Opponent appetitive-aversive neural processes underlie predictive learning of pain relief

Termination of a painful or unpleasant event can be rewarding. However, whether the brain treats relief in a similar way as it treats natural reward is unclear, and the neural processes that underlie its representation as a motivational goal remain poorly understood. We used fMRI (functional magnetic resonance imaging) to investigate how humans learn to generate expectations of pain relief. Using a pavlovian conditioning procedure, we show that subjects experiencing prolonged experimentally induced pain can be conditioned to predict pain relief. This proceeds in a manner consistent with contemporary reward-learning theory (average reward/loss reinforcement learning), reflected by neural activity in the amygdala and midbrain. Furthermore, these reward-like learning signals are mirrored by opposite aversion-like signals in lateral orbitofrontal cortex and anterior cingulate cortex. This dual coding has parallels to 'opponent process' theories in psychology and promotes a formal account of prediction and expectation during pain.     

Duration of paradoxical sleep necessary for the acquisition of conditioned avoidance in the rat

In a previous work we have shown, in the rat, that an increase of the duration of paradoxical sleep (PS) occurs after each conditioning session of different tasks, without any alteration of the duration of slow wave sleep. Furthermore, our findings suggested that the increase phenomenon shows a short latency and a short duration. This experiment was designed for the purpose of studying the useful duration of the increase of paradoxical sleep following an avoidance conditioning in the rat. we have observed that a period of 90 min free sleep immediately consecutive to each conditioning session (15 trials) is sufficient for good retention to occur. Whereas, a period of 30 min free sleep during which we do not observe PS increase, does not allow conditioning to be established; 60 min of free sleep, with PS increase, only slightly disturbs the learning curve. Therefore, the time period, immediately consecutive to conditioning, during which the integrity of sleep is necessary, is, in our experimental conditions, between 60 and 90 min. Throughout the course of this period, the duration of PS is augmented during the initial days of conditioning.     

Concomitants physiologiques de l'apprentissage et sommeil paradoxal consécutif,chez le chat

During avoidance conditioning in the Cat, arousal, heart rate and respiratory reactions produced by the conditioned stimulus (CS) were recorded. The development of these reactions was compared with the paradoxical sleep (PS) length measured between the trials of each experimental session. The results of this analysis point to the existence of a critical learning period characterised by a high rate of central and peripheral reactions and by an increase in PS length. This period precedes the stabilization of performances. The functional relationship of these two phenomena with each other and with learning is discussed.     

REM sleep deprivation affects extinction of cued but not contextual fear conditioning

Previous research has demonstrated that rapid eye movement (REM), or paradoxical, sleep deprivation can interfere with the retention of certain types of learning tasks, particularly spatial learning. The present study investigated the effects of 6 h of REM sleep deprivation on the retention and extinction of both cued and contextual conditioning tasks in rats. Sleep-deprived animals showed normal retention of both types of conditioning tasks but retarded extinction of the cued task and a trend toward attenuated spontaneous recovery of the contextual task. The results provide further evidence for the involvement of REM sleep in learning and memory processes.     

Conditioning of amitriptyline‐induced REM sleep suppression in healthy participants: A randomized controlled trial

Clinical trials in sleep disorders report substantial improvement in symptoms in their placebo groups. Behavioral conditioning is one of the underlying mechanisms of the placebo response. However, we do not know whether, and if so, the extent to which sleep architecture is influenced by behavioral conditioning, similarly to other physiological responses (i.e., those in the immune system). We therefore applied a conditioning paradigm to 39 healthy adults pairing a novel‐tasting drink (conditioned stimulus, CS) with the REM sleep suppressing tricyclic antidepressant amitriptyline as unconditioned stimulus during the acquisition phase. Subsequent sole presentation of the CS (together with a placebo pill) in an evocation night led to significantly more REM sleep in the amitriptyline group. Instead of the expected REM sleep suppression in the evocation night, we observed more REM sleep, indicating a rebound that interferes with the conditioned response.     

Temporal characteristics of the augmentation of paradoxal sleep following learning in the rat

In a previous work, we have shown that an avoidance conditioning is followed by an increased number of Paradoxical Sleep (PS) phases during the first hour after learning. In Experiment 1, sleep is experimentally delayed after each conditioning session. When sleep is delayed for 180 min, learning is severely impaired and PS doesn't increase; but the 90-min sleep delay after the conditioning session is followed by the same PS increase as that when sleep is free immediately after learning. In Experiment 2, we show that a 90-min free sleep period, between learning and a 180-min sleep deprivation allowed a learning as good as that without any sleep deprivation. In our experimental conditions, PS increase after avoidance conditioning is brief and immediate when sleep is possible and if it begins less than 180 min after learning.     

Pupil dilation as an implicit measure of appetitive Pavlovian learning

Appetitive Pavlovian conditioning is a learning mechanism of fundamental biological and pathophysiological significance. Nonetheless, its exploration in humans remains sparse, which is partly attributed to the lack of an established psychophysiological parameter that aptly represents conditioned responding. This study evaluated pupil diameter and other ocular response measures (gaze dwelling time, blink duration and count) as indices of conditioning. Additionally, a learning model was used to infer participants’ learning progress on the basis of their pupil dilation. Twenty‐nine healthy volunteers completed an appetitive differential delay conditioning paradigm with a primary reward, while the ocular response measures along with other psychophysiological (heart rate, electrodermal activity, postauricular and eyeblink reflex) and behavioral (ratings, contingency awareness) parameters were obtained to examine the relation among different measures. A significantly stronger increase in pupil diameter, longer gaze duration and shorter eyeblink duration was observed in response to the reward‐predicting cue compared to the control cue. The Pearce‐Hall attention model best predicted the trial‐by‐trial pupil diameter. This conditioned response was corroborated by a pronounced heart rate deceleration to the reward‐predicting cue, while no conditioning effect was observed in the electrodermal activity or startle responses. There was no discernible correlation between the psychophysiological response measures. These results highlight the potential value of ocular response measures as sensitive indices for representing appetitive conditioning.     

Olfactory associative conditioning in infant rats with brain stimulation as reward: II. Norepinephrine mediates a specific component of the bulb response to reward.

One of the circuits modified by early olfactory learning is in the olfactory bulb. Specifically, response patterns of mitral-tufted cells are modified by associative conditioning during the early postnatal period. In addition, previous work has demonstrated that mitral-tufted cell single units respond to both olfactory conditioned stimuli and rewarding stimulation of the medial forebrain bundle-lateral hypothalamus (MFB-LH). The present study suggests that norepinephrine beta-receptor activation is required for early olfactory learning using MFB-LH stimulation as reward. Propranolol injected before odor-MFB-LH pairings blocks the acquisition of conditioned behavioral responses and their neural correlates to the conditioned odor. Furthermore, propranolol blocks a specific class of the mitral-tufted cell responses to MFB-LH reward stimulation. The relationship of this response to reward and early learning is discussed.     

Sleep patterns and avoidance conditioning in the rat.

For 19 male rats of the Wistar strain, percentages of wakefulness (W), slow sleep (SS) and paradoxical sleep (PS) were determined by recording EEG activity of neo-cortex and EMG of neck muscles, for 48 consecutive hours. After the recording periods, the locomotor activity of the animals was measured in an open-field; then they were trained in a two-way shuttle-box. Statistical analysis showed significant correlations between physiological and behavioral variables. The most interesting correlation was that between percentage of PS and number of shocks received during avoidance conditioning: r = ?0.521. Number of shocks was also significantly correlated with the ratio PS/W (r = ?0.567). On the contrary, percentages of W and SS were not significantly correlated with learning scores. Multivariate analysis of the data showed a direct relationship between PS, avoidance and activity scores. These results may reflect a relationship between individual patterns of central activation and shuttle-box situation as well as a direct involvement of PS in memory processes.     

Glucocorticoids are not responsible for paradoxical sleep deprivation-induced memory impairments

STUDY OBJECTIVES: To evaluate whether paradoxical sleep deprivation-induced memory impairments are due to release of glucocorticoids, by means of corticosterone inhibition with metyrapone. DESIGN: The design was a 2 (Groups [control, paradoxical sleep-deprived]) x 2 (Treatments [vehicle, metyrapone]) study, performed in 2 experiments: Acute treatment (single injection given immediately after 96 hours of sleep deprivation) and chronic treatment (8 injections, twice per day, throughout the sleep-deprivation period). Animals were either paradoxical sleep-deprived or remained in their home cages for 96 hours before training in contextual fear conditioning and received intraperitoneal injections of a corticosterone synthesis inhibitor, metyrapone. Memory performance was tested 24 hours after training. SUBJECTS: Three-month old Wistar male rats. Measurements: Freezing behavior was considered as the conditioning index, and adrenocorticotropic hormone and corticosterone plasma levels were determined from trunk blood of animals sacrificed in different time points. Animals were weighed before and after the paradoxical sleep-deprivation period. RESULTS: Acute metyrapone treatment impaired memory in control animals and did not prevent paradoxical sleep deprivation-induced memory impairment. Likewise, in the chronic treatment, paradoxical sleep-deprived animals did not differ from control rats in their corticosterone or adrenocorticotropic hormone response to training, but still did not learn as well, and did not show any stress responses to the testing. Chronic metyrapone was, however, effective in preventing the weight loss typically observed in paradoxical sleep-deprived animals. CONCLUSIONS: Our results suggest that glucocorticoids do not mediate memory impairments but might be responsible for the weight loss induced by paradoxical sleep deprivation.     

GRP78 counteracts cell death and protein aggregation caused by mutant huntingtin proteins

Pain and reward are opponent, interacting processes. Such interactions are enabled by neuroanatomical and neurochemical overlaps of brain systems that process pain and reward. Cerebral processing of hedonic ('liking') and motivational ('wanting') aspects of reward can be separated: the orbitofrontal cortex and opioids play an important role for the hedonic experience, and the ventral striatum and dopamine predominantly process motivation for reward. Supported by neuroimaging studies, we present here the hypothesis that the orbitofrontal cortex and opioids are responsible for pain modulation by hedonic experience, while the ventral striatum and dopamine mediate motivational effects on pain. A rewarding stimulus that appears to be particularly important in the context of pain is pain relief. Further, reward, including pain relief, leads to operant learning, which can affect pain sensitivity. Indirect evidence points at brain mechanisms that might underlie pain relief as a reward and related operant learning but studies are scarce. Investigating the cerebral systems underlying pain-reward interactions as well as related operant learning holds the potential of better understanding mechanisms that contribute to the development and maintenance of chronic pain, as detailed in the last section of this review.     

The placebo effect in pain reduction: The influence of conditioning experiences and response expectancies

We investigated the role of conditioning experiences and response expectancies in the generation of placebo effects. On 3 sequential days (Test 1, Experimental Session, Test 2), 66 female undergraduates were presented with a series of pain stimuli. For the experimental group, placebo administration (analgesic cream) was paired with a decrease in the painful stimulus. Two control groups were used to explore the relative contributions of verbally induced expectancies and contingent unconditional stimulus experiences per se. The results show that placebo-induced pain reduction can he obtained as a result or a conditioning procedure, independent of verbally induced expectancies. Mere verbal persuasion was not sufficient to elicit placebo-induced pain reduction. Irrespective of the experimental manipulations, the placebo effect was related to both reduced pain expectations and reduced fear of pain. Although conditioned placebo responses were evident at the subjective level, no placebo effects emerged at the physiological level.     

Selective deprivation of paradoxical sleep and consolidation of shuttle-box avoidance.

Investigated whether paradoxical sleep is implicated in the storage of information acquired during shuttle-box avoidance. Wistar rats were given 5 brief training sessions distributed over the light period of the diurnal cycle. During the intervals between sessions the animals were selectively deprived of paradoxical sleep by awakening them every time they showed this type of sleep. The onset of paradoxical sleep was identified when hippocampal theta rhythm occurred during behavioural sleep. Yoked control animals got the same treatment irrespective of their sleep-waking behaviour, whereas free sleep rats were allowed to sleep undisturbed. In spite of large differences in the amount of paradoxical sleep during the intersession intervals no differences in learning performances were found among the groups. A tendency toward more intertrial crossings was noted in the paradoxical sleep deprived group at the end of training. It is concluded that storage of information acquired during distributed shuttle-box avoidance is not dependent on the presence of paradoxical sleep immediately following learning. Some possibilities are considered that paradoxical sleep may still be involved in memory storage processes.     

Ventromedial prefrontal cortex activity and rapid eye movement sleep are associated with subsequent fear expression in human subjects

In humans, activity patterns in the ventromedial prefrontal cortex (vmPFC) have been found to be predictive of subsequent fear memory consolidation. Pioneering work in rodents has further shown that vmPFC–amygdala theta synchronization is correlated with fear memory consolidation. We aimed to evaluate whether vmPFC activity during fear conditioning is (1) correlated with fear expression the subsequent day and whether (2) this relationship is mediated by rapid eye movement (REM) sleep. We analyzed data from 17 young healthy subjects undergoing a fear conditioning task, followed by a fear extinction task 24 h later, both recorded with simultaneous skin conductance response (SCR) and functional magnetic resonance imaging measurements, with a polysomnographically recorded night sleep in between. Our results showed a correlation between vmPFC activity during fear conditioning and subsequent REM sleep amount, as well as between REM sleep amount and SCR to the conditioned stimulus 24 h later. Moreover, we observed a significant correlation between vmPFC activity during fear conditioning and SCR responses during extinction, which was no longer significant after controlling for REM sleep amount. vmPFC activity during fear conditioning was further correlated with sleep latency. Interestingly, hippocampus activity during fear conditioning was correlated with stage 2 and stage 4 sleep amount. Our results provide preliminary evidence that the relationship between REM sleep and fear conditioning and extinction observed in rodents can be modeled in healthy human subjects, highlighting an interrelated set of potentially relevant trait markers.     

Polygraphic study of vigilance states in the guinea pig fetus

The ontogenesis of the states of sleep in guinea pig foetus was studied by polygraphic method. Long-lasting records have been made in utero between the 40th and the 64th day of gestation. The ECoG activation pattern of paradoxical sleep (PS) and wakefulness appear from the 40th day (0,6 of term); the slow-wave sleep (SWS) appear about the 49th day (0,7 of term) and is characterized by cortical spindles. Between the 40th and the 47th day, cerebral maturation is accompanied by a progressive decrease of a discontinuous ECoG activity state. From 53 days (0,8 of term), the ECoG patterns of states of vigilance are similar to those of the newborn guinea pig. The percentage of time spent in PS is very high (80–90% at 48 days) before the SWS appearance. These observations prove the existence of a prenatal differentiation of the states of vigilance. The differentiation stages are similar to those observed after birth in immature newborn mammals. No relationship exists between the sleep of mother and foetus.     

Associative learning mediates dynamic shifts in dopamine signaling in the nucleus accumbens

The ability to predict favorable outcomes using environmental cues is an essential part of learned behavior. Dopamine neurons in the midbrain encode such stimulus-reward relationships in a manner consistent with contemporary learning models, but it is unclear how encoding this translates into actual dopamine release in target regions. Here, we sampled dopamine levels in the rat nucleus accumbens on a rapid (100 ms) timescale using electrochemical technology during a classical conditioning procedure. Early in conditioning, transient dopamine-release events signaled a primary reward, but not predictive cues. After repeated cue-reward pairings, dopamine signals shifted in time to predictive cue onset and were no longer observed at reward delivery. In the absence of stimulus-reward conditioning, there was no shift in the dopamine signal. Consistent with proposed roles in reward prediction and incentive salience, these results indicate that rapid dopamine release provides a reward signal that is dynamically modified by associative learning.     

How expectations shape pain

Pain is highly modifiable by psychological factors, including expectations. However, pain is a complex phenomenon, and expectations may work by influencing any number of processes that underlie the construction of pain. Neuroimaging has begun to provide a window into these brain processes, and how expectations influence them. In this article, we review findings regarding expectancy effects on brain markers of nociception and how expectations lead to changes in subjective pain. We address both expectations about treatments (placebo analgesia and nocebo effects) and expectations about the environment (e.g. expectations about pain itself). The body of work reviewed indicates that expectancies shape pain-intensity processing in the central nervous system, with strong effects on nociceptive portions of insula, cingulate and thalamus. Expectancy effects on subjective experience are driven by responses in these regions as well as regions less reliably activated by changes in noxious input, including the dorsolateral prefrontal cortex and the orbitofrontal cortex. Thus, multiple systems are likely to interact and mediate the pain-modulatory effects of expectancies. Finally, we address open questions regarding the psychological processes likely to play an intervening role in expectancy effects on pain.     

Correlations between paradoxical sleep and shuttle-box conditioning in rats

Eighteen male Wistar rats were given one daily two-way active avoidance conditioning session followed immediately by 5 hr of sleep recording, for 5 consecutive days. The group of rats that achieved 80% or greater avoidance in some of the 5 training sessions showed significant linear increases of paradoxical sleep (PS), compared with baseline levels, throughout the successive conditioning sessions. Furthermore, (a) the group of rats showing PS increases (more than 1 SD above baseline) after some of the training sessions achieved a significantly higher final number of avoidances than the remaining animals: (b) a high and positive correlation was observed between avoidance increases in the 3rd conditioning session and previous PS; and (c) maximum increases in correct performance often occurred following high PS increases. It is concluded that PS increases facilitate the consolidation of learning.     

Effects of unconditioned stimulus intensity and fear extinction on subsequent sleep architecture in an afternoon nap

Impaired fear extinction and disturbed sleep coincide in post‐traumatic stress disorder (PTSD), but the nature of this relationship is unclear. Rapid eye movement (REM) sleep deprivation impairs fear extinction recall in rodents and young healthy subjects, and animal models have demonstrated both disrupted sleep after fear conditioning and normalized sleep after extinction learning. As a correlation between unconditioned stimulus (US) responding and subsequent sleep architecture has been observed in healthy subjects, the goal of this study was to test whether US intensity would causally affect subsequent sleep. Twenty‐four young healthy subjects underwent a fear conditioning session with skin conductance response measurements before an afternoon session of polysomnographically recorded sleep (up to 120 min) in the sleep laboratory. Two factors were manipulated experimentally in a 2 × 2 design: US (electrical shock) was set at high or low intensity, and subjects did or did not receive an extinction session after fear conditioning. We observed that neither factor affected REM sleep amount, that high US intensity nominally increased sleep fragmentation (more Stage 1 sleep, stage shifts and wake after sleep onset), and that extinction increased Stage 4 amount. Moreover, reduced Stage 1 and increased Stage 4 and REM sleep were associated with subjective sleep quality of the afternoon nap. These results provide evidence for the notion that US intensity and extinction affect subsequent sleep architecture in young healthy subjects, which may provide a translational bridge from findings in animal studies to correlations observed in PTSD patients.     

The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil

Evidence from behavioral and self-reported data suggests that the patients' beliefs and expectations can shape both therapeutic and adverse effects of any given drug. We investigated how divergent expectancies alter the analgesic efficacy of a potent opioid in healthy volunteers by using brain imaging. The effect of a fixed concentration of the μ-opioid agonist remifentanil on constant heat pain was assessed under three experimental conditions using a within-subject design: with no expectation of analgesia, with expectancy of a positive analgesic effect, and with negative expectancy of analgesia (that is, expectation of hyperalgesia or exacerbation of pain). We used functional magnetic resonance imaging to record brain activity to corroborate the effects of expectations on the analgesic efficacy of the opioid and to elucidate the underlying neural mechanisms. Positive treatment expectancy substantially enhanced (doubled) the analgesic benefit of remifentanil. In contrast, negative treatment expectancy abolished remifentanil analgesia. These subjective effects were substantiated by significant changes in the neural activity in brain regions involved with the coding of pain intensity. The positive expectancy effects were associated with activity in the endogenous pain modulatory system, and the negative expectancy effects with activity in the hippocampus. On the basis of subjective and objective evidence, we contend that an individual's expectation of a drug's effect critically influences its therapeutic efficacy and that regulatory brain mechanisms differ as a function of expectancy. We propose that it may be necessary to integrate patients' beliefs and expectations into drug treatment regimes alongside traditional considerations in order to optimize treatment outcomes.