Empathic Accuracy Deficits in Patients with Neurodegenerative Disease: Association with Caregiver Depression.

OBJECTIVES: To investigate whether deficits in empathic accuracy (i.e., ability to recognize emotion in others) in patients with neurodegenerative disease are associated with greater depression in their caregivers. DESIGN: Two cross-sectional studies. SETTING: Academic medical center and research university. PARTICIPANTS: Two independent samples (N = 172, N = 63) of patients with a variety of neurodegenerative diseases and their caregivers; comparison group of healthy couples. MEASUREMENT: Patients' empathic accuracy was assessed in the laboratory using a novel dynamic tracking task (rating another person's changing emotions over time) and more traditional measures (recognizing the emotion expressed in photographs of facial expressions and by characters in films). Caregivers completed self-report inventories of depression. RESULTS: Lower empathic accuracy in patients was associated with greater depression in caregivers in both studies. In study 1, this association was found when empathic accuracy was measured using the dynamic tracking measure but not when measured using the more traditional photograph and film measures. In study 2, we found preliminary support for our theoretical model wherein lower empathic accuracy in patients is associated with increased caregiver stress (loneliness, strain, and burden), which in turn is associated with greater caregiver depression. CONCLUSIONS: Caring for a patient with deficits in empathic accuracy is associated with greater loneliness, strain, and burden for caregivers, and increased depression. Caregivers may benefit from interventions designed to compensate for the stress and interpersonal loss associated with patients' declining empathic accuracy.

The impact of executive function on response to cognitive behavioral therapy in late-life depression.

OBJECTIVE: Late-life depression (LLD) is a common and debilitating condition among older adults. Cognitive behavioral therapy (CBT) has strong empirical support for the treatment of depression in all ages, including in LLD. In teaching patients to identify, monitor, and challenge negative patterns in their thinking, CBT for LLD relies heavily on cognitive processes and, in particular, executive functioning, such as planning, sequencing, organizing, and selectively inhibiting information. It may be that the effectiveness of CBT lies in its ability to train these cognitive areas. METHODS: Participants with LLD completed a comprehensive neuropsychological battery before enrolling in CBT. The current study examined the relationship between neuropsychological function prior to treatment and response to CBT. RESULTS: When using three baseline measures of executive functioning that quantify set shifting, cognitive flexibility, and response inhibition to predict treatment response, only baseline Wisconsin Card Sort Task performance was associated with a significant drop in depression symptoms after CBT. Specifically, worse performance on the Wisconsin Card Sort Task was associated with better treatment response. CONCLUSIONS: These results suggest that CBT, which teaches cognitive techniques for improving psychiatric symptoms, may be especially beneficial in LLD if relative weaknesses in specific areas of executive functioning are present.

Tracking emotional valence: the role of the orbitofrontal cortex.

Successful navigation of the social world requires the ability to recognize and track emotions as they unfold and change dynamically. Neuroimaging and neurological studies of emotion recognition have primarily focused on the ability to identify the emotion shown in static photographs of facial expressions, showing correlations with the amygdala as well as temporal and frontal brain regions. In this study, we examined the neural correlates of continuously tracking dynamically changing emotions. Fifty-nine patients with diverse neurodegenerative diseases used a rating dial to track continuously how positive or how negative the character in a film clip felt. Tracking accuracy was determined by comparing participants' ratings with the ratings of 10 normal control participants. The relationship between tracking accuracy and regional brain tissue content was examined using voxel-based morphometry. Low tracking accuracy was primarily associated with gray matter loss in the right lateral orbitofrontal cortex (OFC). Our finding that the right OFC is critical to the ability to track dynamically changing emotions is consistent with previous research showing right OFC involvement in both socioemotional understanding and modifying responding in changing situations.

Behaviour, physiology and experience of pathological laughing and crying in amyotrophic lateral sclerosis.

Pathological laughing and crying is a disorder of emotional expression seen in a number of neurological diseases. The aetiology is poorly understood, but clinical descriptions suggest a disorder of emotion regulation. The goals of this study were: (i) to characterize the subjective, behavioural and physiological emotional reactions that occur during episodes of pathological laughing and crying; (ii) to compare responses during these episodes to those that occur when emotions are elicited under standard conditions (watching sad and amusing emotional films, being startled); and (iii) to examine the ability of patients with this disorder to regulate their emotions under standardized conditions. Twenty-one patients with pathological laughing and crying due to amyotrophic lateral sclerosis and 14 with amyotrophic lateral sclerosis but no pathological laughing and crying were studied. Emotional measures included self-reported emotional experience, video recordings of facial reactivity and peripheral physiological responses (skin conductance, heart rate and somatic activity). Nineteen of the 21 patients with histories of pathological laughing and crying had at least one episode in the laboratory that they agreed constituted pathological laughing or crying (a total of 56 episodes were documented). Compared with viewing sad and amusing films, the episodes were associated with greater facial and physiological activation. Contrary to many clinical descriptions, episodes were often induced by contextually appropriate stimuli and associated with strong experiences of emotion that were consistent with the display. When instructed to regulate their facial responses to emotion-eliciting films, patients with pathological laughing and crying showed impairments compared with patients who did not have a history of this disorder. These findings support the idea that pathological laughing and crying represents activation of all channels of emotional responding (i.e. behavioural, physiological and subjective). Furthermore, they support previously advanced theories that, rather than being associated with general emotional hyperreactivity, this disorder may be due to dysfunction in frontal neural systems that support voluntary regulation of emotion.

Executive functions and the down-regulation and up-regulation of emotion.

This study examined the relationship between individual differences in executive functions (EF; assessed by measures of working memory, Stroop, trail making, and verbal fluency) and ability to down-regulate and up-regulate responses to emotionally evocative film clips. To ensure a wide range of EF, 48 participants with diverse neurodegenerative disorders and 21 older neurologically normal ageing participants were included. Participants were exposed to three different movie clips that were designed to elicit a mix of disgust and amusement. While watching the films they were either instructed to watch, down-regulate, and up-regulate their visible emotional responses. Heart rate and facial behaviours were monitored throughout. Emotion regulatory ability was operationalised as changes in heart rate and facial behaviour in the down- and up-regulation conditions, controlling for responses in the watch condition. Results indicated that higher verbal fluency scores were related to greater ability to regulate emotion in both the down-regulation and up-regulation conditions. This finding remained significant even after controlling for age and general cognitive functioning. No relationships were found between emotion regulation and the other EF measures. We believe these results derive from differences among EF measures, with verbal-fluency performance best capturing the complex sequence of controlled planning, activation, and monitoring required for successful emotion regulation. These findings contribute to our understanding of emotion-cognition interaction, suggesting a link between emotion-regulatory abilities and individual differences in complex executive functions.

Amygdala and Insula Connectivity Changes Following Psychotherapy for Posttraumatic Stress Disorder: A Randomized Clinical Trial.

BACKGROUND: Exposure-based psychotherapy is a first-line treatment for posttraumatic stress disorder (PTSD), but its mechanisms are poorly understood. Functional brain connectivity is a promising metric for identifying treatment mechanisms and biosignatures of therapeutic response. To this end, we assessed amygdala and insula treatment-related connectivity changes and their relationship to PTSD symptom improvements. METHODS: Individuals with a primary PTSD diagnosis (N = 66) participated in a randomized clinical trial of prolonged exposure therapy (n = 36) versus treatment waiting list (n = 30). Task-free functional magnetic resonance imaging was completed prior to randomization and 1 month following cessation of treatment/waiting list. Whole-brain blood oxygenation level-dependent responses were acquired. Intrinsic connectivity was assessed by subregion in the amygdala and insula, limbic structures key to the disorder pathophysiology. Dynamic causal modeling assessed evidence for effective connectivity changes in select nodes informed by intrinsic connectivity findings. RESULTS: The amygdala and insula displayed widespread patterns of primarily subregion-uniform intrinsic connectivity change, including increased connectivity between the amygdala and insula; increased connectivity of both regions with the ventral prefrontal cortex and frontopolar and sensory cortices; and decreased connectivity of both regions with the left frontoparietal nodes of the executive control network. Larger decreases in amygdala-frontal connectivity and insula-parietal connectivity were associated with larger PTSD symptom reductions. Dynamic causal modeling evidence suggested that treatment decreased left frontal inhibition of the left amygdala, and larger decreases were associated with larger symptom reductions. CONCLUSIONS: PTSD psychotherapy adaptively attenuates functional interactions between frontoparietal and limbic brain circuitry at rest, which may reflect a potential mechanism or biosignature of recovery.

Identification of psychiatric disorder subtypes from functional connectivity patterns in resting-state electroencephalography.

The understanding and treatment of psychiatric disorders, which are known to be neurobiologically and clinically heterogeneous, could benefit from the data-driven identification of disease subtypes. Here, we report the identification of two clinically relevant subtypes of post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) on the basis of robust and distinct functional connectivity patterns, prominently within the frontoparietal control network and the default mode network. We identified the disease subtypes by analysing, via unsupervised and supervised machine learning, the power-envelope-based connectivity of signals reconstructed from high-density resting-state electroencephalography in four datasets of patients with PTSD and MDD, and show that the subtypes are transferable across independent datasets recorded under different conditions. The subtype whose functional connectivity differed most from those of healthy controls was less responsive to psychotherapy treatment for PTSD and failed to respond to an antidepressant medication for MDD. By contrast, both subtypes responded equally well to two different forms of repetitive transcranial magnetic stimulation therapy for MDD. Our data-driven approach may constitute a generalizable solution for connectome-based diagnosis.

Using fMRI connectivity to define a treatment-resistant form of post-traumatic stress disorder.

A mechanistic understanding of the pathology of psychiatric disorders has been hampered by extensive heterogeneity in biology, symptoms, and behavior within diagnostic categories that are defined subjectively. We investigated whether leveraging individual differences in information-processing impairments in patients with post-traumatic stress disorder (PTSD) could reveal phenotypes within the disorder. We found that a subgroup of patients with PTSD from two independent cohorts displayed both aberrant functional connectivity within the ventral attention network (VAN) as revealed by functional magnetic resonance imaging (fMRI) neuroimaging and impaired verbal memory on a word list learning task. This combined phenotype was not associated with differences in symptoms or comorbidities, but nonetheless could be used to predict a poor response to psychotherapy, the best-validated treatment for PTSD. Using concurrent focal noninvasive transcranial magnetic stimulation and electroencephalography, we then identified alterations in neural signal flow in the VAN that were evoked by direct stimulation of that network. These alterations were associated with individual differences in functional fMRI connectivity within the VAN. Our findings define specific neurobiological mechanisms in a subgroup of patients with PTSD that could contribute to the poor response to psychotherapy.

PTSD Psychotherapy Outcome Predicted by Brain Activation During Emotional Reactivity and Regulation.

OBJECTIVE: Exposure therapy is an effective treatment for posttraumatic stress disorder (PTSD), but many patients do not respond. Brain functions governing treatment outcome are not well characterized. The authors examined brain systems relevant to emotional reactivity and regulation, constructs that are thought to be central to PTSD and exposure therapy effects, to identify the functional traits of individuals most likely to benefit from treatment. METHOD: Individuals with PTSD underwent functional MRI (fMRI) while completing three tasks assessing emotional reactivity and regulation. Participants were then randomly assigned to immediate prolonged exposure treatment (N=36) or a waiting list condition (N=30). A random subset of the prolonged exposure group (N=17) underwent single-pulse transcranial magnetic stimulation (TMS) concurrent with fMRI to examine whether predictive activation patterns reflect causal influence within circuits. Linear mixed-effects modeling in line with the intent-to-treat principle was used to examine how baseline brain function moderated the effect of treatment on PTSD symptoms. RESULTS: At baseline, individuals with larger treatment-related symptom reductions (compared with the waiting list condition) demonstrated 1) greater dorsal prefrontal activation and 2) less left amygdala activation, both during emotion reactivity; 3) better inhibition of the left amygdala induced by single TMS pulses to the right dorsolateral prefrontal cortex; and 4) greater ventromedial prefrontal/ventral striatal activation during emotional conflict regulation. Reappraisal-related activation was not a significant moderator of the treatment effect. CONCLUSIONS: Capacity to benefit from prolonged exposure in PTSD is gated by the degree to which prefrontal resources are spontaneously engaged when superficially processing threat and adaptively mitigating emotional interference, but not when deliberately reducing negative emotionality.

Selective Effects of Psychotherapy on Frontopolar Cortical Function in PTSD.

OBJECTIVE: Exposure therapy is an effective treatment for posttraumatic stress disorder (PTSD), but a comprehensive, emotion-focused perspective on how psychotherapy affects brain function is lacking. The authors assessed changes in brain function after prolonged exposure therapy across three emotional reactivity and regulation paradigms. METHOD: Individuals with PTSD underwent functional MRI (fMRI) at rest and while completing three tasks assessing emotional reactivity and regulation. Individuals were then randomly assigned to immediate prolonged exposure treatment (N=36) or a waiting list condition (N=30) and underwent a second scan approximately 4 weeks after the last treatment session or a comparable waiting period, respectively. RESULTS: Treatment-specific changes were observed only during cognitive reappraisal of negative images. Psychotherapy increased lateral frontopolar cortex activity and connectivity with the ventromedial prefrontal cortex/ventral striatum. Greater increases in frontopolar activation were associated with improvement in hyperarousal symptoms and psychological well-being. The frontopolar cortex also displayed a greater variety of temporal resting-state signal pattern changes after treatment. Concurrent transcranial magnetic stimulation and fMRI in healthy participants demonstrated that the lateral frontopolar cortex exerts downstream influence on the ventromedial prefrontal cortex/ventral striatum. CONCLUSIONS: Changes in frontopolar function during deliberate regulation of negative affect is one key mechanism of adaptive psychotherapeutic change in PTSD. Given that frontopolar connectivity with ventromedial regions during emotion regulation is enhanced by psychotherapy and that the frontopolar cortex exerts downstream influence on ventromedial regions in healthy individuals, these findings inform a novel conceptualization of how psychotherapy works, and they identify a promising target for stimulation-based therapeutics.

Transdiagnostic impairment of cognitive control in mental illness.

Intact cognitive control or executive function has characteristic patterns in both behavior and functional neurocircuitry. Functional neuroimaging studies have shown that a frontal-cingulate-parietal-insular (i.e., "multiple demand") network forms a common functional substrate undergirding successful adaptation to diverse cognitive processing demands. Separate work on intact neurocognitive performance implicates a higher order factor that largely explains performance across domains and may reflect trait cognitive control capacity. In the current review we highlight findings from respective psychiatric disorders (i.e., psychotic, bipolar and unipolar depressive, anxiety, and substance use disorders) suggesting that cognitive control perturbations amidst psychopathology are most pronounced within these common brain and behavioral indices of adaptive cognitive functioning and moreover, are evident across disorders (i.e., transdiagnostically). Specifically, within each of the disorder classes impairments are consistent in the multiple demand network across a wide range of cognitive tasks. While severity varies between disorders, broad as opposed to domain-specific impairments consistently emerge in neurocognitive performance. Accumulating findings have revealed that phenotypically diverse psychiatric disorders share a common factor or vulnerability to dysfunction that is in turn related to broad neurocognitive deficits. Furthermore, we have observed that regions of the multiple demand network, which overlap with the salience network (dorsal anterior cingulate and bilateral anterior insula) are characterized by reduced gray matter transdiagnostically and predict weaker neurocognitive performance. In summary, transdiagnostic (as opposed to disorder-specific) patterns of symptomatic distress and neurocognitive performance deficits, concurrent with parallel anomalies of brain structure and function may largely contribute to the real-world socio-occupational impairment common across disorders.

Emotion recognition in frontotemporal dementia and Alzheimer's disease: A new film-based assessment.

Deficits in recognizing others' emotions are reported in many psychiatric and neurological disorders, including autism, schizophrenia, behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD). Most previous emotion recognition studies have required participants to identify emotional expressions in photographs. This type of assessment differs from real-world emotion recognition in important ways: Images are static rather than dynamic, include only 1 modality of emotional information (i.e., visual information), and are presented absent a social context. Additionally, existing emotion recognition batteries typically include multiple negative emotions, but only 1 positive emotion (i.e., happiness) and no self-conscious emotions (e.g., embarrassment). We present initial results using a new task for assessing emotion recognition that was developed to address these limitations. In this task, respondents view a series of short film clips and are asked to identify the main characters' emotions. The task assesses multiple negative, positive, and self-conscious emotions based on information that is multimodal, dynamic, and socially embedded. We evaluate this approach in a sample of patients with bvFTD, AD, and normal controls. Results indicate that patients with bvFTD have emotion recognition deficits in all 3 categories of emotion compared to the other groups. These deficits were especially pronounced for negative and self-conscious emotions. Emotion recognition in this sample of patients with AD was indistinguishable from controls. These findings underscore the utility of this approach to assessing emotion recognition and suggest that previous findings that recognition of positive emotion was preserved in dementia patients may have resulted from the limited sampling of positive emotion in traditional tests.

The effect of the serotonin transporter polymorphism (5-HTTLPR) on empathic and self-conscious emotional reactivity.

We examined the relationship between a functional polymorphism of the serotonin transporter gene (5-HTTLPR) and individual differences in emotional reactivity in two laboratory studies. In Study 1, empathic responding and physiological reactivity to viewing films of others in distress were assessed in healthy adults in three age groups. In Study 2, emotional responding to watching oneself in an embarrassing situation was assessed in healthy adults and in patients with neurodegenerative diseases. In Study 1, participants with two short alleles of 5-HTTLPR reported more personal distress and showed higher levels of physiological responses in response to the films than participants with long alleles. In Study 2, participants with two short alleles reported more anger and amusement and displayed more emotional expressive behaviors in response to the embarrassing situation than participants with long alleles. These two findings from diverse samples of participants converge to indicate that individuals who are homozygous for the short allele variant of 5-HTTLPR have greater levels of emotional reactivity in two quite different socially embedded contexts.

Greater emotional empathy and prosocial behavior in late life.

Emotional empathy and prosocial behavior were assessed in older, middle-aged, and young adults. Participants watched two films depicting individuals in need, one uplifting and the other distressing. Physiological responses were monitored during the films, and participants rated their levels of emotional empathy following each film. As a measure of prosocial behavior, participants were given an additional payment they could contribute to charities supporting the individuals in the films. Age-related linear increases were found for both emotional empathy (self-reported empathic concern and cardiac and electrodermal responding) and prosocial behavior (size of contribution) across both films and in self-reported personal distress to the distressing film. Empathic concern and cardiac reactivity to both films, along with personal distress to the distressing film only, were associated with greater prosocial behavior. Empathic concern partially mediated the age-related differences in prosocial behavior. Results are discussed in terms of our understanding both of adult development and of the nature of these vital aspects of human emotion.

Aging and emotion recognition: not just a losing matter.

Past studies on emotion recognition and aging have found evidence of age-related decline when emotion recognition was assessed by having participants detect single emotions depicted in static images of full or partial (e.g., eye region) faces. These tests afford good experimental control but do not capture the dynamic nature of real-world emotion recognition, which is often characterized by continuous emotional judgments and dynamic multimodal stimuli. Research suggests that older adults often perform better under conditions that better mimic real-world social contexts. We assessed emotion recognition in young, middle-aged, and older adults using two traditional methods (single emotion judgments of static images of faces and eyes) and an additional method in which participants made continuous emotion judgments of dynamic, multimodal stimuli (videotaped interactions between young, middle-aged, and older couples). Results revealed an Age × Test interaction. Largely consistent with prior research, we found some evidence that older adults performed worse than young adults when judging single emotions from images of faces (for sad and disgust faces only) and eyes (for older eyes only), with middle-aged adults falling in between. In contrast, older adults did better than young adults on the test involving continuous emotion judgments of dyadic interactions, with middle-aged adults falling in between. In tests in which target stimuli differed in age, emotion recognition was not facilitated by an age match between participant and target. These findings are discussed in terms of theoretical and methodological implications for the study of aging and emotional processing.

Emotion regulation deficits in frontotemporal lobar degeneration and Alzheimer's disease.

We examined instructed and spontaneous emotion regulation in patients with frontotemporal lobar degeneration (FTLD, N = 32), which presents with profound emotional and personality changes; patients with Alzheimer's disease (AD, N = 17), which presents with profound memory impairment; and neurologically normal controls (N = 25). Participants were exposed to an aversive acoustic startle stimulus (115 dB) under 3 different conditions: (a) unwarned without instructions to down-regulate, (b) warned without instructions to down-regulate, and (c) warned with instructions to down-regulate. In the last 2 conditions, the warning took the form of a 20-s countdown. In all conditions, visible aspects of the startle response were assessed by measuring overall somatic activity and coding emotional facial expressions. FTLD patients, AD patients, and control participants showed similar patterns of down-regulation in somatic activity across the 3 startle trials. However, differences between the 3 groups emerged in the amount of emotional facial behavior expressed in the startle trials. There were no group differences in response in the unwarned condition, indicating that the startle response was intact in the patients. In the warned with instructions condition, both FTLD and AD patients were moderately impaired in down-regulatory ability compared with controls. In the warned without instructions condition, AD patients and normal controls spontaneously down-regulated their emotional responses, but FTLD patients did not. These findings illuminate specific problems that these patients have in the emotional realm.

Do tests of executive functioning predict ability to downregulate emotions spontaneously and when instructed to suppress?

Behavioral regulation is a hallmark feature of executive functioning (EF). The present study investigated whether commonly used neuropsychological test measures of EF (i.e., working memory, Stroop, trail making, and verbal fluency) were related to ability to downregulate emotion both spontaneously and when instructed to suppress emotional expressions. To ensure a wide range of EF, 24 frontotemporal lobar degeneration patients, 7 Alzheimer's patients, and 17 neurologically normal controls participated. Participants were exposed to an acoustic startle stimulus (single aversive noise burst) under three conditions: (1) unwarned, (2) warned with no instructions (to measure spontaneous emotion downregulation), and (3) warned with instructions to suppress (to measure instructed emotion downregulation). Results indicated that higher verbal fluency scores were related to greater emotion regulation (operationalized as reduction in body movement and emotional facial behavior when warned of the impending startle) in both regulation conditions. No relationships were found between emotion regulation in these conditions and the other EF measures. We conclude that, of four commonly used measures of EF, verbal fluency best indexes the complex processes of monitoring, evaluation, and control necessary for successful emotion regulation, both spontaneously and following instructions to suppress.

Thinking of critical words during study is unnecessary for false memory in the Deese, Roediger, and McDermott procedure.

Do participants in the Deese, Roediger, and McDermott (DRM) procedure demonstrate false memory because they think of nonpresented critical words during study and confuse them with words that were actually presented? In two experiments, 160 participants studied eight visually presented DRM lists at a rate of 2 s or 5 s per word. Half of the participants rehearsed silently: the other half rehearsed overtly. Following study, the participants' memory for the lists was tested by recall or recognition. Typical false memory results were obtained for both memory measures. More important, two new results were observed. First, a large majority of the overt-rehearsal participants spontaneously rehearsed approximately half of the critical words during study. Second, critical-word rehearsal at study enhanced subsequent false recall, but it had no effect on false recognition or remember judgments for falsely recognized critical words. Thinking of critical words during study was unnecessary for producing false memory.

"If I didn't write it, why would I remember it?" Effects of encoding, attention, and practice on accurate and false memory.

In two experiments involving recall and recognition, we manipulated encoding strategies, attention, and practice in the Deese, Roediger, and McDermott false memory procedure. During the study of auditory word lists, participants listened to the words, wrote the words, wrote the second letter of the words, or counted backward by threes and wrote numbers in time with the words. The results from both experiments showed that, relative to the full-attention hear word condition, the divided-attention write number condition impaired accurate memory, but not false memory. In contrast, the focused-attention write word and write second letter conditions were comparable to the hear word condition in producing accurate memory, yet they were better at reducing false memory. But even after multiple study-test trials, people still falsely recalled or recognized words that they had never written during study. These results are consistent with predictions generated from fuzzy trace theory and the activation/monitoring framework.