Comparing Neural Correlates of Consciousness: From Psychedelics to Hypnosis and Meditation.

BACKGROUND: Pharmacological and nonpharmacological methods of inducing altered states of consciousness (ASCs) are becoming increasingly relevant in the treatment of psychiatric disorders. While comparisons between them are often drawn, to date no study has directly compared their neural correlates. METHODS: To address this knowledge gap, we directly compared 2 pharmacological methods (psilocybin 0.2 mg/kg orally [n = 23] and lysergic acid diethylamide [LSD] 100 µg orally [n = 25]) and 2 nonpharmacological methods (hypnosis [n = 30] and meditation [n = 29]) using resting-state functional connectivity magnetic resonance imaging and assessed the predictive value of the data using a machine learning approach. RESULTS: We found that 1) no network reached significance in all 4 ASC methods; 2) pharmacological and nonpharmacological interventions of inducing ASCs showed distinct connectivity patterns that were predictive at the individual level; 3) hypnosis and meditation showed differences in functional connectivity when compared directly and also drove distinct differences when jointly compared with the pharmacological ASC interventions; and 4) psilocybin and LSD showed no differences in functional connectivity when directly compared with each other, but they did show distinct behavioral-neural relationships. CONCLUSIONS: Overall, these results extend our understanding of the mechanisms of action of ASCs and highlight the importance of exploring how these effects can be leveraged in the treatment of psychiatric disorders.

Evaluating the Effects of Acupuncture Using a Dental Pain Model in Healthy Subjects - A Randomized, Cross-Over Trial.

Acupuncture is a complementary and nonpharmacological intervention that can be effective for the management of chronic pain in addition to or instead of medication. Various animal models for neuropathic pain, inflammatory pain, cancer-related pain, and visceral pain already exist in acupuncture research. We used a newly validated human pain model and examined whether acupuncture can influence experimentally induced dental pain. For this study, we compared the impact of manual acupuncture (real acupuncture), manual stimulation of a needle inserted at nonacupuncture points (sham acupuncture) and no acupuncture on experimentally induced dental pain in 35 healthy men who were randomized to different sequences of all 3 interventions in a within-subject design. BORG CR10 pain ratings and autonomic responses (electrodermal activity and heart rate variability) were investigated. An initial mixed model with repeated measures included preintervention pain ratings and the trial sequence as covariates. The results showed that acupuncture was effective in reducing pain intensity when compared to no acupuncture (ß = -.708, P = .002), corresponding to a medium Cohen's d effect size of .56. The comparison to the sham acupuncture revealed no statistically significant difference. No differences in autonomic responses between real and sham acupuncture were found during the intervention procedures. PERSPECTIVE: This study established a dental pain model for acupuncture research and provided evidence that experimentally induced dental pain can be influenced by either real acupuncture or manual stimulation of needles at nonacupuncture points. The data do not support that acupoint specificity is a significant factor in reducing experimental pain.

Neurochemical dynamics of acute orofacial pain in the human trigeminal brainstem nuclear complex.

The trigeminal brainstem sensory nuclear complex is the first central relay structure mediating orofacial somatosensory and nociceptive perception. Animal studies suggest a substantial involvement of neurochemical alterations at such basal CNS levels in acute and chronic pain processing. Translating this animal based knowledge to humans is challenging. Human related examining of brainstem functions are challenged by MR related peculiarities as well as applicability aspects of experimentally standardized paradigms. Based on our experience with an MR compatible human orofacial pain model, the aims of the present study were twofold: 1) from a technical perspective, the evaluation of proton magnetic resonance spectroscopy at 3 T regarding measurement accuracy of neurochemical profiles in this small brainstem nuclear complex and 2) the examination of possible neurochemical alterations induced by an experimental orofacial pain model. Data from 13 healthy volunteers aged 19-46 years were analyzed and revealed high quality spectra with significant reductions in total N-acetylaspartate (N-acetylaspartate + N-acetylaspartylglutamate) (-3.7%, p = 0.009) and GABA (-10.88%, p = 0.041) during the pain condition. These results might reflect contributions of N-acetylaspartate and N-acetylaspartylglutamate in neuronal activity-dependent physiologic processes and/or excitatory neurotransmission, whereas changes in GABA might indicate towards a reduction in tonic GABAergic functioning during nociceptive signaling. Summarized, the present study indicates the applicability of 1H-MRS to obtain neurochemical dynamics within the human trigeminal brainstem sensory nuclear complex. Further developments are needed to pave the way towards bridging important animal based knowledge with human research to understand the neurochemistry of orofacial nociception and pain.

Reproducibility of Neurochemical Profile Quantification in Pregenual Cingulate, Anterior Midcingulate, and Bilateral Posterior Insular Subdivisions Measured at 3 Tesla.

The current report assessed measurement reproducibility of proton magnetic resonance spectroscopy at 3 Tesla in the left and right posterior insular, pregenual anterior cingulate, and anterior midcingulate cortices. Ten healthy male volunteers aged 21-30 years were tested at four different days, of which nine were included in the data analysis. Intra- and inter-subject variability of myo-inositol, creatine, glutamate, total-choline, total-N-acetylaspartate, and combined glutamine-glutamate were calculated considering the influence of movement parameters, age, daytime of measurements, and tissue composition. Overall mean intra-/inter-subject variability for all neurochemicals combined revealed small mean coefficients of variation across the four regions: 5.3/9.05% in anterior midcingulate, 6.6/8.84% in pregenual anterior cingulate, 7.3/10.00% in left posterior and 8.2/10.55% in right posterior insula. Head movement, tissue composition and day time revealed no significant explanatory variance contribution suggesting a negligible influence on the data. A strong correlation between Cramer-Rao Lower Bounds (a measure of fitting errors) and the mean intra-subject coefficients of variation (r = 0.799, p < 0.001) outlined the importance of low fitting errors in order to obtain robust and finally meaningful measurements. The present findings confirm proton magnetic resonance spectroscopy as a reliable tool to measure brain neurochemistry in small subregions of the human brain.

Equal pain-Unequal fear response: enhanced susceptibility of tooth pain to fear conditioning.

Experimental fear conditioning in humans is widely used as a model to investigate the neural basis of fear learning and to unravel the pathogenesis of anxiety disorders. It has been observed that fear conditioning depends on stimulus salience and subject vulnerability to fear. It is further known that the prevalence of dental-related fear and phobia is exceedingly high in the population. Dental phobia is unique as no other body part is associated with a specific phobia. Therefore, we hypothesized that painful dental stimuli exhibit an enhanced susceptibility to fear conditioning when comparing to equal perceived stimuli applied to other body sites. Differential susceptibility to pain-related fear was investigated by analyzing responses to an unconditioned stimulus (UCS) applied to the right maxillary canine (UCS-c) vs. the right tibia (UCS-t). For fear conditioning, UCS-c and USC-t consisted of painful electric stimuli, carefully matched at both application sites for equal intensity and quality perception. UCSs were paired to simple geometrical forms which served as conditioned stimuli (CS+). Unpaired CS+ were presented for eliciting and analyzing conditioned fear responses. Outcome parameter were (1) skin conductance changes and (2) time-dependent brain activity (BOLD responses) in fear-related brain regions such as the amygdala, anterior cingulate cortex, insula, thalamus, orbitofrontal cortex, and medial prefrontal cortex. A preferential susceptibility of dental pain to fear conditioning was observed, reflected by heightened skin conductance responses and enhanced time-dependent brain activity (BOLD responses) in the fear network. For the first time, this study demonstrates fear-related neurobiological mechanisms that point toward a superior conditionability of tooth pain. Beside traumatic dental experiences our results offer novel evidence that might explain the high prevalence of dental-related fears in the population.

A reliability study on brain activation during active and passive arm movements supported by an MRI-compatible robot.

In neurorehabilitation, longitudinal assessment of arm movement related brain function in patients with motor disability is challenging due to variability in task performance. MRI-compatible robots monitor and control task performance, yielding more reliable evaluation of brain function over time. The main goals of the present study were first to define the brain network activated while performing active and passive elbow movements with an MRI-compatible arm robot (MaRIA) in healthy subjects, and second to test the reproducibility of this activation over time. For the fMRI analysis two models were compared. In model 1 movement onset and duration were included, whereas in model 2 force and range of motion were added to the analysis. Reliability of brain activation was tested with several statistical approaches applied on individual and group activation maps and on summary statistics. The activated network included mainly the primary motor cortex, primary and secondary somatosensory cortex, superior and inferior parietal cortex, medial and lateral premotor regions, and subcortical structures. Reliability analyses revealed robust activation for active movements with both fMRI models and all the statistical methods used. Imposed passive movements also elicited mainly robust brain activation for individual and group activation maps, and reliability was improved by including additional force and range of motion using model 2. These findings demonstrate that the use of robotic devices, such as MaRIA, can be useful to reliably assess arm movement related brain activation in longitudinal studies and may contribute in studies evaluating therapies and brain plasticity following injury in the nervous system.

Insula-specific H magnetic resonance spectroscopy reactions in heavy smokers under acute nicotine withdrawal and after oral nicotine substitution.

The aim of this study was to clarify whether addiction-specific neurometabolic reaction patterns occur in the insular cortex during acute nicotine withdrawal in tobacco smokers in comparison to nonsmokers. Fourteen male smokers and 10 male nonsmokers were included. Neurometabolites of the right and the left insular cortices were quantified by magnetic resonance spectroscopy (MRS) on a 3-Tesla scanner. Three separate MRS measurements were performed in each subject: among the smokers, the first measurement was done during normal smoking behavior, the second measurement during acute withdrawal (after 24 h of smoking abstinence), and the third shortly after administration of an oral nicotine substitute. Simultaneously, craving, withdrawal symptoms, and CO levels in exhaled air were determined during the three phases. The participants in the control group underwent the same MR protocol. In the smokers, during withdrawal, the insular cortex showed a significant increase in glutamine (Gln; p = 0.023) as well as a slight increase not reaching significance for glutamine/glutamate (Glx; p = 0.085) and a nonsignificant drop in myoinositol (mI; p = 0.381). These values tended to normalize after oral nicotine substitution treatment, even though differences were not significant: Gln (p = 0.225), Glx (p = 0.107) and mI (p = 0.810). Overall, the nonsmokers (control group) did not show any metabolic changes over all three phases (p > 0.05). In smokers, acute nicotine withdrawal produces a neurometabolic reaction pattern that is partly reversed by the administration of an oral nicotine substitute. The results are consistent with the expression of an addiction-specific neurometabolic shift in the brain and confirm the fact that the insular cortex seems to play a possible role in nicotine dependence.

Differential NMR spectroscopy reactions of anterior/posterior and right/left insular subdivisions due to acute dental pain.

OBJECTIVES: The insular cortex has an important role within the cerebral pain circuitry. The aim of this study was to measure metabolic alterations by MR spectroscopy due to experimentally induced trigeminal pain in the anterior/posterior and right/left insular subdivisions. METHODS: Sixteen male volunteers were investigated using magnetic resonance (MR) spectroscopy before, during and after experimentally induced dental pain. Biphasic bipolar electric current pulses of 1 ms duration were administered based on the subjectively determined pain threshold. Volunteers were instructed to rate every stimulus using a MR compatible rating scale. RESULTS: Due to the pain stimulation a significant absolute increase in glutamate (Glu, F = 6.1; P = 0.001), glutamine (Gln, F = 11.2; P = 0.001) as well as glutamate/glutamine (Glx, F = 17.7; P = 0.001) were observed, whereas myo-inositol (mI, F = 9.5;P = 0.001) showed a significant drop. Additionally, these metabolites showed a significant effect towards lateralisation, meaning that metabolic concentration differed either in left or right insular subdivision. Creatine demonstrated also an absolute significant decrease during stimulation (F = 2.8; P = 0.022) with a significant anterior-posterior difference (F = 40.7; P = 0.001). CONCLUSIONS: Results confirm that the insular cortex is a metabolically high active region in pain processing within the brain. Quantitative metabolic changes show that there is a distinct but locally diverse neurometabolic activity under acute pain. The known cytoarchitectonic subdivisions show different metabolic reactions and give new insights into pain-processing physiology.

Brain activity during stepping: a novel MRI-compatible device.

Little is known about the impact of supraspinal centers on the control of human locomotion. Analyzing brain activity can help to clarify their impact and to improve the effects of locomotor training. A fMRI-compatible pneumatic robotic device is presented that can generate freely programmable, highly repetitive periodic active and passive leg movements comprised by hip, knee, and ankle joint displacements. Forces of up to 400N can be applied to each foot while the subject is lying in a supine position. Magnetic interference of the device with the magnetic field of the scanner is measurable, but does not affect the image quality as obtained by a usual image analysis procedure. In a first experiment, brain activity of one healthy subject was acquired during nine different gait-like movement conditions. Brain activity in the somatosensory and motor function related areas increased more when the subject actively moved the legs than when the legs were passively moved by the device. In almost all conditions, mean head motion could be limited to 2mm within the duration of one fMRI scan by a specifically developed head and trunk fixation system. Based on these results, it is concluded that our device will significantly contribute to a better understanding of human locomotor control and related therapeutic effects in spinal cord injured and stroke patients, and thereby, to improve training approaches.

Taking Sides with Pain - Lateralization aspects Related to Cerebral Processing of Dental Pain.

The current fMRI study investigated cortical processing of electrically induced painful tooth stimulation of both maxillary canines and central incisors in 21 healthy, right-handed volunteers. A constant current, 150% above tooth specific pain perception thresholds was applied and corresponding online ratings of perceived pain intensity were recorded with a computerized visual analog scale during fMRI measurements. Lateralization of cortical activations was investigated by a region of interest analysis. A wide cortical network distributed over several areas, typically described as the pain or nociceptive matrix, was activated on a conservative significance level. Distinct lateralization patterns of analyzed structures allow functional classification of the dental pain processing system. Namely, certain parts are activated independent of the stimulation site, and hence are interpreted to reflect cognitive emotional aspects. Other parts represent somatotopic processing and therefore reflect discriminative perceptive analysis. Of particular interest is the observed amygdala activity depending on the stimulated tooth that might indicate a role in somatotopic encoding.

An fMRI pilot study to evaluate brain activation associated with locomotion adaptation.

The goal of robotic therapy is to provoke motor plasticity via the application of robotic training strategies. Although robotic haptic guidance is the commonly used motor-training strategy to reduce performance errors while training, research on motor learning has emphasized that errors are a fundamental neural signal that drives motor adaptation. Thus, researchers have proposed robotic therapy algorithms that amplify movement errors rather than decrease them. Studying the particular brain regions involved in learning under different training strategies might help tailoring motor training conditions to the anatomical location of a focal brain insult. In this paper, we evaluate the brain regions involved in locomotion adaptation when training with three different conditions: without robotic guidance, with a random-varying force disturbance, and with repulsive forces proportional to errors. We performed an fMRI pilot study with four healthy subjects who stepped in an fMRI compatible walking robotic device. Subjects were instructed to actively synchronize their left leg with respect to their right leg (passively guided by the robot) while their left leg was affected by any of the three conditions. We observed activation in areas known to be involved in error processing. Although we found that all conditions required the similar cortical network to fulfill the task, we observed a tendency towards more activity in the motor/sensory network as more "challenged" the subjects were.

Cortisol reduces recall of explicit contextual pain memory in healthy young men.

Remembering painful incidents has important adaptive value but may also contribute to clinical symptoms of posttraumatic stress disorder and chronic pain states. Because glucocorticoids are known to impair memory retrieval processes, we investigated whether cortisol affects recall of previously experienced pain in healthy young men. In a double-blind, placebo-controlled crossover study, 20 male participants were presented pictures, half of them combined with a heat-pain stimulus. The next day, the same pictures were shown in the absence of pain. Cortisol (20 mg) administered 1h before retention testing reduced recall of explicit contextual pain memory, whereas it did not affect pain threshold or pain tolerance.