High Hypnotizability Impairs the Cerebellar Control of Pain.

In the general population, transcranial anodal direct current stimulation of the cerebellum (ctDCS) reduces pain intensity and the amplitude of nociceptive laser evoked potentials (LEPs), whereas cathodal ctDCS elicits opposite effects. Since behavioral findings suggest that the cerebellar activity of highly hypnotizable individuals (highs) differs from the general population, we investigated whether hypnotizability-related differences occur in the modulation of pain by ctDCS. Sixteen healthy highs (according to the Stanford Hypnotic Susceptibility Scale, form A) and 16 participants not selected according to hypnotizability (controls) volunteered to undergo laser nociceptive stimulation of the dorsum of the left hand before and after anodal or cathodal ctDCS. LEPs amplitudes and latencies and the subjective pain experience (Numerical Rating Scale) were analyzed. Smaller LEP amplitudes and longer latencies were observed in highs with respect to controls independently of stimulation. After anodal and cathodal cerebellar stimulation, controls reported lower and higher pain than before it, respectively. In contrast, highs did not report significant changes in the perceived pain after both stimulations. They increased significantly their N2/P2 amplitude after anodal ctDCS and did not exhibit any significant change after cathodal tDCS, whereas controls decreased the N1 and N2P2 amplitude and increased their latency after anodal cerebellar stimulation and did the opposite after cathodal ctDCS. In conclusion, the study showed impaired cerebellar pain modulation and suggested altered cerebral cortical representation of pain in subjects with high hypnotizability scores.

Effect of melatonin injection into the periaqueductal gray on antinociception and tonic immobility in male rats.

Melatonin (MLT) is a neurohormone with significant involvement in several biological functions, of which antinociception and tonic immobility (TI) may be the key neurobehavioral components to survive in adverse conditions such as a predator attack. TI-induced antinociception can be elicited, facilitated, or increased through opioid and γ-aminobutyric acid (GABA) among other chemical mediators at several levels of the central nervous system, mainly in the periaqueductal gray (PAG). The aim of this study was to assess the effect of the microinjection of MLT into the main PAG regions that are related to different integrated defensive responses, namely dorsal (D) and ventrolateral (VL), on both antinociception through the tail-flick (TF) test and TI duration as single behavioral response and on combined behavioral responses (TF/TI). We found that the microinjection of MLT into the main PAG areas produced antinociception but did not affect the TI duration. The microinjection of MLT into the D-PAG decreased TF latency during TI in the combined trial (TF/TI), which implies that TI-induced antinociception was blocked. The microinjection of MLT into the VL-PAG maintained the antinociceptive capability of the TI without addition or increase in the antinociceptive effects, implying a permissive effect by MLT on the TI-induced antinociception. MLT administration into the D-PAG decreased the TI duration on the TF/TI, whereas MLT administration into the VL-PAG had the opposite effect of significantly increasing TI duration with the TF/TI trial.

Hypnotizability and Performance on a Prism Adaptation Test.

The susceptibility to hypnosis, which can be measured by scales, is not merely a cognitive trait. In fact, it is associated with a number of physiological correlates in the ordinary state of consciousness and in the absence of suggestions. The hypnotizability-related differences observed in sensorimotor integration suggested a major role of the cerebellum in the peculiar performance of healthy subjects with high scores of hypnotic susceptibility (highs). In order to provide behavioral evidence of this hypothesis, we submitted 20 highs and 21 low hypnotizable participants (lows) to the classical cerebellar Prism Adaptation Test (PAT). We found that the highs' performance was significantly less accurate and more variable than the lows' one, even though the two groups shared the same characteristics of adaptation to prismatic lenses. Although further studies are required to interpret these findings, they could account for earlier reports of hypnotizability-related differences in postural control and blink rate, as they indicate that hypnotizability influences the cerebellar control of sensorimotor integration.

Body sway modulation by hypnotizability and gender during low and high demanding postural conditions.

The cognitive trait of hypnotizability, associated with the proneness to accept suggestions, exhibits several physiological correlates including the modulation of sensorimotor integration and, in particular, of postural control. In this respect, we have shown that, at eyes closure, healthy subjects with high hypnotizability scores (highs) having their feet 2 cm apart show larger and faster body sway with respect to low hypnotizable individuals (lows). The aim of the present study was to investigate whether hypnotizability modulates body sway during slightly more demanding and very difficult postural conditions such as feet together bipedal posture and one legged stance, respectively. The Center of Pressure (CoP) Area, mean Velocity, the CoP mean position (Xmean, Ymean) and its variability (SDx, SDy) in the frontal and sagittal planes were acquired in 18 highs (9 females) and 18 lows (9 females). Results showed that the previously observed lows' smaller and slower body sway was not present any longer. Nonetheless, hypnotizability interacted with gender in the modulation of the variability of the CoP movement in the frontal plane during both the bipedal feet together posture and one legged stance, as significant gender differences were observed only among lows. In conclusion, results confirm a role of hypnotizability in sensorimotor integration and support the relevance of hypnotic assessment in clinical settings, as hypnotizability may be responsible for part of the postural variability.

Can interoceptive sensitivity provide information on the difference in the perceptual mechanisms of recurrent and chronic pain? Part I. A retrospective clinical study related to multidimensional pain assessment.

OBJECTIVES: Although neurobiological research has shown that interoception plays a role in the perception of pain and its chronification, the relationship between interoceptive sensitivity and pain has not been definitively confirmed by clinical studies. The aim of this study was therefore to better understand the relationship between interoceptive sensitivity, somatization, and clinical pain, and to identify any differences in the interoceptive sensitivity of patients with recurrent vs. chronic pain. METHODS: Scores from 43 Chronic pain subjects, assessed using ICD-11 Criteria; 42 healthy subjects (without pain or psychiatric disorders); and 38 recurrent pain subjects on the Multidimensional Assessment of Interoceptive Awareness (MAIA), Body Perception Questionnaire (BPQ-SF), Somatosensory amplification scale (SSAS), Patient Health Questionnaire (PHQ-15), Symptom Checklist-Revised (SCL-90-R), and Italian Pain Questionnaire (IPQ) were compared. RESULTS: Negative attention to the body was indicated by higher scores of psychosomatic dimensions as SSAS, SCL90R somatization, and PHQ-15 in recurrent, but especially chronic pain (p<0.000 for all). An increase in psychosomatic dimension scores (i.e., somatization, somatosensory amplification) was associated with an increase in both autonomic nervous system reactivity (ANSR) dimension scores and the negative influence of the Not-worrying, attention regulation and trusting of the MAIA. In contrast, the presence of pain and scores for its dimensions with associated with lower supra-diaphragmatic activity as per the BPQ. CONCLUSIONS: Pain chronification might depend on both the impairment of interoceptive sensitivity and an increase on psychosomatic dimensions via modification of ANSR hyperactivity and a reduction of the MAIA Not-worrying dimension.

Hypnotizability-dependent accuracy in the reproduction of haptically explored paths.

The study assessed differences between highly (Highs) and low hypnotizable (Lows) subjects in the blindfolded reproduction of paths connected at acute or obtuse angles. Reproduction attempts were made after path exploration performed by one finger, with or without concomitant cognitive activities (mental computation or imagery of exploring an angle larger than the explored one). The variables analyzed were: subjective experience (scores of the exploring effort, reproduction difficulty, perceived accuracy of reproduction, attention to mental computation and efficacy of imagery), exploration time, relative error in reproduction (under or overestimation) and the percentage of "successful" trials (absolute error <10°). The results showed that the subjective experience of exploration/reproduction and the exploration times are similar in Highs and Lows and that all subjects underestimate the explored angles and reproduce the acute angle more accurately than the obtuse one. Exploration of the acute angle concomitant with imagery of a larger one reduced its underestimation in both groups. Highs exhibited a larger number of successful trials after exploration of the obtuse angle, while Lows (males) decreased their relative error in the reproduction of the acute angle. In conclusion, in the more demanding condition of reproducing an obtuse angle, the Highs' reproduction was more accurate and more independent of cognitive load than that of the Lows.

Postural effects of imagined leg pain as a function of hypnotizability.

It has been shown that, in subjects with high hypnotizability (Highs), imagined somatosensory stimulation can involuntarily activate the neural circuits involved in the modulation of reflex action. In this vein, aim of the study was to investigate whether the imagery of nociceptive stimulation in one leg may produce both subjective experience of pain and congruent postural adjustments during normal upright stance. The displacement of the centre of pressure (CoP) was studied during imagery of leg pain (LP) and during the control conditions of imagery of tactile stimulation of the same leg and of throat pain (TP) in 12 Highs and 12 low hypnotizable subjects (Lows). The results showed that the vividness of imagery was higher in Highs than in Lows for all tasks and that only Highs reported actually feeling pain during LP and TP. Congruently, during LP only Highs displaced their CoP towards the leg opposite to the one that was the object of painful imagery and increased their CoP mean velocity and area of excursion. Since the Highs' postural changes were not accounted for only by vividness of imagery and perceived pain intensity, high hypnotizability is apparently responsible for part of the postural effects of pain imagery.

Defensive responses in invertebrates: Evolutionary and neural aspects.

Lower invertebrates exhibit both morphological and behavioral defensive responses to aversive stimuli, characterized by withdrawal. Typical immobility responses are "sinking" in Rotifers and "crumpling" in Cnidaria. They also display individual adaptation and phenotypic plasticity but not tonic immobility (TI). The higher phyla with a more organized nervous system have developed morphological and behavioral defensive strategies including TI, occurring both in natural and laboratory conditions. There are general but also specific prey-predator mechanisms, that have coevolved leading to reciprocal phenotypic plasticity. The evolution of traits differentiated in subpopulations has been described in many species (animal personality). In insects the variability in TI is heritable and inversely related to boldness. In two genetic lines of beetles with long and short TI duration, the long duration line has higher survival rate but lower mating success (behavioral syndromes). TI may have an adaptive significance also in intraspecific interactions in the context of sexual selection.

Environmental, ecological and methodological factors of Tonic Immobility (TI) modulation.

Modulation of Tonic Immobility (TI) concerns environmental and individual factors. TI is modulated by processes of habituation and sensitization. In poikilotherm frog and lizard, TI duration is much shorter at usual environmental temperatures and is potentiated at higher or lower temperatures, as the last resource for survival. During ontogeny, age may differentially affect TI susceptibility to the induction procedures, as in the case of newborn ectothermic and older endothermic rabbits. TI duration displays a daily rhythm, with longer TI in the night. Its resistance to habituation indicates that in the dark TI is the most prominent defense against nocturnal predators. In all studied species, there is synchronization of the prey's defensive responses with the feeding activity of predators. Ecological factors and exposure to different anthropogenic environmental pressures may alter morphology, behavior and TI in wild populations. TI duration has been associated with a genomic region comprising the dystrophin gene on quail chromosome 1.

The neuroethological approach to defense in rabbit.

In this chapter we review the neuroethological approach correlating behavior and dorsal hippocampal activity recorded in rabbits in laboratory conditions or in a semi-natural enclosure and exposed to intra and interspecific confrontations. Behaviors of the same modality, i.e., immobility, and the same motivation, i.e., defense, can be distinguished by a different pattern of hippocampal activity, in terms of the relative ratio of RSA (rhythmic slow activity), and LIA (large amplitude irregular activity), and of RSA frequencies. In addition, the frequency and the duration of RSA episodes represent critical indicators of the amount of awareness during immobility conditions. The neural pattern is also differentially affected by dynamic (a live cat) and static (a stuffed sparrow hawk) stimuli. On a neuroethological basis, the hippocampal profile of TI, characterized by the prevalence of LIA, is similar to a sparrow-hawk exposure and to the submissive posture in a conspecific confrontation.

Neurophysiological mechanisms involved in tonic immobility (TI).

This chapter summarizes the main neurophysiological characteristics of tonic immobility (TI), in many susceptible species of mammals and birds. During TI, cortical EEG shows high voltage slow waves whose amount is affected by events preceding TI induction and is positively correlated with TI duration. The pattern of hippocampal activity helps to predict TI onset and TI termination. Both polysynaptic flexor and monosynaptic heteronymous reflexes are depressed independently from the EEG activity. Brain metabolism, signaled by glycogen mobilization and glucose utilization, indicates a reduced neuronal activity during TI. Learned avoidance responses to shock can be extinguished during TI and recover after TI. Moreover, during TI animals may learn how to avoid the shock by a motor response that may be followed by TI interruption. Decortication, decerebellation and telencephalic sections do not affect TI characteristics, whereas ponto-mesencephalic sections abolish both righting reflexes and TI.

Neuromediators and defensive responses including tonic immobility (TI): Brain areas and circuits involved.

Serotonin, acetylcholine and GABA are the neuromediators most involved in tonic immobility (TI). TI duration, in fact, decreases in rabbits following systemic serotonin administration and in guinea pigs following serotonin microinjection administration into the amygdala owing to the activation of fear-related GABAergic inhibitory mechanisms. On the other hand, repeated TI inductions in rabbits and guinea pigs reduce brain serotonin turnover in several brain areas. Microinjections of the acetylcholine agonist carbachol into amygdala, hypothalamus and PAG increase TI duration and reduces other defensive responses to threatening stimuli in several animal species. The cholinergic and serotonergic systems exert different effects on TI in different regions of the PAG according to the receptors stimulated. Their combined action activates opioid-GABAergic neurons ultimately affecting TI duration. Mammals TI and human cataplexy are innate responses induced by different stimuli, although both characterized by deficiency in orexin, reduced muscle tone, normal jerk reflexes and preserved consciousness.

Neuroendocrine correlates of stress and tonic immobility.

Threatening stimuli challenging animal homeostasis are the primary events triggering defensive responses, including TI. The stress-response system (allostasis) is signaled by increased corticosteroid basal levels. In bird animal lines genetically selected for stress-induced corticosterone, there is a covariation between stress physiology and coping styles. Rabbit studies, in which the effects of TI are dissociated from those of induction per se, support the view that TI takes part in the homeostatic stress-response system. An increase of corticosterone is recorded just after the end of the induction procedure but not in the corresponding groups in which induction is followed by TI, suggesting a recovery process during TI. Similarly to corticosterone but in opposite direction, testosterone plasma levels decrease following induction and recover during TI. Recovery mechanisms are also suggested in two bird genotypes selected for long and short TI duration. The positive relation between corticosterone levels and TI duration has been confirmed after exogenous corticosterone administration.

Autonomic correlates of defense responses, including tonic immobility (TI).

Animal models of autonomic correlates of defense behavior range from fish to mammals. There is however no study reporting heart and respiratory rate, blood pressure and body temperature simultaneously recorded in the same animal in association to different forms of immobility in response to threat: freezing, restraint-sustained immobility and tonic immobility (TI). In a prey/ predator context freezing behavior is associated with bradycardia and no change in blood pressure but in other conditions (e.g., extreme stressful stimuli) may be associated with tachycardia and hypertension. Restraint-sustained immobility does not affect blood pressure but may reduce heart rate according to the type of stimulus and mechanical pressure. Blood pressure and heart rate oscillate during TI induction and adjust at basal levels during TI, sometimes gradually decreasing below basal levels. In conclusion, in all these passive defense responses, the immobility is not due to a blood pressure collapse.

Pain control in tonic immobility (TI) and other immobility models.

This chapter deals with the mechanisms modulating pain during TI and other immobility responses in different animal species. In mammals the presence of high voltage slow waves in the electroencephalogram during TI suggests the activation of the thalamic gate, a mechanism blocking all sensory information, including pain. In rabbits TI transiently suppresses all the behavioral responses to persistent nociceptive stimulation by the activation of an opioid mechanism outlasting TI offset by 1h. On the other hand, in rodents, also not injuring nociceptive stimuli applied during TI elicit a delayed opioid analgesia that develops within 45min. Moreover, both opioid and non-opioid mechanisms of analgesia have been observed. TI strongly reduces inflammatory responses by activating the vagal-neocortical-sympathetic axis, a feedback control of neuro-immune mechanisms. Several models of noxious and non-noxious restraint and of post-restraint immobility resembling TI have been proposed. Moreover in lizards, hyperalgesia occurs during and after TI.

Tonic immobility as a survival, adaptive response and as a recovery mechanism.

In this conclusive chapter, we review findings giving support to the hypothesis that TI represents an adaptive, survival response to threatening situations. In models of prey-predator interactions, in vertebrates and invertebrates, there are evidence that immobility per se contributes to survival, as the predator loses interest for a prey in which TI is experimentally induced. TI duration is also reciprocally modulated by the evaluation of the risk factors in the environment, and by the opportunity to reach a safe refuge. This supports the adaptive value of TI and suggests that, during TI, the animal may be transiently aware of the environmental situation. As for the adaptive value of TI, genetic correlations with other behavioral systems contributing to fitness (e.g., mating) are taken into account. Moreover, neurophysiological and endocrine findings in mammals support our hypothesis that TI activates the mechanisms responsible for recovery from disruptive experiences and body lesions.

Synthesis of defense response characteristics.

In previous chapters, the available theories and experimental findings related to animals' defense responses have been reported and discussed in detail. This chapter reports their comprehensive synthesis, considering the main immobility-related responses in defense. Within the same modality (i.e., immobility) different kinds of immobility may in fact correspond to different functions and motivations, as proved by their neurobiological correlates profile.

Introduction to defensive behavior in vertebrates.

In this introductory chapter we describe the ethological basis of defensive behavior, including tonic immobility (TI). The defensive repertoire activated in response to threatening stimuli, both in natural and experimental conditions, consists of a system of interrelated behaviors influenced by two main dimensions, as distance from the threat and escapable/inescapable context. When the active strategy of escape is not feasible, passive immobility forms are adopted, the latter representing substitutes of actual escape. In an inescapable context, and at very short distance or in contact with the threatening stimulus, TI is adopted, or submissive posture in a social context. Physical restraint represents the strongest stimulus for TI induction. As a result of behavioral flexibility, subsets of animals within a population show a different capacity and modality to cope with aversive stimuli (animal personality). TI can be regarded as a trait of behavioral syndromes in species as mammals and avians.

Neural circuits of fear and defensive behavior.

Innate fear-related behavioral responses have evolved as strategies for survival. The neural circuits responsible for defensive responses, studied mainly in rodents, have been substantially preserved across evolution. Amygdala collects sensory information (visual, auditory and olfactory) in the cortical division and conveys it to the striatal output division. Distinct amygdala nuclei/subnuclei are activated by different fearful stimuli, such as exposure to a predator or to an aggressive conspecific. The same stimuli segregation is observed in downstream structures, i.e., hypothalamus and PAG. In guinea pigs, the circuits underlying Tonic Immobility (TI) and freezing in response to a natural predator, have been mapped in different subnuclei of the same amygdala area. In the PAG circuits, defensive responses are differentially represented along the dorso-ventral and rostro-caudal axis. The coordination of behavioral, anti-nociceptive and autonomic responses is due to the overlapping of the involved neurons in longitudinal columns.

The fear hypothesis and tonic immobility (TI) modulation: Early studies in chickens.

The hypothesis that fear is involved in the mechanisms of tonic immobility (TI) has been supported by early studies conducted in newborn and adult chickens. The susceptibility to TI changes during development in parallel to other fear responses. TI duration increases following exposure before induction to threatening stimuli such as electric shock, loud sound, stuffed sparrow hawk, as well as in unfamiliar conditions applied before and/or during testing. TI duration and susceptibility are increased by prey/predator eye contact and inversely related with the predator distance. TI duration increases following exposure before induction to threatening stimuli such as electric shock, loud sound, stuffed sparrow hawk, as well as in unfamiliar conditions applied before and/or during testing. The fact that the experimenter presence or the experimenter eye visibility represent a potential source of fear like a natural predator in chicks and in adult hens is controversial. The likely explanations for the contradictory results are discussed in the text. The rearing conditions, for instance, seem to be critical: repeated handling in the first days after hatching reduces the fear of human beings, decreasing TI duration in adulthood with a parallel increase in proximity scores to the experimenter. In chicks, exposure to withdrawal from a positive imprinting stimulus increases and decreases TI duration, respectively.