Anxiety Symptoms in Young Children Are Associated With a Maladaptive Neurobehavioral Profile of Error Responding.

BACKGROUND: Childhood anxiety symptoms have been linked to alterations in cognitive control and error processing, but the diverse findings on neural markers of anxiety in young children, which vary by severity and developmental stage, suggest the need for a wider perspective. Integrating new neural markers with established ones, such as the error-related negativity, the error positivity, and frontal theta, could clarify this association. Error-related alpha suppression (ERAS) is a recently proposed index of post-error attentional engagement that has not yet been explored in children with anxiety. METHODS: To identify neurobehavioral profiles of anxiety in young children by integrating ERAS with the error-related negativity, error positivity, frontal theta, and post-error performance indicators, we employed K-means clustering as an unsupervised multimetric approach. For this, we first aimed to confirm the presence and scalp distribution of ERAS in young children. We performed event-related potentials and spectral analysis of electroencephalogram data collected during a Go/NoGo task (Zoo Task) completed by 181 children (ages 4-7 years; 103 female) who were sampled from across the clinical-to-nonclinical range of anxiety severity using the Child Behavior Checklist. RESULTS: Results confirmed ERAS, showing lower post-error alpha power, maximal suppression at occipital sites, and less ERAS in younger children. K-means clustering revealed that high anxiety and younger age were associated with reduction in ERAS and frontal theta, less negative error-related negativity, enlarged error positivity, more post-error slowing, and reduced post-error accuracy. CONCLUSIONS: Our findings indicate a link between ERAS, maladaptive neural mechanisms of attention elicited by errors, and anxiety in young children, suggesting that anxiety may arise from or interfere with attention and error processing.

Electrophysiological signatures of reward learning in the rodent touchscreen-based Probabilistic Reward Task.

Blunted reward learning and reward-related activation within the corticostriatal-midbrain circuitry have been implicated in the pathophysiology of anhedonia and depression. Unfortunately, the search for more efficacious interventions for anhedonic behaviors has been hampered by the use of vastly different preclinical and clinical assays. In a first step in addressing this gap, in the current study, we used event-related potentials and spectral analyses in conjunction with a touchscreen version of the rodent Probabilistic Reward Task (PRT) to identify the electrophysiological signatures of reward learning in rats. We trained 11 rats (5 females and 6 males) on the rodent touchscreen-based PRT and subsequently implanted them with deep electrodes in the anterior cingulate cortex (ACC) and nucleus accumbens (NAc) for local field potentials recordings during the PRT. Behaviorally, the expected responsivity-to-reward profile was observed. At the electrophysiological level, we identified a negative amplitude deflection 250-500 ms after feedback in the ACC and NAc electrodes, as well as power increase in feedback-locked delta (1-5 Hz) and alpha/beta (9-17 Hz) bands in both electrodes for rewarded trials. Using a reverse-translational approach, we identified electrophysiological signatures of reward learning in rats similar to those described in humans. These findings and approaches might provide a useful translational platform to efficiently evaluate novel therapeutics targeting anhedonia.

Effects of modafinil on electroencephalographic microstates in healthy adults.

RATIONALE: Modafinil has been proposed as a potentially effective clinical treatment for neuropsychiatric disorders characterized by cognitive control deficits. However, the precise effects of modafinil, particularly on brain network functions, are not completely understood. OBJECTIVES: To address this gap, we examined the effects of modafinil on resting-state brain activity in 30 healthy adults using microstate analysis. Electroencephalographic (EEG) microstates are discrete voltage topographies generated from resting-state network activity. METHODS: Using a placebo-controlled, within-subjects design, we examined changes to microstate parameters following placebo (0 mg), low (100 mg), and high (200 mg) modafinil doses. We also examined the functional significance of these microstates via associations between microstate parameters and event-related potential indexes of conflict monitoring and automatic error processing (N2 and error-related negativity) and behavioral responses (accuracy and RT) from a subsequent flanker interference task. RESULTS: Five microstates emerged following each treatment condition, including four canonical microstates (A-D). Modafinil increased microstate C proportion and occurrence regardless of dose, relative to placebo. Modafinil also decreased microstate A proportion and microstate B proportion and occurrence relative to placebo. These modafinil-related changes in microstate parameters were not associated with similar changes in flanker ERPs or behavior. Finally, modafinil made transitions between microstates A and B less likely and transitions from A and B to C more likely. CONCLUSIONS: Previous fMRI work has correlated microstates A and B with auditory and visual networks and microstate C with a salience network. Thus, our results suggest modafinil may deactivate large-scale sensory networks in favor of a higher order functional network during resting-state in healthy adults.

Error-related Alpha Suppression: Scalp Topography and (Lack of) Modulation by Modafinil.

Errors in performance trigger cognitive and neural changes that are implemented to adaptively adjust to fluctuating demands. Error-related alpha suppression (ERAS)-which refers to decreased power in the alpha frequency band after an incorrect response-is thought to reflect cognitive arousal after errors. Much of this work has been correlational, however, and there are no direct investigations into its pharmacological sensitivity. In Study 1 (n = 61), we evaluated the presence and scalp distribution of ERAS in a novel flanker task specifically developed for cross-species assessments. Using this same task in Study 2 (n = 26), which had a placebo-controlled within-subject design, we evaluated the sensitivity of ERAS to placebo (0 mg), low (100 mg), and high (200 mg) doses of modafinil, a wakefulness promoting agent. Consistent with previous work, ERAS was maximal at parieto-occipital recording sites in both studies. In Study 2, modafinil did not have strong effects on ERAS (a significant Accuracy × Dose interaction emerged, but drug-placebo differences did not reach statistical significance after correction for multiple comparisons and was absent after controlling for accuracy rate). ERAS was correlated with accuracy rates in both studies. Thus, modafinil did not impact ERAS as hypothesized, and findings indicate ERAS may reflect an orienting response to infrequent events.

Concurrent electrophysiological recording and cognitive testing in a rodent touchscreen environment.

Challenges in therapeutics development for neuropsychiatric disorders can be attributed, in part, to a paucity of translational models capable of capturing relevant phenotypes across clinical populations and laboratory animals. Touch-sensitive procedures are increasingly used to develop innovative animal models that better align with testing conditions used in human participants. In addition, advances in electrophysiological techniques have identified neurophysiological signatures associated with characteristics of neuropsychiatric illness. The present studies integrated these methodologies by developing a rat flanker task with electrophysiological recordings based on reverse-translated protocols used in human electroencephalogram (EEG) studies of cognitive control. Various touchscreen-based stimuli were evaluated for their ability to efficiently gain stimulus control and advance to flanker test sessions. Optimized stimuli were then examined for their elicitation of prototypical visual evoked potentials (VEPs) across local field potential (LFP) wires and EEG skull screws. Of the stimuli evaluated, purple and green photographic stimuli were associated with efficient training and expected flanker interference effects. Orderly stimulus-locked outcomes were also observed in VEPs across LFP and EEG recordings. These studies along with others verify the feasibility of concurrent electrophysiological recordings and rodent touchscreen-based cognitive testing and encourage future use of this integrated approach in therapeutics development.

Concordant neurophysiological signatures of cognitive control in humans and rats.

Progress towards understanding neural mechanisms in humans relevant to psychiatric conditions has been hindered by a lack of translationally-relevant cognitive tasks for laboratory animals. Accordingly, there is a critical need to develop parallel neurophysiological assessments of domains of cognition, such as cognitive control, in humans and laboratory animals. To address this, we developed a touchscreen-based cognitive (Eriksen Flanker) task in rats and used its key characteristics to construct a novel human version, with similar testing parameters and endpoints across species. We obtained continuous electroencephalogram (EEG) recordings, including local field potentials in rats, and compared electrophysiological signatures locked to stimulus onset and responses across species. We also assessed whether behavioral or physiological task effects were modulated by modafinil, which enhances aspects of cognitive function in humans. In both species, the task elicited expected flanker interference effects (reduced accuracy) during high-conflict trials. Across homologous neuroanatomical loci, stimulus-locked increases in theta power during high-conflict trials as well as error-related negative potentials were observed. These endpoints were not affected by modafinil in either species. Despite some species-specific patterns, our findings demonstrate the feasibility of a rat Flanker task as well as cross-species behavioral and neurophysiological similarities, which may enable novel insights into the neural correlates of healthy and aberrant behavior and provide mechanistic insights relevant to treatment.