Large Individual Differences in Functional Connectivity in the Context of Major Depression and Antidepressant Pharmacotherapy.

Clinical studies of major depression (MD) generally focus on group effects, yet interindividual differences in brain function are increasingly recognized as important and may even impact effect sizes related to group effects. Here, we examine the magnitude of individual differences in relation to group differences that are commonly investigated (e.g., related to MD diagnosis and treatment response). Functional MRI data from 107 participants (63 female, 44 male) were collected at baseline, 2, and 8 weeks during which patients received pharmacotherapy (escitalopram, N = 68) and controls (N = 39) received no intervention. The unique contributions of different sources of variation were examined by calculating how much variance in functional connectivity was shared across all participants and sessions, within/across groups (patients vs controls, responders vs nonresponders, female vs male participants), recording sessions, and individuals. Individual differences and common connectivity across groups, sessions, and participants contributed most to the explained variance (>95% across analyses). Group differences related to MD diagnosis, treatment response, and biological sex made significant but small contributions (0.3-1.2%). High individual variation was present in cognitive control and attention areas, while low individual variation characterized primary sensorimotor regions. Group differences were much smaller than individual differences in the context of MD and its treatment. These results could be linked to the variable findings and difficulty translating research on MD to clinical practice. Future research should examine brain features with low and high individual variation in relation to psychiatric symptoms and treatment trajectories to explore the clinical relevance of the individual differences identified here.

One size does not fit all: notable individual variation in brain activity correlates of antidepressant treatment response.

Introduction: To date, no robust electroencephalography (EEG) markers of antidepressant treatment response have been identified. Variable findings may arise from the use of group analyses, which neglect individual variation. Using a combination of group and single-participant analyses, we explored individual variability in EEG characteristics of treatment response. Methods: Resting-state EEG data and Montgomery-Åsberg Depression Rating Scale (MADRS) symptom scores were collected from 43 patients with depression before, at 1 and 12 weeks of pharmacotherapy. Partial least squares (PLS) was used to: 1) identify group differences in EEG connectivity (weighted phase lag index) and complexity (multiscale entropy) between eventual medication responders and non-responders, and 2) determine whether group patterns could be identified in individual patients. Results: Responders showed decreased alpha and increased beta connectivity, and early, widespread decreases in complexity over treatment. Non-responders showed an opposite connectivity pattern, and later, spatially confined decreases in complexity. Thus, as in previous studies, our group analyses identified significant differences between groups of patients with different treatment outcomes. These group-level EEG characteristics were only identified in ~40-60% of individual patients, as assessed quantitatively by correlating the spatiotemporal brain patterns between groups and individual results, and by independent raters through visualization. Discussion: Our single-participant analyses suggest that substantial individual variation exists, and needs to be considered when investigating characteristics of antidepressant treatment response for potential clinical applicability. Clinical trial registration: https://clinicaltrials.gov, identifier NCT00519428.

The modulatory effect of adaptive task-switching training on resting-state neural network dynamics in younger and older adults.

With increasing life expectancy and active aging, it becomes crucial to investigate methods which could compensate for generally detected cognitive aging processes. A promising candidate is adaptive cognitive training, during which task difficulty is adjusted to the participants' performance level to enhance the training and potential transfer effects. Measuring intrinsic brain activity is suitable for detecting possible distributed training-effects since resting-state dynamics are linked to the brain's functional flexibility and the effectiveness of different cognitive processes. Therefore, we investigated if adaptive task-switching training could modulate resting-state neural dynamics in younger (18-25 years) and older (60-75 years) adults (79 people altogether). We examined spectral power density on resting-state EEG data for measuring oscillatory activity, and multiscale entropy for detecting intrinsic neural complexity. Decreased coarse timescale entropy and lower frequency band power as well as increased fine timescale entropy and higher frequency band power revealed a shift from more global to local information processing with aging before training. However, cognitive training modulated these age-group differences, as coarse timescale entropy and lower frequency band power increased from pre- to post-training in the old-training group. Overall, our results suggest that cognitive training can modulate neural dynamics even when measured outside of the trained task.

Baseline Functional Connectivity in Resting State Networks Associated with Depression and Remission Status after 16 Weeks of Pharmacotherapy: A CAN-BIND Report.

Understanding the neural underpinnings of major depressive disorder (MDD) and its treatment could improve treatment outcomes. So far, findings are variable and large sample replications scarce. We aimed to replicate and extend altered functional connectivity associated with MDD and pharmacotherapy outcomes in a large, multisite sample. Resting-state fMRI data were collected from 129 patients and 99 controls through the Canadian Biomarker Integration Network in Depression. Symptoms were assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS). Connectivity was measured as correlations between four seeds (anterior and posterior cingulate cortex, insula and dorsolateral prefrontal cortex) and all other brain voxels. Partial least squares was used to compare connectivity prior to treatment between patients and controls, and between patients reaching remission (MADRS ≤ 10) early (within 8 weeks), late (within 16 weeks), or not at all. We replicated previous findings of altered connectivity in patients. In addition, baseline connectivity of the anterior/posterior cingulate and insula seeds differentiated patients with different treatment outcomes. The stability of these differences was established in the largest single-site subsample. Our replication and extension of altered connectivity highlighted previously reported and new differences between patients and controls, and revealed features that might predict remission prior to pharmacotherapy. Trial registration:ClinicalTrials.gov: NCT01655706.

High-resolution virtual brain modeling personalizes deep brain stimulation for treatment-resistant depression: Spatiotemporal response characteristics following stimulation of neural fiber pathways.

Over the past 15 years, deep brain stimulation (DBS) has been actively investigated as a groundbreaking therapy for patients with treatment-resistant depression (TRD); nevertheless, outcomes have varied from patient to patient, with an average response rate of ∼50%. The engagement of specific fiber tracts at the stimulation site has been hypothesized to be an important factor in determining outcomes, however, the resulting individual network effects at the whole-brain scale remain largely unknown. Here we provide a computational framework that can explore each individual's brain response characteristics elicited by selective stimulation of fiber tracts. We use a novel personalized in-silico approach, the Virtual Big Brain, which makes use of high-resolution virtual brain models at a mm-scale and explicitly reconstructs more than 100,000 fiber tracts for each individual. Each fiber tract is active and can be selectively stimulated. Simulation results demonstrate distinct stimulus-induced event-related potentials as a function of stimulation location, parametrized by the contact positions of the electrodes implanted in each patient, even though validation against empirical patient data reveals some limitations (i.e., the need for individual parameter adjustment, and differential accuracy across stimulation locations). This study provides evidence for the capacity of personalized high-resolution virtual brain models to investigate individual network effects in DBS for patients with TRD and opens up novel avenues in the personalized optimization of brain stimulation.

Increased Neural Efficiency in Visual Word Recognition: Evidence from Alterations in Event-Related Potentials and Multiscale Entropy.

Visual word recognition is a relatively effortless process, but recent research suggests the system involved is malleable, with evidence of increases in behavioural efficiency after prolonged lexical decision task (LDT) performance. However, the extent of neural changes has yet to be characterized in this context. The neural changes that occur could be related to a shift from initially effortful performance that is supported by control-related processing, to efficient task performance that is supported by domain-specific processing. To investigate this, we replicated the British Lexicon Project, and had participants complete 16 h of LDT over several days. We recorded electroencephalography (EEG) at three intervals to track neural change during LDT performance and assessed event-related potentials and brain signal complexity. We found that response times decreased during LDT performance, and there was evidence of neural change through N170, P200, N400, and late positive component (LPC) amplitudes across the EEG sessions, which suggested a shift from control-related to domain-specific processing. We also found widespread complexity decreases alongside localized increases, suggesting that processing became more efficient with specific increases in processing flexibility. Together, these findings suggest that neural processing becomes more efficient and optimized to support prolonged LDT performance.

Unaltered EEG spectral power and functional connectivity in REM microstates in frequent nightmare recallers: are nightmares really a REM parasomnia?

BACKGROUND: Frequent nightmares show signs of hyperarousal in NREM sleep. Nevertheless, idiopathic nightmare disorder is considered a REM parasomnia, but the pathophysiology of REM sleep in relation to frequent nightmares is controversial. Cortical oscillatory activity in REM sleep is largely modulated by phasic and tonic REM periods and seems to be linked to different functions and dysfunctions of REM sleep. Here, we examined cortical activity and functional synchronization in frequent nightmare recallers and healthy controls, during phasic and tonic REM. METHODS: Frequent nightmare recallers (N = 22) and healthy controls (N = 22) matched for high dream recall spent two nights in the laboratory. Phasic and tonic REM periods from the second nights' recordings were selected to examine differences in EEG spectral power and weighted phase lag index (WPLI) across groups and REM states. RESULTS: Phasic REM showed increased power and synchronization in delta and gamma frequency bands, whereas tonic REM featured increased power and synchronization in the alpha and beta bands. In the theta band, power was higher during tonic, and synchronization was higher during phasic REM sleep. No differences across nightmare and control participants or patterns representing interactions between the groups and REM microstates emerged. CONCLUSIONS: Our findings do not support the idea that abnormal REM sleep power and synchronization play a role in the pathophysiology of frequent nightmares. Altered REM sleep in nightmare disorder could have been confounded with comorbid pathologies and increased dream recall, or might be linked to more specific state factors (nightmare episodes).

The microstructure of REM sleep: Why phasic and tonic?

Rapid eye movement (REM) sleep is a peculiar neural state that occupies 20-25% of nighttime sleep in healthy human adults and seems to play critical roles in a variety of functions spanning from basic physiological mechanisms to complex cognitive processes. REM sleep exhibits a plethora of transient neurophysiological features, such as eye movements, muscle twitches, and changes in autonomic activity, however, despite its heterogeneous nature, it is usually conceptualized as a homogeneous sleep state. We propose here that differentiating and exploring the fine microstructure of REM sleep, especially its phasic and tonic constituents would provide a novel framework to examine the mechanisms and putative functions of REM sleep. In this review, we show that phasic and tonic REM periods are remarkably different neural states with respect to environmental alertness, spontaneous and evoked cortical activity, information processing, and seem to contribute differently to the dysfunctions of REM sleep in several neurological and psychiatric disorders. We highlight that a distinctive view on phasic and tonic REM microstates would facilitate the understanding of the mechanisms and functions of REM sleep in healthy and pathological conditions.

The paradox of rapid eye movement sleep in the light of oscillatory activity and cortical synchronization during phasic and tonic microstates.

Rapid Eye Movement (REM) sleep is a peculiar neural state showing a combination of muscle atonia and intense cortical activity. REM sleep is usually considered as a unitary state in neuroscientific research; however, it is composed of two different microstates: phasic and tonic REM. These differ in awakening thresholds, sensory processing, and cortical oscillations. Nevertheless, studies examining cortical oscillations during REM microstates are scarce, and used low spatial sampling. Here, we analyzed the data of 18 healthy individuals assessed by high-density sleep EEG recordings. We systematically contrasted phasic and tonic REM periods in terms of topographical distribution, source localization, as well as local, global and long-range synchronization of frequency-specific cortical activity. Tonic periods showed relatively increased high alpha and beta power over frontocentral derivations. In addition, higher frequency components of beta power exhibited increased global synchronization during tonic compared to phasic states. In contrast, in phasic periods we found increased power and synchronization of low frequency oscillations coexisting with increased and synchronized gamma activity. Source localization revealed several multimodal, higher-order associative, as well as sensorimotor areas as potential sources of increased high alpha/beta power during tonic compared to phasic REM. Increased gamma power in phasic REM was attributed to medial prefrontal and right lateralized temporal areas associated with emotional processing. Our findings emphasize the heterogeneous nature of REM sleep, expressed in two microstates with remarkably different neural activity. Considering the microarchitecture of REM sleep may provide new insights into the mechanisms of REM sleep in health and disease.