Effect of sleep deprivation on emotional working memory

The emotional dysregulation and impaired working memory found after sleep loss can have severe implications for our daily functioning. Considering the intertwined relationship between emotion and cognition in stimuli processing, there could be further implications of sleep deprivation in high‐complex emotional situations. Although studied separately, this interaction between emotion and cognitive processes has been neglected in sleep research. The aim of the present study was to investigate the effect of 1 night of sleep deprivation on emotional working memory. Sixty‐one healthy participants (mean age: 23.4 years) were either sleep deprived for 1 night (n = 30) or had a normal night’s sleep (n = 31). They performed an N‐back task with two levels of working memory load (1‐back and 3‐back) using positive, neutral and negative picture scenes. Sleep deprivation, compared with full night sleep, impaired emotional working memory accuracy, but not reaction times. The sleep‐deprived participants, but not the controls, responded faster to positive than to negative and neutral pictures. The effect of sleep deprivation was similar for both high and low working memory loads. The results showed that although detrimental in terms of accuracy, sleep deprivation did not impair working memory speed. In fact, our findings indicate that positive stimuli may facilitate working memory processing speed after sleep deprivation.     

Functional correlates of distractor suppression during spatial working memory encoding

Executive working memory operations are related to prefrontal regions in the healthy brain. Moreover, neuroimaging data provide evidence for a functional dissociation of ventrolateral and dorsolateral prefrontal cortex. Most authors either suggest a modality-specific or a function-specific prefrontal cortex organization. In the present study we particularly aimed at the identification of different prefrontal cerebral areas that are involved in executive inhibitory processes during spatial working memory encoding. In an fMRI study (functional magnetic resonance imaging) we examined the neural correlates of spatial working memory processing by varying the amount of executive demands of the task. Twenty healthy volunteers performed the Corsi Block-Tapping test (CBT) during fMRI. The CBT requires the storage and reproduction of spatial target sequences. In a second condition, we presented an adapted version of the Block-Suppression-Test (BST). The BST is based on the original CBT but additionally requires the active suppression of visual distraction within the target sequences. In comparison to the CBT performance, particularly the left dorsolateral prefrontal cortex (BA 9) showed more activity during the BST condition. Our results show that the left dorsolateral prefrontal cortex plays a crucial role for executive controlled inhibition of spatial distraction. Furthermore, our findings are in line with the processing model of a functional dorsolateral-ventrolateral prefrontal cortex organization.     

Interfering with working memory in humans

The interference method transcranial magnetic stimulation has to be seen as a complimentary tool to the other noninvasive correlational techniques such as positron emission tomography, functional magnetic resonance imaging or electroencephalography in cognitive neuroscience. However, the combination of two methods e.g. transcranial magnetic stimulation and positron emission tomography seems to be the strongest approach to validate or postulate new hypotheses. In this review several studies using transcranial magnetic stimulation to disentangle working memory functions are presented. The conclusion is drawn that there exists a superordinated amodal central executive within the dorsolateral prefrontal cortex strongly connected with modality specific areas mainly within the prefrontal cortex.     

Variability in neuronal activity in primate cortex during working memory tasks

Persistent elevated neuronal activity has been identified as the neuronal correlate of working memory. It is generally assumed in the literature and in computational and theoretical models of working memory that memory-cell activity is stable and replicable; however, this assumption may be an artifact of the averaging of data collected across trials, and needs experimental verification. In this study, we introduce a classification scheme to characterize the firing frequency trends of cells recorded from the cortex of monkeys during performance of working memory tasks. We examine the frequency statistics and variability of firing during baseline and memory periods. We also study the behavior of cells on individual trials and across trials, and explore the stability of cellular firing during the memory period. We find that cells from different firing-trend classes possess markedly different statistics. We also find that individual cells show substantial variability in their firing behavior across trials, and that firing frequency also varies markedly over the course of a single trial. Finally, the average frequency distribution is wider, the magnitude of the frequency increases from baseline to memory smaller, and the magnitude of frequency decreases larger than is generally assumed. These results may serve as a guide in the evaluation of current theories of the cortical mechanisms of working memory.     

Neural substrates of manipulation in visuospatial working memory

The present study aimed to investigate in humans whether similar neuronal mechanisms underlie the manipulation and active processing of visual and visuospatial stimuli. Simultaneous and successive mental rotation and identity judgment of 2-D matrices and 3-D cube figures were contrasted using functional magnetic resonance imaging (fMRI). Results demonstrate that activation patterns during mental rotation with low working memory demands differ depending on stimulus type (2-D vs. 3-D). Comparison of simultaneous mental rotation of matrices and 3-D cubes resulted in activation of frontal as well as inferior and superior parietal cortices. The opposite contrast (mental rotation of 3-D cubes vs. 2-D matrices) yielded only frontal cortex activation. The findings also yield evidence for converging, overlapping activation patterns for 2-D and 3-D stimuli if working memory demands are increased. Results are discussed within the framework of current working memory models.     

Effects of chewing in working memory processing

It has been generally suggested that chewing produces an enhancing effect on cognitive performance-related aspects of memory by the test battery. Furthermore, recent studies have shown that chewing is associated with activation of various brain regions, including the prefrontal cortex. However, little is known about the relation between cognitive performances affected by chewing and the neuronal activity in specified regions in the brain. We therefore examined the effects of chewing on neuronal activities in the brain during a working memory task using fMRI. The subjects chewed gum, without odor and taste components, between continuously performed two- or three-back (n-back) working memory tasks. Chewing increased the BOLD signals in the middle frontal gyrus (Brodmann's areas 9 and 46) in the dorsolateral prefrontal cortex during the n-back tasks. Furthermore, there were more prominent activations in the right premotor cortex, precuneus, thalamus, hippocampus and inferior parietal lobe during the n-back tasks after the chewing trial. These results suggest that chewing may accelerate or recover the process of working memory besides inducing improvement in the arousal level by the chewing motion.     

Performance and alertness effects of caffeine, dextroamphetamine, and modafinil during sleep deprivation

Stimulants may provide short-term performance and alertness enhancement during sleep loss. Caffeine 600 mg, d-amphetamine 20 mg, and modafinil 400 mg were compared during 85 h of total sleep deprivation to determine the extent to which the three agents restored performance on simple psychomotor tasks, objective alertness and tasks of executive functions. Forty-eight healthy young adults remained awake for 85 h. Performance and alertness tests were administered bi-hourly from 8:00 hours day 2 to 19:00 hours day 5. At 23:50 hours on day 4 (after 64 h awake), subjects ingested placebo, caffeine 600 mg, dextroamphetamine 20 mg, or modafinil 400 mg (n=12 per group). Performance and alertness testing continued, and probe tasks of executive function were administered intermittently until the recovery sleep period (20:00 hours day 5 to 8:00 hours day 5). Bi-hourly postrecovery sleep testing occurred from 10:00 hours to 16:00 hours day 6. All three agents improved psychomotor vigilance speed and objectively measured alertness relative to placebo. Drugs did not affect recovery sleep, and postrecovery sleep performance for all drug groups was at presleep deprivation levels. Effects on executive function tasks were mixed, with improvement on some tasks with caffeine and modafinil, and apparent decrements with dextroamphetamine on others. At the doses tested, caffeine, dextroamphetamine, and modafinil are equally effective for approximately 2-4 h in restoring simple psychomotor performance and objective alertness. The duration of these benefits vary in accordance with the different elimination rates of the drugs. Whether caffeine, dextroamphetamine, and modafinil differentially restore executive functions during sleep deprivation remains unclear.     

The impact of five nights of sleep restriction on emotional reactivity

An inadequate amount of sleep can negatively affect emotional processing, causing behavioural and neurofunctional changes. However, unlike the condition of total sleep deprivation, which has been extensively studied, the effects of prolonged sleep restriction have received less attention. In this study, we evaluated, for the first time, the effects of five nights of sleep restriction (5 hr a night) on emotional reactivity in healthy subjects. Forty‐two subjects were selected to participate, over two consecutive weeks, in two experimental conditions in counterbalanced order. The subjects were tested the morning after five nights of regular sleep and after five consecutive nights of sleep restriction. During the test, participants evaluated valence and arousal of 90 images selected from the International Affective Picture System. The subjects perceived pleasant and neutral pictures in a more negative way in the sleep‐restriction condition compared to the sleep condition. This effect survived after removing the contribution of mood changes. In contrast, there was no significant difference between conditions for ratings of unpleasant pictures. These results provide the first evidence that an inadequate amount of sleep for five consecutive nights determines an alteration of the evaluation of pleasant and neutral stimuli, imposing a negative emotional bias. Considering the pervasiveness of insufficient sleep in modern society, our results have potential implications for daily life, as well as in clinical settings.     

Prefrontal cortex and working memory processes

Working memory is a mechanism for short-term active maintenance of information as well as for processing maintained information. The dorsolateral prefrontal cortex has been known to participate in working memory. The analysis of task-related dorsolateral prefrontal cortex activity while monkeys performed a variety of working memory tasks revealed that delay-period activity is a neural correlate of a mechanism for temporary active maintenance of information, because this activity persisted throughout the delay period, showed selectivity to a particular visual feature, and was related to correct behavioral performances. Information processing can be considered as a change of the information represented by a population of neural activities during the progress of the trial. Using population vectors calculated by a population of task-related dorsolateral prefrontal cortex activities, we demonstrated the temporal change of information represented by a population of dorsolateral prefrontal cortex activities during performances of spatial working memory tasks. Cross-correlation analysis using spike firings of simultaneously isolated pairs of neurons reveals widespread functional interactions among neighboring neurons, especially neurons having delay-period activity, and their dynamic modulation depending on the context of the trial. Functional interactions among neurons and their dynamic modulation could be a mechanism of information processing in the dorsolateral prefrontal cortex.     

Role of anterior cingulate cortex during semantic coding in verbal working memory

The relationship between working memory and long-term memory was one of the main problems in recent studies of working memory. As part of this problem, we examined the neural substrates that sustain the semantic coding process in verbal working memory using fMRI. In past experiments, we behaviorally explored whether central executive plays an important role in the process of semantic coding; thus, we especially focused on the function of anterior cingulate cortex (ACC) that is assumed to form the main neural basis of central executive. We accomplished our purpose by examining the concreteness effect reflecting semantic information. The ACC was strongly activated under the Concrete condition in contrast to the Abstract condition. Based on this result, we argue that the ACC is responsible for the semantic coding process in verbal working memory.     

Banishing the homunculus: making working memory work

The prefrontal cortex has long been thought to subserve both working memory and "executive" function, but the mechanistic basis of their integrated function has remained poorly understood, often amounting to a homunculus. This paper reviews the progress in our laboratory and others pursuing a long-term research agenda to deconstruct this homunculus by elucidating the precise computational and neural mechanisms underlying these phenomena. We outline six key functional demands underlying working memory, and then describe the current state of our computational model of the prefrontal cortex and associated systems in the basal ganglia (BG). The model, called PBWM (prefrontal cortex, basal ganglia working memory model), relies on actively maintained representations in the prefrontal cortex, which are dynamically updated/gated by the basal ganglia. It is capable of developing human-like performance largely on its own by taking advantage of powerful reinforcement learning mechanisms, based on the midbrain dopaminergic system and its activation via the basal ganglia and amygdala. These learning mechanisms enable the model to learn to control both itself and other brain areas in a strategic, task-appropriate manner. The model can learn challenging working memory tasks, and has been corroborated by several important empirical studies.     

Aging-related changes of neural mechanisms underlying visual-spatial working memory

Capacities of the prefrontal cortex (PFC) such as working memory (WM) are known to decline with increasing age. However, it is unclear which neurofunctional mechanisms may underlie this aging-related cognitive decline. The finding that PFC activity tends to be less lateralized in older subjects has led to the assumption of a hemispheric asymmetry reduction in the PFC associated with aging (HAROLD). Using functional magnetic resonance imaging (fMRI), we here investigated aging-related neurofunctional alterations during the performance of a visual-spatial WM task with differential levels of difficulty. Older volunteers activated dorsolateral PFC regions bilaterally while young subjects recruited these areas only in the left hemisphere. These data corroborate the hemispheric asymmetry reduction in the PFC associated with aging (HAROLD) account. However, we also observed functional reorganizations in parieto-occipital areas, and with increasing WM demands, an aging-related reversed hemispheric asymmetry of prefrontal activations. Importantly, neither PFC nor parieto-occipital reorganizations prevented older participants from showing worse WM performance than young volunteers. We conclude that frontal-parietal functional reorganizations may reflect compensational mechanisms related to aging, but do not obviate diminished visual-spatial WM performance in older people.     

Level of arousal and the ability to maintain wakefulness

The ability to maintain wakefulness under baseline and sleep deprivation conditions was examined in a group of 14 normal young adults. Subjects participated in both standard and manipulation Maintenance of Wakefulness tests after being awake for 7, 19, and 31 h. In the manipulation Maintenance of Wakefulness tests, subjects performed varying degrees of physical activity at the onset of stage 1 to allow them to preserve wakefulness. As expected, ability to maintain wakefulness declined as time awake increased. With amount of time awake held constant, wakefulness was enhanced most after standing and doing knee bends, less after standing, less after sitting up, and least after subjects were spoken to. The improvement in alertness after doing knee bends as compared to being spoken to was of the same relative magnitude as the decrease in alertness after one night of total sleep deprivation. As expected, heart rate also increased consistently as activity increased. Each subject had a negative correlation between their EEG sleep latencies and their minimum r-r interval during the manipulation, i.e. the higher the heart rate, the longer the latency. These data were interpreted as a demonstration of the impact of discrete phasic arousal on the ability to maintain wakefulness.     

Dopaminergic control of working memory and its relevance to schizophrenia: a circuit dynamics perspective

This article argues how dopamine controls working memory and how the dysregulation of the dopaminergic system is related to schizophrenia. In the dorsolateral prefrontal cortex, which is the principal part of the working memory system, recurrent excitation is subtly balanced with intracortical inhibition. A potent controller of the dorsolateral prefrontal cortical circuit is the mesocortical dopaminergic system. To understand the characteristics of the dopaminergic control of working memory, the stability of the circuit dynamics under the influence of dopamine has been studied. Recent computational studies suggest that the hyperdopaminergic state is usually stable but the hypodopaminergic state tends to be unstable. The stability also depends on the efficacy of the glutamatergic transmission in the corticomesencephalic projections to dopamine neurons. When this cortical feedback is hypoglutamatergic, the circuit of the dorsolateral prefrontal cortex tends to be unstable, such that a slight increase in dopamine releasability causes a catastrophic jump of the dorsolateral prefrontal cortex activity from a low to a high level. This may account for the seemingly paradoxical overactivation of the dorsolateral prefrontal cortex observed in schizophrenic patients. Given that dopamine transmission is abnormal in the brains of patients with schizophrenia and working memory deficit is a core dysfunction in schizophrenia, the concept of circuit stability would be useful not only for understanding the mechanisms of working memory processing but for developing therapeutic strategies to enhance cognitive functions in schizophrenia.     

Under the curve: critical issues for elucidating D1 receptor function in working memory

It has been postulated that spatial working memory operates optimally within a limited range of dopamine transmission and D1 dopamine receptor signaling in prefrontal cortex. Insufficiency in prefrontal dopamine, as in aging, and excessive transmission, as in acute stress, lead to impairments in working memory that can be ameliorated by D1 receptor agonist and antagonist treatment, respectively. Iontophoretic investigations of dopamine's influence on the cellular mechanisms of working memory have revealed that moderate D1 blockade can enhance memory fields in primate prefrontal pyramidal neurons while strong blockade abolishes them. The combined behavioral and physiological evidence indicates that there is a normal range of dopamine function in prefrontal cortex that can be described as an "inverted-U" relationship between dopamine transmission and the integrity of working memory. Both in vivo and in vitro studies have demonstrated a role for dopamine in promoting the excitability of prefrontal pyramidal cells and facilitating their N-methyl-d-aspartate inputs, while simultaneously restraining recurrent excitation and facilitating feedforward inhibition. This evidence indicates that there is a fine balance between the synergistic mechanisms of D1 modulation in working memory. Given the critical role of prefrontal function for cognition, it is not surprising that this balancing act is perturbed by both subtle genetic influences and environmental events. Further, there is evidence for an imbalance in these dopaminergic mechanisms in multiple neuropsychiatric disorders, particularly schizophrenia, and in related nonhuman primate models. Elucidating the orchestration of dopamine signaling in key nodes within prefrontal microcircuitry is therefore pivotal for understanding the influence of dopamine transmission on the dynamics of working memory. Here, we explore the hypothesis that the window of optimal dopamine signaling changes on a behavioral time-scale, dependent upon current cognitive demands and local neuronal activity as well as long-term alterations in signaling pathways and gene expression. If we look under the bell-shaped curve of prefrontal dopamine function, it is the relationship between neuromodulation and cognitive function that promises to bridge our knowledge between molecule and mind.     

The functional neuroanatomy of working memory: contributions of human brain lesion studies

Studies of patients with focal brain lesions remain critical components of research programs attempting to understand human brain function. Whereas functional imaging typically reveals activity in distributed brain regions that are involved in a task, lesion studies can define which of these brain regions are necessary for a cognitive process. Further, lesion studies are less critical regarding the selection of baseline conditions needed in functional brain imaging research. Lesion studies suggest a functional subdivision of the visuospatial sketchpad of working memory with a ventral stream reaching from occipital to temporal cortex supporting object recognition and a dorsal stream connecting the occipital with parietal cortex enabling spatial operations. The phonological loop can be divided into a phonological short-term store in inferior parietal cortex and an articulatory subvocal rehearsal process relying on brain areas necessary for speech production, i.e. Broca's area, the supplementary motor association area and possibly the cerebellum. More uncertainty exists regarding the role of the prefrontal cortex in working memory. Whereas single cell studies in non-human primates and functional imaging studies in humans have suggested an extension of the ventral and dorsal path into different subregions of the prefrontal cortex, lesion studies together with recent single-cell and imaging studies point to a non-mnemonic role of the prefrontal cortex, including attentional control of sensory processing, integration of information from different domains, stimulus selection and monitoring of information held in memory. Our own data argue against a modulatory view of the prefrontal cortex and suggest that processes supporting working memory are distributed along ventral and dorsal lateral prefrontal cortex.     

Self-rated arousal concurrent with the antidepressant response to total sleep deprivation of patients with a major depressive disorder: a disinhibition hypothesis

SUMMARY In view of the opposing theories regarding the arousing or de-arousing action of total sleep deprivation (TSD) in producing antidepressant effects, 23 patients with a major depressive disorder were deprived of a night's sleep twice weekly for two weeks, and self-rated their condition 38 times using von Zerssen's scale for depression and, concurrently, Thayer's Activation Deactivation Adjective Check List (AD ACL). Transient relief of depression after TSD, indicated by eight patients, was mimicked by their AD ACL scores, which revealed the same underlying factors as were found in Thayer's studies. TSD appears to be simultaneously arousing (giving more energy) and de-arousing (leading to less tension), while this response takes place against a background of increased tiredness/sleepiness. It is argued that TSD sets off a psychological disinhibition process on the basis of cerebral fatigue; in particular the prefrontal (orbital?) areas of the cerebral cortex may be implicated, possibly in relation to a dampening down of subcortical arousal systems.     

Impaired decision making following 49 h of sleep deprivation

Sleep deprivation reduces regional cerebral metabolism within the prefrontal cortex, the brain region most responsible for higher-order cognitive processes, including judgment and decision making. Accordingly, we hypothesized that two nights of sleep loss would impair decision making quality and lead to increased risk-taking behavior on the Iowa Gambling Task (IGT), which mimics real-world decision making under conditions of uncertainty. Thirty-four healthy participants completed the IGT at rested baseline and again following 49.5 h of sleep deprivation. At baseline, volunteers performed in a manner similar to that seen in most samples of healthy normal individuals, rapidly learning to avoid high-risk decks and selecting more frequently from advantageous low-risk decks as the game progressed. After sleep loss, however, volunteers showed a strikingly different pattern of performance. Relative to rested baseline, sleep-deprived individuals tended to choose more frequently from risky decks as the game progressed, a pattern similar to, though less severe than, previously published reports of patients with lesions to the ventromedial prefrontal cortex. Although risky decision making was not related to participant age when tested at rested baseline, age was negatively correlated with advantageous decision making on the IGT, when tested following sleep deprivation (i.e. older subjects made more risky choices). These findings suggest that cognitive functions known to be mediated by the ventromedial prefrontal cortex, including decision making under conditions of uncertainty, may be particularly vulnerable to sleep loss and that this vulnerability may become more pronounced with increased age.