Conditioned Autonomic Responses Research Articles

Dimensionality and optimal combination of autonomic fear-conditioning measures in humans

Fear conditioning, also termed threat conditioning, is a commonly used learning model with clinical relevance. Quantification of threat conditioning in humans often relies on conditioned autonomic responses such as skin conductance responses (SCR), pupil size responses (PSR), heart period responses (HPR), or respiration amplitude responses (RAR), which are usually analyzed separately. Here, we investigate whether inter-individual variability in differential conditioned responses, averaged across acquisition, exhibits a multi-dimensional structure, and the extent to which their linear combination could enhance the precision of inference on whether threat conditioning has occurred. In a mega-analytic approach, we re-analyze nine data sets including 256 individuals, acquired by the group of the last author, using standard routines in the framework of psychophysiological modeling (PsPM). Our analysis revealed systematic differences in effect size between measures across datasets, but no evidence for a multidimensional structure across various combinations of measures. We derive the statistically optimal weights for combining the four measures and subsets thereof, and we provide out-of-sample performance metrics for these weights, accompanied by bias-corrected confidence intervals. We show that to achieve the same statistical power, combining measures allows for a relevant reduction in sample size, which in a common scenario amounts to roughly 24%. To summarize, we demonstrate a one-dimensional structure of threat conditioning measures, systematic differences in effect size between measures, and provide weights for their optimal linear combination in terms of maximal retrodictive validity.

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.

Human serotonin transporter availability predicts fear conditioning

Serotonin facilitates fear learning in animals. We therefore predicted that individual differences in the capacity to regulate serotonergic transmission in the human neural fear circuit would be inversely related to fear conditioning. The capacity to regulate serotonergic transmission was indexed by serotonin transporter availability measured with [11C]-DASB positron emission tomography. Results indicate that lower serotonin transporter availability in the amygdala, insula and dorsal anterior cingulate cortex predicts enhanced conditioned autonomic fear responses. Our finding supports serotonergic modulation of fear conditioning in humans and may aid in understanding susceptibility for developing anxiety conditions such as post-traumatic stress disorder.

The effects of autonomic arousal on speech production in adults who stutter: A preliminary study

The purpose of this study was to investigate the influence of autonomic system reactivity and response on the speech production of people who stutter. Participants included three adults who stutter (AWS) and three who did not (AWNS). An aversive acoustic stimulus was paired with a set of neutral pictures to condition an autonomic system response as measured by skin conductance response (SCR). Speech production probes were placed in trials where a conditioned autonomic response was expected in order to record fundamental frequency (F0) and temporal acoustic measures of segments of speech from utterances at different levels of autonomic arousal. Analyses of SRC indicated that AWS had a significantly greater autonomic response to the aversive stimulus compared to AWNS. All of the AWS, but none of the AWNS, acquired a conditioned response. In addition, AWS exhibited F0, voice onset time, and frication durations that were positively correlated with SCR. This study provides evidence that AWS show a greater susceptibility to classical conditioning, along with higher autonomic reactivity and related changes in speech production than AWNS. Findings are discussed as they pertain to risk factors in the development of stuttering.

Lesions of Ventrolateral Prefrontal or Anterior Orbitofrontal Cortex in Primates Heighten Negative Emotion

Heightened fear and anxiety are core symptoms of a variety of neuropsychiatric disorders. They are associated with structural and activity changes throughout neural circuitry that includes the ventral and medial prefrontal cortices (PFC), the amygdala, and hippocampus. Although the contributions of the medial PFC, amygdala, and hippocampus to fear and anxiety have been studied extensively with animal models, the selective roles of the ventral PFC-including the ventrolateral prefrontal cortex (vlPFC) and orbitofrontal cortex-are poorly understood. We investigated the effects of selective excitotoxic lesions of either the vlPFC or anterior orbitofrontal cortex (antOFC) on anxious behavior and Pavlovian conditioned autonomic and behavioral fear responses in the New World primate, the common marmoset. Both vlPFC and antOFC lesions resulted in stronger, less adaptable conditioned fear responses. They also heightened the anxiety responses of a marmoset to a human intruder. In contrast, only a lesion of the vlPFC affected the coping style that a marmoset displayed in the presence of the human intruder, increasing the likelihood of proactive mobbing. These results suggest that both the antOFC and vlPFC can downregulate fear and anxiety and, together, provide necessary but independent contributions to the top-down control of negative emotion.

Serotonin at the level of the amygdala and orbitofrontal cortex modulates distinct aspects of positive emotion in primates.

Impaired top-down regulation of the amygdala, and its modulation by serotonin (5-HT), is strongly implicated in the dysregulation of negative emotion that characterizes a number of affective disorders. However, the contribution of these mechanisms to the regulation of positive emotion is not well understood. This study investigated the role of 5-HT within the amygdala and the orbitofrontal cortex (OFC), on the expression of appetitive Pavlovian conditioned emotional responses and their reversal in a primate, the common marmoset. Its effects were compared to those of the amygdala itself. Having developed conditioned autonomic and behavioural responses to an appetitive cue prior to surgery, marmosets with excitotoxic amygdala lesions failed to display such conditioned autonomic arousal at retention, but still displayed intact cue-directed conditioned behaviours. In contrast, 5,7-DHT infusions into the amygdala, reducing extracellular 5-HT levels, selectively enhanced the expression of appetitive conditioned behaviour at retention. Similar infusions into the OFC, producing marked reductions in post-mortem 5-HT tissue levels, had no overall effect on autonomic or behavioural responses, either at retention or during reversal learning, but caused an uncoupling of these responses, thereby fractionating emotional output. These data demonstrate the critical role of the amygdala in the expression of appetitive autonomic conditioning, and the region-selective contribution of 5-HT in the amygdala and OFC, respectively, to the expression of conditioned behaviour and the overall coordination of the emotional response. They provide insight into the neurochemical mechanisms underlying the regulation of positive emotional responses, advancing our understanding of the neural basis of pathologically dysregulated emotion.

Autonomic, behavioral, and neural analyses of mild conditioned negative affect in marmosets.

Avoidance and alerting behaviors and accompanying physiological responses, including changes in heart rate (HR), are core components of negative emotion. Investigations into the neural mechanisms underlying the regulation and integration of these responses require animal models that simultaneously measure both the physiological and behavioral components of emotion. A primate model is of particular importance in view of the well developed prefrontal cortex of primates, and this region's critical role in emotion regulation and the etiology of affective disorders. Therefore, we have developed a simple aversive conditioning paradigm to assess, simultaneously, cardiovascular and behavioral responses in the marmoset (Callithrix jacchus). Validation of the paradigm was achieved by (1) comparing conditioned responses to a predictive cue with pseudoconditioned responses to a nonpredictive cue; (2) assessing the acquisition of conditioning following lesions of the amygdala, a region essential for associative learning in humans and rats; and (3) determining the contributions of the sympathetic and parasympathetic nervous system to the conditioned autonomic responses. Marmosets acquired conditioned HR and behavioral responses in the conditioned, but not the pseudoconditioned or amygdala lesioned groups. Conditioned HR accelerations were reduced by both parasympathetic and sympathetic blockade. Thus, a model of associative learning of mild negative emotion in the marmoset has been validated by psychological, neurological, and pharmacological investigation. Future studies will determine the role of the prefrontal cortex in the regulation of these negative emotional responses, to provide insights into the neuropathology of affective disorders.

Synergistic and Regulatory Effects of Orbitofrontal Cortex on Amygdala‐Dependent Appetitive Behavior

This paper will review two avenues of our research in marmosets that have focused on the role of the orbitofrontal cortex (OFC) in amygdala-dependent appetitive behavior. The first demonstrates the important contribution of both the OFC and the amygdala to conditioned reinforcement (CRF). The second reveals the regulatory effects of the OFC on amygdala-dependent autonomic and behavioral arousal in appetitive conditioning. The process of CRF is one way in which an environmental cue can guide emotional behavior. As a consequence of its previous relationship with reward, a cue can take on affective value and reinforce behavior. Lesion studies in marmosets are described that show that CRF is dependent upon both the amygdala and OFC. The synergistic interactions between these structures that have been shown to underlie other aspects of reward processing are then considered with respect to CRF. The results are contrasted with those that show the importance of the OFC in suppressing positive affective responses elicited by the amygdala in response to a conditioned stimulus (CS). Specifically, it will be shown that the OFC is involved in the rapid suppression of conditioned autonomic arousal upon CS withdrawal and in the co-ordination of conditioned autonomic and behavioral responses when adapting to changing reward contingencies. It will be argued that, overall, the OFC plays a critical role in the context-dependent regulation of positive affective responding governed by external cues, in keeping with a role in executive control.

Origin of EEG biofeedback for remediating misbehavior.

ABSTRACT In the 1960s, behavior therapy techniques were emerging from the laboratory. These techniques were proving successful in changing a variety of behavioral problems. In the area of psychiatric rehabilitation, Quirk learned to apply Mary Cover Jones' method of desensitization to psychotics despite Wolpe's self-reported inability to make Reciprocal Inhibition Therapy (RIT) work with psychotics. Von Hilsheimer suggested that he monitor stress by Galvanic Skin Resistance (GSR) and Quirk developed a library of lanternslides to substitute for verbal statements in the Wolpe hierarchies of stressful stimuli. He automated this method and named it. SCARS (Stimulus Conditioned Autonomic Response Suppression). This method was later used in offender rehabilation with correctional populations. This paper reviews this history. Quirk then applied the same methods and Sterman's EEG biofeedback training (increasing SMR at C-3/C-4) in a pilot study of 40 matched pairs of jailed felons at the Ontario Correctional Institute (OCI) near Toronto, Canada; and in a larger pilot study of 110 matched pairs. From 1970 through 1995 Quirk and von Hilsheimer trained 2776 felons at the OCI by this combined method (temperature, GSR and EEG). 15% were rearrested in the 3 years following release. This compares well to the range of re-arrest in studies summarized by Alter et al (1996)--42 % to 78%. This line of research represents an early beginning to the field of applied behavioral neurology and the work has strong implications for behavior analysts treating offenders today. Keywords: EEG biofeedback, behavior therapy, applied behavioral neurology, desensitization, offender treatment Introduction In the late 1950s, behavior therapy based on operant and respondent conditioning procedures moved out of the laboratory (see Wolpe, 1958) and into the direct treatment of people. Many of the procedures were used to reduce anxiety (e.g., Paul, 1966 or Lang, and Lazovik, 1963). Basic research studies were showing that operant conditioning procedures could be applied without the subject's awareness and could change autonomic responses (Gavalas, 1967). Studies at Harvard Medical showed that operant conditioning could be used through biofeedback technology to change blood flow and blood pressure (Shapiro, Crider, Tursky, 1964; Shapiro & Crider, 1967; Shapiro, Tursky, & Schwartz, 1970; Schwartz, 1973) and studies with post stroke patients, cerebral palsy, spinal injuries showed that biofeedback could restore motor control (Basmajian, 1977; Fernando & Basmajian, 1978; Runck, 1980). This encouraged many in clinical practice to begin to experiment with the idea of directly manipulating brainwave frequencies through operant procedures, which were correlated with behavioral disruption. This research could be seen as the early beginning of work called applied behavioral neuroscience (today referred to as Neurotherapy), as you will see it is a area of research that might be of value to current behavior analysts, especially those working within the prison or criminal justice systems. This paper represents a brief and at times a personal history of this area. INTRODUCTION: ICTAL AND SUBICTAL DYSFUNCTION Two of Quirk's colleagues, North and Breen, liked a method of scoring the Bender-Gestalt published in a book by Hutt. However, the Bender figures weren't really adaptable to the Hutt method. So North and Breen created new figures and called the test the Diagnostic Differential Test (DDT). Quirk took a course in administering the DDT and became expert at its interpretation. One of the neurologists on staff who used Doug as a consultant gave him a list of 10 patients, whose serial EEGs eventually demonstrated epilepsy but who did not have seizures. He was asked what test to use to figure out how to recognize them more reliably than with the EEG. Doug found a file into which he had put the DDT's those individuals' had taken. …

The cardiovascular and behavioral response to cat odor in rats: unconditioned and conditioned effects

Cardiovascular and behavioral responses were recorded in rats during exposure to cat odor. Rats were habituated to an open rectangular arena that contained a small enclosed wooden box in which they could hide. On day 1 of the experiment, after 30 min in the apparatus, rats were presented with a piece of fabric collar for 60 min. On day 2, rats were presented with an identical piece of fabric collar, except that it had been worn by a cat and therefore exuded cat odor. On day 3, rats were again presented with an unworn cat collar, to determine any conditioned responses to the environment or stimulus (collar) previously associated with cat odor. Results showed significantly increased blood pressure and decreased activity during exposure to cat odor as well as avoidance of the odor stimulus and an increase in vigilance and risk-assessment measures. No significant change in heart rate was found during cat odor exposure. On day 3, a transient increase in blood pressure was seen as well as reduced activity and a range of defensive behaviors. This suggests some conditioning of fear to a context in which cat odor had previously been experienced. Heart rate was also significantly decreased on day 3. A transient rise in blood pressure was also seen when the unworn cat collar was placed into the apparatus on day 3, suggesting a conditioned response to a stimulus that has been previously associated with cat odor. This study demonstrates that a natural stressful stimulus can induce both unconditioned and conditioned autonomic and behavioral responses.

Nonaware classical conditioning to pictorial facial stimuli in a between-groups paradigm

The present experiment investigated the effects of aware and nonaware modes of extinction in classical conditioning to facial emotional stimuli. The subjects participated in three different experimental phases. In the first (habituation) phase they were presented with a 500 ms angry face. In the second (acquisition) phase, for half of the subjects the 500 ms face was paired with an aversive noise (experimental group) while for the other half of the subjects the face and the noise presentations were separated by 6-10 s intervals (sensitization control group). In the third (extinction) phase, these two groups were further divided into two subgroups. One subgroup of both the experimental and control group had the face stimulus presented for 30 ms, and immediately masked with a neutral picture. The other two subgroups had the face presented for 500 ms with no mask. The results showed that conditioning only occurred in the experimental subgroups which was indicated by a significant difference between skin conductance responses during habituation and corresponding responses during extinction. Secondly, comparing the experimental and control groups during the extinction phase, a significant conditioning effect was observed for both the aware and nonaware masked modes of extinction for the experimental group. The results suggest that conditioned autonomic responses may be elicited in a nonaware mode.

Conditioned salivation and associated dreams from REM sleep.

Although research has investigated the feasibility of establishing classically conditioned physiological responses during sleep, very few experimental studies have considered whether classically conditioned cognitive associations are possible. Since dreams have previously been described as a state of “hyper-association,” an experiment involving classical conditioning of the human salivary response and associated dream content was conducted. During wakefulness, repeated pairings of a conditioned stimulus (CS; a red light) with an unconditioned stimulus (UCS; citrus juice) yielded a conditioned autonomic response (CR; salivation) on presentation of the CS alone. After exposure to the CS during REM sleep, salivary excretion rates measured upon awakening were significantly higher than measures taken from baseline REM awakenings. However, no CR-related dreams were reported by the participants. This result could be interpreted as evidence that participants in this experiment did not experience higher-order memory associations to the external stimuli presented during REM. Alternatively, the lack of CR-related dreams could be explained by previous findings that the autonomic nervous system often works independently of higher-order cognitive activity. Therefore, if an autonomic association is formed, this does not necessarily imply a cognitive one.

Retention of conditioned autonomic and behavioral responses in preweanling rats: Forgetting and reinstatement

Preweanling rats, 16 days of age, responded to an olfactory conditioned stimulus (CS) paired with a shock unconditioned stimulus (US) with increases in heart rate and behavioral activation. In two experiments this finding was replicated and, in addition, it was found that the form of these conditioned responses (CRs) changed after a retention interval. When tested 24 h after CS-US pairings, the subjects displayed a decrease in heart rate accompanied by CS-elicited freezing. Giving two unsignaled shocks prior to the delayed test effectively reinstated the tachycardia and behavioral arousal CRs. The results are discussed in terms of contextual influences on the form of the CR and how changes in the magnitude of context fear may alter responding to an olfactory CS.

Autonomic and behavioral correlates of appetitive conditioning in rats.

The cardiac responses accompanying conditioned stimulus- (CS)-generated (orienting) and unconditioned stimulus- (US)-generated appetitively motivated behaviors (P. C. Holland, 1977) were investigated. On the basis of contemporary psychophysiological research, CS-generated responses were predicted to produce bradycardia, and US-generated responses to produce tachycardia. Pairing a 10-s visual CS with food delivery produced conditioned behavioral orienting (rearing) during the initial portion of the CS, followed by magazine approach (US-generated) responses as the CS progressed. CS onset produced a decrease in heart rate, mediated by an increase in parasympathetic stimulation of the heart, which persisted throughout the 10-s CS; no support for a biphasic cardiac response was observed. These data are discussed with respect to other conditioned autonomic responses and their relevance to foraging and food ingestion.

Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans.

A patient with selective bilateral damage to the amygdala did not acquire conditioned autonomic responses to visual or auditory stimuli but did acquire the declarative facts about which visual or auditory stimuli were paired with the unconditioned stimulus. By contrast, a patient with selective bilateral damage to the hippocampus failed to acquire the facts but did acquire the conditioning. Finally, a patient with bilateral damage to both amygdala and hippocampal formation acquired neither the conditioning nor the facts. These findings demonstrate a double dissociation of conditioning and declarative knowledge relative to the human amygdala and hippocampus.

Purkinje cell responses in the anterior cerebellar vermis during Pavlovian fear conditioning in the rabbit

Extracellular single-unit recordings of Purkinje cells in the anterior cerebellar vermis (ACV) of the rabbit found evidence of short-latency (20-30 ms) differential responses to discriminatively-conditioned auditory stimuli during Pavlovian fear conditioning procedures. These differential unit responses appeared to be a function of learning as differential ACV Purkinje cell responses were not observed in naive (untrained) animals. Some of these evoked neurophysiological responses were also correlated with the behavioral conditioned autonomic response. (CAR); a conditioned bradycardiac response. These electrophysiological data, coupled with previous lesion results, suggest that the ACV is part of an important neural circuit for Pavlovian conditioned bradycardia.

Calcitonin gene‐related peptide (CGRP) immunoreactive projections from the thalamus to the striatum and amygdala in the rat

The organization of calcitonin gene-related peptide-like immunoreactive (CGRPir) innervation of the amygdala and caudate-putamen in the rat was examined by using immunohistochemistry for CGRP combined with retrograde transport of the fluorescent dye fluoro-gold, as well as anterograde transport of Phaseoleus vulgaris leucoagglutinin (PHA-L). The lateral part of the central nucleus of the amygdala and the amygdalostriatal transition zone was densely innervated by CGRPir terminals at all anterior-posterior levels. More caudally, the lateral part of the caudate-putamen also had large numbers of CGRPir terminals. Injections of fluoro-gold into the amygdala and amygdalostriatal transition area followed by immunohistochemistry for CGRP revealed double-labeled neurons in the subparafascicular, lateral subparafascicular, and posterior intralaminar nuclei of the thalamus and peripeduncular nucleus. Injections into the caudate-putamen demonstrated double-labeled neurons in the more lateral parts of this same nuclear complex. PHA-L injections into the posterior thalamic nuclei from which the CGRPir projections arise confirmed the medial-to-lateral organization of the projections to the amygdala and striatum. The subparafascicular nucleus and the rostral portion of the lateral subparafascicular nucleus primarily projected to the medial amygdala and the amygdalostriatal transition area, while the more lateral cell groups, including the caudal part of the lateral parafascicular, posterior intralaminar, and peripeduncular nuclei projected to the lateral amygdala and the caudate-putamen. These CGRPir projections may be involved in mediating conditioned autonomic and behavioral responses to acoustic stimuli or somatosensory stimuli.

Face the Beast and Fear the Face: Animal and Social Fears as Prototypes for Evolutionary Analyses of Emotion

ABSTRACTThis paper applies a functional‐evolutionary perspective to fear in the context of encounters with animals and threatening humans. It is argued that animal fear originates in a predatory defense system whose function is to allow animals to avoid and escape predators. Animal stimuli are postulated to be differentially prepared to become learned elicitors of fear within this system. Social fears are viewed as originating in a dominance/submissiveness system. The function of submissiveness is to avert attacks from dominating conspecifics. Signs of dominance paired with aversive outcomes provide for learning fear to specific individuals. Data which in general are interpreted as supportive of this conceptualization are reviewed. To explain the mechanism behind the causal relationships suggested in the evolutionary analysis, an information‐processing model is presented and empirically tested. It is argued that responses to evolutionary fear‐relevant stimuli can elicit the physiological concomitants of fear after only a very quick, “unconsciousness,’ or preattentive stimulus analysis. Support for this notion is presented from backward masking studies where it is demonstrated that conditioned autonomic responses to fear‐relevant stimuli can be elicited even with masked stimuli.

Facial expressions as excitatory and inhibitory stimuli for conditioned autonomic responses

Several lines of evidence suggest that emotional responses to facial expressions of emotion have a biological basis. The present study involved 4 experiments where pictures of angry, happy or neutral facial expressions were used as conditioned stimuli in aversive Pavlovian electrodermal conditioning. From an evolutionary perspective it was expected that an angry face should have an excitatory effect on aversively conditioned responses, whereas a happy face should have an inhibitory effect. It was also expected that the effect should be specific for the stimulus person showing the display. The data showed that the stimulus person was a critical mediating factor for obtaining persistent conditioning effects, that is to say, responses which showed resistance to extinction. Persistent responding was primarily manifested when the stimulus person displayed anger during extinction. On the other hand, this effect was inhibited when the person displayed a happy face during extinction. Furthermore, resistance to extinction was increased or decreased dependent on whether the person expressed anger or happiness during acquisition. Thus, consistent with predictions, angry and happy faces exhibited an excitatory and inhibitory effect, respectively, and these effects were mediated by the stimulus person.

Human conditioned compensatory response to alcohol cues: Initial evidence

Alcohol cues elicited a conditioned autonomic response that was opposite in direction to the effect of alcohol. Normal male social drinkers given placebo following four alcohol conditioning sessions showed a compensatory response consisting of decreased pulse transit time, vasomotor activity, and finger temperature. This pilot research supports the application of a classical conditioning model to human alcohol problems.