Daniel W. Grupe

Uncertainty and anticipation in anxiety: an integrated neurobiological and psychological perspective

Uncertainty about a possible future threat disrupts our ability to avoid it or to mitigate its negative impact and thus results in anxiety. Here, we focus the broad literature on the neurobiology of anxiety through the lens of uncertainty. We identify five processes that are essential for adaptive anticipatory responses to future threat uncertainty and propose that alterations in the neural instantiation of these processes result in maladaptive responses to uncertainty in pathological anxiety. This framework has the potential to advance the classification, diagnosis and treatment of clinical anxiety.

Uncertainty during anticipation modulates neural responses to aversion in human insula and amygdala.

Uncertainty about potential negative future outcomes can cause stress and is a central feature of anxiety disorders. The stress and anxiety associated with uncertain situations may lead individuals to overestimate the frequency with which uncertain cues are followed by negative outcomes, an example of covariation bias. Using functional magnetic resonance imaging, we found that uncertainty-related expectations modulated neural responses to aversion. Insula and amygdala responses to aversive pictures were larger after an uncertain cue (that preceded aversive or neutral pictures) than a certain cue (that always preceded aversive pictures). Anticipatory anterior cingulate cortex (ACC) activity elicited by the cues was inversely associated with the insula and amygdala responses to aversive pictures following the cues. Nearly 75% of subjects overestimated the frequency of aversive pictures following uncertain cues, and ACC and insula activity predicted this uncertainty-related covariation bias. Findings provide the first evidence of the brain mechanisms of covariation bias and highlight the temporal dynamics of ACC, insula, and amygdala recruitment for processing aversion in the context of uncertainty.

Reduced Structural Connectivity of a Major Frontolimbic Pathway in Generalized Anxiety Disorder

CONTEXT Emotion regulation deficits figure prominently in generalized anxiety disorder (GAD) and in other anxiety and mood disorders. Research examining emotion regulation and top-down modulation has implicated reduced coupling of the amygdala with prefrontal cortex and anterior cingulate cortex, suggesting altered frontolimbic white matter connectivity in GAD. OBJECTIVES To investigate structural connectivity between ventral prefrontal cortex or anterior cingulate cortex areas and the amygdala in GAD and to assess associations with functional connectivity between those areas. DESIGN Participants underwent diffusion-tensor imaging and functional magnetic resonance imaging. SETTING University magnetic resonance imaging facility. PARTICIPANTS Forty-nine patients with GAD and 39 healthy volunteer control subjects, including a matched subset of 21 patients having GAD without comorbid Axis I diagnoses and 21 healthy volunteers matched for age, sex, and education. MAIN OUTCOME MEASURES The mean fractional anisotropy values in the left and right uncinate fasciculus, as measured by tract-based analysis for diffusion-tensor imaging data. RESULTS Lower mean fractional anisotropy values in the bilateral uncinate fasciculus indicated reduced frontolimbic structural connectivity in patients with GAD. This reduction in uncinate fasciculus integrity was most pronounced for patients without comorbidity and was not observed in other white matter tracts. Across all participants, higher fractional anisotropy values were associated with more negative functional coupling between the pregenual anterior cingulate cortex and the amygdala during the anticipation of aversion. CONCLUSIONS Reduced structural connectivity of a major frontolimbic pathway suggests a neural basis for emotion regulation deficits in GAD. The functional significance of these structural differences is underscored by decreased functional connectivity between the anterior cingulate cortex and the amygdala in individuals with reduced structural integrity of the uncinate fasciculus.

Self, mother and abstract other: an fMRI study of reflective social processing.

Using fMRI, we studied the neural correlates of self-referential processing by comparing BOLD signal changes during self and mother conditions of a self-reference effect (SRE) task. Conjunction analysis of these two conditions showed several common areas of significant activation, including the medial aspects of the superior frontal gyri, left inferior frontal gyrus, bilateral temporal poles, left superior temporal sulcus and left precuneus. The locations of the 7 strongest peak activations for the self condition and for the mother condition were compared on a subject-by-subject basis in native space. Of the 119 pairs of peaks explored, 87% were located within 2 voxels of each other, demonstrating the commonality of the brain regions subserving both self- and mother-referential processing within an individual subject. In group analyses of the self-referential vs. mother-referential contrast, small differences in activation strength were observed in the left superior frontal sulcus, right cingulate gyrus and the left fusiform gyrus. Greater activation for mother than for self was observed in bilateral temporal lobes. Subjects also performed a social attribution task (SAT) in which they inferred mental states about interacting geometric shapes. Activations from this visual theory of mind task were compared with the activations demonstrated during self-referential processing. Striking similarities were found, including overlapping activations in bilateral medial prefrontal cortices, left inferior frontal gyrus and precuneus. These data suggest that reflective analysis of self, mother and abstract others relies predominantly on the same neural architecture.

Dissecting the Anticipation of Aversion Reveals Dissociable Neural Networks

The anticipation of future adversity confers adaptive benefits by engaging a suite of preparatory mechanisms, but this process can also be deleterious when carried out in excess. Neuroscientific investigations have largely treated anticipation as a unitary process, but we show here using functional magnetic resonance imaging that distinct stages of aversive anticipation are supported by dissociable neural mechanisms. Immediate anticipatory responses were observed in regions associated with threat detection and early processing of predictive cues, including the orbitofrontal cortex and pregenual anterior cingulate cortex, as well as the amygdala for individuals with elevated anxiety symptoms. Sustained anticipatory activity was observed in the forebrain/bed nucleus of the stria terminalis, anterior insula, anterior mid-cingulate cortex (aMCC), and midbrain/periaqueductal gray, regions associated with anxiety, interoception, and defensive behavior. The aMCC showed increased functional coupling with the midbrain during sustained anticipation of aversion, highlighting a circuit critical for the expression of preparatory fear responses. These data implicate distinct sets of regions that are active during different temporal stages of anticipation, and provide insight into how the human brain faces the future both adaptively and maladaptively.

Bidirectional communication between amygdala and fusiform gyrus during facial recognition

Decades of research have documented the specialization of fusiform gyrus (FG) for facial information processes. Recent theories indicate that FG activity is shaped by input from amygdala, but effective connectivity from amygdala to FG remains undocumented. In this fMRI study, 39 participants completed a face recognition task. 11 participants underwent the same experiment approximately four months later. Robust face-selective activation of FG, amygdala, and lateral occipital cortex were observed. Dynamic causal modeling and Bayesian Model Selection (BMS) were used to test the intrinsic connections between these structures, and their modulation by face perception. BMS results strongly favored a dynamic causal model with bidirectional, face-modulated amygdala-FG connections. However, the right hemisphere connections diminished at time 2, with the face modulation parameter no longer surviving Bonferroni correction. These findings suggest that amygdala strongly influences FG function during face perception, and that this influence is shaped by experience and stimulus salience.

Neurobiological correlates of distinct post-traumatic stress disorder symptom profiles during threat anticipation in combat veterans

BACKGROUND Previous research in post-traumatic stress disorder (PTSD) has identified disrupted ventromedial prefrontal cortex (vmPFC) function in those with v. without PTSD. It is unclear whether this brain region is uniformly affected in all individuals with PTSD, or whether vmPFC dysfunction is related to individual differences in discrete features of this heterogeneous disorder. METHOD In a sample of 51 male veterans of Operation Enduring Freedom/Operation Iraqi Freedom, we collected functional magnetic resonance imaging data during a novel threat anticipation task with crossed factors of threat condition and temporal unpredictability. Voxelwise regression analyses related anticipatory brain activation to individual differences in overall PTSD symptom severity, as well as individual differences in discrete symptom subscales (re-experiencing, emotional numbing/avoidance, and hyperarousal). RESULTS The vmPFC showed greater anticipatory responses for safety relative to threat, driven primarily by deactivation during threat anticipation. During unpredictable threat anticipation, increased PTSD symptoms were associated with relatively greater activation for threat v. SAFETY However, simultaneous regression on individual symptom subscales demonstrated that this effect was driven specifically by individual differences in hyperarousal symptoms. Furthermore, this analysis revealed an additional, anatomically distinct region of the vmPFC in which re-experiencing symptoms were associated with greater activation during threat anticipation. CONCLUSIONS Increased anticipatory responses to unpredictable threat in distinct vmPFC subregions were uniquely associated with elevated hyperarousal and re-experiencing symptoms in combat veterans. These results underscore the disruptive impact of uncertainty for veterans, and suggest that investigating individual differences in discrete aspects of PTSD may advance our understanding of underlying neurobiological mechanisms.

Successful face recognition is associated with increased prefrontal cortex activation in autism spectrum disorder.

This study examines whether deficits in visual information processing in autism-spectrum disorder (ASD) can be offset by the recruitment of brain structures involved in selective attention. During functional MRI, 12 children with ASD and 19 control participants completed a selective attention one-back task in which images of faces and houses were superimposed. When attending to faces, the ASD group showed increased activation relative to control participants within multiple prefrontal cortex areas, including dorsolateral prefrontal cortex (DLPFC). DLPFC activation in ASD was associated with increased response times for faces. These data suggest that prefrontal cortex activation may represent a compensatory mechanism for diminished visual information processing abilities in ASD.

Brain Imaging Alterations in Posttraumatic Stress Disorder

Posttraumatic stress disorder (PTSD) is associated with a host of neurobiological changes, including abnormalities in subcortical and cortical structure and function. The majority of neuroimaging studies have been motivated by a fear-conditioning perspective to examine neural changes associated with PTSD, with several studies finding alterations in the amygdala, hippocampus, and medial prefrontal cortex. However, not all studies have replicated these findings, suggesting that perhaps more nuanced models of PTSD may be needed to account for the pathophysiology of the disorder. We review neuroimaging findings related to the fear model, encouraging researchers to consider additional factors such as trauma type, age of trauma, and affective neurodynamics. Explicit consideration of these factors may facilitate greater coherence among studies going forward and advance our understanding of the neurobiological alterations associated with PTSD. [Psychiatr Ann. 2016;46(9):519-526.] Posttraumatic stress disorder (PTSD), resulting from a traumatic experience (or set of experiences), is a debilitating disorder with a lifetime prevalence in US adults of approximately 7.8%.1 PTSD symptoms include avoidance, re-experiencing of the trauma, hyperarousal and hypervigilance, sleep disturbances, and anhedonia. People suffering from PTSD show signs of hypothalamic-pituitary-adrenal (HPA) axis dysregulation, alterations to neural circuits involved in emotional and stress regulation, and heightened fearpotentiated startle responses. This article highlights the current state of neuroimaging research in PTSD, with a particular focus on shortcomings of the “status quo” picture of brainimaging alterations and how the field Daniel W. Grupe, PhD, is an Assistant Scientist, Center for Healthy Minds and Waisman Laboratory for Brain Imaging and Behavior. Aaron S. Heller, PhD, is an Assistant Professor, Departments of Psychology and Psychiatry, University of Miami. Address correspondence to Daniel W. Grupe, PhD, Center for Healthy Minds and Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, 902 University Bay Drive, Madison, WI 53705; email: grupe@wisc.edu. Disclosure: The authors have no relevant financial relationships to disclose. doi: 10.3928/00485713-20160803-01 Daniel W. Grupe, PhD; and Aaron S. Heller, PhD

Behavioral and neural indices of affective coloring for neutral social stimuli

Abstract Emotional processing often continues beyond the presentation of emotionally evocative stimuli, which can result in affective biasing or coloring of subsequently encountered events. Here, we describe neural correlates of affective coloring and examine how individual differences in affective style impact the magnitude of affective coloring. We conducted functional magnetic resonance imaging in 117 adults who passively viewed negative, neutral and positive pictures presented 2 s prior to neutral faces. Brain responses to neutral faces were modulated by the valence of preceding pictures, with greater activation for faces following negative (vs positive) pictures in the amygdala, dorsomedial and lateral prefrontal cortex, ventral visual cortices, posterior superior temporal sulcus, and angular gyrus. Three days after the magnetic resonance imaging scan, participants rated their memory and liking of previously encountered neutral faces. Individuals higher in trait positive affect and emotional reappraisal rated faces as more likable when preceded by emotionally arousing (negative or positive) pictures. In addition, greater amygdala responses to neutral faces preceded by positively valenced pictures were associated with greater memory for these faces 3 days later. Collectively, these results reveal individual differences in how emotions spill over onto the processing of unrelated social stimuli, resulting in persistent and affectively biased evaluations of such stimuli.