Limits of decoding mental states with fMRI.

A growing number of studies claim to decode mental states using multi-voxel decoders of brain activity. It has been proposed that the fixed, fine-grained, multi-voxel patterns in these decoders are necessary for discriminating between and identifying mental states. Here, we present evidence that the efficacy of these decoders might be overstated. Across various tasks, decoder patterns were spatially imprecise, as decoder performance was unaffected by spatial smoothing; 90% redundant, as selecting a random 10% of a decoder's constituent voxels recovered full decoder performance; and performed similarly to brain activity maps used as decoders. We distinguish decoder performance in discriminating between mental states from performance in identifying a given mental state, and show that even when discrimination performance is adequate, identification can be poor. Finally, we demonstrate that simple and intuitive similarity metrics explain 91% and 62% of discrimination performance within- and across-subjects, respectively. These findings indicate that currently used across-subject decoders of mental states are superfluous and inappropriate for decision-making.

Fine-Grained Mapping of Cortical Somatotopies in Chronic Complex Regional Pain Syndrome.

It has long been thought that severe chronic pain conditions, such as complex regional pain syndrome (CRPS), are not only associated with, but even maintained by a reorganization of the somatotopic representation of the affected limb in primary somatosensory cortex (S1). This notion has driven treatments that aim to restore S1 representations in CRPS patients, such as sensory discrimination training and mirror therapy. However, this notion is based on both indirect and incomplete evidence obtained with imaging methods with low spatial resolution. Here, we used fMRI to characterize the S1 representation of the affected and unaffected hand in humans (of either sex) with unilateral CRPS. The cortical area, location, and geometry of the S1 representation of the CRPS hand were largely comparable with those of both the unaffected hand and healthy controls. We found no differential relation between affected versus unaffected hand map measures and clinical measures (pain severity, upper limb disability, disease duration). Thus, if any map reorganization occurs, it does not appear to be directly related to pain and disease severity. These findings compel us to reconsider the cortical mechanisms underlying CRPS and the rationale for interventions that aim to "restore" somatotopic representations to treat pain.SIGNIFICANCE STATEMENT This study shows that the spatial map of the fingers in somatosensory cortex is largely preserved in chronic complex regional pain syndrome (CRPS). These findings challenge the treatment rationale for restoring somatotopic representations in complex regional pain syndrome patients.

Brain oscillations reflecting pain-related behavior in freely moving rats.

Recording oscillatory brain activity holds great promise in pain research. However, experimental results are variable and often difficult to reconcile. Some of these inconsistencies arise from the use of hypothesis-driven analysis approaches that (1) do not assess the consistency of the observed responses within and across individuals, and (2) do not fully exploit information sampled across the entire cortex. Here, we address these issues by recording the electrocorticogram directly from the brain surface of 12 freely moving rats. Using a hypothesis-free approach, we isolated brain oscillations induced by graded nociceptive stimuli and characterized their relation to pain-related behavior. We isolated 4 responses, one phase-locked event-related potential, 2 non-phase-locked event-related synchronizations, and one non-phase-locked event-related desynchronization (ERD), in different frequency bands (δ/θ-ERD, θ/α-event-related synchronization, and gamma-band event-related synchronization). All responses except the δ/θ-ERD correlated with pain-related behavior at within-subject level. Notably, the gamma-band event-related synchronization was the only response that reliably correlated with pain-related behavior between subjects. These results comprehensively characterize the physiological properties of the brain oscillations elicited by nociceptive stimuli in freely moving rodents and provide a foundational work to improve the translation of experimental animal findings to human physiology and pathophysiology.

Perceptual learning to discriminate the intensity and spatial location of nociceptive stimuli.

Accurate discrimination of the intensity and spatial location of nociceptive stimuli is essential to guide appropriate behaviour. The ability to discriminate the attributes of sensory stimuli is continuously refined by practice, even throughout adulthood - a phenomenon called perceptual learning. In the visual domain, perceptual learning to discriminate one of the features that define a visual stimulus (e.g., its orientation) can transfer to a different feature of the same stimulus (e.g., its contrast). Here, we performed two experiments on 48 volunteers to characterize perceptual learning in nociception, which has been rarely studied. We investigated whether learning to discriminate either the intensity or the location of nociceptive stimuli (1) occurs during practice and is subsequently maintained, (2) requires feedback on performance, and (3) transfers to the other, unpractised stimulus feature. First, we found clear evidence that perceptual learning in discriminating both the intensity and the location of nociceptive stimuli occurs, and is maintained for at least 3 hours after practice. Second, learning occurs only when feedback is provided during practice. Finally, learning is largely confined to the feature for which feedback was provided. We discuss these effects in a predictive coding framework, and consider implications for future studies.

Was it a pain or a sound? Across-species variability in sensory sensitivity.

Natural selection has shaped the physiological properties of sensory systems across species, yielding large variations in their sensitivity. Here, we used laser stimulation of skin nociceptors, a widely used technique to investigate pain in rats and humans, to provide a vivid example of how ignoring these variations can lead to serious misconceptions in sensory neuroscience. In 6 experiments, we characterized and compared the physiological properties of the electrocortical responses elicited by laser stimulation in rats and humans. We recorded the electroencephalogram from the surface of the brain in freely moving rats and from the scalp in healthy humans. Laser stimuli elicited 2 temporally distinct responses, traditionally interpreted as reflecting the concomitant activation of different populations of nociceptors with different conduction velocities: small-myelinated Aδ-fibres and unmyelinated C-fibres. Our results show that this interpretation is valid in humans, but not in rats. Indeed, the early response recorded in rats does not reflect the activation of the somatosensory system, but of the auditory system by laser-generated ultrasounds. These results have wide implications: retrospectively, as they prompt for a reconsideration of a large number of previous interpretations of electrocortical rat recordings in basic, preclinical, and pharmacological research, and prospectively, as they will allow recording truly pain-related cortical responses in rats.

Seeing facial expressions enhances placebo analgesia.

The strength of the placebo effect is influenced by social contexts and individual personality. Although facial expressions provide important contextual cues, no study of their influence on the placebo response has been performed hitherto. Here we tested (1) whether the observation of facial expressions with different emotional content (Neutral, Pain, and Happy) affects the magnitude of placebo analgesia, and (2) whether interindividual differences in personality traits interact with any modulation of placebo response induced by facial expression. Twenty-seven healthy participants underwent classical placebo conditioning, and subsequently rated the intensity and unpleasantness of their pain experience associated with nociceptive-specific laser pulses delivered to the right hand dorsum. On each trial, different visual cues signalled the occurrence of a laser stimulus alone or of a laser stimulus accompanied by a sham analgesic treatment. In the conditioning period, cues signalling the sham treatment were followed by laser stimuli whose intensity was surreptitiously lowered. In the test period, either cue was followed by laser stimuli of the same intensity. The observation of facial expressions with different emotional content enhanced significantly the placebo analgesia. In particular, a significantly greater analgesic effect was observed when facial expressions with emotional content were presented concomitantly to the nociceptive stimulation. The enhancement of placebo analgesia during the observation of facial expressions was not correlated with personality traits like empathy and behavioural activation/inhibition. These findings quantify for the first time the effect of facial expressions on the magnitude of placebo analgesia.

Occurrence of adrenergic nerve fibers in human thymus during immune response.

The adrenergic nerve fibers (ANF), the neuropeptide Y-like immunoreactive nerve fibers (NPY-NF) and the noradrenaline (NA) amount were studied in the human thymus in subjects previously treated or not treated with interferon therapy with the aim to identify the changes due to the interferon therapy. This therapy has been used in patients affected by multiple sclerosis (MS). Biochemical and morphological methods were used associated with quantitative analysis of images. The whole thymuses were removed during autopsies in young and adult patients not treated with interferon. Moreover, samples of thymus were removed from patients, either young or adult who had previously been treated with interferon therapy, and subjected, for diagnostic reasons, to thymic biopsy. All samples of thymus were weighed, measured and dissected. Thymic slices were stained with Eosin-orange for detection of the microanatomical details, or with Bodian's reaction for recognition of nervous structures. Histofluorescence microscopy was used for detection of ANF, and immunofluorescence microscopy for recognition of NPY-like immunoreactive structures. All morphological results were subjected to quantitative analysis of images. Noradrenaline contained in thymic structures was measured by biochemical methods. Our results only concerned the effects of the therapy and suggested that treatment with interferon therapy induces many changes in the thymic structures: (1) The protein content of thymus is significantly increased; (2) the NA content in the thymus is also significantly increased; (3) NPY-like immunoreactive structures in the thymus are significantly increased; (4) occurrence of NPY-like immunoreactivity is particularly and significantly increased both in thymic microenvironment and in structures resembling nerve fibers; (5) ANF are significantly increased in the same thymic structures in which NPY-like immunoreactivity is also increased (i.e. thymic microenvironment and structures resembling nerve fibers). The morphological and biochemical changes observed can also explain the immunological changes induced in the thymus after immunostimulating therapy.