Evidence accumulation is a powerful mechanism to explain the temporal dynamics of decisions, as well as their metacognitive components such as confidence judgments and changes of mind. However, it is still unclear how and where in the brain evidence accumulation leads to these two metacognitive components. We report intracranial high-gamma activity in patients with epilepsy recorded while they perform a visual discrimination task and estimate their confidence level. Our results indicate an anatomical overlap between the neural correlates of evidence accumulation, confidence, and changes of mind in the pre-supplementary motor area, as well as in the orbitofrontal, inferior frontal, and insular cortices. Behavioural and electrophysiological results are reproduced with a post-decisional evidence accumulation model, and the temporal dynamics of decision-making is characterized with mouse-tracking and intracranial electrophysiology. We conclude that confidence and changes of mind result from evidence accumulation, instantiated before the decision in the pre-supplementary motor area, and after the decision in the insula.

Perception is a multi-faceted, dynamical process that can be tackled empirically through measures of stimulus detectability and confidence. We recorded stereo-electroencephalographic data of 29 participants partaking in three pre-registered experiments to assess if evidence accumulation, a form of sequential sampling of sensory evidence, can explain perception. In an immediate-response experiment, high-gamma activity from individual channels and decoded multivariate latent variables in the visual, inferior frontal, and anterior insular cortices display a correlation between the slope of their increase and reaction times. In two further experiments, this signal in the ventral visual cortex differentiates between (1) stimuli reported as seen vs. unseen in delayed detection, (2) high and low intensity stimuli during passive viewing, and (3) levels of confidence when stimuli were detected. A computational model of leaky evidence accumulation can successfully reproduce both behavioral and neural data. Overall, we show that evidence accumulation explains subjective aspects of visual perception.

Evidence accumulation models have proven to be powerful tools to explain the temporal dynamics of decisions, as well as their metacognitive components such as confidence judgments and changes of mind. However, it is still unclear how and where in the brain evidence accumulation leads to these two metacognitive components. To better understand the functional overlap between evidence accumulation, confidence, and changes of mind, we recorded intracranial high-gamma activity in patients with focal epilepsy while they reported the motion direction of a random dot kinetogram with a computer mouse, and estimated their confidence level. We found an anatomical overlap between the neural correlates of evidence accumulation, confidence, and changes of mind in the pre-supplementary motor area, as well as in the orbitofrontal, inferior frontal, and insular cortices. Both mouse-tracking behaviour and electrophysiological results were reproduced with a post-decisional evidence accumulation model. After characterising the temporal dynamics of decision-making with mouse-tracking and intracranial electrophysiology, we conclude that confidence and changes of mind result from evidence accumulation instantiated before the decision in the pre-supplementary motor area, and after the decision in the insula. ### Competing Interest Statement The authors have declared no competing interest.

Perceptual experience is a multi-faceted, dynamical process, tackled empirically through measures of stimulus detectability and confidence. To assess if stimulus detection and confidence can be explained by evidence accumulation, a form of sequential sampling of sensory evidence, we analyzed high-gamma activity from stereo-electroencephalographic data of 29 participants partaking in 3 pre-registered experiments. In an immediate-response experiment, individual channels and decoded multivariate latent variables in the visual, inferior frontal, and anterior insular cortices displayed functional markers of evidence accumulation. In two further experiments, this signal in the ventral visual cortex differentiated between (1) seen and unseen stimuli in delayed detection, (2) high and low intensity stimuli during passive viewing, and (3) levels of confidence when stimuli were seen. A computational model of leaky evidence accumulation successfully reproduced both behavioral and neural data. Overall, these results indicate that evidence accumulation explains key aspects of perceptual experience, encompassing both conscious access and monitoring. ### Competing Interest Statement The authors have declared no competing interest.

BACKGROUND:The exact architecture of the human auditory cortex remains a subject of debate, with discrepancies between functional and microstructural studies. In a hierarchical framework for sensory perception, simple sound perception is expected to take place in the primary auditory cortex, while the processing of complex, or more integrated perceptions is proposed to rely on associative and higher-order cortices.OBJECTIVES:We hypothesize that auditory symptoms induced by direct electrical stimulation (DES) offer a window into the architecture of the brain networks involved in auditory hallucinations and illusions. The intracranial recordings of these evoked perceptions of varying levels of integration provide the evidence to discuss the theoretical model.METHODS:We analyzed SEEG recordings from 50 epileptic patients presenting auditory symptoms induced by DES. First, using the Juelich cytoarchitectonic parcellation, we quantified which regions induced auditory symptoms when stimulated (ROI approach). Then, for each evoked auditory symptom type (illusion or hallucination), we mapped the cortical networks showing concurrent high-frequency activity modulation (HFA approach).RESULTS:Although on average, illusions were found more laterally and hallucinations more posteromedially in the temporal lobe, both perceptions were elicited in all levels of the sensory hierarchy, with mixed responses found in the overlap. The spatial range was larger for illusions, both in the ROI and HFA approaches. The limbic system was specific to the hallucinations network, and the inferior parietal lobule was specific to the illusions network.DISCUSSION:Our results confirm a network-based organization underlying conscious sound perception, for both simple and complex components. While symptom localization is interesting from an epilepsy semiology perspective, the hallucination-specific modulation of the limbic system is particularly relevant to tinnitus and schizophrenia.

Insular epilepsy has caught increasing attention in the presurgical evaluation of drug-resistant focal epilepsies, and it is evident that intracranial EEG recordings can be considered the best method to investigate such a deep-seated area of the brain, especially in non-lesional patients. Intracranial EEG recordings allow us to better understand the organization of epileptic EEG discharges involving the insular cortex and the complexity of the relationships between the insula and the different connected regions of the brain, particularly the opercular region. This peculiarity thus explains the heterogeneous clinical presentation of seizures arising from insular or insulo-opercular structures. While most patients have an epileptogenic zone extending beyond the insula, some have very focal ictal insular discharges, allowing the possibility of a restricted surgical resection. Consequently, only an appropriate sampling of the insula and of extra-insular connected structures can permit a precise identification of the epileptogenic zone and planning for a tailored resection.

Direct cortical stimulation (DCS) in epilepsy surgery patients has a long history of functional brain mapping and seizure triggering. Here, we review its findings when applied to the insula in order to map the insular functions, evaluate its local and distant connections, and trigger seizures. Clinical responses to insular DCS are frequent and diverse, showing a partial segregation with spatial overlap, including a posterior somatosensory, auditory, and vestibular part, a central olfactory-gustatory region, and an anterior visceral and cognitive-emotional portion. The study of cortico-cortical evoked potentials (CCEPs) has shown that the anterior (resp. posterior) insula has a higher connectivity rate with itself than with the posterior (resp. anterior) insula, and that both the anterior and posterior insula are closely connected, notably between the homologous insular subdivisions. All insular gyri show extensive and complex ipsilateral and contralateral extra-insular connections, more anteriorly for the anterior insula and more posteriorly for the posterior insula. As a rule, CCEPs propagate first and with a higher probability around the insular DCS site, then to the homologous region, and later to more distal regions with fast cortico-cortical axonal conduction delays. Seizures elicited by insular DCS have rarely been specifically studied, but their rate does not seem to differ from those of other DCS studies. They are mainly provoked from the insular seizure onset zone but can also be triggered by stimulating intra- and extra-insular early propagation zones. Overall, in line with the neuroimaging studies, insular DCS studies converge on the view that the insula is a multimodal functional hub with a fast propagation of information, whose organization helps understand where insular seizures start and how they propagate.

Introduction Women often develop postmenopausal osteoporosis after the menopause due to the decline in the levels of sex hormones. Recently, we have observed that a combination therapy of non-steroidal selective androgen and estrogen receptor modulators (ostarine and raloxifen) improved bone tissue in osteoporotic rats. The present study evaluates the effect of combination therapy (OS+RAL) on bone healing in an ovariectomized rat model of postmenopausal osteoporosis and compared its effect with the single therapies of OS or RAL

Introduction After menopause, the levels of sex hormones decline, and women often develop postmenopausal osteoporosis. Since steroid hormone therapy has negative side effects, use of non-steroidal selective androgen and estrogen receptor modulators (SARMs or SERMs) could be a possible treatment option. Raloxifene (RAL), a SERM is approved for treatment of postmenopausal osteoporosis. Ostarine (OS), a SARM has been shown to improve bone parameters in ovariectomized rats. The present study analyzes the effect of OS and RAL applied as a combination therapy or alone on bone properties in an ovariectomized rat model of postmenopausal osteoporosis.

Background The vagus nerve has anti-inflammatory properties. We aimed to investigate vagus nerve stimulation (VNS) as a new therapeutic strategy targeting an intrinsic anti-inflammatory pathway in a pilot study in Crohn's disease patients. The main objectives addressed the questions of long-term safety, tolerability, and anti-inflammatory effects of this therapy. This study is the continuation of previous reported findings at 6 months. Methods Nine patients with moderate active disease underwent VNS. An electrode wrapped around the left cervical vagus nerve was continuously stimulated over 1 year. Clinical, biological, endoscopic parameters, cytokines (plasma, gut), and mucosal metabolites were followed-up. Key Results After 1 year of VNS, five patients were in clinical remission and six in endoscopic remission. C-reactive protein (CRP) and fecal calprotectin decreased in six and five patients, respectively. Seven patients restored their vagal tone and decreased their digestive pain score. The patients' cytokinergic profile evolved toward a more "healthy profile": Interleukins 6, 23, 12, tumor necrosis factor alpha, and transforming growth factor beta 1 were the most impacted cytokines. Correlations were observed between CRP and tumor necrosis factor alpha, and some gut mucosa metabolites as taurine, lactate, alanine, and beta-hydroxybutyrate. VNS was well tolerated. Conclusion & Inferences Vagus nerve stimulation appears as an innovative and well-tolerated treatment in moderate Crohn's disease. After 12 months, VNS has restored a homeostatic vagal tone and reduced the inflammatory state of the patients. VNS has probably a global modulatory effect on the immune system along with gut metabolic regulations. This pilot study needs replication in a larger randomized double-blinded control study.

ZusammenfassungHintergrundBei Patienten, die im Rahmen eines Traumas an Knie- und Sprunggelenk eine Verletzung mit Abscheren eines osteochondralen „flake“ erleiden, ist heute die Refixation mittels resorbierbarer Implantate eine häufig verwendete Therapieoption. Hierzu gibt es bisher wenige Studien mit klinischen Langzeitergebnissen. Ziel dieser Studie war die Erfassung der klinischen und MR-morphologischen Langzeitergebnisse nach Refixation mittels resorbierbarer PLLA-Implantate.Material und MethodenIn dieser retrospektiven Studie wurden 12 Patienten mit 13 Läsionen erfasst, die im Schnitt 13,9 (±1,2) Jahre zuvor eine Refixation eines durchschnittlich 3,33 cm2(±2,33) großen osteochondralen Flake an Knie- (10 Patienten) und oberem Sprunggelenk (2 Patienten) mit resorbierbaren Implantaten (Nägel, Stifte, Schrauben) aus Polylactid (PLLA) (Fa. Bionx, Tampere, Finnland) erhalten hatten. Zur Objektivierung des klinischen Ergebnisses wurden 8 etablierte Scores (VASS, Tegner, Lysholm, McDermott, KSS, WOMAC, AOFAS, FADI+Sports) verwendet. Des Weiteren wurden die knöcherne Integration und Knorpelmorphologie mittels protonengewichteter und knorpelsensitiver „3D-double-echo-steady-state“(DESS)-Sequenzen im MRT (3 T) erfasst. Zur Objektivierung der Ergebnisse diente ein modifizierter MRT-Score nach Henderson et al.ErgebnisseNach 13,9 (±1,2) Jahren zeigten sich sowohl für die Knie- als auch die Sprunggelenkpatienten sehr gute Ergebnisse (Knie: VASS: 1,2 (±1,7); Tegner 4,4 (±1,3); Lysholm 85,7 (±12,2); McDermott 90,7 (±8,6); KSS 189 (±14,2); WOMAC (6,16 % (±8,45))), (OSG: VASS: 2,5 (±2,5); Tegner 5,5 (±1,5); Lysholm 87 (±13), McDermott 88 (±12); WOMAC (8,54 % (±8,54); AOFAS 75,5 (±24,5); FADI+Sports 118 (±18))). In der MRT zeigte sich in allen 12 Fällen eine gute Integration des refixierten Flake. In 5 Fällen kam es zu einer moderaten subchondralen Zystenbildung (∅ ≤1 mm). Allerdings zeigten alle Patienten milde Veränderungen der Knorpelkontur. Hieraus ergab sich ein durchschnittlicher modifizierter Henderson-Score-Wert von 14,4 (±2,0) (Bestwert: 8, schlechtester Wert: 32), was einem guten MR-morphologischen Ergebnis entspricht.SchlussfolgerungAufgrund der klinischen und auch MR-morphologischen Langzeitergebnisse ist die Refixation von osteochondralen Flakes mittels resorbierbarer Implantate (PLLA) als empfehlenswertes Verfahren zu werten.

Objective Insula epilepsy is rare and can be evaluated effectively by Stereotactic intracerebral EEG (SEEG). Many previous studies of insulo‐opercular seizures have been unable to separate insular and opercular onset. With adequate sampling of the insula, this study shows this is possible. Methods We analyzed intrainsular dynamics and extrainsular propagation in 12 patients with “pure” insula epilepsy (n = 9) or insular and only deepest opercular involvement (n = 3) at seizure onset. Review of semiology defined clinical groups, agglomerative cluster, and principal component analysis of semiological features were performed. Quantitative epileptogenicity, and intrainsular and extrainsular propagation were computed via time frequency analysis and epileptogenicity mapping. Results Seizure onset patterns were heterogeneous; the seizure onset zone was focal. Seizure onset and first ictal change within insula functional subdivision correlated with aura and reflex component. No paninsular spread occurred; contralateral insular spread was very early. While the discharge was intrainsular, clinical signs related to aura or vegetative signs. Extrainsular propagation was early and related to the emergence of the majority of clinical signs. Cluster analysis found an anterior, intermediate, and posterior insula seizure onset group. The largest principal component separated anterior insula manifestations, including early hypermotor signs, early recovery, and no aura from posterior insula features of early dystonia, early tonic motor features, and sensorimotor aura. Interpretation Aura is vital to identifying seizure onset and relates to insula functional subdivision. Seizures are heterogenous; extrainsular propagation occurs early, accounting for most of the semiology. With adequate sampling, "pure" insula epilepsy can be identified and focal curative resection is possible. ANN NEUROL 2020;88:477–488

Stereo-electro-encephalography (SEEG) is an invasive, surgical, and electrophysiological method for three-dimensional registration and mapping of seizure activity in drug-resistant epilepsy. It allows the accurate analysis of spatio-temporal seizure activity by multiple intraparenchymal depth electrodes. The technique requires rigorous non-invasive pre-SEEG evaluation (clinical, video-EEG, and neuroimaging investigations) in order to plan the insertion of the SEEG electrodes with minimal risk and maximal recording accuracy. The resulting recordings are used to precisely define the surgical limits of resection of the epileptogenic zone in relation to adjacent eloquent structures. Since the initial description of the technique by Talairach and Bancaud in the 1950's, several techniques of electrode insertion have been used with accuracy and relatively few complications. In the last decade, robot-assisted surgery has emerged as a safe, accurate, and time-saving electrode insertion technique due to its unparalleled potential for orthogonal and oblique insertion trajectories, guided by rigorous computer-assisted planning. SEEG exploration of the insular cortex remains difficult due to its anatomical location, hidden by the temporal and frontoparietal opercula. Furthermore, the close vicinity of Sylvian vessels makes surgical electrode insertion challenging. Some epilepsy surgery teams remain cautious about insular exploration due to the potential of neurovascular injury. However, several authors have published encouraging results regarding the technique's accuracy and safety in both children and adults. We will review the indications, techniques, and outcomes of insular SEEG exploration with emphasis on robot-assisted implantation.

Direct electrical stimulation (DES) at 50 Hz is used as a gold standard to map cognitive functions but little is known about its ability to map large-scale networks and specific subnetwork. In the present study, we aim to propose a new methodological approach to evaluate the specific hypothesis suggesting that language errors/dysfunction induced by DES are the result of large-scale network modification rather than of a single cortical region, which explains that similar language symptoms may be observed after stimulation of different cortical regions belonging to this network. We retrospectively examined 29 patients suffering from focal drug-resistant epilepsy who benefitted from stereo-electroencephalographic (SEEG) exploration and exhibited language symptoms during a naming task following 50 Hz DES. We assessed the large-scale language network correlated with behavioral DES-induced responses (naming errors) by quantifying DES-induced changes in high frequency activity (HFA, 70-150 Hz) outside the stimulated cortical region. We developed a probabilistic approach to report the spatial pattern of HFA modulations during DES-induced language errors. Similarly, we mapped the pattern of after-discharges (3-35 Hz) occurring after DES. HFA modulations concurrent to language symptoms revealed a brain network similar to our current knowledge of language gathered from standard brain mapping. In addition, specific subnetworks could be identified within the global language network, related to different language processes, generally described in relation to the classical language regions. Spatial patterns of after-discharges were similar to HFA induced during DES. Our results suggest that this new methodological DES-HFA mapping is a relevant approach to map functional networks during SEEG explorations, which would allow to shift from "local" to "network" perspectives.

Fragestellung Fragilitätsfrakturen nehmen auf Grund der demographischen Entwicklung weltweit stetig zu und stellen eine immense medizinische sowie sozioökonomische Herausforderung dar.

Background: Deep brain stimulation of the subthalamic nucleus is a therapeutic option for improving motor symptoms in advanced and medication-refractory Parkinsonâ€TMs disease. The exact target for stimulation, however, is still uncertain and not well defined in the biomedical literature. Objective: To localize the optimal targets for deep brain stimulation of the subthalamic nucleus in Parkinsonâ€TMs disease. Methods: Systematic review and meta-analysis of the stimulation targets identified or reported in the biomedical literature. The total number of subjects includes 1190 patients who underwent STN DBS for Parkinsonâ€TMs disease. Results: We report mean values for x, y, and z coordinates expressed in the Schaltenbrand-Wahren Atlas coordinate system as the best stimulation target location (x = 11.98, y = 2.63, z = 3.36). Conclusion: The target identified in our study was within the subthalamic nucleus. The lack of standardized reporting of clinical scores made it impossible to calculate statistical correlations between three-dimensional coordinates and clinical scores. More rigorous reporting is suggested for further analysis and to provide evidence-based recommendations for an optimal stimulation site. 104

OBJECTIVE The authors assessed the clinical relevance of preoperative task-induced high-frequency activity (HFA) for language mapping in patients with refractory epilepsy during stereoelectroencephalography recording. Although HFA evaluation was described as a putative biomarker of cognition, its clinical relevance for mapping language networks was assessed predominantly by studies using electrocorticography (ECOG). METHODS Forty-two patients with epilepsy who underwent intracranial electrode implantation during both task-induced HFA and direct cortical stimulation (DCS) language mapping were evaluated. The spatial and functional relevance of each method in terms of specificity and sensitivity were evaluated. RESULTS The results showed that the two methods were able to map classic language regions, and a large and bilateral language network was obtained with induced HFA. At a regional level, differences were observed between methods for parietal and temporal lobes: HFA recruited a larger number of cortical parietal sites, while DCS involved more cortical temporal sites. Importantly, the results showed that HFA predicts language interference induced by DCS with high specificity (92.4%; negative predictive value 95.9%) and very low sensitivity (8.9%; positive predictive value 4.8%). CONCLUSIONS DCS language mapping appears to be more appropriate for an extensive temporal mapping than induced HFA mapping. Furthermore, induced HFA should be used as a complement to DCS to preselect the number of stimulated sites during DCS, by omitting those reported as HFA-. This may be a considerable advantage because it allows a reduction in the duration of the stimulation procedure. Several parameters to be used for each method are discussed and the results are interpreted in relation to previous results reported in ECOG studies.

Background Refixation with resorbable implants is a common surgical treatment in patients who suffer an injury with shearing of an osteochondral flake due to trauma of the knee or the upper ankle joint. To date there are no studies which outline long-term outcomes for this procedure. The aim of this study was to evaluate long-term clinical and magnetic resonance imaging (MRI) results after refixation with resorbable polylactide (PLLA) implants. Material and methods In this retrospective study 12 patients with 13 injuries were examined 13.9 years (+/- 1.2 years) after refixation of an osteochondral fragment of the knee (10 patients) and the upper ankle joint (2 patients) with a mean size of 3.33 & x202f;cm(2) (+/- 2.33) by resorbable polylactide (PLLA) implants (nails, pins, screws, Bionx, Tampere, Finland). To objectify the clinical results eight established clinical scores (VASS, Tegner, Lysholm, McDermott, KSS, WOMAC, AOFAS, FADI+Sports) were used. Furthermore, the morphological integration of bone and cartilage was assessed by MRI (3 & x202f;T) using proton-weighted and cartilage-sensitive 3D double-echo steady-state (DESS) sequences. The morphological results were objectified with a modified MRI score according to Henderson et al. Results After 13.9 years (+/- 1.2) the patients with an injury of the knee as well as of the upper ankle joint showed good to excellent results (knee: VASS 1.2 (+/- 1.7), Tegner 4.4 (+/- 1.3), Lysholm 85.7 (+/- 12.2), McDermott 90.7 (+/- 8.6), KSS 189 (+/- 14.2), WOMAC (6.16% (+/- 8.45)) (upper ankle joint: VASS 2.5 (+/- 2.5), Tegner 5.5 (+/- 1.5), Lysholm 87 (+/- 13), McDermott 88 (+/- 12); WOMAC (8.54% (+/- 8.54), AOFAS 75.5 (+/- 24.5), FADI+Sports 118 (+/- 18)). In all cases there was evidence of good integration of the osteochondral fragment in MRI. In five patients there was moderate subchondral cyst formation ( null <= 1 & x202f;mm); however, mild changes of the cartilage contour were found in all patients. The mean modified Henderson score achieved was 14.4 (+/- 2.0, best 8, worst 32), which corresponds to a good morphological result. Conclusion Because of good clinical and morphological results shown by MRI, refixation through resorbable implants (PLLA) can be recommended for treatment of traumatic osteochondral flakes.

Osteoporose ist eine der größten Belastungen der Welt im 21. Jahrhundert, die aufgrund des sozioökonomischen Wandels immer deutlicher wird. Die pharmazeutische Intervention konzentriert sich derzeit auf die Verlangsamung des Knochenverlusts, aber Phytochemikalien wie Baicalein, ein Lipoxygenaseinhibitor mit antioxidativer Wirkung, können den Knochenverlust retten. Es wurde gezeigt, dass Baicalein in den Osteoblasten-Osteoklasten-Metabolismus in vitro eingreift. Ziel der Studie war es, die Wirkung von Baicalein in vivo zu bewerten und die Effekte auf Knochenheilung zu analysieren.

Rebalancing the RANKL/OPG-system is an effective treatment-strategy for osteoporosis. Here we used virus-like particles (VLPs) as a small RNA based gene delivery vehicle to inhibit RANKL expression. In our former studies we showed a significant short-term knockdown of RANKL by VLP mediated RNA-interference via weekly i.p. injection. Chitosan is a promising possibility for prolonged (up to 21 days) drug delivery in vivo. In the present study we investigated the effects of RANKL-knockdown by chitosan embedded siRNA-VLPs.