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BackgroundGlioma is associated with pathologically high peritumoral brain activity, which relates to faster progression. Functional connectivity is disturbed locally and throughout the entire brain, associating with symptomatology. We, therefore, investigated how local activity and network measures relate to better understand how the intricate relationship between the tumor and the rest of the brain may impact disease and symptom progression.MethodsWe obtained magnetoencephalography in 84de novoglioma patients and 61 matched healthy controls. The offset of the power spectrum, a proxy of neuronal activity, was calculated for 210 cortical regions. We calculated patients’ regional deviations in delta, theta and lower alpha network connectivity as compared to controls, using two network measures: clustering coefficient, a measure of local connectivity, and eigenvector centrality (integrative connectivity). We then tested group differences in activity and connectivity between peritumoral, contralateral homologue regions, and the rest of the brain. We also correlated regional offset to connectivity.ResultsAs expected, patients’ peritumoral activity was pathologically high, and patients showed higher clustering and lower centrality than controls. At the group-level, regionally high activity related to high clustering in controls and patients alike. However, within-patient analyses revealed negative associations between regional deviations in brain activity and clustering, such that pathologically high activity coincided with low network clustering, while regions with ‘normal’ activity levels showed high network clustering.ConclusionsOur results indicate that pathological activity and connectivity co-localize in a complex manner in glioma. This insight is relevant to our understanding of disease progression and cognitive symptomatology.KeypointsRegional activity and network clustering are pathologically high in gliomaHowever, high-activity regions show low clustering and vice versaThis finding could be relevant to understand functioning and prognosis in gliomaImportance of the studyGlioma patients show high peritumoral brain activity, which relates to faster tumor progression. Moreover, patients have local and global functional network disturbances, which associate with cognitive dysfunction and other symptoms. However, how such activity and network deviations correlate across and within patients is unclear. We, therefore, studied a large cohort of newly diagnosed glioma patients and matched healthy controls, extracting activity and connectivity from the entire cortex. We find a surprising relationship between deviations in activity and local clustering: while higher activity and clustering go hand in hand in controls, the pathologically high activity we observe in individual glioma patients coincides with exceedingly low clustering, while areas with normal activity levels have pathologically high clustering. These insights indicate an intricate relationship between aberrant activity and connectivity throughout the brain in glioma. It remains to be seen how this complex relationship impacts tumor growth and potentially cognitive deficits.

Epilepsy surgery is the treatment of choice for drug-resistant epilepsy patients, but up to 50% of patients continue to have seizures one year after the resection. In order to aid presurgical planning and predict postsurgical outcome in a patient-by-patient basis, we developed a framework of individualized computational models that combine epidemic spreading with patient-specific connectivity and epileptogeneity maps: the Epidemic Spreading Seizure and Epilepsy Surgery framework (ESSES). The ESSES parameters were fitted in a retrospective study (N= 15) to reproduce invasive electroencephalography (iEEG)-recorded seizures. ESSES could not only reproduce the iEEG-recorded seizures, but significantly better so for patients with good (seizure-free, SF) than bad (non-seizure-free, NSF) outcome (area under the curveAUC= 0.73). Once the model parameters were set in the retrospective study, ESSES can be applied also to patients without iEEG data. We illustrate here the clinical applicability of ESSES with apseudo-prospective study(N= 34) with a blind setting (to the resection strategy and surgical outcome) that emulated the presurgical conditions. ESSES could predict the chances of good outcome afteranyresection by finding patient-specific optimal resection strategies, which we found to be smaller for SF than NSF patients, suggesting an intrinsic difference in the network organization or presurgical evaluation results of NSF patients. The actual surgical plan also overlapped more with the optimal resection, and had a larger effect in decreasing modeled seizure propagation, for SF patients than for NSF patients. Overall, ESSES could correctly predict 75% of NSF and 80.8% of SF cases pseudo-prospectively. Our results show that individualised computational models may inform surgical planning by suggesting optimal resections and providing information on the likelihood of a good outcome after a proposed resection. This is the first time that such a model is validated on a fully independent cohort without the need for iEEG recordings.

Magneto- and Electroencephalography (MEG/EEG) are important techniques for the diagnosis and pre-surgical evaluation of epilepsy. Yet, in current cryogen-based MEG systems the sensors are offset from the scalp, which limits the signal-to-noise ratio (SNR) and thereby the sensitivity to activity from deep structures such as the hippocampus. This effect is amplified in children, for whom adult-sized fixed-helmet systems are typically too big. Moreover, ictal recordings with fixed-helmet systems are problematic because of limited movement tolerance. Optically Pumped Magnetometers (OPMs) can be placed directly on the scalp, thereby improving SNR and consequently the sensitivity to, and localisation accuracy of, epileptiform activity. In addition, recording during seizures becomes feasible with these wearable sensors.We aimed to demonstrate these advantages of OPMs in a clinical population. Three adults with known weak sources of interictal epileptiform discharges (IEDs), along with three children with focal epilepsy and one adult with frequent seizures underwent MEG recordings using a 12-channel OPM-system and a 306-channel cryogen-based whole-head system. Performance of the two systems was compared in terms of IED-rate and SNR.In one patient the OPMs detected IEDs that were not found with the SQUID-system. In one patient the spike yield was higher for the OPM data (9.00 versus 6.76), with negligible difference in SNR compared to the SQUID data (3.85 versus 3.93; U = -2.86, d = -0.14). This was also the case for a patient with a spike yield that was comparable to that for the SQUID data (after accounting for unilateral coverage with the OPMs; SNR 4.47 versus 4.57; U = -3.81, d = -0.14). For one patient the spike yield (11.03 versus 24.50) and SNR (4.39 versus 4.05; U = 9.53, d = -0.36) were both lower for the OPMs. In two patients no IEDs were found with either system. Importantly, the wearability of OPMs enabled the recording of seizure activity in a patient with hyperkinetic movements during the seizure. The observed ictal onset and semiology were in agreement with previous video- and stereo-EEG recordings.Overall, OPM data were very much comparable to those obtained with a cryogenic system: OPMs outperformed SQUIDs for two of the four patients with IEDs, with either a higher spike yield, or an ability to detect IEDs that were not observable in the SQUID data. For three patients the SNRs of IEDs were (slightly) lower in the OPM data than in the SQUID data, but with negligible effect sizes for two of these patients. The relatively cheap technology, in combination with reduced running and maintenance costs, means that OPM-based MEG could be used more widely than current MEG systems, and may become an affordable alternative to scalp EEG, with the potential benefits of increased spatial accuracy, reduced sensitivity to volume conduction/field spread, and increased sensitivity to deep sources. Wearable MEG thus provides an unprecedented opportunity for epilepsy, and given its patient-friendliness, we envisage that it will not only be used for presurgical evaluation of epilepsy patients, but also for diagnosis after a first seizure.

It is unclear why exactly gliomas show preferential occurrence in certain brain areas. Increased spiking activity around gliomas leads to faster tumour growth in animal models, while higher non-invasively measured brain activity is related to shorter survival in patients. However, it is unknown how regional intrinsic brain activity, as measured in healthy controls, relates to glioma occurrence. We first investigated whether gliomas occur more frequently in regions with intrinsically higher brain activity. Second, we explored whether intrinsic cortical activity at individual patients’ tumour locations relates to tumour and patient characteristics. Across three cross-sectional cohorts, 413 patients were included. Individual tumour masks were created. Intrinsic regional brain activity was assessed through resting-state magnetoencephalography acquired in healthy controls and source-localized to 210 cortical brain regions. Brain activity was operationalized as: (i) broadband power; and (ii) offset of the aperiodic component of the power spectrum, which both reflect neuronal spiking of the underlying neuronal population. We additionally assessed (iii) the slope of the aperiodic component of the power spectrum, which is thought to reflect the neuronal excitation/inhibition ratio. First, correlation coefficients were calculated between group-level regional glioma occurrence, as obtained by concatenating tumour masks across patients, and group-averaged regional intrinsic brain activity. Second, intrinsic brain activity at specific tumour locations was calculated by overlaying patients’ individual tumour masks with regional intrinsic brain activity of the controls and was associated with tumour and patient characteristics. As proposed, glioma preferentially occurred in brain regions characterized by higher intrinsic brain activity in controls as reflected by higher offset. Second, intrinsic brain activity at patients’ individual tumour locations differed according to glioma subtype and performance status: the most malignant isocitrate dehydrogenase-wild-type glioblastoma patients had the lowest excitation/inhibition ratio at their individual tumour locations as compared to isocitrate dehydrogenase-mutant, 1p/19q-codeleted glioma patients, while a lower excitation/inhibition ratio related to poorer Karnofsky Performance Status, particularly in codeleted glioma patients. In conclusion, gliomas more frequently occur in cortical brain regions with intrinsically higher activity levels, suggesting that more active regions are more vulnerable to glioma development. Moreover, indices of healthy, intrinsic excitation/inhibition ratio at patients’ individual tumour locations may capture both tumour biology and patients’ performance status. These findings contribute to our understanding of the complex and bidirectional relationship between normal brain functioning and glioma growth, which is at the core of the relatively new field of ‘cancer neuroscience’.

Understanding recovery of consciousness and elucidating its underlying mechanism is believed to be crucial in the field of basic neuroscience and medicine. Ideas such as the global neuronal workspace and the mesocircuit theory hypothesize that failure of recovery in conscious states coincide with loss of connectivity between subcortical and frontoparietal areas, a loss of the repertoire of functional networks states and metastable brain activation. We adopted a time-resolved functional connectivity framework to explore these ideas and assessed the repertoire of functional network states as a potential marker of consciousness and its potential ability to tell apart patients in the unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS). In addition, prediction of these functional network states by underlying hidden spatial patterns in the anatomical network, i.e. so-called eigenmodes, were supplemented as potential markers. By analysing time-resolved functional connectivity from fMRI data, we demonstrated a reduction of metastability and functional network repertoire in UWS compared to MCS patients. This was expressed in terms of diminished dwell times and loss of nonstationarity in the default mode network and fronto-parietal subcortical network in UWS compared to MCS patients. We further demonstrated that these findings co-occurred with a loss of dynamic interplay between structural eigenmodes and emerging time-resolved functional connectivity in UWS. These results are, amongst others, in support of the global neuronal workspace theory and the mesocircuit hypothesis, underpinning the role of time-resolved thalamo-cortical connections and metastability in the recovery of consciousness.

Executive functioning is a higher-order cognitive process that is thought to depend on a brain network organization facilitating network integration across specialized subnetworks. The frontoparietal network (FPN), a subnetwork that has diverse connections to other brain modules, seems pivotal to this integration, and a more central role of regions in the FPN has been related to better executive functioning. Brain networks can be constructed using different modalities: diffusion MRI (dMRI) can be used to reconstruct structural networks, while resting-state fMRI (rsfMRI) and magnetoencephalography (MEG) yield functional networks. These networks are often studied in a unimodal way, which cannot capture potential complementary or synergistic modal information. The multilayer framework is a relatively new approach that allows for the integration of different modalities into one ‘network of networks’. It has already yielded promising results in the field of neuroscience, having been related to e.g. cognitive dysfunction in Alzheimer’s disease. Multilayer analyses thus have the potential to help us better understand the relation between brain network organization and executive functioning. Here, we hypothesized a positive association between centrality of the FPN and executive functioning, and we expected that multimodal multilayer centrality would supersede unilayer centrality in explaining executive functioning. We used dMRI, rsfMRI, MEG, and neuropsychological data obtained from 33 healthy adults (age range 22-70 years) to construct eight modality-specific unilayer networks (dMRI, fMRI, and six MEG frequency bands), as well as a multilayer network comprising all unilayer networks. Interlayer links in the multilayer network were present only between a node’s counterpart across layers. We then computed and averaged eigenvector centrality of the nodes within the FPN for every uni- and multilayer network and used multiple regression models to examine the relation between uni- or multilayer centrality and executive functioning. We found that higher multilayer FPN centrality, but not unilayer FPN centrality, was related to better executive functioning. To further validate multilayer FPN centrality as a relevant measure, we assessed its relation with age. Network organization has been shown to change across the life span, becoming increasingly efficient up to middle age and regressing to a more segregated topology at higher age. Indeed, the relation between age and multilayer centrality followed an inverted-U shape. These results show the importance of FPN integration for executive functioning as well as the value of a multilayer framework in network analyses of the brain. Multilayer network analysis may particularly advance our understanding of the interplay between different brain network aspects in clinical populations, where network alterations differ across modalities.Highlights:Multimodal neuroimaging and neurophysiology data were collected in healthy adultsMultilayer frontoparietal centrality was positively associated with executive functioningUnilayer (unimodal) centralities were not associated with executive functioningThere was an inverted-U relationship between multilayer centrality and age

Non-invasively measured brain activity is related to progression-free survival in glioma patients, suggesting its potential as a marker of glioma progression. We therefore assessed the relationship between brain activity and increasing tumor volumes on routine clinical magnetic resonance imaging (MRI) in glioma patients. Postoperative magnetoencephalography (MEG) was recorded in 45 diffuse glioma patients. Brain activity was estimated using three measures (absolute broadband power, offset and slope) calculated at three spatial levels: global average, averaged across the peritumoral areas, and averaged across the homologues of these peritumoral areas in the contralateral hemisphere. Tumors were segmented on MRI. Changes in tumor volume between the two scans surrounding the MEG were calculated and correlated with brain activity. Brain activity was compared between patient groups classified into having increasing or stable tumor volume. Results show that brain activity was significantly increased in the tumor hemisphere in general, and in peritumoral regions specifically. However, none of the measures and spatial levels of brain activity correlated with changes in tumor volume, nor did they differ between patients with increasing versus stable tumor volumes. Longitudinal studies in more homogeneous subgroups of glioma patients are necessary to further explore the clinical potential of non-invasively measured brain activity.

Accumulating evidence across species indicates that brain oscillations are superimposed upon an aperiodic 1/f - like power spectrum. Maturational changes in neuronal oscillations have not been assessed in tandem with this underlying aperiodic spectrum. The current study uncovers co-maturation of the aperiodic component alongside the periodic components (oscillations) in spontaneous magnetoencephalography (MEG) data. Beamformer-reconstructed MEG time-series allowed a direct comparison of power in the source domain between 24 children (8.0 ± 2.5 years, 17 males) and 24 adults (40.6 ± 17.4 years, 16 males). Our results suggest that the redistribution of oscillatory power from lower to higher frequencies that is observed in childhood does not hold once the age-related changes in the aperiodic signal are controlled for. When estimating both the periodic and aperiodic components, we found that power increases with age in the beta band only, and that the 1/f signal is flattened in adults compared to children. These results suggest a pattern of co-maturing beta oscillatory power with the aperiodic 1/f signal in typical childhood development.

Rapid reconfigurations of brain activity support efficient neuronal communication and flexible behaviour. Suboptimal brain dynamics impair this adaptability, possibly leading to functional deficiencies. We hypothesize that impaired flexibility in brain activity can lead to motor and cognitive symptoms of Parkinson’s disease (PD). To test this hypothesis, we studied the ‘functional repertoire’ – the number of distinct configurations of neural activity – using source-reconstructed magnetoencephalography in PD patients and controls. We found stereotyped brain dynamics and reduced flexibility in PD. The intensity of this reduction was proportional to symptoms severity, which can be explained by beta-band hyper-synchronization. Moreover, the basal ganglia were prominently involved in the abnormal patterns of brain activity. Our findings support the hypotheses that: symptoms in PD reflect impaired brain flexibility, this impairment preferentially involves the basal ganglia, and beta-band hypersynchronization is associated with reduced brain flexibility. These findings highlight the importance of extensive functional repertoires for behaviour and motor.

A growing literature conceptualises human brain development from a network perspective, but it remains unknown how functional brain networks are refined during the preschool years. The extant literature diverges in its characterisation of functional network development, with little agreement between haemodynamic- and electrophysiology-based measures. In children aged from 4 to 12 years, as well as adults, age appropriate magnetoencephalography was used to estimate unbiased network topology, using minimum spanning tree (MST) constructed from phase synchrony between beamformer-reconstructed time-series. During childhood, network topology becomes increasingly segregated, while cortical regions decrease in centrality. We propose a heuristic MST model, in which a clear developmental trajectory for the emergence of complex brain networks is delineated. Our results resolve topological reorganisation of functional networks across temporal and special scales in youth and fill a gap in the literature regarding neurophysiological mechanisms of functional brain maturation during the preschool years.

Amyotrophic Lateral Sclerosis (ALS) is one of the most severe neurodegenerative diseases, which is known to affect upper and lower motor neurons. In contrast to the classical tenet that ALS represents the outcome of extensive and progressive impairment of a fixed set of motor connections, recent neuroimaging findings suggest that the disease spreads along vast non-motor connections. Here, we hypothesised that functional network topology is perturbed in ALS, and that this reorganization is associated with disability. We tested this hypothesis in 21 patients affected by ALS at several stages of impairment using resting-state electroencephalography (EEG) and compared the results to 16 age-matched healthy controls. We estimated functional connectivity using the Phase Lag Index (PLI), and characterized the network topology using the minimum spanning tree (MST). We found a significant difference between groups in terms of MST dissimilarity and MST leaf fraction in the beta band. Moreover, some MST parameters (leaf, hierarchy and kappa) significantly correlated with disability. These findings suggest that the topology of resting-state functional networks in ALS is affected by the disease in relation to disability. EEG network analysis may be of help in monitoring and evaluating the clinical status of ALS patients.