Gregory A. Fonzo

Exaggerated and Disconnected Insular-Amygdalar Blood Oxygenation Level-Dependent Response to Threat-Related Emotional Faces in Women with Intimate-Partner Violence Posttraumatic Stress Disorder

BACKGROUND Intimate-partner violence (IPV) is one of the most common causes of posttraumatic stress disorder (PTSD) among women. PTSD neuroimaging studies have identified functional differences in the amygdala and anterior cingulate cortex (ACC)/medial prefrontal cortex during emotion processing. Recent investigations of the limbic sensory system and its associated neural substrate, the insular cortex, have demonstrated its importance for emotional awareness. This study examined the hypothesis that women with IPV-PTSD show a dysregulation of this limbic sensory system while processing threat-related emotional faces. METHODS 12 women with IPV-PTSD and 12 nontraumatized comparison women underwent blood oxygenation level-dependent functional magnetic resonance imaging while completing an emotional face-matching task. RESULTS IPV-PTSD subjects relative to comparison subjects displayed increased activation of the anterior insula and amygdala and decreased connectivity among the anterior insula, amygdala, and ACC while matching to fearful versus happy target faces. A similar pattern of activation differences was also observed for angry versus happy target faces. IPV-PTSD subjects relative to comparison subjects also displayed increased dorsal ACC/medial prefrontal cortex activation and decreased ventral ACC activation when matching to a male versus a female target, and the extent of increased dorsal ACC activation correlated positively with hyperarousal symptoms. CONCLUSIONS Women with IPV-PTSD display hyperactivity and disconnection among affective and limbic sensory systems while processing threat-related emotion. Furthermore, hyperactivity of cognitive-appraisal networks in IPV-PTSD may promote hypervigilant states of awareness through an exaggerated sensitivity to contextual cues, i.e., male gender, which relate to past trauma.

Red Brain, Blue Brain: Evaluative Processes Differ in Democrats and Republicans

Liberals and conservatives exhibit different cognitive styles and converging lines of evidence suggest that biology influences differences in their political attitudes and beliefs. In particular, a recent study of young adults suggests that liberals and conservatives have significantly different brain structure, with liberals showing increased gray matter volume in the anterior cingulate cortex, and conservatives showing increased gray matter volume in the in the amygdala. Here, we explore differences in brain function in liberals and conservatives by matching publicly-available voter records to 82 subjects who performed a risk-taking task during functional imaging. Although the risk-taking behavior of Democrats (liberals) and Republicans (conservatives) did not differ, their brain activity did. Democrats showed significantly greater activity in the left insula, while Republicans showed significantly greater activity in the right amygdala. In fact, a two parameter model of partisanship based on amygdala and insula activations yields a better fitting model of partisanship than a well-established model based on parental socialization of party identification long thought to be one of the core findings of political science. These results suggest that liberals and conservatives engage different cognitive processes when they think about risk, and they support recent evidence that conservatives show greater sensitivity to threatening stimuli.

Neural functional and structural correlates of childhood maltreatment in women with intimate-partner violence-related posttraumatic stress disorder

Childhood maltreatment (CM) is a strong risk factor for development of posttraumatic stress disorder (PTSD) upon adult exposure to extreme adverse events. However, the neural underpinnings of this relationship are not well understood. Here, we test the hypothesis that severity of CM history is positively correlated with emotion-processing limbic and prefrontal brain activation/connectivity and negatively correlated with prefrontal gray matter volumes in women with PTSD due to intimate-partner violence (IPV-PTSD). Thirty-three women with IPV-PTSD underwent structural and functional magnetic resonance imaging while completing a facial emotion processing task. Multivariate regressions examined the relationship of CM to patterns of activation, connectivity, and gray matter volumes. CM severity was: (a) positively correlated with ventral ACC activation while processing angry faces; (b) negatively correlated with dorsal ACC and insula activation while processing fear and angry faces, arising from positive correlations with the shape-matching baseline; (c) positively correlated with limbic-prefrontal connectivity while processing fear faces but negatively correlated with amygdalo-insular connectivity while processing fear and angry; and (d) negatively correlated with prefrontal gray matter volumes. These results suggest CM exposure may account for variability in limbic/prefrontal brain function and prefrontal structure in adulthood PTSD and offer one potential mechanism through which CM confers risk to future development of PTSD.

Common and disorder-specific neural responses to emotional faces in generalised anxiety, social anxiety and panic disorders.

BACKGROUND Although evidence exists for abnormal brain function across various anxiety disorders, direct comparison of neural function across diagnoses is needed to elicit abnormalities common across disorders and those distinct to a particular diagnosis. AIMS To delineate common and distinct abnormalities within generalised anxiety (GAD), panic and social anxiety disorder (SAD) during affective processing. METHOD Fifty-nine adults (15 with GAD, 15 with panic disorder, 14 with SAD, and 15 healthy controls) underwent functional magnetic resonance imaging while completing a facial emotion matching task with fearful, angry and happy faces. RESULTS Greater differential right amygdala activation to matching fearful v. happy facial expressions related to greater negative affectivity (i.e. trait anxiety) and was heightened across all anxiety disorder groups compared with controls. Collapsing across emotional face types, participants with panic disorder uniquely displayed greater posterior insula activation. CONCLUSIONS These preliminary results highlight a common neural basis for clinical anxiety in these diagnoses and also suggest the presence of disorder-specific dysfunction.

Cognitive-Behavioral Therapy for Generalized Anxiety Disorder is Associated with Attenuation of Limbic Activation to Threat-Related Facial Emotions

BACKGROUND The neural processes underlying the benefits of cognitive behavioral treatment (CBT) for generalized anxiety disorder (GAD) are not well understood. METHODS Twenty-one (n=21) adults with a principal diagnosis of GAD and eleven (n=11) non-anxious healthy controls (HC) underwent functional magnetic resonance imaging while completing a facial emotion processing task. Responses to threat-related emotionality (i.e., the contrast of fear and angry vs. happy faces) were assessed at pretreatment and again following 10 sessions of CBT in the GAD group and a comparable waiting period in the HC group. RESULTS At pretreatment, GAD participants displayed blunted responses in the amygdala, insula, and anterior cingulate to the happy face-processing comparison condition, and greater amygdalo-insular connectivity. CBT was associated with attenuated amygdalar and subgenual anterior cingulate activation to fear/angry faces and heightened insular responses to the happy face comparison condition, but had no apparent effects on connectivity. Pre-treatment abnormalities and treatment-related changes were not associated with symptoms of worry. LIMITATIONS There was no active control condition (e.g., treatment waitlist) for comparison of treatment effects. CONCLUSIONS Taken together, these results provide evidence for a dual-process psychotherapeutic model of neural systems changes in GAD in which cingulo-amygdalar reactivity to threat-cues is attenuated while insular responses to positive facial emotions are potentiated. Future work is needed to determine the clinical implications of these changes and their specificity to CBT.

Early life stress and the anxious brain: evidence for a neural mechanism linking childhood emotional maltreatment to anxiety in adulthood.

BACKGROUND Childhood emotional maltreatment (CEM) increases the likelihood of developing an anxiety disorder in adulthood, but the neural processes underlying conferment of this risk have not been established. Here, we test the potential for neuroimaging the adult brain to inform understanding of the mechanism linking CEM to adult anxiety symptoms. METHOD One hundred eighty-two adults (148 females, 34 males) with a normal-to-clinical range of anxiety symptoms underwent structural and functional magnetic resonance imaging while completing an emotion-processing paradigm with facial expressions of fear, anger, and happiness. Participants completed self-report measures of CEM and current anxiety symptoms. Voxelwise mediation analyses on gray-matter volumes and activation to each emotion condition were used to identify candidate brain mechanisms relating CEM to anxiety in adulthood. RESULTS During processing of fear and anger faces, greater amygdala and less right dorsolateral prefrontal (dlPFC) activation partially mediated the positive relationship between CEM and anxiety symptoms. Greater right posterior insula activation to fear also partially mediated this relationship, as did greater ventral anterior cingulate (ACC) and less dorsal ACC activation to anger. Responses to happy faces in these regions did not mediate the CEM-anxiety relationship. Smaller right dlPFC gray-matter volumes also partially mediated the CEM-anxiety relationship. CONCLUSIONS Activation patterns of the adult brain demonstrate the potential to inform mechanistic accounts of the CEM conferment of anxiety symptoms. Results support the hypothesis that exaggerated limbic activation to negative valence facial emotions links CEM to anxiety symptoms, which may be consequent to a breakdown of cortical regulatory processes.

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.

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.

Brain Connectivity Reflects Mental and Physical States in Generalized Anxiety Disorder

Since Rene Descartes proposed that the mind and body are distinct interacting entities, the mind–body relationship has fueled intense philosophical inquiry and scientific study. Modern neuroscience and physiology have since demonstrated that mind–body interactions occur via complex feedback mechanisms on various levels. However, our understanding of the mind–body relationship still falls short of a unified conceptualization, particularly in the area of mental illness. Consider generalized anxiety disorder (GAD), a highly impairing condition identified by core symptoms segregated into these two very distinct domains: chronic, pervasive worry and difficulty concentrating (the mind); and feeling restless/on edge, easily fatigued, and experiencing muscle tension (the body). Cartesian mind–body dualism continues to influence the field of psychiatry, where attempts to conceptualize a disorder such as GAD emphasize the distinctiveness of the two. Worry is thought to defend against future stressorinduced physiological reactivity, and this reactivity reduction is thought to reinforce the propensity for the mind to engage in worry (1). Although studies have probed how worry engages brain circuitry in GAD, none have examined how brain circuitry mediates the interface between the pathological worry and alterations in peripheral physiology that characterize the disorder. In this issue, Makovac et al. (2) address this question by examining the relationship between heart rate variability (HRV) and amygdala connectivity at rest and following the induction of perseverative dysphoric cognition (rumination or worry). HRV is of particular relevance to GAD given that 1) it is an indicator of parasympathetic modulatory capacity, i.e., how well one can inhibit a tonic cardiac input for sympathetic activation; 2) it serves as an autonomic marker of worry states; and 3) HRV is chronically decreased in GAD (3). The amygdala is a core neural substrate for GAD (4) and is crucial to the detection of salient emotional stimuli, the engagement of physiological fight-or-flight readiness, and the subjective experience of fear (5). Prior work in GAD has demonstrated that the amygdala displays highly variable patterns of connectivity abnormalities at rest—both increased (6) and decreased (7) connectivity with prefrontal regions, important for cognitive control and emotion regulation, and both increased (7) and decreased (6) connectivity with paralimbic substrates, e.g., the insula and anterior cingulate cortex, important for awareness of one’s physiological state and how this fits into the context of one’s experience. Thus, understanding how patterns of amygdala connectivity with these targets change from rest to induction of perseverative dysphoric cognition and how these changes relate to changes in peripheral physiology are both of key importance in

Learning in Generalized Anxiety Disorder Benefits From Neither the Carrot Nor the Stick

Wemake many decisions every day, based on factors such as our goals at the moment and the value we perceive in certain actions or choices (i.e., “good for me” or “bad for me”). With many of these decisions, we have the opportunity to experience their outcome. At times, that outcome is expected, while at others it can be surprising. By comparing what we had expected would happen towhat really did, we learn how tomakebetter choices next time.This process is so prevalent, and so often automatic, thatmany individualsmay not realize how frequently it happens. Yet, a great many neural resources are dedicated to continually making predictions, experiencing the consequences of choices, and adjusting behavior to optimize outcomes. Our brains have been described as Bayesianmachines thatoptimizebehaviorbasedonpredictions andoutcomes (1). It is thennot surprising that this adaptiveprocess is perturbed in various ways across psychopathology. Patients with generalized anxiety disorder, the focus of a study byWhite et al. (2) reported in this issue of the Journal, seem at least phenomenologically to be impaired in this process of prediction, feedback, and learning (3). The degree to which these patients may seemmaladaptively “stuck in their ways” can frustrate even the most experienced clinician. Despite what might appear as persistent negative feedback for this style of decision making, often little seems to change for these patients. How do we go about understanding the processes that have gone awry in their brains? Andwhat does investigating biological perturbations in decision making teach us about the pathophysiology and treatment of generalized anxiety disorder? Such answers may be found by applying computational models to an experimental probe of decision making: operant reinforcement learning. A method for understanding a process like learning and decision making can be considered computational when it utilizes complex mathematics to model mechanistic components describing how specificmental functions interact to drive behavior. Such models can be very powerful in that they can predict future behavior and explain which components of information processing may be altered under certain conditions or in certain populations. The study of operant learning via reinforcing decisions through rewards or punishments has developed iterations of these models over the past decade and found that they do a fairly accurate job of tracking and predicting choice behavior (4). Central to these models is calculation of the expected value of a stimulus or action, encoding of the reward or punishment that was received after a choice was made, and the calculation of the discrepancy between what was received and what was expected (called a prediction error). A positive prediction error indicates a better outcome than expected, while a negative prediction error indicates a worse outcome. The signaling of a prediction error, which a large body ofwork in experimental animals and humans has attributed to dopaminergic neurons, results in updating of the expected value signal (moderated by a learning rate, which dictates the degree to which information from the previous trial is carried into the next one). If this process works well, the individual quickly minimizes prediction errors by adjusting the expected value of a choice, and hence its selection, to its most optimal level. Brain imaging studies have picked up on this modeling work over the past decade (4) and found that trial-to-trial variations in signals such as value and prediction error can be observed in trial-to-trial variations in brain activity. Often value signaling has been linked to activity in the ventromedial prefrontal cortex and ventral striatum (5, 6), while prediction error signaling has been linked to activity in the ventral tegmental area, the striatum, the dorsal cingulate andmedial prefrontal cortices, the anterior insula, and other locations (7). While the terminology associated with computational neuroscience (or in this context often called “computational psychiatry”) can seem foreign to the general clinical reader, it is meant to describe a learning process that is inherently intuitive to all. In their experiment, White et al. gave patients with generalized anxiety disorder andhealthy comparison participants a decision-making task in which responses were associated with different probabilities of reward and punishment, thus presenting an opportunity to learn from both reward and punishment. Patients failed to learn from both rewards and punishments as well as healthy individuals did, as reflected in a persistently high error rate among patients, while healthy subjects progressively decreased their errors. Turning to the brain, the authors’ primary finding was a profound and widespread reduction in prediction error signaling in patients. That is, activity in regions like the cingulate and medial prefrontal The authors’ primary finding was a profound and widespread reduction in prediction error signaling in patients.