Anatomo-functional basis of emotional and motor resonance elicited by facial expressions.

Simulation theories predict that the observation of other's expressions modulates neural activity in the same centers controlling their production. This hypothesis has been developed by two models, postulating that the visual input is directly projected either to the motor system for action recognition (motor resonance) or to emotional/interoceptive regions for emotional contagion and social synchronization (emotional resonance). Here we investigated the role of frontal/insular regions in the processing of observed emotional expressions by combining intracranial recording, electrical stimulation and effective connectivity. First, we intracranially recorded from prefrontal, premotor or anterior insular regions of 44 patients during the passive observation of emotional expressions, finding widespread modulations in prefrontal/insular regions (anterior cingulate cortex, anterior insula, orbitofrontal cortex and inferior frontal gyrus) and motor territories (rolandic operculum and inferior frontal junction). Subsequently, we electrically stimulated the activated sites, finding that (a) in the anterior cingulate cortex and anterior insula, the stimulation elicited emotional/interoceptive responses, as predicted by the 'emotional resonance model', (b) in the rolandic operculum it evoked face/mouth sensorimotor responses, in line with the 'motor resonance' model, and (c) all other regions were unresponsive or revealed functions unrelated to the processing of facial expressions. Finally, we traced the effective connectivity to sketch a network-level description of these regions, finding that the anterior cingulate cortex and the anterior insula are reciprocally interconnected while the rolandic operculum is part of the parieto-frontal circuits and poorly connected with the formers. These results support the hypothesis that the pathways hypothesized by the 'emotional resonance' and the 'motor resonance' models work in parallel, differing in terms of spatio-temporal fingerprints, reactivity to electrical stimulation and connectivity patterns.

Language lateralization mapping (reversibly) masked by non-dominant focal epilepsy: a case report.

Language lateralization in patients with focal epilepsy frequently diverges from the left-lateralized pattern that prevails in healthy right-handed people, but the mechanistic explanations are still a matter of debate. Here, we debate the complex interaction between focal epilepsy, language lateralization, and functional neuroimaging techniques by introducing the case of a right-handed patient with unaware focal seizures preceded by aphasia, in whom video-EEG and PET examination suggested the presence of focal cortical dysplasia in the right superior temporal gyrus, despite a normal structural MRI. The functional MRI for language was inconclusive, and the neuropsychological evaluation showed mild deficits in language functions. A bilateral stereo-EEG was proposed confirming the right superior temporal gyrus origin of seizures, revealing how ictal aphasia emerged only once seizures propagated to the left superior temporal gyrus and confirming, by cortical mapping, the left lateralization of the posterior language region. Stereo-EEG-guided radiofrequency thermocoagulations of the (right) focal cortical dysplasia not only reduced seizure frequency but led to the normalization of the neuropsychological assessment and the "restoring" of a classical left-lateralized functional MRI pattern of language. This representative case demonstrates that epileptiform activity in the superior temporal gyrus can interfere with the functioning of the contralateral homologous cortex and its associated network. In the case of presurgical evaluation in patients with epilepsy, this interference effect must be carefully taken into consideration. The multimodal language lateralization assessment reported for this patient further suggests the sensitivity of different explorations to this interference effect. Finally, the neuropsychological and functional MRI changes after thermocoagulations provide unique cues on the network pathophysiology of focal cortical dysplasia and the role of diverse techniques in indexing language lateralization in complex scenarios.

70 Years of Human Cingulate Cortex Stimulation. Functions and Dysfunctions Through the Lens of Electrical Stimulation.

SUMMARY: In this review, we retrace the results of 70 years of human cingulate cortex (CC) intracerebral electrical stimulation and discuss its contribution to our understanding of the anatomofunctional and clinical aspects of this wide cortical region. The review is divided into three main sections. In the first section, we report the results obtained by the stimulation of the anterior, middle, and posterior CC, in 30 studies conducted on approximately 1,000 patients from the 1950s to the present day. These studies show that specific manifestations can be reliably associated with specific cingulate subfields, with autonomic, interoceptive, and emotional manifestations clustered in the anterior cingulate, goal-oriented motor behaviors elicited from the anterior midcingulate and a variety of sensory symptoms characterizing the posterior cingulate regions. In the second section, we compare the effect of CC intracerebral electrical stimulation with signs and manifestations characterizing cingulate epilepsy, showing that the stimulation mapping of CC subfields provides precious information for understanding cingulate epileptic manifestations. The last section tackles the issue of the discrepancy emerging when comparing the results of clinical (electrical stimulation, epilepsy) studies-revealing the quintessential affective and motor nature of the CC-with that reported by neuroimaging studies-which focus on high-level cognitive functions. Particular attention will be paid to the hypothesis that CC hosts a "Pain Matrix" specifically involved in pain perception, which we will discuss in the light of the fact that the stimulation of CC (as well as cingulate epileptic seizures) does not induce nociceptive effects.

EEG-EMG coupling as a hybrid method for steering detection in car driving settings.

Understanding mental processes in complex human behavior is a key issue in driving, representing a milestone for developing user-centered assistive driving devices. Here, we propose a hybrid method based on electroencephalographic (EEG) and electromyographic (EMG) signatures to distinguish left and right steering in driving scenarios. Twenty-four participants took part in the experiment consisting of recordings of 128-channel EEG and EMG activity from deltoids and forearm extensors in non-ecological and ecological steering tasks. Specifically, we identified the EEG mu rhythm modulation correlates with motor preparation of self-paced steering actions in the non-ecological task, while the concurrent EMG activity of the left (right) deltoids correlates with right (left) steering. Consequently, we exploited the mu rhythm de-synchronization resulting from the non-ecological task to detect the steering side using cross-correlation analysis with the ecological EMG signals. Results returned significant cross-correlation values showing the coupling between the non-ecological EEG feature and the muscular activity collected in ecological driving conditions. Moreover, such cross-correlation patterns discriminate the steering side earlier relative to the single EMG signal. This hybrid system overcomes the limitation of the EEG signals collected in ecological settings such as low reliability, accuracy, and adaptability, thus adding to the EMG the characteristic predictive power of the cerebral data. These results prove how it is possible to complement different physiological signals to control the level of assistance needed by the driver. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-021-09776-w.

The vision of haptics tunes the somatosensory threshold.

The interaction between different sensory modalities represents a crucial issue in the neuroscience of consciousness: when the processing of one modality is deficient, the concomitant presentation of stimuli of other spared modalities may sustain the restoration of the damaged sensory functions. In this regard, visual enhancement of touch may represent a viable tool in rehabilitating tactile disorders, yet the specific visual features mostly modulating the somatosensory experience remain unsettled. In this study, healthy subjects underwent a tactile detection task during the observation of videos displaying different contents, including static gratings, meaningless motions and natural or point-lights reach-to-grasp-and-manipulate actions. Concurrently, near-threshold stimuli were delivered to the median nerve at different time-points. The subjective report was collected after each trial; the sensory detection rate was computed and compared across video conditions. Our results indicate that the specific presence of haptic contents (i.e., the vision of manipulation), either fully displayed or implied by point-lights, magnifies tactile sensitivity. The notion that such stimuli prompt a conscious tactile experience opens to novel rehabilitation approaches for tactile consciousness disorders.

Robust anticipation of continuous steering actions from electroencephalographic data during simulated driving.

Driving a car requires high cognitive demands, from sustained attention to perception and action planning. Recent research investigated the neural processes reflecting the planning of driving actions, aiming to better understand the factors leading to driving errors and to devise methodologies to anticipate and prevent such errors by monitoring the driver's cognitive state and intention. While such anticipation was shown for discrete driving actions, such as emergency braking, there is no evidence for robust neural signatures of continuous action planning. This study aims to fill this gap by investigating continuous steering actions during a driving task in a car simulator with multimodal recordings of behavioural and electroencephalography (EEG) signals. System identification is used to assess whether robust neurophysiological signatures emerge before steering actions. Linear decoding models are then used to determine whether such cortical signals can predict continuous steering actions with progressively longer anticipation. Results point to significant EEG signatures of continuous action planning. Such neural signals show consistent dynamics across participants for anticipations up to 1 s, while individual-subject neural activity could reliably decode steering actions and predict future actions for anticipations up to 1.8 s. Finally, we use canonical correlation analysis to attempt disentangling brain and non-brain contributors to the EEG-based decoding. Our results suggest that low-frequency cortical dynamics are involved in the planning of steering actions and that EEG is sensitive to that neural activity. As a result, we propose a framework to investigate anticipatory neural activity in realistic continuous motor tasks.

Tonic somatosensory responses and deficits of tactile awareness converge in the parietal operculum.

Although clinical neuroscience and the neuroscience of consciousness have long sought mechanistic explanations of tactile-awareness disorders, mechanistic insights are rare, mainly because of the difficulty of depicting the fine-grained neural dynamics underlying somatosensory processes. Here, we combined the stereo-EEG responses to somatosensory stimulation with the lesion mapping of patients with a tactile-awareness disorder, namely tactile extinction. Whereas stereo-EEG responses present different temporal patterns, including early/phasic and long-lasting/tonic activities, tactile-extinction lesion mapping co-localizes only with the latter. Overlaps are limited to the posterior part of the perisylvian regions, suggesting that tonic activities may play a role in sustaining tactile awareness. To assess this hypothesis further, we correlated the prevalence of tonic responses with the tactile-extinction lesion mapping, showing that they follow the same topographical gradient. Finally, in parallel with the notion that visuotactile stimulation improves detection in tactile-extinction patients, we demonstrated an enhancement of tonic responses to visuotactile stimuli, with a strong voxel-wise correlation with the lesion mapping. The combination of these results establishes tonic responses in the parietal operculum as the ideal neural correlate of tactile awareness.

Perspective-dependent activation of frontoparietal circuits during the observation of a static body effector.

The perspective from which body-related stimuli are observed plays a fundamental role in modulating cerebral activity during the processing of others' bodies and actions. Previous research has shown perspective-dependent cerebral responses during the observation of both ongoing actions and static images of an acting body with implied motion information, with an advantage for the egocentric viewpoint. The present high-density EEG study assessed event-related potentials triggered by the presentation of a forearm at rest before reach-to-grasp actions, shown from four different viewpoints. Through a spatiotemporal analysis of the scalp electric field and the localization of cortical generators, our study revealed overall different processing for the third-person perspective relative to other viewpoints, mainly due to a later activation of motor-premotor regions. Since observing a static body effector often precedes action observation, our results integrate previous evidence of perspective-dependent encoding, with cascade implications on the design of neurorehabilitative or motor learning interventions based on action observation.

Don't tell anyone: the importance of no-report paradigms in neuroscience of consciousness.

The neural correlates of perceptual awareness are usually investigated by comparing experimental conditions in which subjects are aware or not aware of the delivered stimulus. This, however, implies that subjects report their experience, possibly biasing the neural responses with the postperceptual processes involved. This Neuro Forum article reviews evidence from an electroencephalography (EEG) study by Cohen and colleagues (Cohen M, Ortego K, Kyroudis A, Pitts M. J Neurosci 40: 4925-4935, 2020) addressing the importance of no-report paradigms in the neuroscience of consciousness. In particular, authors show that P3b, one of the proposed canonical "signatures" of the conscious processing, is strongly elicited only when subjects have to report their experience, proposing a reconsideration in the approach to the neuroscience of consciousness.

Mirroring other's laughter. Cingulate, opercular and temporal contributions to laughter expression and observation.

Simulation theories predict that the observation of other's laughter modulates activity in the same centers controlling its production. Investigating this issue is particularly challenging, given the technical difficulties of studying laughter production. Previous observations from surgical patients reported laughter production following the electrical stimulation (ES) of the pregenual anterior cingulate (pACC), the frontal operculum (FO) and the temporal pole (TP), deemed to control emotional, communicative and cognitive aspects of laughter, respectively. Here we investigated which region is recruited during laughter observation and production, by adopting a twofold strategy which combines ES and intracranial recording in the same patients. We identified nine sites equally distributed in the pACC, FO and TP, where ES elicited laughter. Subsequently, we presented the patients with visual stimuli depicting dynamic (video) and static (pictures) expressions of laughter, along with emotional and neutral controls, while intracranially recording high-frequency gamma activity (50-150 Hz) from the same sites. pACC sites showed a selective activation during laughter observation, but only if laughter is presented in a dynamical fashion. FO and TP failed to respond during both dynamic and static expressions. We conclude that pACC host a mirror mechanism directly mapping other's laughter onto the neural substrate responsible for the production of emotional laughter.

Action execution and action observation elicit mirror responses with the same temporal profile in human SII.

The properties of the secondary somatosensory area (SII) have been described by many studies in monkeys and humans. Recent studies on monkeys, however, showed that beyond somatosensory stimuli, SII responds to a wider number of stimuli, a finding requiring a revision that human SII is purely sensorimotor. By recording cortical activity with stereotactic electroencephalography (stereo-EEG), we examined the properties of SI and SII in response to a motor task requiring reaching, grasping and manipulation, as well as the observation of the same actions. Furthermore, we functionally characterized this area with a set of clinical tests, including tactile, acoustical, and visual stimuli. The results showed that only SII activates both during execution and observation with a common temporal profile, whereas SI response were limited to execution. Together with their peculiar response to tactile stimuli, we conclude that the role of SII is pivotal also in the observation of actions involving haptic control.

Progression of Celiac Disease in Children With Antibodies Against Tissue Transglutaminase and Normal Duodenal Architecture.

BACKGROUND & AIMS: Potential celiac disease is characterized by positive results from serologic tests for tissue transglutaminase antibodies (anti-TG2) but normal duodenal architecture (Marsh stages 0-1). There is controversy over the best way to manage these patients. We investigated risk factors associated with the development of villous atrophy in children with potential celiac disease. METHODS: We performed a prospective study of 280 children (ages 2-18 years) in Italy with suspected celiac disease, followed for up to 12 years (range, 18-150 months; median 60 months). The subjects had 2 consecutive positive results from tests for anti-TG2, tested positive for the endomysial antibody (anti-EMA), had total serum levels of immunoglobulin A in the normal range, normal duodenal architecture (Marsh stages 0-1) in 5 biopsies, and HLA DQ2- or DQ8-positive haplotypes. The children underwent serologic tests and clinical analyses every 6 months and a small bowel biopsy was taken every 2 years. A total of 210 patients of the original cohort were assessed at the 9-year follow-up evaluation. We performed multivariate analyses of clinical, genetic, and histologic data to identify factors associated with progression to villous atrophy. RESULTS: During the follow-up period, 42 (15%) of 280 children developed villous atrophy, whereas 89 (32%) children no longer tested positive for anti-TG2 or anti-EMA. The cumulative incidence of progression to villous atrophy was 43% at 12 years. In multivariate analysis, the baseline factors most strongly associated with development of villous atrophy were numbers of γδ intraepithelial lymphocyte cells followed by age and homozygosity for the HLA DQB1*02. In discriminant analysis, these baseline factors identified 80% of the children who developed baseline atrophy. CONCLUSIONS: In a long-term study of 280 children with suspected celiac disease (based on anti-TG2 and anti-EMA) on gluten-containing diets, the cumulative incidence of progression to villous atrophy was 43% over a 12-year period. We identified factors that can be used to identify children at highest risk for villous atrophy. This approach might be used to determine whether children with suspected celiac disease should immediately start a gluten-free diet or be monitored on their regular diet.

Ipsilateral somatosensory responses in humans: the tonic activity of SII and posterior insular cortex.

In the present study, we mapped the spatio-temporal dynamics of cortical responses to ipsilateral median nerve stimulation using intracerebral recordings (stereo-EEG) in 38 drug-resistant epileptic patients. Furthermore, we compared the pattern of responsiveness obtained in the same leads across ipsilateral and contralateral stimulations. Ipsilateral responses were found mostly confined to SII and posterior insula, while no activity was found in ipsilateral SI. By examining the temporal profiles of activation, ipsilateral SII showed a prominent tonic pattern, while contralateral SII exhibited both phasic and tonic responses. Beyond the localization of the active cortical nodes, these data contributed to identify the cortico-cortical connections carrying the somatosensory information to the ipsilateral hemisphere, with a major role of transcallosal projections from contralateral SII. In light of previous literature and of its localization, the functional role possibly covered by long lasting discharge in SII and insular cortex is also discussed. Overall, the presence of tonic activities was neglected so far due to the impossibility to identify deep sources along with a resolved description of their time course. The use of stereo-EEG, instead, allows one to achieve a four-dimensional characterization, complementing the classical view about the somatosensory system organization.

The Effect of Gluten-free Diet on Clinical Symptoms and the Intestinal Mucosa of Patients With Potential Celiac Disease.

In this prospective study, we evaluated the effect of gluten-free diet (GFD) in a cohort of 65 children with potential celiac disease. Patients received GFD for signs/symptoms (N = 47) or parents' choice (N = 18). Most frequent signs/symptoms were low body mass index (36%), recurrent abdominal pain (34%), and diarrhea (19%). Of the 35/47 patients followed-up on GFD, only 54% (19/35) showed a complete clinical response. In 9 of 65 patients an intestinal biopsy was also performed after at least 1 year of GFD. No significant differences were observed in terms of Marsh grade (P = 0.33), lamina propria CD25+ cells (P = 0.80), CD3+ (P = 0.9), and γδ+ (P = 0.59) intraepithelial lymphocytes density and intestinal anti-TG2 deposits (P = 0.60). In conclusion, caution is necessary before attributing all symptoms to gluten in this condition.

Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse.

Tumor immunologic microenvironment is strongly involved in tumor progression and the presence of tumor infiltrating lymphocytes (TIL) with different phenotypes has been demonstrated to be of prognostic relevance in different malignancies. We investigated whether TIL infiltration of tumor tissues could also predict the outcome of prostate cancer patients. To this end, we carried out a retrospective analysis correlating the outcome of locally advanced prostate cancer patients undergone salvage radiotherapy upon relapse after radical surgery with the infiltration by different TIL populations. Twenty-two patients with resectable prostate cancer, with a mean age of 67 (+/-3.93) years, who received salvage radiotherapy with a mean of 69.66 (+/- 3.178) Gy in 8 weeks, between June 1999 and January 2009 and with a median follow up of 123 (+/- 55.82) months, were enrolled in this study. We evaluated, by immunohistochemistry, the intratumoral (t) and peripheral stroma (p) infiltration by CD45, CD3, CD4, CD8, CCR7, FoxP3 or PD-1-positive cells on tumor samples taken at the diagnosis (d) and relapse times (R). We correlated these variables with patients' biochemical progression free survival (bPFS), post-radiotherapy progression free survival (PFS), and overall survival (OS). Substantial changes in the rate of TIL subsets were found between the first and the second biopsy with progressive increase in CD4, CCR7, FoxP3, PD-1+ cells. Our analysis revealed that higher CD8p,R+ and lower PD-1R+ TIL scores correlated to a longer bPFS. Higher CD8p,R+ and CCR7t,R+ TIL scores and lower CD45p,R+ and FoxP3p,R+ TIL scores correlated to a prolonged PFS and OS. These results suggest that the immunological microenvironment of primary tumor is strictly correlated with patient outcome and provide the rationale for immunological treatment of prostate cancer.

Carbonic anhydrase IX is a marker of hypoxia and correlates with higher Gleason scores and ISUP grading in prostate cancer.

BACKGROUND: Carbonic anhydrase IX is a member of α-carbonic anhydrases that is preferentially expressed in solid tumors. It enables bicarbonate transport across the plasma membrane, neutralizing intracellular pH and conferring to cancer cells a survival advantage in hypoxic/acidic microenvironments. Overexpression of carbonic anhydrase IX in cancer tissues is regulated by hypoxia inducible factor 1α - mediated transcription and the enzyme is considered a marker of tumor hypoxia and poor outcome. The role of carbonic anhydrase IX in prostate cancer has not been fully clarified and controversy has arisen on whether this enzyme is overexpressed in hypoxic prostate cancer tissues. METHODS: We analyzed the expression of carbonic anhydrase IX and hypoxia inducible factor 1α in two prostate cancer cell lines, LNCaP and PC-3, and in 110 cancer biopsies, by western blotting and immunocyto/histochemistry. RESULTS: In LNCaP and PC-3 cells, carbonic anhydrase IX was mostly cytoplasmic/nuclear, with very limited membrane localization. Nuclear staining became stronger under hypoxia. When we analyzed carbonic anhydrase IX expression in human prostate cancer biopsies, we found that protein staining positively correlated with hypoxia inducible factor 1α and with Gleason pattern and score, as well as with the novel grading system proposed by the International Society of Urological Pathology for prostate cancer. Once more, carbonic anhydrase IX was mainly cytoplasmic in low grade carcinomas, whereas in high grade tumors was strongly expressed in the nucleus of the neoplastic cell. An association between carbonic anhydrase IX expression level and the main clinic-pathological features involved in prostate cancer aggressiveness was identified. CONCLUSIONS: There was a statistically significant association between carbonic anhydrase IX and hypoxia inducible factor 1α in prostate cancer tissues, that identifies the enzyme as a reliable marker of tumor hypoxia. In addition, carbonic anhydrase IX expression positively correlated with prostate cancer grading and staging, and with outcome, suggesting that the protein may be an independent prognosticator for the disease. The nuclear translocation of the enzyme in hypoxic cancer cells may epitomize a biological switch of the tumor towards a less favorable phenotype.

Emerging Targets For Prostate Adenocarcinoma Therapy: How Molecular Biology May Drive Towards a More Tailored Approach.

Prostate adenocarcinoma is the most diagnosed male cancer in the Western world and the second leading cause of cancer-related mortality. Albeit most of the patients with prostate adenocarcinoma are currently treated by surgery and/or radiation therapy, more than 30-40% of affected subjects will eventually progress and develop advanced disease. To date, management decisions depend on the clinical stage of the patient and the histological diagnosis which unfortunately often lack to predict the real prognosis. Current therapies have shown to be insufficient, mainly in the metastatic disease. For clear-cut diagnosis and follow-up, we promptly need molecular markers also useful in predicting patient's outcome. Advances in cancer genomics have led to a plethora of biomarkers, which must now to be rigorously validated in the clinical setting. Recent insights on prostate adenocarcinoma biology which unveiled some of the biological mechanisms leading to this tumour, have managed in devising novel strategies for therapy. Immunotherapeutic agents, selective adrenal inhibitors, anti-angiogenic molecules, newly engineered androgen receptor inhibitors, compounds targeting the bone microenvironment are demonstrated to limit cancer growth by blocking specific signaling pathways. Such strategies can be complemented to existing therapeutic paradigm in improving beneficial outcome. Moreover, other emerging pharmacological compounds have shown encouraging results and several clinical trials are ongoing. This review summarizes the developing targeted therapies for prostate adenocarcinoma and discuss their potential benefit mainly in the castration- resistant forms.

Expression of Translationally Controlled Tumor Protein in Human Kidney and in Renal Cell Carcinoma.

Translationally controlled tumor protein is a multifaceted protein involved in several physiological and biological functions. Its expression in normal kidney and in renal carcinomas, once corroborated by functional data, may add elements to elucidate renal physiology and carcinogenesis. In this study, translationally controlled tumor protein expression was evaluated by quantitative real time polymerase chain reaction and western blotting, and its localization was examined by immunohistochemistry on 84 nephrectomies for cancer. In normal kidney protein expression was found in the cytoplasm of proximal and distal tubular cells, in cells of the thick segment of the loop of Henle, and in urothelial cells of the pelvis. It was also detectable in cells of renal carcinoma with different pattern of localization (membranous and cytoplasmic) depending on tumor histotype. Our data may suggest an involvement of translationally controlled tumor protein in normal physiology and carcinogenesis. However, functional in vitro and in vivo studies are needed to verify this hypothesis.