James R. Blair

Social reasoning, emotion and empathy in frontotemporal dementia

INTRODUCTION Social cognition is crucial for human interaction, and is markedly impaired in the frontal variant of frontotemporal dementia (fvFTD). The relationship of various aspects of social functioning, however, remains controversial in this group. METHODS Patients with fvFTD (n = 18), and matched controls (n = 13), were tested using tasks designed to assess their Theory of Mind (ToM), moral reasoning, emotion recognition and executive function. Caregivers documented changes in empathy compared to premorbid functioning. RESULTS We found marked impairments in the abilities of fvFTD patients, relative to controls, in ability to mentalise (ToM), which was evident on a cartoon test, but not on a story-based ToM task. Knowledge of social rules was intact, but moral reasoning was defective, and was due, in part, to an inability to rate the seriousness of moral and conventional transgressions appropriately. Executive function was impaired in this group, and compromised aspects of moral reasoning, but ToM performance was independent of this. Emotion recognition was globally impaired in fvFTD, but was particularly so for anger and disgust which may partly explain the difficulty these patients have with identifying social violations. Empathy, as rated by carers, was also shown to be abnormal. CONCLUSION It appears that social reasoning is disrupted in a number of ways in fvFTD, and the findings provide a basis for the understanding and further study of abnormal behaviour in this disease. The results are discussed in light of neuroimaging findings in studies of social cognition and the locus of pathology in fvFTD.

Abnormal ventromedial prefrontal cortex function in children with psychopathic traits during reversal learning.

CONTEXT Children and adults with psychopathic traits and conduct or oppositional defiant disorder demonstrate poor decision making and are impaired in reversal learning. However, the neural basis of this impairment has not previously been investigated. Furthermore, despite high comorbidity of psychopathic traits and attention-deficit/hyperactivity disorder, to our knowledge, no research has attempted to distinguish neural correlates of childhood psychopathic traits and attention-deficit/hyperactivity disorder. OBJECTIVE To determine the neural regions that underlie the reversal learning impairments in children with psychopathic traits plus conduct or oppositional defiant disorder. DESIGN Case-control study. SETTING Government clinical research institute. PARTICIPANTS Forty-two adolescents aged 10 to 17 years: 14 with psychopathic traits and oppositional defiant disorder or conduct disorder, 14 with attention-deficit/hyperactivity disorder only, and 14 healthy controls. MAIN OUTCOME MEASURE Blood oxygenation level-dependent signal as measured via functional magnetic resonance imaging during a probabilistic reversal task. RESULTS Children with psychopathic traits showed abnormal responses within the ventromedial prefrontal cortex (Brodmann area 10) during punished reversal errors compared with children with attention-deficit/hyperactivity disorder and healthy children (P < .05 corrected for multiple comparisons). CONCLUSIONS To our knowledge, this study provides the first evidence of abnormal ventromedial prefrontal cortex responsiveness in children with psychopathic traits and demonstrates this dysfunction was not attributable to comorbid attention-deficit/hyperactivity disorder. These findings suggest that reversal learning impairments in patients with developmental psychopathic traits relate to abnormal processing of reinforcement information.

Choosing the Lesser of Two Evils, the Better of Two Goods: Specifying the Roles of Ventromedial Prefrontal Cortex and Dorsal Anterior Cingulate in Object Choice

The ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortices (ACd) are considered important for reward-based decision making. However, work distinguishing their individual functional contributions has only begun. One aspect of decision making that has received little attention is that making the right choice often translates to making the better choice. Thus, response choice often occurs in situations where both options are desirable (e.g., choosing between mousse au chocolat or crème caramel cheesecake from a menu) or, alternatively, in situations where both options are undesirable. Moreover, response choice is easier when the reinforcements associated with the objects are far apart, rather than close together, in value. We used functional magnetic resonance imaging to delineate the functional roles of the vmPFC and ACd by investigating these two aspects of decision making: (1) decision form (i.e., choosing between two objects to gain the greater reward or the lesser punishment), and (2) between-object reinforcement distance (i.e., the difference in reinforcements associated with the two objects). Blood oxygen level-dependent (BOLD) responses within the ACd and vmPFC were both related to decision form but differentially. Whereas ACd showed greater responses when deciding between objects to gain the lesser punishment, vmPFC showed greater responses when deciding between objects to gain the greater reward. Moreover, vmPFC was sensitive to reinforcement expectations associated with both the chosen and the forgone choice. In contrast, BOLD responses within ACd, but not vmPFC, related to between-object reinforcement distance, increasing as the distance between the reinforcements of the two objects decreased. These data are interpreted with reference to models of ACd and vmPFC functioning.

Reduced dorsal anterior cingulate cortical activity during emotional regulation and top-down attentional control in generalized social phobia, generalized anxiety disorder, and comorbid generalized social phobia/generalized anxiety disorder

BACKGROUND Generalized social phobia (GSP) and generalized anxiety disorder (GAD) are both associated with emotion dysregulation. Research implicates dorsal anterior cingulate cortex in both explicit emotion regulation (EER) and top-down attentional control (TAC). Although studies have examined these processes in GSP or GAD, no work compares findings across the two disorders or examines functioning in cases comorbid for both disorders (GSP/GAD). Here we compare the neural correlates of EER and TAC in GSP, GAD, and GSP/GAD. METHODS Medication-free adults with GSP (EER n = 19; TAC n = 18), GAD (EER n = 17; TAC n = 17), GSP/GAD (EER n = 17; TAC n = 15), and no psychopathology (EER n = 18; TAC n = 18) participated. During EER, individuals alternatively viewed and upregulated and downregulated responses to emotional pictures. During TAC, they performed an emotional Stroop task. RESULTS For both tasks, significant group × condition interactions emerged in dorsal anterior cingulate cortex and parietal cortices. Healthy adults showed significantly increased recruitment during emotion regulation, relative to emotion-picture viewing. GAD, GSP, and GSP/GAD subjects showed no such increases, with all groups differing from healthy adults but not from each other. Evidence of emotion-related disorder-specificity emerged in medial prefrontal cortex and amygdala. This disorder-specific responding varied as a function of emotion content but not emotion-regulatory demands. CONCLUSIONS GSP and GAD both involve reduced capacity for engaging emotion-regulation brain networks, whether explicitly or via TAC. A reduced ability to recruit regions implicated in top-down attention might represent a general risk factor for anxiety disorders.

Risk for Bipolar Disorder is Associated with Face-Processing Deficits across Emotions.

OBJECTIVE Youths with euthymic bipolar disorder (BD) have a deficit in face-emotion labeling that is present across multiple emotions. Recent research indicates that youths at familial risk for BD, but without a history of mood disorder, also have a deficit in face-emotion labeling, suggesting that such impairments may be an endophenotype for BD. It is unclear whether this deficit in at-risk youths is present across all emotions or if the impairment presents initially as an emotion-specific dysfunction that then generalizes to other emotions as the symptoms of BD become manifest. METHOD Thirty-seven patients with pediatric BD, 25 unaffected children with a first-degree relative with BD, and 36 typically developing youths were administered the Emotional Expression Multimorph Task, a computerized behavioral task, which presents gradations of facial emotions from 100% neutrality to 100% emotional expression (happiness, surprise, fear, sadness, anger, and disgust). RESULTS Repeated-measures analysis of covariance revealed that, compared with the control youths, the patients and the at-risk youths required significantly more intense emotional information to identify and correctly label face emotions. The patients with BD and the at-risk youths did not differ from each other. Group-by-emotion interactions were not significant, indicating that the group effects did not differ based on the facial emotion. CONCLUSIONS The youths at risk for BD demonstrate nonspecific deficits in face-emotion recognition, similar to patients with the illness. Further research is needed to determine whether such deficits meet all the criteria for an endophenotype.

Caught in the act: The impact of audience on the neural response to morally and socially inappropriate behavior

We examined the impact of witnesses on the neural response to moral and social transgressions using fMRI. In this study, participants (N=16) read short vignettes describing moral and social transgressions in the presence or absence of an audience. In line with our hypothesis, ventrolateral (BA 47) and dorsomedial (BA 8) frontal cortex showed increased BOLD responses to moral transgressions regardless of audience and to social transgressions in the presence of an audience relative to neutral situations. These findings are consistent with the suggestion that these regions of prefrontal cortex modify behavioral responses in response to social cues. Greater activity was observed in left temporal-parietal junction, medial prefrontal cortex and temporal poles to moral and to a lesser extent social transgressions relative to neutral stories, regardless of audience. These regions have been implicated in the representation of the mental states of others (Theory of Mind). The presence of an audience was associated with increased left amygdala activity across all conditions.

The Impact of Tryptophan Depletion and 5-HTTLPR Genotype on Passive Avoidance and Response Reversal Instrumental Learning Tasks

Transient reductions in serotonin levels during tryptophan depletion (TD) are thought to impair reward processing in healthy volunteers, while another facet of the serotonergic system, the serotonin transporter (5-HTTLPR) short allele polymorphism, is implicated in augmented processing of aversive stimuli. We examined the impact and interactions of TD and the serotonin promoter polymorphism genotype on reward and punishment via two forms of instrumental learning: passive avoidance and response reversal. In this study, healthy volunteers (n=35) underwent rapid TD or control procedures and genotyping (n=26) of the 5-HTTLPR for long and short allele variants. In the passive avoidance task, tryptophan-depleted volunteers failed to respond sufficiently to rewarded stimuli compared to the control group. Additionally, long allele homozygous individuals (n=11) were slower to learn to avoid punished stimuli compared to short allele carriers (n=15). TD alone did not produce measurable deficits in probabilistic response reversal errors. However, a significant drug group by genotype interaction was found indicating that in comparison to short allele carriers, tryptophan-depleted individuals homozygous for the long allele failed to appropriately use punishment information to guide responding. These findings extend prior reports of impaired reward processing in TD to include instrumental learning. Furthermore, they demonstrate behavioral differences in responses to punishing stimuli between long allele homozygotes and short allele carriers when serotonin levels are acutely reduced.

Impaired probabilistic reversal learning in youths with mood and anxiety disorders

BACKGROUND From an affective neuroscience perspective, our understanding of psychiatric illness may be advanced by neuropsychological test paradigms probing emotional processes. Reversal learning is one such process, whereby subjects must first acquire stimulus/reward and stimulus/punishment associations through trial and error and then reverse them. We sought to determine the specificity of previously demonstrated reversal learning impairments in youths with bipolar disorder (BD) by now comparing BD youths to those with severe mood dysregulation (SMD), major depressive disorder (MDD), anxiety (ANX), and healthy controls. METHOD We administered the probabilistic response reversal (PRR) task to 165 pediatric participants aged 7-17 years with BD (n=35), SMD (n=35), ANX (n=42), MDD (n=18) and normal controls (NC; n=35). Our primary analysis compared PRR performance across all five groups matched for age, sex and IQ. RESULTS Compared to typically developing controls, probabilistic reversal learning was impaired in BD youths, with a trend in those with MDD (p=0.07). CONCLUSIONS Our results suggest that reversal learning deficits are present in youths with BD and possibly those with MDD. Further work is necessary to elucidate the specificity of neural mechanisms underlying such behavioral deficits.

Altered neural function in pediatric bipolar disorder during reversal learning.

OBJECTIVE Data documenting the functional impairment associated with the diagnosis of bipolar disorder (BD) in children and adolescents highlight the need for greater understanding of its pathophysiology. Toward that end, we demonstrated previously that BD youth have behavioral deficits on reversal learning tasks. On such tasks, participants must first acquire a stimulus/response relationship through trial-and-error learning, and then discern when the stimulus/reward relationship reverses. Here, we use event-related functional magnetic resonance imaging (fMRI) to elucidate neural correlates of reversal learning deficits in euthymic BD youth compared to typically developing controls. METHOD   We compared euthymic pediatric BD participants (n = 16) versus age-, sex-, and IQ-matched controls (n = 16). Our main outcome measure was blood oxygen level-dependent (BOLD) signal measured with fMRI during an event-related probabilistic reversal task. RESULTS Pediatric BD participants had significantly greater neural activity than controls in fronto-parietal regions during the reversal phase, particularly in response to punished reversal errors (p < 0.05 corrected for multiple comparisons). CONCLUSIONS Our current study suggests that during reversal learning, BD youths inefficiently recruit regions associated with processing response conflict and implementing alternative responses, including subdivisions of the frontal cortex and the parietal cortex. Such deficits are present in euthymic BD youth. Further work is necessary to evaluate the specificity of such alterations.

Impact of emotion on cognition in trauma survivors: What is the role of posttraumatic stress disorder?

BACKGROUND Cognitive theories of anxiety disorders postulate an increased attentional bias to environmental cues associated with threat that underlies the exaggerated fear response. The role of trauma, which may represent strong competitive advantage for attention, remains unclear. We investigated the influence of trauma exposure and the presence of anxiety/stress disorders on the impact of emotional distractors on cognitive performance. METHODS Fourteen trauma-exposed subjects with PTSD, 12 trauma-exposed subjects with anxiety disorders other than PTSD, 12 trauma-exposed healthy subjects and 19 non-trauma-exposed healthy controls participated in this study. The impact of emotion on cognition was determined by the Affective Stroop task that measures the effect of irrelevant emotional distractors on the speed of operant responding. RESULTS The speed of cognitive performance was significantly reduced in the presence of negative distractors versus neutral or positive distractors in subjects with PTSD, while there was no significant influence of the distractor type on performance in the other diagnostic groups (diagnosis-by-distractor type interaction, p<0.001). While negative distractors induced the same levels of anxiety and depersonalization in subjects with PTSD and subjects with other anxiety disorders, distractor-induced depersonalization was associated with slowing of cognitive performance in PTSD (p=0.02) but not in other groups. LIMITATIONS Different types of anxiety disorders in the non-PTSD group might reduce the selectivity of the results; some subjects received medication possibly impacting on their cognitive functioning. CONCLUSIONS The cognitive impairments in the presence of negative distractors specifically found in PTSD call for research into novel psychotherapeutic approaches, e.g. attentional training, for PTSD.