Neurobiological Underpinnings of Hyperarousal in Depression: A Comprehensive Review.

Patients with major depressive disorder (MDD) exhibit an abnormal physiological arousal pattern known as hyperarousal, which may contribute to their depressive symptoms. However, the neurobiological mechanisms linking this abnormal arousal to depressive symptoms are not yet fully understood. In this review, we summarize the physiological and neural features of arousal, and review the literature indicating abnormal arousal in depressed patients. Evidence suggests that a hyperarousal state in depression is characterized by abnormalities in sleep behavior, physiological (e.g., heart rate, skin conductance, pupil diameter) and electroencephalography (EEG) features, and altered activity in subcortical (e.g., hypothalamus and locus coeruleus) and cortical regions. While recent studies highlight the importance of subcortical-cortical interactions in arousal, few have explored the relationship between subcortical-cortical interactions and hyperarousal in depressed patients. This gap limits our understanding of the neural mechanism through which hyperarousal affects depressive symptoms, which involves various cognitive processes and the cerebral cortex. Based on the current literature, we propose that the hyperconnectivity in the thalamocortical circuit may contribute to both the hyperarousal pattern and depressive symptoms. Future research should investigate the relationship between thalamocortical connections and abnormal arousal in depression, and explore its implications for non-invasive treatments for depression.

The neural correlates of arousal: Ventral posterolateral nucleus-global transient co-activation.

Arousal and awareness are two components of consciousness whose neural mechanisms remain unclear. Spontaneous peaks of global (brain-wide) blood-oxygenation-level-dependent (BOLD) signal have been found to be sensitive to changes in arousal. By contrasting BOLD signals at different arousal levels, we find decreased activation of the ventral posterolateral nucleus (VPL) during transient peaks in the global signal in low arousal and awareness states (non-rapid eye movement sleep and anesthesia) compared to wakefulness and in eyes-closed compared to eyes-open conditions in healthy awake individuals. Intriguingly, VPL-global co-activation remains high in patients with unresponsive wakefulness syndrome (UWS), who exhibit high arousal without awareness, while it reduces in rapid eye movement sleep, a state characterized by low arousal but high awareness. Furthermore, lower co-activation is found in individuals during N3 sleep compared to patients with UWS. These results demonstrate that co-activation of VPL and global activity is critical to arousal but not to awareness.

Brain State Relays Self-Processing and Heartbeat-Evoked Cortical Responses.

The self has been proposed to be grounded in interoceptive processing, with heartbeat-evoked cortical activity as a neurophysiological marker of this processing. However, inconsistent findings have been reported on the relationship between heartbeat-evoked cortical responses and self-processing (including exteroceptive- and mental-self-processing). In this review, we examine previous research on the association between self-processing and heartbeat-evoked cortical responses and highlight the divergent temporal-spatial characteristics and brain regions involved. We propose that the brain state relays the interaction between self-processing and heartbeat-evoked cortical responses and thus accounts for the inconsistency. The brain state, spontaneous brain activity which highly and continuously changes in a nonrandom way, serves as the foundation upon which the brain functions and was proposed as a point in an extremely high-dimensional space. To elucidate our assumption, we provide reviews on the interactions between dimensions of brain state with both self-processing and heartbeat-evoked cortical responses. These interactions suggest the relay of self-processing and heartbeat-evoked cortical responses by brain state. Finally, we discuss possible approaches to investigate whether and how the brain state impacts the self-heart interaction.

Identifying patients with cognitive motor dissociation using resting-state temporal stability.

Using task-dependent neuroimaging techniques, recent studies discovered a fraction of patients with disorders of consciousness (DOC) who had no command-following behaviors but showed a clear sign of awareness as healthy controls, which was defined as cognitive motor dissociation (CMD). However, existing task-dependent approaches might fail when CMD patients have cognitive function (e.g., attention, memory) impairments, in which patients with covert awareness cannot perform a specific task accurately and are thus wrongly considered unconscious, which leads to false-negative findings. Recent studies have suggested that sustaining a stable functional organization over time, i.e., high temporal stability, is crucial for supporting consciousness. Thus, temporal stability could be a powerful tool to detect the patient's cognitive functions (e.g., consciousness), while its alteration in the DOC and its capacity for identifying CMD were unclear. The resting-state fMRI (rs-fMRI) study included 119 participants from three independent research sites. A sliding-window approach was used to investigate global and regional temporal stability, which measured how stable the brain's functional architecture was across time. The temporal stability was compared in the first dataset (36/16 DOC/controls), and then a Support Vector Machine (SVM) classifier was built to discriminate DOC from controls. Furthermore, the generalizability of the SVM classifier was tested in the second independent dataset (35/21 DOC/controls). Finally, the SVM classifier was applied to the third independent dataset, where patients underwent rs-fMRI and brain-computer interface assessment (4/7 CMD/potential non-CMD), to test its performance in identifying CMD. Our results showed that global and regional temporal stability was impaired in DOC patients, especially in regions of the cingulo-opercular task control network, default-mode network, fronto-parietal task control network, and salience network. Using temporal stability as the feature, the SVM model not only showed good performance in the first dataset (accuracy = 90%), but also good generalizability in the second dataset (accuracy = 84%). Most importantly, the SVM model generalized well in identifying CMD in the third dataset (accuracy = 91%). Our preliminary findings suggested that temporal stability could be a potential tool to assist in diagnosing CMD. Furthermore, the temporal stability investigated in this study also contributed to a deeper understanding of the neural mechanism of consciousness.

Eyes-Open and Eyes-Closed Resting State Network Connectivity Differences.

Resting state networks comprise several brain regions that exhibit complex patterns of interaction. Switching from eyes closed (EC) to eyes open (EO) during the resting state modifies these patterns of connectivity, but precisely how these change remains unclear. Here we use functional magnetic resonance imaging to scan healthy participants in two resting conditions (viz., EC and EO). Seven resting state networks were chosen for this study: salience network (SN), default mode network (DMN), central executive network (CEN), dorsal attention network (DAN), visual network (VN), motor network (MN) and auditory network (AN). We performed functional connectivity (FC) analysis for each network, comparing the FC maps for both EC and EO. Our results show increased connectivity between most networks during EC relative to EO, thereby suggesting enhanced integration during EC and greater modularity or specialization during EO. Among these networks, SN is distinctive: during the transition from EO to EC it evinces increased connectivity with DMN and decreased connectivity with VN. This change might imply that SN functions in a manner analogous to a circuit switch, modulating resting state relations with DMN and VN, when transitioning between EO and EC.