Imaging distributed and massed repetitions of natural scenes: spontaneous retrieval and maintenance.

Repetitions that are distributed (spaced) across time prompt enhancement of a memory-related event-related potential, compared to when repetitions are massed (contiguous). Here, we used fMRI to investigate neural enhancement and suppression effects during free viewing of natural scenes that were either novel or repeated four times with massed or distributed repetitions. Distributed repetition was uniquely associated with a repetition enhancement effect in a bilateral posterior parietal cluster that included the precuneus and posterior cingulate and which has previously been implicated in episodic memory retrieval. Unique to massed repetition, conversely, was enhancement in a right dorsolateral prefrontal cluster that has been implicated in short-term maintenance. Repetition suppression effects for both types of spacing were widespread in regions activated during novel picture processing. Taken together, the data are consistent with a hypothesis that distributed repetition prompts spontaneous retrieval of prior occurrences, whereas massed repetition prompts short-term maintenance of the episodic representation, due to contiguous presentation. These processing differences may mediate the classic spacing effect in learning and memory.

Encoding and reinstatement of threat: recognition potentials.

On a recognition test, stimuli originally encoded in the context of shock threat show an enhanced late parietal positivity during later recognition compared to stimuli encoded during safety, particularly for emotionally arousing stimuli. The present study investigated whether this ERP old/new effect is further influenced when a threat context is reinstated during the recognition test. ERPs were measured in a yes-no recognition test for words rated high or low in emotional arousal that were encoded and recognized in the context of cues that signaled threat of shock or safety. Correct recognition of words encoded under threat, irrespective of reinstatement, was associated with an enhanced old-new ERP difference (500-700ms; centro-parietal), and this difference was only reliable for emotionally arousing words. Taken together, the data suggest that information processed in a stressful context are associated with better recollection on later recognition, an effect that was not modulated by reinstating the stressful context at retrieval.

Allogeneic hematopoietic cell transplantation for adult metachromatic leukodystrophy: a case series.

ABSTRACT: Metachromatic leukodystrophy (MLD) is a rare genetic disorder caused by pathogenic variants of the ARSA gene, leading to a deficiency of the arylsulfatase A enzyme (ARSA) and consecutive accumulation of galactosylceramide-3-0-sulfate in the nervous system. The condition leads to severe neurological deficits and subsequently results in profound intellectual and motoric disability. Especially, the adult form of MLD, which occurs in individuals aged >16 years, poses significant challenges for treating physicians because of the rarity of cases, limited therapeutic options, and different allogeneic hematopoietic cell transplantation (allo-HCT) protocols worldwide. Here, we report the results of allo-HCT treatment in 4 patients with a confirmed adult MLD diagnosis. Bone marrow or mobilized peripheral progenitor cells were infused after a reduced intensity conditioning regime consisting of fludarabine and treosulfan. In 3 patients, allo-HCT was followed by an infusion of mesenchymal cells to further consolidate ARSA production. We observed a good tolerability and an increase in ARSA levels up to normal range values in all patients. A full donor chimerism was detected in 3 patients within the first 12 months. In a 1-year follow-up, patients with complete donor chimerism showed a neurological stable condition. Only 1 patient with an increasing autologous chimerism showed neurological deterioration and a decline in ARSA levels in the first year. In summary, allo-HCT offers a therapeutic option for reconstituting ARSA enzyme levels in adult patients with MLD, with tolerable side effects.

Perceptual processing of natural scenes at rapid rates: effects of complexity, content, and emotional arousal.

During rapid serial visual presentation (RSVP), the perceptual system is confronted with a rapidly changing array of sensory information demanding resolution. At rapid rates of presentation, previous studies have found an early (e.g., 150-280 ms) negativity over occipital sensors that is enhanced when emotional, as compared with neutral, pictures are viewed, suggesting facilitated perception. In the present study, we explored how picture composition and the presence of people in the image affect perceptual processing of pictures of natural scenes. Using RSVP, pictures that differed in perceptual composition (figure-ground or scenes), content (presence of people or not), and emotional content (emotionally arousing or neutral) were presented in a continuous stream for 330 ms each with no intertrial interval. In both subject and picture analyses, all three variables affected the amplitude of occipital negativity, with the greatest enhancement for figure-ground compositions (as compared with scenes), irrespective of content and emotional arousal, supporting an interpretation that ease of perceptual processing is associated with enhanced occipital negativity. Viewing emotional pictures prompted enhanced negativity only for pictures that depicted people, suggesting that specific features of emotionally arousing images are associated with facilitated perceptual processing, rather than all emotional content.

Imagery, emotion, and bioinformational theory: From body to brain.

The bioinformational theory of emotional imagery is a model of the hypothetical mental representations activated when people imagine emotionally engaging events, and was initially proposed to guide research and practice in the use of imaginal exposure as a treatment for fear and anxiety (Lang, 1979). In this 50 year overview, we discuss the development of bioinformational theory and its impact on the study of psychophysiology and psychopathology, most importantly assessing its viability and predictions in light of more recent brain-based studies of neural functional activation. Bioinformational theory proposes that narrative imagery, typically cued by language scripts, activates an associative memory network in the brain that includes stimulus (e.g., agents, contexts), semantic (e.g., facts and beliefs) and, most critically for emotion, response information (e.g., autonomic and somatic) that represents relevant real-world coping actions and reactions. Psychophysiological studies in healthy and clinical samples reliably find measurable response output during aversive and appetitive narrative imagery. Neuroimaging studies confirm that emotional imagery is associated with significant activation in motor regions of the brain, as well as in regions implicated in episodic and semantic memory retrieval, supporting the bioinformational view that narrative imagery prompts mental simulation of events that critically includes the actions and reactions engaged in emotional contexts.

Hippocampal and amygdala volumes vary with transdiagnostic psychopathological dimensions of distress, anxious arousal, and trauma.

Reduced hippocampal and/or amygdala volumes have been reported in patients with a variety of different anxiety diagnoses, suggesting that structural alterations may vary transdiagnostically across the internalizing disorders. The current study measured hippocampal and amygdala volumes in anxiety and mood disorder patients assessing differences that vary dimensionally with transdiagnostic factors of distress, anxious arousal, and trauma, based on a principal components analysis of questionnaires relating to symptomology. High-resolution structural images were collected in a sample of 165 patients, and volumes extracted from the hippocampal formation (including CA1, CA2/3, CA4/DG, subiculum, and molecular layer) and the amygdala. Transdiagnostically, increasing distress was associated with reduced hippocampal CA1 volume, increasing anxious arousal was associated with reduced hippocampal CA4/DG volume, and increasing trauma severity was associated with reduced amygdala volume in women. Taken together, the data indicate that subcortical brain volumes decrease as the severity of transdiagnostic psychopathological symptomology increases.

Dimensional distress and orbitofrontal thickness in anxiety patients.

Thickness of the medial orbitofrontal cortex (mOFC) was assessed as it varied with reported symptoms of anxiety and depression in a large sample of anxiety patients. A principal component analysis identified a primary factor of transdiagnostic dimensional distress that predicted 24% of the mOFC variance. Severity of distress symptomology was associated with thinning of the mOFC in both hemispheres for both men and women, regardless of the primary DSM diagnosis. Taken together, the data indicate that mOFC thickness might be useful as an objective measure of disorder severity as well as to assess pharmacological or psychological treatment outcome.

Tagging cortical networks in emotion: a topographical analysis.

Viewing emotional pictures is associated with heightened perception and attention, indexed by a relative increase in visual cortical activity. Visual cortical modulation by emotion is hypothesized to reflect re-entrant connectivity originating in higher-order cortical and/or limbic structures. The present study used dense-array electroencephalography and individual brain anatomy to investigate functional coupling between the visual cortex and other cortical areas during affective picture viewing. Participants viewed pleasant, neutral, and unpleasant pictures that flickered at a rate of 10 Hz to evoke steady-state visual evoked potentials (ssVEPs) in the EEG. The spectral power of ssVEPs was quantified using Fourier transform, and cortical sources were estimated using beamformer spatial filters based on individual structural magnetic resonance images. In addition to lower-tier visual cortex, a network of occipito-temporal and parietal (bilateral precuneus, inferior parietal lobules) structures showed enhanced ssVEP power when participants viewed emotional (either pleasant or unpleasant), compared to neutral pictures. Functional coupling during emotional processing was enhanced between the bilateral occipital poles and a network of temporal (left middle/inferior temporal gyrus), parietal (bilateral parietal lobules), and frontal (left middle/inferior frontal gyrus) structures. These results converge with findings from hemodynamic analyses of emotional picture viewing and suggest that viewing emotionally engaging stimuli is associated with the formation of functional links between visual cortex and the cortical regions underlying attention modulation and preparation for action.

The anxiety spectrum and the reflex physiology of defense: from circumscribed fear to broad distress.

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.

Neural correlates of repeated retrieval of emotional autobiographical events.

Understanding the neural correlates of repetitive retrieval of emotional events is critical in addressing pathological emotional processing, as repeated processing is central for a number of different therapeutic interventions. In the current study, single-trial functional brain activity was assessed in key regions implicated in episodic retrieval, including the medial prefrontal cortex (mPFC), anterior hippocampus, posterior hippocampus, and the posteromedial parietal cortex (i.e., posterior cingulate cortex and the precuneus) following repeated retrieval of pleasant and unpleasant autobiographical events. Replicating previous studies, repetition prompted reduced blood-oxygen-level-dependent (BOLD) amplitude in the anterior hippocampus and the mPFC, but not in the posterior hippocampus, due to no functional activity during mental imagery, or in the posteromedial parietal cortex, due to enhanced activation that was sustained across repetitions. Neural activation during pleasant and unpleasant autobiographical retrieval did not differ as a function of repetition, indicating similar processing effects regardless of motivational relevance. Taken together, the hedonic valence of retrieved memories does not affect functional activity associated with repeated retrieval of episodic events, in which the pattern of BOLD amplitude change suggests a dissociation between the hippocampal-prefrontal circuit, which shows repetition suppression, and the posteromedial parietal cortex, which shows sustained activation.

Narrative imagery: Emotional modulation in the default mode network.

The default mode network (DMN) is activated when constructing and imagining narrative events, with functional brain activity in the medial-prefrontal cortex hypothesized to be modulated during emotional processing by adding value (or pleasure) to the episodic representation. However, since enhanced reactivity during emotional, compared to neutral, content is a more frequent finding in both the brain and body in physiological, neural, and behavioral measures, the current study directly assesses the effects of pleasure and emotion during narrative imagery in the DMN by using a within-subject design to first identify the DMN during resting state and then assess activation during pleasant, neutral, or unpleasant imagery. Replicating previous findings, enhanced functional activity in the medial prefrontal cortex was found when imagining pleasant, compared to unpleasant, events. On the other hand, emotion-related activation was found when imagining either pleasant or unpleasant, compared to neutral, events in other nodes of the DMN including the posterior cingulate cortex (PCC), angular gyrus, anterior hippocampus, lateral temporal cortex, temporal pole, dorsomedial prefrontal cortex (dmPFC), and ventrolateral prefrontal cortex (vlPFC). Pervasive emotional modulation in the DMN is consistent with the view that a primary function of event retrieval and construction is to remember, recreate, and imagine motivationally relevant events important for planning adaptive behavior.

Social vision: sustained perceptual enhancement of affective facial cues in social anxiety.

Heightened perception of facial cues is at the core of many theories of social behavior and its disorders. In the present study, we continuously measured electrocortical dynamics in human visual cortex, as evoked by happy, neutral, fearful, and angry faces. Thirty-seven participants endorsing high versus low generalized social anxiety (upper and lower tertiles of 2104 screened undergraduates) viewed naturalistic faces flickering at 17.5 Hz to evoke steady-state visual evoked potentials (ssVEPs), recorded from 129 scalp electrodes. Electrophysiological data were evaluated in the time-frequency domain after linear source space projection using the minimum norm method. Source estimation indicated an early visual cortical origin of the face-evoked ssVEP, which showed sustained amplitude enhancement for emotional expressions specifically in individuals with pervasive social anxiety. Participants in the low symptom group showed no such sensitivity, and a correlational analysis across the entire sample revealed a strong relationship between self-reported interpersonal anxiety/avoidance and enhanced visual cortical response amplitude for emotional, versus neutral expressions. This pattern was maintained across the 3500 ms viewing epoch, suggesting that temporally sustained, heightened perceptual bias towards affective facial cues is associated with generalized social anxiety.

The impact of anxiety on the neural processing of respiratory sensations.

Previous studies demonstrated that anxiety considerably impacts the reported perceptions of respiratory sensations. A novel feature of the current study is exploring the impact of anxiety on the neural processing of respiratory sensations elicited by short inspiratory occlusions during different affective contexts. Using high-density EEG, respiratory-related evoked potentials (RREP) were recorded in 23 low and 23 matched higher anxious individuals when viewing unpleasant or neutral picture series. Low anxious individuals showed the expected pattern of reduced magnitudes of later RREP components P2 and P3 during the unpleasant compared to the neutral affective context (p<0.05 and p<0.01). In contrast, higher anxious individuals showed greater magnitudes of P2 and P3 during the unpleasant compared to the neutral affective context (p's<0.05). Moreover, higher anxiety levels were correlated with greater magnitudes for P2 (r=0.44, p<0.01) and P3 (r=0.54, p<0.001) during the unpleasant relative to the neutral affective context. Earlier components of the RREP (Nf, P1, N1) were not affected by anxiety. This study demonstrates that anxiety affects the later, higher-order neural processing of respiratory sensations, but not its earlier, first-order sensory processing. These findings might represent a neural mechanism that underlies the increased perception of respiratory sensations in anxious individuals.

Trauma-related dysfunction in the fronto-striatal reward circuit.

INTRODUCTION: Reduced reactivity to pleasurable stimulation is a defining symptom of post-traumatic stress disorder (PTSD), but trauma exposure also increases the severity of many anxiety and mood disorders, including depression, social anxiety, and panic disorder, suggesting that reward system dysfunction might be pervasive in the internalizing disorders. The ventromedial prefrontal cortex (vmPFC) and ventral striatum are core components of the reward circuit and the current study assesses functional activity and connectivity in this circuit during emotional picture viewing in anxiety and mood disorder patients. METHOD: Functional brain activity (fMRI) and functional connectivity in the fronto-striatal circuit were measured in a large sample of patients diagnosed with anxiety and mood disorders (n=155) during affective scene viewing as it varied with trauma exposure and temperament. RESULTS: In women, but not men, blunted fronto-striatal connectivity was associated with increased posttraumatic anhedonic symptoms, whereas the amplitude of functional activity was not related to trauma exposure. In both men and women, reduced fronto-striatal connectivity was associated with decreases in temperamental positive affect. When predicting fronto-striatal connectivity, temperament and posttraumatic symptomology accounted for independent proportions of variance. LIMITATIONS: In this civilian sample of anxiety disorder patients, men reported very little trauma-related symptomology. CONCLUSIONS: Because dysfunctional reward processing due to trauma and temperament is pervasive across the internalizing disorder spectrum, assessing the integrity of the fronto-striatal reward circuit could provide important information in diagnostic and treatment protocols.

The timing of emotional discrimination in human amygdala and ventral visual cortex.

Models of visual emotional perception suggest a reentrant organization of the ventral visual system with the amygdala. Using focused functional magnetic resonance imaging in humans with a sampling rate of 100 ms, here we determine the relative timing of emotional discrimination in amygdala and ventral visual cortical structures during emotional perception. Results show that amygdala and inferotemporal visual cortex differentiate emotional from nonemotional scenes approximately 1 s before extrastriate occipital cortex, whereas primary occipital cortex shows consistent activity across all scenes. This pattern of discrimination is consistent with a reentrant organization of emotional perception in visual processing, in which transaction between rostral ventral visual cortex and amygdala originates the identification of emotional relevance.

Detecting novelty and significance.

Studies of cognition often use an "oddball" paradigm to study effects of stimulus novelty and significance on information processing. However, an oddball tends to be perceptually more novel than the standard, repeated stimulus as well as more relevant to the ongoing task, making it difficult to disentangle effects due to perceptual novelty and stimulus significance. In the current study, effects of perceptual novelty and significance on ERPs were assessed in a passive viewing context by presenting repeated and novel pictures (natural scenes) that either signaled significant information regarding the current context or not. A fronto-central N2 component was primarily affected by perceptual novelty, whereas a centro-parietal P3 component was modulated by both stimulus significance and novelty. The data support an interpretation that the N2 reflects perceptual fluency and is attenuated when a current stimulus matches an active memory representation and that the amplitude of the P3 reflects stimulus meaning and significance.

Emotional imagery: assessing pleasure and arousal in the brain's reward circuitry.

Research on emotional perception and learning indicates appetitive cues engage nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), whereas amygdala activity is modulated by the emotional intensity of appetitive and aversive cues. This study sought to determine patterns of functional activation and connectivity among these regions during narrative emotional imagery. Using event-related fMRI, we investigate activation of these structures when participants vividly imagine pleasant, neutral, and unpleasant scenes. Results indicate that pleasant imagery selectively activates NAc and mPFC, whereas amygdala activation was enhanced during both pleasant and unpleasant imagery. NAc and mPFC activity were each correlated with the rated pleasure of the imagined scenes, while amygdala activity was correlated with rated emotional arousal. Functional connectivity of NAc and mPFC was evident throughout imagery, regardless of hedonic content, while correlated activation of the amygdala with NAc and mPFC was specific to imagining pleasant scenes. These findings provide strong evidence that pleasurable text-driven imagery engages a core appetitive circuit, including NAc, mPFC, and the amygdala.

Memory and event-related potentials for rapidly presented emotional pictures.

Dense array event-related potentials (ERPs) and memory performance were assessed following rapid serial visual presentation (RSVP) of emotional and neutral pictures. Despite the extremely brief presentation, emotionally arousing pictures prompted an enhanced negative voltage over occipital sensors, compared to neutral pictures, replicating previous encoding effects. Emotionally arousing pictures were also remembered better in a subsequent recognition test, with higher hit rates and better discrimination performance. ERPs measured during the recognition test showed both an early (250-350 ms) frontally distributed difference between hits and correct rejections, and a later (400-500 ms), more centrally distributed difference, consistent with effects of recognition on ERPs typically found using slower presentation rates. The data are consistent with the hypothesis that features of affective pictures pop out during rapid serial visual presentation, prompting better memory performance.

Motivated action: Pupil diameter during active coping.

Pupil diameter is dynamically modulated by a number of factors, including emotion, motor activity, and attention. Here, pupil modulation was examined as it varies with locus of control during aversive processing. Participants could control aversive exposure either by escape (terminating the event) or avoidance (blocking the event entirely), or they had no control. Highly anxious (n = 19), moderately anxious (n = 23), and less anxious (n = 23) participants saw cues that signaled whether a fast button press would terminate, prevent, or not affect subsequent presentation of an aversive picture. Pupil diameter was measured throughout the cuing interval. Pupil diameter was larger when preparing to escape or avoid compared to anticipating uncontrollable exposure. All participants, regardless of reported anxiety, showed increased pupil diameter in coping, relative to uncontrollable, contexts. Results support hypotheses that pupil diameter reflects action preparation and that differences in trait anxiety do not modulate this aspect of coping behavior in healthy subjects.

Assessing the role of the amygdala in fear of pain: Neural activation under threat of shock.

INTRODUCTION: The DSM-5 explicitly states that the neural system model of specific phobia is centered on the amygdala. However, this hypothesis is predominantly supported by human studies on animal phobia, whereas visual cuing of other specific phobias, such as dental fear, do not consistently show amygdala activation. Considering that fear of anticipated pain is one of the best predictors of dental phobia, the current study investigated neural and autonomic activity of pain anticipation in individuals varying in the degree of fear of dental pain. METHOD: Functional brain activity (fMRI) was measured in women (n = 31) selected to vary in the degree of self-reported fear of dental pain when under the threat of shock, in which one color signaled the possibility of receiving a painful electric shock and another color signaled safety. RESULTS: Enhanced functional activity during threat, compared to safety, was found in regions including anterior insula and anterior/mid cingulate cortex. Importantly, threat reactivity in the anterior insula increased as reported fear of pain increased and further predicted skin conductance changes during pain anticipation. LIMITATIONS: The sample was comprised of women. CONCLUSIONS: Individual differences in fear of pain vary with activation in the anterior insula, rather than with the amygdala, indicating that fear is not uniquely associated with amygdala activation. Whereas coping techniques such as emotion regulation have been found to vary with activation in a frontal-amygdala circuit when confronted with visual cues, precision psychiatry may need to target specific brain circuits to diagnose and treat different types of specific phobia.