Intracranial Recordings of the Human Orbitofrontal Cortical Activity during Self-Referential Episodic and Valenced Self-Judgments.

We recorded directly from the orbital (oPFC) and ventromedial (vmPFC) subregions of the orbitofrontal cortex (OFC) in 22 (9 female, 13 male) epilepsy patients undergoing intracranial electroencephalography (iEEG) monitoring during an experimental task in which the participants judged the accuracy of self-referential autobiographical statements as well as valenced self-judgments (SJs). We found significantly increased high-frequency activity (HFA) in ∼13% of oPFC sites (10/18 subjects) and 16% of vmPFC sites (4/12 subjects) during both of these self-referential thought processes, with the HFA power being modulated by the content of self-referential stimuli. The location of these activated sites corresponded with the location of fMRI-identified limbic network. Furthermore, the onset of HFA in the vmPFC was significantly earlier than that in the oPFC in all patients with simultaneous recordings in both regions. In 11 patients with available depression scores from comprehensive neuropsychological assessments, we documented diminished HFA in the OFC during positive SJ trials among individuals with higher depression scores; responses during negative SJ trials were not related to the patients' depression scores. Our findings provide new temporal and anatomical information about the mode of engagement in two important subregions of the OFC during autobiographical memory and SJ conditions. Our findings from the OFC support the hypothesis that diminished brain activity during positive self-evaluations, rather than heightened activity during negative self-evaluations, plays a key role in the pathophysiology of depression.

Macroscopic resting state model predicts theta burst stimulation response: A randomized trial.

Repetitive transcranial magnetic stimulation (rTMS) is a promising alternative therapy for treatment-resistant depression, although its limited remission rate indicates room for improvement. As depression is a phenomenological construction, the biological heterogeneity within this syndrome needs to be considered to improve the existing therapies. Whole-brain modeling provides an integrative multi-modal framework for capturing disease heterogeneity in a holistic manner. Computational modelling combined with probabilistic nonparametric fitting was applied to the resting-state fMRI data from 42 patients (21 women), to parametrize baseline brain dynamics in depression. All patients were randomly assigned to two treatment groups, namely active (i.e., rTMS, n = 22) or sham (n = 20). The active treatment group received rTMS treatment with an accelerated intermittent theta burst protocol over the dorsomedial prefrontal cortex. The sham treatment group underwent the identical procedure but with the magnetically shielded side of the coil. We stratified the depression sample into distinct covert subtypes based on their baseline attractor dynamics captured by different model parameters. Notably, the two detected depression subtypes exhibited different phenotypic behaviors at baseline. Our stratification could predict the diverse response to the active treatment that could not be explained by the sham treatment. Critically, we further found that one group exhibited more distinct improvement in certain affective and negative symptoms. The subgroup of patients with higher responsiveness to treatment exhibited blunted frequency dynamics for intrinsic activity at baseline, as indexed by lower global metastability and synchrony. Our findings suggested that whole-brain modeling of intrinsic dynamics may constitute a determinant for stratifying patients into treatment groups and bringing us closer towards precision medicine.

Multisite thalamic recordings to characterize seizure propagation in the human brain.

Neuromodulation of the anterior nuclei of the thalamus (ANT) has shown to be efficacious in a subset of patients with refractory focal epilepsy. One important uncertainty is to what extent thalamic subregions other than the ANT could be recruited more prominently in the propagation of focal onset seizures. We designed the current study to simultaneously monitor the engagement of the ANT, mediodorsal (MD) and pulvinar (PUL) nuclei during seizures in patients who could be candidates for thalamic neuromodulation. We studied 11 patients with clinical manifestations of presumed temporal lobe epilepsy (TLE) undergoing invasive stereo-encephalography (sEEG) monitoring to confirm the source of their seizures. We extended cortical electrodes to reach the ANT, MD and PUL nuclei of the thalamus. More than one thalamic subdivision was simultaneously interrogated in nine patients. We recorded seizures with implanted electrodes across various regions of the brain and documented seizure onset zones (SOZ) in each recorded seizure. We visually identified the first thalamic subregion to be involved in seizure propagation. Additionally, in eight patients, we applied repeated single pulse electrical stimulation in each SOZ and recorded the time and prominence of evoked responses across the implanted thalamic regions. Our approach for multisite thalamic sampling was safe and caused no adverse events. Intracranial EEG recordings confirmed SOZ in medial temporal lobe, insula, orbitofrontal and temporal neocortical sites, highlighting the importance of invasive monitoring for accurate localization of SOZs. In all patients, seizures with the same propagation network and originating from the same SOZ involved the same thalamic subregion, with a stereotyped thalamic EEG signature. Qualitative visual reviews of ictal EEGs were largely consistent with the quantitative analysis of the corticothalamic evoked potentials, and both documented that thalamic nuclei other than ANT could have the earliest participation in seizure propagation. Specifically, pulvinar nuclei were involved earlier and more prominently than ANT in more than half of the patients. However, which specific thalamic subregion first demonstrated ictal activity could not be reliably predicted based on clinical semiology or lobar localization of SOZs. Our findings document the feasibility and safety of bilateral multisite sampling from the human thalamus. This may allow more personalized thalamic targets to be identified for neuromodulation. Future studies are needed to determine if a personalized thalamic neuromodulation leads to greater improvements in clinical outcome.

Whole-Brain Modelling: Past, Present, and Future.

Whole-Brain Modelling is a scientific field with a short history and a long past. Its various disciplinary roots and conceptual ingredients extend back to as early as the 1940s. It was not until the late 2000s, however, that a nascent paradigm emerged in roughly its current form-concurrently, and in many ways joined at the hip, with its sister field of macro-connectomics. This period saw a handful of seminal papers authored by a certain motley crew of notable theoretical and cognitive neuroscientists, which have served to define much of the landscape of whole-brain modelling as it stands at the start of the 2020s. At the same time, the field has over the past decade expanded in a dozen or more fascinating new methodological, theoretical, and clinical directions. In this chapter we offer a potted Past, Present, and Future of whole-brain modelling, noting what we take to be some of its greatest successes, hardest challenges, and most exciting opportunities.

Whole-brain modelling of resting state fMRI differentiates ADHD subtypes and facilitates stratified neuro-stimulation therapy.

Recent advances in non-linear computational and dynamical modelling have opened up the possibility to parametrize dynamic neural mechanisms that drive complex behavior. Importantly, building models of neuronal processes is of key importance to fully understand disorders of the brain as it may provide a quantitative platform that is capable of binding multiple neurophysiological processes to phenotype profiles. In this study, we apply a newly developed adaptive frequency-based model of whole-brain oscillations to resting-state fMRI data acquired from healthy controls and a cohort of attention deficit hyperactivity disorder (ADHD) subjects. As expected, we found that healthy control subjects differed from ADHD in terms of attractor dynamics. However, we also found a marked dichotomy in neural dynamics within the ADHD cohort. Next, we classified the ADHD group according to the level of distance of each individual's empirical network from the two model-based simulated networks. Critically, the model was mirrored in the empirical behavior data with the two ADHD subgroups displaying distinct behavioral phenotypes related to emotional instability (i.e., depression and hypomanic personality traits). Finally, we investigated the applicability and feasibility of our whole-brain model in a therapeutic setting by conducting in silico excitatory stimulations to parsimoniously mimic clinical neuro-stimulation paradigms in ADHD. We tested the effect of stimulating any individual brain region on the key network measures derived from the simulated brain network and its contribution in rectifying the brain dynamics to that of the healthy brain, separately for each ADHD subgroup. This showed that this was indeed possible for both subgroups. However, the current effect sizes were small suggesting that the stimulation protocol needs to be tailored at the individual level. These findings demonstrate the potential of this new modelling framework to unveil hidden neurophysiological profiles and establish tailored clinical interventions.

Dynamic synergetic configurations of resting-state networks in ADHD.

Attention deficit hyperactivity disorder (ADHD) is characterized by high distractibility and impaired executive functions. Notably, there is mounting evidence suggesting that ADHD could be regarded as a default mode network (DMN) disorder. In particular, failure in regulating the dynamics of activity and interactions of the DMN and cognitive control networks have been hypothesized as the main source of task interference causing attentional problems. On the other hand, previous studies indicated pronounced fluctuations in the strength of functional connections over time, particularly for the inter-network connections between the DMN and fronto-parietal control networks. Hence, characterization of connectivity disturbances in ADHD requires a thorough assessment of time-varying functional connectivity (FC). In this study, we proposed a dynamical systems perspective to assess how the DMN over time recruits different configurations of network segregation and integration. Specifically, we were interested in configurations for which both intra- and inter-network connections are retained, as opposed to commonly used methods which assess network segregation as a single measure. From resting-state fMRI data, we extracted three different stable configurations of FC patterns for the DMN, namely synergies. We provided evidence supporting our hypothesis that ADHD differs compared to controls, both in terms of recruitment rate and topology of specific synergies between resting-state networks. In addition, we found a relationship between synergetic cooperation patterns of the DMN with cognitive control networks and a behavioral measure which is sensitive to ADHD-related symptoms, namely the Stroop color-word task.

The retrosplenial cortex: A memory gateway between the cortical default mode network and the medial temporal lobe.

The default mode network (DMN) involves interacting cortical areas, including the posterior cingulate cortex (PCC) and the retrosplenial cortex (RSC), and subcortical areas, including the medial temporal lobe (MTL). The degree of functional connectivity (FC) within the DMN, particularly between MTL and medial-parietal subsystems, relates to episodic memory (EM) processes. However, past resting-state studies investigating the link between posterior DMN-MTL FC and EM performance yielded inconsistent results, possibly reflecting heterogeneity in the degree of connectivity between MTL and specific cortical DMN regions. Animal work suggests that RSC has structural connections to both cortical DMN regions and MTL, and may thus serve as an intermediate layer that facilitates information transfer between cortical and subcortical DMNs. We studied 180 healthy old adults (aged 64-68 years), who underwent comprehensive assessment of EM, along with resting-state fMRI. We found greater FC between MTL and RSC than between MTL and the other cortical DMN regions (e.g., PCC), with the only significant association with EM observed for MTL-RSC FC. Mediational analysis showed that MTL-cortical DMN connectivity increased with RSC as a mediator. Further analysis using a graph-theoretical approach on DMN nodes revealed the highest betweenness centrality for RSC, confirming that a high proportion of short paths among DMN regions pass through RSC. Importantly, the degree of RSC mediation was associated with EM performance, suggesting that individuals with greater mediation have an EM advantage. These findings suggest that RSC forms a critical gateway between MTL and cortical DMN to support EM in older adults.

Longitudinal Evidence for Dissociation of Anterior and Posterior MTL Resting-State Connectivity in Aging: Links to Perfusion and Memory.

Neuroimaging studies of spontaneous signal fluctuations as measured by resting-state functional magnetic resonance imaging have revealed age-related alterations in the functional architecture of brain networks. One such network is located in the medial temporal lobe (MTL), showing structural and functional variations along the anterior-posterior axis. Past cross-sectional studies of MTL functional connectivity (FC) have yielded discrepant findings, likely reflecting the fact that specific MTL subregions are differentially affected in aging. Here, using longitudinal resting-state data from 198 participants, we investigated 5-year changes in FC of the anterior and posterior MTL. We found an opposite pattern, such that the degree of FC within the anterior MTL declined after age 60, whereas elevated FC within the posterior MTL was observed along with attenuated posterior MTL-cortical connectivity. A significant negative change-change relation was observed between episodic-memory decline and elevated FC in the posterior MTL. Additional analyses revealed age-related cerebral blood flow (CBF) increases in posterior MTL at the follow-up session, along with a positive relation of elevated FC and CBF, suggesting that elevated FC is a metabolically demanding alteration. Collectively, our findings indicate that elevated FC in posterior MTL along with increased local perfusion is a sign of brain aging that underlie episodic-memory decline.

Neural correlates of impulsivity in amphetamine use disorder.

Impulsivity is a trait associated with several psychiatric conditions, not least addictive disorders. While the neural mechanisms behind certain aspects of impulsivity have been studied extensively, there are few imaging studies examining this neurocircuitry in populations with substance use disorders. Therefore, we aimed to examine the functional connectivity of relevant neural networks, and their possible association with trait impulsivity, in a sample with severe amphetamine use disorder and a control group of healthy subjects. We used data collected in a randomized clinical trial studying the acute effects of oral naltrexone in amphetamine use disorder. Our final sample included 32 amphetamine users and 27 healthy controls. Trait impulsivity was rated with the Barratt Impulsiveness Scale-11, and functional connectivity was measured during resting-state fMRI, looking specifically at networks involving prefrontal regions previously implicated in studies of impulsivity. Amphetamine users had higher subjective ratings of impulsivity as compared to healthy controls, and these scores correlated positively with a wide-spread prefrontal hyperconnectivity that was found among the amphetamine users. These findings highlight the importance of aberrant prefrontal function in severe addiction.

Parkinson's disease is characterized by sub-second resting-state spatio-oscillatory patterns: A contribution from deep convolutional neural network.

Deep convolutional neural network (DCNN) provides a multivariate framework to detect relevant spatio-oscillatory patterns in the data beyond common mass-univariate statistics. Yet, its practical application is limited due to the low interpretability of the results beyond accuracy. We opted to use DCNN with a minimalistic architecture design and large penalized terms to yield a generalizable and clinically relevant network model. Our network was trained based on the scalp topology of the electroencephalography (EEG) from an open access dataset, constituting our primary sample of healthy controls (n = 25) and Parkinson's disease (PD) patients (n = 25), with and without medication. Next, we validated the model on another independent, yet comparable open access EEG dataset (healthy controls (n = 20) and PD patients (n = 20)), which was unseen to the network. We applied Gradient-weighted Class Activation Mapping (Grad-CAM) interpretability technique to create a localization map exhibiting the key network predictors, based on the gradients of the classification score flowing into the last convolutional layer. Accordingly, our results indicated that a sub-second of intrinsic oscillatory power pattern in the beta band over the occipitoparietal, gamma band over the left motor cortex as well as theta band over the frontoparietal cluster, had the largest impact on the network score for dissociating the PD patients from age- and gender-matched healthy controls, across the two datasets. We further found that the off-medication motor symptoms were related to the occipitoparietal off-medication beta power whereas the disease duration was associated with the off-medication beta power of the motor cortex. The on-medication theta power of the frontoparietal was related to the improvement of the motor symptoms. In conclusion, our method enabled us to characterize PD patho-electrophysiology according to the multivariate topographic analysis approach, where both spatial and frequency aspects of the oscillations were simultaneously considered. Moreover, our approach was free from common reference problem of the EEG data analyses.

Adaptive frequency-based modeling of whole-brain oscillations: Predicting regional vulnerability and hazardousness rates.

Whole-brain computational modeling based on structural connectivity has shown great promise in successfully simulating fMRI BOLD signals with temporal coactivation patterns that are highly similar to empirical functional connectivity patterns during resting state. Importantly, previous studies have shown that spontaneous fluctuations in coactivation patterns of distributed brain regions have an inherent dynamic nature with regard to the frequency spectrum of intrinsic brain oscillations. In this modeling study, we introduced frequency dynamics into a system of coupled oscillators, where each oscillator represents the local mean-field model of a brain region. We first showed that the collective behavior of interacting oscillators reproduces previously shown features of brain dynamics. Second, we examined the effect of simulated lesions in gray matter by applying an in silico perturbation protocol to the brain model. We present a new approach to map the effects of vulnerability in brain networks and introduce a measure of regional hazardousness based on mapping of the degree of divergence in a feature space.