Single neurons in the thalamus and subthalamic nucleus process cardiac and respiratory signals in humans.

Visceral signals are constantly processed by our central nervous system, enable homeostatic regulation, and influence perception, emotion, and cognition. While visceral processes at the cortical level have been extensively studied using non-invasive imaging techniques, very few studies have investigated how this information is processed at the single neuron level, both in humans and animals. Subcortical regions, relaying signals from peripheral interoceptors to cortical structures, are particularly understudied and how visceral information is processed in thalamic and subthalamic structures remains largely unknown. Here, we took advantage of intraoperative microelectrode recordings in patients undergoing surgery for deep brain stimulation (DBS) to investigate the activity of single neurons related to cardiac and respiratory functions in three subcortical regions: ventral intermedius nucleus (Vim) and ventral caudalis nucleus (Vc) of the thalamus, and subthalamic nucleus (STN). We report that the activity of a large portion of the recorded neurons (about 70%) was modulated by either the heartbeat, the cardiac inter-beat interval, or the respiration. These cardiac and respiratory response patterns varied largely across neurons both in terms of timing and their kind of modulation. A substantial proportion of these visceral neurons (30%) was responsive to more than one of the tested signals, underlining specialization and integration of cardiac and respiratory signals in STN and thalamic neurons. By extensively describing single unit activity related to cardiorespiratory function in thalamic and subthalamic neurons, our results highlight the major role of these subcortical regions in the processing of visceral signals.

Cardiac interoception in Anorexia Nervosa: A resting-state heartbeat-evoked potential study.

OBJECTIVE: A deficit in interoception - the ability to perceive, interpret and integrate afferent signals about the physiological state of the body - has been shown in Anorexia Nervosa (AN), and linked to altered hunger sensations, body dysmorphia, and abnormal emotional awareness. The present high-density electroencephalography (hdEEG) study aims to assess cardiac interoception in AN and to investigate its neural correlates, using an objective neurophysiological measure. METHOD: Heartbeat-evoked potentials (HEPs) were computed from 5 min of resting-state EEG and electrocardiogram (ECG) data and compared between individuals with AN (N = 22) and healthy controls (HC) (N = 19) with waveform, topographic, and source imaging analyses. RESULTS: Differences in the cortical representation of heartbeats were present between AN and HC at a time window of 332-348 ms after the ECG R-peak. Source imaging analyses revealed a right-sided hypoactivation in AN of brain regions linked to interoceptive processing, such as the anterior cingulate and orbitofrontal areas. CONCLUSIONS: To the best of our knowledge, this is the first study using hdEEG to localise the underlying sources of HEPs in AN. Results point to altered interoceptive processing during resting-state in AN. As our participants had a short duration of illness, this might not be the consequence of prolonged starvation. Interventions targeted at interoception could provide an additional tool to facilitate recovery.

Interoceptive rhythms in the brain.

Sensing internal bodily signals, or interoception, is fundamental to maintain life. However, interoception should not be viewed as an isolated domain, as it interacts with exteroception, cognition and action to ensure the integrity of the organism. Focusing on cardiac, respiratory and gastric rhythms, we review evidence that interoception is anatomically and functionally intertwined with the processing of signals from the external environment. Interactions arise at all stages, from the peripheral transduction of interoceptive signals to sensory processing and cortical integration, in a network that extends beyond core interoceptive regions. Interoceptive rhythms contribute to functions ranging from perceptual detection up to sense of self, or conversely compete with external inputs. Renewed interest in interoception revives long-standing issues on how the brain integrates and coordinates information in distributed regions, by means of oscillatory synchrony, predictive coding or multisensory integration. Considering interoception and exteroception in the same framework paves the way for biological modes of information processing specific to living organisms.

Human primary motor cortex indexes the onset of subjective intention in brain-machine-interface mediated actions.

Self-initiated behavior is accompanied by the experience of willing our actions. Here, we leverage the unique opportunity to examine the full intentional chain - from will (W) to action (A) to environmental effects (E) - in a tetraplegic person fitted with a primary motor cortex (M1) brain machine interface (BMI) generating hand movements via neuromuscular electrical stimulation (NMES). This combined BMI-NMES approach allowed us to selectively manipulate each element of the intentional chain (W, A, and E) while performing extra-cellular recordings and probing subjective experience. Our results reveal single-cell, multi-unit, and population-level dynamics in human M1 that encode W and may predict its subjective onset. Further, we show that the proficiency of a neural decoder in M1 reflects the degree of W-A binding, tracking the participant's subjective experience of intention in (near) real time. These results point to M1 as a critical node in forming the subjective experience of intention and demonstrate the relevance of intention-related signals for translational neuroprosthetics.

Sense of agency for intracortical brain-machine interfaces.

Intracortical brain-machine interfaces decode motor commands from neural signals and translate them into actions, enabling movement for paralysed individuals. The subjective sense of agency associated with actions generated via intracortical brain-machine interfaces, the neural mechanisms involved and its clinical relevance are currently unknown. By experimentally manipulating the coherence between decoded motor commands and sensory feedback in a tetraplegic individual using a brain-machine interface, we provide evidence that primary motor cortex processes sensory feedback, sensorimotor conflicts and subjective states of actions generated via the brain-machine interface. Neural signals processing the sense of agency affected the proficiency of the brain-machine interface, underlining the clinical potential of the present approach. These findings show that primary motor cortex encodes information related to action and sensing, but also sensorimotor and subjective agency signals, which in turn are relevant for clinical applications of brain-machine interfaces.

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.

Enhancing analgesic spinal cord stimulation for chronic pain with personalized immersive virtual reality.

ABSTRACT: Spinal cord stimulation (SCS) is an approved treatment for truncal and limb neuropathic pain. However, pain relief is often suboptimal and SCS efficacy may reduce over time, requiring sometimes the addition of other pain therapies, stimulator revision, or even explantation. We designed and tested a new procedure by combining SCS with immersive virtual reality (VR) to enable analgesia in patients with chronic leg pain. We coupled SCS and VR by linking SCS-induced paresthesia with personalized visual bodily feedback that was provided by VR and matched to the spatiotemporal patterns of SCS-induced paresthesia. In this cross-sectional prospective interventional study, 15 patients with severe chronic pain and an SCS implant underwent congruent SCS-VR (personalized visual feedback of the perceived SCS-induced paresthesia displayed on the patient's virtual body) and 2 control conditions (incongruent SCS-VR and VR alone). We demonstrate the efficacy of neuromodulation-enhanced VR for the treatment of chronic pain by showing that congruent SCS-VR reduced pain ratings on average by 44%. Spinal cord stimulation-VR analgesia was stronger than that in both control conditions (enabling stronger analgesic effects than incongruent SCS-VR analgesia or VR alone) and kept increasing over successive stimulations, revealing the selectivity and consistency of the observed effects. We also show that analgesia persists after congruent SCS-VR had stopped, indicating carry over effects and underlining its therapeutic potential. Linking latest VR technology with recent insights from the neuroscience of body perception and SCS neuromodulation, our personalized new SCS-VR platform highlights the impact of immersive digiceutical therapies for chronic pain.Registration: clinicaltrials.gov, Identifier: NCT02970006.

Behavioral and neurophysiological evidence for altered interoceptive bodily processing in chronic pain.

Whereas impaired multisensory processing of bodily stimuli and distorted body representation are well-established in various chronic pain disorders, such research has focused on exteroceptive bodily cues and neglected bodily signals from the inside of the body (or interoceptive signals). Extending existing basic and clinical research, we investigated for the first time interoception and its neurophysiological correlates in patients with complex regional pain syndrome (CRPS). In three different experiments, including a total of 36 patients with CRPS and 42 aged-gender matched healthy controls, we measured interoceptive sensitivity (heart beat counting task, HBC) and neural responses to heartbeats (heartbeat evoked potentials, HEPs). As hypothesized, we observed reduced sensitivity in perceiving interoceptive bodily stimuli, i.e. their heartbeat, in two independent samples of CRPS patients (studies 1 and 2). Moreover, the cortical processing of their heartbeat, i.e. the HEP, was reduced compared to controls (study 3) and reduced interoceptive sensitivity and HEPs were related to CRPS patients' motor impairment and pain duration. By providing consistent evidence for impaired processing of interoceptive bodily cues in CRPS, this study shows that the perceptual changes occurring in chronic pain include signals originating from the visceral organs, suggesting changes in the neural body representation, that includes next to exteroceptive, also interoceptive bodily signals. By showing that impaired interoceptive processing is associated with clinical symptoms, our findings also encourage the use of interoceptive-related information in future rehabilitation for chronic pain.

Early Urinary Biomarkers in Pediatric Autosomal Dominant Polycystic Kidney Disease (ADPKD): No Evidence in the Interest of Urinary Neutrophil Gelatinase-Associated Lipocalin (uNGAL).

Background: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is increasingly diagnosed during childhood by the presence of renal cysts in patients with a positive familial history. No curative treatment is available and early detection and diagnosis confronts pediatricians with the lack of early markers to decide whether to introduce renal-protective agents and prevent the progression of renal failure. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a tubular protein that has been recently proposed as an early biomarker of renal impairment in the ADPKD adult population. Methods: Urinary NGAL (uNGAL) levels were measured in 15 ADPKD children and compared with 15 age and gender matched controls using parametric, non-parametric, and Bayesian statistics. We also tested the association of uNGAL levels with markers of disease progression, such as proteinuria, albuminuria, blood pressure, and Total Kidney Volume (TKV) using correlation analysis. TKV was calculated by ultrasound, using the ellipsoid method. Results: No difference in mean uNGAL levels was observed between groups (ADPKD: 26.36 ng/ml; Controls: 27.24 ng/ml; P = 0.96). Moreover, no correlation was found between uNGAL and proteinuria (P = 0.51), albuminuria (P = 0.69), TKV (P = 0.68), or mean arterial pressure (P = 0.90). By contrast, TKV was positively correlated with proteinuria (P = 0.04), albuminuria (P = 0.001), and mean arterial pressure (P = 0.03). Conclusion: uNGAL did not confirm its superiority as a marker of disease progression in a pediatric ADPKD population. In the contrary, TKV appears to be an easy measurable variable and may be promising as a surrogate marker to follow ADPKD progression in children.

Heartbeat-enhanced immersive virtual reality to treat complex regional pain syndrome.

OBJECTIVES: To develop and test a new immersive digital technology for complex regional pain syndrome (CRPS) that combines principles from mirror therapy and immersive virtual reality and the latest research from multisensory body processing. METHODS: In this crossover double-blind study, 24 patients with CRPS and 24 age- and sex-matched healthy controls were immersed in a virtual environment and shown a virtual depiction of their affected limb that was flashing in synchrony (or in asynchrony in the control condition) with their own online detected heartbeat (heartbeat-enhanced virtual reality [HEVR]). The primary outcome measures for pain reduction were subjective pain ratings, force strength, and heart rate variability (HRV). RESULTS: HEVR reduced pain ratings, improved motor limb function, and modulated a physiologic pain marker (HRV). These significant improvements were reliable and highly selective, absent in control HEVR conditions, not observed in healthy controls, and obtained without the application of tactile stimulation (or movement) of the painful limb, using a readily available biological signal (the heartbeat) that is most often not consciously perceived (thus preventing placebo effects). CONCLUSIONS: Next to these specific and well-controlled analgesic effects, immersive HEVR allows the application of prolonged and repeated doses of digital therapy, enables the automatized integration with existing pain treatments, and avoids application of painful bodily cues while minimizing the active involvement of the patient and therapist. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that HEVR reduces pain and increases force strength in patients with CRPS.

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.

Binaural beats increase interhemispheric alpha-band coherence between auditory cortices.

Binaural beats (BBs) are an auditory illusion occurring when two tones of slightly different frequency are presented separately to each ear. BBs have been suggested to alter physiological and cognitive processes through synchronization of the brain hemispheres. To test this, we recorded electroencephalograms (EEG) at rest and while participants listened to BBs or a monaural control condition during which both tones were presented to both ears. We calculated for each condition the interhemispheric coherence, which expressed the synchrony between neural oscillations of both hemispheres. Compared to monaural beats and resting state, BBs enhanced interhemispheric coherence between the auditory cortices. Beat frequencies in the alpha (10 Hz) and theta (4 Hz) frequency range both increased interhemispheric coherence selectively at alpha frequencies. In a second experiment, we evaluated whether this coherence increase has a behavioral aftereffect on binaural listening. No effects were observed in a dichotic digit task performed immediately after BBs presentation. Our results suggest that BBs enhance alpha-band oscillation synchrony between the auditory cortices during auditory stimulation. This effect seems to reflect binaural integration rather than entrainment.

Facial blindsight.

Blindsight denotes unconscious residual visual capacities in the context of an inability to consciously recollect or identify visual information. It has been described for color and shape discrimination, movement or facial emotion recognition. The present study investigates a patient suffering from cortical blindness whilst maintaining select residual abilities in face detection. Our patient presented the capacity to distinguish between jumbled/normal faces, known/unknown faces or famous people's categories although he failed to explicitly recognize or describe them. Conversely, performance was at chance level when asked to categorize non-facial stimuli. Our results provide clinical evidence for the notion that some aspects of facial processing can occur without perceptual awareness, possibly using direct tracts from the thalamus to associative visual cortex, bypassing the primary visual cortex.

Neurofeedback training of alpha-band coherence enhances motor performance.

OBJECTIVE: Neurofeedback training of motor cortex activations with brain-computer interface systems can enhance recovery in stroke patients. Here we propose a new approach which trains resting-state functional connectivity associated with motor performance instead of activations related to movements. METHODS: Ten healthy subjects and one stroke patient trained alpha-band coherence between their hand motor area and the rest of the brain using neurofeedback with source functional connectivity analysis and visual feedback. RESULTS: Seven out of ten healthy subjects were able to increase alpha-band coherence between the hand motor cortex and the rest of the brain in a single session. The patient with chronic stroke learned to enhance alpha-band coherence of his affected primary motor cortex in 7 neurofeedback sessions applied over one month. Coherence increased specifically in the targeted motor cortex and in alpha frequencies. This increase was associated with clinically meaningful and lasting improvement of motor function after stroke. CONCLUSIONS: These results provide proof of concept that neurofeedback training of alpha-band coherence is feasible and behaviorally useful. SIGNIFICANCE: The study presents evidence for a role of alpha-band coherence in motor learning and may lead to new strategies for rehabilitation.

Impairment of semantic memory after basal forebrain and fornix lesion.

Semantic memory impairment is classically associated with lesion of the anterior temporal lobe. We report the case of a patient with severe semantic knowledge impairment and anterograde amnesia after bilateral ischemic lesion of the fornix and of the basal forebrain following surgical clipping of an aneurysm of the anterior communicating artery. Fluorodeoxyglucose positron emission tomography (FDG-PET) showed a temporal hypometabolism. Severe semantic impairment is a rare complication after rupture of an anterior communicating artery aneurysm and may result from disconnection of the temporal lobe.