Periodic Reporting for period 1 - OVERNIGHT (Overnight Vulnerable Emotion Reset Normalizing Invalidating Generalized Hyperaroused Tension)
Período documentado: 2023-01-01 hasta 2025-06-30
Anxiety and insomnia account for one-third of the global mental health burden. Prognosis is poor: chronicity and relapse are common because treatment effectiveness is moderate. While this situation calls for treatment innovation, the required knowledge on targetable key mechanisms is lacking.
Their shared core symptom is hyperarousal, covering subjective, physiological and clinical indicators. Hyperarousal is not 'just another overlapping symptom': individual differences in hyperarousal determine severity, prognosis and treatment response across insomnia-, anxiety- and stress-disorders. Hyperarousal links their genetic and phenotypic overlap.
Since hyperarousal plays such a pivotal role in the development and chronicity of these disorders, a transdiagnostic mechanistic understanding of hyperarousal would have major implications for the direly needed development of better treatment. This project aims for a transdiagnostic mechanistic understanding of hyperarousal across wake and sleep and use to this insight to innovate treatment.
The project will do so by combining large-scale data-driven approaches with targeted testing of the novel hypothesis that hyperarousal may be reset overnight. Crossing disciplines and diagnoses, the project will first deliver an integrated account of the subjective, brain structural, brain functional and physiological hyperarousal landscape. This approach will deliver unprecedented transdiagnostic insights into the lifetime development and underlying brain mechanisms of hyperarousal vulnerability and its consequences for mental health. Moreover, this approach will yield both innovative state-of-the art tools, as well as practical tools, to quantify hyperarousal. These tools will be employed in both experimental preclinical studies and immediately applicable transdiagnostic clinical interventions expected to considerably improve the perspectives of people suffering from the most common mental disorders by alleviating hyperarousal overnight.
Their shared core symptom is hyperarousal, covering subjective, physiological and clinical indicators. Hyperarousal is not 'just another overlapping symptom': individual differences in hyperarousal determine severity, prognosis and treatment response across insomnia-, anxiety- and stress-disorders. Hyperarousal links their genetic and phenotypic overlap.
Since hyperarousal plays such a pivotal role in the development and chronicity of these disorders, a transdiagnostic mechanistic understanding of hyperarousal would have major implications for the direly needed development of better treatment. This project aims for a transdiagnostic mechanistic understanding of hyperarousal across wake and sleep and use to this insight to innovate treatment.
The project will do so by combining large-scale data-driven approaches with targeted testing of the novel hypothesis that hyperarousal may be reset overnight. Crossing disciplines and diagnoses, the project will first deliver an integrated account of the subjective, brain structural, brain functional and physiological hyperarousal landscape. This approach will deliver unprecedented transdiagnostic insights into the lifetime development and underlying brain mechanisms of hyperarousal vulnerability and its consequences for mental health. Moreover, this approach will yield both innovative state-of-the art tools, as well as practical tools, to quantify hyperarousal. These tools will be employed in both experimental preclinical studies and immediately applicable transdiagnostic clinical interventions expected to considerably improve the perspectives of people suffering from the most common mental disorders by alleviating hyperarousal overnight.
WP1 determined whether different hyperarousal scales actually measure one common transdiagnostic hyperarousal construct or rather multiple, possibly disorder-specific, dimensions. WP1 led to a novel interdisciplinary methodology for hyperarousal assessment (THDQ), therefore detailed below in 1.2.
In WP2 so far, 115 people completed assessment of the THDQ (see WP1 above) complementary to extensive multimodal magnetic resonance imaging (MRI) assessment including T1 imaging (3D MPRAGE), T2 imaging (FLAIR, 3D SPACE), susceptibility-weighted MRI (swMRI, 3D GRE), diffusion MRI (dMRI), resting-state functional MRI (rfMRI) and task-based functional MRI (tfMRI) using the emotional faces task known to activate a limbic circuit of key relevance to hyperarousal. We currently aim to increase the number to include in the analyses aiming to reveal the functional anatomy of the different transdiagnostic hyperarousal dimensions. We expect these to be represented by distributed deviations that may be differentially detectable across imaging modalities.
In WP3 so far, 115 people completed assessment of the THDQ (see WP1 above) complementary to complementary to extensive sleep and wake assessments of high-density electroencephalography and event related potentials (HD-EEG and HD-ERP) and electrocardiography (ECG). We currently aim to increase the number to include in the analyses aiming to reveal how different transdiagnostic hyperarousal dimensions are represented in the millisecond-precision evoked potentials and sleep spectrograms.
In WP4, we established the pharmacokinetic and pharmacodynamic profiles of oro-mucosal (sublingual, buccal) application of the highly selective α2-receptor agonist, dexmedetomidine (Dex) in 8 healthy good sleepers and 17 poor sleepers suffering from subclinical insomnia. Studies followed a randomized, double-blind, placebo-controlled, cross-over design with 20 and 40 µg of Dex. Particularly the buccal formulation was rapidly absorbed and exhibited excellent dose-proportionality with minimal between-subject variation in exposure. In the poor sleepers, 40 µg of buccal Dex shortened the sleep latency by 11.5 min, increased the time spent NREM sleep by 37.2 min, and elevated EEG slow wave energy (0.75-4.0 Hz) in NREM sleep by roughly 23 %. The first occurrence of REM sleep was dose-dependently delayed (20 µg: 55.0 min; 40 µg: 115.3 min). Nocturnal cortisol, melatonin and heart rate, and morning cortisol were not significantly affected by Dex, nor did post-awakening orthostatic regulation, subjective sleepiness and mood, and psychomotor vigilance differ among the conditions. We currently study the effects of 64 and 96 µg of Dex in healthy individuals and patients suffering from insomnia and PTSD.
In WP5, so far, we completed pre-, post- and follow-up assessments in 157 pre-diagnostic people with clinically relevant complaints, 75 people in basic mental health care, and 116 people in specialized mental health care. Multiple subjective and objective outcome measures are assessed to evaluate overnight dissipation of hyperarousal. Vulnerability and sensitivity intrinsic to the suffering of our sample made that not all participants fully adhered to the planned home self-assessments with a headband measuring EEG, EOG, cardiac pulse and restlessness repeatedly three times across ten months. So far, we have assessed these data for ~2100 nights out of which ~1500 are of sufficient quality for further analysis. While awaiting the 'best proxy' set of features for these overnight home assessments of sleep-related physiological hyperarousal, to be validated in WP3, we have commenced to analyse the effect of subjectively experienced sleep quality on overnight changes in subjective hyperarousal. The interim analysis could include 2788 nights with complete pre- and post-sleep experience-sampled hyperarousal ratings next to subjectively assessed sleep. Mixed effect covariance analyses provided strong support for our hypothesis that sleep quality strongly affects overnight changes in hyperarousal: depending on subjective sleep quality, feeling tense, anxious or depressed could all change from worsening to improving overnight.
In WP2 so far, 115 people completed assessment of the THDQ (see WP1 above) complementary to extensive multimodal magnetic resonance imaging (MRI) assessment including T1 imaging (3D MPRAGE), T2 imaging (FLAIR, 3D SPACE), susceptibility-weighted MRI (swMRI, 3D GRE), diffusion MRI (dMRI), resting-state functional MRI (rfMRI) and task-based functional MRI (tfMRI) using the emotional faces task known to activate a limbic circuit of key relevance to hyperarousal. We currently aim to increase the number to include in the analyses aiming to reveal the functional anatomy of the different transdiagnostic hyperarousal dimensions. We expect these to be represented by distributed deviations that may be differentially detectable across imaging modalities.
In WP3 so far, 115 people completed assessment of the THDQ (see WP1 above) complementary to complementary to extensive sleep and wake assessments of high-density electroencephalography and event related potentials (HD-EEG and HD-ERP) and electrocardiography (ECG). We currently aim to increase the number to include in the analyses aiming to reveal how different transdiagnostic hyperarousal dimensions are represented in the millisecond-precision evoked potentials and sleep spectrograms.
In WP4, we established the pharmacokinetic and pharmacodynamic profiles of oro-mucosal (sublingual, buccal) application of the highly selective α2-receptor agonist, dexmedetomidine (Dex) in 8 healthy good sleepers and 17 poor sleepers suffering from subclinical insomnia. Studies followed a randomized, double-blind, placebo-controlled, cross-over design with 20 and 40 µg of Dex. Particularly the buccal formulation was rapidly absorbed and exhibited excellent dose-proportionality with minimal between-subject variation in exposure. In the poor sleepers, 40 µg of buccal Dex shortened the sleep latency by 11.5 min, increased the time spent NREM sleep by 37.2 min, and elevated EEG slow wave energy (0.75-4.0 Hz) in NREM sleep by roughly 23 %. The first occurrence of REM sleep was dose-dependently delayed (20 µg: 55.0 min; 40 µg: 115.3 min). Nocturnal cortisol, melatonin and heart rate, and morning cortisol were not significantly affected by Dex, nor did post-awakening orthostatic regulation, subjective sleepiness and mood, and psychomotor vigilance differ among the conditions. We currently study the effects of 64 and 96 µg of Dex in healthy individuals and patients suffering from insomnia and PTSD.
In WP5, so far, we completed pre-, post- and follow-up assessments in 157 pre-diagnostic people with clinically relevant complaints, 75 people in basic mental health care, and 116 people in specialized mental health care. Multiple subjective and objective outcome measures are assessed to evaluate overnight dissipation of hyperarousal. Vulnerability and sensitivity intrinsic to the suffering of our sample made that not all participants fully adhered to the planned home self-assessments with a headband measuring EEG, EOG, cardiac pulse and restlessness repeatedly three times across ten months. So far, we have assessed these data for ~2100 nights out of which ~1500 are of sufficient quality for further analysis. While awaiting the 'best proxy' set of features for these overnight home assessments of sleep-related physiological hyperarousal, to be validated in WP3, we have commenced to analyse the effect of subjectively experienced sleep quality on overnight changes in subjective hyperarousal. The interim analysis could include 2788 nights with complete pre- and post-sleep experience-sampled hyperarousal ratings next to subjectively assessed sleep. Mixed effect covariance analyses provided strong support for our hypothesis that sleep quality strongly affects overnight changes in hyperarousal: depending on subjective sleep quality, feeling tense, anxious or depressed could all change from worsening to improving overnight.
One significant breakthrough is the discovery that different subtypes of insomnia, characterized by different traits including the severity of hyperarousal features, show differentiating deviations in brain structural connectivity and attentional brain responses.
Another significant breakthrough is the multimodal brain imaging dissection of transdiagnostic commonalities and differences in insomnia, depression and anxiety disorders.
Advancing the field beyond the state-of-the-art, is our Nature Reviews Neuroscience paper that opens up the interdisciplinary study of hyperarousal from molecular-cellular to psychological.
Another significant breakthrough is the multimodal brain imaging dissection of transdiagnostic commonalities and differences in insomnia, depression and anxiety disorders.
Advancing the field beyond the state-of-the-art, is our Nature Reviews Neuroscience paper that opens up the interdisciplinary study of hyperarousal from molecular-cellular to psychological.