Affective Processing Bias Research Articles

Association of Lithium and Second-Generation Antipsychotics with Neurocognition in Youth with Bipolar Disorder.

Objective: Numerous studies have examined the association of antimanic medications with neurocognition in adults with bipolar disorder (BD). However, few studies have examined this topic in youth. Thus, we aimed to examine the association of lithium and second-generation antipsychotics (SGAs), the first-line antimanic medications for youth with BD, with neurocognition in a relatively large sample of youth with BD.Methods: Participants included 91 youth with BD-I, -II, or -Not Otherwise Specified, aged 13–20 years (n = 14 current lithium use, n = 51 current SGA use). We examined four tests from the Cambridge Neuropsychological Test Automated Battery: Intra/Extra Dimensional Set-Shifting Task (IED), Rapid Visual Information Processing Task (RVP), Stockings of Cambridge Test (SOC), and Affective Go/No-Go (AGN). Within-sample Z-scores were computed, and a global neurocognitive composite score and g factor derived from these tests comprised the primary outcomes. Multivariable analyses controlled for age, sex, and IQ.Results: Current lithium use was significantly associated with poorer cognitive flexibility/set-shifting (IED). After further controlling for lifetime comorbid attention-deficit/hyperactivity disorder and current depression symptoms in sensitivity analyses, the lithium finding was no longer significant. Current SGA use was significantly associated with greater affective processing bias (AGN). No significant findings survived correction for multiple comparisons. All other cognitive outcomes were not significantly associated with current lithium use, current SGA use, or total number of current medications.Conclusions: Treatment with lithium or SGAs was associated with minimal neurocognitive impairments, with small effect sizes in primary multivariable analyses. This study adds to the limited body of literature examining medication use in relation to neurocognition in youth with BD. While the current study cannot rule out associations of smaller effect size, present findings suggest that leading mood-stabilizing medications are not associated with frank neurocognitive impairments in youth with BD.

Negative bias effects during audiovisual emotional processing in major depression disorder.

Aberrant affective neural processing and negative emotional bias are trait‐marks of major depression disorders (MDDs). However, most research on biased emotional perception in depression has only focused on unimodal experimental stimuli, the neural basis of potentially biased emotional processing of multimodal inputs remains unclear. Here, we addressed this issue by implementing an audiovisual emotional task during functional MRI scanning sessions with 37 patients with MDD and 37 gender‐, age‐ and education‐matched healthy controls. Participants were asked to distinguish laughing and crying sounds while being exposed to faces with different emotional valences as background. We combined general linear model and psychophysiological interaction analyses to identify abnormal local functional activity and integrative processes during audiovisual emotional processing in MDD patients. At the local neural level, MDD patients showed increased bias activity in the ventromedial prefrontal cortex (vmPFC) while listening to negative auditory stimuli and concurrently processing visual facial expressions, along with decreased dorsolateral prefrontal cortex (dlPFC) activity in both the positive and negative visual facial conditions. At the network level, MDD exhibited significantly decreased connectivity in areas involved in automatic emotional processes and voluntary control systems during perception of negative stimuli, including the vmPFC, dlPFC, insula, as well as the subcortical regions of posterior cingulate cortex and striatum. These findings support a multimodal emotion dysregulation hypothesis for MDD by demonstrating that negative bias effects may be facilitated by the excessive ventral bottom‐up negative emotional influences along with incapability in dorsal prefrontal top‐down control system.

Affective Processing Biases in Relation to Past, Current, and Future Depression in Children and Adolescents

BackgroundThe affective go/no-go (AGN) task has been used to assess affective biases in attention set-shifting and deficits in inhibitory control of emotional information among depressed youth, but results have been inconsistent. We aimed to test AGN robustness and clarify temporal relationships between depressive symptoms and affective processing in youth. MethodsWe evaluated AGN performance twice (Time 1 N = 306; Time 2 N = 238) in relation to current, previous, and future depression in the same children/adolescents with depression and those without diagnoses who participated in the Longitudinal Assessment of Manic Symptoms (LAMS) study. Mixed repeated ANCOVAs were powered to detect small-medium group by valence interactions in response latency and errors. Supplemental regression analyses examined depressive symptoms as a continuous variable in relation to AGN performance. ResultsNo clear pattern emerged, mirroring the broader AGN literature. In primary analyses, group by valence interactions were only observed at one AGN administration; none replicated across administrations. Similarly, in regression analyses depressive symptoms had no relation to affective processing biases/deficits at AGN Time 1, though some relationships were detected between symptoms and AGN Time 2. LimitationsRelatively few youth met criteria for a depressive disorder, though analyses were appropriately powered and supplemental analyses examined depressive symptoms continuously. Comparison groups were not healthy controls at recruitment but were free from any Axis I disorder at AGN administration. ConclusionsGiven the inconsistency of AGN findings, attention should be focused on tasks that provide more sensitive, robust measures of emotional information processing in depressed youth.

Counter-regulation in affective attentional biases: Evidence in the additional singleton paradigm.

We investigated motivational influences on affective processing biases; specifically, we were interested in whether anticipating positive versus negative future outcomes during goal pursuit affects attentional biases toward positive or negative stimuli. Attentional valence biases were assessed with the additional singleton task, with the task-irrelevant singleton colors being positive, negative or neutral. The motivational relevance of colors was established in a preceding task: In a balanced design, one color acquired positive valence by indicating the chance to win money, and a different color acquired negative valence by indicating the danger to lose money. Blocks of the additional singleton task were associated with either the chance of winning money (positive outcome focus) or the danger of losing money (negative outcome focus). We found an interaction of outcome focus and singleton valence in the accuracy rates, indicating an incongruency effect: Attentional capture was stronger for positive (negative) singletons in the negative (positive) outcome focus conditions. This result further corroborates the counter-regulation hypothesis, extending previous findings on the motivational top-down regulation of affective processing to the domain of early attentional processes.

Decision mechanisms underlying mood-congruent emotional classification

ABSTRACT There is great interest in understanding whether and how mood influences affective processing. Results in the literature have been mixed: some studies show mood-congruent processing but others do not. One limitation of previous work is that decision components for affective processing and responses biases are not dissociated. The present study explored the roles of affective processing and response biases using a drift-diffusion model (DDM) of simple choice. In two experiments, participants decided if words were emotionally positive or negative while listening to music that induced positive or negative mood. The behavioural results showed weak, inconsistent mood-congruency effects. In contrast, the DDM showed consistent effects that were selectively driven by an a-priori bias in response expectation, suggesting that music-induced mood influences expectations about the emotionality of upcoming stimuli, but not the emotionality of the stimuli themselves. Implications for future studies of emotional classification and mood are subsequently discussed.

Cognitive-Affective Verbal Learning Test: An integrated measure of affective and neutral words.

Despite growing affective-memory research, only 2 potential clinical measures have been published, each with limitations. We describe the development and piloting of an integrated memory measure for neutral and affectively valenced words, the Cognitive-Affective Verbal Learning Test (C-AVLT). The C-AVLT and mood self-report measures were administered to 124 healthy university students in Study 1, with readministration to 40 students after 1 week. In Study 2, the C-AVLT and other neuropsychological measures of memory and emotion were administered to 61 patients referred for polysomnogram evaluation of obstructive sleep apnea (OSA). Study 1 supported the C-AVLT's internal and test-retest reliabilities, as well as concurrent validity, that is, the affective-bias scores but not performance scores correlated with self-reported mood. In Study 2, convergent, criterion (specifically cross-sectional concurrent validity), and incremental validity were supported with regard to both performance and affective-bias scores within the OSA sample. We demonstrated the C-AVLT is a reliable and clinically useful measure of both memory and affective-processing bias in 2 samples. Future clinical and research recommendations for the C-AVLT are discussed, including broadening normative data and criterion validity data in psychiatric and neurological samples. (PsycINFO Database Record

The role of white matter in personality traits and affective processing in bipolar disorder

BackgroundBipolar disorder (BD) is characterized by affective processing bias and variations in personality traits. It is still unknown whether these features are linked to the same structural brain alterations. The aim of this study was to investigate relationships between specific personality traits, white matter (WM) properties, and affective processing in BD and HC. Methods24 healthy controls (HC) and 38 adults with BDI (HC: 29.47 ± 2.23 years, 15 females; BDI: 32.44 ± 1.84 years, 20 females) completed clinical scales and the Big Five Inventory. They were also administered the Affective Go/No-Go (AGN) and the Rapid Visual Processing (RVP) tasks of the Cambridge Neuropsychological Test Automated Battery. Diffusion Tensor Imaging (DTI) assessed the microstructure of WM tracts. ResultsIn BDI measures of WM properties were reduced across all major brain white matter tracts. As expected, individuals with BDI reported greater neuroticism, lower agreeableness and conscientiousness, and made a greater number of errors in response to affective stimuli in the AGN task compared to HC. High neuroticism scores were associated with faster AGN latency, and overall reduced AGN accuracy in both HC and BDI. Elevated FA values were associated with reduced neuroticism and increased cognitive processing in HC but not in BDI. ConclusionsOur findings showed important potential links between personality, affective processing and WM integrity in BD. In the future therapeutic interventions for BD using brain stimulation protocols might benefit from the use of DTI to target pathways underlying abnormal affective processing.

Moral fixations: The role of moral integrity and social anxiety in the selective avoidance of social threat

People derive their sense of belonging from perceptions of being a moral person. Research moreover suggests that social cues of rejection rapidly influence visual scanning, and result in avoidant gaze behavior, especially in socially anxious individuals. With the current eye-tracking experiment, we therefore examined whether moral integrity threats and affirmations influence selective avoidance of social threat, and how this varies with individual differences in social anxiety. Fifty-nine participants retrieved a memory of a past immoral, moral, or neutral act. Next, participants passively viewed angry, happy, and neutral faces, while we recorded how often they first fixated on the eyes. In addition, we administered the Liebowitz Social Anxiety Scale (1987). Participants first fixated less on angry eyes compared to happy or neutral eyes when their moral integrity was threatened, and this selective avoidance was enhanced with increasing social anxiety. Following a moral affirmation, however, participants no longer selectively avoided the eyes of angry faces, regardless of individual differences in social anxiety. The results thus suggest that both low and high socially anxious people adjust their social gaze behavior in response to threats and affirmations of their moral integrity, pointing to the importance of the social context when considering affective processing biases.

Fusiform Gyrus Dysfunction is Associated with Perceptual Processing Efficiency to Emotional Faces in Adolescent Depression: A Model-Based Approach.

While the extant literature has focused on major depressive disorder (MDD) as being characterized by abnormalities in processing affective stimuli (e.g., facial expressions), little is known regarding which specific aspects of cognition influence the evaluation of affective stimuli, and what are the underlying neural correlates. To investigate these issues, we assessed 26 adolescents diagnosed with MDD and 37 well-matched healthy controls (HCL) who completed an emotion identification task of dynamically morphing faces during functional magnetic resonance imaging (fMRI). We analyzed the behavioral data using a sequential sampling model of response time (RT) commonly used to elucidate aspects of cognition in binary perceptual decision making tasks: the Linear Ballistic Accumulator (LBA) model. Using a hierarchical Bayesian estimation method, we obtained group-level and individual-level estimates of LBA parameters on the facial emotion identification task. While the MDD and HCL groups did not differ in mean RT, accuracy, or group-level estimates of perceptual processing efficiency (i.e., drift rate parameter of the LBA), the MDD group showed significantly reduced responses in left fusiform gyrus compared to the HCL group during the facial emotion identification task. Furthermore, within the MDD group, fMRI signal in the left fusiform gyrus during affective face processing was significantly associated with greater individual-level estimates of perceptual processing efficiency. Our results therefore suggest that affective processing biases in adolescents with MDD are characterized by greater perceptual processing efficiency of affective visual information in sensory brain regions responsible for the early processing of visual information. The theoretical, methodological, and clinical implications of our results are discussed.

The Utility of Impulsive Bias and Altered Decision Making as Predictors of Drug Efficacy and Target Selection: Rethinking Behavioral Screening for Antidepressant Drugs.

Cognitive dysfunction may be a core feature of major depressive disorder, including affective processing bias, abnormal response to negative feedback, changes in decision making, and increased impulsivity. Accordingly, a translational medicine paradigm predicts clinical action of novel antidepressants by examining drug-induced changes in affective processing bias. With some exceptions, these concepts have not been systematically applied to preclinical models to test new chemical entities. The purpose of this review is to examine whether an empirically derived behavioral screen for antidepressant drugs may screen for compounds, at least in part, by modulating an impulsive biasing of responding and altered decision making. The differential-reinforcement-of-low-rate (DRL) 72-second schedule is an operant schedule with a documented fidelity for discriminating antidepressant drugs from nonantidepressant drugs. However, a theoretical basis for this empirical relationship has been lacking. Therefore, this review will discuss whether response bias toward impulsive behavior may be a critical screening characteristic of DRL behavior requiring long inter-response times to obtain rewards. This review will compare and contrast DRL behavior with the five-choice serial reaction time task, a test specifically designed for assessing motoric impulsivity, with respect to psychopharmacological testing and the neural basis of distributed macrocircuits underlying these tasks. This comparison suggests that the existing empirical basis for the DRL 72-second schedule as a pharmacological screen for antidepressant drugs is complemented by a novel hypothesis that altering impulsive response bias for rodents trained on this operant schedule is a previously unrecognized theoretical cornerstone for this screening paradigm.

Predisposition to depression and implicit emotion processing

Depression, one of the most widespread mental disorders, is associated with considerable alterations in emotional functioning. It is unclear whether these alterations are associated with clinical depression or exist already at preclinical stages. Here, in clinically healthy individuals, a combination of neuroticism and introversion was used as a predisposition to depression (PD) scale. Participants were presented with pictures of emotional facial expressions and performed the gender discrimination task, while their electroencephalogram (EEG) was recorded. The affective processing bias (i.e., longer reaction time and higher error rate for angry faces) was found in low, but not in high PD scorers. High PD scorers also showed reduced theta synchronization and enhanced alpha desynchronization in the test interval and higher delta and theta power in the interstimuli interval. The latter effect implies that activity of emotional circuits, which is mirrored in low-frequency oscillations, is tonically increased in predisposed-to-depression individuals, thus precluding an adequate response to external emotional cues. This results in unspecific general activation reflected in enhanced alpha desynchronization and in disrupted ability to differentiate incoming emotional information.

Affective processing bias in youth with primary bipolar disorder or primary attention-deficit/hyperactivity disorder.

High rates of comorbidity and overlapping diagnostic criteria between pediatric bipolar disorder (BD) and attention-deficit/hyperactivity disorder (ADHD) contribute to diagnostic and treatment confusion. To advance what is known about both disorders, we compared effect of emotional stimuli on response control in children with primary BD, primary ADHD and typically developing controls (TDC). Participants included 7-17 year olds with either "narrow-phenotype" pediatric BD (n = 25), ADHD (n = 25) or TDC (n = 25). Groups were matched on participant age and FSIQ. The effect of emotional stimuli on response control was assessed using the Cambridge Neuropsychological Test Automated Battery Affective Go/No-Go task (CANTAB AGN). We found a group by target valence interaction on commission errors [F(2,71) = 5.34, p < 0.01, ƞ p (2) = 0.13] whereby ADHD, but not TDC participants, made more errors on negative than positive words [t(24) = -2.58, p < 0.05, r = 0.47]. In contrast, there was a nonsignificant trend for BD participants to make fewer errors on negative versus positive words compared to ADHD and TDC participants. Between-subjects effects showed that ADHD participants made more errors than TDC, but not BD participants. Our main finding advances what is known about the effect of emotional stimuli on response control in children with ADHD. Our results suggesting a positive affective processing bias in children with ADHD compliment emerging literature show that difficulties with emotional processing and regulation may be core features of ADHD. Further, given the observed pattern of results in children with ADHD compared to BD children, our behavioral results suggest the importance of examining differences in the brain-behavior mechanisms involved in affective processing in children with ADHD compared to BD children.

Processing of ambiguous emotional messages in brain injured patients with and without subcortical lesions

Background: Emotional information in communicative messages is conveyed through a combination of linguistic and paralinguistic cues. Listeners must simultaneously process affective prosody, facial expressions, body gestures, and semantic information in order to determine the speaker's emotional intent. Findings from recent research support the involvement of subcortical structures in unimodal emotion recognition; however, given the propensity for emotional information to be conveyed across multiple modalities simultaneously, clinical advances require an understanding of how subcortical and cortical structures are involved in the recognition of multi-modal stimuli. Aims: To determine if individuals with and without a history of brain damage demonstrate affective processing biases on ambiguous and congruous multi-modal emotive stimuli.1 Methods & Procedures: Twenty individuals with brain damage and five individuals without a history of brain injury (NC) were included in the study. Participants with brain damage were grouped by depth and location of lesion site (left cortical [LC], right cortical [RC], left subcortical-cortical [LS], and right subcortical-cortical [RS]) to determine the effects of damage location on emotion processing. Participants identified emotions from stimuli containing incongruent affective information across two tasks using combinations of verbal, prosodic, and visual (i.e. facial expression) information. In Task 1, affectively charged sentences were presented with conflicting paralinguistic information (speech prosody, facial expression, and a combined modality condition). Task 2 involved the presentation of conflicting facial expression and prosodic information in linguistically neutral sentences. Response preferences for specific modalities were examined to understand potential processing biases. Outcomes & Results: The NC and LC groups demonstrated a bias for selecting emotions displayed by paralinguistic information in all Task 1 conditions. The RC group exhibited a similar preference when facial expression was included in the stimulus, but a decreased bias for selecting paralinguistic information when speech prosody was presented alone. In contrast to the NC and cortical damage groups, the RS group consistently selected emotions based on linguistic cues. The LS group exhibited the greatest inter-subject variability. Group patterns suggested no clear preference for either linguistic or paralinguistic information when speech prosody was included in the stimulus. In the task involving conflicting facial expression and linguistic information, the LS group exhibited a bias for facial expression information. All groups demonstrated a preference for facial expression information over speech prosody; however, the RS group's preference was significantly weaker. Conclusions: The data suggest that combined cortical and subcortical damage disrupts typical processing strategies for emotion recognition.

Motivation and affective processing biases in risky decision making: A counter-regulation account

We hypothesized that framing possible outcomes of decisions in terms of gains vs. losses should increase the salience of information that is incongruent in valence (counter-regulation principle: gain frame – negativity bias, loss frame – positivity bias). These incongruent attentional biases in the processing of positive and negative outcomes of risky options can explain why people tend to avoid risky options in a gain frame but tend to choose risky options in a loss frame. In line with our expectations, Experiment 1 revealed incongruent effects of framing on attentional biases for positive vs. negative stimuli in an evaluation task. In addition, valence bias predicted risk-seeking vs. risk-averse decisions and mediated the effect of framing on decision making. Two additional experiments investigated effects of valence biases on risky decision making by manipulating affective processing directly with an attention training task. Inducing a positivity (negativity) bias produced risk-seeking (risk-averse) decision behavior by enhancing the salience of win- or loss-related information in a gambling task with ambivalent color stimuli (Experiment 2) and by enhancing the impact of gain or loss outcomes on decision making in a coin toss (Experiment 3).

Never-depressed females with a family history of depression demonstrate affective bias

According to cognitive theories of depression, individuals susceptible to depression attend selectively to negative information. The purpose of the study was to examine if such an affective processing bias is present in never-depressed individuals with a family history of major depressive disorder (MDD). Formerly depressed female patients having at least one first-degree relative with a history of MDD (n=23), their never-depressed female siblings (n=21) and never-depressed female controls (n=21) performed a conventional and an emotional Stroop task using negative, positive and neutral words. A significant effect was found of group on negative processing bias; post hoc comparisons indicated that never-depressed siblings showed a larger negative processing bias than never-depressed controls. No significant differences were observed in positive bias or conventional interference between the three groups. Our findings suggest that never-depressed females with a family history of depression, like depressed patients, have more difficulties to inhibit negative material and to direct their attention towards task-specific material. This adds to the existing evidence that affective processing bias is a trait characteristic that contributes to the onset of depression and that could be a useful endophenotype for MDD.

Emotional bias in unaffected siblings of patients with bipolar I disorder.

Bipolar disorder (BPD) research has identified a number of neurocognitive deficits as potential vulnerability markers; however, very few studies have focused on patterns of performance on affective processing tasks (e.g. affective Go/No-Go tasks) which may be more closely tied to the pathophysiology of the illness. We previously reported that stable BPD patients demonstrate a response bias toward negative affective stimuli as compared with healthy controls and schizophrenia patients. The goal of the current study was to expand upon these prior findings to investigate these patterns in the unaffected siblings of BPD patients. An affective Go/No-Go test was used to evaluate inhibitory response to negatively-valenced, positively-valenced, and neutral stimuli in 20 unaffected siblings of bipolar I patients versus 20 healthy controls. Accuracy (d') and response bias (beta) served as dependent variables in a series of repeated measures ANCOVAs. We found a non-significant main effect for group when comparing accuracy performance (d') on the affective Go/No-Go of unaffected siblings versus healthy controls. However, very similar to the pattern that we previously reported in stable BPD patients, unaffected siblings showed a response bias (beta) toward negatively-valenced stimuli versus healthy controls [F=3.81; p=0.03]. Small sample size. The current results extend our recent work which suggested that stable bipolar patients attend more readily to negative target stimuli than do schizophrenic or healthy subjects. These data, indicating that unaffected siblings also demonstrate an affective processing bias, implicate this task as a potential endophenotype in BPD.

Incongruency effects in affective processing: Automatic motivational counter-regulation or mismatch-induced salience?

Attention is automatically allocated to stimuli that are opposite in valence to the current motivational focus (Rothermund, 2003; Rothermund, Voss, & Wentura, 2008). We tested whether this incongruency effect is due to affective–motivational counter-regulation or to an increased salience of stimuli that mismatch with cognitively activated information. Affective processing biases were assessed with a search task in which participants had to detect the spatial position at which a positive or negative stimulus was presented. In the motivational condition, positive or negative affective–motivational states were induced by performance feedback after each trial. In the cognitive activation condition, participants memorised the word “good” or “bad” during the search task. The affective incongruency effect was replicated in the motivational condition, whereas an affective congruency effect obtained in the cognitive activation condition. These findings support an explanation of affective incongruency effects in terms of automatic counter-regulation that is motivational in nature.

Time course of affective processing bias in major depression: An ERP study

The current study investigated the time course of the affective processing bias in major depressive disorder (MDD) in a visual three-stimulus semantic oddball task using event-related potentials (ERPs). MDD patients showed decreased P1 latency over right posterior regions to negative relative to positive target stimuli, reflecting a very early onset of the negativity bias in emotional perception. Compared to controls, MDD patients showed enlarged anterior P2 amplitude to positive target stimuli, reflecting an affective bias in the early attentional stages of processing. In addition, MDD patients showed relatively high N2 and reduced P3 amplitudes to negative compared with positive target stimuli, as well as marginally reduced N2 amplitude to positive target stimuli compared with controls. This suggests that the negativity bias also occurs during later strategic evaluation stages. Therefore, the present study extended previous findings by demonstrating that the affective processing bias in MDD begins in the early stages of perceptual processing and continues at later cognitive stages.

Altered representation of expected value in the orbitofrontal cortex in mania

Increased responsiveness to appetitive and reduced responsiveness to aversive anticipatory cues may be associated with dysfunction of the brain reward system in mania. Here we studied neural correlates of gain and loss expectation in mania using functional magnetic resonance imaging (fMRI). Fifteen manic patients and 26 matched healthy control individuals performed a monetary incentive delay task, during which subjects anticipated to win or lose a varying amount of money. Varying both magnitude and valence (win, loss) of anticipatory cues allowed us to isolate the effects of magnitude, valence and expected value (magnitude-by-valence interaction). Response times and total gain amount did not differ significantly between groups. FMRI data indicated that the ventral striatum responded according to cued incentive magnitude in both groups, and this effect did not significantly differ between groups. However, a significant group difference was observed for expected value representation in the left lateral orbitofrontal cortex (OFC; BA 11 and 47). In this region, patients showed increasing BOLD responses during expectation of increasing gain and decreasing responses during expectation of increasing loss, while healthy subjects tended to show the inverse effect. In seven patients retested after remission OFC responses adapted to the response pattern of healthy controls. The observed alterations are consistent with a state-related affective processing bias during the expectation of gains and losses which may contribute to clinical features of mania, such as the enhanced motivation for seeking rewards and the underestimation of risks and potential punishments.

The neuropsychology of mood disorders

Cognitive dysfunction is central to our understanding of mood disorders in terms of patient experiences, Diagnostic and Statistical Manual of Mental Disorders criteria, and psychological models. In this article, we highlight key findings from studies that have used neuropsychological tests and functional neuroimaging techniques to explore cognitive dysfunction in patients with depression and mania. In particular, we focus on affective processing bias, abnormal response to negative feedback, and decision making. Results are discussed in the context of current conceptualizations of dysfunctional neural circuitry, and in relation to important clinical research implications.