Heart rate and breathing effects on attention and memory (HeartBEAM): study protocol for a randomized controlled trial in older adults.

BACKGROUND: In healthy people, the "fight-or-flight" sympathetic system is counterbalanced by the "rest-and-digest" parasympathetic system. As we grow older, the parasympathetic system declines as the sympathetic system becomes hyperactive. In our prior heart rate variability biofeedback and emotion regulation (HRV-ER) clinical trial, we found that increasing parasympathetic activity through daily practice of slow-paced breathing significantly decreased plasma amyloid-ß (Aß) in healthy younger and older adults. In healthy adults, higher plasma Aß is associated with greater risk of Alzheimer's disease (AD). Our primary goal of this trial is to reproduce and extend our initial findings regarding effects of slow-paced breathing on Aß. Our secondary objectives are to examine the effects of daily slow-paced breathing on brain structure and the rate of learning. METHODS: Adults aged 50-70 have been randomized to practice one of two breathing protocols twice daily for 9 weeks: (1) "slow-paced breathing condition" involving daily cognitive training followed by slow-paced breathing designed to maximize heart rate oscillations or (2) "random-paced breathing condition" involving daily cognitive training followed by random-paced breathing to avoid increasing heart rate oscillations. The primary outcomes are plasma Aß40 and Aß42 levels and plasma Aß42/40 ratio. The secondary outcomes are brain perivascular space volume, hippocampal volume, and learning rates measured by cognitive training performance. Other pre-registered outcomes include plasma pTau-181/tTau ratio and urine Aß42. Recruitment began in January 2023. Interventions are ongoing and will be completed by the end of 2023. DISCUSSION: Our HRV-ER trial was groundbreaking in demonstrating that a behavioral intervention can reduce plasma Aß levels relative to a randomized control group. We aim to reproduce these findings while testing effects on brain clearance pathways and cognition. TRIAL REGISTRATION: ClinicalTrials.gov NCT05602220. Registered on January 12, 2023.

Microstructural integrity of the locus coeruleus and its tracts reflect noradrenergic degeneration in Alzheimer's disease and Parkinson's disease.

BACKGROUND: Degeneration of the locus coeruleus (LC) noradrenergic system contributes to clinical symptoms in Alzheimer's disease (AD) and Parkinson's disease (PD). Diffusion magnetic resonance imaging (MRI) has the potential to evaluate the integrity of the LC noradrenergic system. The aim of the current study was to determine whether the diffusion MRI-measured integrity of the LC and its tracts are sensitive to noradrenergic degeneration in AD and PD. METHODS: Post-mortem in situ T1-weighted and multi-shell diffusion MRI was performed for 9 AD, 14 PD, and 8 control brain donors. Fractional anisotropy (FA) and mean diffusivity were derived from the LC, and from tracts between the LC and the anterior cingulate cortex, the dorsolateral prefrontal cortex (DLPFC), the primary motor cortex (M1) or the hippocampus. Brain tissue sections of the LC and cortical regions were obtained and immunostained for dopamine-beta hydroxylase (DBH) to quantify noradrenergic cell density and fiber load. Group comparisons and correlations between outcome measures were performed using linear regression and partial correlations. RESULTS: The AD and PD cases showed loss of LC noradrenergic cells and fibers. In the cortex, the AD cases showed increased DBH + immunoreactivity in the DLPFC compared to PD cases and controls, while PD cases showed reduced DBH + immunoreactivity in the M1 compared to controls. Higher FA within the LC was found for AD, which was correlated with loss of noradrenergic cells and fibers in the LC. Increased FA of the LC-DLPFC tract was correlated with LC noradrenergic fiber loss in the combined AD and control group, whereas the increased FA of the LC-M1 tract was correlated with LC noradrenergic neuronal loss in the combined PD and control group. The tract alterations were not correlated with cortical DBH + immunoreactivity. CONCLUSIONS: In AD and PD, the diffusion MRI-detected alterations within the LC and its tracts to the DLPFC and the M1 were associated with local noradrenergic neuronal loss within the LC, rather than noradrenergic changes in the cortex.

Interactive effects of locus coeruleus structure and catecholamine synthesis capacity on cognitive function.

Background: The locus coeruleus (LC) produces catecholamines (norepinephrine and dopamine) and is implicated in a broad range of cognitive functions including attention and executive function. Recent advancements in magnetic resonance imaging (MRI) approaches allow for the visualization and quantification of LC structure. Human research focused on the LC has since exploded given the LC's role in cognition and relevance to current models of psychopathology and neurodegenerative disease. However, it is unclear to what extent LC structure reflects underlying catecholamine function, and how LC structure and neurochemical function are collectively associated with cognitive performance. Methods: A partial least squares correlation (PLSC) analysis was applied to 19 participants' LC structural MRI measures and catecholamine synthesis capacity measures assessed using [18F]Fluoro-m-tyrosine ([18F]FMT) positron emission tomography (PET). Results: We found no direct association between LC-MRI and LC-[18F]FMT measures for rostral, middle, or caudal portions of the LC. We found significant associations between LC neuroimaging measures and neuropsychological performance that were driven by rostral and middle portions of the LC, which is in line with LC cortical projection patterns. Specifically, associations with executive function and processing speed arose from contributions of both LC structure and interactions between LC structure and catecholamine synthesis capacity. Conclusion: These findings leave open the possibility that LC MRI and PET measures contribute unique information and suggest that their conjoint use may increase sensitivity to brain-behavior associations in small samples.

Effects of Adult Age and Functioning of the Locus Coeruleus Norepinephrinergic System on Reward-Based Learning.

Age-related impairments in value representations and updating during decision-making and reward-based learning are often related to age-related attenuation in the catecholamine system such as dopamine (DA) and norepinephrine (NE). However, it is unclear to what extent age-related declines in NE functioning in humans affect reward-based decision-making. We conducted a probabilistic decision-making task and applied a Q-learning model to investigate participants' anticipatory values and value sensitivities. Task-related pupil dilations and locus coeruleus (LC) magnetic resonance imaging (MRI) contrast, which served as a potential window of the LC-NE functions, were assessed in younger and older adults. Results showed that in both choice and feedback phases, younger adults' (N = 42, 22 males) pupil dilations negatively correlated with anticipatory values, indicating uncertainty about outcome probabilities. Uncertainty-evoked pupil dilations in older adults (N = 41, 27 males) were smaller, indicating age-related impairments in value estimation and updating. In both age groups, participants who showed a larger uncertainty-evoked pupil dilation exhibited a higher value sensitivity as reflected in the ß parameter of the reinforcement Q-learning model. Furthermore, older adults (N = 34, 29 males) showed a lower LC-MRI contrast than younger adults (N = 25, 15 males). The LC-MRI contrast positively correlated with value sensitivity only in older but not in younger adults. These findings suggest that task-related pupillary responses can reflect age-related deficits in value estimation and updating during reward-based decision-making. Our evidence with the LC-MRI contrast further showed the age-related decline of the LC structure in modulating value representations during reward-based learning.SIGNIFICANCE STATEMENT Age-related impairments in value representation and updating during reward-based learning are associated with declines in the catecholamine modulation with age. However, it is unclear how age-related declines in the LC-NE system may affect reward-based learning. Here, we show that compared with younger adults, older adults exhibited reduced uncertainty-induced pupil dilations, suggesting age-related deficits in value estimation and updating. Older adults showed a lower structural MRI of the LC contrast than younger adults, indicating age-related degeneration of the LC structure. The association between the LC-MRI contrast and value sensitivity was only observed in older adults. Our findings may demonstrate a pioneering model to unravel the role of the LC-NE system in reward-based learning in aging.

Declining locus coeruleus-dopaminergic and noradrenergic modulation of long-term memory in aging and Alzheimer's disease.

Memory is essential in defining our identity by guiding behavior based on past experiences. However, aging leads to declining memory, disrupting older adult's lives. Memories are encoded through experience-dependent modifications of synaptic strength, which are regulated by the catecholamines dopamine and noradrenaline. While cognitive aging research demonstrates how dopaminergic neuromodulation from the substantia nigra-ventral tegmental area regulates hippocampal synaptic plasticity and memory, recent findings indicate that the noradrenergic locus coeruleus sends denser inputs to the hippocampus. The locus coeruleus produces dopamine as biosynthetic precursor of noradrenaline, and releases both to modulate hippocampal plasticity and memory. Crucially, the locus coeruleus is also the first site to accumulate Alzheimer's-related abnormal tau and severely degenerates with disease development. New in-vivo assessments of locus coeruleus integrity reveal associations with Alzheimer's markers and late-life memory impairments, which likely stem from impaired dopaminergic and noradrenergic neurotransmission. Bridging research across species, the reviewed findings suggest that degeneration of the locus coeruleus results in deficient dopaminergic and noradrenergic modulation of hippocampal plasticity and thus memory decline.

The integrity of dopaminergic and noradrenergic brain regions is associated with different aspects of late-life memory performance.

Changes in dopaminergic neuromodulation play a key role in adult memory decline. Recent research has also implicated noradrenaline in shaping late-life memory. However, it is unclear whether these two neuromodulators have distinct roles in age-related cognitive changes. Here, combining longitudinal MRI of the dopaminergic substantia nigra-ventral tegmental area (SN-VTA) and noradrenergic locus coeruleus (LC) in younger (n = 69) and older (n = 251) adults, we found that dopaminergic and noradrenergic integrity are differentially associated with memory performance. While LC integrity was related to better episodic memory across several tasks, SN-VTA integrity was linked to working memory. Longitudinally, we found that older age was associated with more negative change in SN-VTA and LC integrity. Notably, changes in LC integrity reliably predicted future episodic memory. These differential associations of dopaminergic and noradrenergic nuclei with late-life cognitive decline have potential clinical utility, given their degeneration in several age-associated diseases.

Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART.

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies.

Age differences in diffusivity in the locus coeruleus and its ascending noradrenergic tract.

The noradrenergic locus coeruleus (LC) is a small brainstem nucleus that promotes arousal and attention. Recent studies have examined the microstructural properties of the LC using diffusion-weighted magnetic resonance imaging and found unexpected age-related differences in fractional anisotropy - a measure of white matter integrity. Here, we used two datasets (Berlin Aging Study-II, N = 301, the Leipzig Study for Mind-Body-Emotion Interactions, N = 220), to replicate published findings and expand them by investigating diffusivity in the LC's ascending noradrenergic bundle. In younger adults, LC fractional anisotropy was significantly lower, compared to older adults. However, in the LC's ascending noradrenergic bundle, we observed significantly higher fractional anisotropy in younger adults, relative to older adults. These findings indicate that diffusivity in the LC versus the ascending noradrenergic bundle are both susceptible to structural changes in aging that have opposing effects on fractional anisotropy.

Locus coeruleus integrity is related to tau burden and memory loss in autosomal-dominant Alzheimer's disease.

Abnormally phosphorylated tau, an indicator of Alzheimer's disease, accumulates in the first decades of life in the locus coeruleus (LC), the brain's main noradrenaline supply. However, technical challenges in in-vivo assessments have impeded research into the role of the LC in Alzheimer's disease. We studied participants with or known to be at-risk for mutations in genes causing autosomal-dominant Alzheimer's disease (ADAD) with early onset, providing a unique window into the pathogenesis of Alzheimer's largely disentangled from age-related factors. Using high-resolution MRI and tau PET, we found lower rostral LC integrity in symptomatic participants. LC integrity was associated with individual differences in tau burden and memory decline. Post-mortem analyses in a separate set of carriers of the same mutation confirmed substantial neuronal loss in the LC. Our findings link LC degeneration to tau burden and memory in Alzheimer's, and highlight a role of the noradrenergic system in this neurodegenerative disease.

Noradrenergic modulation of rhythmic neural activity shapes selective attention.

During moments involving selective attention, the thalamus orchestrates the preferential processing of prioritized information by coordinating rhythmic neural activity within a distributed frontoparietal network. The timed release of neuromodulators from subcortical structures dynamically sculpts neural synchronization in thalamocortical networks to meet current attentional demands. In particular, noradrenaline modulates the balance of cortical excitation and inhibition, as reflected by thalamocortical alpha synchronization (~8-12 Hz). These neuromodulatory adjustments facilitate the selective processing of prioritized information. Thus, by disrupting effective rhythmic coordination in attention networks, age-related locus coeruleus (LC) degeneration can impair higher levels of neural processing. In sum, findings across different levels of analysis and modalities shed light on how the noradrenergic modulation of neural synchronization helps to shape selective attention.

Locus coeruleus MRI contrast is associated with cortical thickness in older adults.

There is growing evidence that neuronal integrity of the noradrenergic locus coeruleus (LC) is important for later-life cognition. Less understood is how LC integrity relates to brain correlates of cognition, such as brain structure. Here, we examined the relationship between cortical thickness and a measure reflecting LC integrity in 229 older and 67 younger adults. Using a magnetic resonance imaging sequence which yields high signal intensity in the LC, we assessed the contrast between signal intensity of the LC and that of neighboring pontine reference tissue. The FreeSurfer software suite was used to quantify cortical thickness. LC contrast was positively related to cortical thickness in older adults, and this association was prominent in parietal, frontal, and occipital regions. Brain regions where LC contrast was related to cortical thickness include portions of the frontoparietal network which have been implicated in noradrenergically modulated cognitive functions. These findings provide novel evidence for a link between LC structure and cortical brain structure in later adulthood.

Noradrenergic Responsiveness Supports Selective Attention across the Adult Lifespan.

Selectively attending to relevant information while blocking out distractors is crucial for goal-directed behavior, yet with advancing age, deficits emerge in attentional selectivity. Decrements in attention have been associated with altered noradrenergic activity in animals. However, research linking noradrenergic functioning to attention in aging humans is scarce, likely reflecting long-standing methodological challenges in noninvasive assessments. We studied whether age-related differences in the noradrenergic system predict differences in attention. We measured pupil dilation, a noninvasive marker of arousal-related norepinephrine (NE) release, while concurrently recording the EEG of male younger (N = 39; 25.2 ± 3.2 years) and older adults (N = 38; 70.6 ± 2.7 years). Arousal was modulated on a trial-by-trial basis using fear-conditioned (CS+) stimuli. During conditioning, pupil and EEG markers related to heightened arousal were identified. Afterward, in a dichotic listening task, participants were cued to direct attention to either the left or right ear while highly similar syllable pairs were presented simultaneously to both ears. During the dichotic listening task, presentation of fear-conditioned stimuli reinstated the acquired arousal response, as reflected in pupil and EEG α-ß band responses. Critically, pupil dilation to CS+ was correlated with stronger EEG α-ß desynchronization, suggesting a common dependence on NE release. On a behavioral level, stronger arousal reactions were associated with better attention. In particular, structural equation modeling revealed that the responsiveness of the NE system is associated with attention on a latent construct level, measured by several indicator tasks. Overall, our results suggest that the responsiveness of the NE system supports attention across the lifespan.SIGNIFICANCE STATEMENT In old age, the ability to selectively process relevant aspects of the environment fades. Animal research suggests that the neuromodulator norepinephrine helps to maintain selective attention. We tested younger and older adults across a variety of attention tasks. In addition, we used arousing stimuli to experimentally activate participants' noradrenergic system while recording pupillometry and EEG to infer its functional capacity. Older adults showed compromised attention and reduced noradrenergic responsiveness as indicated by interrelated pupil and EEG markers. Crucially, in both age groups, a more responsive noradrenergic system was strongly associated with attention. Our findings link animal and human studies on the neural underpinning of attention in aging and underscore the importance of the noradrenergic system in late-life cognition.

Rostral locus coeruleus integrity is associated with better memory performance in older adults.

For decades, research into memory decline in human cognitive ageing has focused on neocortical regions, the hippocampus and dopaminergic neuromodulation. Recent findings indicate that the locus coeruleus (LC) and noradrenergic neuromodulation may also play an important role in shaping memory development in later life. However, technical challenges in quantification of LC integrity have hindered the study of LC-cognition associations in humans. Using high-resolution, neuromelanin-sensitive magnetic resonance imaging, we found that individual differences in learning and memory were positively associated with LC integrity across a variety of memory tasks in both younger (n = 66) and older adults (n = 228). Moreover, we observed functionally relevant age differences confined to rostral LC. Older adults with a more 'youth-like' rostral LC also showed higher memory performance. These findings link non-invasive, in vivo indices of LC integrity to memory in ageing and highlight the role of the LC norepinephrine system in the decline of cognition.

Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases.

Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer's disease, atypical neurodegenerative dementias and Parkinson's disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases.

Diminished pre-stimulus alpha-lateralization suggests compromised self-initiated attentional control of auditory processing in old age.

Older adults experience difficulties in daily situations that require flexible information selection in the presence of multiple competing sensory inputs, like for instance multi-talker situations. Modulations of rhythmic neural activity in the alpha-beta (8-30 Hz) frequency range in posterior brain areas have been established as a cross-modal neural correlate of selective attention. However, research linking compromised auditory selective attention to changes in rhythmic neural activity in aging is sparse. We tested younger (n = 25; 22-35 years) and older adults (n = 26; 63-76 years) in an attention modulated dichotic listening task. In this, two streams of highly similar auditory input were simultaneously presented to participants' both ears (i.e., dichotically) while attention had to be focused on the input to only one ear (i.e. target) and the other, distracting information had to be ignored. We here demonstrate a link between severely compromised auditory selective attention in aging and a partial reorganization of attention-related rhythmic neural responses. In particular, in old age we observed a shift from a self-initiated, preparatory modulation of lateralized alpha rhythmic activity to an externally driven response in the alpha-beta range. Critically, moment-to-moment fluctuations in the age-specific patterns of self-initiated and externally driven lateralized rhythmic activity were associated with behavioral performance. We conclude that adult age differences in spatial selective attention likely derive from a functional reorganization of rhythmic neural activity within the aging brain.

The neural dynamics of deficient memory control in heavily traumatized refugees.

Victims of war, torture and natural catastrophes are prone to develop posttraumatic stress disorder (PTSD). These individuals experience the recurrent, involuntary intrusion of traumatic memories. What neurocognitive mechanisms are driving this memory disorder? Here we show that PTSD symptoms in heavily traumatized refugees are related to deficits in the effective control of memory retrieval. In a think/no-think task, PTSD patients were unable to forget memories that they had previously tried to suppress when compared to control participants with the same trauma history but without PTSD. Deficits in voluntary forgetting were clinically relevant since they correlated with memory intrusions in everyday life. Magnetoencephalography (MEG) recorded during suppression attempts revealed that PTSD patients were unable to downregulate signatures of sensory long-term memory traces in the gamma frequency band (70-120 Hz). Thus, our data suggest that the inability to suppress unwanted memories through modulation of gamma activity is related to PTSD symptom severity.