Objective Cognitive deficits are a common feature of psychiatric disorders. We investigated the nature of disruptions in neural circuitry underlying cognitive control capacities across psychiatric disorders through a transdiagnostic neuroimaging meta-analysis. Method We searched PubMed for whole-brain functional neuroimaging articles published through June 2015 that compared activation in patients with Axis I disorders to matched healthy control participants during cognitive control tasks. Tasks that probed performance or conflict monitoring, response inhibition or selection, set shifting, verbal fluency, and recognition or working memory were included. Activation likelihood estimation meta-analyses were conducted on peak voxel coordinates. Results The 283 experiments submitted to meta-analysis included 5,728 control participants and 5,493 patients with different disorders (schizophrenia, bipolar or unipolar depression, anxiety, substance use). Transdiagnostically abnormal activation was evident in the left prefrontal cortex, as well as anterior insula, right ventrolateral prefrontal cortex, right intraparietal sulcus, and mid-cingulate/pre-supplementary motor area. Disruption was also observed in a more anterior cluster in the dorsal cingulate cortex, which overlapped with a network of structural perturbation we previously observed in a transdiagnostic meta-analysis of gray matter volume. Conclusion These findings demonstrate a common pattern of disruption across major psychiatric disorders that parallels the “multiple demand network” observed in intact cognition. This network interfaces with the anterior-cingulo-insular or “salience network” demonstrated to be transdiagnostically vulnerable to gray matter reduction. Thus, networks intrinsic to adaptive, flexible cognition are vulnerable to broad spectrum psychopathology. Dysfunction in these networks may reflect an intermediate transdiagnostic phenotype, which could be leveraged to advance therapeutics.

Stimulation of the tragus activates the cerebral afferents of the vagal pathway and combined with our review of the literature suggest that taVNS is a promising form of VNS. Future taVNS/fMRI studies should systematically explore various parameters and alternative stimulation targets aimed to optimize this novel form of neuromodulation.

Guided by the diagnostic nosology, anxiety patients are expected to show defensive hyperarousal during affective challenge, irrespective of the principal phenotype. In the current study, patients representing the whole spectrum of anxiety disorders (i.e., specific phobia, social phobia, panic disorder with or without agoraphobia, obsessive-compulsive disorder, generalized anxiety disorder (GAD), posttraumatic stress disorder(PTSD)), and healthy community control participants, completed an imagery-based fear elicitation paradigm paralleling conventional intervention techniques. Participants imagined threatening and neutral narratives as physiological responses were recorded. Clear evidence emerged for exaggerated reactivity to clinically relevant imagery—most pronounced in startle reflex responding. However, defensive propensity varied across principal anxiety disorders. Disorders characterized by focal fear and impairment (e.g., specific phobia) showed robust fear potentiation. Conversely, for disorders of long-enduring, pervasive apprehension and avoidance with broad anxiety and depression comorbidity (e.g., PTSD secondary to cumulative trauma, GAD), startle responses were paradoxically diminished to all aversive contents. Patients whose expressed symptom profiles were intermediate between focal fearfulness and broad anxious-misery in both severity and chronicity exhibited a still heightened but more generalized physiological propensity to respond defensively. Importantly, this defensive physiological gradient—the inverse of self-reported distress—was evident not only between but also within disorders. These results highlight that fear circuitry could be dysregulated in chronic, pervasive anxiety, and preliminary functional neuroimaging findings suggest that deficient amygdala recruitment could underlie attenuated reflex responding. In summary, adaptive defensive engagement during imagery may be compromised by long-term dysphoria and stress—a phenomenon with implications for prognosis and treatment planning. Depression and Anxiety 29:264–281, 2012.

Background Posttraumatic stress disorder (PTSD) is characterized as a disorder of exaggerated defensive physiological arousal. The novel aim of the present research was to investigate within PTSD a potential dose-response relationship between past trauma recurrence and current comorbidity and intensity of physiological reactions to imagery of trauma and other aversive scenarios. Methods A community sample of principal PTSD (n = 49; 22 single-trauma exposed, 27 multiple-trauma exposed) and control (n = 76; 46 never-trauma exposed, 30 trauma exposed) participants imagined threatening and neutral events while acoustic startle probes were presented and the eye-blink response (orbicularis occuli) was recorded. Changes in heart rate, skin conductance level, and facial expressivity were also indexed. Results Overall, PTSD patients exceeded control participants in startle reflex, autonomic responding, and facial expressivity during idiographic trauma imagery and, though less pronounced, showed heightened reactivity to standard anger, panic, and physical danger imagery. Concerning subgroups, control participants with and without trauma exposure showed isomorphic patterns. Within PTSD, only the single-trauma patients evinced robust startle and autonomic responses, exceeding both control participants and multiple-trauma PTSD. Despite greater reported arousal, the multiple-trauma relative to single-trauma PTSD group showed blunted defensive reactivity associated with more chronic and severe PTSD, greater mood and anxiety disorder comorbidity, and more pervasive dimensional dysphoria (e.g., depression, trait anxiety). Conclusions Whereas PTSD patients generally show marked physiological arousal during aversive imagery, concordant with self-reported distress, the most symptomatic patients with histories of severe, cumulative traumatization show discordant physiological hyporeactivity, perhaps attributable to sustained high stress and an egregious, persistent negative affectivity that ultimately compromises defensive responding.

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.

Background Social phobia has been characterized as a disorder of exaggerated fear of social threat and heightened sensitivity to imagery of social failure. Methods To assess the physiological basis of this description, social phobia patients (n=75) and demographically-matched controls (n=75) imagined neutral and fearful events while acoustic startle probes were occasionally presented and eye-blink responses (orbicularis occuli) recorded. Changes in heart rate, skin conductance level, and facial expressivity were also indexed. In addition to comparing controls and social phobia patients, the influences of diagnostic subtype (circumscribed, generalized), comorbid depression, and chronicity were assessed. Results Patients exceeded controls in startle reflex and autonomic responding during imagery of social threat whereas the groups evinced commensurate reactivity to contents depicting commonly shared fears (survival threat). Individuals with circumscribed performance phobia were similar to controls, with the exception of more robust reactions to idiographic, performance fear imagery. In contrast, generalized phobic patients were characterized by longer disorder chronicity and demonstrated heightened sensitivity to a broader range of fear contents. Those with generalized phobia plus comorbid depression showed attenuation of fear-potentiated startle and reported the most protracted social anxiety. Conclusions Subtypes of social phobia can be objectively distinguished in patterns of physiological reactivity. Furthermore, subtypes vary systematically in chronicity and defensive engagement with the shortest disorder duration (circumscribed phobia) associated with the most robust and focal physiological reactivity, followed by broader defensive sensitivity in more chronic generalized phobia, and finally attenuation of the formerly exaggerated fear potentiation in the comorbidly depressed—the most chronic form.

The responses of sensory cortical neurons are shaped by experience. As a result, perceptual biases evolve, selectively facilitating the detection and identification of sensory events that are relevant for adaptive behavior. Here we examine the involvement of human visual cortex in the formation of learned perceptual biases. We use classical aversive conditioning to associate one out of a series of oriented gratings with a noxious sound stimulus. After as few as two grating-sound pairings, visual cortical responses to the sound-paired grating show selective amplification. Furthermore, as learning progresses, responses to the orientations with greatest similarity to the sound-paired grating are increasingly suppressed, suggesting inhibitory interactions between orientation-selective neuronal populations. Changes in cortical connectivity between occipital and fronto-temporal regions mirror the changes in visuo-cortical response amplitudes. These findings suggest that short-term behaviorally driven retuning of human visual cortical neurons involves distal top-down projections as well as local inhibitory interactions.

This review considers recent research assessing psychophysiological reactivity to fear imagery in anxiety disorder patients. As in animal subjects, fear cues prompt in humans a state of defensive motivation in which autonomic and somatic survival reflexes are markedly enhanced. Thus, a startle stimulus presented in a fear context yields a stronger (potentiated) reflex, providing a quantitative measure of fearful arousal. This fear potentiation is further exaggerated in specific or social phobia individuals when viewing pictures or imagining the phobic object. Paradoxically, fear imagery studies with more severe anxiety disorder patients—panic disorder with agoraphobia, generalized anxiety disorder, or anxious patients with comorbid depression—show a blunted, less robust fear potentiated response. Furthermore, this reflex blunting appears to systematically be more pronounced over the anxiety disorder spectrum, coincident with lengthier chronicity, worsening clinician-based judgments of severity and prognosis, and increased questionnaire-based indices of negative affectivity, suggesting that normal defensive reactivity may be compromised by an experience of long-term stress.