Higher-order functional connectivity analysis of resting-state functional magnetic resonance imaging data using multivariate cumulants.

Blood-level oxygenation-dependent (BOLD) functional magnetic resonance imaging (fMRI) is the most common modality to study functional connectivity in the human brain. Most research to date has focused on connectivity between pairs of brain regions. However, attention has recently turned towards connectivity involving more than two regions, that is, higher-order connectivity. It is not yet clear how higher-order connectivity can best be quantified. The measures that are currently in use cannot distinguish between pairwise (i.e., second-order) and higher-order connectivity. We show that genuine higher-order connectivity can be quantified by using multivariate cumulants. We explore the use of multivariate cumulants for quantifying higher-order connectivity and the performance of block bootstrapping for statistical inference. In particular, we formulate a generative model for fMRI signals exhibiting higher-order connectivity and use it to assess bias, standard errors, and detection probabilities. Application to resting-state fMRI data from the Human Connectome Project demonstrates that spontaneous fMRI signals are organized into higher-order networks that are distinct from second-order resting-state networks. Application to a clinical cohort of patients with multiple sclerosis further demonstrates that cumulants can be used to classify disease groups and explain behavioral variability. Hence, we present a novel framework to reliably estimate genuine higher-order connectivity in fMRI data which can be used for constructing hyperedges, and finally, which can readily be applied to fMRI data from populations with neuropsychiatric disease or cognitive neuroscientific experiments.

Deep brain stimulation of the central thalamus restores arousal and motivation in a zolpidem-responsive patient with akinetic mutism after severe brain injury.

After severe brain injury, zolpidem is known to cause spectacular, often short-lived, restorations of brain functions in a small subgroup of patients. Previously, we showed that these zolpidem-induced neurological recoveries can be paralleled by significant changes in functional connectivity throughout the brain. Deep brain stimulation (DBS) is a neurosurgical intervention known to modulate functional connectivity in a wide variety of neurological disorders. In this study, we used DBS to restore arousal and motivation in a zolpidem-responsive patient with severe brain injury and a concomitant disorder of diminished motivation, more than 10 years after surviving hypoxic ischemia. We found that DBS of the central thalamus, targeted at the centromedian-parafascicular complex, immediately restored arousal and was able to transition the patient from a state of deep sleep to full wakefulness. Moreover, DBS was associated with temporary restoration of communication and ability to walk and eat in an otherwise wheelchair-bound and mute patient. With the use of magnetoencephalography (MEG), we revealed that DBS was generally associated with a marked decrease in aberrantly high levels of functional connectivity throughout the brain, mimicking the effects of zolpidem. These results imply that 'pathological hyperconnectivity' after severe brain injury can be associated with reduced arousal and behavioral performance and that DBS is able to modulate connectivity towards a 'healthier baseline' with lower synchronization, and, can restore functional brain networks long after severe brain injury. The presence of hyperconnectivity after brain injury may be a possible future marker for a patient's responsiveness for restorative interventions, such as DBS, and suggests that lower degrees of overall brain synchronization may be conducive to cognition and behavioral responsiveness.

Non-reversibility outperforms functional connectivity in characterisation of brain states in MEG data.

Characterising brain states during tasks is common practice for many neuroscientific experiments using electrophysiological modalities such as electroencephalography (EEG) and magnetoencephalography (MEG). Brain states are often described in terms of oscillatory power and correlated brain activity, i.e. functional connectivity. It is, however, not unusual to observe weak task induced functional connectivity alterations in the presence of strong task induced power modulations using classical time-frequency representation of the data. Here, we propose that non-reversibility, or the temporal asymmetry in functional interactions, may be more sensitive to characterise task induced brain states than functional connectivity. As a second step, we explore causal mechanisms of non-reversibility in MEG data using whole brain computational models. We include working memory, motor, language tasks and resting-state data from participants of the Human Connectome Project (HCP). Non-reversibility is derived from the lagged amplitude envelope correlation (LAEC), and is based on asymmetry of the forward and reversed cross-correlations of the amplitude envelopes. Using random forests, we find that non-reversibility outperforms functional connectivity in the identification of task induced brain states. Non-reversibility shows especially better sensitivity to capture bottom-up gamma induced brain states across all tasks, but also alpha band associated brain states. Using whole brain computational models we find that asymmetry in the effective connectivity and axonal conduction delays play a major role in shaping non-reversibility across the brain. Our work paves the way for better sensitivity in characterising brain states during both bottom-up as well as top-down modulation in future neuroscientific experiments.

Preservation of thalamocortical circuitry is essential for good recovery after cardiac arrest.

Continuous electroencephalographam (EEG) monitoring contributes to prediction of neurological outcome in comatose cardiac arrest survivors. While the phenomenology of EEG abnormalities in postanoxic encephalopathy is well known, the pathophysiology, especially the presumed role of selective synaptic failure, is less understood. To further this understanding, we estimate biophysical model parameters from the EEG power spectra from individual patients with a good or poor recovery from a postanoxic encephalopathy. This biophysical model includes intracortical, intrathalamic, and corticothalamic synaptic strengths, as well as synaptic time constants and axonal conduction delays. We used continuous EEG measurements from hundred comatose patients recorded during the first 48 h postcardiac arrest, 50 with a poor neurological outcome [cerebral performance category ( CPC = 5 ) ] and 50 with a good neurological outcome ( CPC = 1 ). We only included patients that developed (dis-)continuous EEG activity within 48 h postcardiac arrest. For patients with a good outcome, we observed an initial relative excitation in the corticothalamic loop and corticothalamic propagation that subsequently evolved towards values observed in healthy controls. For patients with a poor outcome, we observed an initial increase in the cortical excitation-inhibition ratio, increased relative inhibition in the corticothalamic loop, delayed corticothalamic propagation of neuronal activity, and severely prolonged synaptic time constants that did not return to physiological values. We conclude that the abnormal EEG evolution in patients with a poor neurological recovery after cardiac arrest may result from persistent and selective synaptic failure that includes corticothalamic circuitry and also delayed corticothalamic propagation.

Dissociation between phase and power correlation networks in the human brain is driven by co-occurrent bursts.

Well-known haemodynamic resting-state networks are better mirrored in power correlation networks than phase coupling networks in electrophysiological data. However, what do these power correlation networks reflect? We address this long-outstanding question in neuroscience using rigorous mathematical analysis, biophysical simulations with ground truth and application of these mathematical concepts to empirical magnetoencephalography (MEG) data. Our mathematical derivations show that for two non-Gaussian electrophysiological signals, their power correlation depends on their coherence, cokurtosis and conjugate-coherence. Only coherence and cokurtosis contribute to power correlation networks in MEG data, but cokurtosis is less affected by artefactual signal leakage and better mirrors haemodynamic resting-state networks. Simulations and MEG data show that cokurtosis may reflect co-occurrent bursting events. Our findings shed light on the origin of the complementary nature of power correlation networks to phase coupling networks and suggests that the origin of resting-state networks is partly reflected in co-occurent bursts in neuronal activity.

Early EEG monitoring predicts clinical outcome in patients with moderate to severe traumatic brain injury.

There is a need for reliable predictors in patients with moderate to severe traumatic brain injury to assist clinical decision making. We assess the ability of early continuous EEG monitoring at the intensive care unit (ICU) in patients with traumatic brain injury (TBI) to predict long term clinical outcome and evaluate its complementary value to current clinical standards. We performed continuous EEG measurements in patients with moderate to severe TBI during the first week of ICU admission. We assessed the Extended Glasgow Outcome Scale (GOSE) at 12 months, dichotomized into poor (GOSE 1-3) and good (GOSE 4-8) outcome. We extracted EEG spectral features, brain symmetry index, coherence, aperiodic exponent of the power spectrum, long range temporal correlations, and broken detailed balance. A random forest classifier using feature selection was trained to predict poor clinical outcome based on EEG features at 12, 24, 48, 72 and 96 h after trauma. We compared our predictor with the IMPACT score, the best available predictor, based on clinical, radiological and laboratory findings. In addition we created a combined model using EEG as well as the clinical, radiological and laboratory findings. We included hundred-seven patients. The best prediction model using EEG parameters was found at 72 h after trauma with an AUC of 0.82 (0.69-0.92), specificity of 0.83 (0.67-0.99) and sensitivity of 0.74 (0.63-0.93). The IMPACT score predicted poor outcome with an AUC of 0.81 (0.62-0.93), sensitivity of 0.86 (0.74-0.96) and specificity of 0.70 (0.43-0.83). A model using EEG and clinical, radiological and laboratory parameters resulted in a better prediction of poor outcome (p < 0.001) with an AUC of 0.89 (0.72-0.99), sensitivity of 0.83 (0.62-0.93) and specificity of 0.85 (0.75-1.00). EEG features have potential use for predicting clinical outcome and decision making in patients with moderate to severe TBI and provide complementary information to current clinical standards.

Using The Virtual Brain to study the relationship between structural and functional connectivity in patients with multiple sclerosis: a multicenter study.

The relationship between structural connectivity (SC) and functional connectivity (FC) captured from magnetic resonance imaging, as well as its interaction with disability and cognitive impairment, is not well understood in people with multiple sclerosis (pwMS). The Virtual Brain (TVB) is an open-source brain simulator for creating personalized brain models using SC and FC. The aim of this study was to explore SC-FC relationship in MS using TVB. Two different model regimes have been studied: stable and oscillatory, with the latter including conduction delays in the brain. The models were applied to 513 pwMS and 208 healthy controls (HC) from 7 different centers. Models were analyzed using structural damage, global diffusion properties, clinical disability, cognitive scores, and graph-derived metrics from both simulated and empirical FC. For the stable model, higher SC-FC coupling was associated with pwMS with low Single Digit Modalities Test (SDMT) score (F=3.48, P$\lt$0.05), suggesting that cognitive impairment in pwMS is associated with a higher SC-FC coupling. Differences in entropy of the simulated FC between HC, high and low SDMT groups (F=31.57, P$\lt$1e-5), show that the model captures subtle differences not detected in the empirical FC, suggesting the existence of compensatory and maladaptive mechanisms between SC and FC in MS.

Inhibitory synaptic loss drives network changes in multiple sclerosis: An ex vivo to in silico translational study.

BACKGROUND: Synaptic and neuronal loss contribute to network dysfunction and disability in multiple sclerosis (MS). However, it is unknown whether excitatory or inhibitory synapses and neurons are more vulnerable and how their losses impact network functioning. OBJECTIVE: To quantify excitatory and inhibitory synapses and neurons and to investigate how synaptic loss affects network functioning through computational modeling. METHODS: Using immunofluorescent staining and confocal microscopy, densities of glutamatergic and GABAergic synapses and neurons were compared between post-mortem MS and non-neurological control cases. Then, a corticothalamic biophysical model was employed to study how MS-induced excitatory and inhibitory synaptic loss affect network functioning. RESULTS: In layer VI of normal-appearing MS cortex, excitatory and inhibitory synaptic densities were significantly lower than controls (reductions up to 14.9%), but demyelinated cortex showed larger losses of inhibitory synapses (29%). In our computational model, reducing inhibitory synapses impacted the network most, leading to a disinhibitory increase in neuronal activity and connectivity. CONCLUSION: In MS, excitatory and inhibitory synaptic losses were observed, predominantly for inhibitory synapses in demyelinated cortex. Inhibitory synaptic loss affected network functioning most, leading to increased neuronal activity and connectivity. As network disinhibition relates to cognitive impairment, inhibitory synaptic loss seems particularly relevant in MS.

Disruption in structural-functional network repertoire and time-resolved subcortical fronto-temporoparietal connectivity in disorders of consciousness.

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 (GNW) 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, the prediction of these functional network states by underlying hidden spatial patterns in the anatomical network, that is so-called eigenmodes, was supplemented as potential markers. By analysing time-resolved functional connectivity from functional MRI 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 subcortical fronto-temporoparietal 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 GNW theory and the mesocircuit hypothesis, underpinning the role of time-resolved thalamo-cortical connections and metastability in the recovery of consciousness.

Clinical and neurophysiological effects of central thalamic deep brain stimulation in the minimally conscious state after severe brain injury.

Deep brain stimulation (DBS) of the central thalamus is an experimental treatment for restoration of impaired consciousness in patients with severe acquired brain injury. Previous results of experimental DBS are heterogeneous, but significant improvements in consciousness have been reported. However, the mechanism of action of DBS remains unknown. We used magnetoencephalography to study the direct effects of DBS of the central thalamus on oscillatory activity and functional connectivity throughout the brain in a patient with a prolonged minimally conscious state. Different DBS settings were used to improve consciousness, including two different stimulation frequencies (50 Hz and 130 Hz) with different effective volumes of tissue activation within the central thalamus. While both types of DBS resulted in a direct increase in arousal, we found that DBS with a lower frequency (50 Hz) and larger volume of tissue activation was associated with a stronger increase in functional connectivity and neural variability throughout the brain. Moreover, this form of DBS was associated with improvements in visual pursuit, a reduction in spasticity, and improvement of swallowing, eight years after loss of consciousness. However, after DBS, all neurophysiological markers remained significantly lower than in healthy controls and objective increases in consciousness remained limited. Our findings provide new insights on the mechanistic understanding of neuromodulatory effects of DBS of the central thalamus in humans and suggest that DBS can re-activate dormant functional brain networks, but that the severely injured stimulated brain still lacks the ability to serve cognitive demands.

Predicting time-resolved electrophysiological brain networks from structural eigenmodes.

How temporal modulations in functional interactions are shaped by the underlying anatomical connections remains an open question. Here, we analyse the role of structural eigenmodes, in the formation and dissolution of temporally evolving functional brain networks using resting-state magnetoencephalography and diffusion magnetic resonance imaging data at the individual subject level. Our results show that even at short timescales, phase and amplitude connectivity can partly be expressed by structural eigenmodes, but hardly by direct structural connections. Albeit a stronger relationship was found between structural eigenmodes and time-resolved amplitude connectivity. Time-resolved connectivity for both phase and amplitude was mostly characterised by a stationary process, superimposed with very brief periods that showed deviations from this stationary process. For these brief periods, dynamic network states were extracted that showed different expressions of eigenmodes. Furthermore, the eigenmode expression was related to overall cognitive performance and co-occurred with fluctuations in community structure of functional networks. These results implicate that ongoing time-resolved resting-state networks, even at short timescales, can to some extent be understood in terms of activation and deactivation of structural eigenmodes and that these eigenmodes play a role in the dynamic integration and segregation of information across the cortex, subserving cognitive functions.

Structure-function coupling as a correlate and potential biomarker of cognitive impairment in multiple sclerosis.

Multiple sclerosis (MS) features extensive connectivity changes, but how structural and functional connectivity relate, and whether this relation could be a useful biomarker for cognitive impairment in MS is unclear. This study included 79 MS patients and 40 healthy controls (HCs). Patients were classified as cognitively impaired (CI) or cognitively preserved (CP). Structural connectivity was determined using diffusion MRI and functional connectivity using resting-state magnetoencephalography (MEG) data (theta, alpha1, and alpha2 bands). Structure-function coupling was assessed by correlating modalities, and further explored in frequency bands that significantly correlated with whole-brain structural connectivity. Functional correlates of short- and long-range structural connections (based on tract length) were then specifically assessed. Receiving operating curve analyses were performed on coupling values to identify biomarker potential. Only the theta band showed significant correlations between whole-brain structural and functional connectivity (rho = -0.26, p = 0.023, only in MS). Long-range structure-function coupling was stronger in CI patients compared to HCs (p = 0.005). Short-range coupling showed no group differences. Structure-function coupling was not a significant classifier of cognitive impairment for any tract length (short-range area under the curve (AUC) = 0.498, p = 0.976, long-range AUC = 0.611, p = 0.095). Long-range structure-function coupling was stronger in CI MS compared to HCs, but more research is needed to further explore this measure as biomarkers in MS.

Schizophrenia induces abnormal frequency-dependent patterns of dynamic brain network reconfiguration during an auditory oddball task.

Objective.Schizophrenia is a psychiatric disorder that has been shown to disturb the dynamic top-down processing of sensory information. Various imaging techniques have revealed abnormalities in brain activity associated with this disorder, both locally and between cerebral regions. However, there is increasing interest in investigating dynamic network response to novel and relevant events at the network level during an attention-demanding task with high-temporal-resolution techniques. The aim of the work was: (i) to test the capacity of a novel algorithm to detect recurrent brain meta-states from auditory oddball task recordings; and (ii) to evaluate how the dynamic activation and behavior of the aforementioned meta-states were altered in schizophrenia, since it has been shown to impair top-down processing of sensory information.Approach.A novel unsupervised method for the detection of brain meta-states based on recurrence plots and community detection algorithms, previously tested on resting-state data, was used on auditory oddball task recordings. Brain meta-states and several properties related to their activation during target trials in the task were extracted from electroencephalography data from patients with schizophrenia and cognitively healthy controls.Main results.The methodology successfully detected meta-states during an auditory oddball task, and they appeared to show both frequency-dependent time-locked and non-time-locked activity with respect to the stimulus onset. Moreover, patients with schizophrenia displayed higher network diversity, and showed more sluggish meta-state transitions, reflected in increased dwell times, less complex meta-state sequences, decreased meta-state space speed, and abnormal ratio of negative meta-state correlations.Significance.Abnormal cognition in schizophrenia is also reflected in decreased brain flexibility at the dynamic network level, which may hamper top-down processing, possibly indicating impaired decision-making linked to dysfunctional predictive coding. Moreover, the results showed the ability of the methodology to find meaningful and task-relevant changes in dynamic connectivity and pathology-related group differences.

Longitudinal consistency of source-space spectral power and functional connectivity using different magnetoencephalography recording systems.

Longitudinal analyses of magnetoencephalography (MEG) data are essential for a full understanding of the pathophysiology of brain diseases and the development of brain activity over time. However, time-dependent factors, such as the recording environment and the type of MEG recording system may affect such longitudinal analyses. We hypothesized that, using source-space analysis, hardware and software differences between two recordings systems may be overcome, with the aim of finding consistent neurophysiological results. We studied eight healthy subjects who underwent three consecutive MEG recordings over 7 years, using two different MEG recordings systems; a 151-channel VSM-CTF system for the first two time points and a 306-channel Elekta Vectorview system for the third time point. We assessed the within (longitudinal) and between-subject (cross-sectional) consistency of power spectra and functional connectivity matrices. Consistency of within-subject spectral power and functional connectivity matrices was good and was not significantly different when using different MEG recording systems as compared to using the same system. Importantly, we confirmed that within-subject consistency values were higher than between-subject values. We demonstrated consistent neurophysiological findings in healthy subjects over a time span of seven years, despite using data recorded on different MEG systems and different implementations of the analysis pipeline.

Abnormal meta-state activation of dynamic brain networks across the Alzheimer spectrum.

The characterization of the distinct dynamic functional connectivity (dFC) patterns that activate in the brain during rest can help to understand the underlying time-varying network organization. The presence and behavior of these patterns (known as meta-states) have been widely studied by means of functional magnetic resonance imaging (fMRI). However, modalities with high-temporal resolution, such as electroencephalography (EEG), enable the characterization of fast temporally evolving meta-state sequences. Mild cognitive impairment (MCI) and dementia due to Alzheimer's disease (AD) have been shown to disrupt spatially localized activation and dFC between different brain regions, but not much is known about how they affect meta-state network topologies and their network dynamics. The main hypothesis of the study was that MCI and dementia due to AD alter normal meta-state sequences by inducing a loss of structure in their patterns and a reduction of their dynamics. Moreover, we expected that patients with MCI would display more flexible behavior compared to patients with dementia due to AD. Thus, the aim of the current study was twofold: (i) to find repeating, distinctly organized network patterns (meta-states) in neural activity; and (ii) to extract information about meta-state fluctuations and how they are influenced by MCI and dementia due to AD. To accomplish these goals, we present a novel methodology to characterize dynamic meta-states and their temporal fluctuations by capturing aspects based on both their discrete activation and the continuous evolution of their individual strength. These properties were extracted from 60-s resting-state EEG recordings from 67 patients with MCI due to AD, 50 patients with dementia due to AD, and 43 cognitively healthy controls. First, the instantaneous amplitude correlation (IAC) was used to estimate instantaneous functional connectivity with a high temporal resolution. We then extracted meta-states by means of graph community detection based on recurrence plots (RPs), both at the individual- and group-level. Subsequently, a diverse set of properties of the continuous and discrete fluctuation patterns of the meta-states was extracted and analyzed. The main novelty of the methodology lies in the usage of Louvain GJA community detection to extract meta-states from IAC-derived RPs and the extended analysis of their discrete and continuous activation. Our findings showed that distinct dynamic functional connectivity meta-states can be found on the EEG time-scale, and that these were not affected by the oscillatory slowing induced by MCI or dementia due to AD. However, both conditions displayed a loss of meta-state modularity, coupled with shorter dwell times and higher complexity of the meta-state sequences. Furthermore, we found evidence that meta-state sequencing is not entirely random; it shows an underlying structure that is partially lost in MCI and dementia due to AD. These results show evidence that AD progression is associated with alterations in meta-state switching, and a degradation of dynamic brain flexibility.

Functional brain network organization measured with magnetoencephalography predicts cognitive decline in multiple sclerosis.

BACKGROUND: Cognitive decline remains difficult to predict as structural brain damage cannot fully explain the extensive heterogeneity found between MS patients. OBJECTIVE: To investigate whether functional brain network organization measured with magnetoencephalography (MEG) predicts cognitive decline in MS patients after 5 years and to explore its value beyond structural pathology. METHODS: Resting-state MEG recordings, structural MRI, and neuropsychological assessments were analyzed of 146 MS patients, and 100 patients had a 5-year follow-up neuropsychological assessment. Network properties of the minimum spanning tree (i.e. backbone of the functional brain network) indicating network integration and overload were related to baseline and longitudinal cognition, correcting for structural damage. RESULTS: A more integrated beta band network (i.e. smaller diameter) and a less integrated delta band network (i.e. lower leaf fraction) predicted cognitive decline after 5 years (Radj2=15%), independent of structural damage. Cross-sectional analyses showed that a less integrated network (e.g. lower tree hierarchy) related to worse cognition, independent of frequency band. CONCLUSIONS: The level of functional brain network integration was an independent predictive marker of cognitive decline, in addition to the severity of structural damage. This work thereby indicates the promise of MEG-derived network measures in predicting disease progression in MS.

Age-related differences in myeloarchitecture measured at 7 T.

We have used the magnetisation transfer (MT) MRI measure as a primary measure of myelination in both the gray matter (GM) of the 78 cortical automated anatomical labeling (AAL) regions of the brain, and the underlying white matter in each region, in a cohort of healthy adults (aged 19-62 year old). The results revealed a significant quadratic trend in myelination with age, with average global myelination peaking at 42.9 year old in gray matter, and at 41.7 year old in white matter. We also explored the possibility of using the Nuclear Overhauser Enhancement (NOE) effect, which is acquired in a similar method to MT, as an additional measure of myelination. We found that the MT and NOE signals were strongly correlated in the brain and that the NOE effects displayed similar (albeit weaker) parabolic trends with age. We also investigated differences in cortical thickness with age, and confirmed a previous result of a linear decline of 4.5 ± 1.2 µm/y.

Multilayer MEG functional connectivity as a potential marker for suicidal thoughts in major depressive disorder.

Major depressive disorder (MDD) is highly heterogeneous in its clinical presentation. The present exploratory study used magnetoencephalography (MEG) to investigate electrophysiological intrinsic connectivity differences between healthy volunteers and unmedicated participants with treatment-resistant MDD. The study examined canonical frequency bands from delta through gamma. In addition to group comparisons, correlational studies were conducted to determine whether connectivity was related to five symptom factors: depressed mood, tension, negative cognition, suicidal thoughts, and amotivation. The MDD and healthy volunteer groups did not differ significantly at baseline when corrected across all frequencies and clusters, although evidence of generalized slowing in MDD was observed. Notably, however, electrophysiological connectivity was strongly related to suicidal thoughts, particularly as coupling of low frequency power fluctuations (delta and theta) with alpha and beta power. This analysis revealed hub areas underlying this symptom cluster, including left hippocampus, left anterior insula, and bilateral dorsolateral prefrontal cortex. No other symptom cluster demonstrated a relationship with neurophysiological connectivity, suggesting a specificity to these results as markers of suicidal ideation.