Effects of the perceived temporal distance of events on mental time travel and on its underlying brain circuits.

Mental Time Travel (MTT) allows us to remember past events and imagine future ones. According to previous literature, the Temporal Distance of events affects MTT: our ability to order events worsens for close, compared to far, events. However, those studies established distances a-priori, albeit the way we perceive events' temporal distance may subjectively differ from their objective distance. Thus, in the current study, we aimed to investigate the effects of Perceived Temporal Distance (PTD) on the MTT ability and the brain areas mediating this process. Thirty-three healthy volunteers took part in an fMRI MTT task. Participants were asked to project themselves into the past, present, or future, and to judge a series of events as relative-past or relative-future, in relation to the adopted time location. Outside the scanner, participants provided PTD estimates for each stimulus of the MTT task. Participants' performance and functional activity were analyzed as a function of these estimations. At the behavioural level, PTD predicts the modulation of the performance for relative-past and relative-future. Bilateral angular gyrus, retrosplenial cortex, temporo-parietal region and medial, middle and superior frontal gyri mediate the PTD effect. In addition to these areas, the closer the relative-future events are perceived, the higher the involvement of left parahippocampal and lingual gyri and right cerebellum. Thus, perceived proximity of events activates frontal and posterior parietal areas, which therefore might mediate the processing of PTD in the cognitive spatial representation of time. Future proximity also activates cerebellum and medial temporal areas, known to be involved in imaginative and constructive cognitive functions.

Effectiveness of patients' involvement in a medical and nursing pain education programme: a protocol for an open-label randomised controlled trial including qualitative data.

INTRODUCTION: Pain is a multidimensional experience that varies among individuals and has a significant impact on their health. A biopsychosocial approach is recommended for effective pain management; however, health professionals' education is weak on this issue. Patient involvement is a promising didactic methodology in developing a more holistic perspective, however there is a lack of reliable evidence on this topic. The aim of the present study is to evaluate the effectiveness of patient involvement in pain education in undergraduate medicine and nursing students. METHODS AND ANALYSIS: An open-label randomised controlled trial including qualitative data will be conducted. After an introductory lesson, each student will be randomly assigned to the intervention group, which includes an educational session conducted by a patient-partner along with an educator, or to the control group in which the session is exclusively conducted by an educator. Both sessions will be carried out according to the Case-Based Learning approach. Primary outcomes will be students' knowledge, attitudes, opinions and beliefs about pain management, whereas the secondary outcome will be students' satisfaction. The Pain Knowledge and Attitudes (PAK) and Chronic Pain Myth Scale (CPMS) will be administered preintervention and postintervention to measure primary outcomes. Students' satisfaction will be measured by a questionnaire at the end of the session. Two focus groups will be conducted to evaluate non-quantifiable aspects of learning. ETHICS AND DISSEMINATION: The protocol of this study was approved by the independent Area Vasta Emilia Nord ethics committee.Adherence to The Declaration of Helsinki and Good Clinical Practice will ensure that the rights, safety and well-being of the participants in the study are safeguarded, as well as data reliability. The results will be disseminated through scientific publications and used to improve the educational offer. A version of the anonymised data set will be released for public access. TRIAL REGISTRATION: Trial was not registered on ClinicalTrials.gov as the interventions being compared only concern educational programmes and the outcomes considered do not refer to any clinical dimension.

Spatial attention modulation of the brain network involved in mental time travel.

OBJECTIVES: The ability to mental time travel (MTT) consists in moving along a cognitive and spatially oriented representation of time, that is, an ideal mental time line, where past and future events are, respectively, located on the left and on the right portion of such a line. A shift of spatial attention by prismatic adaptation (PA) influences this spatial coding of time, thus affecting MTT. Here, we investigated the neural correlates of such a spatial modulation on MTT in a functional Magnetic Resonance Imaging protocol. METHOD: To study MTT ability, participants were asked to indicate if a series of events took place before or after (Self-Reference component) an imagined self-location in time (Past, Present or Future; Self-Projection component), where they had to project themselves. The MTT task was performed before and after PA inducing a leftward shift of spatial attention, which is supposed to move toward the left portion of mental time line (MTL), where Past is represented. RESULTS: Following PA, we observed a facilitation in responding to past as compared to future events when participants projected themselves to the Past projection. As a functional counterpart of this behavioral finding, we propose a model of the brain activity modulations following the PA effects on MTT. CONCLUSIONS: As a result of the shift of spatial attention toward the left, the facilitation in having access to past events is associated with the inhibition of superior frontal gyrus in the left hemisphere, whereas the facilitation in projecting toward the Past may result from the activity modulation in right and left inferior parietal lobule. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Evaluation of an interprofessional education intervention in partnership with patient educators.

BACKGROUND AND AIM: Patient involvement in interprofessional education is a novel approach to building collaborative and empathic skills in students. However, this area of teaching is lacking in rigorous studies. The project aimed to evaluate whether an interprofessional education intervention in partnership with patient educators (IPE-PE) would increase readiness for interprofessional learning and empathy in health sciences students. METHODS: This is the report of a didactic innovation project. Participants included 310 undergraduate health sciences students who took part in an IPE-PE intervention. Data were collected before and after the training, using the Readiness for Interprofessional Learning Scale (RIPLS) and the Jefferson Scale of Empathy-Health Professions Student version (JSE-HPS). Only at the end of the intervention, a data collection form was administered to explore the value of the patient educator in the training and to investigate the socio-demographic variables. RESULTS: The mean age of participants was 21±3.2 SD years and 76% were female. A paired t-test showed significant changes from before to after the IPE-PE in the mean total RIPLS score (42.7±5.8 SD vs 44.62±5.9 SD, P<0.001) and the mean total JSE-HPS score (112.7±12.5 SD vs 116.03±12.8 SD, P<0.001).            Conclusions: Our students reported that IPE-PE had helped them to become more effective healthcare team members, to think positively about other professionals, and to gain empathic understanding of the perspective of the person being cared for. The results of the project confirm that the intervention promoted the development of empathy, fostering a better understanding of the patient-centred perspective.

Words hurt: common and distinct neural substrates underlying nociceptive and semantic pain.

Introduction: Recent studies have shown that processing semantic pain, such as words associated with physical pain, modulates pain perception and enhances activity in regions of the pain matrix. A direct comparison between activations due to noxious stimulation and processing of words conveying physical pain may clarify whether and to what extent the neural substrates of nociceptive pain are shared by semantic pain. Pain is triggered also by experiences of social exclusion, rejection or loss of significant others (the so-called social pain), therefore words expressing social pain may modulate pain perception similarly to what happens with words associated with physical pain. This event-related fMRI study aims to compare the brain activity related to perceiving nociceptive pain and that emerging from processing semantic pain, i.e., words related to either physical or social pain, in order to identify common and distinct neural substrates. Methods: Thirty-four healthy women underwent two fMRI sessions each. In the Semantic session, participants were presented with positive words, negative pain-unrelated words, physical pain-related words, and social pain-related words. In the Nociceptive session, participants received cutaneous mechanical stimulations that could be either painful or not. During both sessions, participants were asked to rate the unpleasantness of each stimulus. Linguistic stimuli were also rated in terms of valence, arousal, pain relatedness, and pain intensity, immediately after the Semantic session. Results: In the Nociceptive session, the 'nociceptive stimuli' vs. 'non-nociceptive stimuli' contrast revealed extensive activations in SI, SII, insula, cingulate cortex, thalamus, and dorsolateral prefrontal cortex. In the Semantic session, words associated with social pain, compared to negative pain-unrelated words, showed increased activity in most of the same areas, whereas words associated with physical pain, compared to negative pain-unrelated words, only activated the left supramarginal gyrus and partly the postcentral gyrus. Discussion: Our results confirm that semantic pain partly shares the neural substrates of nociceptive pain. Specifically, social pain-related words activate a wide network of regions, mostly overlapping with those pertaining to the affective-motivational aspects of nociception, whereas physical pain-related words overlap with a small cluster including regions related to the sensory-discriminative aspects of nociception. However, most regions of overlap are differentially activated in different conditions.

"When You're Smiling": How Posed Facial Expressions Affect Visual Recognition of Emotions.

Facial imitation occurs automatically during the perception of an emotional facial expression, and preventing it may interfere with the accuracy of emotion recognition. In the present fMRI study, we evaluated the effect of posing a facial expression on the recognition of ambiguous facial expressions. Since facial activity is affected by various factors, such as empathic aptitudes, the Interpersonal Reactivity Index (IRI) questionnaire was administered and scores were correlated with brain activity. Twenty-six healthy female subjects took part in the experiment. The volunteers were asked to pose a facial expression (happy, disgusted, neutral), then to watch an ambiguous emotional face, finally to indicate whether the emotion perceived was happiness or disgust. As stimuli, blends of happy and disgusted faces were used. Behavioral results showed that posing an emotional face increased the percentage of congruence with the perceived emotion. When participants posed a facial expression and perceived a non-congruent emotion, a neural network comprising bilateral anterior insula was activated. Brain activity was also correlated with empathic traits, particularly with empathic concern, fantasy and personal distress. Our findings support the idea that facial mimicry plays a crucial role in identifying emotions, and that empathic emotional abilities can modulate the brain circuits involved in this process.

Neural correlates of emotional valence for faces and words.

Stimuli with negative emotional valence are especially apt to influence perception and action because of their crucial role in survival, a property that may not be precisely mirrored by positive emotional stimuli of equal intensity. The aim of this study was to identify the neural circuits differentially coding for positive and negative valence in the implicit processing of facial expressions and words, which are among the main ways human beings use to express emotions. Thirty-six healthy subjects took part in an event-related fMRI experiment. We used an implicit emotional processing task with the visual presentation of negative, positive, and neutral faces and words, as primary stimuli. Dynamic Causal Modeling (DCM) of the fMRI data was used to test effective brain connectivity within two different anatomo-functional models, for the processing of words and faces, respectively. In our models, the only areas showing a significant differential response to negative and positive valence across both face and word stimuli were early visual cortices, with faces eliciting stronger activations. For faces, DCM revealed that this effect was mediated by a facilitation of activity in the amygdala by positive faces and in the fusiform face area by negative faces; for words, the effect was mainly imputable to a facilitation of activity in the primary visual cortex by positive words. These findings support a role of early sensory cortices in discriminating the emotional valence of both faces and words, where the effect may be mediated chiefly by the subcortical/limbic visual route for faces, and rely more on the direct thalamic pathway to primary visual cortex for words.

Can Disruption of Basal Ganglia-Thalamocortical Circuit in Wilson Disease Be Associated with Juvenile Myoclonic Epilepsy Phenotype?

In this paper, we describe the multimodal MRI findings in a patient with Wilson disease and a seizure disorder, characterized by an electroclinical picture resembling juvenile myoclonic epilepsy. The brain structural MRI showed a deposition of ferromagnetic materials in the basal ganglia, with marked hypointensities in T2-weighted images of globus pallidus internus bilaterally. A resting-state fMRI study revealed increased functional connectivity in the patient, compared to control subjects, in the following networks: (1) between the primary motor cortex and several cortical regions, including the secondary somatosensory cortex and (2) between the globus pallidus and the thalamo-frontal network. These findings suggest that globus pallidus alterations, due to metal accumulation, can lead to a reduction in the normal globus pallidus inhibitory tone on the thalamo-(motor)-cortical pathway. This, in turn, can result in hyperconnectivity in the motor cortex circuitry, leading to myoclonus and tonic-clonic seizures. We suppose that, in this patient, Wilson disease generated a 'lesion model' of myoclonic epilepsy.

Changes in Cancer Patients' and Caregivers' Disease Perceptions While Receiving Early Palliative Care: A Qualitative and Quantitative Analysis.

BACKGROUND: Little is known about the underlying mechanisms through which early palliative care (EPC) improves multiple outcomes in patients with cancer and their caregivers. The aim of this study was to qualitatively and quantitatively analyze patients' and caregivers' thoughts and emotional and cognitive perceptions about the disease prior to and during the EPC intervention, and in the end of life, following the exposure to EPC. MATERIALS AND METHODS: Seventy-seven patients with advanced cancer and 48 caregivers from two cancer centers participated in semistructured interviews. Their reports were qualitatively and quantitatively analyzed by the means of the grounded theory and a text-analysis program. RESULTS: Participants reported their past as overwhelmed by unmanaged symptoms, with detrimental physical and psychosocial consequences. The EPC intervention allowed a prompt resolution of symptoms and of their consequences and empowerment, an appreciation of its multidimensional approach, its focus on the person and its environment, and the need for EPC for oncologic populations. Patients reported that conversations with the EPC team increased their acceptance of end of life and their expectation of a painless future. Quantitative analysis revealed higher use of Negative Affects (p < .001) and Biological Processes words (p < .001) when discussing the past; Agency words when discussing the present (p < .001); Positive Affects (p < .001), Optimism (p = .002), and Insight Thinking words (p < .001) when discussing the present and the future; and Anxiety (p = .002) and Sadness words (p = .003) when discussing the future. CONCLUSION: Overall, participants perceived EPC to be beneficial. Our findings suggest that emotional and cognitive processes centered on communication underlie the benefits experienced by participants on EPC. IMPLICATIONS FOR PRACTICE: By qualitative and quantitative analyses of the emotional and cognitive perceptions of cancer patients and their caregivers about their experiences before and during EPC interventions, this study may help physicians/nurses to focus on the disease perception by patients/caregivers and the benefits of EPC, as a standard practice. The analysis of words used by patients/caregivers provides a proxy for their psychological condition and support in tailoring an EPC intervention, based on individual needs. This study highlights that the relationship of the triad EPC team/patients/caregivers may rise as a therapeutic tool, allowing increasing awareness and progressive acceptance of the idea of death.

Different semantic and affective meaning of the words associated to physical and social pain in cancer patients on early palliative/supportive care and in healthy, pain-free individuals.

Early palliative/supportive care (ePSC) is a medical intervention focused on patient's needs, that integrates standard oncological treatment, shortly after a diagnosis of advanced/metastatic cancer. ePSC improves the appropriate management of cancer pain. Understanding the semantic and emotional impact of the words used by patients to describe their pain may further improve its assessment in the ePSC setting. Psycholinguistics assumes that the semantic and affective properties of words affect the ease by which they are processed and comprehended. Therefore, in this cross-sectional survey study we collected normative data about the semantic and affective properties of words associated to physical and social pain, in order to investigate how patients with cancer pain on ePSC process them compared to healthy, pain-free individuals. One hundred ninety patients and 124 matched controls rated the Familiarity, Valence, Arousal, Pain-relatedness, Intensity, and Unpleasantness of 94 words expressing physical and social pain. Descriptive and inferential statistics were performed on ratings in order to unveil patients' semantic and affective representation of pain and compare it with those from controls. Possible effects of variables associated to the illness experience were also tested. Both groups perceived the words conveying social pain as more negative and pain-related than those expressing physical pain, confirming previous evidence of social pain described as worse than physical pain. Patients rated pain words as less negative, less pain-related, and conveying a lower intense and unpleasant pain than controls, suggesting either an adaptation to the pain experience or the role played by ePSC in improving patients' ability to cope with it. This exploratory study suggests that a chronic pain experience as the one experienced by cancer patients on ePSC affects the semantic and affective representation of pain words.

Eight Weddings and Six Funerals: An fMRI Study on Autobiographical Memories.

"Autobiographical memory" (AM) refers to remote memories from one's own life. Previous neuroimaging studies have highlighted that voluntary retrieval processes from AM involve different forms of memory and cognitive functions. Thus, a complex and widespread brain functional network has been found to support AM. The present functional magnetic resonance imaging (fMRI) study used a multivariate approach to determine whether neural activity within the AM circuit would recognize memories of real autobiographical events, and to evaluate individual differences in the recruitment of this network. Fourteen right-handed females took part in the study. During scanning, subjects were presented with sentences representing a detail of a highly emotional real event (positive or negative) and were asked to indicate whether the sentence described something that had or had not really happened to them. Group analysis showed a set of cortical areas able to discriminate the truthfulness of the recalled events: medial prefrontal cortex, posterior cingulate/retrosplenial cortex, precuneus, bilateral angular, superior frontal gyri, and early visual cortical areas. Single-subject results showed that the decoding occurred at different time points. No differences were found between recalling a positive or a negative event. Our results show that the entire AM network is engaged in monitoring the veracity of AMs. This process is not affected by the emotional valence of the experience but rather by individual differences in cognitive strategies used to retrieve AMs.

Pain Mirrors: Neural Correlates of Observing Self or Others' Facial Expressions of Pain.

Facial expressions of pain are able to elicit empathy and adaptive behavioral responses in the observer. An influential theory posits that empathy relies on an affective mirror mechanism, according to which emotion recognition relies upon the internal simulation of motor and interoceptive states triggered by emotional stimuli. We tested this hypothesis comparing representations of self or others' expressions of pain in nineteen young healthy female volunteers by means of functional magnetic resonance imaging (fMRI). We hypothesized that one's own facial expressions are more likely to elicit the internal simulation of emotions, being more strictly related to self. Video-clips of the facial expressions of each volunteer receiving either painful or non-painful mechanical stimulations to their right hand dorsum were recorded and used as stimuli in a 2 × 2 (Self/Other; Pain/No-Pain) within-subject design. During each trial, a 2 s video clip was presented, displaying either the subject's own neutral or painful facial expressions (Self No-Pain, SNP; Self Pain, SP), or the expressions of other unfamiliar volunteers (Others' No-Pain, ONP; Others' Pain, OP), displaying a comparable emotional intensity. Participants were asked to indicate whether each video displayed a pain expression. fMRI signals were higher while viewing Pain than No-Pain stimuli in a large bilateral array of cortical areas including middle and superior temporal, supramarginal, superior mesial and inferior frontal (IFG) gyri, anterior insula (AI), anterior cingulate (ACC), and anterior mid-cingulate (aMCC) cortex, as well as right fusiform gyrus. Bilateral activations were also detected in thalamus and basal ganglia. The Self vs. Other contrast showed signal changes in ACC and aMCC, IFG, AI, and parietal cortex. A significant interaction between Self and Pain [(SP vs. SNP) >(OP vs. ONP)] was found in a pre-defined region of aMCC known to be also active during noxious stimulation. These findings demonstrate that the observation of one's own and others' facial expressions share a largely common neural network, but self-related stimuli induce generally higher activations. In line with our hypothesis, selectively greater activity for self pain-related stimuli was found in aMCC, a medial-wall region critical for pain perception and recognition.

Modulation of neural circuits underlying temporal production by facial expressions of pain.

According to the Scalar Expectancy Theory, humans are equipped with a biological internal clock, possibly modulated by attention and arousal. Both emotions and pain are arousing and can absorb attentional resources, thus causing distortions of temporal perception. The aims of the present single-event fMRI study were to investigate: a) whether observation of facial expressions of pain interferes with time production; and b) the neural network subserving this kind of temporal distortions. Thirty healthy volunteers took part in the study. Subjects were asked to perform a temporal production task and a concurrent gender discrimination task, while viewing faces of unknown people with either pain-related or neutral expressions. Behavioural data showed temporal underestimation (i.e., longer produced intervals) during implicit pain expression processing; this was accompanied by increased activity of right middle temporal gyrus, a region known to be active during the perception of emotional and painful faces. Psycho-Physiological Interaction analyses showed that: 1) the activity of middle temporal gyrus was positively related to that of areas previously reported to play a role in timing: left primary motor cortex, middle cingulate cortex, supplementary motor area, right anterior insula, inferior frontal gyrus, bilateral cerebellum and basal ganglia; 2) the functional connectivity of supplementary motor area with several frontal regions, anterior cingulate cortex and right angular gyrus was correlated to the produced interval during painful expression processing. Our data support the hypothesis that observing emotional expressions distorts subjective time perception through the interaction of the neural network subserving processing of facial expressions with the brain network involved in timing. Within this frame, middle temporal gyrus appears to be the key region of the interplay between the two neural systems.

Recovery from emotion recognition impairment after temporal lobectomy.

Mesial temporal lobe epilepsy (MTLE) can be associated with emotion recognition impairment that can be particularly severe in patients with early onset seizures (1-3). Whereas, there is growing evidence that memory and language can improve in seizure-free patients after anterior temporal lobectomy (ATL) (4), the effects of surgery on emotional processing are still unknown. We used functional magnetic resonance imaging (fMRI) to investigate short-term reorganization of networks engaged in facial emotion recognition in MTLE patients. Behavioral and fMRI data were collected from six patients before and after ATL. During the fMRI scan, patients were asked to make a gender decision on fearful and neutral faces. Behavioral data demonstrated that two patients with early onset right MTLE were impaired in fear recognition while fMRI results showed they lacked specific activations for fearful faces. Post-ATL behavioral data showed improved emotion recognition ability, while fMRI demonstrated the recruitment of a functional network for fearful face processing. Our results suggest that ATL elicited brain plasticity mechanisms allowing behavioral and fMRI improvement in emotion recognition.

Whole-body mapping of spatial acuity for pain and touch.

OBJECTIVE: Tactile spatial acuity is routinely tested in neurology to assess the state of the dorsal column system. In contrast, spatial acuity for pain is not assessed, having never been systematically characterized. More than a century after the initial description of tactile acuity across the body, we provide the first systematic whole-body mapping of spatial acuity for pain. METHODS: We evaluated the 2-point discrimination thresholds for both nociceptive-selective and tactile stimuli across several skin regions. Thresholds were estimated using pairs of simultaneous stimuli, and also using successive stimuli. RESULTS AND INTERPRETATION: These two approaches produced convergent results. The fingertip was the area of highest spatial acuity, for both pain and touch. On the glabrous skin of the hand, the gradient of spatial acuity for pain followed that observed for touch. On the hairy skin of the upper limb, spatial acuity for pain and touch followed opposite proximal-distal gradients, consistent with the known innervation density of this body territory. Finally, by testing spatial acuity for pain in a rare participant completely lacking Aß fibers, we demonstrate that spatial acuity for pain does not rely on a functioning system of tactile primary afferents. This study represents the first systematic characterization of spatial acuity for pain across multiple regions of the body surface.

Structural and functional cerebral correlates of hypnotic suggestibility.

Little is known about the neural bases of hypnotic suggestibility, a cognitive trait referring to the tendency to respond to hypnotic suggestions. In the present magnetic resonance imaging study, we performed regression analyses to assess hypnotic suggestibility-related differences in local gray matter volume, using voxel-based morphometry, and in waking resting state functional connectivity of 10 resting state networks, in 37 healthy women. Hypnotic suggestibility was positively correlated with gray matter volume in portions of the left superior and medial frontal gyri, roughly overlapping with the supplementary and pre-supplementary motor area, and negatively correlated with gray matter volume in the left superior temporal gyrus and insula. In the functional connectivity analysis, hypnotic suggestibility was positively correlated with functional connectivity between medial posterior areas, including bilateral posterior cingulate cortex and precuneus, and both the lateral visual network and the left fronto-parietal network; a positive correlation was also found with functional connectivity between the executive-control network and a right postcentral/parietal area. In contrast, hypnotic suggestibility was negatively correlated with functional connectivity between the right fronto-parietal network and the right lateral thalamus. These findings demonstrate for the first time a correlation between hypnotic suggestibility, the structural features of specific cortical regions, and the functional connectivity during the normal resting state of brain structures involved in imagery and self-monitoring activity.

Ranking brain areas encoding the perceived level of pain from fMRI data.

Pain perception is thought to emerge from the integrated activity of a distributed brain system, but the relative contribution of the different network nodes is still incompletely understood. In the present functional magnetic resonance imaging (fMRI) study, we aimed to identify the more relevant brain regions to explain the time profile of the perceived pain intensity in healthy volunteers, during noxious chemical stimulation (ascorbic acid injection) of the left hand. To this end, we performed multi-way partial least squares regression of fMRI data from twenty-two a-priori defined brain regions of interest (ROI) in each hemisphere, to build a model that could efficiently reproduce the psychophysical pain profiles in the same individuals; moreover, we applied a novel three-way extension of the variable importance in projection (VIP) method to summarize each ROI contribution to the model. Brain regions showing the highest VIP scores included the bilateral mid-cingulate, anterior and posterior insular, and parietal operculum cortices, the contralateral paracentral lobule, bilateral putamen and ipsilateral medial thalamus. Most of these regions, with the exception of medial thalamus, were also identified by a statistical analysis on mean ROI beta values estimated using the time course of the psychophysical rating as a regressor at the voxel level. Our results provide the first rank-ordering of brain regions involved in coding the perceived level of pain. These findings in a model of acute prolonged pain confirm and extend previous data, suggesting that a bilateral array of cortical areas and subcortical structures is involved in pain perception.

Hypnotic susceptibility modulates brain activity related to experimental placebo analgesia.

Identifying personality traits and neural signatures that predict placebo responsiveness is important, both on theoretical and practical grounds. In the present functional magnetic resonance imaging (fMRI) study, we performed multiple-regression interaction analysis to investigate whether hypnotic susceptibility (HS), a cognitive trait referring to the responsiveness to suggestions, explains interindividual differences in the neural mechanisms related to conditioned placebo analgesia in healthy volunteers. HS was not related to the overall strength of placebo analgesia. However, we found several HS-related differences in the patterns of fMRI activity and seed-based functional connectivity that accompanied placebo analgesia. Specifically, in subjects with higher HS, the placebo response was related to increased anticipatory activity in a right dorsolateral prefrontal cortex focus, and to reduced functional connectivity of that focus with brain regions related to emotional and evaluative pain processing (anterior mid-cingulate cortex/medial prefrontal cortex); an opposite pattern of fMRI activity and functional connectivity was found in subjects with lower HS. During pain perception, activity in the regions reflecting attention/arousal (bilateral anterior thalamus/left caudate) and self-related processing (left precuneus and bilateral posterior temporal foci) was negatively related to the strength of the analgesic placebo response in subjects with higher HS, but not in subjects with lower HS. These findings highlight HS influences on brain circuits related to the placebo analgesic effects. More generally, they demonstrate that different neural mechanisms can be involved in placebo responsiveness, depending on individual cognitive traits.

Neural bases of conditioned placebo analgesia.

Despite growing interest in the placebo effect, the neural correlates of conditioned analgesia are still incompletely understood. We investigated herein on brain activity during the conditioning and post-conditioning phases of a placebo experimental paradigm, using event-related fMRI in 31 healthy volunteers. Brief laser heat stimuli delivered to one foot (either right or left) were preceded by different visual cues, signalling either painful stimuli alone, or painful stimuli accompanied by a (sham) analgesic procedure. Cues signalling the analgesic procedure were followed by stimuli of lower intensity in the conditioning session, whereas in the test session both cues were followed by painful stimuli of the same intensity. During the first conditioning trials, progressive signal increases over time were found during anticipation of analgesia compared to anticipation of pain, in a medial prefrontal focus centered on medial area BA8, and in bilateral lateral prefrontal foci. These frontal foci were adjacent to, and partially overlapped, those active during anticipation of analgesia in the test session, whose signal changes were related to the magnitude of the placebo behavioral response, and those active during placebo analgesia. Specifically, a large focus in the right prefrontal cortex showed activity related to analgesia, irrespective of the expected side of stimulation. Analgesia was also related to decreased activity, detectable immediately following noxious stimulation, in parietal, insular and cingulate pain-related clusters. Our findings of dynamic changes in prefrontal areas during placebo conditioning, and of direct placebo effects on cortical nociceptive processing, add new insights into the neural bases of conditioned placebo analgesia.