Structural connectivity in recovery after coma: Connectome atlas approach.

AIM: Pathological states of recovery after coma as a result of a severe brain injury are marked with changes in structural connectivity of the brain. This study aimed to identify a topological correlation between white matter integrity and the level of functional and cognitive impairment in patients recovering after coma. METHODS: Structural connectomes were computed based on fractional anisotropy maps from 40 patients using a probabilistic human connectome atlas. We used a network based statistics approach to identify potential brain networks associated with a more favorable outcome, assessed with clinical neurobehavioral scores at the patient's discharge from the acute neurorehabilitation unit. RESULTS: We identified a subnetwork whose strength of connectivity correlated with a more favorable outcome as measured with the Disability Rating Scale (network based statistics: t >3.5, P =.010). The subnetwork predominated in the left hemisphere and included the thalamic nuclei, putamen, precentral and postcentral gyri, and medial parietal regions. Spearman correlation between the mean fractional anisotropy value of the subnetwork and the score was ρ = -0.60 (P <.0001). A less extensive overlapping subnetwork correlated with the Coma Recovery Scale Revised score, consisting mostly of the left hemisphere connectivity between the thalamic nuclei and pre- and post-central gyri (network based statistics: t >3.5, P =.033; Spearman's ρ = 0.58, P <.0001). CONCLUSION: The present findings suggest an important role of structural connectivity between the thalamus, putamen and somatomotor cortex in the recovery from coma as evaluated with neurobehavioral scores. These structures are part of the motor circuit involved in the generation and modulation of voluntary movement, as well as the forebrain mesocircuit supposedly underlying the maintenance of consciousness. As behavioural assessment of consciousness depends heavily on the signs of voluntary motor behaviour, further work will elucidate whether the identified subnetwork reflects the structural architecture underlying the recovery of consciousness or rather the ability to communicate its content.

A Focus on Subtle Signs and Motor Behavior to Unveil Awareness in Unresponsive Brain-Impaired Patients: The Importance of Being Clinical.

Brain-injured patients in a state of cognitive motor dissociation (CMD) exhibit a lack of command following using conventional neurobehavioral examination tools but a high level of awareness and language processing when assessed using advanced imaging and electrophysiology techniques. Because of their behavioral unresponsiveness, patients with CMD may seem clinically indistinguishable from those with a true disorder of consciousness that affects awareness on a substantial level (coma, vegetative state/unresponsive wakefulness state, or minimally conscious state minus). Yet, by expanding the range of motor testing across limb, facial, and ocular motricity, we may detect subtle, purposeful movements even in the subset of patients classified as vegetative state/unresponsive wakefulness state. We propose the term of clinical CMD to describe patients showing these slight but determined motor responses and exhibiting a characteristic akinetic motor behavior as opposed to a pyramidal motor system behavior. These patients may harbor hidden cognitive capabilities and significant potential for a good long-term outcome. Indeed, we envision CMD as ranging from complete (no motor response) to partial (subtle clinical motor response) forms, falling within a spectrum of progressively better motor output in patients with considerable cognitive capabilities. In addition to providing a decisional flowchart, we present this novel approach to classification as a graphical model that illustrates the range of clinical manifestations and recovery trajectories fundamentally differentiating true disorders of consciousness from the spectrum of CMD.

Discriminating cognitive motor dissociation from disorders of consciousness using structural MRI.

An accurate evaluation and detection of awareness after a severe brain injury is crucial to a patient's diagnosis, therapy, and end-of-life decisions. Misdiagnosis is frequent as behavior-based assessments often overlook subtle signs of consciousness. This study aimed to identify brain MRI characteristics of patients with residual consciousness after a severe brain injury and to develop a simple MRI-based scoring system according to the findings. We retrieved data from 128 patients and split them into a development or validation set. Structural brain MRIs were qualitatively assessed for lesions in 18 brain regions. We used logistic regression and support vector machine algorithms to first identify the most relevant brain regions predicting a patient's outcome in the development set. We next built a diagnostic MRI-based score and estimated its optimal diagnostic cut-off point. The classifiers were then tested on the validation set and their performance compared using the receiver operating characteristic curve. Relevant brain regions predicting negative outcome highly overlapped between both classifiers and included the left mesencephalon, right basal ganglia, right thalamus, right parietal cortex, and left frontal cortex. The support vector machine classifier showed higher accuracy (0.93, 95% CI: 0.81-0.96) and specificity (0.97, 95% CI: 0.85-1) than logistic regression (accuracy: 0.87, 95% CI: 0.73 - 0.95; specificity: 0.90, 95% CI: 0.75-0.97), but equal sensitivity (0.67, 95% CI: 0.24-0.94 and 0.22-0.96, respectively) for distinguishing patients with and without residual consciousness. The novel MRI-based score assessing brain lesions in patients with disorders of consciousness accurately detects patients with residual consciousness. It could complement valuably behavioral evaluation as it is time-efficient and requires only conventional MRI.

Thought consciousness and source monitoring depend on robotically controlled sensorimotor conflicts and illusory states.

Thought insertion (TI) is characterized by the experience that certain thoughts, occurring in one's mind, are not one's own, but the thoughts of somebody else and suggestive of a psychotic disorder. We report a robotics-based method able to investigate the behavioral and subjective mechanisms of TI in healthy participants. We used a robotic device to alter body perception by providing online sensorimotor stimulation, while participants performed cognitive tasks implying source monitoring of mental states attributed to either oneself or another person. Across several experiments, conflicting sensorimotor stimulation reduced the distinction between self- and other-generated thoughts and was, moreover, associated with the experimentally generated feeling of being in the presence of an alien agent and subjective aspects of TI. Introducing a new robotics-based approach that enables the experimental study of the brain mechanisms of TI, these results link TI to predictable self-other shifts in source monitoring and specific sensorimotor processes.

Re: Does Gadoterate Meglumine Cause Gadolinium Retention in the Brain of Children? A Case-Control Study.

LEVEL OF EVIDENCE: 5 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2020;52:636-637.

Age, But Not Repeated Exposure to Gadoterate Meglumine, Is Associated With T1- and T2-Weighted Signal Intensity Changes in the Deep Brain Nuclei of Pediatric Patients.

OBJECTIVES: Current findings on gadolinium deposition in the pediatric brain due to repeated exposure to macrocyclic contrast agents are inconclusive and possibly confounded by brain maturation processes. We evaluated the longitudinal effects of repeated gadoterate meglumine exposure (Dotarem; Guerbet, Villepinte, France) on the T1- and T2-weighted signal intensity (SI) in pediatric patients, and assessed the magnitude of age-related increase in T1-weighted (and decrease in T2-weighted) SI in a control cohort without prior gadolinium exposure. MATERIALS AND METHODS: In this retrospective, double-cohort study, magnetic resonance imaging (MRI) data of 24 patients (0.7-16.4 years, M = 5.74, SD = 4.15) who received at least 10 doses of exclusively gadoterate meglumine were included in the longitudinal study. The MRI data of 190 controls (age range, 1-20 years; 10 patients/bin; bin width, 1 year) without any prior gadolinium-based contrast exposure were included in the control, cross-sectional study to assess the age-dependent SI changes in the regions of interest (ROIs). We measured SI (native), T1-weighted gradient echo, and T2-weighted fast spin-echo of 12 deep brain nuclei. The ROIs were measured at each of the first 11 MRI examinations of the contrast-exposed patients and in the control subject's MRI. Regions of interest's SIs, normalized by the pons, were analyzed with mixed effects models, accounting for the potential confounding factors, such as radiotherapy and chemotherapy. RESULTS: The number of gadoterate meglumine administrations had no effect on the SI increase in any of the ROIs (all P > 0.05), but age significantly correlated with increased SI in T1-weighted globus pallidus (GP; P < 0.01) and caudate (P < 0.05), and with decreased SI in T2-weighted GP (P < 0.001) and dentate nucleus (P < 0.005) in the contrast-exposed group. The cross-sectional analyses of the control cohort showed a significant age-dependent T1-weighted SI increase in multiple ROIs, including the GP and caudate, and decrease in the T2-weighted GP and dentate nucleus (P < 0.05). CONCLUSIONS: Repeated exposure to gadoterate meglumine was not associated with brain hyperintensity in the pediatric patients, whereas age importantly contributed to the SI changes in several deep brain nuclei.

Spatiotemporal Pattern of Gadodiamide-Related T1 Hyperintensity Increase Within the Deep Brain Nuclei.

OBJECTIVES: The purpose of the study was to systematically evaluate the precise spatial and temporal pattern of gadolinium-related changes in T1-weighted signal intensity on unenhanced magnetic resonance (MR) images, occurring in the deep brain nuclei of adult patients exposed to at least 10 consecutive doses of gadodiamide. MATERIALS AND METHODS: In this monocentric retrospective longitudinal study, we analyzed the brain MR images of 30 patients (12 women, 18 men; mean age, 43 ± 11.6 years) acquired between December 1998 and March 2008. We drew the regions of interest in the dentate nucleus, globus pallidus, putamen, pulvinar, ventral posterior nucleus of the thalamus, superior colliculus, substantia nigra, and white matter on unenhanced T1-weighted images. Each region of interest's mean signal intensity was normalized by the mean intensity of the pons. The normalized signal intensities were measured at the baseline before first gadodiamide administration and at each of 10 successive MR imaging examinations. We used linear mixed effects models to analyze the data. RESULTS: We observed a significant linear increase of signal intensity ratios across 10 successive gadodiamide administrations (all basal nuclei were significant at P < 0.001, except the ventral posterior thalamus, where P < 0.05), with the fastest signal intensity increase in the dentate nucleus (B = 0.010), followed by the globus pallidus (B = 0.0068), putamen (B = 0.0063), pulvinar (B = 0.0062), superior colliculus (B = 0.0057), substantia nigra (B = 0.0034), and ventral posterior nucleus of the thalamus (B = 0.0031). No significant signal increase was observed in the white matter (P > 0.05). CONCLUSIONS: Multiple consecutive administration of gadodiamide is associated with an increase in T1-weighted hypersignal on the unenhanced scans, displaying a gradual and nonuniform pattern across different deep brain nuclei, including the ventral posterior thalamus, which was used as a reference tissue in previous studies.

Virtual reality improves embodiment and neuropathic pain caused by spinal cord injury.

OBJECTIVE: To investigate changes in body ownership and chronic neuropathic pain in patients with spinal cord injury (SCI) using multisensory own body illusions and virtual reality (VR). METHODS: Twenty patients with SCI with paraplegia and 20 healthy control participants (HC) participated in 2 factorial, randomized, repeated-measures design studies. In the virtual leg illusion (VLI), we applied asynchronous or synchronous visuotactile stimulation to the participant's back (either immediately above the lesion level or at the shoulder) and to the virtual legs as seen on a VR head-mounted display. We tested the effect of the VLI on the sense of leg ownership (questionnaires) and on perceived neuropathic pain (visual analogue scale pain ratings). We compared illusory leg ownership with illusory global body ownership (induced in the full body illusion [FBI]), by applying asynchronous or synchronous visuotactile stimulation to the participant's back and the back of a virtual body as seen on a head-mounted display. RESULTS: Our data show that patients with SCI are less sensitive to multisensory stimulations inducing illusory leg ownership (as compared to HC) and that leg ownership decreased with time since SCI. In contrast, we found no differences between groups in global body ownership as tested in the FBI. VLI and FBI were both associated with mild analgesia that was only during the VLI specific for synchronous visuotactile stimulation and the lower back position. CONCLUSIONS: The present findings show that VR exposure using multisensory stimulation differently affected leg vs body ownership, and is associated with mild analgesia with potential for SCI neurorehabilitation protocols.

Motor imagery in spinal cord injured people is modulated by somatotopic coding, perspective taking, and post-lesional chronic pain.

Motor imagery (MI) allows one to mentally represent an action without necessarily performing it. Importantly, however, MI is profoundly influenced by the ability to actually execute actions, as demonstrated by the impairment of this ability as a consequence of lesions in motor cortices, limb amputations, movement limiting chronic pain, and spinal cord injury. Understanding MI and its deficits in patients with motor limitations is fundamentally important as development of some brain-computer interfaces and daily life strategies for coping with motor disorders are based on this ability. We explored MI in a large sample of patients with spinal cord injury (SCI) using a comprehensive battery of questionnaires to assess the ability to imagine actions from a first-person or a third-person perspective and also imagine the proprioceptive components of actions. Moreover, we correlated MI skills with personality measures and clinical variables such as the level and completeness of the lesion and the presence of chronic pain. We found that the MI deficits (1) concerned the body parts affected by deafferentation and deefferentation, (2) were present in first- but not in third-person perspectives, and (3) were more altered in the presence of chronic pain. MI is thus closely related to bodily perceptions and representations. Every attempt to devise tools and trainings aimed at improving autonomy needs to consider the cognitive changes due to the body-brain disconnection.

Those are Your Legs: The Effect of Visuo-Spatial Viewpoint on Visuo-Tactile Integration and Body Ownership.

Experiencing a body part as one's own, i.e., body ownership, depends on the integration of multisensory bodily signals (including visual, tactile, and proprioceptive information) with the visual top-down signals from peripersonal space. Although it has been shown that the visuo-spatial viewpoint from where the body is seen is an important visual top-down factor for body ownership, different studies have reported diverging results. Furthermore, the role of visuo-spatial viewpoint (sometime also called first-person perspective) has only been studied for hands or the whole body, but not for the lower limbs. We thus investigated whether and how leg visuo-tactile integration and leg ownership depended on the visuo-spatial viewpoint from which the legs were seen and the anatomical similarity of the visual leg stimuli. Using a virtual leg illusion, we tested the strength of visuo-tactile integration of leg stimuli using the crossmodal congruency effect (CCE) as well as the subjective sense of leg ownership (assessed by a questionnaire). Fifteen participants viewed virtual legs or non-corporeal control objects, presented either from their habitual first-person viewpoint or from a viewpoint that was rotated by 90°(third-person viewpoint), while applying visuo-tactile stroking between the participants legs and the virtual legs shown on a head-mounted display. The data show that the first-person visuo-spatial viewpoint significantly boosts the visuo-tactile integration as well as the sense of leg ownership. Moreover, the viewpoint-dependent increment of the visuo-tactile integration was only found in the conditions when participants viewed the virtual legs (absent for control objects). These results confirm the importance of first person visuo-spatial viewpoint for the integration of visuo-tactile stimuli and extend findings from the upper extremity and the trunk to visuo-tactile integration and ownership for the legs.

Voluntary self-touch increases body ownership.

Experimental manipulations of body ownership have indicated that multisensory integration is central to forming bodily self-representation. Voluntary self-touch is a unique multisensory situation involving corresponding motor, tactile and proprioceptive signals. Yet, even though self-touch is frequent in everyday life, its contribution to the formation of body ownership is not well understood. Here we investigated the role of voluntary self-touch in body ownership using a novel adaptation of the rubber hand illusion (RHI), in which a robotic system and virtual reality allowed participants self-touch of real and virtual hands. In the first experiment, active and passive self-touch were applied in the absence of visual feedback. In the second experiment, we tested the role of visual feedback in this bodily illusion. Finally, in the third experiment, we compared active and passive self-touch to the classical RHI in which the touch is administered by the experimenter. We hypothesized that active self-touch would increase ownership over the virtual hand through the addition of motor signals strengthening the bodily illusion. The results indicated that active self-touch elicited stronger illusory ownership compared to passive self-touch and sensory only stimulation, and show an important role for active self-touch in the formation of bodily self.

Neurological and robot-controlled induction of an apparition.

Tales of ghosts, wraiths, and other apparitions have been reported in virtually all cultures. The strange sensation that somebody is nearby when no one is actually present and cannot be seen (feeling of a presence, FoP) is a fascinating feat of the human mind, and this apparition is often covered in the literature of divinity, occultism, and fiction. Although it is described by neurological and psychiatric patients and healthy individuals in different situations, it is not yet understood how the phenomenon is triggered by the brain. Here, we performed lesion analysis in neurological FoP patients, supported by an analysis of associated neurological deficits. Our data show that the FoP is an illusory own-body perception with well-defined characteristics that is associated with sensorimotor loss and caused by lesions in three distinct brain regions: temporoparietal, insular, and especially frontoparietal cortex. Based on these data and recent experimental advances of multisensory own-body illusions, we designed a master-slave robotic system that generated specific sensorimotor conflicts and enabled us to induce the FoP and related illusory own-body perceptions experimentally in normal participants. These data show that the illusion of feeling another person nearby is caused by misperceiving the source and identity of sensorimotor (tactile, proprioceptive, and motor) signals of one's own body. Our findings reveal the neural mechanisms of the FoP, highlight the subtle balance of brain mechanisms that generate the experience of "self" and "other," and advance the understanding of the brain mechanisms responsible for hallucinations in schizophrenia.

Crossing the hands increases illusory self-touch.

Manipulation of hand posture, such as crossing the hands, has been frequently used to study how the body and its immediately surrounding space are represented in the brain. Abundant data show that crossed arms posture impairs remapping of tactile stimuli from somatotopic to external space reference frame and deteriorates performance on several tactile processing tasks. Here we investigated how impaired tactile remapping affects the illusory self-touch, induced by the non-visual variant of the rubber hand illusion (RHI) paradigm. In this paradigm blindfolded participants (Experiment 1) had their hands either uncrossed or crossed over the body midline. The strength of illusory self-touch was measured with questionnaire ratings and proprioceptive drift. Our results showed that, during synchronous tactile stimulation, the strength of illusory self-touch increased when hands were crossed compared to the uncrossed posture. Follow-up experiments showed that the increase in illusion strength was not related to unfamiliar hand position (Experiment 2) and that it was equally strengthened regardless of where in the peripersonal space the hands were crossed (Experiment 3). However, while the boosting effect of crossing the hands was evident from subjective ratings, the proprioceptive drift was not modulated by crossed posture. Finally, in contrast to the illusion increase in the non-visual RHI, the crossed hand postures did not alter illusory ownership or proprioceptive drift in the classical, visuo-tactile version of RHI (Experiment 4). We argue that the increase in illusory self-touch is related to misalignment of somatotopic and external reference frames and consequently inadequate tactile-proprioceptive integration, leading to re-weighting of the tactile and proprioceptive signals.The present study not only shows that illusory self-touch can be induced by crossing the hands, but importantly, that this posture is associated with a stronger illusion.