Template MRI scans reliably approximate individual and group-level tES and TMS electric fields induced in motor and prefrontal circuits.

Background: Electric field (E-field) modeling is a valuable method of elucidating the cortical target engagement from transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES), but it is typically dependent on individual MRI scans. In this study, we systematically tested whether E-field models in template MNI-152 and Ernie scans can reliably approximate group-level E-fields induced in N = 195 individuals across 5 diagnoses (healthy, alcohol use disorder, tobacco use disorder, anxiety, depression). Methods: We computed 788 E-field models using the CHARM-SimNIBS 4.0.0 pipeline with 4 E-field models per participant (motor and prefrontal targets for TMS and tES). We additionally calculated permutation analyses to determine the point of stability of E-fields to assess whether the 152 brains represented in the MNI-152 template is sufficient. Results: Group-level E-fields did not significantly differ between the individual vs. MNI-152 template and Ernie scans for any stimulation modality or location (p > 0.05). However, TMS-induced E-field magnitudes significantly varied by diagnosis; individuals with generalized anxiety had significantly higher prefrontal and motor E-field magnitudes than healthy controls and those with alcohol use disorder and depression (p < 0.001). The point of stability for group-level E-field magnitudes ranged from 42 (motor tES) to 52 participants (prefrontal TMS). Conclusion: MNI-152 and Ernie models reliably estimate group-average TMS and tES-induced E-fields transdiagnostically. The MNI-152 template includes sufficient scans to control for interindividual anatomical differences (i.e., above the point of stability). Taken together, using the MNI-152 and Ernie brains to approximate group-level E-fields is a valid and reliable approach.

Transcutaneous Auricular Vagus Nerve Stimulation Attenuates Early Increases in Heart Rate Associated With the Cold Pressor Test.

INTRODUCTION: Transcutaneous auricular vagus nerve stimulation (taVNS) may be useful in treating disorders characterized by chronic parasympathetic disinhibition. Acute taVNS decreases resting heart rate in healthy individuals, but little is known regarding the effects of taVNS on the cardiac response to an acute stressor. To investigate effects on the acute stress response, we investigated how taVNS affected heart rate changes during a cold pressor test (CPT), a validated stress induction technique that reliably elicits a sympathetic stress response with marked increases in heart rate, anxiety, stress, and pain. MATERIALS AND METHODS: We recruited 24 healthy adults (ten women, mean age = 29 years) to participate in this randomized, crossover, exploratory trial. Each subject completed two taVNS treatments (one active, one sham) paired with CPTs in the same session. Order of active versus sham stimulation was randomized. Heart rate, along with ratings of anxiety, stress, and pain, was collected before, during, and after each round of taVNS/sham + CPT. RESULTS: In both stimulation conditions, heart rate was elevated from baseline in response to the CPT. Analyses also revealed a difference between active and sham taVNS during the first 40 seconds of the CPT (Δ heart rate [HR] = 12.75 ± 7.85 in the active condition; Δ HR = 16.09 ± 11.43 in the sham condition, p = 0.044). There were no significant differences in subjective ratings between active and sham taVNS. CONCLUSIONS: In this randomized, sham-controlled study, taVNS attenuated initial increases in HR in response to the CPT. Future studies are needed to investigate the effects of various taVNS doses and parameters on the CPT, in addition to other forms of stress induction. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT00113453.

Neurophysiology of predictable unpleasant event processing in pre-adolescents and early adolescents, part II: Reflex and event-related potential markers of defensive reactivity and peripheral attention modulation.

The ability to anticipate and process predictable unpleasant events, while also regulating emotional reactivity, is an adaptive skill. The current article and a companion in this issue test for potential changes in predictable event processing across the childhood-to-adolescence transition, a key developmental period for biological systems that support cognitive/ emotional abilities. While the companion article focuses on neurophysiology of predictable event processing itself, the present article examines peripheral emotional response regulation and attention modulation that coincides with event processing. A total of 315 third-, sixth-, or ninth-grade individuals saw 5-s cues predicting "scary," "every day," or uncertain pictures, and here, blink reflexes and brain event-related potentials (ERPs) elicited by peripheral noise probes are analyzed. During the cue, blink reflexes and probe ERP (P200) amplitudes were increased when the cue predicted scary, compared to everyday, content. After picture onset, reflex enhancement by scary content then disappeared for predictable images, whereas ERP modulation was similar regardless of predictability. Patterns are similar to those in adults and suggest (1) sustained defensive response priming and enhancement of peripheral attention during aversive anticipation, and (2) an ability, even in pre-adolescents, to downregulate defensive priming while maintaining attentional modulation once an awaited predictable aversive event occurs.

Neurophysiology of predictable unpleasant event processing in preadolescents and early adolescents, part I: Event-related potential markers of unpleasant image anticipation and processing.

The ability to anticipate and process predictable unpleasant events, while also regulating emotional reactivity, is an adaptive skill. The current article and a companion in this issue test for potential changes in predictable event processing across the childhood-to-adolescence transition, a key developmental period for biological systems that support cognitive/emotional abilities. While the companion article focuses on emotion regulation and peripheral attention modulation in predictable unpleasant contexts, the current paper presents neurophysiological markers of predictable event processing itself. 315 third-, sixth-, or ninth-grade individuals saw 5-s cues predicting "scary," "every day," or uncertain image content; in this paper, cue- and picture-locked event-related potentials (ERPs) are analyzed. During the cue, early ERP positivities were increased and later slow-wave negativities were reduced when predicted content was scary as compared with mundane. After picture onset, a picture processing-related positivity was then increased for scary compared with everyday images regardless of predictability. Cue-interval data suggest enhanced processing of scary cues and reduced anticipatory processing of scary images-opposite to adults. After event onset, meanwhile, emotional ERP enhancement regardless of predictability is similar to adults and suggests that even preadolescent individuals maintain preferential engagement with unpleasant events when they are predictable.

Coping in the Clinic: Effects of Clinically Elevated Anxiety on Dynamic Neurophysiological Mechanisms of Escape/Avoidance Preparation.

BACKGROUND: Treatments for anxiety and related disorders target exaggerated escape/avoidance as a core feature, but current methods fail to improve escape/avoidance habits for many treatment-seeking individuals. To support developing tools that increase treatment efficacy by targeting mechanisms more directly, the current work examined potential distinctions in the neurophysiologies of escape and avoidance and tested how clinical anxiety affects these neurophysiologies. METHODS: Twenty-five treatment-seeking individuals with varied principal diagnoses (e.g., generalized anxiety disorder, posttraumatic stress disorder) and 20 non-treatment-seeking control subjects participated. In the study task, approximately 5.25-second cues predicted aversive images that could be avoided (blocked by a button press before image onset), escaped (ended by a button press after image onset), or not controlled. To examine neural processing and defensive response modulation, anticipatory event-related potentials were derived, and startle reflexes were probed throughout each cue. RESULTS: Multidimensional profiles were observed such that 1) anticipatory event-related potential enhancement was only reliable during avoidance preparation, and event-related potentials potentially reflected perceived/instrumental control; and 2) startle reflexes were inhibited during avoidance preparation, relatively enhanced during escape preparation, and further enhanced during uncontrollable anticipation, thus potentially reflecting fear-related activation. Treatment-seeking status, then, did not affect cortical processing, but it did moderate context-dependent fear (if individuals with severe depression were excluded) such that treatment-seeking individuals without depression showed exaggerated startle during escape, but not avoidance, preparation. CONCLUSIONS: Data suggest a specific effect of anxiety on fear system activation during preparation to escape aversion. This effect warrants further investigation as a precision target for interventions that directly modulate the specific underlying neural circuitry.

Anxiety-related shifts in smell function in children and adolescents.

Anxious adults show changes in smell function that are consistent with a durable shift in sensitivity toward particular odorants and away from others. Little is known regarding the development of these changes, including whether they exist in youth, are stable during the transition from childhood to adolescence, and whether odorant properties (e.g. trigeminal features, hedonic valence) affect anxiety-related differences in detection. To address this, we measured smell detection thresholds to phenyl ethyl alanine (PEA), a rose-like odorant with little trigeminal properties, and guaiacol (GUA), a smoke-like odorant with high trigeminal properties. These thresholds were measured at baseline and after an acute stress challenge, the Trier Social Stress Tests, in 131 healthy youth (in 4th, 7th, and 10th grades, age 9-16 years) that reported normal to elevated levels of anxiety. At baseline, high anxious youth exhibited heightened sensitivity to GUA coupled with reduced sensitivity to PEA, as well as a further exaggeration of this bias with acute stress. Importantly, sex, age, and hedonic valence moderated the relationship between trait anxiety and sensitivity to both odorants. Smell function and its aberrations are often overlooked in the literature on biomarkers of stress and anxiety. Taken together with the extant literature, these findings suggest that greater attention is warranted to characterize potential novel olfactory therapeutic targets-across the lifespan.

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.

The Startle-Evoked Potential: Negative Affect and Severity of Pathology in Anxiety/Mood Disorders.

BACKGROUND: The National Institute of Mental Health Research Domain Criteria initiative encourages a search for dimensional biological measures of psychopathology unconstrained by current diagnostic categories. Consistent with this aim, the presented research studies a large sample of anxiety and mood disorder patients, assessing differences in principal diagnoses and comorbidity patterns, clinicians' ratings, and questionnaire measures of negative affect and life dysfunction as they relate to a potential brain marker of pathology: the amplitude of the event-related potential (ERP) elicited by a startle-evoking stimulus. METHODS: Patients seeking evaluation or treatment for anxiety and mood disorders (N = 208) participated in two tasks at the University of Florida (Gainesville, FL): 1) imagining emotional and neutral events and 2) viewing emotional and neutral pictures while acoustic startle probes were presented and the ERP was recorded. For a comparison patient group (N = 120), startle probes were administered and ERPs recorded at the University of Greifswald (Greifswald, Germany) while performing the same imagery task. RESULTS: Reduced positive amplitude of a centroparietal startle-evoked ERP (156-352 ms after onset) significantly predicted higher questionnaire scores of anxiety/depression, reports of increased life dysfunction, greater comorbidity, and clinician ratings of heightened severity and poorer prognosis. The effect was general across principal diagnoses, found for both the Florida and German samples, and consistent in pattern despite differences in the tasks administered. CONCLUSIONS: The startle-evoked ERP reliably predicts severity and breadth of psychopathology, independent of task context. It is a potential significant contributor to a needed array of biological measures that might improve classification of anxiety and mood disorders.

Neural activation and memory for natural scenes: Explicit and spontaneous retrieval.

Stimulus repetition elicits either enhancement or suppression in neural activity, and a recent fMRI meta-analysis of repetition effects for visual stimuli (Kim, 2017) reported cross-stimulus repetition enhancement in medial and lateral parietal cortex, as well as regions of prefrontal, temporal, and posterior cingulate cortex. Repetition enhancement was assessed here for repeated and novel scenes presented in the context of either an explicit episodic recognition task or an implicit judgment task, in order to study the role of spontaneous retrieval of episodic memories. Regardless of whether episodic memory was explicitly probed or not, repetition enhancement was found in medial posterior parietal (precuneus/cuneus), lateral parietal cortex (angular gyrus), as well as in medial prefrontal cortex (frontopolar), which did not differ by task. Enhancement effects in the posterior cingulate cortex were significantly larger during explicit compared to implicit task, primarily due to a lack of functional activity for new scenes. Taken together, the data are consistent with an interpretation that medial and (ventral) lateral parietal cortex are associated with spontaneous episodic retrieval, whereas posterior cingulate cortical regions may reflect task or decision processes.

Avoidance and escape: Defensive reactivity and trait anxiety.

Although avoidance and escape behaviors each contribute to maintaining anxiety disorders, only avoidance completely eliminates exposure to the aversive context. Current research compared anticipatory defensive engagement when aversion could either be completely avoided or escaped after initial exposure; in addition, this research examined the impact of trait anxiety on coping-related defensive engagement. Cues signaled that upcoming rapid action would avoid (block), escape (terminate), or not affect subsequent aversive exposure; the acoustic startle reflex was measured during each anticipatory interval to index defensive engagement, and blink magnitudes were compared across low-, moderate-, and high-anxious individuals. For all participants, startle was potentiated when aversive exposure was uncontrollable and attenuated when aversion was avoidable. On escape trials, on the other hand, startle potentiation increased with rising participant anxiety. Results suggest 1) defensive engagement is generally reduced in avoidance contexts relative to contexts in which exposure is certain, and; 2) trait anxiety increases defensive engagement specifically when aversive exposure can be controlled but remains certain.

A direct comparison of appetitive and aversive anticipation: Overlapping and distinct neural activation.

fMRI studies of reward find increased neural activity in ventral striatum and medial prefrontal cortex (mPFC), whereas other regions, including the dorsolateral prefrontal cortex (dlPFC), anterior cingulate cortex (ACC), and anterior insula, are activated when anticipating aversive exposure. Although these data suggest differential activation during anticipation of pleasant or of unpleasant exposure, they also arise in the context of different paradigms (e.g., preparation for reward vs. threat of shock) and participants. To determine overlapping and unique regions active during emotional anticipation, we compared neural activity during anticipation of pleasant or unpleasant exposure in the same participants. Cues signalled the upcoming presentation of erotic/romantic, violent, or everyday pictures while BOLD activity during the 9-s anticipatory period was measured using fMRI. Ventral striatum and a ventral mPFC subregion were activated when anticipating pleasant, but not unpleasant or neutral, pictures, whereas activation in other regions was enhanced when anticipating appetitive or aversive scenes.

Escaping aversive exposure.

This research examined human defensive reactivity when exposure to an aversive event could be escaped but not entirely avoided. Prolonged visual cues indicated whether exposure to an upcoming aversive (i.e., disgusting) picture could be terminated after onset (escaped) or not, or that a neutral go signal would appear. Acoustically elicited startle reflexes were measured during each cue interval, as were cardiac and skin conductance activity. Early in the cuing interval, startle reflexes were potentiated during both escape and inescapable exposure trials, compared to the simple motor context. Later in the interval, reflexes remained potentiated for both escapable and inescapable trials, with potentiation further enhanced when aversive exposure could not be escaped compared to when exposure could be escaped. Heart rate deceleration in the cuing interval indicated increased vigilance when preparing any (escape or neutral) action, whereas skin conductance responding indicated enhanced sympathetic action mobilization particularly in an escape context. These data suggest that startle reflexes engaged in an escape context reflect both motor-related response inhibition and aversive potentiation, and they indicate that defensive motivation is engaged whenever aversive exposure is guaranteed, regardless of whether it can be escaped or not.

Emotional Modulation of the Late Positive Potential during Picture Free Viewing in Older and Young Adults.

Hedonic bias during free viewing of novel emotional and neutral scenes was investigated in older adults and college students. A neurophysiological index of emotional picture processing-the amplitude of the centroparietal late positive potential (LPP)-was recorded from the scalp using a dense sensor array while participants (29 older adults; 21 college students) viewed emotionally engaging or mundane natural scenes that varied in specific content. Both students and older adults showed LPP enhancement when viewing affective, compared to neutral, scenes, and there was no difference in LPP amplitude between older individuals and college students when viewing neutral everyday scenes. However, compared to the college students, older individuals showed attenuated LPP amplitude when viewing emotional scenes, regardless of hedonic valence or specific content. Age related differences could be mediated by a reduction in reactive emotional arousal with age, possible mediated by repeated life exposure to emotional stimuli.

Prediction and perception: Defensive startle modulation.

Previous research indicates that predictive cues can dampen subsequent defensive reactions. The present study investigated whether effects of cuing are specific to aversive stimuli, using modulation of the blink startle reflex as a measure of emotional reactivity. Participants viewed pictures depicting violence, romance/erotica, or mundane content. On half of all trials, a cue (color) predicted the content of the upcoming picture; on the remaining trials, scenes were presented without a cue. Acoustic startle probes were presented during picture viewing on trials with predictive cues and trials without a cue. Replicating previous studies, blink reflexes elicited when viewing violent pictures that had not been preceded by a cue were potentiated compared to uncued mundane scenes, and reflexes were attenuated when viewing scenes of erotica/romance that had not been cued. On the other hand, reflex potentiation when viewing scenes of violence (relative to mundane scenes) was eliminated when these pictures were preceded by a predictive cue, whereas scenes of romance prompted reliable reflex attenuation regardless of whether pictures were cued or not. Taken together, the data suggest that cuing elicits an anticipatory coping process that is specific to aversive stimuli.

Startle modulation during emotional anticipation and perception.

The startle reflex is potentiated when anticipating emotional, compared to neutral, pictures. This study investigated the time course of reflex modulation during anticipation and the impact of informative cuing on picture perception. Colors were used to signal the thematic content of emotional and neutral scenes; blink response modulation was measured by presenting acoustic startle probes 3, 2, or 1 s before picture onset or 2 s after picture onset. During anticipation of neutral scenes, blink magnitude showed increasing attenuation as picture onset approached, consistent with a modality-directed vigilance account. Conversely, when anticipating emotional scenes, reflex magnitude did not change over time, and blinks elicited closest to picture onset were potentiated compared to neutral. During perception, the expected reflex potentiation for unpleasant pictures was not found, suggesting that cuing may dampen defensive activation.

Emotional processing in borderline personality disorder.

This study examines whether individuals with borderline personality disorder (BPD) would exhibit augmented emotional responses to picture stimuli after being challenged with an ideographic interpersonal conflict script. Participants were 24 adults diagnosed with BPD, 23 adults diagnosed with obsessive-compulsive personality disorder (OCPD), and 28 normal controls. Participants viewed emotionally evocative pictures before and after listening to the interpersonal script while a variety of physiological measures were recorded. Findings indicated that the interpersonal script was effective in eliciting enduring emotional responses from the BPD group relative to the control groups. However, despite the effectiveness of the interpersonal challenge task, there were no group differences in emotional responding to the affect eliciting stimuli. The findings underscore the complexities involved in examining emotional dysregulation in BPD in a laboratory setting.

Development of a borderline personality disorder-relevant picture stimulus set.

Individuals with borderline personality disorder (BPD) report erratic and poorly regulated emotional behavior. However, these abnormalities have not been confirmed in laboratory studies. This may be because the emotional stimuli employed have not been sufficiently relevant or evocative of psychological themes germane to BPD (e.g., threats to attachment). The aim of this study was to develop a picture stimulus set relevant to BPD that could be employed in research to examine emotion dysregulation thought to be central to BPD. Ninety pictures were initially selected from the International Affective Picture System that had putative interpersonal and social content across a range of pleasantness and intensity. The set was then rated by 19 clinical BPD research experts on two dimensions: How self-referential the picture would be to someone with BPD and the extent to which the picture represented an ideal-other to a prototypic BPD case. Two sets of pictures were generated for future research with BPD participants.