Cross-Frequency Coupling as a Biomarker for Early Stroke Recovery.

BACKGROUND: The application of neuroimaging-based biomarkers in stroke has enriched our understanding of post-stroke recovery mechanisms, including alterations in functional connectivity based on synchronous oscillatory activity across various cortical regions. Phase-amplitude coupling, a type of cross-frequency coupling, may provide additional mechanistic insight. OBJECTIVE: To determine how the phase of prefrontal cortex delta (1-3 Hz) oscillatory activity mediates the amplitude of motor cortex beta (13-20 Hz) oscillations in individual's early post-stroke. METHODS: Participants admitted to an inpatient rehabilitation facility completed resting and task-based EEG recordings and motor assessments around the time of admission and discharge along with structural neuroimaging. Unimpaired controls completed EEG procedures during a single visit. Mixed-effects linear models were performed to assess within- and between-group differences in delta-beta prefrontomotor coupling. Associations between coupling and motor status and injury were also determined. RESULTS: Thirty individuals with stroke and 17 unimpaired controls participated. Coupling was greater during task versus rest conditions for all participants. Though coupling during affected extremity task performance decreased during hospitalization, coupling remained elevated at discharge compared to controls. Greater baseline coupling was associated with better motor status at admission and discharge and positively related to motor recovery. Coupling demonstrated both positive and negative associations with injury involving measures of lesion volume and overlap injury to anterior thalamic radiation, respectively. CONCLUSIONS: This work highlights the utility of prefrontomotor cross-frequency coupling as a potential motor status and recovery biomarker in stroke. The frequency- and region-specific neurocircuitry featured in this work may also facilitate novel treatment strategies in stroke.

Hierarchical consciousness: the Nested Observer Windows model.

Foremost in our experience is the intuition that we possess a unified conscious experience. However, many observations run counter to this intuition: we experience paralyzing indecision when faced with two appealing behavioral choices, we simultaneously hold contradictory beliefs, and the content of our thought is often characterized by an internal debate. Here, we propose the Nested Observer Windows (NOW) Model, a framework for hierarchical consciousness wherein information processed across many spatiotemporal scales of the brain feeds into subjective experience. The model likens the mind to a hierarchy of nested mosaic tiles-where an image is composed of mosaic tiles, and each of these tiles is itself an image composed of mosaic tiles. Unitary consciousness exists at the apex of this nested hierarchy where perceptual constructs become fully integrated and complex behaviors are initiated via abstract commands. We define an observer window as a spatially and temporally constrained system within which information is integrated, e.g. in functional brain regions and neurons. Three principles from the signal analysis of electrical activity describe the nested hierarchy and generate testable predictions. First, nested observer windows disseminate information across spatiotemporal scales with cross-frequency coupling. Second, observer windows are characterized by a high degree of internal synchrony (with zero phase lag). Third, observer windows at the same spatiotemporal level share information with each other through coherence (with non-zero phase lag). The theoretical framework of the NOW Model accounts for a wide range of subjective experiences and a novel approach for integrating prominent theories of consciousness.

Multiplexed Levels of Cognitive Control through Delta and Theta Neural Oscillations.

Cognitive control allows behavior to be guided according to environmental contexts and internal goals. During cognitive control tasks, fMRI analyses typically reveal increased activation in frontal and parietal networks, and EEG analyses reveal increased amplitude of neural oscillations in the delta/theta band (2-3, 4-7 Hz) in frontal electrodes. Previous studies proposed that theta-band activity reflects the maintenance of rules associating stimuli to appropriate actions (i.e., the rule set), whereas delta synchrony is specifically associated with the control over the context for when to apply a set of rules (i.e., the rule abstraction). We tested these predictions using EEG and fMRI data collected during the performance of a hierarchical cognitive control task that manipulated the level of abstraction of task rules and their set-size. Our results show a clear separation of delta and theta oscillations in the control of rule abstraction and of stimulus-action associations, respectively, in distinct frontoparietal association networks. These findings support a model by which frontoparietal networks operate through dynamic, multiplexed neural processes.

Internal Representations Are Prioritized by Frontoparietal Theta Connectivity and Suppressed by alpha Oscillation Dynamics: Evidence from Concurrent Transcranial Magnetic Stimulation EEG and Invasive EEG.

Control over internal representations requires the prioritization of relevant information and suppression of irrelevant information. The frontoparietal network exhibits prominent neural oscillations during these distinct cognitive processes. Yet, the causal role of this network-scale activity is unclear. Here, we targeted theta-frequency frontoparietal coherence and dynamic alpha oscillations in the posterior parietal cortex using online rhythmic transcranial magnetic stimulation (TMS) in women and men while they prioritized or suppressed internally maintained working memory (WM) representations. Using concurrent high-density EEG, we provided evidence that we acutely drove the targeted neural oscillation and TMS improved WM capacity only when the evoked activity corresponded with the desired cognitive process. To suppress an internal representation, we increased the amplitude of lateralized alpha oscillations in the posterior parietal cortex contralateral to the irrelevant visual field. For prioritization, we found that TMS to the prefrontal cortex increased theta-frequency connectivity in the prefrontoparietal network contralateral to the relevant visual field. To understand the spatial specificity of these effects, we administered the WM task to participants with implanted electrodes. We found that theta connectivity during prioritization was directed from the lateral prefrontal to the superior posterior parietal cortex. Together, these findings provide causal evidence in support of a model where a frontoparietal theta network prioritizes internally maintained representations and alpha oscillations in the posterior parietal cortex suppress irrelevant representations.

Mental Activity as the Bridge between Neural Biomarkers and Symptoms of Psychiatric Illness.

The Research Domain Criteria (RDoC) initiative challenges researchers to build neurobehavioral models of psychiatric illness with the hope that such models identify better targets that will yield more effective treatment. However, a guide for building such models was not provided and symptom heterogeneity within Diagnostic Statistical Manual categories has hampered progress in identifying endophenotypes that underlie mental illness. We propose that the best chance to discover viable biomarkers and treatment targets for psychiatric illness is to investigate a triangle of relationships: severity of a specific psychiatric symptom that correlates to mental activity that correlates to a neural activity signature. We propose that this is the minimal model complexity required to advance the field of psychiatry. With an understanding of how neural activity relates to the experience of the patient, a genuine understanding for how treatment imparts its therapeutic effect is possible. After the discovery of this three-fold relationship, causal testing is required in which the neural activity pattern is directly enhanced or suppressed to provide causal, instead of just correlational, evidence for the biomarker. We suggest using non-invasive brain stimulation (NIBS) as these techniques provide tools to precisely manipulate spatial and temporal activity patterns. We detail how this approach enabled the discovery of two orthogonal electroencephalography (EEG) activity patterns associated with anhedonia and anxiosomatic symptoms in depression that can serve as future treatment targets. Altogether, we propose a systematic approach for building neurobehavioral models for dimensional psychiatry.

Reward-Based Decision-Making Engages Distinct Modes of Cross-Frequency Coupling.

Prefrontal cortex exerts control over sensory and motor systems via cross-frequency coupling. However, it is unknown whether these signals play a role in reward-based decision-making and whether such dynamic network configuration is altered in a major depressive episode. We recruited men and women with and without depression to perform a streamlined version of the Expenditure of Effort for Reward Task during recording of electroencephalography. Goal-directed behavior was quantified as willingness to exert physical effort to obtain reward, and reward-evaluation was the degree to which the decision to exert effort was modulated by incentive level. We found that the amplitude of frontal-midline theta oscillations was greatest in participants with the greatest reward-evaluation. Furthermore, coupling between frontal theta phase and parieto-occipital gamma amplitude was positively correlated with reward-evaluation. In addition, goal-directed behavior was positively correlated with coupling between frontal delta phase to motor beta amplitude. Finally, we performed a factor analysis to derive 2 symptom dimensions and found that mood symptoms positively tracked with reward-evaluation and motivation symptoms negatively tracked with goal-directed behavior. Altogether, these results provide evidence that 2 aspects of reward-based decision-making are instantiated by different modes of prefrontal top-down control and are modulated in different symptom dimensions of depression.

Reduction in Left Frontal Alpha Oscillations by Transcranial Alternating Current Stimulation in Major Depressive Disorder Is Context Dependent in a Randomized Clinical Trial.

BACKGROUND: Left frontal alpha oscillations are associated with decreased approach motivation and have been proposed as a target for noninvasive brain stimulation for the treatment of depression and anhedonia. Indeed, transcranial alternating current stimulation (tACS) at the alpha frequency reduced left frontal alpha power and was associated with a higher response rate than placebo stimulation in patients with major depressive disorder (MDD) in a recent double-blind, placebo-controlled clinical trial. METHODS: In this current study, we aimed to replicate successful target engagement by delineating the effects of a single session of bifrontal tACS at the individualized alpha frequency (IAF-tACS) on alpha oscillations in patients with MDD. Eighty-four participants were randomized to receive verum or sham IAF-tACS. Electrical brain activity was recorded during rest and while viewing emotionally salient images before and after stimulation to investigate whether the modulation of alpha oscillation by tACS exhibited specificity with regard to valence. RESULTS: In agreement with the previous study of tACS in MDD, we found that a single session of bifrontal IAF-tACS reduced left frontal alpha power during the resting state when compared with placebo. Furthermore, the reduction of left frontal alpha oscillation by tACS was specific for stimuli with positive valence. In contrast, these effects on left frontal alpha power were not found in healthy control participants. CONCLUSIONS: Together, these results support an important role of tACS in reducing left frontal alpha oscillations as a future treatment for MDD.

A guide for concurrent TMS-fMRI to investigate functional brain networks.

Transcranial Magnetic Stimulation (TMS) allows for the direct activation of neurons in the human neocortex and has proven to be fundamental for causal hypothesis testing in cognitive neuroscience. By administering TMS concurrently with functional Magnetic Resonance Imaging (fMRI), the effect of cortical TMS on activity in distant cortical and subcortical structures can be quantified by varying the levels of TMS output intensity. However, TMS generates significant fluctuations in the fMRI time series, and their complex interaction warrants caution before interpreting findings. We present the methodological challenges of concurrent TMS-fMRI and a guide to minimize induced artifacts in experimental design and post-processing. Our study targeted two frontal-striatal circuits: primary motor cortex (M1) projections to the putamen and lateral prefrontal cortex (PFC) projections to the caudate in healthy human participants. We found that TMS parametrically increased the BOLD signal in the targeted region and subcortical projections as a function of stimulation intensity. Together, this work provides practical steps to overcome common challenges with concurrent TMS-fMRI and demonstrates how TMS-fMRI can be used to investigate functional brain networks.

Causal role of frontal-midline theta in cognitive effort: a pilot study.

Frontal-midline theta (FMT) oscillations are increased in amplitude during cognitive control tasks. Since these tasks often conflate cognitive control and cognitive effort, it remains unknown if FMT amplitude maps onto cognitive control or effort. To address this gap, we utilized the glucose facilitation effect to manipulate cognitive effort without changing cognitive control demands. We performed a single-blind, crossover human study in which we provided participants with a glucose drink (control session: volume-matched water) to reduce cognitive effort and improve performance on a visuospatial working memory task. Following glucose consumption, participants performed the working memory task at multiple time points of a 3-h window to sample across the rise and fall of blood glucose. Using high-density electroencephalography (EEG), we calculated FMT amplitude during the delay period of the working memory task. Source localization analysis revealed that FMT oscillations originated from bilateral prefrontal cortex. We found that glucose increased working memory accuracy during the high working memory load condition but decreased FMT amplitude. The decrease in FMT amplitude coincided with both peak blood glucose elevation and peak performance enhancement for glucose relative to water. Therefore, the positive association between glucose consumption and task performance provided causal evidence that the amplitude of FMT oscillations may correspond to cognitive effort, rather than cognitive control. Due to the COVID-19 pandemic, data collection was terminated prematurely; the preliminary nature of these findings due to small sample size should be contextualized by rigorous experimental design and use of a novel causal perturbation to dissociate cognitive effort and cognitive control.NEW & NOTEWORTHY We investigated whether frontal-midline theta (FMT) oscillations tracked with cognitive control or cognitive effort by simultaneous manipulation of cognitive control demands in a working memory task and causal perturbation of cognitive effort using glucose consumption. Facilitation of performance from glucose consumption corresponded with decreased FMT amplitude, which provided preliminary causal evidence for a relationship between FMT amplitude with cognitive effort.

The development of theta and alpha neural oscillations from ages 3 to 24 years.

Intrinsic, unconstrained neural activity exhibits rich spatial, temporal, and spectral organization that undergoes continuous refinement from childhood through adolescence. The goal of this study was to investigate the development of theta (4-8 Hertz) and alpha (8-12 Hertz) oscillations from early childhood to adulthood (years 3-24), as these oscillations play a fundamental role in cognitive function. We analyzed eyes-open, resting-state EEG data from 96 participants to estimate genuine oscillations separately from the aperiodic (1/f) signal. We examined age-related differences in the aperiodic signal (slope and offset), as well as the peak frequency and power of the dominant posterior oscillation. For the aperiodic signal, we found that both the aperiodic slope and offset decreased with age. For the dominant oscillation, we found that peak frequency, but not power, increased with age. Critically, early childhood (ages 3-7) was characterized by a dominance of theta oscillations in posterior electrodes, whereas peak frequency of the dominant oscillation in the alpha range increased between ages 7 and 24. Furthermore, theta oscillations displayed a topographical transition from dominance in posterior electrodes in early childhood to anterior electrodes in adulthood. Our results provide a quantitative description of the development of theta and alpha oscillations.

Conducting double-blind placebo-controlled clinical trials of transcranial alternating current stimulation (tACS).

Many psychiatric and neurological illnesses can be conceptualized as oscillopathies defined as pathological changes in brain network oscillations. We previously proposed the application of rational design for the development of non-invasive brain stimulation for the modulation and restoration of cortical oscillations as a network therapeutic. Here, we show how transcranial alternating current stimulation (tACS), which applies a weak sine-wave electric current to the scalp, may serve as a therapeutic platform for the treatment of CNS illnesses. Recently, an initial series of double-blind, placebo-controlled treatment trials of tACS have been published. Here, we first map out the conceptual underpinnings of such trials with focus on target identification, engagement, and validation. Then, we discuss practical aspects that need to be considered for successful trial execution, with particular regards to ensuring successful study blind. Finally, we briefly review the few published double-blind tACS trials and conclude with a proposed roadmap to move the field forward with the goal of moving from pilot trials to convincing efficacy studies of tACS.

Targeting neural oscillations with transcranial alternating current stimulation.

Neural oscillations at the network level synchronize activity between regions and temporal scales. Transcranial alternating current stimulation (tACS), the delivery of low-amplitude electric current to the scalp, provides a tool for investigating the causal role of neural oscillations in cognition. The parameter space for tACS is vast and optimization is required in terms of temporal and spatial targeting. We review emerging techniques and suggest novel approaches that capitalize on the non-sinusoidal and transient nature of neural oscillations and leverage the flexibility provided by a customizable electrode montage and electrical waveform. The customizability and safety profile of tACS make it a promising tool for precision intervention in psychiatric illnesses.

Disinhibition of right inferior frontal gyrus underlies alpha asymmetry in women with low testosterone.

Asymmetrical expression of alpha oscillations in the frontal cortex, increased left relative to right, is a phenotype associated with increased behavioral inhibition and mood-related psychiatric illnesses. However, investigations of frontal alpha asymmetry in mood-disorders have yielded inconsistent findings. A better understanding of factors that contribute to individual differences is required to establish a useful biomarker for the diagnosis and treatment of mood and stress related disorders. A novel factor is hormone concentration, as steroid hormones play a prominent role in regulating mood and stress. To investigate this question, concentrations of testosterone and estradiol were sampled. Multiple linear regression revealed that low levels of testosterone correlated with greater frontal alpha asymmetry in women. Source localization found that frontal asymmetry was driven by decreased alpha power in right inferior frontal gyrus that correlated with increased behavioral inhibition in women. Together, these findings might explain inconsistencies in previous investigation on frontal alpha asymmetry.

Causal role of cross-frequency coupling in distinct components of cognitive control.

Cognitive control is the capacity to guide motor and perceptual systems towards abstract goals. High-frequency neural oscillations related to motor activity in the beta band (13-30 Hz) and to visual processing in the gamma band (>30 Hz) are known to be modulated by cognitive control signals. One proposed mechanism for cognitive control is via cross-frequency coupling whereby low frequency network oscillations in prefrontal cortex (delta from 2-3 Hz and theta from 4-8 Hz) guide the expression of motor-related activity in action planning and guide perception-related activity in memory access. However, there is no causal evidence for cross-frequency coupling in these dissociable components of cognitive control. To address this important gap in knowledge, we delivered cross-frequency transcranial alternating current stimulation (CF-tACS) during performance of a task that manipulated cognitive control demands along two dimensions: the abstraction of the rules of the task (nested levels of action selection) that increased delta-beta coupling and the number of rules (set-size held in memory) that increased theta-gamma coupling. As hypothesized, we found that CF-tACS increased the targeted phase-amplitude coupling and modulated task performance of the associated cognitive control component. These findings provide causal evidence that prefrontal cortex orchestrates different components of cognitive control via two different cross-frequency coupling modalities.