Distinct and opposite profiles of connectivity during self-reference task and rest in youth at clinical high risk for psychosis.

Self-reference is impaired in psychotic disorders such as schizophrenia, associated with disability, and closely related to characteristic patterns of aberrant brain connectivity. However, at present, it is unclear whether self-reference is impacted in pathogenesis of the disorder. Alterations in connectivity during a self-reference task or resting-state in the psychosis risk (i.e., prodromal) period may yield important clues for biomarker development, as well as for novel treatment targets. This study examined a task-based and resting-state functional magnetic resonance imaging in individuals at clinical high risk (CHR) for psychosis (n = 22) and healthy control unaffected peers (n = 20). The self-reference task comprised three task conditions where subjects were asked if an adjective was relevant to themselves (self), a designated other individual (other), or to evaluate the word's spelling (letter). Connectivity analyses examined medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC), regions commonly found in conjunction analyses of self-reference, during both the self-reference task and rest. In task connectivity analyses, CHR individuals exhibited decreased mPFC-PCC connectivity when compared to controls. In resting-state analyses, CHR participants showed greater mPFC-PCC connectivity. Taken together, results suggest that psychosis-like alterations in mPFC-PCC connectivity is present prior to psychosis onset across both task and rest.

Striatal-frontal network activation during voluntary task selection under conditions of monetary reward.

During voluntary task selection, a number of internal and external biases may guide such a choice. However, it is not well understood how reward influences task selection when multiple options are possible. To address this issue, we examined brain activation in a voluntary task-switching paradigm while participants underwent fMRI (n = 19). To reinforce the overall goal to choose the tasks randomly, participants were told of a large bonus that they would receive at the end of the experiment for making random task choices. We also examined how occasional, random rewards influenced both task performance and brain activation. We hypothesized that these transient rewards would increase the value of the just-performed task, and therefore bias participants to choose to repeat the same task on the subsequent trial. Contrary to expectations, transient reward had no consistent behavioral effect on subsequent task choice. Nevertheless, the receipt of such rewards did influence activation in brain regions associated with reward processing as well as those associated with goal-directed control. In addition, reward on a prior trial was found to influence activation during task choice on a subsequent trial, with greater activation in a number of executive function regions compared with no-reward trials. We posit that both the random presentation of transient rewards and the overall task bonus for random task choices together reinforced the goal to choose the tasks randomly, which in turn influenced activation in both reward-related regions and those regions involved in abstract goal processing.

Correction to: Striatal-frontal network activation during voluntary task selection under conditions of monetary reward.

Conflict of interest statement: Although co-author Marie T. Banich is the Editor-in-Chief of Cognitive, Affective, and Behavioral Neuroscience, Stan Floresco served as the action editor for this manuscript.

Differential motor and prefrontal cerebello-cortical network development: Evidence from multimodal neuroimaging.

While our understanding of cerebellar structural development through adolescence and young adulthood has expanded, we still lack knowledge of the developmental patterns of cerebellar networks during this critical portion of the lifespan. Volume in lateral posterior cerebellar regions associated with cognition and the prefrontal cortex develops more slowly, reaching their peak volume in adulthood, particularly as compared to motor Lobule V. We predicted that resting state functional connectivity of the lateral posterior regions would show a similar pattern of development during adolescence and young adulthood. That is, we expected to see changes over time in Crus I and Crus II connectivity with the cortex, but no changes in Lobule V connectivity. Additionally, we were interested in how structural connectivity changes in cerebello-thalamo-cortical white matter are related to changes in functional connectivity. A sample of 23 individuals between 12 and 21years old underwent neuroimaging scans at baseline and 12months later. Functional networks of Crus I and Crus II showed significant connectivity decreases over 12months, though there were no differences in Lobule V. Furthermore, these functional connectivity changes were correlated with increases in white matter structural integrity in the corresponding cerebello-thalamo-cortical white matter tract. We suggest that these functional network changes are due to both later pruning in the prefrontal cortex as well as further development of the white matter tracts linking these brain regions.

Toward a more sophisticated response representation in theories of medial frontal performance monitoring: The effects of motor similarity and motor asymmetries.

Cognitive control in the posterior medial frontal cortex (pMFC) is formulated in models that emphasize adaptive behavior driven by a computation evaluating the degree of difference between 2 conflicting responses. These functions are manifested by an event-related brain potential component coined the error-related negativity (ERN). We hypothesized that the ERN represents a regulative rather than evaluative pMFC process, exerted over the error motor representation, expediting the execution of a corrective response. We manipulated the motor representations of the error and the correct response to varying degrees. The ERN was greater when 1) the error response was more potent than when the correct response was more potent, 2) more errors were committed, 3) fewer and slower corrections were observed, and 4) the error response shared fewer motor features with the correct response. In their current forms, several prominent models of the pMFC cannot be reconciled with these findings. We suggest that a prepotent, unintended error is prone to reach the manual motor processor responsible for response execution before a nonpotent, intended correct response. In this case, the correct response is a correction and its execution must wait until the error is aborted. The ERN may reflect pMFC activity that aimed to suppress the error.

The neural mechanisms underlying internally and externally guided task selection.

While some prior work suggests that medial prefrontal cortex (MFC) regions mediate freely chosen actions, other work suggests that the lateral frontal pole (LFP) is responsible for control of abstract, internal goals. The present study uses fMRI to determine whether the voluntary selection of a task in pursuit of an overall goal relies on MFC regions or the LFP. To do so, we used a modified voluntary task switching (VTS) paradigm, in which participants choose an individual task to perform on each trial (i.e., a subgoal), under instructions to perform the tasks equally often and in a random order (i.e. the overall goal). In conjunction, we examined patterns of activation in the face of irrelevant, but task-related external stimuli that might nonetheless influence task selection. While there was some evidence that the MFC was involved in voluntary task selection, we found that the LFP and anterior insula (AI) were crucial to task selection in the pursuit of an overall goal. In addition, activation of the LFP and AI increased in the face of environmental stimuli that might serve as an interfering or conflicting external bias on voluntary task choice. These findings suggest that the LFP supports task selection according to abstract, internal goals, and leaves open the possibility that MFC may guide action selection in situations lacking in such top-down biases. As such, the current study represents a critical step towards understanding the neural underpinnings of how tasks are selected voluntarily to enable an overarching goal.

Cerebellar networks in individuals at ultra high-risk of psychosis: impact on postural sway and symptom severity.

Despite known deficits in postural control in patients with schizophrenia, this domain has not been investigated in youth at ultra high-risk (UHR) for psychosis. This is particularly relevant as postural control implicates dysfunction in the cerebellum-a region implicated in cognitive dysmetria conceptions of schizophrenia but poorly understood in the prodrome. Here, we extended our understanding of movement abnormalities in UHR individuals to include postural control, and have linked these deficits to both symptom severity and cerebello-cortical network connectivity. UHR and healthy control participants completed an instrumentally based balance task to quantify postural control along with a resting state brain imaging scan to investigate cerebellar networks. We also quantified positive and negative symptom severity with structured clinical interviews. The UHR group showed overall increased postural sway and decreased cerebello-cortical resting state connectivity, relative to controls. The decreased cerebello-cortical connectivity was seen across multiple networks. Postural sway was also correlated with cerebellar connectivity in this population and uniquely positively correlated with the severity of negative symptoms. Finally, symptom severity was also associated with cerebellar connectivity. Together, our results point to a potential deficit in sensory integration as an underlying contributor to the increased postural sway, and provide evidence of cerebellar abnormalities in UHR individuals. These results extend our understanding of the motor abnormalities of UHR individuals beyond striatum-based dyskinesias to include postural control and sensory integration deficits, and implicate the cerebellum as a distinct neural substrate preceding the onset of psychosis. Taken together, our results extend the cognitive dysmetria framework to UHR populations.

The influence of response conflict on voluntary task switching: a novel test of the conflict monitoring model.

The conflict monitoring model of cognitive control posits that response conflict triggers a top-down enhancement of a task's representation in working memory. In the present study, we conducted a novel test of the conflict monitoring model using a voluntary task switching paradigm. We predicted that a task's representation would be enhanced following events associated with high response conflict (i.e., incongruent trials and incorrect responses), leading participants to voluntarily choose to repeat that task more often after these events than after events associated with low response conflict (i.e., congruent trials and correct responses). In two experiments, performance following incongruent trials was consistent with the conflict monitoring model. However, performance following incorrect trials did not fit with the model's predictions. These findings provide novel support for the conflict monitoring model while revealing new effects of incorrect trials that the model cannot explain.

Effects of media multitasking frequency on a novel volitional multitasking paradigm.

The effect of media multitasking (e.g., listening to podcasts while studying) on cognitive processes has seen mixed results thus far. To date, the tasks used in the literature to study this phenomenon have been classical paradigms primarily used to examine processes such as working memory. While perfectly valid on their own, these paradigms do not approximate a real-world volitional multitasking environment. To remedy this, as well as attempt to further validate previously found effects in the literature, we designed a novel experimental framework that mimics a desktop computer environment where a "popup" associated with a secondary task would occasionally appear. Participants could choose to attend to the popup, or to ignore it. Attending to the popup would prompt a word stem completion task, while ignoring it would continue the primary math problem verification task. We predicted that individuals who are more impulsive, more frequent media multitaskers, and individuals who prefer to multitask (quantified with the Barratt Impulsiveness Scale, a modified version of the Media Use Questionnaire, and the Multitasking Preference Inventory) would be more distracted by popups, choose to switch tasks more often and more quickly, and be slower to return to the primary task compared to those who media multitask to a lesser degree. We found that as individuals media multitask to a greater extent, they are slower to return to the previous (primary) task set and are slower to complete the primary task overall whether a popup was present or not, among other task performance measures. We found a similar pattern of effects within individuals who prefer to multitask. Our findings suggest that overall, more frequent media multitaskers show a marginal decrease in task performance, as do preferential multitaskers. Attentional impulsivity was not found to influence any task performance measures, but was positively related to a preference for multitasking. While our findings may lack generalizability due to the modifications to the Media Use Questionnaire, and this initial study is statically underpowered, this paradigm is a crucial first step in establishing a more ecologically valid method to study real-world multitasking.

Component processes underlying voluntary task selection: Separable contributions of task-set inertia and reconfiguration.

Most theories describing the cognitive processes underlying task switching allow for contributions of active task-set reconfiguration and task set inertia. Manipulations of the Cue-to-Stimulus-Interval (CSI) are generally thought to influence task set reconfiguration, while Response-to-Cue (RCI) manipulations are thought to influence task set inertia. Together, these intervals compose the Response-to-Stimulus (RSI) interval. However, these theories do not adequately account for voluntary task switching, because a participant can theoretically prepare for an upcoming trial at any point. We used drift diffusion models to examine the contributions of reconfiguration and task set inertia to performance in single- and double-registrant-registrant voluntary task switching. In both paradigms, RSI length moderated nondecision time, suggesting both switch-specific and general preparation prior to cue presentation. In only the double-registrant registrant paradigm, RSI length additionally moderated task set inertia and CSI length affected general (but not switch-specific) preparation. The effects of cue timing (CSI length) depended upon required response to the cue. Future work should attempt to corroborate our findings regarding switch-specific and general preparation effects of interval lengths using EEG.

Preliminary effects of prefrontal tDCS on dopamine-mediated behavior and psychophysiology.

The ability to manipulate dopamine in vivo through non-invasive, reversible mechanisms has the potential to impact clinical, translational, and basic research. Recent PET studies have demonstrated increased dopamine release in the striatum after bifrontal transcranial direct current stimulation (tDCS). We sought to extend this work by examining whether bifrontal tDCS could demonstrate an effect on behavioral and physiological correlates of subcortical dopamine activity. We conducted a preliminary between-subjects study (n = 30) with active and sham tDCS and used spontaneous eye blink rate (EBR), facial attractiveness ratings, and greyscales orienting bias as indirect proxies for dopamine functioning. The initial design and analyses were pre-registered (https://osf.io/gmnpc). Stimulation did not significantly affect any of the three measures, though effect sizes were often moderately large and were all in the predicted directions. Additional exploratory analyses suggested that stimulation's effect on EBR might depend on pre-stimulation dopamine levels. Our results suggest that larger samples than those that are standard in tDCS literature should be used to assess the effect of tDCS on dopamine using indirect measures. Further, exploratory results add to a growing body of work demonstrating the importance of accounting for individual differences in tDCS response.

Anterior cingulate cortex makes 2 contributions to minimizing distraction.

When we detect conflicting irrelevant stimuli (e.g., nearby conversations), we often minimize distraction by increasing attention to relevant stimuli. However, dissociating the neural substrates of processes that detect conflict and processes that increase attention has proven exceptionally difficult. Using a novel cross-modal attentional cueing task in humans, we observed regional specialization for these processes in the cognitive division of the anterior cingulate cortex (ACC(cd)). Activity in a dorsal subregion was associated with increasing attention to relevant stimuli, correlated with behavioral measures of orienting attention to those stimuli, and resembled activity in dorsolateral prefrontal regions that are also thought to bias attention toward relevant stimuli. In contrast, activity in a rostral subregion was associated only with detecting response conflict caused by irrelevant stimuli. These findings support a 2-component model for minimizing distraction and speak to a longstanding debate over how the ACC(cd) contributes to cognitive control.

Cerebellar and prefrontal-cortical engagement during higher-order rule learning in older adulthood.

To date most aging research has focused on cortical systems and networks, ignoring the cerebellum which has been implicated in both cognitive and motor function. Critically, older adults (OA) show marked differences in cerebellar volume and functional networks, suggesting it may play a key role in the behavioral differences observed in advanced age. OA may be less able to recruit cerebellar resources due to network and structural differences. Here, 26 young adults (YA) and 25 OA performed a second-order learning task, known to activate the cerebellum in the fMRI environment. Behavioral results indicated that YA performed significantly better and learned more quickly compared to OA. Functional imaging detailed robust parietal and cerebellar activity during learning (compared to control) blocks within each group. OA showed increased activity (relative to YA) in the left inferior parietal lobe in response to instruction cues during learning (compared to control); whereas, YA showed increased activity (relative to OA) in the left anterior cingulate to feedback cues during learning, potentially explaining age-related performance differences. Visual interpretation of effect size maps showed more bilateral posterior cerebellar activation in OA compared to YA during learning blocks, but early learning showed widespread cerebellar activation in YA compared to OA. There were qualitatively large age-related differences in cerebellar recruitment in terms of effect sizes, yet no statistical difference. These findings serve to further elucidate age-related differences and similarities in cerebellar and cortical brain function and implicate the cerebellum and its networks as regions of interest in aging research.

Age Differences in the Subcomponents of Executive Functioning.

OBJECTIVES: Across the life span, deficits in executive functioning (EF) are associated with poor behavioral control and failure to achieve goals. Though EF is often discussed as one broad construct, a prominent model of EF suggests that it is composed of three subdomains: inhibition, set shifting, and updating. These subdomains are seen in both younger (YA) and older adults (OA), with performance deficits across subdomains in OA. Therefore, our goal was to investigate whether subdomains of EF might be differentially affected by age, and how these differences may relate to broader global age differences in EF. METHODS: To assess these age differences, we conducted a meta-analysis at multiple levels, including task level, subdomain level, and of global EF. Based on previous work, we hypothesized that there would be overall differences in EF in OA. RESULTS: Using 1,268 effect sizes from 401 articles, we found overall differences in EF with age. Results suggested that differences in performance are not uniform, such that variability in age effects emerged at the task level, and updating was not as affected by age as other subdomains. DISCUSSION: These findings advance our understanding of age differences in EF, and stand to inform early detection of EF decline.

Social reward processing: A biomarker for predicting psychosis risk?

The desire to obtain social rewards (e.g. positive feedback) features prominently in our lives and relationships, and is relevant to understanding psychopathology - where behavior is often impaired. Investigating social rewards within the psychosis-spectrum offers an especially useful opportunity, given the high rates of impaired social functioning and social isolation. The goal of this study was to investigate hedonic experience associated with social reward processing as a potential biomarker for psychosis risk. This study used a task-based functional magnetic resonance imaging (fMRI) paradigm in adolescents at clinical high-risk for the development of psychosis (CHR, n = 19) and healthy unaffected peers (healthy controls - HC, n = 20). Regional activation and connectivity of the ventromedial prefrontal cortex and ventral striatum were examined in response to receiving positive social feedback relative to an ambiguous feedback condition. Expectations of impaired hedonic processes in CHR youth were generally not supported, as there were no group differences in neural response or task-based connectivity. Although interesting relationships were found linking neural reward response and connectivity with social, anticipatory, and consummatory anhedonia in the CHR group, results are difficult to interpret in light of task limitations. We discuss potential implications for future study designs that seek to investigate social reward processing as a biomarker for psychosis risk.

Longitudinal Assessment and Functional Neuroimaging of Movement Variability Reveal Novel Insights Into Motor Dysfunction in Clinical High Risk for Psychosis.

Motor dysfunction in youth at clinical high risk (CHR) for psychosis is thought to reflect abnormal neurodevelopment within cortical-subcortical motor circuits and may be important for understanding clinical trajectories of CHR individuals. However, to date, our perspective of brain-behavior relationships has been informed solely by cross-sectional correlational studies linking behavior in the lab to brain structure or respective resting-state network connectivity. Here, we assess movement dysfunction from 2 perspectives: study 1 investigates the longitudinal progression of handwriting variability and positive symptoms in a sample of 91 CHR and healthy controls during a 12-month follow-up and study 2 involves a multiband functional magnetic resonance imaging task exploring the relationship between power grip force stability and motor network brain activation in a subset of participants. In study 1, we found that greater handwriting variability was a stable feature of CHR participants who experienced worse symptom progression. Study 2 results showed that CHR individuals had greater variability in their grip force and greater variability was related to decreased activation in the associative cortico-striatal network compared to controls. Motor variability may be a stable marker of vulnerability for psychosis risk and possible indicator of a vulnerable cortico-striatal brain network functioning in CHR participants, although the effects of antipsychotic medication should be considered.

Adolescents at clinical high risk for psychosis show qualitatively altered patterns of activation during rule learning.

BACKGROUND: The ability to flexibly apply rules to novel situations is a critical aspect of adaptive human behavior. While executive function deficits are known to appear early in the course of psychosis, it is unclear which specific facets are affected. Identifying whether rule learning is impacted at the early stages of psychosis is necessary for truly understanding the etiology of psychosis and may be critical for designing novel treatments. Therefore, we examined rule learning in healthy adolescents and those meeting criteria for clinical high risk (CHR) for psychosis. METHODS: 24 control and 22 CHR adolescents underwent rapid, high-resolution fMRI while performing a paradigm which required them to apply novel or practiced task rules. RESULTS: Previous work has suggested that practiced rules rely on rostrolateral prefrontal cortex (RLPFC) during rule encoding and dorsolateral prefrontal cortex (DLPFC) during task performance, while novel rules show the opposite pattern. We failed to replicate this finding, with greater activity for novel rules during performance. Comparing the HC and CHR group, there were no statistically significant effects, but an effect size analysis found that the CHR group showed less activation during encoding and greater activation during performance. This suggests the CHR group may use less efficient reactive control to retrieve task rules at the time of task performance, rather than proactively during rule encoding. CONCLUSIONS: These findings suggest that flexibility is qualitatively altered in the clinical high risk state, however, more data is needed to determine whether these deficits predict disease progression.

Generalized signaling for control: evidence from postconflict and posterror performance adjustments.

Goal-directed behavior requires cognitive control to effect online adjustments in response to ongoing processing demands. How signaling for these adjustments occurs has been a question of much interest. A basic question regarding the architecture of the cognitive control system is whether such signaling for control is specific to task context or generalizes across contexts. In this study, the authors explored this issue using a stimulus-response compatibility paradigm. They examined trial-to-trial adjustments, specifically, the findings that incompatible trials elicit improved performance on subsequent incompatible trials and that responses are slower after errors. The critical question was, Do such control effects-typically observed within a single task context-occur across task contexts? The paradigm involved 2 orthogonal, stimulus-response sets: Stimuli in the horizontal direction mapped only to responses in the horizontal direction, and likewise for the vertical direction. Cues indicated that either compatible (same direction as stimulus) or incompatible (opposite to stimulus) responses were required. The results showed that trial-to-trial adjustments exist for both direction-repeat and direction-switch trials, demonstrating that signaling for control adjustments can extend beyond the task context within which they arise.

Cortical Morphometry in the Psychosis Risk Period: A Comprehensive Perspective of Surface Features.

BACKGROUND: Gyrification features reflect brain development in the early prenatal environment. Clarifying the nature of these features in psychosis can help shed light on the role of early developmental insult. However, the literature is currently widely discrepant, which may reflect confounds related to formally psychotic patient populations or overreliance on a single feature of cortical surface morphometry (CSM). METHODS: This study compares CSM features of gyrification in clinical high-risk (n = 43) youths during the prodromal risk period to typically developing control subjects over two time points across three metrics: local gyrification index, mean curvature index, and sulcal depth (improving resolution and examination of change over 1 year). RESULTS: Gyrification was stable over time, supporting the idea that gyrification reflects early insult rather than abnormal development or reorganization associated with the disease state. Each of the indices highlighted unique, aberrant features in the clinical high-risk group with respect to control subjects. Specifically, the local gyrification index reflected hypogyrification in the lateral orbitofrontal cortex, superior bank of the superior temporal sulcus, anterior isthmus of the cingulate gyrus, and temporal poles; the mean curvature index indicated sharper gyral and flatter or wider sulcal peaks in the cingulate, postcentral, and lingual gyrus; sulcal depth identified shallow features in the parietal, superior temporal sulcus, and cingulate regions. Further, both the mean curvature index and sulcal depth converged on abnormal features in the parietal cortex. CONCLUSIONS: Gyrification metrics suggest early developmental insult and provide support for neurodevelopmental hypotheses. Observations of stable CSM features across time provide context for interpreting extant studies and speak to CSM as a promising stable marker and/or endophenotype. Collectively, findings support the importance of considering multiple CSM features.

Effects of prefrontal tDCS on executive function: Methodological considerations revealed by meta-analysis.

A meta-analysis of studies using single-session transcranial direct current stimulation (tDCS) to target the dorsolateral prefrontal cortex (DLPFC) was undertaken to examine the effect of stimulation on executive function (EF) in healthy samples. 27 studies were included in analyses, yielding 71 effect sizes. The most relevant measure for each task was determined a priori and used to calculate Hedge's g. Methodological characteristics of each study were examined individually as potential moderators of effect size. Stimulation effects on three domains of EF (inhibition of prepotent responses, mental set shifting, and information updating and monitoring) were analyzed separately. In line with previous work, the current study found no significant effect of anodal unilateral tDCS, cathodal unilateral tDCS, or bilateral tDCS on EF. Further moderator and subgroup analyses were only carried out for anodal unilateral montages due to the small number of studies using other montages. Subgroup analyses revealed a significant effect of anodal unilateral tDCS on updating tasks, but not on inhibition or set-shifting tasks. Cathode location significantly moderated the effect of anodal unilateral tDCS. Extracranial cathodes yielded a significant effect on EF while cranial cathodes yielded no effect. Anode size also significantly moderated effect of anodal unilateral tDCS, with smaller anodes being more effective than larger anodes. In summary, anodal DLPFC stimulation is more effective at improving updating ability than inhibition and set-shifting ability, but anodal stimulation can significantly improve general executive function when extracranial cathodes or small anodes are used. Future meta-analyses may examine how stimulation's effects on specific behavioral tasks, rather than broader domains, might be affected by methodological moderators.