The consequences of the new European reclassification of non-invasive brain stimulation devices and the medical device regulations pose an existential threat to research and treatment: An invited opinion paper.

A significant amount of European basic and clinical neuroscience research includes the use of transcranial magnetic stimulation (TMS) and low intensity transcranial electrical stimulation (tES), mainly transcranial direct current stimulation (tDCS). Two recent changes in the EU regulations, the introduction of the Medical Device Regulation (MDR) (2017/745) and the Annex XVI have caused significant problems and confusions in the brain stimulation field. The negative consequences of the MDR for non-invasive brain stimulation (NIBS) have been largely overlooked and until today, have not been consequently addressed by National Competent Authorities, local ethical committees, politicians and by the scientific communities. In addition, a rushed bureaucratic decision led to seemingly wrong classification of NIBS products without an intended medical purpose into the same risk group III as invasive stimulators. Overregulation is detrimental for any research and for future developments, therefore researchers, clinicians, industry, patient representatives and an ethicist were invited to contribute to this document with the aim of starting a constructive dialogue and enacting positive changes in the regulatory environment.

Reduced stereotypicality and spared use of facial expression predictions for social evaluation in autism.

Background/Objective: Autism has been investigated through traditional emotion recognition paradigms, merely investigating accuracy, thereby constraining how potential differences across autistic and control individuals may be observed, identified, and described. Moreover, the use of emotional facial expression information for social functioning in autism is of relevance to provide a deeper understanding of the condition. Method: Adult autistic individuals (n = 34) and adult control individuals (n = 34) were assessed with a social perception behavioral paradigm exploring facial expression predictions and their impact on social evaluation. Results: Autistic individuals held less stereotypical predictions than controls. Importantly, despite such differences in predictions, the use of such predictions for social evaluation did not differ significantly between groups, as autistic individuals relied on their predictions to evaluate others to the same extent as controls. Conclusions: These results help to understand how autistic individuals perceive social stimuli and evaluate others, revealing a deviation from stereotypicality beyond which social evaluation strategies may be intact.

Noninvasive modulation of predictive coding in humans: causal evidence for frequency-specific temporal dynamics.

Increasing evidence indicates that the brain predicts sensory input based on past experiences, importantly constraining how we experience the world. Despite a growing interest on this framework, known as predictive coding, most of such approaches to multiple psychological domains continue to be theoretical or primarily provide correlational evidence. We here explored the neural basis of predictive processing using noninvasive brain stimulation and provide causal evidence of frequency-specific modulations in humans. Participants received 20 Hz (associated with top-down/predictions), 50 Hz (associated with bottom-up/prediction errors), or sham transcranial alternating current stimulation on the left dorsolateral prefrontal cortex while performing a social perception task in which facial expression predictions were induced and subsequently confirmed or violated. Left prefrontal 20 Hz stimulation reinforced stereotypical predictions. In contrast, 50 Hz and sham stimulation failed to yield any significant behavioral effects. Moreover, the frequency-specific effect observed was further supported by electroencephalography data, which showed a boost of brain activity at the stimulated frequency band. These observations provide causal evidence for how predictive processing may be enabled in the human brain, setting up a needed framework to understand how it may be disrupted across brain-related conditions and potentially restored through noninvasive methods.

Predictive processing in depression: Increased prediction error following negative valence contexts and influence of recent mood-congruent yet irrelevant experiences.

BACKGROUND: Novel theoretical models of depression have recently emerged based on an influential new perspective in neuroscience known as predictive processing. In these models, depression may be understood as an imbalance of predictive signals in the brain; more specifically, a dominance of predictions leading to a relative insensitivity to prediction error. Despite these important theoretical advances, empirical evidence remains limited, and how expectations are generated and used dynamically in individuals with depression remains largely unexplored. METHODS: In this study, we induced facial expression predictions using emotion contexts in 34 individuals with depression and 34 healthy controls. RESULTS: Compared to controls, individuals with depression perceived displayed facial expressions as less similar to their expectations (i.e., increased difference between expectations and actual sensory input) following contexts evoking negative valence emotions, indicating that depressed individuals have increased prediction error in such contexts. This effect was amplified by recent mood-congruent yet irrelevant experiences. LIMITATIONS: The clinical sample included participants with comorbid psychopathology and taking medication. Additionally, the two groups were not evaluated in the same setting, and only three emotion categories (fear, sadness, and happiness) were explored. CONCLUSIONS: Our results shed light on potential mechanisms underlying processing abnormalities regarding negative information, which has been consistently reported in depression, and may be a relevant point of departure for exploring transdiagnostic vulnerability to mental illness. Our data also has the potential to improve clinical practice through the implementation of novel diagnostic and therapeutic tools based on the assessment and modulation of predictive signals.

Self and Other Mentalizing Polarities and Dimensions of Mental Health: Association With Types of Symptoms, Functioning and Well-Being.

Research suggests that the ability to understand one's own and others' minds, or mentalizing, is a key factor for mental health. Most studies have focused the attention on the association between global measures of mentalizing and specific disorders. In contrast, very few studies have analyzed the association between specific mentalizing polarities and global measures of mental health. This study aimed to evaluate whether self and other polarities of mentalizing are associated with a multidimensional notion of mental health, which considers symptoms, functioning, and well-being. Additionally, the level or depth of mentalizing within each polarity was also analyzed. A sample of 214 adolescents (12-18 years old, M = 14.7, and SD = 1.7; 53.3% female) was evaluated on measures of self- (Trait Meta-Mood Scale or TMMS-24) and other- mentalizing (Adolescent Mentalizing Interview or AMI), multi-informed measures of psychopathology and functioning based on Achenbach's system, and measures of psychological well-being (self-esteem, happiness, and motivation to life goals). Results revealed no association between mentalizing polarities and higher-order symptom factors (internalizing, externalizing, and global symptoms or "p" factor). Self-mentalizing was associated with self-esteem (B = 0.076, p < 0.0005) and motivation to life goals (B = 0.209, p = 0.002), and other-mentalizing was associated to general, social and role functioning (B = 0.475, p < 0.0005; B = 0.380, p = 0.005; and B = 0.364, p = 0.004). This association between aspects of self-other mentalizing and self-other function has important implications for treatment and prevention. Deeper mentalizing within each polarity (i.e., comprehension beyond simple attention to one's own mental states, and mentalizing referred to attachment figures vs. mentalizing referred to the characters of a story) revealed stronger associations with functioning and well-being. Because mentalizing polarities are associated with functioning and well-being but not with symptoms, a new hypothesis is developed: mentalizing does not contribute to resiliency by preventing symptoms, but by helping to deal with them, thus improving functioning and well-being independently of psychopathology. These findings support that promoting mentalizing across development may improve mental health, even in non-clinical population.

Ultra High Field fMRI of Human Superior Colliculi Activity during Affective Visual Processing.

Research on rodents and non-human primates has established the involvement of the superior colliculus in defensive behaviours and visual threat detection. The superior colliculus has been well-studied in humans for its functional roles in saccade and visual processing, but less is known about its involvement in affect. In standard functional MRI studies of the human superior colliculus, it is challenging to discern activity in the superior colliculus from activity in surrounding nuclei such as the periaqueductal gray due to technological and methodological limitations. Employing high-field strength (7 Tesla) fMRI techniques, this study imaged the superior colliculus at high (0.75 mm isotropic) resolution, which enabled isolation of the superior colliculus from other brainstem nuclei. Superior colliculus activation during emotionally aversive image viewing blocks was greater than that during neutral image viewing blocks. These findings suggest that the superior colliculus may play a role in shaping subjective emotional experiences in addition to its visuomotor functions, bridging the gap between affective research on humans and non-human animals.

Topography Impacts Topology: Anatomically Central Areas Exhibit a "High-Level Connector" Profile in the Human Cortex.

Degree centrality is a widely used measure in complex networks. Within the brain, degree relates to other topological features, with high-degree nodes (i.e., hubs) exhibiting high betweenness centrality, participation coefficient, and within-module z-score. However, increasing evidence from neuroanatomical and predictive processing literature suggests that topological properties of a brain network may also be impacted by topography, that is, anatomical (spatial) distribution. More specifically, cortical limbic areas (agranular and dysgranular cortices), which occupy an anatomically central position, have been proposed to be topologically central and well suited to initiate predictions in the cerebral cortex. We estimated anatomical centrality and showed that it positively correlated with betweenness centrality, participation coefficient, and communicability, analogously to degree. In contrast to degree, however, anatomical centrality negatively correlated with within-module z-score. Our data suggest that degree centrality and anatomical centrality reflect distinct contributions to cortical organization. Whereas degree would be more related to the amount of information integration performed by an area, anatomical centrality would be more related to an area's position in the predictive hierarchy. Highly anatomically central areas may function as "high-level connectors," integrating already highly integrated information across modules. These results are consistent with a high-level, domain-general limbic workspace, integrated by highly anatomically central cortical areas.

Cross-modal cueing effects of visuospatial attention on conscious somatosensory perception.

OBJECTIVE: The impact of visuospatial attention on perception with supraliminal stimuli and stimuli at the threshold of conscious perception has been previously investigated. In this study, we assess the cross-modal effects of visuospatial attention on conscious perception for near-threshold somatosensory stimuli applied to the face. METHODS: Fifteen healthy participants completed two sessions of a near-threshold cross-modality cue-target discrimination/conscious detection paradigm. Each trial began with an endogenous visuospatial cue that predicted the location of a weak near-threshold electrical pulse delivered to the right or left cheek with high probability (∼75%). Participants then completed two tasks: first, a forced-choice somatosensory discrimination task (felt once or twice?) and then, a somatosensory conscious detection task (did you feel the stimulus and, if yes, where (left/right)?). Somatosensory discrimination was evaluated with the response reaction times of correctly detected targets, whereas the somatosensory conscious detection was quantified using perceptual sensitivity (d') and response bias (beta). A 2 × 2 repeated measures ANOVA was used for statistical analysis. RESULTS: In the somatosensory discrimination task (1st task), participants were significantly faster in responding to correctly detected targets (p < 0.001). In the somatosensory conscious detection task (2nd task), a significant effect of visuospatial attention on response bias (p = 0.008) was observed, suggesting that participants had a less strict criterion for stimuli preceded by spatially valid than invalid visuospatial cues. CONCLUSIONS: We showed that spatial attention has the potential to modulate the discrimination and the conscious detection of near-threshold somatosensory stimuli as measured, respectively, by a reduction of reaction times and a shift in response bias toward less conservative responses when the cue predicted stimulus location. A shift in response bias indicates possible effects of spatial attention on internal decision processes. The lack of significant results in perceptual sensitivity (d') could be due to weaker effects of endogenous attention on perception.

Facial expression predictions as drivers of social perception.

Emerging perspectives in neuroscience indicate that the brain functions predictively, constantly anticipating sensory input based on past experience. According to these perspectives, prediction signals impact perception, guiding and constraining experience. In a series of six behavioral experiments, we show that predictions about facial expressions drive social perception, deeply influencing how others are evaluated: individuals are judged as more likable and trustworthy when their facial expressions are anticipated, even in the absence of any conscious changes in felt affect. Moreover, the effect of predictions on social judgments extends to both real-world situations where such judgments have particularly high consequence (i.e., evaluating presidential candidates for an upcoming election), as well as to more basic perceptual processes that may underlie judgment (i.e., facilitated visual processing of expected expressions). The implications of these findings, including relevance for cross-cultural interactions, social stereotypes and mental illness, are discussed. (PsycINFO Database Record

Evidence for a Large-Scale Brain System Supporting Allostasis and Interoception in Humans.

Large-scale intrinsic brain systems have been identified for exteroceptive senses (e.g., sight, hearing, touch). We introduce an analogous system for representing sensations from within the body, called interoception, and demonstrate its relation to regulating peripheral systems in the body, called allostasis. Employing the recently introduced Embodied Predictive Interoception Coding (EPIC) model, we used tract-tracing studies of macaque monkeys, followed by two intrinsic functional magnetic resonance imaging samples (N = 280 and N = 270) to evaluate the existence of an intrinsic allostatic/interoceptive system in the human brain. Another sample (N = 41) allowed us to evaluate the convergent validity of the hypothesized allostatic/interoceptive system by showing that individuals with stronger connectivity between system hubs performed better on an implicit index of interoceptive ability related to autonomic fluctuations. Implications include insights for the brain's functional architecture, dissolving the artificial boundary between mind and body, and unifying mental and physical illness.

Visual Contrast Sensitivity Improvement by Right Frontal High-Beta Activity Is Mediated by Contrast Gain Mechanisms and Influenced by Fronto-Parietal White Matter Microstructure.

Behavioral and electrophysiological studies in humans and non-human primates have correlated frontal high-beta activity with the orienting of endogenous attention and shown the ability of the latter function to modulate visual performance. We here combined rhythmic transcranial magnetic stimulation (TMS) and diffusion imaging to study the relation between frontal oscillatory activity and visual performance, and we associated these phenomena to a specific set of white matter pathways that in humans subtend attentional processes. High-beta rhythmic activity on the right frontal eye field (FEF) was induced with TMS and its causal effects on a contrast sensitivity function were recorded to explore its ability to improve visual detection performance across different stimulus contrast levels. Our results show that frequency-specific activity patterns engaged in the right FEF have the ability to induce a leftward shift of the psychometric function. This increase in visual performance across different levels of stimulus contrast is likely mediated by a contrast gain mechanism. Interestingly, microstructural measures of white matter connectivity suggest a strong implication of right fronto-parietal connectivity linking the FEF and the intraparietal sulcus in propagating high-beta rhythmic signals across brain networks and subtending top-down frontal influences on visual performance.

Redefining the Role of Limbic Areas in Cortical Processing.

There is increasing evidence that the brain actively constructs action and perception using past experience. In this paper, we propose that the direction of information flow along gradients of laminar differentiation provides important insight on the role of limbic cortices in cortical processing. Cortical limbic areas, with a simple laminar structure (e.g., no or rudimentary layer IV), send 'feedback' projections to lower level better laminated areas. We propose that this 'feedback' functions as predictions that drive processing throughout the cerebral cortex. This hypothesis has the potential to provide a unifying framework for an increasing number of proposals that use predictive coding to explain a myriad of neural processes and disorders, and has important implications for hypotheses about consciousness.

Arrhythmic activity in the left frontal eye field facilitates conscious visual perception in humans.

The frontal eye field (FEF) is a brain region involved in several processes relevant for visual performance, including visuo-spatial attention, conscious access and decision-making. Prior research has causally demonstrated that high-beta FEF activity in the right hemisphere enhances conscious visual perception, an outcome that is in agreement with evidence of neural synchronization along a right dorsal fronto-parietal network during attentional orienting and a right-hemisphere dominance for visuospatial processing. Nonetheless, frontal regions in the left hemisphere have also been shown to modulate perceptual performance. To causally explore the neural basis of these modulations, we delivered high-beta frequency-specific bursts of transcranial magnetic stimulation (TMS) to the left FEF and report that, in this region, these patterns failed to modulate conscious perception. In contrast, non-frequency-specific TMS patterns yielded visual performance improvements similar to those formerly causally associated to the induction of high-beta activity on its right-hemisphere homotopic area. This noise-induced facilitation of conscious vision suggests a relevant role of the left frontal cortex in visual perception. Furthermore, taken together with prior causal right-FEF evidence, our study indicates that frontal regions of each hemisphere employ different coding strategies to modulate conscious perception.

Fronto-Parietal Anatomical Connections Influence the Modulation of Conscious Visual Perception by High-Beta Frontal Oscillatory Activity.

May white matter connectivity influence rhythmic brain activity underlying visual cognition? We here employed diffusion imaging to reconstruct the fronto-parietal white matter pathways in a group of healthy participants who displayed frequency-specific ameliorations of visual sensitivity during the entrainment of high-beta oscillatory activity by rhythmic transcranial magnetic stimulation over their right frontal eye field. Our analyses reveal a strong tract-specific association between the volume of the first branch of the superior longitudinal fasciculus and improvements of conscious visual detection driven by frontal beta oscillation patterns. These data indicate that the architecture of specific white matter pathways has the ability to influence the distributed effects of rhythmic spatio-temporal activity, and suggest a potentially relevant role for long-range connectivity in the synchronization of oscillatory patterns across fronto-parietal networks subtending the modulation of conscious visual perception.

Frontal eye field, where art thou? Anatomy, function, and non-invasive manipulation of frontal regions involved in eye movements and associated cognitive operations.

The planning, control and execution of eye movements in 3D space relies on a distributed system of cortical and subcortical brain regions. Within this network, the Eye Fields have been described in animals as cortical regions in which electrical stimulation is able to trigger eye movements and influence their latency or accuracy. This review focuses on the Frontal Eye Field (FEF) a "hub" region located in Humans in the vicinity of the pre-central sulcus and the dorsal-most portion of the superior frontal sulcus. The straightforward localization of the FEF through electrical stimulation in animals is difficult to translate to the healthy human brain, particularly with non-invasive neuroimaging techniques. Hence, in the first part of this review, we describe attempts made to characterize the anatomical localization of this area in the human brain. The outcome of functional Magnetic Resonance Imaging (fMRI), Magneto-encephalography (MEG) and particularly, non-invasive mapping methods such a Transcranial Magnetic Stimulation (TMS) are described and the variability of FEF localization across individuals and mapping techniques are discussed. In the second part of this review, we will address the role of the FEF. We explore its involvement both in the physiology of fixation, saccade, pursuit, and vergence movements and in associated cognitive processes such as attentional orienting, visual awareness and perceptual modulation. Finally in the third part, we review recent evidence suggesting the high level of malleability and plasticity of these regions and associated networks to non-invasive stimulation. The exploratory, diagnostic, and therapeutic interest of such interventions for the modulation and improvement of perception in 3D space are discussed.

Fronto-tectal white matter connectivity mediates facilitatory effects of non-invasive neurostimulation on visual detection.

The causal ability of pre-target FEF activity to modulate visual detection for perithreshold stimuli has been recently demonstrated in humans by means of non-invasive neurostimulation. Yet in spite of the network-distributed effects of these type of techniques, the white matter (WM) tracts and distant visual nodes contributing to such behavioral impact remain unknown. We hereby used individual data from a group of healthy human subjects, who received time-locked pulses of active or sham Transcranial Magnetic Stimulation (TMS) to the right Frontal Eye Field (FEF) region, and experienced increases in visual detection sensitivity. We then studied the extent to which interindividual differences in visual modulation might be dependent on the WM patterns linking the targeted area to other regions relevant for visuo-attentional behaviors. We report a statistically significant correlation between the probability of connection in a right fronto-tectal pathway (FEF-Superior Colliculus) and the modulation of visual sensitivity during a detection task. Our findings support the potential contribution of this pathway and the superior colliculus in the mediation of visual performance from frontal regions in humans. Furthermore, we also show the ability of a TMS/DTI correlational approach to contribute to the disambiguation of the specific long-range pathways driving network-wide neurostimulatory effects on behavior, anticipating their future role in guiding a more efficient use of focal neurostimulation.

Causal frequency-specific contributions of frontal spatiotemporal patterns induced by non-invasive neurostimulation to human visual performance.

Neural oscillatory activity is known to play a crucial role in brain function. In the particular domain of visual perception, specific frequency bands in different brain regions and networks, from sensory areas to large-scale frontoparietal systems, have been associated with distinct aspects of visual behavior. Nonetheless, their contributions to human visual cognition remain to be causally demonstrated. We hereby used non-uniform (and thus non-frequency-specific) and uniform (frequency-specific) high-beta and gamma patterns of noninvasive neurostimulation over the right frontal eye field (FEF) to isolate the behavioral effects of oscillation frequency and provide causal evidence that distinct visual behavioral outcomes could be modulated by frequency-specific activity emerging from a single cortical region. In a visual detection task using near-threshold targets, high-beta frequency enhanced perceptual sensitivity (d') without changing response criterion (beta), whereas gamma frequency shifted response criterion but showed no effects on perceptual sensitivity. The lack of behavioral modulations by non-frequency-specific patterns demonstrates that these behavioral effects were specifically driven by burst frequency. We hypothesize that such frequency-coded behavioral impact of oscillatory activity may reflect a general brain mechanism to multiplex functions within the same neural substrate. Furthermore, pathological conditions involving impaired cerebral oscillations could potentially benefit in the near future from the use of neurostimulation to restore the characteristic oscillatory patterns of healthy systems.

Manipulation of pre-target activity on the right frontal eye field enhances conscious visual perception in humans.

The right Frontal Eye Field (FEF) is a region of the human brain, which has been consistently involved in visuo-spatial attention and access to consciousness. Nonetheless, the extent of this cortical site's ability to influence specific aspects of visual performance remains debated. We hereby manipulated pre-target activity on the right FEF and explored its influence on the detection and categorization of low-contrast near-threshold visual stimuli. Our data show that pre-target frontal neurostimulation has the potential when used alone to induce enhancements of conscious visual detection. More interestingly, when FEF stimulation was combined with visuo-spatial cues, improvements remained present only for trials in which the cue correctly predicted the location of the subsequent target. Our data provide evidence for the causal role of the right FEF pre-target activity in the modulation of human conscious vision and reveal the dependence of such neurostimulatory effects on the state of activity set up by cue validity in the dorsal attentional orienting network.