Hemispheric Asymmetry and Human Electrodermal Conditioning: The Dichotic Extinction Paradigm

It was hypothesized that classically conditioned responses to an auditory verbal CS initially presented only to the left cerebral hemisphere would be greater than when the same CS was presented to the right hemisphere. The experiment consisted of three different phases in a dichotic extinction paradigm. During the habituation phase the CS+ and CS? were presented binaurally, and separated. All subjects were treated alike. During the acquisition phase the conditioning subjects had the CS+ but not the CS? followed by the UCS. The CS+ and CS? were presented binaurally and separated. The control subjects received no UCS presentations. During the dichotic extinction phase, half of the conditioned subjects had the CS+ presented in the right ear (i.e., with initial left hemisphere input), with the CS? simultaneously presented in the left ear (i.e., with initial right hemisphere input). The other half had the earphones reversed. The control group was similar to the two conditioning groups. During the acquisition phase, significantly larger electrodermal responses were observed to the CS+ compared to the CS? in the conditioning groups, but not in the control group. During the dichotic extinction phase, significantly more resistance to extinction was observed in the CS+ Right-Ear group compared to the CS+ Left-Ear group, with the control group revealing virtually no responding at all. It was concluded that the present results have demonstrated effects of cerebral asymmetry on rate of extinction of the classically conditioned response.     

Hemispheric Asymmetry in Conditioning to Facial Emotional Expressions

In the present experiment, we report a right hemisphere advantage for autonomic conditioning to facial emotional expressions. Specifically, angry, but not happy, facial expressions showed significantly more resistance to extinction when presented initially to the right as compared to the left hemisphere. Slides of happy and angry faces were used as conditioned stimuli (CS+ and CS-) with shock as the unconditioned stimulus (UCS). Half of the subjects (n = 15) had the angry face as CS+ (and the happy face as CS-), the other half had the happy face as CS+ (and the angry face as CS-). During acquisition, the CSs were presented foveally. During extinction, using the Visual Half-Field (VHF) technique, half of the CS+ and CS- trials were randomly presented in the right visual half-field (initially to the left hemisphere), and half of the trials were presented in the left half-field (initially to the right hemisphere). Stimuli were presented for 210 ms during acquisition, and for 30 ms during extinction. Bilateral skin conductance responses (SCRs) were recorded. The results showed effects of acquisition only for the angry CS+ group. During extinction, there was a significant Conditioning X Half-field interaction which was due to greater SCRs to the CS+ angry face when it was presented in the left half-field. It is concluded that the present results reveal hemisphere asymmetry effects in facial emotional conditioning.     

Fear conditioning and extinction: influence of sex and menstrual cycle in healthy humans

Although sex differences have been demonstrated in behavioral paradigms of fear conditioning, the findings have been inconsistent, and fear extinction has been little studied. The present study investigated the influence of sex and menstrual cycle phase on the recall of fear extinction. Three groups of healthy adult participants were studied: women at 2 different phases of the menstrual cycle (early follicular [early cycle] and late follicular [midcycle]) and men. Participants underwent a 2-day fear conditioning and extinction protocol. The paradigm entailed habituation, fear conditioning, and extinction learning on Day 1 and extinction recall and fear renewal on Day 2. Skin conductance served as the dependent variable. During fear acquisition on Day 1, men showed significantly larger conditioned responses relative to women; early cycle and midcycle women did not differ. No significant group differences were found during extinction learning. On Day 2, men and early cycle women expressed greater extinction memory than midcycle women. These data confirm sex differences in conditioned fear acquisition and suggest that midcycle hormones attenuate extinction recall.     

A right‐ear bias of auditory selective attention is evident in alpha oscillations

Auditory selective attention makes it possible to pick out one speech stream that is embedded in a multispeaker environment. We adapted a cued dichotic listening task to examine suppression of a speech stream lateralized to the nonattended ear, and to evaluate the effects of attention on the right ear's well‐known advantage in the perception of linguistic stimuli. After being cued to attend to input from either their left or right ear, participants heard two different four‐word streams presented simultaneously to the separate ears. Following each dichotic presentation, participants judged whether a spoken probe word had been in the attended ear's stream. We used EEG signals to track participants' spatial lateralization of auditory attention, which is marked by interhemispheric differences in EEG alpha (8–14 Hz) power. A right‐ear advantage (REA) was evident in faster response times and greater sensitivity in distinguishing attended from unattended words. Consistent with the REA, we found strongest parietal and right frontotemporal alpha modulation during the attend‐right condition. These findings provide evidence for a link between selective attention and the REA during directed dichotic listening.     

Cortical control of human classical conditioning: Autonomic and positron emission tomography data

A recent positron emission tomography (PET) study on brain mechanisms in classical, or Pavlovian, conditioning is reviewed. The PET data were compared with skin conductance data recorded off-line. The participants were five men who participated in three different experimental phases. In the first (habituation) phase, a tone was repeated 24 times at random intervals. In the second (acquisition) phase, the tone was paired with a brief shock to the wrist. In the third (extinction) phase, the tone was presented alone again. Statistical parametric mapping analysis of the PET data showed significantly increased activation of the right hemisphere in the orbitofrontal cortex, dorsolateral prefrontal cortex, inferior and superior frontal cortices, and inferior and middle temporal cortices. In the left hemisphere, only Area 19 and the superior frontal cortex showed significant activation. The findings are discussed within a theoretical framework that argues for different brain mechanisms in acquisition and extinction in classical conditioning.     

Differential conditioning to facial emotional expressions: effects of hemispheric asymmetries and CS identification

Previous studies on aversive learning have suggested a right hemispheric advantage for eliciting autonomic reactions to a masked conditioned facial stimulus (CS) depicting anger. The present study investigated the effects of visual field (VF), stimulus awareness, and emotional valence of the CSs on indicators of conditioning (bilateral SCRs, HR) using a differential conditioning paradigm (N = 41). In Group 1, four different negatively valenced facial expressions (CS+) but not four positively valenced CS- were associated with an unconditioned stimulus (US, aversive vocalization, 97 dB, 3 s) during acquisition. Group 2 received a treatment reversal with positive CS+ associated with the US. In a repeated measures design, CSs were presented with or without awareness during extinction (two weeks interval, order counterbalanced). SOAs were adapted for each subject and condition prior to the experiment so that identification performance was approaching chance level. The results revealed that both negative and positive facial expressions could be aversively conditioned providing evidence for a generalization of learning in the valence dimension. During extinction, preattentive negative CS+ presented to the left VF showed a trend towards greater electrodermal and cardiac reactions. However, no such effect emerged under full awareness of the CSs. These results confirm and further specify the nature of hemispheric asymmetries in emotional associative learning.     

Brain morphology correlates of interindividual differences in conditioned fear acquisition and extinction learning

The neural circuits underlying fear learning have been intensively investigated in pavlovian fear conditioning paradigms across species. These studies established a predominant role for the amygdala in fear acquisition, while the ventromedial prefrontal cortex (vmPFC) has been shown to be important in the extinction of conditioned fear. However, studies on morphological correlates of fear learning could not consistently confirm an association with these structures. The objective of the present study was to investigate if interindividual differences in morphology of the amygdala and the vmPFC are related to differences in fear acquisition and extinction learning in humans. We performed structural magnetic resonance imaging in 68 healthy participants who underwent a differential cued fear conditioning paradigm. Volumes of subcortical structures as well as cortical thickness were computed by the semi-automated segmentation software Freesurfer. Stronger acquisition of fear as indexed by skin conductance responses was associated with larger right amygdala volume, while the degree of extinction learning was positively correlated with cortical thickness of the right vmPFC. Both findings could be conceptually replicated in an independent sample of 53 subjects. The data complement our understanding of the role of human brain morphology in the mechanisms of the acquisition and extinction of conditioned fear.     

Aversive learning in patients with unilateral lesions of the amygdala and hippocampus

The present study applied a visual half field paradigm with emotional facial expressions in patients with selective unilateral amygdalo-hippocampectomy (AHE) to elucidate the contributions of the left and right medial temporal lobe and amygdala to emotional learning. Electrodermal indicators of aversive learning were studied in 14 left AHE and 12 right AHE patients, as well as 13 controls matched in sex and age. In a differential conditioning paradigm with negative (CS+) and positive (CS-) facial expressions, CS+ were associated with an aversive vocalization (US, 95 dB, 3 s). During extinction, stimuli were presented laterally and preattentively using backward masking. Appropriate CS durations yielding preattentive presentation were individually determined prior to conditioning. In contrast to controls, both left and right AHE patients failed to show an autonomic conditioning effect following left visual field presentations of masked negative CS+ during extinction. AHE patients also showed no clear differential acquisition. Moreover, right AHE patients poorly recognised that negative valence was an affiliating dimension of the CS-US compound.     

Hemispheric Asymmetry and Human Classical Conditioning to Verbal and Non-Verbal Visual CSs

A new paradigm called “the dichoplic acquisition paradigm” was developed to study Ihc effects of hemispheric asymmetry on classical etcctrodcrmal conditioning. The paradigm involves three phases: 1) A habituation phase where two different color-words written in two incongruent colors are tachistoscopically displayed bilaterally to the visual half-fields left and right of center fixation; 2) An acquisition phase, wherein the display is followed by a 105dB white noise on each trial; and 3) An extinction phase, where each of the four CS cues (two color-words and two colors) are separately presented bilaterally for simultaneous input to both hemispheres. Here the color-words are now presented in grey against a black background, and the colors as color-bars against the same background. A control group had no UCS presentations. Bilateral skin conductance responses (SCRs) of right-handed males were used to evaluate conditioning. Conditioning to the CS color-word previously presented in the right half-field (i.e. initial left-hemisphere input) during acquisition led to larger SCRs during extinction, than the color-word previously presented in the left half-held (i.e. initial right-hemisphere input). In contrast, the CS color cue previously presented in the left half-field during acquisition resulted in larger SCRs during the first extinction trial, than the CS color cue previously presented in the right half-field. Thus, the present experiment revealed effects of hemispheric asymmetry on human electrodermal conditioning.     

The Effects of Directional Facial Cues on Electrodermal Conditioning to Facial Stimuli

The present two Experiments demonstrate that the orientation of angry facial expressions is a critical cue when faces serve as conditioned stimuli during aversive electrodermal conditioning. Experiment 1 demonstrated that responses conditioned to angry faces directed toward the subjects showed significant resistance to extinction whereas responses conditioned to angry faces directed away extinguished immediately during extinction. Experiment 2 was designed to investigate whether the orientation factor was effective only during extinction, i.e. whether the orientation was a performance variable, or if the observed effect originated from factors active during acquisition, i.e. if the orientation primarily influenced learning. When the orientation was shifted between the acquisition and the extinction phase, it was found that it did not matter what direction the faces had during acquisition; it was only during extinction that the faces needed to be directed toward the subjects to evoke persistent responding. These results suggest that the subjects acquired a conditioned response to the angry face regardless of its direction, but that this learning effect remained only when the angry face was directed toward the subject during extinction.     

The influence of gonadal hormones on conditioned fear extinction in healthy humans

Recent rodent studies suggest that gonadal hormones influence extinction of conditioned fear. Here we investigated sex differences in, and the influence of estradiol and progesterone on, fear extinction in healthy humans. Men and women underwent a two-day paradigm in which fear conditioning and extinction learning took place on day 1 and extinction recall was tested on day 2. Visual cues were used as the conditioned stimuli and a mild electric shock was used as the unconditioned stimulus. Skin conductance was recorded throughout the experiment and used to measure conditioned responses (CRs). Blood samples were obtained from all women to measure estradiol and progesterone levels. We found that higher estradiol during extinction learning enhanced subsequent extinction recall but had no effects on fear acquisition or extinction learning itself. Sex differences were only observed during acquisition, with men exhibiting significantly higher CRs. After dividing women into low- and high-estradiol groups, men showed comparable extinction recall to high-estradiol women, and both of these groups showed higher extinction recall than low-estradiol women. Therefore, sex differences in extinction memory emerged only after taking into account women's estradiol levels. Lower estradiol may impair extinction consolidation in women. These findings could have practical applications in the treatment of anxiety disorders through cognitive and behavioral therapies.     

Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder

BACKGROUND: In the conditioned fear paradigm, repeated pairing of an aversive unconditioned stimulus (US) (e.g. electric shock) with a neutral conditioned stimulus (CS) (e.g. bright light) results in a conditioned fear response to the light alone. Animal studies have shown that the amygdala plays a critical role in acquisition of conditioned fear responses, while the medial prefrontal cortex (including anterior cingulate), through inhibition of amygdala responsiveness, has been hypothesized to play a role in extinction of fear responses. No studies have examined neural correlates of fear conditioning and extinction in patients with post-traumatic stress disorder (PTSD). METHOD: Women with early childhood sexual-abuse-related PTSD (n = 8) and women without abuse or PTSD (n = 11) underwent measurement of psychophysiological (skin conductance) responding as well as positron emission tomographic (PET) measurement of cerebral blood flow during habituation, acquisition and extinction conditions. During habituation subjects were repeatedly exposed to a blue square on a screen. During acquisition, exposure to the blue square (CS) was paired with an electric shock to the forearm (US). With extinction, subjects were again exposed to the blue squares without shock. On a different day subjects went through the same procedure with electric shocks administered randomly in the absence of the blue square. RESULTS: Skin conductance responding to the CS was consistent with the development of conditioned responses with this paradigm. PTSD patients had increased left amygdala activation with fear acquisition, and decreased anterior cingulate function during extinction, relative to controls. CONCLUSIONS: These findings implicate amygdala and anterior cingulate in the acquisition and extinction of fear responses, respectively, in PTSD.     

Hemispheric differences in protein kinase C betaII levels in the rat amygdala: baseline asymmetry and lateralized changes associated with cue and context in a classical fear conditioning paradigm

The amygdala is critically important for fear learning, and specific kinases have been implicated as contributors to the mechanisms that underlie learning. We examined levels of protein kinase C betaII (PKC betaII) in the left and right lateral and basolateral nuclei (LA/BLA) of the amygdala from animals that were classically fear conditioned with tones as cues and footshocks. Groups consisted of animals that received neither tones nor shocks, paired tones and shocks, or unpaired tones and shocks. At 1 h after conditioning, some animals from each group were used for biochemical measurements of PKC betaII levels and other animals were given probe trials to assess freezing behavior to cue and context. The levels of PKC betaII were greater in the left hemisphere in animals receiving neither tones nor shocks and animals receiving paired tones and shocks. PKC betaII levels were greater in the right hemisphere of animals receiving randomly presented tones and shocks. Freezing times to cue were long (>80% of probe trial time) in both the paired tone/shock and randomly unpaired tone/shock groups. Freezing times to context were long in the unpaired tone/shock group, but not the paired tone/shock group. Correlational analyses showed that freezing times to context, but not cue, precisely predicted the right/left relation of PKC betaII levels in the LA/BLA: the greater the time spent freezing to context, the greater the increase in right hemisphere PKC betaII levels. We conclude that fear conditioning causes hemisphere and input specific increases in PKC betaII in the rat LA/BLA.     

Greater Resistance to Extinction of Electrodermal Responses Conditioned to Potentially Phobic CSs: A Noncognitive Process?

Previous results have suggested that electrodermal responses classically conditioned to potentially phobic CSs (e.g., pictures of snakes or spiders) are highly resistant to extinction and occur largely independently of cognitive expectancies. In order to test stringently for these possibilities, 144 college student subjects were administered differential classical conditioning acquisition and extinction paradigms while expectancies of the shock UCS were closely monitored. Half the subjects had potentially phobic CSs, whereas the other half had neutral CSs. Regardless of type of CS, during acquisition no evidence of electrodermal conditioning was found among subjects unaware of the CS?UCS contingency, nor was conditioning found on the pre-aware trials of subjects who became aware. During extinction, there was significantly greater resistance to extinction of electrodermal responses conditioned to potentially phobic CSs as well as a similar trend with expectancies of the UCS. However, when expectancies were equated, there was no greater resistance to extinction of electrodermal responses conditioned to potentially phobic CSs. Thus, while electrodermal responses conditioned to potentially phobic CSs did exhibit greater resistance to extinction, this conditioning was no more independent of expectancies than is conditioning with neutral CSs.     

Learning to fear suffocation: a new paradigm for interoceptive fear conditioning

The present study aimed to establish a new interoceptive fear conditioning paradigm. The conditioned stimulus (CS) was a flow resistor that slightly obstructs breathing; the unconditional stimulus (US) was a breathing occlusion. The paired group (N = 21) received 6 acquisition trials with paired CS–US presentations. The unpaired group (N = 19) received 6 trials of unpaired CS–US presentations. In the extinction phase, both groups were administered 6 CS‐only trials. Measurements included startle eyeblink response, electrodermal responses, and self‐reported US expectancy. In the paired group, startle blink responses were larger during CS compared to intertrial interval during acquisition and extinction. Electrodermal and US expectancies were larger for the paired than for the unpaired group during acquisition, but not during extinction. The present paradigm successfully established interoceptive fear conditioning with panic‐relevant stimuli.     

Reduced amygdala responsivity during conditioning to trauma‐related stimuli in posttraumatic stress disorder

Exaggerated conditioned fear responses and impaired extinction along with amygdala overactivation have been observed in posttraumatic stress disorder (PTSD). These fear responses might be triggered by cues related to the trauma through higher‐order conditioning, where reminders of the trauma may serve as unconditioned stimuli (US) and could maintain the fear response. We compared arousal, valence, and US expectancy ratings and BOLD brain responses using fMRI in 14 traumatized persons with PTSD and 14 without PTSD (NPTSD) and 13 matched healthy controls (HC) in a differential aversive conditioning paradigm. The US were trauma‐specific pictures for the PTSD and NPTSD group and equally aversive and arousing for the HC; the conditioned stimuli (CS) were graphic displays. During conditioning, the PTSD patients compared to the NPTSD and HC indicated higher arousal to the conditioned stimulus that was paired with the trauma picture (CS+) compared to the unpaired (CS?), increased dissociation during acquisition and extinction, and failure to extinguish the CS/US‐association compared to NPTSD. During early and late acquisition, the PTSD patients showed a significantly lower amygdala activation to CS+ versus CS? and a negative interaction between activation in the amygdala and dorsolateral prefrontal cortex (PFC), while NPTSD and HC displayed a negative interaction between amygdala and medial PFC. These findings suggest maladaptive anticipatory coping with trauma‐related stimuli in patients with PTSD, indicated by enhanced conditioning, with related abnormal amygdala reactivity and connectivity, and delayed extinction.     

Sex difference in rabbit eyelid conditioning

The rabbit eyelid conditioned reflex has been used to compare associative learning in males and ovariectomized females. A new method for monitoring eyelid movements is described. Rabbits were trained on simple delay classical conditioning. Conditioned responses were recorded during 8 acquisition days and 6 days of extinction training. Analysis of variance (ANOVA) and the least significant difference (LSD) post hoc test was used to analyze the data. The results showed that males achieved significantly better learning than females during the first day of acquisition but later they slowly attained the best result, contrary to females. Moreover, extinction of the conditioned reflex was significantly faster in females than in males. It is postulated that females learn and extinguish faster than males because of a higher level of brain plasticity.     

Effects of conditioned stimulus pre-exposure on human electrodermal conditioning to fear-relevant and fear-irrelevant stimuli

The effects of conditioned stimulus (CS) pre-exposure and fear-relevance of the CS on human Pavlovian electrodermal conditioning were investigated. A differential delayed conditioning paradigm was used with a CS-unconditioned stimulus (US; shock) interval of 8 s. In Experiment 1, 64 subjects were randomized into four groups, two of which received fear-relevant stimuli and the other two fear-irrelevant stimuli. Half of the subjects were pre-exposed to the to-be-CSs and the other half to two not-to-be-CSs, with 15 exposure of each stimulus. During acquisition, subjects received 8 reinforced and 8 nonreinforced CS+ and CS- trials, and during the extinction phase 15 nonreinforced trials of each CS. Pre-exposure to the to-be-CSs retarded conditioning for the first and second interval anticipatory responses (FIRs and SIRs); that is, a latent inhibition effect was demonstrated, although the results for the FIR were inconclusive. The expected effects of fear-relevance were not revealed. Experiment 2 addressed the question whether the long pre-exposure period interfered with the frequently observed "preparedness effect" of higher resistance to extinction to fear-relevant stimuli. The design was similar to that of Experiment 1, but for half of the subjects the acquisition phase was initiated immediately after a short rest period, and for the other half acquisition started after an extended rest period, equal to the duration of the pre-exposure phase in Experiment 1. Twenty extinction trials of each CS were presented. A reliable difference in arousal in terms of spontaneous fluctuations was produced by the rest periods, but although differential conditioning was observed, no effect of fear-relevance was seen during extinction.     

Posttraining effects of amphetamine, chlorpromazine, ketamine, and scopolamine on the acquisition and extinction of the rabbit's conditioned nictitating membrane response.

Four experiments examined whether posttraining deliveries of drugs modified the performance of the rabbit's conditioned nictitating membrane response (NMR) during acquisition and extinction. The results show that ketamine accelerated, but that amphetamine, chlorpromazine, and scopolamine retarded, conditioning when the drugs were injected immediately after the completion of daily training sessions. However, all conditioning effects of the drugs were lost when their deliveries were delayed by 2 hr after the end of training. During extinction, the only drug that altered conditioned performance was ketamine. Specifically, ketamine retarded the rate of extinction when the drug was given immediately after training. However, delaying ketamine by 2 hr after training neutralized the drug's influence. These findings indicate that the NMR preparation should be useful in examining how the posttraining delivery of drugs influences associative processes in conditioning.     

Differential involvement of medial prefrontal cortex and basolateral amygdala extracellular signal-regulated kinase in extinction of conditioned taste aversion is dependent on different intervals of extinction following conditioning

Extinction reflects a decrease in the conditioned response (CR) following non-reinforcement of a conditioned stimulus. Behavioral evidence indicates that extinction involves an inhibitory learning mechanism in which the extinguished CR reappears with presentation of an unconditioned stimulus. However, recent studies on fear conditioning suggest that extinction erases the original conditioning if the time interval between fear acquisition and extinction is short. The present study examined the effects of different intervals between acquisition and extinction of the original memory in conditioned taste aversion (CTA). Male Long-Evans rats acquired CTA by associating a 0.2% sucrose solution with malaise induced by i.p. injection of 4 ml/kg 0.15 M LiCl. Two different time intervals, 5 and 24 h, between CTA acquisition and extinction were used. Five or 24 h after CTA acquisition, extinction trials were performed, in which a bottle containing 20 ml of a 0.2% sucrose solution was provided for 10 min without subsequent LiCl injection. If sucrose consumption during the extinction trials was greater than the average water consumption, then rats were considered to have reached CTA extinction. Rats subjected to extinction trials lasting 24 h, but not 5 h, after acquisition re-exhibited the extinguished CR following injection of 0.15 M LiCl alone 7 days after acquisition. Extracellular signal-regulated kinase (ERK) in the medial prefrontal cortex (mPFC) and basolateral nucleus of the amygdala (BLA) was examined by Western blot after the first extinction trial. ERK activation in the mPFC was induced after the extinction trial beginning 5 h after acquisition, whereas the extinction trial performed 24 h after acquisition induced ERK activation in the BLA. These data suggest that the original conditioning can be inhibited or retained by CTA extinction depending on the time interval between acquisition and extinction and that the ERK transduction pathway in the mPFC and BLA is differentially involved in these processes.