Influence of anxiety and alexithymia on brain activations associated with the perception of others' pain in autism.

The circumstances under which empathy is altered in ASD remain unclear, as previous studies did not systematically find differences in brain activation between ASD and controls in empathy-eliciting paradigms, and did not always monitor whether differences were primarily due to ASD "per se", or to conditions overlapping with ASD, such as alexithymia and anxiety. Here, we collected fMRI data from 47 participants (22 ASD) viewing pictures depicting hands and feet of unknown others in painful, disgusting, or neutral situations. We computed brain activity for painful and disgusting stimuli (vs. neutral) in whole brain and in regions of interest among the brain areas typically activated during the perception of nociceptive stimuli. Group differences in brain activation disappeared when either alexithymia or anxiety - both elevated in the ASD group - were controlled for. Regression analyses indicated that the influence of symptoms was mainly shared between autistic symptomatology, alexithymia and anxiety or driven by unique contributions from alexithymia or anxiety. Our results suggest that affective empathy may be affected in ASD, but that this association is complex. The respective contribution of alexithymia and anxiety to decreased affective empathy of people with ASD may be due to the association of those psychiatric conditions with reduced motor resonance/Theory of Mind.

Effect of visual stimuli of pain on empathy brain network in people with and without Autism Spectrum Disorder.

The extent to which affective empathy is impaired in Autism Spectrum Disorder (ASD) remains unclear, as some-but not all-previous neuroimaging studies investigating empathy for pain in ASD have shown similar activation levels to those of neurotypicals individuals. These inconsistent results could be due to the use of different empathy-eliciting stimuli. While some studies used pictures of faces exhibiting a painful expression, others used pictures of limbs in painful situations. In this study, we used fMRI to compare activation in areas associated with empathy processing (empathy network) for these two types of stimuli in 31 participants (16 with ASD, 15 controls). We found a group difference in the inferior frontal gyrus (IFG) and the thalamus when participants viewed stimuli of limbs in painful situations, but not when they viewed face stimuli with a painful expression. Both groups of participants activated their empathy network more when viewing pictures of limbs in painful situations than when viewing pictures of faces with a painful expression; this increased activation for limbs versus faces was significantly enhanced in controls relative to ASD participants, especially in the secondary somatosensory cortex (SII). Our findings suggest that empathy defect of people with ASD is contingent upon the type of stimuli used, and may be related to the level of Mirror Neuron System involvement, as brain regions showing group differences (IFG, SII) underlie embodiment. We discuss the potential clinical implications of our findings in terms of developing interventions boosting the empathetic abilities of people with ASD.

Voluntary modulation of mental effort investment: an fMRI study.

Mental effort is a common phenomenological construct deeply linked to volition and self-control. While it is often assumed that the amount of exertion invested in a task can be voluntarily regulated, the neural bases of such faculty and its behavioural effects are yet insufficiently understood. In this study, we investigated how the instructions to execute a demanding cognitive task either "with maximum exertion" or "as relaxed as possible" affected performance and brain activity. The maximum exertion condition, compared to relaxed execution, was associated with speeded motor responses without an accuracy trade-off, and an amplification of both task-related activations in dorsal frontoparietal and cerebellar regions, and task-related deactivations in default mode network (DMN) areas. Furthermore, the visual cue to engage maximum effort triggered an anticipatory widespread increase of activity in attentional, sensory and executive regions, with its peak in the brain stem reticular activating system. Across individuals, this surge of activity in the brain stem, but also in medial wall cortical regions projecting to the adrenal medulla, positively correlated with increases in heart rate, suggesting that the intention to willfully modulate invested effort involves mechanisms related to catecholaminergic transmission and a suppression of DMN activity in favor of externally-directed attentional processes.

Diagnosing and assessing pain in neurorehabilitation: from translational research to the clinical setting. Evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation.

Pain is very common in neurorehabilitation, where it may be a target for treatment and have a negative effect on rehabilitation procedures and outcomes. Promising preliminary preclinical data support certain therapeutic approaches to pain, but there is a strong need of adequate preclinical models, experimental settings, outcome measures, and biomarkers that are more relevant for pain within the neurorehabilitation field. Data on the diagnosis and assessment of nociceptive and neuropathic pain (NP) are very scanty in neurorehabilitation, but those from other contexts can be adapted and translated to this specific setting. The Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN) has searched and evaluated existing evidence on animal models for the treatment of pain, definition and diagnostic criteria for nociceptive and NP, screening tools and questionnaires, along with diagnostic, clinical and instrumental techniques to distinguish nociceptive from NP and, more generally, to assess pain in the field of neurorehabilitation. The present ICCPN recommendations provide information on the relevance of current preclinical models, and may be helpful in ameliorating pain diagnosis and assessment, which are prerequisites for better application and tailoring of current pharmacological and non-pharmacological treatments. They may also be useful for future studies aimed at filling the gaps in the current knowledge of these topics.

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.

Multi-shot turbo spin-echo for 3D vascular space occupancy imaging.

Vascular space occupancy (VASO) is a magnetic resonance imaging technique sensitive to cerebral blood volume, and is a potential alternative to the blood oxygenation level dependent (BOLD) sensitive technique as a basis for functional mapping of the neurovascular response to a task. Many implementations of VASO have made use of echo-planar imaging strategies that allow rapid acquisition, but risk introducing potentially confounding BOLD effects. Recently, multi-slice and 3D VASO techniques have been implemented to increase the imaging volume beyond the single slice of early reports. These techniques usually rely, however, on advanced scanner software or hardware not yet available in many centers. In the present study, we have implemented a short-echo time, multi-shot 3D Turbo Spin-Echo (TSE) VASO sequence that provided 8-slice coverage on a routine clinical scanner. The proposed VASO sequence was tested in assessing the response of the human motor cortex during a block design finger tapping task in 10 healthy subjects. Significant VASO responses, inversely correlated with the task, were found at both individual and group level. The location and extent of VASO responses were in close correspondence to those observed using a conventional BOLD acquisition in the same subjects. Although the spatial coverage and temporal resolution achieved were limited, robust and consistent VASO responses were observed. The use of a susceptibility insensitive volumetric TSE VASO sequence may have advantages in locations where conventional BOLD and echo-planar based VASO imaging is compromised.

Human parietofrontal networks related to action observation detected at rest.

Recent data show a broad correspondence between human resting-state and task-related brain networks. We performed a functional magnetic resonance imaging (fMRI) study to compare, in the same subjects, the spatial independent component analysis (ICA) maps obtained at rest and during the observation of either reaching/grasping hand actions or matching static pictures. Two parietofrontal networks were identified by ICA from action observation task data. One network, specific to reaching/grasping observation, included portions of the anterior intraparietal cortex and of the dorsal and ventral lateral premotor cortices. A second network included more posterior portions of the parietal lobe, the dorsomedial frontal cortex, and more anterior and ventral parts, respectively, of the dorsal and ventral premotor cortices, extending toward Broca's area; this network was more generally related to the observation of hand action and static pictures. A good spatial correspondence was found between the 2 observation-related ICA maps and 2 ICA maps identified from resting-state data. The anatomical connectivity among the identified clusters was tested in the same volunteers, using persistent angular structure-MRI and deterministic tractography. These findings extend available knowledge of human parietofrontal circuits and further support the hypothesis of a persistent coherence within functionally relevant networks during rest.

Activation likelihood estimation meta-analysis of brain correlates of placebo analgesia in human experimental pain.

Placebo analgesia (PA) is one of the most studied placebo effects. Brain imaging studies published over the last decade, using either positron emission tomography (PET) or functional magnetic resonance imaging (fMRI), suggest that multiple brain regions may play a pivotal role in this process. However, there continues to be much debate as to which areas consistently contribute to placebo analgesia-related networks. In the present study, we used activation likelihood estimation (ALE) meta-analysis, a state-of-the-art approach, to search for the cortical areas involved in PA in human experimental pain models. Nine fMRI studies and two PET studies investigating cerebral hemodynamic changes were included in the analysis. During expectation of analgesia, activated foci were found in the left anterior cingulate, right precentral, and lateral prefrontal cortex and in the left periaqueductal gray (PAG). During noxious stimulation, placebo-related activations were detected in the anterior cingulate and medial and lateral prefrontal cortices, in the left inferior parietal lobule and postcentral gyrus, anterior insula, thalamus, hypothalamus, PAG, and pons; deactivations were found in the left mid- and posterior cingulate cortex, superior temporal and precentral gyri, in the left anterior and right posterior insula, in the claustrum and putamen, and in the right thalamus and caudate body. Our results suggest on one hand that the modulatory cortical networks involved in PA largely overlap those involved in the regulation of emotional processes, on the other that brain nociceptive networks are downregulated in parallel with behavioral analgesia.

An algorithm to estimate anatomical connectivity between brain regions using diffusion MRI.

The study of anatomical connectivity is essential for interpreting functional MRI data and for establishing how brain areas are linked together into networks to support higher-order functions. Diffusion-weighted MR images (DWI) and tractography provide a unique noninvasive tool to explore the connectional architecture of the brain. The identification of anatomical circuits associated with a specific function can be better accomplished by the joint application of diffusion and functional MRI. In this article, we propose a simple algorithm to identify the set of pathways between two regions of interest. The method is based upon running deterministic tractography from all possible starting positions in the brain and selecting trajectories that intersect both regions. We compare results from single-fiber tractography using diffusion tensor imaging and from multi-fiber tractography using reduced-encoding persistent angular structure (PAS) MRI on standard DWI datasets from healthy human volunteers. Our results show that, in comparison with single-fiber tractography, the multi-fiber technique reveals additional putative routes of connection. We demonstrate highly consistent results of the proposed technique over a cohort of 16 healthy subjects.

Semiautomated segmentation of the human spine based on echoplanar images.

The number of functional magnetic resonance imaging (fMRI) studies performed on the human spinal cord (SC) has considerably increased in recent years. The lack of a validated processing pipeline is, however, a significant obstacle to the spread of SC fMRI. One component likely to be involved in any such pipeline is the process of SC masking, analogous to brain extraction in cerebral fMRI. In general, SC masking has been performed manually, with the incumbent costs of being very time consuming and operator dependent. To overcome these drawbacks, we have developed a tailored semiautomatic method for segmenting echoplanar images (EPI) of human spine that is able to identify the spinal canal and the SC. The method exploits both temporal and spatial features of the EPI series and was tested and optimized on EPI images of cervical spine acquired at 3 T. The dependence of algorithm performance on the degree of EPI image distortion was assessed by computing the displacement warping field that best matched the EPI to the corresponding high-resolution T(2) images. Segmentation accuracy was above 80%, a significant improvement over values obtained with similar approaches, but not exploiting temporal information. Geometric distortion was found to explain about 50% of the variance of algorithm classification efficiency.

A regularization algorithm for decoding perceptual temporal profiles from fMRI data.

In several biomedical fields, researchers are faced with regression problems that can be stated as Statistical Learning problems. One example is given by decoding brain states from functional magnetic resonance imaging (fMRI) data. Recently, it has been shown that the general Statistical Learning problem can be restated as a linear inverse problem. Hence, new algorithms were proposed to solve this inverse problem in the context of Reproducing Kernel Hilbert Spaces. In this paper, we detail one iterative learning algorithm belonging to this class, called ν-method, and test its effectiveness in a between-subjects regression framework. Specifically, our goal was to predict the perceived pain intensity based on fMRI signals, during an experimental model of acute prolonged noxious stimulation. We found that, using a linear kernel, the psychophysical time profile was well reconstructed, while pain intensity was in some cases significantly over/underestimated. No substantial differences in terms of accuracy were found between the proposed approach and one of the state-of-the-art learning methods, the Support Vector Machines. Nonetheless, adopting the ν-method yielded a significant reduction in computational time, an advantage that became more evident when a relevant feature selection procedure was implemented. The ν-method can be easily extended and included in typical approaches for binary or multiple classification problems, and therefore it seems well-suited to build effective brain activity estimators.

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.

Functional exploration of the human spinal cord during voluntary movement and somatosensory stimulation.

Demonstrations of the possibility of obtaining functional information from the spinal cord in humans using functional magnetic resonance imaging (fMRI) have been growing in number and sophistication, but the technique and the results that it provides are still perceived by the scientific community with a greater degree of scepticism than fMRI investigations of brain function. Here we review the literature on spinal fMRI in humans during voluntary movements and somatosensory stimulation. Particular attention is given to study design, acquisition and statistical analysis of the images, and to the agreement between the obtained results and existing knowledge regarding spinal cord anatomy and physiology. A striking weakness of many spinal fMRI studies is the use of small numbers of subjects and of time-points in the acquired functional image series. In addition, spinal fMRI is characterised by large physiological noise, while the recorded functional responses are poorly characterised. For all these reasons, spinal fMRI experiments risk having low statistical power, and few spinal fMRI studies have yielded physiologically relevant information. Thus, while available evidence indicates that spinal fMRI is feasible, we are only approaching the stage at which the technique can be considered to have been rigorously established as a viable means of noninvasively investigating spinal cord functioning in humans.

A quantitative comparison of BOLD fMRI responses to noxious and innocuous stimuli in the human spinal cord.

Recent studies have shown that functional magnetic resonance imaging (fMRI) can non-invasively assess spinal cord activity. Yet, a quantitative description of nociceptive and non-nociceptive responses in the human spinal cord, compared with random signal fluctuations in resting state data, is still lacking. Here we have investigated the intensity and spatial extent of blood oxygenation level dependent (BOLD) fMRI responses in the cervical spinal cord of healthy volunteers, elicited by stimulation of the hand dorsum (C6-C7 dermatomes). In a block design fMRI paradigm, periods (20 s each) of repetitive noxious (laser heat) or innocuous (brushing) stimulation were alternated with rest. To estimate the level of false positive responses, functional images were acquired during a separate run while subjects were at rest. In a first analysis of averaged peristimulus signals from all voxels within each half of the spinal cord, we found bilateral fMRI responses to both stimuli. These responses were significantly larger during noxious than during innocuous stimulation. No significant fMRI signal change was evident over corresponding time periods during the Rest run. In a second, general linear model analysis, we identified a voxel population preferentially responding to noxious stimulation, which extended rostro-caudally over the length (4 cm) of the explored spinal cord region. By contrast, we found no evidence of voxel populations responding uniquely to innocuous stimuli, or showing decreased activity following either kind of somatosensory stimulus. These results provide the first false-positive-controlled comparison of spinal BOLD fMRI responses to noxious and innocuous stimuli in humans, confirming and extending physiological information obtained in other species.

Does it look painful or disgusting? Ask your parietal and cingulate cortex.

Looking at still images of body parts in situations that are likely to cause pain has been shown to be associated with activation in some brain areas involved in pain processing. Because pain involves both sensory components and negative affect, it is of interest to explore whether the visually evoked representations of pain and of other negative emotions overlap. By means of event-related functional magnetic resonance imaging, here we compare the brain areas recruited, in female volunteers, by the observation of painful, disgusting, or neutral stimuli delivered to one hand or foot. Several cortical foci were activated by the observation of both painful and disgusting video clips, including portions of the medial prefrontal cortex, anterior, mid-, and posterior cingulate cortex, left posterior insula, and right parietal operculum. Signal changes in perigenual cingulate and left anterior insula were linearly related to the perceived unpleasantness, when the individual differences in susceptibility to aversive stimuli were taken into account. Painful scenes selectively induced activation of left parietal foci, including the parietal operculum, the postcentral gyrus, and adjacent portions of the posterior parietal cortex. In contrast, brain foci specific for disgusting scenes were found in the posterior cingulate cortex. These data show both similarities and differences between the brain patterns of activity related to the observation of noxious or disgusting stimuli. Namely, the parietal cortex appears to be particularly involved in the recognition of noxious environmental stimuli, suggesting that areas involved in sensory aspects of pain are specifically triggered by observing noxious events.

Physiological noise modelling for spinal functional magnetic resonance imaging studies.

Spinal cord functional imaging allows assessment of activity in primary synaptic connections made by sensory neurons relaying information about the state of the body. However, reported human data based on gradient-echo techniques have been largely inconsistent, with no clear patterns of activation emerging. One reason for this variability is the influence of physiological noise, which is typically not corrected for. By acquiring single-slice resting data from the spinal cord with a conventional gradient-echo EPI pulse sequence at TR=200 ms (critically sampled) and TR=3 s (under-sampled), we have characterised various sources of physiological noise. In 8 healthy subjects, the presence of physiologically dependent signal was explored using probabilistic independent component analysis (PICA). Based on the insights provided by PICA, we defined a new physiological noise model (PNM) based on retrospective image correction (RETROICOR), which uses independent physiological measurements taken from the subject to model sources of noise. Statistical significance of individual components included in the PNM was assessed by F-tests, which demonstrated that the optimal PNM included cardiac, respiratory, interaction and low-frequency regressors. In a group of 10 healthy subjects, activation data were acquired from the cervical spinal region (T1 to C5) during painful thermal stimulation of the right and left hands. The improvement obtained when using a PNM in estimating spinal cord activation was reflected in a reduction of false-positive activation (active voxels in the CSF space surrounding the cord), when compared to conventional GLM modelling without a PNM.

Enhancement of force after action observation: behavioural and neurophysiological studies.

We tested here the hypothesis that observing others' actions can facilitate basic aspects of motor performance, such as force production, even if subjects are not required to immediately reproduce the observed actions and if they are not aware that observation can form the basis for procedural training. To this end, we compared in healthy volunteers the effects of repeated actual execution (MOV) or observation (OBS) of a simple intransitive movement (abduction of the right index and middle fingers). In a first experiment, we found that both actual and observational training significantly increased the finger abduction force of both hands. In the MOV group, force increases over pre-training values were significantly higher in the trained than in the untrained hand (50% versus 33%), whereas they were similar for the two hands in the OBS group (32% versus 30%). No force change was found in the control, untrained group. In a second experiment, we found that both training conditions significantly increased the isometric force exerted during right index finger abduction, whereas no post-training change in isometric force was found during abduction of the right little finger. Actual performance, imagination and, to a lower extent, observation of fingers movement enhanced the excitability of the corticospinal system targeting the first dorsal interosseus muscle, as tested by transcranial magnetic stimulation; pre- and post-training effects were of similar magnitude. These results show a powerful, specific role of action observation in motor training, likely exerted through premotor areas, which may prove useful in physiological and rehabilitative conditions.

An ARX model-based approach to trial by trial identification of fMRI-BOLD responses.

Being able to estimate the fMRI-BOLD response following a single task or stimulus is certainly of value, since it allows to characterize its relationship to different aspects either of the stimulus, or of the subject's performance. In order to detect and characterize BOLD responses in single trials, we developed and validated a procedure based on an AutoRegressive model with eXogenous Input (ARX). The use of an individual exogenous input for each voxel makes the modeling sensitive enough to reveal differences across regions, avoiding any a priori assumption about the reference signal. The detection of variability across trials is ensured by a suitable choice, for each voxel, of the order of the moving average, which in our implementation determines the relative delay between the recorded and the reference signal. This is a quality useful in finding different time profiles of activation from high temporal resolution fMRI data. The results obtained from simulated fMRI data resulting from synthetic activations in actual noise indicate that such approach allows to evaluate important features of the response, such as the time to onset, and time to peak. Moreover, the results obtained from real high temporal resolution fMRI data acquired at l.5 T during a motor task are consistent with previous knowledge about the responses of different cortical areas in motor programming and execution. The proposed procedure should also prove useful as a pre-processing step in different approaches to the analysis of fMRI data.