Subspace partitioning in the human prefrontal cortex resolves cognitive interference.

The human prefrontal cortex (PFC) constitutes the structural basis underlying flexible cognitive control, where mixed-selective neural populations encode multiple task features to guide subsequent behavior. The mechanisms by which the brain simultaneously encodes multiple task-relevant variables while minimizing interference from task-irrelevant features remain unknown. Leveraging intracranial recordings from the human PFC, we first demonstrate that competition between coexisting representations of past and present task variables incurs a behavioral switch cost. Our results reveal that this interference between past and present states in the PFC is resolved through coding partitioning into distinct low-dimensional neural states; thereby strongly attenuating behavioral switch costs. In sum, these findings uncover a fundamental coding mechanism that constitutes a central building block of flexible cognitive control.

Attentional modulation of beta-power aligns with the timing of behaviorally relevant rhythmic sounds.

It is largely unknown how attention adapts to the timing of acoustic stimuli. To address this, we investigated how hemispheric lateralization of alpha (7-13 Hz) and beta (14-24 Hz) oscillations, reflecting voluntary allocation of auditory spatial attention, is influenced by tempo and predictability of sounds. We recorded electroencephalography while healthy adults listened to rhythmic sound streams with different tempos that were presented dichotically to separate ears, thus permitting manipulation of spatial-temporal attention. Participants responded to stimulus-onset-asynchrony (SOA) deviants (-90 ms) for given tones in the attended rhythm. Rhythm predictability was controlled via the probability of SOA deviants per block. First, the results revealed hemispheric lateralization of beta-power according to attention direction, reflected as ipsilateral enhancement and contralateral suppression, which was amplified in high- relative to low-predictability conditions. Second, fluctuations in the time-resolved beta-lateralization aligned more strongly with the attended than the unattended tempo. Finally, a trend-level association was found between the degree of beta-lateralization and improved ability to distinguish between SOA-deviants in the attended versus unattended ear. Differently from previous studies, we presented continuous rhythms in which task-relevant and irrelevant stimuli had different tempo, thereby demonstrating that temporal alignment of beta-lateralization with attended sounds reflects top-down attention to sound timing.

Top-Down Attentional Modulation in Human Frontal Cortex: Differential Engagement during External and Internal Attention.

Decades of electrophysiological research on top-down control converge on the role of the lateral frontal cortex in facilitating attention to behaviorally relevant external inputs. However, the involvement of frontal cortex in the top-down control of attention directed to the external versus internal environment remains poorly understood. To address this, we recorded intracranial electrocorticography while subjects directed their attention externally to tones and responded to infrequent target tones, or internally to their own thoughts while ignoring the tones. Our analyses focused on frontal and temporal cortices. We first computed the target effect, as indexed by the difference in high frequency activity (70-150 Hz) between target and standard tones. Importantly, we then compared the target effect between external and internal attention, reflecting a top-down attentional effect elicited by task demands, in each region of interest. Both frontal and temporal cortices showed target effects during external and internal attention, suggesting this effect is present irrespective of attention states. However, only the frontal cortex showed an enhanced target effect during external relative to internal attention. These findings provide electrophysiological evidence for top-down attentional modulation in the lateral frontal cortex, revealing preferential engagement with external attention.

Patients with Ventromedial Prefrontal Lesions Show an Implicit Approach Bias to Angry Faces.

Damage to the ventromedial PFC (VMPFC) can cause maladaptive social behavior, but the cognitive processes underlying these behavioral changes are still uncertain. Here, we tested whether patients with acquired VMPFC lesions show altered approach-avoidance tendencies to emotional facial expressions. Thirteen patients with focal VMPFC lesions and 31 age- and gender-matched healthy controls performed an implicit approach-avoidance task in which they either pushed or pulled a joystick depending on stimulus color. Whereas controls avoided angry faces, VMPFC patients displayed an incongruent response pattern characterized by both increased approach and reduced avoidance of angry facial expressions. The approach bias was stronger in patients with higher self-reported impulsivity and disinhibition and in those with larger lesions. We further used linear ballistic accumulator modeling to investigate latent parameters underlying approach-avoidance decisions. Controls displayed negative drift rates when approaching angry faces, whereas VMPFC lesions abolished this pattern. In addition, VMPFC patients had weaker response drifts than controls during avoidance. Finally, patients showed reduced drift rate variability and shorter nondecision times, indicating impulsive and rigid decision-making. Our findings thus suggest that VMPFC damage alters the pace of evidence accumulation in response to social signals, eliminating a default, protective avoidant bias and facilitating a dysfunctional approach behavior.

Intracranial Recordings Demonstrate Both Cortical and Medial Temporal Lobe Engagement in Visual Search in Humans.

Visual search is a fundamental human behavior, providing a gateway to understanding other sensory domains as well as the role of search in higher-order cognition. Search has been proposed to include two component processes: inefficient search (Search) and efficient search (Pop-out). According to extant research, these two processes map onto two separable neural systems located in the frontal and parietal association cortices. In this study, we use intracranial recordings from 23 participants to delineate the neural correlates of Search and Pop-out with an unprecedented combination of spatiotemporal resolution and coverage across cortical and subcortical structures. First, we demonstrate a role for the medial temporal lobe in visual search, on par with engagement in frontal and parietal association cortex. Second, we show a gradient of increasing engagement over anatomical space from dorsal to ventral lateral frontal cortex. Third, we confirm previous intracranial work demonstrating nearly complete overlap in neural engagement across cortical regions in Search and Pop-out. We further demonstrate Pop-out selectivity, manifesting as activity increase in Pop-out as compared to Search, in a distributed set of sites including frontal cortex. This result is at odds with the view that Pop-out is implemented in low-level visual cortex or parietal cortex alone. Finally, we affirm a central role for the right lateral frontal cortex in Search.

Monitoring of Self-Paced Action Timing and Sensory Outcomes After Lesions to the Orbitofrontal Cortex.

Anticipation, monitoring, and evaluation of the outcome of one's actions are at the core of proactive control. Individuals with lesions to OFC often demonstrate behaviors that indicate a lack of recognition or concern for the negative effects of their actions. Altered action timing has also been reported in these patients. We investigated the role of OFC in predicting and monitoring the sensory outcomes of self-paced actions. We studied patients with focal OFC lesions (n = 15) and healthy controls (n = 20) while they produced actions that infrequently evoked unexpected outcomes. Participants performed a self-paced, random generation task where they repeatedly pressed right and left buttons that were associated with specific sensory outcomes: a 1- and 2-kHz tone, respectively. Occasional unexpected action outcomes occurred (mismatch) that inverted the learned button-tone association (match). We analyzed ERPs to the expected and unexpected outcomes as well as action timing. Neither group showed post-mismatch slowing of button presses, but OFC patients had a higher number of fast button presses, indicating that they were inferior to controls at producing regularly timed actions. Mismatch trials elicited enhanced N2b-P3a responses across groups as indicated by the significant main effect of task condition. Planned within-group analyses showed, however, that patients did not have a significant condition effect, suggesting that the result of the omnibus analysis was driven primarily by the controls. Altogether, our findings indicate that monitoring of action timing and the sensory outcomes of self-paced actions as indexed by ERPs is impacted by OFC damage.

Dynamic frontotemporal systems process space and time in working memory.

How do we rapidly process incoming streams of information in working memory, a cognitive mechanism central to human behavior? Dominant views of working memory focus on the prefrontal cortex (PFC), but human hippocampal recordings provide a neurophysiological signature distinct from the PFC. Are these regions independent, or do they interact in the service of working memory? We addressed this core issue in behavior by recording directly from frontotemporal sites in humans performing a visuospatial working memory task that operationalizes the types of identity and spatiotemporal information we encounter every day. Theta band oscillations drove bidirectional interactions between the PFC and medial temporal lobe (MTL; including the hippocampus). MTL theta oscillations directed the PFC preferentially during the processing of spatiotemporal information, while PFC theta oscillations directed the MTL for all types of information being processed in working memory. These findings reveal an MTL theta mechanism for processing space and time and a domain-general PFC theta mechanism, providing evidence that rapid, dynamic MTL-PFC interactions underlie working memory for everyday experiences.

Altered functional connectivity in adolescent anorexia nervosa is related to age and cortical thickness.

INTRODUCTION: Functional networks develop throughout adolescence when anorexia nervosa (AN) normally debuts. In AN, cerebral structural alterations are found in most brain regions and may be related to the observed functional brain changes. Few studies have investigated the functional networks of the brain in adolescent AN patients.. The aim of this explorative study was to investigate multiple functional networks in adolescent AN patients compared to healthy age-matched controls (HC) and the relationship with age, eating disorder symptoms and structural alterations. METHODS: Included were 29 female inpatients with restrictive AN, and 27 HC. All participants were between the ages of 12 to 18 years. Independent component analysis (ICA) identified 21 functional networks that were analyzed with multivariate and univariate analyses of components and group affiliation (AN vs HC). Age, age × group interaction and AN symptoms were included as covariates. Follow-up correlational analyses of selected components and structural measures (cortical thickness and subcortical volume) were carried out. RESULTS: Decreased functional connectivity (FC) in AN patients was found in one cortical network, involving mainly the precuneus, and identified as a default mode network (DMN). Cortical thickness in the precuneus was significantly correlated with functional connectivity in this network. Significant group differences were also found in two subcortical networks involving mainly the hippocampus and the amygdala respectively, and a significant interaction effect of age and group was found in both these networks. There were no significant associations between FC and the clinical measures used in the study. CONCLUSION: The findings from the present study may imply that functional alterations are related to structural alterations in selected regions and that the restricted food intake in AN patients disrupt normal age-related development of functional networks involving the amygdala and hippocampus.

Lesions to the Fronto-Parietal Network Impact Alpha-Band Phase Synchrony and Cognitive Control.

Long-range phase synchrony in the α-oscillation band (near 10 Hz) has been proposed to facilitate information integration across anatomically segregated regions. Which areas may top-down regulate such cross-regional integration is largely unknown. We previously found that the moment-to-moment strength of high-α band (10-12 Hz) phase synchrony co-varies with activity in a fronto-parietal (FP) network. This network is critical for adaptive cognitive control functions such as cognitive flexibility required during set-shifting. Using electroencephalography (EEG) in 23 patients with focal frontal lobe lesions (resected tumors), we tested the hypothesis that the FP network is necessary for modulation of high-α band phase synchrony. Global phase-synchrony was measured using an adaptation of the phase-locking value (PLV) in a sliding window procedure, which allowed for measurement of changes in EEG-based resting-state functional connectivity across time. As hypothesized, the temporal modulation (range and standard deviation) of high-α phase synchrony was reduced as a function of FP network lesion extent, mostly due to dorsolateral prefrontal cortex (dlPFC) lesions. Furthermore, patients with dlPFC lesions exhibited reduced cognitive flexibility as measured by the Trail-Making Test (set-shifting). Our findings provide evidence that the FP network is necessary for modulatory control of high-α band long-range phase synchrony, and linked to cognitive flexibility.

Cerebral cortical thickness and surface area in adolescent anorexia nervosa: Separate and joint analyses with a permutation-based nonparametric method.

OBJECTIVE: Reduction in cerebral volume is often found in underweight patients with anorexia nervosa (AN), but few studies have investigated other morphological measures. Cortical thickness (CTh) and surface area (CSA), often used to produce the measure of cortical volume, are developmentally distinct measures that may be differentially affected in AN, particularly in the developing brain. In the present study, we investigated CTh and CSA both separately and jointly to gain further insight into structural alterations in adolescent AN patients. METHOD: Thirty female AN inpatients 12-18 years of age, and 27 age-matched healthy controls (HC) underwent structural magnetic resonance imaging. Group differences in CTh and CSA were investigated separately and jointly with a permutation-based nonparametric combination method (NPC) which may be more sensitive in detecting group differences compared to traditional volumetric methods. RESULTS: Results showed significant reduction in in both CTh and CSA in several cortical regions in AN compared to HC and the reduction was related to BMI. Different results for the two morphological measures were found in a small number of cortical regions. The joint NPC analyses showed significant group differences across most of the cortical mantle. DISCUSSION: Results from this study give novel insight to areal reduction in adolescent AN patients and indicate that both CTh and CSA reduction is related to BMI. The study is the first to use the NPC method to reveal large structural alterations covering most of the brain in adolescent AN.

Prefrontal glutamate levels predict altered amygdala-prefrontal connectivity in traumatized youths.

BACKGROUND: Neurobiological models of stress and stress-related mental illness, including post-traumatic stress disorder, converge on the amygdala and the prefrontal cortex (PFC). While a surge of research has reported altered structural and functional connectivity between amygdala and the medial PFC following severe stress, few have addressed the underlying neurochemistry. METHODS: We combined resting-state functional magnetic resonance imaging measures of amygdala connectivity with in vivo MR-spectroscopy (1H-MRS) measurements of glutamate in 26 survivors from the 2011 Norwegian terror attack and 34 control subjects. RESULTS: Traumatized youths showed altered amygdala-anterior midcingulate cortex (aMCC) and amygdala-ventromedial prefrontal cortex (vmPFC) connectivity. Moreover, the trauma survivors exhibited reduced levels of glutamate in the vmPFC which fits with the previous findings of reduced levels of Glx (glutamate + glutamine) in the aMCC (Ousdal et al., 2017) and together suggest long-term impact of a traumatic experience on glutamatergic pathways. Importantly, local glutamatergic metabolite levels predicted the individual amygdala-aMCC and amygdala-vmPFC functional connectivity, and also mediated the observed group difference in amygdala-aMCC connectivity. CONCLUSIONS: Our findings suggest that traumatic stress may influence amygdala-prefrontal neuronal connectivity through an effect on prefrontal glutamate and its compounds. Understanding the neurochemical underpinning of altered amygdala connectivity after trauma may ultimately lead to the discovery of new pharmacological agents which can prevent or treat stress-related mental illness.

Lateral prefrontal cortex lesion impairs regulation of internally and externally directed attention.

Our capacity to flexibly shift between internally and externally directed attention is crucial for successful performance of activities in our daily lives. Neuroimaging studies have implicated the lateral prefrontal cortex (LPFC) in both internally directed processes, including autobiographical memory retrieval and future planning, and externally directed processes, including cognitive control and selective attention. However, the causal involvement of the LPFC in regulating internally directed attention states is unknown. The current study recorded scalp EEG from patients with LPFC lesions and healthy controls as they performed an attention task that instructed them to direct their attention either to the external environment or their internal milieu. We compared frontocentral midline theta and posterior alpha between externally and internally directed attention states. While healthy controls showed increased theta power during externally directed attention and increased alpha power during internally directed attention, LPFC patients revealed no differences between the two attention states in either electrophysiological measure in the analyzed time windows. These findings provide evidence that damage to the LPFC leads to dysregulation of both types of attention, establishing the important role of LPFC in supporting sustained periods of internally and externally directed attention.

Effects of prefrontal cortex damage on emotion understanding: EEG and behavioural evidence.

Humans are highly social beings that interact with each other on a daily basis. In these complex interactions, we get along by being able to identify others' actions and infer their intentions, thoughts and feelings. One of the major theories accounting for this critical ability assumes that the understanding of social signals is based on a primordial tendency to simulate observed actions by activating a mirror neuron system. If mirror neuron regions are important for action and emotion recognition, damage to regions in this network should lead to deficits in these domains. In the current behavioural and EEG study, we focused on the lateral prefrontal cortex including dorsal and ventral prefrontal cortex and utilized a series of task paradigms, each measuring a different aspect of recognizing others' actions or emotions from body cues. We examined 17 patients with lesions including (n = 8) or not including (n = 9) the inferior frontal gyrus, a core mirror neuron system region, and compared their performance to matched healthy control subjects (n = 18), in behavioural tasks and in an EEG observation-execution task measuring mu suppression. Our results provide support for the role of the lateral prefrontal cortex in understanding others' emotions, by showing that even unilateral lesions result in deficits in both accuracy and reaction time in tasks involving the recognition of others' emotions. In tasks involving the recognition of actions, patients showed a general increase in reaction time, but not a reduction in accuracy. Deficits in emotion recognition can be seen by either direct damage to the inferior frontal gyrus, or via damage to dorsal lateral prefrontal cortex regions, resulting in deteriorated performance and less EEG mu suppression over sensorimotor cortex.

Normal white matter microstructure in women long-term recovered from anorexia nervosa: A diffusion tensor imaging study.

OBJECTIVES: Studies point to white matter (WM) microstructure alterations in both adolescent and adult patients with anorexia nervosa (AN). These include reduced fractional anisotropy in several WM fiber tracts, suggesting reduced WM integrity. The extent to which these alterations are reversible with recovery from AN is unclear. There is a paucity of research investigating the presence of WM microstructure alterations in recovered AN patients, and results are inconsistent. This study aimed to investigate the presence of WM microstructure alterations in women long-term recovered from AN. METHOD: Twenty-one adult women who were recovered from AN for at least 1 year were compared to 21 adult comparison women. Participants were recruited via user-organizations for eating disorders, local advertisements, and online forums. Diffusion tensor imaging was used to compare WM microstructure between groups. Correlations between WM microstructure and clinical characteristics were also explored. RESULTS: There were no statistically significant between-group differences in WM microstructure. These null findings remained when employing liberal alpha level thresholds. Furthermore, there were no statistically significant correlations between WM microstructure and clinical characteristics. DISCUSSION: Our findings showed normal WM microstructure in long-term recovered patients, indicating the alterations observed during the acute phase are reversible. Given the paucity of research and inconsistent findings, future studies are warranted to determine the presence of WM microstructure alterations following recovery from AN.

Life Threat and Sleep Disturbances in Adolescents: A Two-Year Follow-Up of Survivors From the 2011 Utøya, Norway, Terror Attack.

A significant number of adolescents have been exposed to traumatic life events. However, knowledge about the specific sleep disturbance that occurs in individuals after trauma exposure is predominantly based on studies of adults. This study reports specific sleep disturbance in 42 survivors of the 2011 mass shooting at a youth summer camp on the Norwegian island Utøya, mean age = 20.91 years, SD = 2.32, 62.5% females. When compared with matched controls, significantly more survivors reported having sleep disturbances, 52.4% versus 13.6%, d = 0.93, of which onset began at the time of the shooting, χ2 = 14.9, p < .001. The prevalence of insomnia, 56.3% versus 11.0%, d = 0.73; excessive daytime sleepiness, 34.4% versus 13.6%, d = 0.61; symptoms of obstructive sleep apnea, 18.8% versus 0%, d = 0.70; and frequent nightmares, 37.5% versus 2.3%, d = 0.90, were all higher in the survivors than in the controls. In a subgroup of survivors (n = 20) with psychiatric diagnoses, sleep disturbances were more prevalent than in survivors without psychiatric diagnosis. Actigraphy data revealed delayed bedtime, sleep onset, and rise time in survivors compared with controls, ts > 1.7, ps = .044 to .028. These results corroborate the effects of a life threat on the range and extent of sleep disturbances, and emphasize the need to better assess and treat sleep disorders in adolescents exposed to trauma.

Threat-Detection and Attentional Bias to Threat in Women Recovered from Anorexia Nervosa: Neural Alterations in Extrastriate and Medial Prefrontal Cortices.

OBJECTIVE: Behavioral studies have shown that anorexia nervosa (AN) is associated with attentional bias to general threat cues. The neurobiological underpinnings of attentional bias to threat in AN are unknown. This study investigated the neural responses associated with threat-detection and attentional bias to threat in AN. METHODS: We measured neural responses to a dot-probe task, involving pairs of angry and neutral face stimuli, in 22 adult women recovered from AN and 21 comparison women. RESULTS: Recovered AN women did not exhibit a behavioral attentional bias to threat. In response to angry faces, recovered women showed significant hypoactivation in the extrastriate cortex. During attentional bias to angry faces, recovered women showed significant hyperactivation in the medial prefrontal cortex. This was because of significant deactivation in comparison women, which was absent in recovered AN women. CONCLUSIONS: Women recovered from AN are characterized by altered neural responses to threat cues. Copyright © 2016 John Wiley & Sons, Ltd and Eating Disorders Association.

Rehabilitation of Executive Functions in Patients with Chronic Acquired Brain Injury with Goal Management Training, External Cuing, and Emotional Regulation: A Randomized Controlled Trial.

Executive dysfunction is a common consequence of acquired brain injury (ABI), causing significant disability in daily life. This randomized controlled trial investigated the efficacy of Goal Management Training (GMT) in improving executive functioning in patients with chronic ABI. Seventy patients with a verified ABI and executive dysfunction were randomly allocated to GMT (n=33) or a psycho-educative active control condition, Brain Health Workshop (BHW) (n=37). In addition, all participants received external cueing by text messages. Neuropsychological tests and self-reported questionnaires of executive functioning were administered pre-intervention, immediately after intervention, and at 6 months follow-up. Assessors were blinded to group allocation. Questionnaire measures indicated significant improvement of everyday executive functioning in the GMT group, with effects lasting at least 6 months post-treatment. Both groups improved on the majority of the applied neuropsychological tests. However, improved performance on tests demanding executive attention was most prominent in the GMT group. The results indicate that GMT combined with external cueing is an effective metacognitive strategy training method, ameliorating executive dysfunction in daily life for patients with chronic ABI. The strongest effects were seen on self-report measures of executive functions 6 months post-treatment, suggesting that strategies learned in GMT were applied and consolidated in everyday life after the end of training. Furthermore, these findings show that executive dysfunction can be improved years after the ABI.

Normal gray matter volumes in women recovered from anorexia nervosa: a voxel-based morphometry study.

BACKGROUND: Anorexia nervosa (AN) has consistently been associated with reduced gray (GM) and white matter (WM) brain volumes. It is unclear whether GM alterations are present following recovery from AN, as previous findings are inconsistent. The aim of the present study was to determine if women recovered from AN exhibit reduced global or regional GM volumes. METHODS: Global GM and WM, as well as regional GM volumes, were investigated in 22 women recovered from AN and 22 age-matched healthy controls using magnetic resonance imaging. Women were considered recovered if they had maintained a body mass index above 18.0 and had not engaged in binge eating, purging, or restrictive eating behaviors during the past year. RESULTS: There were no significant differences between recovered AN women and healthy controls in terms of GM and WM volumes. There were also no significant differences between restricting and binging-purging AN subtypes. Lowest lifetime weight was positively correlated with regional GM volumes in the precuneus and insula. CONCLUSIONS: The present study showed that regional GM and global GM and WM volumes were similar for women long-term recovered from AN and age-matched healthy controls. Further research is needed to determine the extent to which illness severity affect regional GM volumes.

Brain volumes and regional cortical thickness in young females with anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is a severe mental illness, with an unknown etiology. Magnetic resonance imaging studies show reduced brain volumes and cortical thickness in patients compared to healthy controls. However, findings are inconsistent, especially concerning the anatomical location and extent of the differences. The purpose of this study was to estimate and compare brain volumes and regional cortical thickness in young females with AN and healthy controls. METHODS: Magnetic resonance imaging data was acquired from young females with anorexia nervosa (n = 23) and healthy controls (n = 28). Two different scanner sites were used. BMI varied from 13.5 to 20.7 within the patient group, and 11 patients had a BMI > 17.5. FreeSurfer was used to estimate brain volumes and regional cortical thickness. RESULTS: There were no differences between groups in total cerebral cortex volume, white matter volume, or lateral ventricle volume. There were also no volume differences in subcortical grey matter structures. However the results showed reduced cortical thickness bilaterally in the superior parietal gyrus, and in the right inferior parietal and superior frontal gyri. CONCLUSIONS: The functional significance of the findings is undetermined as the majority of the included patients was already partially weight-restored. We discuss whether these regions could be related to predisposing factors of the illness, or whether they are regions that are more vulnerable to starvation, malnutrition or associated processes in AN.

Placebo improves pleasure and pain through opposite modulation of sensory processing.

Placebo analgesia is often conceptualized as a reward mechanism. However, by targeting only negative experiences, such as pain, placebo research may tell only half the story. We compared placebo improvement of painful touch (analgesia) with placebo improvement of pleasant touch (hyperhedonia) using functional MRI and a crossover design. Somatosensory processing was decreased during placebo analgesia and increased during placebo hyperhedonia. Both placebo responses were associated with similar patterns of activation increase in circuitry involved in emotion appraisal, including the pregenual anterior cingulate, medial orbitofrontal cortex, amygdala, accumbens, and midbrain structures. Importantly, placebo-induced coupling between the ventromedial prefrontal cortex and periaqueductal gray correlated with somatosensory decreases to painful touch and somatosensory increases to pleasant touch. These findings suggest that placebo analgesia and hyperhedonia are mediated by activation of shared emotion appraisal neurocircuitry, which down- or up-regulates early sensory processing, depending on whether the expectation is reduced pain or increased pleasure.