Arousal Network Research Articles

Histology-guided MRI segmentation of brainstem nuclei critical to consciousness.

While substantial progress has been made in mapping the connectivity of cortical networks responsible for conscious awareness, neuroimaging analysis of subcortical arousal networks that modulate arousal (i.e., wakefulness) has been limited by a lack of a robust segmentation procedures for brainstem arousal nuclei. Automated segmentation of brainstem arousal nuclei is an essential step toward elucidating the physiology of arousal in human consciousness and the pathophysiology of disorders of consciousness. We created a probabilistic atlas of brainstem arousal nuclei built on diffusion MRI scans of five ex vivo human brain specimens scanned at 750 μm isotropic resolution. Labels of arousal nuclei used to generate the probabilistic atlas were manually annotated with reference to nucleus-specific immunostaining in two of the five brain specimens. We then developed a Bayesian segmentation algorithm that utilizes the probabilistic atlas as a generative model and automatically identifies brainstem arousal nuclei in a resolution- and contrast-agnostic manner. The segmentation method displayed high accuracy in both healthy and lesioned in vivo T1 MRI scans and high test-retest reliability across both T1 and T2 MRI contrasts. Finally, we show that the segmentation algorithm can detect volumetric changes and differences in magnetic susceptibility within brainstem arousal nuclei in Alzheimer's disease and traumatic coma, respectively. We release the probabilistic atlas and Bayesian segmentation tool in FreeSurfer to advance the study of human consciousness and its disorders.

A human brain network linked to restoration of consciousness after deep brain stimulation.

Disorders of consciousness (DoC) are states of impaired arousal or awareness. Deep brain stimulation (DBS) is a potential treatment, but outcomes vary, possibly due to differences in patient characteristics, electrode placement, or stimulation of specific brain networks. We studied 40 patients with DoC who underwent DBS targeting the thalamic centromedian-parafascicular complex. Better-preserved gray matter, especially in the striatum, correlated with consciousness improvement. Stimulation was most effective when electric fields extended into parafascicular and subparafascicular nuclei-ventral to the centromedian nucleus, near the midbrain- and when it engaged projection pathways of the ascending arousal network, including the hypothalamus, brainstem, and frontal lobe. Moreover, effective DBS sites were connected to networks similar to those underlying impaired consciousness due to generalized absence seizures and acquired lesions. These findings support the therapeutic potential of DBS for DoC, emphasizing the importance of precise targeting and revealing a broader link between effective DoC treatment and mechanisms underlying other conscciousness-impairing conditions.

State-specific Regulation of Electrical Stimulation in the Intralaminar Thalamus of Macaque Monkeys: Network and Transcriptional Insights into Arousal.

Long-range thalamocortical communication is central to anesthesia-induced loss of consciousness and its reversal. However, isolating the specific neural networks connecting thalamic nuclei with various cortical regions for state-specific anesthesia regulation is challenging, with the biological underpinnings still largely unknown. Here, simultaneous electroencephalogram-fuctional magnetic resonance imaging(EEG-fMRI) and deep brain stimulation are applied to the intralaminar thalamus in macaques under finely-tuned propofol anesthesia. This approach led to the identification of an intralaminar-driven network responsible for rapid arousal during slow-wave oscillations. A network-based RNA-sequencing analysis is conducted of region-, layer-, and cell-specific gene expression data from independent transcriptomic atlases and identifies 2489 genes preferentially expressed within this arousal network, notably enriched in potassium channels and excitatory, parvalbumin-expressing neurons, and oligodendrocytes. Comparison with human RNA-sequencing data highlights conserved molecular and cellular architectures that enable the matching of homologous genes, protein interactions, and cell types across primates, providing novel insight into network-focused transcriptional signatures of arousal.

Multimodal MRI reveals brainstem connections that sustain wakefulness in human consciousness.

Consciousness is composed of arousal (i.e., wakefulness) and awareness. Substantial progress has been made in mapping the cortical networks that underlie awareness in the human brain, but knowledge about the subcortical networks that sustain arousal in humans is incomplete. Here, we aimed to map the connectivity of a proposed subcortical arousal network that sustains wakefulness in the human brain, analogous to the cortical default mode network (DMN) that has been shown to contribute to awareness. We integrated data from ex vivo diffusion magnetic resonance imaging (MRI) of three human brains, obtained at autopsy from neurologically normal individuals, with immunohistochemical staining of subcortical brain sections. We identified nodes of the proposed default ascending arousal network (dAAN) in the brainstem, hypothalamus, thalamus, and basal forebrain. Deterministic and probabilistic tractography analyses of the ex vivo diffusion MRI data revealed projection, association, and commissural pathways linking dAAN nodes with one another and with DMN nodes. Complementary analyses of in vivo 7-tesla resting-state functional MRI data from the Human Connectome Project identified the dopaminergic ventral tegmental area in the midbrain as a widely connected hub node at the nexus of the subcortical arousal and cortical awareness networks. Our network-based autopsy methods and connectivity data provide a putative neuroanatomic architecture for the integration of arousal and awareness in human consciousness.

In vivo tau deposition in the brain stem nuclei and circadian rest‐activity rhythm change in non‐demented older adults

AbstractBackgroundCircadian rest‐activity rhythm (RAR) alterations are common in the early stage of Alzheimer’s disease (AD) disease. Given that the brainstem nuclei, the locus coeruleus (LC) and dorsal raphe nucleus (DRN) in particular, play key roles in modulating arousal and the sleep‐wake cycle, tau pathology in the brain stem nuclei, which occurs even before cortical tau progression, may relate to circadian RAR alteration in older individuals. Therefore, we aimed to test the hypothesis that in vivo tau deposition in the LC and DRN correlates with circadian RAR in non‐demented older adults.MethodA total of 63 non‐demented older adults from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) were included. All participants underwent [11C] PiB PET and [18F] AV1451‐PET. Circadian RAR variables were measured using actigraphy for 8 consecutive days. Tau deposition of the LC and DRN (LC‐tau and DRN‐tau, respectively) was measured in the regions of interest (ROI) masks for each participant prepared in native space using the Harvard arousal network atlas for the LC and DRN. For the purpose of comparison, tau deposition in the substantia nigra (SN‐tau) was also measured in the neuromelanin sensitive MRI‐based ROI for the SN.ResultIncreased LC‐tau and DRN‐tau were significantly correlated with delayed acrophase (ß = 0.303, p = 0.024 for LC‐tau and ß = 0.398, p = 0.003 for DRN‐tau; Table 1 & Figure 1). In contrast, SN‐tau did not related with any RAR variables. Even after controlling for global tau deposition, the significance did not changed (ß = 0.321, p = 0.021 for LC‐tau and ß = 0.367, p = 0.008 for DRN‐tau, Table 1). In addition, Aß positivity showed a significant moderation effect on the relationship between LC‐tau with acrophase. Subgroup analyses showed that increased LC‐tau significantly related with delayed acrophase in Aß‐positivegroup (ß = 0.427, p = 0.004), but did not in Aß‐negative group (ß = 0.099, p = 0.615)(Figure 2)ConclusionOur findings support the possibility that the tau pathology in the LC and DRN underlie circadian RAR alteration, more specifically delayed phase, in non‐demented older adults. In addition, such relationship appears to be more prominent in individuals with brain Aß pathology.

In vivo tau deposition in the brain stem nuclei and circadian rest‐activity rhythm change in non‐demented older adults

AbstractBackgroundCircadian rest‐activity rhythm (RAR) alterations are common in the early stage of Alzheimer’s disease (AD) disease. Given that the brainstem nuclei, the locus coeruleus (LC) and dorsal raphe nucleus (DRN) in particular, play key roles in modulating arousal and the sleep‐wake cycle, tau pathology in the brain stem nuclei, which occurs even before cortical tau progression, may relate to circadian RAR alteration in older individuals. Therefore, we aimed to test the hypothesis that in vivo tau deposition in the LC and DRN correlates with circadian RAR in non‐demented older adults.MethodA total of 63 non‐demented older adults from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) were included. All participants underwent [11C] PiB PET and [18F] AV1451‐PET. Circadian RAR variables were measured using actigraphy for 8 consecutive days. Tau deposition of the LC and DRN (LC‐tau and DRN‐tau, respectively) was measured in the regions of interest (ROI) masks for each participant prepared in native space using the Harvard arousal network atlas for the LC and DRN. For the purpose of comparison, tau deposition in the substantia nigra (SN‐tau) was also measured in the neuromelanin sensitive MRI‐based ROI for the SN.ResultIncreased LC‐tau and DRN‐tau were significantly correlated with delayed acrophase (β = 0.303, p = 0.024 for LC‐tau and β = 0.398, p = 0.003 for DRN‐tau; Table 1 & Figure 1). In contrast, SN‐tau did not related with any RAR variables. Even after controlling for global tau deposition, the significance did not changed (β = 0.321, p = 0.021 for LC‐tau and β = 0.367, p = 0.008 for DRN‐tau, Table 1). In addition, Aβ positivity showed a significant moderation effect on the relationship between LC‐tau with acrophase. Subgroup analyses showed that increased LC‐tau significantly related with delayed acrophase in Aβ‐positivegroup (β = 0.427, p = 0.004), but did not in Aβ‐negative group (β = 0.099, p = 0.615)(Figure 2)ConclusionOur findings support the possibility that the tau pathology in the LC and DRN underlie circadian RAR alteration, more specifically delayed phase, in non‐demented older adults. In addition, such relationship appears to be more prominent in individuals with brain Aβ pathology.

Persistent cognitive slowing in post-COVID patients: longitudinal study over 6 months

BackgroundFatigue is a frequent and one of the most debilitating symptoms in post-COVID syndrome (PCS). Recently, we proposed that fatigue is caused by hypoactivity of the brain’s arousal network and reflected by a reduction of cognitive processing speed. However, it is unclear whether cognitive slowing is revealed by standard neuropsychological tests, represents a selective deficit, and how it develops over time.ObjectivesThis prospective study assesses whether PCS patients show deficits particularly in tests relying on processing speed and provides the first longitudinal assessment focusing on processing speed in PCS patients.MethodsEighty-eight PCS patients with cognitive complaints and 50 matched healthy controls underwent neuropsychological assessment. Seventy-seven patients were subsequently assessed at 6-month follow-up. The Test for Attentional Performance measured tonic alertness as primary study outcome and additional attentional functions. The Neuropsychological Assessment Battery evaluated all key cognitive domains.ResultsPatients showed cognitive slowing indicated by longer reaction times compared to control participants (r = 0.51, p < 0.001) in a simple-response tonic alertness task and in all more complex tasks requiring speeded performance. Reduced alertness correlated with higher fatigue (r = − 0.408, p < 0.001). Alertness dysfunction remained unchanged at 6-month follow-up (p = 0.240) and the same was true for most attention tasks and cognitive domains.ConclusionHypoarousal is a core deficit in PCS which becomes evident as a selective decrease of processing speed observed in standard neuropsychological tests. This core deficit persists without any signs of amelioration over a 6-month period of time.

Understanding Focal Seizures in Adults: A Comprehensive Review.

Focal or partial seizures are a common neurological disorder affecting adults. This review aims to provide an in-depth understanding of focal seizures in adults, including their classification, clinical presentation, etiology, diagnosis, and management. This article seeks to enhance awareness and knowledge among medical professionals and the general public by exploring the latest research and clinical insights. Standard electroencephalography (EEG) and recordings in presurgical electrode depth in humans provide a clear definition of patterns similar to focal seizures. Models of animals with partial seizures and epilepsy mimic seizure patterns with comparable characteristics. However, the network factors supporting interictal spikes, as well as the start, development, and end of seizures remain obscure. According to recent research, inhibitory networks are heavily implicated at the beginning of seizures, and extracellular potassium alterations help start and maintain seizure continuation. An increase in network synchronization, which may be caused by both excitatory and inhibitory pathways, is correlated with the cessation of a partial seizure. Recent research on temporal lobe focal seizures in human and animal models leads to the hypothesis that the active blocking of subcortical arousal processes brings on unconsciousness. Brainstem, basal forebrain, and thalamic arousal networks' neuronal firing is diminished during focal limbic seizures, and cortical arousal can be recovered when subcortical arousal circuits are engaged. These results suggest that thalamic neurostimulation may be therapeutic to restore arousal and consciousness during and after seizures. Targeted subcortical stimulation may increase arousal and consciousness when current treatments cannot halt seizures, enhancing safety and psychosocial function for epileptic patients. We embark on an investigation into adult focal seizures in this thorough review that goes beyond a cursory knowledge of their clinical symptoms.

Sleep characteristics and pain in middle-aged and older adults: Sex-specific impact of physical and sitting activity

ObjectivesThe relationship between poor sleep health and worse pain is established. Physical activity has been successful in reducing chronic pain and improving sleep in aging adults. Despite known sex differences (more women than men experiencing chronic pain and insomnia), sex-specific patterns of interactive associations between physical activity, sleep, and pain remain unexplored. This study tested whether physical and sitting activity moderated associations between sleep characteristics and pain intensity, and whether sex further moderated these relationships. MethodsParticipants aged 50+ (N = 170, Mage = 64.34, 72 women) completed an online survey measuring pre-sleep arousal (Pre-sleep Arousal Scale), sleep (Pittsburgh Sleep Quality Index), past month average pain intensity, and physical activity (International Physical Activity Questionnaire). Multiple regressions evaluated whether minutes of physical activity (total, vigorous, moderate, walking) or sitting activity, pre-sleep arousal, sleep, sex, or their interaction was associated with pain. Analyses controlled for education, difficulty walking, body mass index, total medical conditions, pain medication, and depressive/anxiety symptoms. ResultsIn women, vigorous activity interacted with total pre-sleep arousal and somatic pre-sleep arousal in its association with pain. Higher total arousal and somatic arousal were associated with worse pain intensity only for women who reported highest levels of vigorous activity. No such associations were observed for men or for other physical or sitting activity levels. ConclusionsVigorous physical activity may exacerbate the association between more pre-sleep arousal and worse pain in middle-aged and older women. Research should explore potential sex-specific mechanisms (e.g., inflammatory cytokines, arousal neural networks) underlying these results.

Pupil-linked arousal modulates network-level EEG signatures of attention reorienting during immersive multitasking

Objective. When multitasking, we must dynamically reorient our attention between different tasks. Attention reorienting is thought to arise through interactions of physiological arousal and brain-wide network dynamics. In this study, we investigated the relationship between pupil-linked arousal and electroencephalography (EEG) brain dynamics in a multitask driving paradigm conducted in virtual reality. We hypothesized that there would be an interaction between arousal and EEG dynamics and that this interaction would correlate with multitasking performance. Approach. We collected EEG and eye tracking data while subjects drove a motorcycle through a simulated city environment, with the instructions to count the number of target images they observed while avoiding crashing into a lead vehicle. The paradigm required the subjects to continuously reorient their attention between the two tasks. Subjects performed the paradigm under two conditions, one more difficult than the other. Main results. We found that task difficulty did not strongly correlate with pupil-linked arousal, and overall task performance increased as arousal level increased. A single-trial analysis revealed several interesting relationships between pupil-linked arousal and task-relevant EEG dynamics. Employing exact low-resolution electromagnetic tomography, we found that higher pupil-linked arousal led to greater EEG oscillatory activity, especially in regions associated with the dorsal attention network and ventral attention network (VAN). Consistent with our hypothesis, we found a relationship between EEG functional connectivity and pupil-linked arousal as a function of multitasking performance. Specifically, we found decreased functional connectivity between regions in the salience network (SN) and the VAN as pupil-linked arousal increased, suggesting that improved multitasking performance at high arousal levels may be due to a down-regulation in coupling between the VAN and the SN. Our results suggest that when multitasking, our brain rebalances arousal-based reorienting so that individual task demands can be met without prematurely reorienting to competing tasks.

Intracranial electrical stimulation of corticolimbic sites modulates arousal in humans

BackgroundHumans routinely shift their sleepiness and wakefulness levels in response to emotional factors. The diversity of emotional factors that modulates sleep-wake levels suggests that the ascending arousal network may be intimately linked with networks that mediate mood. Indeed, while animal studies have identified select limbic structures that play a role in sleep-wake regulation, the breadth of corticolimbic structures that directly modulates arousal in humans remains unknown. ObjectiveWe investigated whether select regional activation of the corticolimbic network through direct electrical stimulation can modulate sleep-wake levels in humans, as measured by subjective experience and behavior. MethodsWe performed intensive inpatient stimulation mapping in two human participants with treatment resistant depression, who underwent intracranial implantation with multi-site, bilateral depth electrodes. Stimulation responses of sleep-wake levels were measured by subjective surveys (i.e. Stanford Sleepiness Scale and visual-analog scale of energy) and a behavioral arousal score. Biomarker analyses of sleep-wake levels were performed by assessing spectral power features of resting-state electrophysiology. ResultsOur findings demonstrated three regions whereby direct stimulation modulated arousal, including the orbitofrontal cortex (OFC), subgenual cingulate (SGC), and, most robustly, ventral capsule (VC). Modulation of sleep-wake levels was frequency-specific: 100Hz OFC, SGC, and VC stimulation promoted wakefulness, whereas 1Hz OFC stimulation increased sleepiness. Sleep-wake levels were correlated with gamma activity across broad brain regions. ConclusionsOur findings provide evidence for the overlapping circuitry between arousal and mood regulation in humans. Furthermore, our findings open the door to new treatment targets and the consideration of therapeutic neurostimulation for sleep-wake disorders.

Tau deposition in the locus coeruleus and depression in cognitively unimpaired older adults

AbstractBackgroundDepression is a common manifestation of Alzheimer’s disease (AD) and frequently observed at the early phase of the disease. Several postmortem studies demonstrated that tau deposition was found at the brainstem nuclei including the locus coeruleus (LC) and dossal raphe nucleus (DRN) (3, 4), even before early Braak stages of neurofibrillary tangle pathology. Given the disturbance of monoaminergic system is related to depression in general, tau deposition in the LC or DRN may underlie depression in late‐life, as suggested in a couple of postmortem studies. In this context, we tried to examine the hypothetical association between in vivo tau depostion at the brain stem monoaminergic nuclei and depression in cognitively unimpaired older adults.MethodA total of 69 cognitively unimpaired older adults from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) were included. All participants underwent comprehensive clinical assessment including the Hamilton Rating Scale for Depression (HRSD) and [18F] AV‐1451 positron emission tomography. Tau deposition in the LC and DRN was measured using the Harvard Ascending Arousal Network Atlas (AAN). Tau deposition in the pons was also assessed as a non‐monoaminergic control for comparison. Age, education, sex, and apolipoprotein E ε4 positivity were controlled as covariates in the analyses for the association between brain stem tau and HRSD score.ResultTau deposition in the LC was significantly associated with HRSD total score (β = 3.861, P = .009). In contrast, there was no significant association between tau deposition in the DRN and HRSD score (β = 2.229, P = .090). Tau deposition in the pons was also not related to HRSD score (β = 1.632, P = .207).ConclusionThe findings support the possibility that alteration of the noradrenergic neurons in the LC by tau pathology may underlie depressive manifestation in cognitively unimpaired older individuals.

Distinct neural signaling characteristics between fibromyalgia and provoked vestibulodynia revealed by means of functional magnetic resonance imaging in the brainstem and spinal cord.

Fibromyalgia and provoked vestibulodynia are two chronic pain conditions that disproportionately affect women. The mechanisms underlying the pain in these conditions are still poorly understood, but there is speculation that both may be linked to altered central sensitization and autonomic regulation. Neuroimaging studies of these conditions focusing on the brainstem and spinal cord to explore changes in pain regulation and autonomic regulation are emerging, but none to date have directly compared pain and autonomic regulation in these conditions. This study compares groups of women with fibromyalgia and provoked vestibulodynia to healthy controls using a threat/safety paradigm with a predictable noxious heat stimulus. Functional magnetic resonance imaging data were acquired at 3 tesla in the cervical spinal cord and brainstem with previously established methods. Imaging data were analyzed with structural equation modeling and ANCOVA methods during: a period of noxious stimulation, and a period before the stimulation when participants were expecting the upcoming pain. The results demonstrate several similarities and differences between brainstem/spinal cord connectivity related to autonomic and pain regulatory networks across the three groups in both time periods. Based on the regions and connections involved in the differences, the altered pain processing in fibromyalgia appears to be related to changes in how autonomic and pain regulation networks are integrated, whereas altered pain processing in provoked vestibulodynia is linked in part to changes in arousal or salience networks as well as changes in affective components of pain regulation.

773 Diffusion-Weighted MRI Tractography of Midline Thalamic Subnuclei Characterizes the Return of Consciousness Following Severe Traumatic Brain Injury

INTRODUCTION: The prefrontal projections of the mediodorsal (MD) and central lateral (CL) thalamus have been implicated in the recovery of consciousness following severe traumatic brain injury (sTBI), but their specific roles are unknown. The CL has been proposed to modulate levels of arousal, while the MD modulates attention. METHODS: We generated tractograms in 25 patients with sTBI using DSI-Studio. The CL and MD were seeds and the orbitofrontal (OFC), dorsolateral prefrontal (dlPFC), medial prefrontal (mPFC), and anterior cingulate (ACC) cortices were targets. Fractional anisotropy (FA), a measure of tract integrity, and apparent diffusion coefficient (ADC), a proxy for neuronal injury, were computed for each tract and compared between the early (within 30 days post-injury) and late/no command followers. Spearman correlations were calculated between tract FA and ADC and final Glasgow Coma Scale (GCS) scores. RESULTS: Tractography revealed significantly increased MD-OFC tract FA in early compared late/no command followers (P = 0.0125). There was a statistically significant decrease in ADC in early compared late/no command followers in CL-dlPFC (P = 0.0281) and MD-dlPFC (P = 0.0454) tracts. GCS scores were significantly correlated with CL-ACC (P = 0.018) and CL-dlPFC (P = 0.0061) FA, and were not found to be significant in all MD tracts. CONCLUSIONS: The FA and ADC differences between early and late/no responders implicate tract integrity of the MD-OFC and dlPFC as key mediators in the return of command-following after TBI, respectively. The CL-ACC and CL-dlPFC tract FA were found to be associated with an increased final GCS score, which grades verbal, eye opening and motor responses. Our results corroborate the MD’s involvement in the content of consciousness, distinct from the CL’s in mediating the ascending arousal network.

Arousal and salience network connectivity alterations in surgical temporal lobe epilepsy.

It is poorly understood why patients with mesial temporal lobe epilepsy (TLE) have cognitive deficits and brain network changes that extend beyond the temporal lobe, including altered extratemporal intrinsic connectivity networks (ICNs). However, subcortical arousal structures project broadly to the neocortex, are affected by TLE, and thus may contribute to these widespread network effects. The authors' objective was to examine functional connectivity (FC) patterns between subcortical arousal structures and neocortical ICNs, possible neurocognitive relationships, and FC changes after epilepsy surgery. The authors obtained resting-state functional magnetic resonance imaging (fMRI) in 50 adults with TLE and 50 controls. They compared nondirected FC (correlation) and directed FC (Granger causality laterality index) within the salience network, default mode network, and central executive network, as well as between subcortical arousal structures; these 3 ICNs were also compared between patients and controls. They also used an fMRI-based vigilance index to relate alertness to arousal center FC. Finally, fMRI was repeated in 29 patients > 12 months after temporal lobe resection. Nondirected FC within the salience (p = 0.042) and default mode (p = 0.0008) networks, but not the central executive network (p = 0.79), was decreased in patients in comparison with controls (t-tests, corrected). Nondirected FC between the salience network and subcortical arousal structures (nucleus basalis of Meynert, thalamic centromedian nucleus, and brainstem pedunculopontine nucleus) was reduced in patients in comparison with controls (p = 0.0028-0.015, t-tests, corrected), and some of these connectivity abnormalities were associated with lower processing speed index, verbal comprehension, and full-scale IQ. Interestingly, directed connectivity measures suggested a loss of top-down influence from the salience network to the arousal nuclei in patients. After resection, certain FC patterns between the arousal nuclei and salience network moved toward control values in the patients, suggesting that some postoperative recovery may be possible. Although an fMRI-based vigilance measure suggested that patients exhibited reduced alertness over time, FC abnormalities between the salience network and arousal structures were not influenced by the alertness levels during the scans. FC abnormalities between subcortical arousal structures and ICNs, such as the salience network, may be related to certain neurocognitive deficits in TLE patients. Although TLE patients demonstrated vigilance abnormalities, baseline FC perturbations between the arousal and salience networks are unlikely to be driven solely by alertness level, and some may improve after surgery. Examination of the arousal network and ICN disturbances may improve our understanding of the downstream clinical effects of TLE.

Activation of brain arousal networks coincident with eye blinks during resting state.

Eye-blinking has been implicated in arousal and attention. Here we test the hypothesis that blinking-moments represent arousal surges associated with activation of the ascending arousal network (AAN) and its thalamic projections. For this purpose, we explored the temporal relationship between eye-blinks and fMRI BOLD activity in AAN and thalamic nuclei, as well as whole brain cluster corrected activations during eyes-open, resting-state fMRI scanning. We show that BOLD activations in the AAN nuclei peaked prior to the eye blinks and in thalamic nuclei peaked prior to and during the blink, consistent with the role of eye blinking in arousal surges. Additionally, we showed visual cortex peak activation prior to the eye blinks, providing further evidence of the visual cortex's role in arousal, and document cerebellar peak activation post eye blinks, which might reflect downstream engagement from arousal surges.

O017 / #712 SELECTIVE ACTIVATION OF CENTRAL THALAMIC FIBER PATHWAY FACILITATES BEHAVIORAL PERFORMANCE IN HEALTHY NON-HUMAN PRIMATES: TRACK 2: DEEP BRAIN STIMULATION FOR MOVEMENT DISORDERS

The central thalamus (CT) is a key node in the arousal regulation network of the mammalian brain hypothesized to modulate large-scale activity patterns across the anterior forebrain in response to internal and external demands during wakefulness. Damage of the CT in humans, due to traumatic brain injury (TBI) or stroke, results in enduring cognitive deficits in the allocation of attention, maintenance of concentration and focus, working memory, impulse control, processing speed, and motivation. Central thalamic deep brain stimulation (CT-DBS) is an investigational therapy to treat these enduring cognitive dysfunctions, however, the mechanisms of CT-DBS promoting restoration of cognitive function are unknown, and the heterogeneous etiology and recovery profiles in structurally brain injured (SBI) patients contribute to variable outcomes using conventional DBS strategies that may have off-target effects due to activation of multiple pathways.

Increased very low frequency pulsations and decreased cardiorespiratory pulsations suggest altered brain clearance in narcolepsy

BackgroundNarcolepsy is a chronic neurological disease characterized by daytime sleep attacks, cataplexy, and fragmented sleep. The disease is hypothesized to arise from destruction or dysfunction of hypothalamic hypocretin-producing cells that innervate wake-promoting systems including the ascending arousal network (AAN), which regulates arousal via release of neurotransmitters like noradrenalin. Brain pulsations are thought to drive intracranial cerebrospinal fluid flow linked to brain metabolite transfer that sustains homeostasis. This flow increases in sleep and is suppressed by noradrenalin in the awake state. Here we tested the hypothesis that narcolepsy is associated with altered brain pulsations, and if these pulsations can differentiate narcolepsy type 1 from healthy controls.MethodsIn this case-control study, 23 patients with narcolepsy type 1 (NT1) were imaged with ultrafast fMRI (MREG) along with 23 age- and sex-matched healthy controls (HC). The physiological brain pulsations were quantified as the frequency-wise signal variance. Clinical relevance of the pulsations was investigated with correlation and receiving operating characteristic analysis.ResultsWe find that variance and fractional variance in the very low frequency (MREGvlf) band are greater in NT1 compared to HC, while cardiac (MREGcard) and respiratory band variances are lower. Interestingly, these pulsations differences are prominent in the AAN region. We further find that fractional variance in MREGvlf shows promise as an effective bi-classification metric (AUC = 81.4%/78.5%), and that disease severity measured with narcolepsy severity score correlates with MREGcard variance (R = −0.48, p = 0.0249).ConclusionsWe suggest that our novel results reflect impaired CSF dynamics that may be linked to altered glymphatic circulation in narcolepsy type 1.

The role of ascending arousal network in patients with chronic insomnia disorder.

The ascending arousal system plays a crucial role in individuals' consciousness. Recently, advanced functional magnetic resonance imaging (fMRI) has made it possible to investigate the ascending arousal network (AAN) in vivo. However, the role of AAN in the neuropathology of human insomnia remains unclear. Our study aimed to explore alterations in AAN and its connections with cortical networks in chronic insomnia disorder (CID). Resting-state fMRI data were acquired from 60 patients with CID and 60 good sleeper controls (GSCs). Changes in the brain's functional connectivity (FC) between the AAN and eight cortical networks were detected in patients with CID and GSCs. Multivariate pattern analysis (MVPA) was employed to differentiate CID patients from GSCs and predict clinical symptoms in patients with CID. Finally, these MVPA findings were further verified using an external data set (32 patients with CID and 33 GSCs). Compared to GSCs, patients with CID exhibited increased FC within the AAN, as well as increased FC between the AAN and default mode, cerebellar, sensorimotor, and dorsal attention networks. These AAN-related FC patterns and the MVPA classification model could be used to differentiate CID patients from GSCs with 88% accuracy in the first cohort and 77% accuracy in the validation cohort. Moreover, the MVPA prediction models could separately predict insomnia (data set 1, R2 = .34; data set 2, R2 = .15) and anxiety symptoms (data set 1, R2 = .35; data set 2, R2 = .34) in the two independent cohorts of patients. Our findings indicated that AAN contributed to the neurobiological mechanism of insomnia and highlighted that fMRI-based markers and machine learning techniques might facilitate the evaluation of insomnia and its comorbid mental symptoms.

Deep Emotional Arousal Network for Multimodal Sentiment Analysis and Emotion Recognition

Multimodal sentiment analysis and emotion recognition has become an increasingly popular research area, where the biggest challenge is to efficiently fuse the input information from different modality. The recent success is largely credited to the attention-based models, e.g., transformer and its variants. However, the attention-based mechanism often neglects the coherency of human emotion due to its parallel structure. Inspired by the emotional arousal model in cognitive science, a Deep Emotional Arousal Network (DEAN) that is capable of simulating the emotional coherence is proposed in this paper, which incorporates the time dependence into the parallel structure of transformer. The proposed DEAN model consists of three components, i.e., a cross-modal transformer is devised to simulate the functions of perception analysis system of humans; a multimodal BiLSTM system is developed to imitate the cognitive comparator, and a multimodal gating block is introduced to mimic the activation mechanism in human emotional arousal model. We perform extensive comparison and ablation studies on three benchmarks for multimodal sentiment analysis and emotion recognition. The empirical results indicate that DEAN achieves state-of-the-art performance, and useful insights are derived from the results.