Affective Startle Modulation Research Articles

Watching with Argus eyes: Characterization of emotional and physiological responding in adults exposed to childhood maltreatment and/or recent adversity.

Exposure to adverse experiences is a well-established major risk factor for affective psychopathology. The vulnerability of deleterious sequelae is assumed in maladaptive processes of the defensive system, particularly in emotional processing. More specifically, childhood maltreatment has been suggested to be associated with the recruitment of specific and distinct defensive response profiles. To date, it remains unclear whether these are specific or generalizable to recent adversity in adulthood. This pre-registered study aimed to investigate the impact of exposure to childhood and recent adversity on emotional processing in 685 healthy adults with the "Affective Startle Modulation" Paradigm (ASM). First, we replicated higher trait anxiety and depression levels in individuals exposed to both types of adversity. Second, we observed increased general skin conductance reactivity in individuals exposed to recent adversity. Third, individuals exposed to childhood maltreatment showed reduced, while individuals exposed to recent adversity showed increased discrimination between pictures of negative and neutral valence, compared with non-exposed individuals in SCR. No association between exposure to adversity and fear potentiated startle was observed. Furthermore, explorative analyses revealed moderate dimensional and categorical agreement between two childhood maltreatment questionnaires and provide insight into potential adversity-type specific effects. Our results support experience-dependent plasticity in sympathetic nervous system reactivity and suggest distinct response profiles in affective modulation in individuals exposed to early versus recent adversity. We emphasize the need to further explore distinct adversity profiles to further our understanding on specific psychophysiological profiles and their potential implication for prevention and intervention.

Increased pupil and heart-rate responses to sexual stimuli in men after physical exertion.

Physical stress has been found to enhance arousability by visual sexual stimuli on a short-term basis, as reflected in higher phasic pupil dilation responses, probably mediated by sympathetic nervous system (SNS)-related processes. However, previous research has not addressed the specificity of this effect in terms of emotional valence, that is, whether it reflects an instance of general excitation transfer or a more specific mechanism. Thus, to further investigate changes in sexual processing after acute stress exposure, 40 male participants underwent either a predominantly sympathetic stressor (3min sustained handgrip) or similar control procedure. After stress induction, pictures varying in valence as well as sexual versus non-sexual arousal were presented (for 5000 ms each). Using principal component analysis, pupillary responses during picture viewing were dissociated into fast and slow components (early vs. late response phases). In addition, startle eyeblink responses were elicited by bursts of white noise (50 ms, 105 dB) in half of the trials and recorded at the orbicularis oculi via electromyography. Skin conductance and heart rate were co-registered, as well. While affective startle modulation and skin conductance responses to emotional stimuli were unaffected by previous stress exposure, both evoked heart-rate deceleration (but not acceleration) and pupil responses were specifically enhanced with sexually arousing stimuli in stressed participants, and this effect was mediated by blood pressure reactivity as an index of preceding SNS activation. Taken together, our findings provide strong evidence for enhancement of sexual processing by acute stress exposure in men and suggest differential involvement of parasympathetic versus sympathetic mechanisms.

Hyperreactivity and Impaired Habituation of Startle Amplitude During Unpleasant Pictures in Borderline but Not Schizotypal Personality Disorder: Quantifying Emotion Dysregulation

BackgroundBorderline personality disorder (BPD) is characterized by greater intensity of reactions to unpleasant emotional cues and a slower-than-normal return of these responses to baseline. Habituation is defined as decreased response to repeated stimulation. Affect-modulated startle (AMS), a translational psychophysiological approach, is mediated by the amygdala and used to study emotion processing in both humans and animals. This is the first study to examine the specificity of habituation anomalies in BPD during passive emotional and neutral picture processing. MethodsA total of 90 participants were studied: patients with BPD (n = 35), patients with schizotypal personality disorder (n = 26; included as a psychopathological comparison group), and healthy control subjects (n = 29). Participants received rigorous clinical assessments, and patients were unmedicated. AMS was examined during a series of intermixed unpleasant, neutral, and pleasant pictures. ResultsCompared with the other groups, patients with BPD showed greater overall AMS during unpleasant pictures and prolonged habituation of startle amplitude during unpleasant pictures from early to later trials. The groups did not differ in AMS during neutral or pleasant pictures or self-reported picture valence. Among the patients with BPD, prolonged habituation to unpleasant pictures was associated with greater symptom severity and suicidal/self-harming behavior. ConclusionsThese findings 1) indicate that abnormal processing of and habituation to unpleasant pictures is observed in BPD but not schizotypal personality disorder, suggesting that these deficits are not simply characteristics of personality disorders in general; 2) are consistent with studies showing deficient amygdala habituation to unpleasant pictures in BPD; and 3) have significant implications for clinical assessment and treatment of BPD, e.g., alternative therapies for BPD such as gradual exposure to unpleasant emotional stimuli or amygdala neurofeedback may aid habituation deficits.

Pleasant touch perception in borderline personality disorder and its relationship with disturbed body representation

BackgroundBorderline personality disorder (BPD) is characterized by altered perception of affective stimuli, including abnormal evaluation of nociceptive input. However, whether or not perceptual alterations are present for its positive counterpart, i.e. pleasant touch (PT), has not yet been examined.MethodsIn the present study, we applied standardized PT stimuli to the hands of 25 patients with BPD and 25 healthy controls (HC) and compared their perception. We used the affect-modulated acoustic startle response as a physiological correlate of affective processing. We further explored the effect of PT stimulation on dissociative experiences in BPD.ResultsCompared to HC, BPD perceived PT as less pleasant and less intense. The effect on perceived valence of touch was large even after controlling for the effect of reduced perceived intensity of touch (ƞ2 = .29). We further found qualitative alterations in touch perception in BPD, who rated the touch as significantly rougher and firmer compared to HC. There was a positive correlation between perceived valence of touch and changes in dissociative experiences in terms of body ownership of the stimulated body part from pre to post stimulation, suggesting that a more negative evaluation of touch is associated with an increase in body-related dissociative experiences, while a positive perception of touch might be related to a reduction of these dissociative experiences.ConclusionsOur results confirm BPD-associated disturbances in the processing of affective somatosensory stimuli and indicate that not only pain perception but also pleasant touch perception is diminished in BPD. We discuss the role of altered touch perception for BPD psychopathology and its potential role for new treatment approaches.

Dissociable impact of childhood trauma and deployment trauma on affective modulation of startle

Trauma disorders are often associated with alterations in aversive anticipation and disruptions in emotion/fear circuits. Heightened or blunted anticipatory responding to negative cues in adulthood may be due to differential trauma exposure during development, and previous trauma exposure in childhood may also modify effects of subsequent trauma in adulthood. The aim of the current investigation was to examine the contributions of childhood trauma on affective modulation of startle before and after trauma exposure in adulthood (a combat deployment). Adult male participants from the Marine Resilience Study with (n = 1145) and without (n = 1312) a history of reported childhood trauma completed an affective modulation of startle task to assess aversive anticipation. Affective startle response was operationalized by electromyography (EMG) recording of the orbicularis oculi muscle in response to acoustic stimuli when anticipating positive and negative affective images. Startle responses to affective images were also assessed. Testing occurred over three time-points; before going on a 7 month combat deployment and 3 and 6 months after returning from deployment. Startle response when anticipating negative images was greater compared to pleasant images across all three test periods. Across all 3 time points, childhood trauma was consistently associated with significantly blunted startle when anticipating negative images, suggesting reliable effects of childhood trauma on aversive anticipation. Conversely, deployment trauma was associated with increased startle reactivity post-deployment compared to pre-deployment, which was independent of childhood trauma and image valence. These results support the hypothesis that trauma exposure during development vs. adulthood may have dissociable effects on aversive anticipation and arousal mechanisms. Further study in women and across more refined age groups is needed to test generalizability and identify potential developmental windows for these differential effects.

Distinguishing veterans with suicidal ideation from suicide attempt history: The role of emotion reactivity.

Growing evidence suggests emotion reactivity-sensitivity and intensity of emotional experience-may represent a diathesis for suicide risk. However, our understanding of its ability to differentiate risk for suicidal ideation (SI) from suicide attempt (SA) is limited. This study compares Veterans with SI (n=81) to Veterans with SA (n=177) history on factors relevant to emotion reactivity to determine which variable(s) best differentiate groups. Variables examined are multimodal: (a) self-report: childhood trauma, combat exposure; (b) clinician-assessed: non-suicidal self-injury (NSSI), structured diagnostic interview of psychopathology; and (c) psychophysiological: affect-modulated startle (AMS; proxy for amygdala reactivity and emotion reactivity) to unpleasant pictures was examined in a subset (n=90). SA history was independently predicted by NSSI history, MDD, PTSD, and SUD diagnosis. Childhood trauma and combat exposure did not differentiate groups. The composite risk index demonstrated good accuracy (AUC=0.71, sensitivity=0.90, specificity=0.49). Only AMS independently predicted SA history when added to the model and accuracy was improved (AUC=0.82, sensitivity=0.85, specificity=0.56). NSSI history, MDD, PTSD, and SUD diagnosis may be salient risk factors for this population. However, emotion reactivity is a more parsimonious predictor of SA history among Veterans suggesting it is an important treatment target among Veterans with SI.

Attention and affect in dysphoria: Insights from startle reflex modulation and cardiac deceleration

The present study investigated the interplay between attention and affective disposition during emotional processing in dysphoria. Attentional and affective startle modulation and cardiac deceleration were assessed during the viewing of emotional pictures in 38 individuals with dysphoria and in 52 controls. Startle probes during picture viewing were presented at 300, 1500, 3500, 4500 ms after picture onset. Whereas controls showed the expected startle potentiation to unpleasant stimuli as compared to neutral and pleasant ones, individuals with dysphoria did not show any significant increase in startle reflex amplitude in response to unpleasant stimuli. Of note, startle potentiation during the viewing of unpleasant stimuli was significantly attenuated in the group with dysphoria relative to controls. Conversely, no significant effect concerning attentional startle modulation was noted. However, whereas individuals with dysphoria showed a prolonged cardiac deceleration when viewing unpleasant compared to neutral stimuli, the same effect was observed in controls only in the initial stage of stimuli processing. This study suggests that dysphoria is characterized by underactivation of the defensive motivational system and by prolonged attentional allocation to unpleasant stimuli. The assessment of affective startle modulation and cardiac deceleration is a valuable paradigm for unraveling dysfunctions in affective disposition and attention in dysphoria.

Reduced emotional responsiveness in individuals with marginal elevation in blood pressure within the normal range: Evidence from altered affect-modulated startle response

Reduced responsiveness to emotional stimuli (‘emotional dampening’) has been observed in normotensives with elevated blood pressure (BP) and hypertensives but it is not known whether this is due to aberrant responding to emotional information at the involuntary level and whether it is also associated with minimal elevations in BP in the normal range. In this study, we examined emotional dampening using the affect-modulated startle paradigm given its proven sensitivity to motivational states of approach and withdrawal, typically independent of conscious intentional control. Acoustically elicited startle eye-blink modulation was measured using electromyography of the orbicularis oculi muscle beneath the left eye in 59 healthy individuals while they viewed pleasant, unpleasant and neutral standardized pictures. The expected startle attenuation to pleasant pictures, and startle potentiation to unpleasant pictures, relative to neutral pictures, was found in people in the comparison (N = 29) but not elevated BP (N = 30) group. This finding was further supported by significant moderating effect (assessed using ANCOVA and sub-sample analysis) of BP on valence-startle amplitude relationship. The comparison BP group also showed slower latencies to response onset for pleasant stimuli compared to neutral and unpleasant, with no effect of valence in the elevated BP group. However, BP did not moderate the valence-onset latency relationship. Our findings indicate that previously reported emotional dampening associated with elevated BP extends to reduced involuntary emotional reactivity and to individuals with even minimal BP elevations (i.e. higher but still within the normal range). Future research needs to confirm these findings in hypertensive individuals, preferably using within-subjects designs.

The Neurofunctional Basis of Affective Startle Modulation in Humans: Evidence From Combined Facial Electromyography and Functional Magnetic Resonance Imaging

BackgroundThe startle eye-blink is the cross-species translational tool to study defensive behavior in affective neuroscience with relevance to a broad range of neuropsychiatric conditions. It makes use of the startle reflex, a defensive response elicited by an immediate, unexpected sensory event, which is potentiated when evoked during threat and inhibited during safety. In contrast to skin conductance responses or pupil dilation, modulation of the startle reflex is valence specific. Rodent models implicate a modulatory pathway centering on the brainstem (i.e., nucleus reticularis pontis caudalis) and the centromedial amygdala as key hubs for flexibly integrating valence information into differential startle magnitude. Technical advances now allow for the investigation of this pathway using combined facial electromyography and functional magnetic resonance imaging in humans. MethodsWe employed a multimethodological approach combining trial-by-trial facial eye-blink startle electromyography and brainstem- and amygdala-specific functional magnetic resonance imaging in humans. Validating the robustness and reproducibility of our findings, we provide evidence from two different paradigms (fear-potentiated startle, affect-modulated startle) in two independent studies (N = 43 and N = 55). ResultsWe provide key evidence for a conserved neural pathway for acoustic startle modulation between humans and rodents. Furthermore, we provide the crucial direct link between electromyography startle eye-blink magnitude and neural response strength. Finally, we demonstrate a dissociation between arousal-specific amygdala responding and triggered valence-specific amygdala responding. ConclusionsWe provide neurobiologically based evidence for the strong translational value of startle responding and argue that startle-evoked amygdala responding and its affective modulation may hold promise as an important novel tool for affective neuroscience and its clinical translation.

The role of physiological arousal for self-reported emotional empathy.

The capacity to represent the emotional and mental states of others is referred to by the concept of empathy. Empathy further differentiates into an emotional and a cognitive subcomponent, which in turn is known to require a tacit perspective-taking process. However, whether the empathizer by himself needs to enter an affective state as a necessary precondition for emotional empathy remains a matter of debate. If empathy would require a vicarious emotional reaction, specific physiological markers of affective responding should be detectable in the empathizing person. In the present study, we investigated the relationship between self-reported empathy and psychophysiological responses in young, healthy participants. We assessed emotional and cognitive empathy with the Multifaceted Empathy Test on the one hand and the corresponding heart rate and skin conductance responses (SCR), affective startle modulation and heart rate variability on the other. We found a negative relationship between SCR and self-reported emotional empathy: higher SCR to emotional stimuli predicted lower empathy ratings. We conclude that physiological arousal is not necessary and might even diminish empathy for others.

Affective startle modulation in young people with first-presentation borderline personality disorder

This study investigated psychophysiological and subjective emotional responses to an affective startle modulation paradigm in first-presentation borderline personality disorder (BPD). Twenty BPD and 20 healthy control participants, aged 15–24 years, viewed a set of standardized pictures with pleasant, neutral, or unpleasant valence, and were instructed to either “maintain” or “suppress” their emotional response to the stimuli. Despite showing markedly higher levels of baseline distress on self-report questionnaires, BPD participants had significantly lower skin conductance responses and showed an absence of the fear potentiated startle response during early picture processing. Both groups showed similar startle responses later in picture processing, and when instructed to “maintain” or “suppress” their emotions. BPD participants were hypo-responsive to aversive stimuli during early processing, and did not react with more intense emotional responses to affective stimuli or show a diminished ability to regulate their responses. These results might be consistent with the finding that hypersensitivity of emotional response in BPD is specific to stimuli with themes of particular relevance to this disorder, such as rejection and abandonment.

Startling similarity: Effects of facial self-resemblance and familiarity on the processing of emotional faces.

Facial self-resemblance has been associated with positive emotional evaluations, but this effect may be biased by self-face familiarity. Here we report two experiments utilizing startle modulation to investigate how the processing of facial expressions of emotion is affected by subtle resemblance to the self as well as to familiar faces. Participants of the first experiment (I) (N = 39) were presented with morphed faces showing happy, neutral, and fearful expressions which were manipulated to resemble either their own or unknown faces. At SOAs of either 300 ms or 3500–4500 ms after picture onset, startle responses were elicited by binaural bursts of white noise (50 ms, 105 dB), and recorded at the orbicularis oculi via EMG. Manual reaction time was measured in a simple emotion discrimination paradigm. Pictures preceding noise bursts by short SOA inhibited startle (prepulse inhibition, PPI). Both affective modulation and PPI of startle in response to emotional faces was altered by physical similarity to the self. As indexed both by relative facilitation of startle and faster manual responses, self-resemblance apparently induced deeper processing of facial affect, particularly in happy faces. Experiment II (N = 54) produced similar findings using morphs of famous faces, yet showed no impact of mere familiarity on PPI effects (or response time, either). The results are discussed with respect to differential (presumably pre-attentive) effects of self-specific vs. familiar information in face processing.

Psychophysiological endophenotypes to characterize mechanisms of known schizophrenia genetic loci.

Endophenotypes are laboratory-based measures hypothesized to lie in the causal chain between genes and clinical disorder, and to serve as a more powerful way to identify genes associated with the disorder. One promise of endophenotypes is that they may assist in elucidating the neurobehavioral mechanisms by which an associated genetic polymorphism affects disorder risk in complex traits. We evaluated this promise by testing the extent to which variants discovered to be associated with schizophrenia through large-scale meta-analysis show associations with psychophysiological endophenotypes. We genome-wide genotyped and imputed 4905 individuals. Of these, 1837 were whole-genome-sequenced at 11× depth. In a community-based sample, we conducted targeted tests of variants within schizophrenia-associated loci, as well as genome-wide polygenic tests of association, with 17 psychophysiological endophenotypes including acoustic startle response and affective startle modulation, antisaccade, multiple frequencies of resting electroencephalogram (EEG), electrodermal activity and P300 event-related potential. Using single variant tests and gene-based tests we found suggestive evidence for an association between contactin 4 (CNTN4) and antisaccade and P300. We were unable to find any other variant or gene within the 108 schizophrenia loci significantly associated with any of our 17 endophenotypes. Polygenic risk scores indexing genetic vulnerability to schizophrenia were not related to any of the psychophysiological endophenotypes after correction for multiple testing. The results indicate significant difficulty in using psychophysiological endophenotypes to characterize the genetically influenced neurobehavioral mechanisms by which risk loci identified in genome-wide association studies affect disorder risk.

Modeling startle eyeblink electromyogram to assess fear learning.

Pavlovian fear conditioning is widely used as a laboratory model of associative learning in human and nonhuman species. In this model, an organism is trained to predict an aversive unconditioned stimulus from initially neutral events (conditioned stimuli, CS). In humans, fear memory is typically measured via conditioned autonomic responses or fear‐potentiated startle. For the latter, various analysis approaches have been developed, but a systematic comparison of competing methodologies is lacking. Here, we investigate the suitability of a model‐based approach to startle eyeblink analysis for assessment of fear memory, and compare this to extant analysis strategies. First, we build a psychophysiological model (PsPM) on a generic startle response. Then, we optimize and validate this PsPM on three independent fear‐conditioning data sets. We demonstrate that our model can robustly distinguish aversive (CS+) from nonaversive stimuli (CS‐, i.e., has high predictive validity). Importantly, our model‐based approach captures fear‐potentiated startle during fear retention as well as fear acquisition. Our results establish a PsPM‐based approach to assessment of fear‐potentiated startle, and qualify previous peak‐scoring methods. Our proposed model represents a generic startle response and can potentially be used beyond fear conditioning, for example, to quantify affective startle modulation or prepulse inhibition of the acoustic startle response.

Startle amplitude during unpleasant pictures is greater in veterans with a history of multiple-suicide attempts and predicts a future suicide attempt.

Recent studies demonstrate that veterans exhibit higher suicide risk compared with the general U.S. A prior suicide attempt is a well-documented predictor of suicide death. Despite increased attention to clinical risk factors of suicide and efforts to develop psychosocial interventions to reduce suicide risk, the underlying biological factors that confer this risk are not well understood. This study examined affect-modulated startle (AMS) during a series of intermixed unpleasant, neutral, and pleasant pictures in a sample of 108 demographically-matched veterans at low (passive ideators: n = 26) and high risk (active ideators: n = 29; single attempters: n = 28; and multiple attempters: n = 25) for suicide based on the Columbia Suicide Severity Rating Scale. An exploratory aim involved a longitudinal component in a subset of the high-risk sample that went on to participate in a randomized 6-month clinical trial. We investigated whether baseline AMS predicts a subsequent suicide attempt at 12-month follow-up. Compared with the other three groups, multiple attempters showed greater startle potentiation during unpleasant pictures and deficient overall startle habituation from early to later trials. The groups did not differ in startle during neutral or pleasant pictures, or self-reported picture valence. Greater startle during unpleasant pictures was associated with greater emotion dysregulation as measured by the Difficulties in Emotion Regulation Scale and a future suicide attempt assessed prospectively at 12-month follow-up. These findings suggest that startle potentiation during unpleasant pictures in multiple-suicide attempters is a promising psychophysiological biomarker of suicide risk and underscore the clinical importance of targeting emotion dysregulation in the treatment of patients at-risk for suicide.

Evidence of anhedonia and differential reward processing in prefrontal cortex among post-withdrawal patients with prescription opiate dependence.

Anhedonia is an important but understudied element of a neuroadaptive model underlying vulnerability to relapse in opioid dependence. Previous research using fMRI has shown reduced activation to pleasant stimuli in rostral prefrontal cortex among heroin-dependent patients in early recovery. This study evaluated the presence of anhedonia among recently withdrawn prescription opiate dependent patients (PODP) in residential treatment compared to control subjects. Anhedonia was assessed using self-report, affect-modulated startle response (AMSR), and a cue reactivity task during which participant's rostral prefrontal cortex (RPFC) and ventrolateral prefrontal cortex (VLPFC) was monitored with functional near infrared spectroscopy (fNIRS). The cue reactivity task included three distinct categories of natural reward stimuli: highly palatable food, positive social situations, and intimate (non-erotic) interactions. PODP reported greater anhedonia on self-report (Snaith-Hamilton Pleasure Scale), and showed reduced hedonic response to positive stimuli in the AMSR task relative to controls. PODP also exhibited reduced neural activation in bilateral RPFC and left VLPFC in response to food images and reduced left VLPFC in response to images depicting positive social situations relative to controls. No differences were found for emotionally intimate stimuli. When patients were divided into groups based on the Snaith-Hamilton criteria for the presence or absence of anhedonia, patients endorsing anhedonia showed reduced neural responses to images depicting positive social stimuli and food relative to patients who did not endorse anhedonia. Activations were in areas of RPFC that support the retrieval of episodic memories. The results suggest the presence of anhedonia in a subsample of PODP.

Affective Modulation of Brain and Autonomic Responses in Patients With Fibromyalgia.

Emotional dysregulation and abnormal processing of affective information are thought to play a significant role for the maintenance of pain in fibromyalgia. The motivational priming hypothesis states that negative emotions could increase pain via activation of the aversive system, thus leading to an affective modulation of defensive reflexes. Nevertheless, little is known about peripheral and central correlates of affective reflex modulation in fibromyalgia. Thirty patients with fibromyalgia and 30 healthy individuals were asked to view three video clips from a self-perspective to induce specific mood states. Video clips consisted of the same virtual walk through different locations of a park under three affective environments (unpleasant, pleasant, and neutral). Startle eyeblink reflex and heart rate response elicited by abrupt startle noises, as well as heart rate variability and electroencephalography (EEG) oscillations were recorded when participants were passively viewing the virtual environments. Patients with fibromyalgia rated all environments as more negative and arousing than did healthy controls (p values < .05). Nevertheless, startle eyeblink reflex and heart rate response were lower in patients with fibromyalgia than in healthy controls when viewing all three environments (p values < .05). Patients with fibromyalgia also displayed lower heart rate variability, as well as higher EEG power (2-22 Hz) during all environments than did healthy controls (p values < .05). Patients with fibromyalgia were characterized by relevant deficits in affective modulation of startle and cardiac responses, heart rate variability, and EEG power spectra in response to sustained induction of affective states. These findings suggest an alteration of emotional and attentional aspects of information processing at subjective, autonomic, and central nervous system levels.

Startle responding in the context of visceral pain

This study aimed to investigate affective modulation of eye blink startle by aversive visceral stimulation. Startle blink EMG responses were measured in 31 healthy participants receiving painful, intermittent balloon distentions in the distal esophagus during 4 blocks (positive, negative, neutral or no pictures), and compared with startles during 3 ‘safe’ blocks without esophageal stimulations (positive, negative or neutral emotional pictures). Women showed enhanced startle during blocks with distentions (as compared with ‘safe’ blocks), both when the balloon was in inflated and deflated states, suggesting that fear and/or expectations may have played a role. Men's startle did not differ between distention and non-distention blocks. In this particular study context affective picture viewing did not further impose any effect on startle eye blink responses. The current results may contribute to a better understanding of emotional reactions to aversive interoceptive stimulation.

The effects of the CACNA1C rs1006737 A/G on affective startle modulation in healthy males

BackgroundThe CACNA1C rs1006737 risk A allele has been associated with affective psychoses and functional studies indicate that it is associated with increased hippocampal/amygdala activity during emotional face-processing. Here we studied the impact of the risk A allele on affective startle modulation. MethodsHundred and ninety-four healthy males stratified for their CACNA1C rs1006737 genotype (GG:111, GA:67, AA:16) were presented with 18 pleasant, 18 unpleasant and 18 neutral pictures with acoustic probes (104dB) occurring during 12 pictures in each affective category. Baseline startle was assessed during blank screens. State mood was self-rated on arrival, pre- and post-test and the emotional valence and arousal of affective pictures at post-test. ResultsRelative to the other genotypes, risk A allele homozygotes presented with higher anxiety/negative affect at pre-test, reduced and exaggerated physiological responses to the pleasant and negative pictures respectively, negative affect with reduced arousal at post-test and rated the affective pictures as less arousing and inconsistently to their physiological responses (all P<0.05). Sustained contextual negative mood predicted reduced baseline and affective startle reactivity in the AA group. ConclusionsHealthy homozygous males for the risk A allele appear to have marked contextual sensitivity, affective reactivity akin to anxiety and depression and inefficient emotional appraisal. Our findings provide phenotypic detail of the CACNA1C AA genotype in non-symptomatic individuals, which suggest primary effects in emotional circuitry, consistent with previously documented alterations in hippocampal/amygdala processing.

Possible evidence for re-regulation of HPA axis and brain reward systems over time in treatment in prescription opioid-dependent patients.

There is growing evidence for a neuroadaptive model underlying vulnerability to relapse in opioid dependence. The purpose of this study was to evaluate clinical measures hypothesized to mirror elements of allostatic dysregulation in patients dependent on prescription opioids at 2 time points after withdrawal, compared with healthy control participants. Recently withdrawn (n = 7) prescription opioid-dependent patients were compared with the patients in supervised residential care for 2 to 3 months (extended care; n = 7) and healthy controls (n = 7) using drug cue reactivity, affect-modulated startle response tasks, salivary cortisol, and 8 days of sleep actigraphy. Prefrontal cortex was monitored with functional near-infrared spectroscopy during the cue reactivity task. Startle response results indicated reduced hedonic response to natural rewards among patients recently withdrawn from opioids relative to extended care patients. The recently withdrawn patients showed increased activation to pill stimuli in right dorsolateral prefrontal cortex relative to extended care patients. Cortisol levels were elevated among recently withdrawn patients and intermediate for extended care relative to healthy controls. Actigraphy indicated disturbed sleep between recently withdrawn patients and extended care patients; extended care patients were similar to controls. Dorsolateral prefrontal cortex activation to drug and natural reward cues, startle responses to natural reward cues, day-time cortisol levels, time in bed, and total time spent sleeping were all correlated with the number of days since last drug use (ie, time in supervised residential treatment). These results suggest possible re-regulation of dysregulated hypothalamic-pituitary-adrenal axis and brain reward systems in prescription opioid-dependent patients over the drug-free period in residential treatment.