A visual representation of the hand in the resting somatomotor regions of the human brain.

Hand visibility affects motor control, perception, and attention, as visual information is integrated into an internal model of somatomotor control. Spontaneous brain activity, i.e., at rest, in the absence of an active task, is correlated among somatomotor regions that are jointly activated during motor tasks. Recent studies suggest that spontaneous activity patterns not only replay task activation patterns but also maintain a model of the body's and environment's statistical regularities (priors), which may be used to predict upcoming behavior. Here, we test whether spontaneous activity in the human somatomotor cortex as measured using fMRI is modulated by visual stimuli that display hands vs. non-hand stimuli and by the use/action they represent. A multivariate pattern analysis was performed to examine the similarity between spontaneous activity patterns and task-evoked patterns to the presentation of natural hands, robot hands, gloves, or control stimuli (food). In the left somatomotor cortex, we observed a stronger (multivoxel) spatial correlation between resting state activity and natural hand picture patterns compared to other stimuli. No task-rest similarity was found in the visual cortex. Spontaneous activity patterns in somatomotor brain regions code for the visual representation of human hands and their use.

Sleep-like cortical dynamics during wakefulness and their network effects following brain injury.

By connecting old and recent notions, different spatial scales, and research domains, we introduce a novel framework on the consequences of brain injury focusing on a key role of slow waves. We argue that the long-standing finding of EEG slow waves after brain injury reflects the intrusion of sleep-like cortical dynamics during wakefulness; we illustrate how these dynamics are generated and how they can lead to functional network disruption and behavioral impairment. Finally, we outline a scenario whereby post-injury slow waves can be modulated to reawaken parts of the brain that have fallen asleep to optimize rehabilitation strategies and promote recovery.

Generative whole-brain dynamics models from healthy subjects predict functional alterations in stroke at the level of individual patients.

Computational whole-brain models describe the resting activity of each brain region based on a local model, inter-regional functional interactions, and a structural connectome that specifies the strength of inter-regional connections. Strokes damage the healthy structural connectome that forms the backbone of these models and produce large alterations in inter-regional functional interactions. These interactions are typically measured by correlating the time series of the activity between two brain regions in a process, called resting functional connectivity. We show that adding information about the structural disconnections produced by a patient's lesion to a whole-brain model previously trained on structural and functional data from a large cohort of healthy subjects enables the prediction of the resting functional connectivity of the patient and fits the model directly to the patient's data (Pearson correlation = 0.37; mean square error = 0.005). Furthermore, the model dynamics reproduce functional connectivity-based measures that are typically abnormal in stroke patients and measures that specifically isolate these abnormalities. Therefore, although whole-brain models typically involve a large number of free parameters, the results show that, even after fixing those parameters, the model reproduces results from a population very different than that on which the model was trained. In addition to validating the model, these results show that the model mechanistically captures the relationships between the anatomical structure and the functional activity of the human brain.

Whole-brain model replicates sleep-like slow-wave dynamics generated by stroke lesions.

Focal brain injuries, such as stroke, cause local structural damage as well as alteration of neuronal activity in distant brain regions. Experimental evidence suggests that one of these changes is the appearance of sleep-like slow waves in the otherwise awake individual. This pattern is prominent in areas surrounding the damaged region and can extend to connected brain regions in a way consistent with the individual's specific long-range connectivity patterns. In this paper we present a generative whole-brain model based on (f)MRI data that, in combination with the disconnection mask associated with a given patient, explains the effects of the sleep-like slow waves originated in the vicinity of the lesion area on the distant brain activity. Our model reveals new aspects of their interaction, being able to reproduce functional connectivity patterns of stroke patients and offering a detailed, causal understanding of how stroke-related effects, in particular slow waves, spread throughout the brain. The presented findings demonstrate that the model effectively captures the links between stroke occurrences, sleep-like slow waves, and their subsequent spread across the human brain.

Glioblastoma and brain connectivity: the need for a paradigm shift.

Despite substantial advances in cancer treatment, for patients with glioblastoma prognosis remains bleak. The emerging field of cancer neuroscience reveals intricate functional interplays between glioblastoma and the cellular architecture of the brain, encompassing neurons, glia, and vessels. New findings underscore the role of structural and functional connections within hierarchical networks, known as the connectome. These connections contribute to the location, spread, and recurrence of a glioblastoma, and a patient's overall survival, revealing a complex interplay between the tumour and the CNS. This mounting evidence prompts a paradigm shift, challenging the perception of glioblastomas as mere foreign bodies within the brain. Instead, these tumours are intricately woven into the structural and functional fabric of the brain. This radical change in thinking holds profound implications for the understanding and treatment of glioblastomas, which could unveil new prognostic factors and surgical strategies and optimise radiotherapy. Additionally, a connectivity approach suggests that non-invasive brain stimulation could disrupt pathological neuron-glioma interactions within specific networks.

Characterization of antiseizure medications effects on the EEG neurodynamic by fractal dimension.

Objectives: An important challenge in epilepsy is to define biomarkers of response to treatment. Many electroencephalography (EEG) methods and indices have been developed mainly using linear methods, e.g., spectral power and individual alpha frequency peak (IAF). However, brain activity is complex and non-linear, hence there is a need to explore EEG neurodynamics using nonlinear approaches. Here, we use the Fractal Dimension (FD), a measure of whole brain signal complexity, to measure the response to anti-seizure therapy in patients with Focal Epilepsy (FE) and compare it with linear methods. Materials: Twenty-five drug-responder (DR) patients with focal epilepsy were studied before (t1, named DR-t1) and after (t2, named DR-t2) the introduction of the anti-seizure medications (ASMs). DR-t1 and DR-t2 EEG results were compared against 40 age-matched healthy controls (HC). Methods: EEG data were investigated from two different angles: frequency domain-spectral properties in δ, θ, α, ß, and γ bands and the IAF peak, and time-domain-FD as a signature of the nonlinear complexity of the EEG signals. Those features were compared among the three groups. Results: The δ power differed between DR patients pre and post-ASM and HC (DR-t1 vs. HC, p < 0.01 and DR-t2 vs. HC, p < 0.01). The θ power differed between DR-t1 and DR-t2 (p = 0.015) and between DR-t1 and HC (p = 0.01). The α power, similar to the δ, differed between DR patients pre and post-ASM and HC (DR-t1 vs. HC, p < 0.01 and DR-t2 vs. HC, p < 0.01). The IAF value was lower for DR-t1 than DR-t2 (p = 0.048) and HC (p = 0.042). The FD value was lower in DR-t1 than in DR-t2 (p = 0.015) and HC (p = 0.011). Finally, Bayes Factor analysis showed that FD was 195 times more likely to separate DR-t1 from DR-t2 than IAF and 231 times than θ. Discussion: FD measured in baseline EEG signals is a non-linear brain measure of complexity more sensitive than EEG power or IAF in detecting a response to ASMs. This likely reflects the non-oscillatory nature of neural activity, which FD better describes. Conclusion: Our work suggests that FD is a promising measure to monitor the response to ASMs in FE.

Indirect functional connectivity does not predict overall survival in glioblastoma.

BACKGROUND: Lesion network mapping (LNM) is a popular framework to assess clinical syndromes following brain injury. The classical approach involves embedding lesions from patients into a normative functional connectome and using the corresponding functional maps as proxies for disconnections. However, previous studies indicated limited predictive power of this approach in behavioral deficits. We hypothesized similarly low predictiveness for overall survival (OS) in glioblastoma (GBM). METHODS: A retrospective dataset of patients with GBM was included (n = 99). Lesion masks were registered in the normative space to compute disconnectivity maps. The brain functional normative connectome consisted in data from 173 healthy subjects obtained from the Human Connectome Project. A modified version of the LNM was then applied to core regions of GBM masks. Linear regression, classification, and principal component (PCA) analyses were conducted to explore the relationship between disconnectivity and OS. OS was considered both as continuous and categorical (low, intermediate, and high survival) variable. RESULTS: The results revealed no significant associations between OS and network disconnection strength when analyzed at both voxel-wise and classification levels. Moreover, patients stratified into different OS groups did not exhibit significant differences in network connectivity patterns. The spatial similarity among the first PCA of network maps for each OS group suggested a lack of distinctive network patterns associated with survival duration. CONCLUSIONS: Compared with indirect structural measures, functional indirect mapping does not provide significant predictive power for OS in patients with GBM. These findings are consistent with previous research that demonstrated the limitations of indirect functional measures in predicting clinical outcomes, underscoring the need for more comprehensive methodologies and a deeper understanding of the factors influencing clinical outcomes in this challenging disease.

The brain's "dark energy" puzzle: How strongly is glucose metabolism linked to resting-state brain activity?

Brain glucose metabolism, which can be investigated at the macroscale level with [18F]FDG PET, displays significant regional variability for reasons that remain unclear. Some of the functional drivers behind this heterogeneity may be captured by resting-state functional magnetic resonance imaging (rs-fMRI). However, the full extent to which an fMRI-based description of the brain's spontaneous activity can describe local metabolism is unknown. Here, using two multimodal datasets of healthy participants, we built a multivariable multilevel model of functional-metabolic associations, assessing multiple functional features, describing the 1) rs-fMRI signal, 2) hemodynamic response, 3) static and 4) time-varying functional connectivity, as predictors of the human brain's metabolic architecture. The full model was trained on one dataset and tested on the other to assess its reproducibility. We found that functional-metabolic spatial coupling is nonlinear and heterogeneous across the brain, and that local measures of rs-fMRI activity and synchrony are more tightly coupled to local metabolism. In the testing dataset, the degree of functional-metabolic spatial coupling was also related to peripheral metabolism. Overall, although a significant proportion of regional metabolic variability can be described by measures of spontaneous activity, additional efforts are needed to explain the remaining variance in the brain's 'dark energy'.

Encoding Manual Dexterity through Modulation of Intrinsic α Band Connectivity.

The human hand possesses both consolidated motor skills and remarkable flexibility in adapting to ongoing task demands. However, the underlying mechanisms by which the brain balances stability and flexibility remain unknown. In the absence of external input or behavior, spontaneous (intrinsic) brain connectivity is thought to represent a prior of stored memories. In this study, we investigated how manual dexterity modulates spontaneous functional connectivity in the motor cortex during hand movement. Using magnetoencephalography, in 47 human participants (both sexes), we examined connectivity modulations in the α and ß frequency bands at rest and during two motor tasks (i.e., finger tapping or toe squeezing). The flexibility and stability of such modulations allowed us to identify two groups of participants with different levels of performance (high and low performers) on the nine-hole peg test, a test of manual dexterity. In the α band, participants with higher manual dexterity showed distributed decreases of connectivity, specifically in the motor cortex, increased segregation, and reduced nodal centrality. Participants with lower manual dexterity showed an opposite pattern. Notably, these patterns from the brain to behavior are mirrored by results from behavior to the brain. Indeed, when participants were divided using the median split of the dexterity score, we found the same connectivity patterns. In summary, this experiment shows that a long-term motor skill-manual dexterity-influences the way the motor systems respond during movements.

Controlling target brain regions by optimal selection of input nodes.

The network control theory framework holds great potential to inform neurostimulation experiments aimed at inducing desired activity states in the brain. However, the current applicability of the framework is limited by inappropriate modeling of brain dynamics, and an overly ambitious focus on whole-brain activity control. In this work, we leverage recent progress in linear modeling of brain dynamics (effective connectivity) and we exploit the concept of target controllability to focus on the control of a single region or a small subnetwork of nodes. We discuss when control may be possible with a reasonably low energy cost and few stimulation loci, and give general predictions on where to stimulate depending on the subset of regions one wishes to control. Importantly, using the robustly asymmetric effective connectome instead of the symmetric structural connectome (as in previous research), we highlight the fundamentally different roles in- and out-hubs have in the control problem, and the relevance of inhibitory connections. The large degree of inter-individual variation in the effective connectome implies that the control problem is best formulated at the individual level, but we discuss to what extent group results may still prove useful.

A recurrent Hopfield network for estimating meso-scale effective connectivity in MEG.

The architecture of communication within the brain, represented by the human connectome, has gained a paramount role in the neuroscience community. Several features of this communication, e.g., the frequency content, spatial topology, and temporal dynamics are currently well established. However, identifying generative models providing the underlying patterns of inhibition/excitation is very challenging. To address this issue, we present a novel generative model to estimate large-scale effective connectivity from MEG. The dynamic evolution of this model is determined by a recurrent Hopfield neural network with asymmetric connections, and thus denoted Recurrent Hopfield Mass Model (RHoMM). Since RHoMM must be applied to binary neurons, it is suitable for analyzing Band Limited Power (BLP) dynamics following a binarization process. We trained RHoMM to predict the MEG dynamics through a gradient descent minimization and we validated it in two steps. First, we showed a significant agreement between the similarity of the effective connectivity patterns and that of the interregional BLP correlation, demonstrating RHoMM's ability to capture individual variability of BLP dynamics. Second, we showed that the simulated BLP correlation connectomes, obtained from RHoMM evolutions of BLP, preserved some important topological features, e.g, the centrality of the real data, assuring the reliability of RHoMM. Compared to other biophysical models, RHoMM is based on recurrent Hopfield neural networks, thus, it has the advantage of being data-driven, less demanding in terms of hyperparameters and scalable to encompass large-scale system interactions. These features are promising for investigating the dynamics of inhibition/excitation at different spatial scales.

Long-term outcome of alcohol withdrawal seizures.

BACKGROUND AND PURPOSE: Alcohol withdrawal seizures (AWS) are a well-known complication of chronic alcohol abuse, but there is currently little knowledge of their long-term relapse rate and prognosis. The aims of this study were to identify risk factors for AWS recurrence and to study the overall outcome of patients after AWS. METHODS: In this retrospective single-center study, we included patients who were admitted to the Emergency Department after an AWS between January 1, 2013 and August 10, 2021 and for whom an electroencephalogram (EEG) was requested. AWS relapses up until April 29, 2022 were researched. We compared history, treatment with benzodiazepines or antiseizure medications (ASMs), laboratory, EEG and computed tomography findings between patients with AWS relapse (r-AWS) and patients with no AWS relapse (nr-AWS). RESULTS: A total of 199 patients were enrolled (mean age 53 ± 12 years; 78.9% men). AWS relapses occurred in 11% of patients, after a median time of 470.5 days. Brain computed tomography (n = 182) showed pathological findings in 35.7%. Risk factors for relapses were history of previous AWS (p = 0.013), skull fractures (p = 0.004) at the index AWS, and possibly epileptiform EEG abnormalities (p = 0.07). Benzodiazepines or other ASMs, taken before or after the index event, did not differ between the r-AWS and the nr-AWS group. The mortality rate was 2.9%/year of follow-up, which was 13 times higher compared to the general population. Risk factors for death were history of AWS (p < 0.001) and encephalopathic EEG (p = 0.043). CONCLUSIONS: Delayed AWS relapses occur in 11% of patients and are associated with risk factors (previous AWS >24 h apart, skull fractures, and pathological EEG findings) that also increase the epilepsy risk, that is, predisposition for seizures, if not treated. Future prospective studies are mandatory to determine appropriate long-term diagnostic and therapeutic strategies, in order to reduce the risk of relapse and mortality associated with AWS.

A common low dimensional structure of cognitive impairment in stroke and brain tumors.

INTRODUCTION: Neuropsychological studies infer brain-behavior relationships from focal lesions like stroke and tumors. However, these pathologies impair brain function through different mechanisms even when they occur at the same brain's location. The aim of this study was to compare the profile of cognitive impairment in patients with brain tumors vs. stroke and examine the correlation with lesion location in each pathology. METHODS: Patients with first time stroke (n = 77) or newly diagnosed brain tumors (n = 76) were assessed with a neuropsychological battery. Their lesions were mapped with MRI scans. Test scores were analyzed using principal component analysis (PCA) to measure their correlation, and logistic regression to examine differences between pathologies. Next, with ridge regression we examined whether lesion features (location, volume) were associated with behavioral performance. RESULTS: The PCA showed a similar cognitive impairment profile in tumors and strokes with three principal components (PCs) accounting for about half of the individual variance. PC1 loaded on language, verbal memory, and executive/working memory; PC2 loaded on general performance, visuo-spatial attention and memory, and executive functions; and, PC3 loaded on calculation, reading and visuo-spatial attention. The average lesion distribution was different, and lesion location was correlated with cognitive deficits only in stroke. Logistic regression found language and calculation more affected in stroke, and verbal memory and verbal fluency more affected in tumors. CONCLUSIONS: A similar low dimensional set of behavioral impairments was found both in stroke and brain tumors, even though each pathology caused some specific deficits in different domains. The lesion distribution was different for stroke and tumors and correlated with behavioral impairment only in stroke.

White Matter Tract Density Index Prediction Model of Overall Survival in Glioblastoma.

Importance: The prognosis of overall survival (OS) in patients with glioblastoma (GBM) may depend on the underlying structural connectivity of the brain. Objective: To examine the association between white matter tracts affected by GBM and patients' OS by means of a new tract density index (TDI). Design, Setting, and Participants: This prognostic study in patients with a histopathologic diagnosis of GBM examined a discovery cohort of 112 patients who underwent surgery between February 1, 2015, and November 30, 2020 (follow-up to May 31, 2023), in Italy and 70 patients in a replicative cohort (n = 70) who underwent surgery between September 1, 2012, and November 30, 2015 (follow-up to May 31, 2023), in Germany. Statistical analyses were performed from June 1, 2021, to May 31, 2023. Thirteen and 12 patients were excluded from the discovery and the replicative sets, respectively, because of magnetic resonance imaging artifacts. Exposure: The density of white matter tracts encompassing GBM. Main Outcomes and Measures: Correlation, linear regression, Cox proportional hazards regression, Kaplan-Meier, and prediction analysis were used to assess the association between the TDI and OS. Results were compared with common prognostic factors of GBM, including age, performance status, O6-methylguanine-DNA methyltransferase methylation, and extent of surgery. Results: In the discovery cohort (n = 99; mean [SD] age, 62.2 [11.5] years; 29 female [29.3%]; 70 male [70.7%]), the TDI was significantly correlated with OS (r = -0.34; P < .001). This association was more stable compared with other prognostic factors. The TDI showed a significant regression pattern (Cox: hazard ratio, 0.28 [95% CI, 0.02-0.55; P = .04]; linear: t = -2.366; P = .02). and a significant Kaplan-Meier stratification of patients as having lower or higher OS based on the TDI (log-rank test = 4.52; P = .03). Results were confirmed in the replicative cohort (n = 58; mean [SD] age, 58.5 [11.1] years, 14 female [24.1%]; 44 male [75.9%]). High (24-month cutoff) and low (18-month cutoff) OS was predicted based on the TDI computed in the discovery cohort (accuracy = 87%). Conclusions and Relevance: In this study, GBMs encompassing regions with low white matter tract density were associated with longer OS. These findings indicate that the TDI is a reliable presurgical outcome predictor that may be considered in clinical trials and clinical practice. These findings support a framework in which the outcome of GBM depends on the patient's brain organization.

Convergence of Visual and Motor Awareness in Human Parietal Cortex.

OBJECTIVE: Brain lesions sometimes induce a failure of recognition of one's own deficits (anosognosia). Lack of deficit awareness may underlie damage of modality-specific systems, for example, visual cortex for visual anosognosia or motor/premotor cortex for motor anosognosia. However, focal lesions induce widespread remote structural and functional disconnection, and anosognosia, independent of modality, may also involve common neural mechanisms. METHODS: Here, we study the neural correlates of Anton syndrome (AS), anosognosia of blindness, and compare them with anosognosia for hemiplegia to test whether they share different or common mechanisms. We measured both local damage and patterns of structural-functional disconnection as predicted from healthy normative atlases. RESULTS: AS depends on bilateral striate and extrastriate occipital damage, and disconnection of ventral and dorsal frontoparietal regions involved in attention control. Visual and motor anosognosia each share damage of modality-specific regions, but also involve the disruption of white matter tracts, leading to functional disconnection within dorsal frontal-parietal regions that play critical roles in motor control, visuospatial attention, and multisensory integration. INTERPRETATION: These results reveal the unique shared combination of content-specific and supramodal mechanisms in anosognosia. ANN NEUROL 2023.

A low dimensional embedding of brain dynamics enhances diagnostic accuracy and behavioral prediction in stroke.

Large-scale brain networks reveal structural connections as well as functional synchronization between distinct regions of the brain. The latter, referred to as functional connectivity (FC), can be derived from neuroimaging techniques such as functional magnetic resonance imaging (fMRI). FC studies have shown that brain networks are severely disrupted by stroke. However, since FC data are usually large and high-dimensional, extracting clinically useful information from this vast amount of data is still a great challenge, and our understanding of the functional consequences of stroke remains limited. Here, we propose a dimensionality reduction approach to simplify the analysis of this complex neural data. By using autoencoders, we find a low-dimensional representation encoding the fMRI data which preserves the typical FC anomalies known to be present in stroke patients. By employing the latent representations emerging from the autoencoders, we enhanced patients' diagnostics and severity classification. Furthermore, we showed how low-dimensional representation increased the accuracy of recovery prediction.

Pupillary dynamics predict long-term outcome in a cohort of acute traumatic brain injury coma patients.

OBJECTIVE: Examining the size and reactivity of the pupils of traumatic brain injury coma patients is fundamental in the Neuro-intensive care unit (ICU). Pupil parameters on admission predict long-term clinical outcomes. However, little is known about the dynamics of pupillary parameters and their potential value for outcome prediction. METHODS: This study applied a time-course analysis of pupillary signals (size and photo-reactivity) in acute traumatic brain injury coma patients (n = 20) to predict outcome at 6 months. RESULTS: The time course of pupillary signals was informative in discriminating favorable (F) versus unfavorable (U) outcomes, with the highest correlation within the 1st week notwithstanding pharmacological sedation. Patients with favorable outcome at 6 months showed more consistent in time isochoric and photo-reactive pupils. In contrast, patients with an unfavorable outcome showed more variable measures that tended to stabilize toward pathological values. INTERPRETATION: Time-dependent tracking of pupils' size and reactivity is a promising application for ICU monitoring and long-term prognosis. These findings support the usefulness of automatic tools for the dynamic, quantitative, and objective measurements of pupils.