The Current View on the Paradox of Pain in Autism Spectrum Disorders.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, which affects 1 in 44 children and may cause severe disabilities. Besides socio-communicational difficulties and repetitive behaviors, ASD also presents as atypical sensorimotor function and pain reactivity. While chronic pain is a frequent co-morbidity in autism, pain management in this population is often insufficient because of difficulties in pain evaluation, worsening their prognosis and perhaps driving higher mortality rates. Previous observations have tended to oversimplify the experience of pain in autism as being insensitive to painful stimuli. Various findings in the past 15 years have challenged and complicated this dogma. However, a relatively small number of studies investigates the physiological correlates of pain reactivity in ASD. We explore the possibility that atypical pain perception in people with ASD is mediated by alterations in pain perception, transmission, expression and modulation, and through interactions between these processes. These complex interactions may account for the great variability and sometimes contradictory findings from the studies. A growing body of evidence is challenging the idea of alterations in pain processing in ASD due to a single factor, and calls for an integrative view. We propose a model of the pain cycle that includes the interplay between the molecular and neurophysiological pathways of pain processing and it conscious appraisal that may interfere with pain reactivity and coping in autism. The role of social factors in pain-induced response is also discussed. Pain assessment in clinical care is mostly based on subjective rather than objective measures. This review clarifies the strong need for a consistent methodology, and describes innovative tools to cope with the heterogeneity of pain expression in ASD, enabling individualized assessment. Multiple measures, including self-reporting, informant reporting, clinician-assessed, and purely physiological metrics may provide more consistent results. An integrative view on the regulation of the pain cycle offers a more robust framework to characterize the experience of pain in autism.

Simulated proximity enhances perceptual and physiological responses to emotional facial expressions.

Physical proximity is important in social interactions. Here, we assessed whether simulated physical proximity modulates the perceived intensity of facial emotional expressions and their associated physiological signatures during observation or imitation of these expressions. Forty-four healthy volunteers rated intensities of dynamic angry or happy facial expressions, presented at two simulated locations, proximal (0.5 m) and distant (3 m) from the participants. We tested whether simulated physical proximity affected the spontaneous (in the observation task) and voluntary (in the imitation task) physiological responses (activity of the corrugator supercilii face muscle and pupil diameter) as well as subsequent ratings of emotional intensity. Angry expressions provoked relative activation of the corrugator supercilii muscle and pupil dilation, whereas happy expressions induced a decrease in corrugator supercilii muscle activity. In proximal condition, these responses were enhanced during both observation and imitation of the facial expressions, and were accompanied by an increase in subsequent affective ratings. In addition, individual variations in condition related EMG activation during imitation of angry expressions predicted increase in subsequent emotional ratings. In sum, our results reveal novel insights about the impact of physical proximity in the perception of emotional expressions, with early proximity-induced enhancements of physiological responses followed by an increased intensity rating of facial emotional expressions.

The Peripersonal Space in a social world.

The PeriPersonal Space (PPS) has been defined as the space surrounding the body, where physical interactions with elements of the environment take place. As our world is social in nature, recent evidence revealed the complex modulation of social factors onto PPS representation. In light of the growing interest in the field, in this review we take a close look at the experimental approaches undertaken to assess the impact of social factors onto PPS representation. Our social world also influences the personal space (PS), a concept stemming from social psychology, defined as the space we keep between us and others to avoid discomfort. Here we analytically compare PPS and PS with the aim of understanding if and how they relate to each other. At the behavioral level, the multiplicity of experimental methodologies, whether well-established or novel, lead to somewhat divergent results and interpretations. Beyond behavior, we review physiological and neural signatures of PPS representation to discuss how interoceptive signals could contribute to PPS representation, as well as how these internal signals could shape the neural responses of PPS representation. In particular, by merging exteroceptive information from the environment and internal signals that come from the body, PPS may promote an integrated representation of the self, as distinct from the environment and the others. We put forward that integrating internal and external signals in the brain for perception of proximal environmental stimuli may also provide us with a better understanding of the processes at play during social interactions. Adopting such an integrative stance may offer novel insights about PPS representation in a social world. Finally, we discuss possible links between PPS research and social cognition, a link that may contribute to the understanding of intentions and feelings of others around us and promote appropriate social interactions.

Reward-related brain activity and behavior are associated with peripheral ghrelin levels in obesity.

BACKGROUND/OBJECTIVES: While excessive food consumption represents a key factor in the development of obesity, the underlying mechanisms are still unclear. Ghrelin, a gut-brain hormone involved in the regulation of appetite, is impaired in obesity. In addition to its role in eating behavior, this hormone was shown to affect brain regions controlling reward, including the striatum and prefrontal cortex, and there is strong evidence of impaired reward processing in obesity. The present study investigated the possibility that disrupted reward-related brain activity in obesity relates to ghrelin deficiency. SUBJECTS/METHODS: Fifteen severely obese subjects (BMI > 35 kg/m2) and fifteen healthy non-obese control subjects (BMI < 30 kg/m2) were recruited. A guessing-task paradigm, previously shown to activate the ventral striatum, was used to assess reward-related brain neural activity by functional magnetic resonance imaging (fMRI). Fasting blood samples were collected for the measurement of circulating ghrelin. RESULTS: Significant activations in the ventral striatum, ventromedial prefrontal cortex and extrastriate visual cortex were elicited by the fMRI task in both obese and control subjects. In addition, greater reward-related activations were present in the dorsolateral prefrontal cortex, and precuneus/posterior cingulate of obese subjects compared to controls. Obese subjects exhibited longer choice times after repeated reward and lower circulating ghrelin levels than lean controls. Reduced ghrelin levels significantly predicted slower post-reward choices and reward-related hyperactivity in dorsolateral prefrontal cortices in obese subjects. CONCLUSION: This study provides evidence of association between circulating ghrelin and reward-related brain activity in obesity and encourages further exploration of the role of ghrelin system in altered eating behavior in obesity.

Dynamics of the straight-ahead preference in human visual cortex.

The objects located straight-ahead of the body are preferentially processed by the visual system. They are more rapidly detected and evoke stronger BOLD responses in early visual areas than elements that are retinotopically identical but located at eccentric spatial positions. To characterize the dynamics of the underlying neural mechanisms, we recorded in 29 subjects the EEG responses to peripheral targets differing solely by their locations with respect to the body. Straight-ahead stimuli led to stronger responses than eccentric stimuli for several components whose latencies ranged between 70 and 350 ms after stimulus onset. The earliest effects were found at 70 ms for a component that originates from occipital areas, the contralateral P1. To determine whether the straight-ahead direction affects primary visual cortex responses, we performed an additional experiment (n = 29) specifically designed to generate two robust components, the C1 and C2, whose cortical origins are constrained within areas V1, V2 and V3. Our analyses confirmed all the results of the first experiment and also revealed that the C2 amplitude between 130 and 160 ms after stimulus onset was significantly stronger for straight-ahead stimuli. A frequency analysis of the pre-stimulus baseline revealed that gaze-driven alterations in the visual hemi-field containing the straight-ahead direction were associated with a decrease in alpha power in the contralateral hemisphere, suggesting the implication of specific neural modulations before stimulus onset. Altogether, our EEG data demonstrate that preferential responses to the straight-ahead direction can be detected in the visual cortex as early as about 70 ms after stimulus onset.

Increased cerebral responses to salient transitions between alternating stimuli in chronic migraine with medication overuse headache and during migraine attacks.

INTRODUCTION: In a previous study exploring central pain modulation with heterotopic stimuli in healthy volunteers, we found that transitions between sustained noxious and innocuous thermal stimulations on the foot activated the "salience matrix". Knowing that central sensory processing is abnormal in migraine, we searched in the present study for possible abnormalities of these salient transitional responses in different forms of migraine and at different time points of the migraine cycle. METHODS: Participants of both sexes, mostly females, took part in a conditioned pain modulation experiment: Migraineurs between (n = 14) and during attacks (n = 5), chronic migraine patients with medication overuse headache (n = 7) and healthy volunteers (n = 24). To evoke the salience response, continuous noxious cold or innocuous warm stimulations were alternatively applied on the right foot. Cerebral blood oxygenation level dependent responses were recorded with fMRI. RESULTS: Switching between the two stimulations caused a significant transition response in the "salience matrix" in all subject groups (effect of the condition). Moreover, some group effects appeared on subsequent post-hoc analyses. Augmented transitional blood oxygenation level dependent responses in the motor cortex and superior temporal sulcus were found in two patient groups compared to healthy controls: chronic migraine with medication overuse headache patients and migraineurs recorded during an attack. In chronic migraine with medication overuse headache patients, salience-related responses were moreover greater in the premotor cortex, supplementary motor area, lingual gyrus and dorso-medial prefrontal cortex and other "salience matrix" areas, such as the anterior cingulate and primary somatosensory cortices. CONCLUSION: This study shows salience-related hyperactivation of affective and motor control areas in chronic migraine with medication overuse headache patients and, to a lesser extent, in episodic migraine patients during an attack. The greater extension of exaggerated blood oxygenation level dependent responses to unspecific salient stimuli in chronic migraine with medication overuse headache than during a migraine attack could be relevant for headache chronification.

Hypobaric hypoxia exposure in rats differentially alters antidepressant efficacy of the selective serotonin reuptake inhibitors fluoxetine, paroxetine, escitalopram and sertraline.

Treatment-resistant depression, a chronic condition that affects 30% of depressed patients on antidepressants, is highly linked to suicidal behavior. Chronic hypoxia exposure via living at altitude (hypobaric hypoxia) or with chronic hypoxic diseases is demographically linked to increased risk for depression and suicide. We previously demonstrated that housing rats at altitude for a week incrementally increases depression-like behavior in the forced swim test (FST) in females, but not males. In animal models, high altitude exposure reduces brain serotonin, and selective serotonin reuptake inhibitors (SSRIs) can lose efficacy when brain serotonin levels are low. To address whether residence at moderate altitude is detrimental to SSRI function, we examined SSRI efficacy in the FST after a week of housing rats at altitudes of 4500 ft. or 10,000 ft. as compared to at sea level. In females, the tricyclic antidepressant desipramine (positive control) functioned well in all groups, increasing latency to immobility and decreasing immobility, by increasing climbing. However, the SSRIs fluoxetine, paroxetine and escitalopram were ineffective in females in all groups: only paroxetine improved swimming in the FST as expected of a SSRI, while all three unexpectedly reduced climbing. Fluoxetine was also ineffective in male rats. Sertraline was the only SSRI with antidepressant efficacy at altitude in both females and males, increasing swimming, climbing and latency to immobility, and reducing immobility. Hypobaric hypoxia thus appears to be detrimental to efficacy of the SSRIs fluoxetine, paroxetine and escitalopram, but not of sertraline. Unlike the other SSRIs, sertraline can improve both serotonergic and dopaminergic transmission, and may be less impacted by a hypoxia-induced serotonin deficit. A targeted approach may thus be necessary for successful antidepressant treatment in patients with depression who live at altitude or with chronic hypoxic diseases, and that sertraline may be the SSRI of choice for prescription for this population.

Hypobaric hypoxia induces depression-like behavior in female Sprague-Dawley rats, but not in males.

Rates of depression and suicide are higher in people living at altitude, and in those with chronic hypoxic disorders like asthma, chronic obstructive pulmonary disorder (COPD), and smoking. Living at altitude exposes people to hypobaric hypoxia, which can lower rat brain serotonin levels, and impair brain bioenergetics in both humans and rats. We therefore examined the effect of hypobaric hypoxia on depression-like behavior in rats. After a week of housing at simulated altitudes of 20,000 ft, 10,000 ft, or sea level, or at local conditions of 4500 ft (Salt Lake City, UT), Sprague Dawley rats were tested for depression-like behavior in the forced swim test (FST). Time spent swimming, climbing, or immobile, and latency to immobility were measured. Female rats housed at altitude display more depression-like behavior in the FST, with significantly more immobility, less swimming, and lower latency to immobility than those at sea level. In contrast, males in all four altitude groups were similar in their FST behavior. Locomotor behavior in the open field test did not change with altitude, thus validating immobility in the FST as depression-like behavior. Hypobaric hypoxia exposure therefore induces depression-like behavior in female rats, but not in males.

Cerebral responses and role of the prefrontal cortex in conditioned pain modulation: an fMRI study in healthy subjects.

The mechanisms underlying conditioned pain modulation (CPM) are multifaceted. We searched for a link between individual differences in prefrontal cortex activity during multi-trial heterotopic noxious cold conditioning and modulation of the cerebral response to phasic heat pain. In 24 healthy female subjects, we conditioned laser heat stimuli to the left hand by applying alternatively ice-cold or lukewarm compresses to the right foot. We compared pain ratings with cerebral fMRI BOLD responses. We also analyzed the relation between CPM and BOLD changes produced by the heterotopic cold conditioning itself, as well as the impact of anxiety and habituation of cold-pain ratings. Specific cerebral activation was identified in precuneus and left posterior insula/SII, respectively, during early and sustained phases of cold application. During cold conditioning, laser pain decreased (n=7), increased (n=10) or stayed unchanged (n=7). At the individual level, the psychophysical effect was directly proportional to the cold-induced modulation of the laser-induced BOLD response in left posterior insula/SII. The latter correlated with the BOLD response recorded 80s earlier during the initial 10-s phase of cold application in anterior cingulate, orbitofrontal and lateral prefrontal cortices. High anxiety and habituation of cold pain were associated with greater laser heat-induced pain during heterotopic cold stimulation. The habituation was also linked to the early cold-induced orbitofrontal responses. We conclude that individual differences in conditioned pain modulation are related to different levels of prefrontal cortical activation by the early part of the conditioning stimulus, possibly due to different levels in trait anxiety.

Neurochemical alterations in frontal cortex of the rat after one week of hypobaric hypoxia.

Residing at high altitude may lead to reduced blood oxygen saturation in the brain and altered metabolism in frontal cortical brain areas, probably due to chronic hypobaric hypoxia. These changes may underlie the increased rates of depression and suicidal behavior that have been associated with life at higher altitudes. To test the hypothesis that hypobaric hypoxia is responsible for development of mood disorders due to alterations in neurochemistry, we assessed depression-like behavior in parallel to levels of brain metabolites in rats housed at simulated altitude. 32 female Sprague Dawley rats were housed either in a hypobaric hypoxia chamber at 10,000 ft of simulated altitude for 1 week or at local conditions (4500 ft of elevation in Salt Lake City, Utah). Depression-like behavior was assessed using the forced swim test (FST) and levels of neurometabolites were estimated by in vivo proton magnetic resonance spectroscopy in the frontal cortex, the striatum and the hippocampus at baseline and after a week of exposure to hypobaric hypoxia. After hypoxia exposure the animals demonstrated increased immobility behavior and shortened latency to immobility in the FST. Elevated ratios of myo-inositol, glutamate, and the sum of myo-inositol and glycine to total creatine were observed in the frontal cortex of hypoxia treated rats. A decrease in the ratio of alanine to total creatine was also noted. This study shows that hypoxia induced alterations in frontal lobe brain metabolites, aggravated depression-like behavior and might be a factor in increased rates of psychiatric disorders observed in populations living at high altitudes.

Alexithymia and empathy predict changes in autonomic arousal during affective stimulation.

BACKGROUND: Alexithymia, the inability to describe one's own emotions, is linked to deficits in empathy, manifesting as a diminished capacity to recognize or understand the emotions and mental states of others. Several brain centers of autonomic control and interoception that are activated in empathy are thought to misfunction in alexithymia. We hypothesized that individual differences in autonomic changes under affective stimulation might be associated with differences in alexithymia and empathy. METHODS: We studied 21 healthy volunteers, comparing their alexithymia and empathy scores with changes in their sympathetic autonomic arousal, indexed by the palmar skin potential level, during 3 tasks: playing a computer game, performing mental arithmetic, and watching a negative emotional valence video. RESULTS: Both autonomic and subjective sense of arousal increased at the beginning of each task and then gradually subsided over the course of the task. Higher autonomic arousal at the onset of the computer game was associated with higher empathy scores, and at the onset of the negative video with higher scores for both empathy and alexithymia. Alexithymia delayed the habituation of autonomic arousal during the computer game, while the empathy score was related to a faster decline in arousal during the negative video task. CONCLUSIONS: High alexithymia and high empathy scores were linked to increased autonomic arousal at the onset of emotional stimulation, but were distinguishable in the rates of habituation of the evoked arousal. Our data provide insight into the relationships among interacting psychological traits, physiologic regulation, and the arousal dimension of emotional experience.

Factors influencing behavior in the forced swim test.

The forced swim test (FST) is a behavioral test in rodents which was developed in 1978 by Porsolt and colleagues as a model for predicting the clinical efficacy of antidepressant drugs. A modified version of the FST added the classification of active behaviors into swimming and climbing, in order to facilitate the differentiation between serotonergic and noradrenergic classes of antidepressant drugs. The FST is now widely used in basic research and the pharmaceutical screening of potential antidepressant treatments. It is also one of the most commonly used tests to assess depressive-like behavior in animal models. Despite the simplicity and sensitivity of the FST procedure, important differences even in baseline immobility rates have been reported between different groups, which complicate the comparison of results across studies. In spite of several methodological papers and reviews published on the FST, the need still exists for clarification of factors which can influence the procedure. While most recent reviews have focused on antidepressant effects observed with the FST, this one considers the methodological aspects of the procedure, aiming to summarize issues beyond antidepressant action in the FST. The previously published literature is analyzed for factors which are known to influence animal behavior in the FST. These include biological factors, such as strain, age, body weight, gender and individual differences between animals; influence of preconditioning before the FST: handling, social isolation or enriched environment, food manipulations, various kinds of stress, endocrine manipulations and surgery; schedule and routes of treatment, dosage and type of the drugs as well as experimental design and laboratory environmental effects. Consideration of these factors in planning experiments may result in more consistent FST results.

Modulation of protein tyrosine phosphorylation in gastric mucosa during re-epithelization processes.

AIM: To investigate the role of protein tyrosine phosphorylation in gastric wound formation and repair following ulceration. METHODS: Gastric lesions were induced in rats using restraint cold stress. To investigate the effect of oxidative and nitrosative cell stress on tyrosine phosphorylation during wound repair, total activity of protein tyrosine kinase (PTK), protein tyrosine phosphatase (PTP), antioxidant enzymes, nitric oxide synthase (NOS), 2',5'-oligoadenylate synthetase, hydroxyl radical and zinc levels were assayed in parallel. RESULTS: Ulcer provocation induced an immediate decrease in tyrosine kinase (40% in plasma membranes and 56% in cytosol, P < 0.05) and phosphatase activity (threefold in plasma membranes and 3.3-fold in cytosol), followed by 2.3-2.4-fold decrease (P < 0.05) in protein phosphotyrosine content in the gastric mucosa. Ulceration induced no immediate change in superoxide dismutase (SOD) activity, 30% increase (P < 0.05) in catalase activity, 2.3-fold inhibition (P < 0.05) of glutathione peroxidase, 3.3-fold increase (P < 0.05) in hydroxyl radical content, and 2.3-fold decrease (P < 0.05) in zinc level in gastric mucosa. NOS activity was three times higher in gastric mucosa cells after cold stress. Following ulceration, PTK activity increased in plasma membranes and reached a maximum on day 4 after stress (twofold increase, P < 0.05), but remained inhibited (1.6-3-fold decrease on days 3, 4 and 5, P < 0.05) in the cytosol. Tyrosine phosphatases remained inhibited both in membranes and cytosol (1.5-2.4-fold, P < 0.05). NOS activity remained increased on days 1, 2 and 3 (3.8-, 2.6-, 2.2-fold, respectively, P < 0.05). Activity of SOD increased 1.6 times (P < 0.05) days 4 and 5 after stress. Catalase activity normalized after day 2. Glutathione peroxidase activity and zinc level decreased (3.3- and 2-fold, respectively, P < 0.05) on the last day. Activity of 2',5'-oligoadenylate synthethase increased 2.8-fold (P < 0.05) at the beginning, and 1.6-2.3-fold (P < 0.05) during ulcer recuperation, and normalized on day 5, consistent with slowing of inflammation processes. CONCLUSION: These studies show diverse changes in total tyrosine kinase activity in gastric mucosa during the recovery process. Oxidative and nitrosative stress during lesion formation might lead to the observed reduction in tyrosine phosphorylation during ulceration.