the directional selectivity of delay-period activity is affected by the directional selectivity of cue-period activity, all of which represented visual information. Preferred directions were also similar between delay- and response-period activities in DcueRcue, CDcueRcue, and DsacRsac, indicating that the directional selectivity of delay-period activity affects the directional selectivity of response-period activity in these neurons. By the comparison of temporal profiles of delay-period activity among these groups, we found (1) cue-period activity could affect directional selectivity of delay-period activity of CDcue and CDcueRcue, (2) cue-period activity of C, CDcue, and CDcueRcue might contribute to the initiation and the maintenance of delay-period activity of CDcue, CDcueRcue, Dcue, and DcueRcue, and (3) saccade-related activity of DsacRsac could be affected by delay-period activity of Dsac and DsacRsac. These results suggest that the combination of task-related activities, the information represented by each activity, and the temporal profile of delay-period activity are important factors to consider information flow and processing and integration of the information in the prefrontal cortex during spatial working memory processes.     

Brain areas involved in spatial working memory

Spatial working memory entails the ability to keep spatial information active in working memory over a short period of time. To study the areas of the brain that are involved in spatial working memory, a group of stroke patients was tested with a spatial search task. Patients and healthy controls were asked to search through a number of boxes shown at different locations on a touch-sensitive computer screen in order to find a target object. In subsequent trials, new target objects were hidden in boxes that were previously empty. Within-search errors were made if a participant returned to an already searched box; between-search errors occurred if a participant returned to a box that was already known to contain a target item. The use of a strategy to remember the locations of the target objects was calculated as well. Damage to the right posterior parietal and right dorsolateral prefrontal cortex impaired the ability to keep spatial information 'on-line', as was indicated by performance on the Corsi Block-Tapping task and the within-search errors. Moreover, patients with damage to the right posterior parietal cortex, the right dorsolateral prefrontal cortex and the hippocampal formation bilaterally made more between-search errors, indicating the importance of these areas in maintaining spatial information in working memory over an extended time period.     

Binding of what and where during working memory maintenance

Prefrontal cortex (PFC) supports the maintenance of currently relevant information in working memory (WM). How the PFC is organized for the maintenance of disparate information, how this information is conjoined into a unified whole, and how the representation may change with task demands is still debated. The pattern of neural activity during maintenance of either abstract visual patterns, locations, or their "conjunction" was measured in two experiments using functional magnetic resonance imaging (fMRI). During delays, common regions in PFC were active, but a dorsal-ventral/spatial-nonspatial functional topography distinguished among the three delay types. During conjunction delays, no additional neural architecture was recruited. Instead, conjunction delays were characterized by a significant reduction compared to the response of that cortical region while maintaining its "preferred" information. A model is presented, extending the principles of "biased competition" to the PFC and the dynamic maintenance of information in WM, that accounts for current and seemingly contradictory previous results from both imaging and physiological studies. In this schema, the PFC is not only the source of biasing signals targeting earlier processing regions, but is also the target of these signals. This model stands as an alternative to traditional "domain specific" and "domain general" models of frontal organization of WM, and as an extension of earlier models of PFC mechanisms related to the cognitive control of goal directed behavior.     

Medial temporal lobe activity at recognition increases with the duration of mnemonic delay during an object working memory task

Object working memory (WM) engages a disseminated neural network, although the extent to which the length of time that data is held in WM influences regional activity within this network is unclear. We used functional magnetic resonance imaging to study a delayed matching to sample task in 14 healthy subjects, manipulating the duration of mnemonic delay. Across all lengths of delay, successful recognition was associated with the bilateral engagement of the inferior and middle frontal gyri and insula, the medial and inferior temporal, dorsal anterior cingulate and the posterior parietal cortices. As the length of time that data was held in WM increased, activation at recognition increased in the medial temporal, medial occipito-temporal, anterior cingulate and posterior parietal cortices. These results confirm the components of an object WM network required for successful recognition, and suggest that parts of this network, including the medial temporal cortex, are sensitive to the duration of mnemonic delay.     

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.     

Cooperative processing in primary somatosensory cortex and posterior parietal cortex during tactile working memory

In the present study, causal roles of both the primary somatosensory cortex (SI) and the posterior parietal cortex (PPC) were investigated in a tactile unimodal working memory (WM) task. Individual magnetic resonance imaging‐based single‐pulse transcranial magnetic stimulation (spTMS) was applied, respectively, to the left SI (ipsilateral to tactile stimuli), right SI (contralateral to tactile stimuli) and right PPC (contralateral to tactile stimuli), while human participants were performing a tactile‐tactile unimodal delayed matching‐to‐sample task. The time points of spTMS were 300, 600 and 900 ms after the onset of the tactile sample stimulus (duration: 200 ms). Compared with ipsilateral SI, application of spTMS over either contralateral SI or contralateral PPC at those time points significantly impaired the accuracy of task performance. Meanwhile, the deterioration in accuracy did not vary with the stimulating time points. Together, these results indicate that the tactile information is processed cooperatively by SI and PPC in the same hemisphere, starting from the early delay of the tactile unimodal WM task. This pattern of processing of tactile information is different from the pattern in tactile‐visual cross‐modal WM. In a tactile‐visual cross‐modal WM task, SI and PPC contribute to the processing sequentially, suggesting a process of sensory information transfer during the early delay between modalities.     

Cortical oscillatory activity during spatial echoic memory

In human magnetoencephalogram, we have found gamma-band activity (GBA), a putative measure of cortical network synchronization, during both bottom-up and top-down auditory processing. When sound positions had to be retained in short-term memory for 800 ms, enhanced GBA was detected over posterior parietal cortex, possibly reflecting the activation of higher sensory storage systems along the hypothesized auditory dorsal space processing stream. Additional prefrontal GBA increases suggested an involvement of central executive networks in stimulus maintenance. The present study assessed spatial echoic memory with the same stimuli but a shorter memorization interval of 200 ms. Statistical probability mapping revealed posterior parietal GBA increases at 80 Hz near the end of the memory phase and both gamma and theta enhancements in response to the test stimulus. In contrast to the previous short-term memory study, no prefrontal gamma or theta enhancements were detected. This suggests that spatial echoic memory is performed by networks along the putative auditory dorsal stream, without requiring an involvement of prefrontal executive regions.     

Phase-specific brain change of spatial working memory processing in genetic and ultra-high risk groups of schizophrenia

Spatial working memory (WM) processing has 3 distinct phases: encoding, maintenance, and retrieval and its dysfunction is a core feature in schizophrenia. We examined phase-specific brain activations associated with spatial WM in first-degree relatives of schizophrenia (genetic high risk, GHR), ultra-high risk (UHR) subjects, patients with schizophrenia, and healthy controls. We used an event-related functional magnetic resonance imaging in 17 GHR subjects, 21 UHR subjects, 15 clinically stable patients with schizophrenia and 16 healthy controls, while subjects were performing a spatial delayed-response task. During the encoding phase, the GHR group showed increased activation in the fronto-parietal regions, whereas the UHR and schizophrenia groups showed significantly less activation in these regions than did the healthy control group. Especially, frontal activation was strongest in GHR subjects, followed by healthy controls, and occurred to a lesser degree in the UHR group, with the least activation occurring in the schizophrenia group. During the maintenance phase, the thalamus showed a differential activation, similar to frontal activation pattern during the encoding phase. During the retrieval phase, no prominent differential activations were found. Increased activations were observed in the superior temporal gyrus during the encoding and maintenance phases in the GHR, UHR, and schizophrenia groups relative to healthy controls. Our findings suggest that functional deficits associated with spatial WM processing emerge in the UHR before the onset of schizophrenia and compensatory neural processes exist in the GHR with genetic liability to schizophrenia.     

Dorsolateral prefrontal cortex, working memory and episodic memory processes: insight through transcranial magnetic stimulation techniques

The ability to recall and recognize facts we experienced in the past is based on a complex mechanism in which several cerebral regions are implicated. Neuroimaging and lesion studies agree in identifying the frontal lobe as a crucial structure for memory processes, and in particular for working memory and episodic memory and their relationships. Furthermore, with the introduction of transcranial magnetic stimulation (TMS) a new way was proposed to investigate the relationships between brain correlates, memory functions and behavior. The aim of this review is to present the main findings that have emerged from experiments which used the TMS technique for memory analysis. They mainly focused on the role of the dorsolateral prefrontal cortex in memory process. Furthermore, we present state-of-the-art evidence supporting a possible use of TMS in the clinic. Specifically we focus on the treatment of memory deficits in depression and anxiety disorders.     

The egocentric spatial reference frame used in dorsal-lateral prefrontal working memory in primates

The dorsal-lateral prefrontal cortex (dlPFC) has been proposed to be the site of spatial working memory (WM), and this concept has had a profound influence on functional studies of the prefrontal cortex (PFC). The concept of spatial WM has been understood to mean that the location of an object is memorized for a short period of time. However, this concept of space is a simplification. To process the spatial information, different spatial frames can be used. In this review, the authors present data from their own laboratory to argue that the dlPFC is related to the egocentric spatial information processing (ESIP) in WM. The goal of this review is to introduce and discuss the egocentric spatial reference frame (ESRF) located in the dlPFC. The ESIP in the PFC might be involved in self-recognition.     

The interaction of perceived control and Gambler's fallacy in risky decision making: An fMRI study

Limited recent evidence implicates the anterior/posterior cingulate (ACC/PCC) and lateral prefrontal networks as the neural substrates of risky decision‐making biases such as illusions of control (IoC) and gambler's fallacy (GF). However, investigation is lacking on the dynamic interactive effect of those biases during decision making. Employing a card‐guessing game that independently manipulates trial‐by‐trial perceived control and gamble outcome among 29 healthy female participants, we observed both IoC‐ and GF‐type behaviors, as well as an interactive effect of previous control and previous outcome, with GF‐type behaviors only following computer‐selected, but not self‐selected, outcomes. Imaging results implicated the ACC and left dorsolateral prefrontal cortex (DLPFC) in agency processing, and the cerebellum and right DLPFC in previous outcome processing, in accordance with past literature. Critically, the right inferior parietal lobule (IPL) exhibited significant betting‐related activities to the interaction of previous control and previous outcome, showing more positive signals to previous computer‐selected winning versus losing outcomes but the reverse pattern following self‐selected outcomes, as well as responding to the interactive effect of control and outcome during feedback. Associations were also found between participants' behavioral sensitivity to the interactive effect of previous control and previous outcome, and right IPL signals, as well as its functional connectivity with neural networks implicated in agency and previous outcome processing. We propose that the right IPL provides the neural substrate for the interaction of perceived control and GF, through coordinating activities in the anterior and posterior cingulate cortices and working conjunctively with lateral PFC and other parietal networks. Hum Brain Mapp 37:1218–1234, 2016. © 2016 Wiley Periodicals, Inc .     

Prefrontal modulation of working memory performance in brain injury and disease

The inter-related cognitive constructs of working memory (WM) and processing speed are fundamental components to general intellectual functioning in humans. Importantly, both WM and processing speed are highly susceptible to disruption in cases of brain injury, neurologic illness, and even in normal aging. A goal of this article is to summarize and critique the functional imaging studies of speeded working memory in neurologically impaired populations. This review focuses specifically on the role of the lateral prefrontal cortex in mediating WM performance and integrates the relevant WM literature in healthy adults with the current findings in the clinical literature. One important finding emerging from a summary of this literature is the dissociable contributions made by ventrolateral and dorsolateral prefrontal cortex (VLPFC and DLPFC) in guiding performance on tasks of WM. Throughout this review, it is shown that when cerebral resources are challenged, it is DLPFC, and often right DLPFC specifically, that plays a critical role in modulating WM functioning. In addition, this article will examine the relationship between task performance and brain activation across studies to clarify the role of increased DLPFC activity in clinical samples. Finally, explanations are offered for the observed increased DLPFC activation and the potentially unique role of right DLPFC in mediating WM performance during periods of cerebral challenge.     

Neural correlates of spatial and nonspatial attention determined using intracranial electroencephalographic signals in humans

Few studies have directly compared the neural correlates of spatial attention (i.e., attention to a particular location) and nonspatial attention (i.e., attention to a feature in the visual scene) using well‐controlled tasks. Here, we investigated the neural correlates of spatial and nonspatial attention in humans using intracranial electroencephalography. The topography and number of electrodes showing significant event‐related desynchronization (ERD) or event‐related synchronization (ERS) in different frequency bands were studied in 13 epileptic patients. Performance was not significantly different between the two conditions. In both conditions, ERD in the low‐frequency bands and ERS in the high‐frequency bands were present bilaterally in the parietal cortex (prominently on the right hemisphere) and frontal regions. In addition to these common changes, spatial attention involved right‐lateralized activity that was maximal in the right superior parietal lobule (SPL), whereas nonspatial attention involved wider brain networks including the bilateral parietal, frontal, and temporal regions, but still had maximal activity in the right parietal lobe. Within the parietal lobe, spatial attention involved ERD or ERS in the right SPL, whereas nonspatial attention involved ERD or ERS in the right inferior parietal lobule. These findings reveal that common as well as different brain networks are engaged in spatial and nonspatial attention. Hum Brain Mapp 37:3041–3054, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.     

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.     

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.     

Dissociating age-related changes in cognitive strategy and neural efficiency using event-related fMRI

We used event-related fMRI to measure brain activity while younger and older adults performed an item-recognition task in which the memory-set size varied between 1 and 8 letters. Each trial was composed of a 4-second encoding period in which subjects viewed random letter strings, a 12-second retention period and a 2-second retrieval period in which subjects decided whether a single probe letter was or was not part of the memory set. For both groups, reaction time increased and accuracy decreased with increasing memory set-size. There were minimal age-related differences in activation patterns with increasing memory set-size in prefrontal cortex (PFC). Regression analyses of individual subjects' performance and cortical activity indicated that speed and accuracy accounted for considerable variance in dorsal and ventral PFC activity during encoding and retrieval. These results suggest that younger and older adults utilize similar working memory (WM) strategies to accommodate increasing memory demand. They support a model of cognitive slowing in which processing rate is related to neural efficiency.