Meta-analysis of real-time fMRI neurofeedback studies using individual participant data: How is brain regulation mediated?

An increasing number of studies using real-time fMRI neurofeedback have demonstrated that successful regulation of neural activity is possible in various brain regions. Since these studies focused on the regulated region(s), little is known about the target-independent mechanisms associated with neurofeedback-guided control of brain activation, i.e. the regulating network. While the specificity of the activation during self-regulation is an important factor, no study has effectively determined the network involved in self-regulation in general. In an effort to detect regions that are responsible for the act of brain regulation, we performed a post-hoc analysis of data involving different target regions based on studies from different research groups. We included twelve suitable studies that examined nine different target regions amounting to a total of 175 subjects and 899 neurofeedback runs. Data analysis included a standard first- (single subject, extracting main paradigm) and second-level (single subject, all runs) general linear model (GLM) analysis of all participants taking into account the individual timing. Subsequently, at the third level, a random effects model GLM included all subjects of all studies, resulting in an overall mixed effects model. Since four of the twelve studies had a reduced field of view (FoV), we repeated the same analysis in a subsample of eight studies that had a well-overlapping FoV to obtain a more global picture of self-regulation. The GLM analysis revealed that the anterior insula as well as the basal ganglia, notably the striatum, were consistently active during the regulation of brain activation across the studies. The anterior insula has been implicated in interoceptive awareness of the body and cognitive control. Basal ganglia are involved in procedural learning, visuomotor integration and other higher cognitive processes including motivation. The larger FoV analysis yielded additional activations in the anterior cingulate cortex, the dorsolateral and ventrolateral prefrontal cortex, the temporo-parietal area and the visual association areas including the temporo-occipital junction. In conclusion, we demonstrate that several key regions, such as the anterior insula and the basal ganglia, are consistently activated during self-regulation in real-time fMRI neurofeedback independent of the targeted region-of-interest. Our results imply that if the real-time fMRI neurofeedback studies target regions of this regulation network, such as the anterior insula, care should be given whether activation changes are related to successful regulation, or related to the regulation process per se. Furthermore, future research is needed to determine how activation within this regulation network is related to neurofeedback success.

Brain-machine interface in chronic stroke rehabilitation: a controlled study.

OBJECTIVE: Chronic stroke patients with severe hand weakness respond poorly to rehabilitation efforts. Here, we evaluated efficacy of daily brain-machine interface (BMI) training to increase the hypothesized beneficial effects of physiotherapy alone in patients with severe paresis in a double-blind sham-controlled design proof of concept study. METHODS: Thirty-two chronic stroke patients with severe hand weakness were randomly assigned to 2 matched groups and participated in 17.8 ± 1.4 days of training rewarding desynchronization of ipsilesional oscillatory sensorimotor rhythms with contingent online movements of hand and arm orthoses (experimental group, n = 16). In the control group (sham group, n = 16), movements of the orthoses occurred randomly. Both groups received identical behavioral physiotherapy immediately following BMI training or the control intervention. Upper limb motor function scores, electromyography from arm and hand muscles, placebo-expectancy effects, and functional magnetic resonance imaging (fMRI) blood oxygenation level-dependent activity were assessed before and after intervention. RESULTS: A significant group × time interaction in upper limb (combined hand and modified arm) Fugl-Meyer assessment (cFMA) motor scores was found. cFMA scores improved more in the experimental than in the control group, presenting a significant improvement of cFMA scores (3.41 ± 0.563-point difference, p = 0.018) reflecting a clinically meaningful change from no activity to some in paretic muscles. cFMA improvements in the experimental group correlated with changes in fMRI laterality index and with paretic hand electromyography activity. Placebo-expectancy scores were comparable for both groups. INTERPRETATION: The addition of BMI training to behaviorally oriented physiotherapy can be used to induce functional improvements in motor function in chronic stroke patients without residual finger movements and may open a new door in stroke neurorehabilitation.

People inflows as a pandemic trigger: Evidence from a quasi-experimental study.

Although it has been established that population density can contribute to the outbreak of the COVID-19 virus, there is no evidence to suggest that economic activities, which imply a significant change in mobility, played a causal role in the unfolding of the pandemic. In this paper, we exploit the particular situation of Sardinia (Italy) in 2020 to examine how changes in mobility due to tourism inflows (a proxy of economic activities) influenced the development of the COVID-19 pandemic. Using a difference-in-differences approach, we identify a strong causal relationship between tourism flows and the emergence of COVID-19 cases in Sardinia. We estimate the elasticity of COVID-19 cases in relation to the share of tourists to be 4.1%, which increases to 5.1% when excluding local residents. Our analysis suggests that, in the absence of tools preventing the spread of infection, changes in population density due to economic activities trigger the pandemic spreading in previously unaffected locations. This work contributes to the debate on the complex relationship between COVID-19 and the characteristics of locations by providing helpful evidence for risk-prevention policies.

Acquired self-control of insula cortex modulates emotion recognition and brain network connectivity in schizophrenia.

Real-time functional magnetic resonance imaging (rtfMRI) is a novel technique that has allowed subjects to achieve self-regulation of circumscribed brain regions. Despite its anticipated therapeutic benefits, there is no report on successful application of this technique in psychiatric populations. The objectives of the present study were to train schizophrenia patients to achieve volitional control of bilateral anterior insula cortex on multiple days, and to explore the effect of learned self-regulation on face emotion recognition (an extensively studied deficit in schizophrenia) and on brain network connectivity. Nine patients with schizophrenia were trained to regulate the hemodynamic response in bilateral anterior insula with contingent rtfMRI neurofeedback, through a 2-weeks training. At the end of the training stage, patients performed a face emotion recognition task to explore behavioral effects of learned self-regulation. A learning effect in self-regulation was found for bilateral anterior insula, which persisted through the training. Following successful self-regulation, patients recognized disgust faces more accurately and happy faces less accurately. Improvements in disgust recognition were correlated with levels of self-activation of right insula. RtfMRI training led to an increase in the number of the incoming and outgoing effective connections of the anterior insula. This study shows for the first time that patients with schizophrenia can learn volitional brain regulation by rtfMRI feedback training leading to changes in the perception of emotions and modulations of the brain network connectivity. These findings open the door for further studies of rtfMRI in severely ill psychiatric populations, and possible therapeutic applications.

A Hypothalamic Perspective of Human Socioemotional Behavior.

Historical evidence from stimulation and lesion studies in animals and humans demonstrated a close association between the hypothalamus and typical and atypical socioemotional behavior. A central hypothalamic contribution to regulation of socioemotional responses was also provided indirectly by studies on oxytocin and arginine vasopressin. However, a limited number of studies have so far directly investigated the contribution of the hypothalamus in human socioemotional behavior. To reconsider the functional role of the evolutionarily conserved hypothalamic region in regulating human social behavior, here I provide a synthesis of neuroimaging investigations showing that the hypothalamus is involved in multiple and diverse facets of human socioemotional behavior through widespread functional interactions with other cortical and subcortical regions. These neuroimaging findings are then integrated with recent optogenetics studies in animals demonstrating that the hypothalamus plays a more active role in eliciting socioemotional responses and is not simply a downstream effector of higher-level brain systems. Building on the aforementioned evidence, the hypothalamus is argued to substantially contribute to a continuum of human socioemotional behaviors promoting survival and preservation of the species that extends from exploratory and approaching responses facilitating social bonding to aggressive and avoidance responses aimed to protect and defend formed relationships.

Hypothalamus, Neuropeptides and Socioemotional Behavior.

A large body of evidence from old stimulation and lesion studies on the hypothalamus in animals and humans demonstrates that this subcortical area significantly affects socioemotional behavior [...].

Neuroanatomical predictors of real-time fMRI-based anterior insula regulation. A supervised machine learning study.

Increasing evidence showed that learned control of metabolic activity in selected brain regions can support emotion regulation. Notably, a number of studies demonstrated that neurofeedback-based regulation of fMRI activity in several emotion-related areas leads to modifications of emotional behavior along with changes of neural activity in local and distributed networks, in both healthy individuals and individuals with emotional disorders. However, the current understanding of the neural mechanisms underlying self-regulation of the emotional brain, as well as their relationship with other emotion regulation strategies, is still limited. In this study, we attempted to delineate neuroanatomical regions mediating real-time fMRI-based emotion regulation by exploring whole brain GM and WM features predictive of self-regulation of anterior insula (AI) activity, a neuromodulation procedure that can successfully support emotional brain regulation in healthy individuals and patients. To this aim, we employed a multivariate kernel ridge regression model to assess brain volumetric features, at regional and network level, predictive of real-time fMRI-based AI regulation. Our results showed that several GM regions including fronto-occipital and medial temporal areas and the basal ganglia as well as WM regions including the fronto-occipital fasciculus, tapetum and fornix significantly predicted learned AI regulation. Remarkably, we observed a substantial contribution of the cerebellum in relation to both the most effective regulation run and average neurofeedback performance. Overall, our findings highlighted specific neurostructural features contributing to individual differences of AI-guided emotion regulation. Notably, such neuroanatomical topography partially overlaps with the neurofunctional network associated with cognitive emotion regulation strategies, suggesting common neural mechanisms.

Species-specific response to human infant faces in the premotor cortex.

The human infant face represents an essential source of communicative signals on the basis of which adults modulate their interactions with infants. Behavioral studies demonstrate that infants' faces activate sensitive and attuned responses in adults through their gaze, face expression, voice, and gesture. In this study we aimed to identify brain responses that underlie adults' general propensity to respond to infant faces. We recorded fMRI during adults' (non-parents) processing of unfamiliar infant faces compared to carefully matched adult faces and infrahuman mammal infant and adult faces. Human infant faces activated several brain systems including the lateral premotor cortex, supplementary motor area, cingulate cortex, anterior insula and the thalamus. Activation of these brain circuits suggests adults' preparation for communicative behavior with infants as well as attachment and caregiving. The same brain regions preferentially responded to human infant faces when compared to animal infant faces, indicating species-specific adult brain responses. Moreover, results of support vector machine based classification analysis indicated that these regions allowed above chance-level prediction of brain state during perception of human infant faces. The complex of brain responses to human infant faces appears to include biological mechanisms that underlie responsiveness and a caring inclination toward young children which appear to transcend adult's biological relationship to the baby.

Functional and dysfunctional brain circuits underlying emotional processing of music in autism spectrum disorders.

Despite intersubject variability, dramatic impairments of socio-communicative skills are core features of autistic spectrum disorder (ASD). A deficit in the ability to express and understand emotions has often been hypothesized to be an important correlate of such impairments. Little is known about individuals with ASD's ability to sense emotions conveyed by nonsocial stimuli such as music. Music has been found to be capable of evoking and conveying strong and consistent positive and negative emotions in healthy subjects. The ability to process perceptual and emotional aspects of music seems to be maintained in ASD. Individuals with ASD and neurotypical (NT) controls underwent a single functional magnetic resonance imaging (fMRI) session while processing happy and sad music excerpts. Overall, fMRI results indicated that while listening to both happy and sad music, individuals with ASD activated cortical and subcortical brain regions known to be involved in emotion processing and reward. A comparison of ASD participants with NT individuals demonstrated decreased brain activity in the premotor area and in the left anterior insula, especially in response to happy music excerpts. Our findings shed new light on the neurobiological correlates of preserved and altered emotional processing in ASD.

Functional Neuroimaging of Human Hypothalamus in Socioemotional Behavior: A Systematic Review.

There exist extensive animal research and lesion studies in humans demonstrating a tight association between the hypothalamus and socioemotional behavior. However, human neuroimaging literature in this direction is still rather limited. In order to reexamine the functional role of this region in regulating human social behavior, we here provided a synthesis of neuroimaging studies showing hypothalamic activation during affiliative, cooperative interactions, and in relation to ticklish laughter and humor. In addition, studies reporting involvement of the hypothalamus during aggressive and antisocial interactions were also considered. Our systematic review revealed a growing number of investigations demonstrating that the evolutionary conserved hypothalamic neural circuity is involved in multiple and diverse aspects of human socioemotional behavior. On the basis of the observed heterogeneity of hypothalamus-mediated socioemotional responses, we concluded that the hypothalamus might play an extended functional role for species survival and preservation, ranging from exploratory and approaching behaviors promoting social interactions to aggressive and avoidance responses protecting and defending the established social bonds.

Rehabilitation of gait after stroke: a review towards a top-down approach.

This document provides a review of the techniques and therapies used in gait rehabilitation after stroke. It also examines the possible benefits of including assistive robotic devices and brain-computer interfaces in this field, according to a top-down approach, in which rehabilitation is driven by neural plasticity.The methods reviewed comprise classical gait rehabilitation techniques (neurophysiological and motor learning approaches), functional electrical stimulation (FES), robotic devices, and brain-computer interfaces (BCI).From the analysis of these approaches, we can draw the following conclusions. Regarding classical rehabilitation techniques, there is insufficient evidence to state that a particular approach is more effective in promoting gait recovery than other. Combination of different rehabilitation strategies seems to be more effective than over-ground gait training alone. Robotic devices need further research to show their suitability for walking training and their effects on over-ground gait. The use of FES combined with different walking retraining strategies has shown to result in improvements in hemiplegic gait. Reports on non-invasive BCIs for stroke recovery are limited to the rehabilitation of upper limbs; however, some works suggest that there might be a common mechanism which influences upper and lower limb recovery simultaneously, independently of the limb chosen for the rehabilitation therapy. Functional near infrared spectroscopy (fNIRS) enables researchers to detect signals from specific regions of the cortex during performance of motor activities for the development of future BCIs. Future research would make possible to analyze the impact of rehabilitation on brain plasticity, in order to adapt treatment resources to meet the needs of each patient and to optimize the recovery process.

Mesocorticolimbic Interactions Mediate fMRI-Guided Regulation of Self-Generated Affective States.

Increasing evidence shows that the generation and regulation of affective responses is associated with activity of large brain networks that also include phylogenetically older regions in the brainstem. Mesencephalic regions not only control autonomic responses but also participate in the modulation of autonomic, emotional, and motivational responses. The specific contribution of the midbrain to emotion regulation in humans remains elusive. Neuroimaging studies grounding on appraisal models of emotion emphasize a major role of prefrontal cortex in modulating emotion-related cortical and subcortical regions but usually neglect the contribution of the midbrain and other brainstem regions. Here, the role of mesolimbic and mesocortical networks in core affect generation and regulation was explored during emotion regulation guided by real-time fMRI feedback of the anterior insula activity. The fMRI and functional connectivity analysis revealed that the upper midbrain significantly contributes to emotion regulation in humans. Moreover, differential functional interactions between the dopaminergic mesocorticolimbic system and frontoparietal networks mediate up and down emotion regulatory processes. Finally, these findings further indicate the potential of real-time fMRI feedback approach in guiding core affect regulation.

Morphofunctional Alterations of the Hypothalamus and Social Behavior in Autism Spectrum Disorders.

An accumulating body of evidence indicates a tight relationship between the endocrine system and abnormal social behavior. Two evolutionarily conserved hypothalamic peptides, oxytocin and arginine-vasopressin, because of their extensively documented function in supporting and regulating affiliative and socio-emotional responses, have attracted great interest for their critical implications for autism spectrum disorders (ASD). A large number of controlled trials demonstrated that exogenous oxytocin or arginine-vasopressin administration can mitigate social behavior impairment in ASD. Furthermore, there exists long-standing evidence of severe socioemotional dysfunctions after hypothalamic lesions in animals and humans. However, despite the major role of the hypothalamus for the synthesis and release of oxytocin and vasopressin, and the evident hypothalamic implication in affiliative behavior in animals and humans, a rather small number of neuroimaging studies showed an association between this region and socioemotional responses in ASD. This review aims to provide a critical synthesis of evidences linking alterations of the hypothalamus with impaired social cognition and behavior in ASD by integrating results of both anatomical and functional studies in individuals with ASD as well as in healthy carriers of oxytocin receptor (OXTR) genetic risk variant for ASD. Current findings, although limited, indicate that morphofunctional anomalies are implicated in the pathophysiology of ASD and call for further investigations aiming to elucidate anatomical and functional properties of hypothalamic nuclei underlying atypical socioemotional behavior in ASD.

Brain-Machine Interface Induced Morpho-Functional Remodeling of the Neural Motor System in Severe Chronic Stroke.

Brain-machine interfaces (BMI) permit bypass motor system disruption by coupling contingent neuroelectric signals related to motor activity with prosthetic devices that enhance afferent and proprioceptive feedback to the somatosensory cortex. In this study, we investigated neural plasticity in the motor network of severely impaired chronic stroke patients after an EEG-BMI-based treatment reinforcing sensorimotor contingency of ipsilesional motor commands. Our structural connectivity analysis revealed decreased fractional anisotropy in the splenium and body of the corpus callosum, and in the contralesional hemisphere in the posterior limb of the internal capsule, the posterior thalamic radiation, and the superior corona radiata. Functional connectivity analysis showed decreased negative interhemispheric coupling between contralesional and ipsilesional sensorimotor regions, and decreased positive intrahemispheric coupling among contralesional sensorimotor regions. These findings indicate that BMI reinforcing ipsilesional brain activity and enhancing proprioceptive function of the affected hand elicits reorganization of contralesional and ipsilesional somatosensory and motor-assemblies as well as afferent and efferent connection-related motor circuits that support the partial re-establishment of the original neurophysiology of the motor system even in severe chronic stroke.

Brain-Machine Interface in Chronic Stroke: Randomized Trial Long-Term Follow-up.

BACKGROUND: Brain-machine interfaces (BMIs) have been recently proposed as a new tool to induce functional recovery in stroke patients. OBJECTIVE: Here we evaluated long-term effects of BMI training and physiotherapy in motor function of severely paralyzed chronic stroke patients 6 months after intervention. METHODS: A total of 30 chronic stroke patients with severe hand paresis from our previous study were invited, and 28 underwent follow-up assessments. BMI training included voluntary desynchronization of ipsilesional EEG-sensorimotor rhythms triggering paretic upper-limb movements via robotic orthoses (experimental group, n = 16) or random orthoses movements (sham group, n = 12). Both groups received identical physiotherapy following BMI sessions and a home-based training program after intervention. Upper-limb motor assessment scores, electromyography (EMG), and functional magnetic resonance imaging (fMRI) were assessed before (Pre), immediately after (Post1), and 6 months after intervention (Post2). RESULTS: The experimental group presented with upper-limb Fugl-Meyer assessment (cFMA) scores significantly higher in Post2 (13.44 ± 1.96) as compared with the Pre session (11.16 ± 1.73; P = .015) and no significant changes between Post1 and Post2 sessions. The Sham group showed no significant changes on cFMA scores. Ashworth scores and EMG activity in both groups increased from Post1 to Post2. Moreover, fMRI-BOLD laterality index showed no significant difference from Pre or Post1 to Post2 sessions. CONCLUSIONS: BMI-based rehabilitation promotes long-lasting improvements in motor function of chronic stroke patients with severe paresis and represents a promising strategy in severe stroke neurorehabilitation.

Think to move: a neuromagnetic brain-computer interface (BCI) system for chronic stroke.

BACKGROUND AND PURPOSE: Stroke is a leading cause of long-term motor disability among adults. Present rehabilitative interventions are largely unsuccessful in improving the most severe cases of motor impairment, particularly in relation to hand function. Here we tested the hypothesis that patients experiencing hand plegia as a result of a single, unilateral subcortical, cortical or mixed stroke occurring at least 1 year previously, could be trained to operate a mechanical hand orthosis through a brain-computer interface (BCI). METHODS: Eight patients with chronic hand plegia resulting from stroke (residual finger extension function rated on the Medical Research Council scale=0/5) were recruited from the Stroke Neurorehabilitation Clinic, Human Cortical Physiology Section of the National Institute for Neurological Disorders and Stroke (NINDS) (n=5) and the Clinic of Neurology of the University of Tübingen (n=3). Diagnostic MRIs revealed single, unilateral subcortical, cortical or mixed lesions in all patients. A magnetoencephalography-based BCI system was used for this study. Patients participated in between 13 to 22 training sessions geared to volitionally modulate micro rhythm amplitude originating in sensorimotor areas of the cortex, which in turn raised or lowered a screen cursor in the direction of a target displayed on the screen through the BCI interface. Performance feedback was provided visually in real-time. Successful trials (in which the cursor made contact with the target) resulted in opening/closing of an orthosis attached to the paralyzed hand. RESULTS: Training resulted in successful BCI control in 6 of 8 patients. This control was associated with increased range and specificity of mu rhythm modulation as recorded from sensors overlying central ipsilesional (4 patients) or contralesional (2 patients) regions of the array. Clinical scales used to rate hand function showed no significant improvement after training. CONCLUSIONS: These results suggest that volitional control of neuromagnetic activity features recorded over central scalp regions can be achieved with BCI training after stroke, and used to control grasping actions through a mechanical hand orthosis.

Differential neural mechanisms for early and late prediction error detection.

Emerging evidence indicates that prediction, instantiated at different perceptual levels, facilitate visual processing and enable prompt and appropriate reactions. Until now, the mechanisms underlying the effect of predictive coding at different stages of visual processing have still remained unclear. Here, we aimed to investigate early and late processing of spatial prediction violation by performing combined recordings of saccadic eye movements and fast event-related fMRI during a continuous visual detection task. Psychophysical reverse correlation analysis revealed that the degree of mismatch between current perceptual input and prior expectations is mainly processed at late rather than early stage, which is instead responsible for fast but general prediction error detection. Furthermore, our results suggest that conscious late detection of deviant stimuli is elicited by the assessment of prediction error's extent more than by prediction error per se. Functional MRI and functional connectivity data analyses indicated that higher-level brain systems interactions modulate conscious detection of prediction error through top-down processes for the analysis of its representational content, and possibly regulate subsequent adaptation of predictive models. Overall, our experimental paradigm allowed to dissect explicit from implicit behavioral and neural responses to deviant stimuli in terms of their reliance on predictive models.

Effects of increasing visual load on aurally and visually guided target acquisition in a virtual environment.

The aim of the present study is to investigate interactions between vision and audition during a target acquisition task performed in a virtual environment. We measured the time taken to locate a visual target (acquisition time) signalled by auditory and/or visual cues in conditions of variable visual load. Visual load was increased by introducing a secondary visual task. The auditory cue was constructed using virtual three-dimensional (3D) sound techniques. The visual cue was constructed in the form of a 3D updating arrow. The results suggested that both auditory and visual cues reduced acquisition time as compared to an uncued condition. Whereas the visual cue elicited faster acquisition time than the auditory cue, the combination of the two cues produced the fastest acquisition time. The introduction of secondary visual task differentially affected acquisition time depending on cue modality. In conditions of high visual load, acquiring a target signalled by the auditory cue led to slower and more error-prone performance than acquiring a target signalled by either the visual cue alone or by both the visual and auditory cues.

Anterior insular cortex regulation in autism spectrum disorders.

Autism spectrum disorders (ASDs) comprise a heterogeneous set of neurodevelopmental disorders characterized by dramatic impairments of interpersonal behavior, communication, and empathy. Recent neuroimaging studies suggested that ASD are disorders characterized by widespread abnormalities involving distributed brain network, though clear evidence of differences in large-scale brain network interactions underlying the cognitive and behavioral symptoms of ASD are still lacking. Consistent findings of anterior insula cortex hypoactivation and dysconnectivity during tasks related to emotional and social processing indicates its dysfunctional role in ASD. In parallel, increasing evidence showed that successful control of anterior insula activity can be attained using real-time fMRI paradigms. More importantly, successful regulation of this region was associated with changes in behavior and brain connectivity in both healthy individuals and psychiatric patients. Building on these results we here propose and discuss the use of real-time fMRI neurofeedback in ASD aiming at improving emotional and social behavior.

Elastic scattering and light transport in three-dimensional collagen gel constructs: a mathematical model and computer simulation approach.

A mathematical modeling approach for elastic scattering and light propagation is presented, which can be used to obtain the scattering coefficient, the index of refraction, and the distribution of the collagen fibrils in a gel. Collagen fibrils can be realistically represented by small cylindrical particles. The analysis of the scattering of light by such particles provides the scattering coefficient. Light transport in multilayered tissues has been modeled and the collagen fibrils scattering coefficient has been considered as main input parameters. Assuming that a gel is composed of fibrils with the same diameter, it is possible to obtain all the input parameters of the model and, therefore, a simulated spectrum. This can be repeated for several diameters. Considering a gel composed of fibrils with different diameters, it is possible to obtain a best-fitting simulated spectrum as a weighted sum (least-square-error based) of the spectra corresponding to several fibril diameters, and, therefore, obtain an estimate of the percentages of fibrils of each diameter in the gel. Moreover, the scattering coefficient and refractive index, which are also provided by the model, are relevant parameters as they relate to tissue properties in their own right.