Delayed-response Working Memory Task Research Articles

Alpha event-related decreases during encoding in adults with ADHD – An investigation of sustained attention and working memory processes

BackgroundExecutive functioning deficits are central to established neuropsychological models of ADHD. Oscillatory activity, particularly the alpha rhythm (8–12 Hz) has been associated with cognitive impairments in ADHD. However, most studies to date examined such neural mechanisms underlying executive dysfunction in children and adolescents with ADHD, raising the question of whether and to what extent those ADHD-related working memory impairments are still present in adults. To this end, the current study aimed to investigate the role of alpha event-related decreases (ERD) during working memory processes in adults with and without ADHD. MethodsWe collected electroencephalographic (EEG) data from 85 adults with a lifetime diagnosis of ADHD and 105 controls (aged 32–64), while they performed a continuous performance (CPT) and a spatial delayed response working memory task (SDRT). Time-frequency and independent component analysis (ICA) was used to identify alpha (8–12 Hz) clusters to examine group and condition effects during the temporal profile of sustained attention and working memory processes (encoding, maintenance, retrieval), loads (low and high) and trial type (go and nogo). ResultsIndividuals with ADHD exhibited higher reaction time-variability in SDRT, and slower response times in SDRT and CPT, despite no differences in task accuracy. Although working memory load was associated with stronger alpha ERD in both tasks and both groups (ADHD, controls), we found no consistent evidence for attenuated alpha ERD in adults with ADHD, failing to replicate effects reported in children. In contrast, when looking at the whole sample, the correlations of alpha power during encoding with inattention and hyperactivity-impulsivity symptoms were significant, replicating prior findings in children with ADHD, but suggesting an alternate source for these effects in adults. ConclusionsOur results corroborate the robustness of alpha as a marker of visual attention and suggest that occipital alpha ERD normalizes in adulthood, but with unique contributions of centro-occipital alpha ERD, suggesting a secondary source. This implies that deviations in processes other than previously reported visuospatial cortex engagement may account for the persistent symptoms and cognitive deficits in adults with a history of ADHD.

Brain morphological changes and functional neuroanatomy related to cognitive and emotional distractors during working memory maintenance in post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is associated with abnormalities in the processing and regulation of emotion as well as cognitive deficits. This study evaluated the differential brain activation patterns associated with cognitive and emotional distractors during working memory (WM) maintenance for human faces between patients with PTSD and healthy controls (HCs) and assessed the relationship between changes in the activation patterns by the opposing effects of distraction types and gray matter volume (GMV). Twenty-two patients with PTSD and twenty-two HCs underwent T1-weighted magnetic resonance imaging (MRI) and event-related functional MRI (fMRI), respectively. Event-related fMRI data were recorded while subjects performed a delayed-response WM task with human face and trauma-related distractors. Compared to the HCs, the patients with PTSD showed significantly reduced GMV of the inferior frontal gyrus (IFG) (p < 0.05, FWE-corrected). For the human face distractor trial, the patients showed significantly decreased activities in the superior frontal gyrus and IFG compared with HCs (p < 0.05, FWE-corrected). The patients showed lower accuracy scores and slower reaction times for the face recognition task with trauma-related distractors compared with HCs as well as significantly increased brain activity in the STG during the trauma-related distractor trial was observed (p < 0.05, FWE-corrected). Such differential brain activation patterns associated with the effects of distraction in PTSD patients may be linked to neural mechanisms associated with impairments in both cognitive control for confusable distractors and the ability to control emotional distraction.

Effects of DPTQ, a novel positive allosteric modulator of the dopamine D1 receptor, on spontaneous eye blink rate and spatial working memory in the nonhuman primate

RationaleDopamine (DA) signaling through the D1 receptor has been shown to be integral to multiple aspects of cognition, including the core process of working memory. The discovery of positive allosteric modulators (PAMs) of the D1 receptor has enabled treatment modalities that may have alternative benefits to orthosteric D1 agonists arising from a synergism of action with functional D1 receptor signaling.ObjectivesTo investigate this potential, we have studied the effects of the novel D1 PAM DPTQ on a spatial delayed response working memory task in the rhesus monkey. Initial studies indicated that DPTQ binds to primate D1R with high affinity and selectivity and elevates spontaneous eye blink rate in rhesus monkeys in a dose-dependent manner consistent with plasma ligand exposures and central D1activation.ResultsBased on those results, DPTQ was tested at 2.5 mg/kg IM in the working memory task. No acute effect was observed 1 h after dosing, but performance was impaired 48 h later. Remarkably, this deficit was immediately followed by a significant enhancement in cognition over the next 3 days. In a second experiment in which DPTQ was administered on days 1 and 5, the early impairment was smaller and did not reach statistical significance, but statistically significant enhancement of performance was observed over the following week. Lower doses of 0.1 and 1.0 mg/kg were also capable of producing this protracted enhancement without inducing any transient impairment.ConclusionsDPTQ exemplifies a class of D1PAMs that may be capable of providing long-term improvements in working memory.

An automated platform for Assessing Working Memory and prefrontal circuit function

Working memory is a process for actively maintaining and updating task-relevant information, despite interference from competing inputs, and is supported in part by sustained activity in prefrontal cortical pyramidal neurons and coordinated interactions with inhibitory interneurons, which may serve to regulate interference. Chronic stress has potent effects on working memory performance, possibly by interfering with these interactions or by disrupting long-range inputs from key upstream brain regions. Still, the mechanisms by which chronic stress disrupts working memory are not well understood, due in part to a need for scalable, easy-to-implement behavioral assays that are compatible with two-photon calcium imaging and other tools for recording from large populations of neurons. Here, we describe the development and validation of a platform that was designed specifically for automated, high-throughput assessments of working memory and simultaneous two-photon imaging in chronic stress studies. This platform is relatively inexpensive and easy to build; fully automated and scalable such that one investigator can test relatively large cohorts of animals concurrently; fully compatible with two-photon imaging, yet also designed to mitigate head-fixation stress; and can be easily adapted for other behavioral paradigms. Our validation data confirm that mice could be trained to perform a delayed response working memory task with relatively high-fidelity over the course of ∼15 days. Two-photon imaging data validate the feasibility of recording from large populations of cells during working memory tasks performance and characterizing their functional properties. Activity patterns in >70% of medial prefrontal cortical neurons were modulated by at least one task feature, and a majority of cells were engaged by multiple task features. We conclude with a brief literature review of the circuit mechanisms supporting working memory and their disruption in chronic stress states—highlighting directions for future research enabled by this platform.

Challenging control over emotions in borderline personality disorder - a tDCS study

BackgroundDeficient cognitive control (CC) over emotional distraction is a central characteristic of borderline personality disorder (BPD). Reduced activation of the left dorsolateral prefrontal cortex (dlPFC) has been linked to this deficit. This study investigates whether it is possible to ameliorate CC deficits via anodal tDCS over the left dlPFC in BPD. Furthermore, we investigate whether the extent of CC impairment influences how well one responds to tDCS. MethodsThe effect of a single-session tDCS (1 mA for 20 min, reference electrode on the contralateral mastoid bone) to the left dlPFC (F3) on the CC of patients with BPD (N = 20) and healthy control participants (HCs, N = 20) was examined in a double-blinded, balanced randomized, sham-controlled crossover trial. A delayed response working memory task with negative, neutral and positive pictures presented during the delay period was conducted to assess CC. Stimulation was applied simultaneously with the task. ResultsNegative pictures caused prolonged response times as compared to a control condition in patients with BPD and HCs. Anodal tDCS to the left dlPFC did not significantly reduce this interference effect in the overall sample. Further analyses showed, however, that participants with impaired CC profited the most from anodal tDCS. In the subgroup of participants who actually showed an interference effect we found the expected significant amelioration of CC under tDCS. ConclusionsThe present study demonstrates that anodal tDCS applied to the left dlPFC improves deficient CC. Thereby, base-level performance moderates tDCS effects. Hence, tDCS might be suitable to support behavioral trainings to enhance CC specifically in people whose impairments in CC are comparably high.

Effects of repeated adolescent exposure to cannabis smoke on cognitive outcomes in adulthood.

Cannabis (marijuana) is the most widely used illicit drug in the USA, and consumption among adolescents is rising. Some animal studies show that adolescent exposure to delta 9-tetrahydrocannabinol or synthetic cannabinoid receptor 1 agonists causes alterations in affect and cognition that can persist into adulthood. It is less clear, however, whether similar alterations result from exposure to cannabis via smoke inhalation, which remains the most frequent route of administration in humans. To begin to address these questions, a rat model was used to determine how cannabis smoke exposure during adolescence affects behavioral and cognitive outcomes in adulthood. Adolescent male Long-Evans rats were assigned to clean air, placebo smoke, or cannabis smoke groups. Clean air or smoke exposure sessions were conducted daily during adolescence (from P29-P49 days of age ) for a total of 21 days, and behavioral testing began on P70. Compared to clean air and placebo smoke conditions, cannabis smoke significantly attenuated the normal developmental increase in body weight, but had no effects on several measures of either affect/motivation (open field activity, elevated plus maze, instrumental responding under a progressive ratio schedule of reinforcement) or cognition (set shifting, reversal learning, intertemporal choice). Surprisingly, however, in comparison to clean air controls rats exposed to either cannabis or placebo smoke in adolescence exhibited enhanced performance on a delayed response working memory task. These findings are consistent with a growing body of evidence for limited long-term adverse cognitive and affective consequences of adolescent exposure to relatively low levels of cannabinoids.

Reward-Sensitive Basal Ganglia Stabilize the Maintenance of Goal-Relevant Neural Patterns in Adolescents.

Maturation of basal ganglia (BG) and frontoparietal circuitry parallels developmental gains in working memory (WM). Neurobiological models posit that adult WM performance is enhanced by communication between reward-sensitive BG and frontoparietal regions, via increased stability in the maintenance of goal-relevant neural patterns. It is not known whether this reward-driven pattern stability mechanism may have a role in WM development. In 34 young adolescents (12.16-14.72 years old) undergoing fMRI, reward-sensitive BG regions were localized using an incentive processing task. WM-sensitive regions were localized using a delayed-response WM task. Functional connectivity analyses were used to examine the stability of goal-relevant functional connectivity patterns during WM delay periods between and within reward-sensitive BG and WM-sensitive frontoparietal regions. Analyses revealed that more stable goal-relevant connectivity patterns between reward-sensitive BG and WM-sensitive frontoparietal regions were associated with both greater adolescent age and WM ability. Computational lesion models also revealed that functional connections to WM-sensitive frontoparietal regions from reward-sensitive BG uniquely increased the stability of goal-relevant functional connectivity patterns within frontoparietal regions. Findings suggested (1) the extent to which goal-relevant communication patterns within reward-frontoparietal circuitry are maintained increases with adolescent development and WM ability and (2) communication from reward-sensitive BG to frontoparietal regions enhances the maintenance of goal-relevant neural patterns in adolescents' WM. The maturation of reward-driven stability of goal-relevant neural patterns may provide a putative mechanism for understanding the developmental enhancement of WM.

Brain Activation Patterns Associated with the Effects of Fearful Distractors during Working Memory Maintenance in Patients with Schizophrenia.

ObjectiveThe neural correlates underlying the effects of emotional distraction during working memory (WM) tasks in patients with schizophrenia have yet to be clearly identified. Thus, the present study employed functional magnetic resonance imaging (fMRI) to investigate the effects of emotional distraction involving fear during WM maintenance in patients with schizophrenia.MethodsThis study included 17 patients with schizophrenia who were diagnosed based on Diagnostic and Statistical Manual of Mental Disorders fourth edition, text revision (DSM-IV-TR) criteria and 17 matched healthy controls. Event-related fMRI data were acquired while the participants performed a delayed-response WM task that included neutral and fearful distractors.ResultsPatients with schizophrenia may have tried to maintain WM function during the presentation of task-irrelevant fearful distractors that induced interruption and required attention. Compared to healthy controls, the schizophrenia patients exhibited significantly increased activity in the dorsolateral prefrontal cortex, medial prefrontal cortex, superior temporal gyrus, middle temporal gyrus, insula, hippocampus, caudate nucleus, and postcentral gyrus in a delayed-response WM task when presented with fearful relative to neutral distractors. In addition to its series of increased brain activations, prefrontal areas exhibited interconnections with more caudal brain regions, including temporal areas and the hippocampus and insula.ConclusionThe present study identified specific brain areas associated with the interaction between emotional regulation and cognitive functioning during fearful distractors presented while patients with schizophrenia performed a WM maintenance task. These findings further the current understanding of the neural correlates underlying the effects of emotional distraction on cognitive functioning in patients with schizophrenia.

Enhancing effects of acute exposure to cannabis smoke on working memory performance.

Numerous preclinical studies show that acute cannabinoid administration impairs cognitive performance. Almost all of this research has employed cannabinoid injections, however, whereas smoking is the preferred route of cannabis administration in humans. The goal of these experiments was to systematically determine how acute exposure to cannabis smoke affects working memory performance in a rat model. Adult male (n = 15) and female (n = 16) Long-Evans rats were trained in a food-motivated delayed response working memory task. Prior to test sessions, rats were exposed to smoke generated by burning different numbers of cannabis or placebo cigarettes, using a within-subjects design. Exposure to cannabis smoke had no effect on male rats' performance, but surprisingly, enhanced working memory accuracy in females, which tended to perform less accurately than males under baseline conditions. In addition, cannabis smoke enhanced working memory accuracy in a subgroup of male rats that performed comparably to the worst-performing females. Exposure to placebo smoke had no effect on performance, suggesting that the cannabinoid content of cannabis smoke was critical for its effects on working memory. Follow-up experiments showed that acute administration of either Δ9-tetrahydrocannabinol (0.0, 0.3, 1.0, 3.0 mg/kg) or the cannabinoid receptor type 1 antagonist rimonabant (0.0, 0.2, 0.6, 2.0 mg/kg) impaired working memory performance. These results indicate that differences in the route, timing, or dose of cannabinoid administration can yield distinct cognitive outcomes, and highlight the need for further investigation of this topic.

Disruption of effective connectivity from the dorsolateral prefrontal cortex to the orbitofrontal cortex by negative emotional distraction in obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) has been associated with abnormal cognitive and emotional functions and these dysfunctions may be dependent on the disruption of dynamic interactions within neuronal circuits associated with emotion regulation. Although several studies have shown the aberrant cognitive-affective processing in OCD patients, little is known about how to characterize effective connectivity of the disrupted neural interactions. In the present study, we applied effective connectivity analysis using dynamic causal modeling to explore the disturbed neural interactions in OCD patients. A total of 20 patients and 21 matched healthy controls performed a delayed-response working memory task under emotional or non-emotional distraction while undergoing functional magnetic resonance imaging. During the delay interval under negative emotional distraction, both groups showed similar patterns of activations in the amygdala. However, under negative emotional distraction, the dorsolateral prefrontal cortex (DLPFC) and the orbitofrontal cortex (OFC) exhibited significant differences between groups. Bayesian model averaging indicated that the connection from the DLPFC to the OFC was negatively modulated by negative emotional distraction in patients, when compared with healthy controls (p < 0.05, Bonferroni-corrected). Exaggerated recruitment of the DLPFC may induce the reduction of top-down prefrontal control input over the OFC, leading to abnormal cortico-cortical interaction. This disrupted cortico-cortical interaction under negative emotional distraction may be responsible for dysfunctions of cognitive and emotional processing in OCD patients and may be a component of the pathophysiology associated with OCD.

P165. Effects of transcranial direct current stimulation on training cognitive control over emotional distraction

Various psychiatric disorders are characterised by insufficient cognitive control on emotion processing. Patients with major depressive disorder (MDD) show a biased attention towards negative information, which leads to impaired cognitive abilities. Previous studies have shown that the dorsolateral prefrontal cortex (dlPFC) is critically involved in cognitive control processes. In MDD the dlPFC has been found to be hypoactivated during emotion processing. Modulating the activity of the dlPFC with noninvasive brain stimulation could be a tool for ameliorating cognitive control in patients. In the present study we use transcranial direct current stimulation (tDCS) over the dlPFC to modulate cognitive control during the training of a working memory task with emotional content. We further assess the activity of the dlPFC with near infrared spectroscopy (NIRS) in order to understand its role during emotion control. In our main experience (EXP I), 24 healthy individuals performed three sessions of a delayed response working memory task (DWM) with pictures of varying content (negative vs. neutral) presented during the delay period. During the first session dlPFC activity was recorded via NIRS. In the second session, participants either received 20 min of 1 mA anodal tDCS or sham stimulation. In the third session, the stimulation condition was reversed. A second experiment (EXP II) with the same task and session number was conducted with 16 other healthy participants in order to observe activation changes of the dlPFC throughout the DWM training. No stimulation was applied during this second experience, but NIRS was recorded during all three sessions. In both experiments, an attentional bias (longer response times after negative distractors) was found in the first DWM session. In EXP I, anodal tDCS over the dlPFC increased working memory performance when neutral distractors were present. In EXP II we found that while the attentional bias was eliminated by training, the activity of the dlPFC during negative compared to neutral distractors increased. Therefore, the tDCS-induced performance increase specifically with neutral distractors could be explained by lower dlPFC activation in the neutral as compared to the negative distractor condition in the course of repeated DWM sessions. This lower prefrontal activity might be more susceptible to anodal, activity increasing tDCS than the higher prefrontal activity observed during the negative condition.

Functional neuroanatomy on the working memory under emotional distraction in patients with generalized anxiety disorder.

Patients with generalized anxiety disorder (GAD) suffer the symptoms of psychological distress, including excessive and uncontrollable anxiety. Until now, the functional neuroanatomy for working memory (WM) in conjunction with the major anxiety symptoms in GAD patients has not yet been clearly identified. This study investigated the neural activation patterns associated with the effect of neutral and anxiety-inducing distractors during the delayed-response WM task in GAD patients. Eighteen patients with GAD and 18 age-matched healthy controls participated in this study. The functional magnetic resonance images were obtained while the subjects performed a delayed-response WM task with neutral and anxiety-inducing distractors. During the neutral distractor, GAD patients compared to controls showed significantly lower activities in the fusiform gyrus, superior parietal gyrus, precuneus, superior occipital gyrus, lingual gyrus, cuneus, calcarine gyrus, parahippocampal gyrus and cerebellar cortex. During the anxiety-inducing distractor, GAD patients showed significantly higher activity in the hippocampus, whereas they showed lower activities in the dorsolateral prefrontal cortex, fusiform gyrus, superior parietal gyrus, precuneus, superior occipital gyrus and cerebellar cortex. The blood-oxygen-level dependent signal changes in the dorsolateral prefrontal cortex in GAD patients during the anxiety-inducing distractor were negatively correlated with Anxiety Sensitivity Index-Revised scores. This study identified the specific brain areas associated with the interaction between emotional regulation and cognitive function associated with neutral and anxiety-inducing distractors during WM maintenance in GAD patients. These findings will be helpful for understanding the neural mechanism on the WM-related cognitive deficits and emotional dysfunction with typical anxiety symptoms in GAD.

Neuroanatomical mechanism on the effect of distraction in working memory maintenance in patients with schizophrenia.

This study utilized functional magnetic resonance imaging (fMRI) to discriminate brain activation patterns associated with the effect of distraction during working memory (WM) maintenance for human faces in healthy controls and patients with schizophrenia. Event-related fMRI data were obtained while the subjects performed WM maintenance in a delayed-response WM task with task-irrelevant distracters. Compared with healthy controls, patients showed significantly decreased activities in the superior frontal gyrus, dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex, anterior cingulate cortex, inferior parietal gyrus, and fusiform gyrus during the delayed-response WM task with human face distracters. The blood-oxygen-level-dependent signal changes in the DLPFC were negatively correlated with both of the scores of the Positive Subscale and General Psychopathology Subscale under the Positive and Negative Syndrome Scale during the WM maintenance for the human faces in the patients. This study will be helpful in understanding the neural mechanisms in the general impairment of the inhibition control in schizophrenia.

Friend or foe? Decoding the facilitative and disruptive effects of emotion on working memory in younger and older adults

A growing body of work on emotion-cognition interactions has revealed both facilitative and disruptive effects of emotion on working memory in younger adults. These differing effects may vary by the goal relevancy of emotion within a task. Additionally, it is possible that these emotional effects would be larger for older adults, considering findings of preserved emotional processing with age. To test these hypotheses, the current study examined the effects of emotional content and aging on working memory for target information in the presence of distraction. Thirty-six younger (ages 18–29) and 36 older adults (ages 65–87) completed a delayed-response working memory task. Participants viewed two target words intermixed with two distracter words, and then judged whether a subsequently presented probe word was one of the target words. The emotional content (valence and arousal) of targets and distracters was systematically manipulated. Results indicated that emotional targets facilitated working memory in both age groups. In contrast, emotional distracters disrupted performance. Negative distracters were particularly disruptive for older adults, but younger adults did not show an emotional interference effect. These findings help clarify discrepancies in the literature and contribute to the sparse research on emotional working memory in older adults.

Negative emotional distraction on neural circuits for working memory in patients with posttraumatic stress disorder

ObjectiveTo study the neural mechanism for the impact of negative emotional distraction on working memory in patients with posttraumatic stress disorder (PTSD) resulting from exposure to motor vehicle accidents. MethodsTwenty PTSD patients and 20 healthy subjects were recruited. Event-related functional magnetic resonance imaging (fMRI) was used to investigate the effects of negative and neutral distractors on a delayed-response working memory task. All experiments were performed on a 3.0T MRI scanner, and the functional imaging data were analyzed using SPM8 software. ResultsThe PTSD group showed poorer performance than the control group when the negative distractors were presented during the delay phase of working memory. The functional imaging indicated that, in the presence of negative relative to neutral distractors, the PTSD group showed higher activation in the emotion processing regions, including amygdala, precuneus and fusiform gyrus, but lower activation in the inferior frontal cortex, insula and left supramarginal gyrus than the control group. ConclusionBased on the results that activation in the PTSD patients in the presence of negative distractors increased in the emotion-related brain regions but decreased in the working memory-related brain regions, we may conclude that the neural basis of working memory is impaired by negative emotion in PTSD patients.

Visuospatial imagery and working memory in schizophrenia

IntroductionThe ability to form mental images that reconstruct former perceptual experiences is closely related to working memory (WM) ability. However, whereas WM deficits are established as a core feature of schizophrenia, an independent body of work suggests that mental imagery ability is enhanced in the disorder. Across two experiments we investigated mental imagery in schizophrenia and its relationship with WM.MethodsIn Experiment 1, individuals with schizophrenia (SZ: n=15) and matched controls (CO: n=14) completed a mental imagery generation and inspection task and a spatial delayed-response WM task. In Experiment 2, SZ (n=16) and CO (n=16) completed a novel version of the mental imagery task modified to increase WM maintenance demand.ResultsIn Experiment 1, SZ demonstrated enhanced mental imagery performance, as evidenced by faster response times relative to CO, with preserved accuracy. However, enhanced mental imagery in SZ was accompanied by impaired WM as assessed by the delayed-response task. In Experiment 2, when WM maintenance load was increased, SZ no longer showed superior imagery performance.ConclusionsWe found evidence for enhanced imagery manipulation in SZ despite their WM maintenance deficit. However, this imagery enhancement was abolished when WM maintenance demands were increased. This profile of enhanced imagery manipulation but impaired maintenance could be used to implement novel remediation strategies in the disorder.

Amelioration of Cognitive Control in Depression by Transcranial Direct Current Stimulation

Deficient cognitive control over emotional distraction is a central characteristic of major depressive disorder (MDD). Hypoactivation of the dorsolateral prefrontal cortex (dlPFC) has been linked with this deficit. In this study, we aimed to enhance the activity of the dlPFC in MDD patients by anodal transcranial direct current stimulation (tDCS) and thus ameliorate cognitive control. In a double-blinded, balanced, randomized, sham-controlled crossover trial, we determined the effect of a single-session tDCS to the left dlPFC on the cognitive control in 22 MDD patients and 22 healthy control subjects. To assess the cognitive control, we used a delayed response working memory task with pictures of varying content (emotional vs. neutral) presented during the delay period. Emotional pictures presented during the delay period impaired accuracy and response time of patients with MDD, indicating an attentional bias for emotional stimuli. Anodal tDCS to the dlPFC was associated with an enhanced working memory performance both in patients and control subjects. Specifically in subjects with MDD, the attentional bias was completely abolished by anodal tDCS. The present study demonstrates that anodal tDCS applied to the left dlPFC improves deficient cognitive control in MDD. Based on these data, tDCS might be suitable to support the effects of behavioral training to enhance cognitive control in MDD.

Serotonin transporter gene polymorphisms and brain function during emotional distraction from cognitive processing in posttraumatic stress disorder

BackgroundSerotonergic system dysfunction has been implicated in posttraumatic stress disorder (PTSD). Genetic polymorphisms associated with serotonin signaling may predict differences in brain circuitry involved in emotion processing and deficits associated with PTSD. In healthy individuals, common functional polymorphisms in the serotonin transporter gene (SLC6A4) have been shown to modulate amygdala and prefrontal cortex (PFC) activity in response to salient emotional stimuli. Similar patterns of differential neural responses to emotional stimuli have been demonstrated in PTSD but genetic factors influencing these activations have yet to be examined.MethodsWe investigated whether SLC6A4 promoter polymorphisms (5-HTTLPR, rs25531) and several downstream single nucleotide polymorphisms (SNPs) modulated activity of brain regions involved in the cognitive control of emotion in post-9/11 veterans with PTSD. We used functional MRI to examine neural activity in a PTSD group (n = 22) and a trauma-exposed control group (n = 20) in response to trauma-related images presented as task-irrelevant distractors during the active maintenance period of a delayed-response working memory task. Regions of interest were derived by contrasting activation for the most distracting and least distracting conditions across participants.ResultsIn patients with PTSD, when compared to trauma-exposed controls, rs16965628 (associated with serotonin transporter gene expression) modulated task-related ventrolateral PFC activation and 5-HTTLPR tended to modulate left amygdala activation. Subsequent to combat-related trauma, these SLC6A4 polymorphisms may bias serotonin signaling and the neural circuitry mediating cognitive control of emotion in patients with PTSD.ConclusionsThe SLC6A4 SNP rs16965628 and 5-HTTLPR are associated with a bias in neural responses to traumatic reminders and cognitive control of emotions in patients with PTSD. Functional MRI may help identify intermediate phenotypes and dimensions of PTSD that clarify the functional link between genes and disease phenotype, and also highlight features of PTSD that show more proximal influence of susceptibility genes compared to current clinical categorizations.

Sleep Deprivation and Interference by Emotional Distracters

We determined if sleep deprivation would amplify the effect of negative emotional distracters on working memory. A crossover design involving 2 functional neuroimaging scans conducted at least one week apart. One scan followed a normal night of sleep and the other followed 24 h of sleep deprivation. Scanning order was counterbalanced across subjects. The study took place in a research laboratory. 24 young, healthy volunteers with no history of any sleep, psychiatric, or neurologic disorders. N/A Study participants were scanned while performing a delayed-response working memory task. Two distracters were presented during the maintenance phase, and these differed in content: highly arousing, negative emotional scenes; low-arousing, neutral scenes; and digitally scrambled versions of the pictures. Irrespective of whether volunteers were sleep deprived, negative emotional (relative to neutral) distracters elicited greater maintenance-related activity in the amygdala, ventrolateral prefrontal cortex, and fusiform gyri, while concurrently depressing activity in cognitive control regions. Individuals who maintained or increased distracter-related amygdala activation after sleep deprivation showed increased working memory disruptions by negative emotional distracters. These individuals also showed reduced functional connectivity between the amygdala and the ventromedial and dorsolateral prefrontal cortices, regions postulated to mediate cognitive control against emotional distraction. Increased distraction by emotional stimuli following sleep deprivation is accompanied by increases in amygdala activation and reduced functional connectivity between the amygdala and prefrontal cognitive control regions. These findings shed light on the neural basis for interindividual variation in how negative emotional stimuli might distract sleep deprived persons.

Sleep Deprivation and Interference by Emotional Distracters

We determined if sleep deprivation would amplify the effect of negative emotional distracters on working memory. A crossover design involving 2 functional neuroimaging scans conducted at least one week apart. One scan followed a normal night of sleep and the other followed 24 h of sleep deprivation. Scanning order was counterbalanced across subjects. The study took place in a research laboratory. 24 young, healthy volunteers with no history of any sleep, psychiatric, or neurologic disorders. N/A. Study participants were scanned while performing a delayed-response working memory task. Two distracters were presented during the maintenance phase, and these differed in content: highly arousing, negative emotional scenes; low-arousing, neutral scenes; and digitally scrambled versions of the pictures. Irrespective of whether volunteers were sleep deprived, negative emotional (relative to neutral) distracters elicited greater maintenance-related activity in the amygdala, ventrolateral prefrontal cortex, and fusiform gyri, while concurrently depressing activity in cognitive control regions. Individuals who maintained or increased distracter-related amygdala activation after sleep deprivation showed increased working memory disruptions by negative emotional distracters. These individuals also showed reduced functional connectivity between the amygdala and the ventromedial and dorsolateral prefrontal cortices, regions postulated to mediate cognitive control against emotional distraction. Increased distraction by emotional stimuli following sleep deprivation is accompanied by increases in amygdala activation and reduced functional connectivity between the amygdala and prefrontal cognitive control regions. These findings shed light on the neural basis for interindividual variation in how negative emotional stimuli might distract sleep deprived persons.