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.

Evaluating phasic transcutaneous vagus nerve stimulation (taVNS) with pupil dilation: the importance of stimulation intensity and sensory perception.

The efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) as a non-invasive method to modulate physiological markers of noradrenergic activity of the Locus Coeruleus (LC), such as pupil dilation, is increasingly more discussed. However, taVNS studies show high heterogeneity of stimulation effects. Therefore, a taVNS setup was established here to test different frequencies (10 Hz and 25 Hz) and intensities (3 mA and 5 mA) during phasic stimulation (3 s) with time-synchronous recording of pupil dilation in younger adults. Specifically, phasic real taVNS and higher intensity led to increased pupil dilation, which is consistent with phasic invasive VNS studies in animals. The results also suggest that the influence of intensity on pupil dilation may be stronger than that of frequency. However, there was an attenuation of taVNS-induced pupil dilation when differences in perception of sensations were considered. Specifically, pupil dilation during phasic stimulation increased with perceived stimulation intensity. The extent to which the effect of taVNS induces pupil dilation and the involvement of sensory perception in the stimulation process are discussed here and require more extensive research. Additionally, it is crucial to strive for comparable stimulation sensations during systematic parameter testing in order to investigate possible effects of phasic taVNS on pupil dilation in more detail.

Evaluating phasic transcutaneous vagus nerve stimulation (taVNS) with pupil dilation: the importance of stimulation intensity and sensory perception.

The efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) as a non-invasive method to modulate physiological markers of noradrenergic activity of the Locus Coeruleus (LC), such as pupil dilation, is increasingly more discussed. However, taVNS studies show high heterogeneity of stimulation effects. Therefore, a taVNS setup was established here to test different frequencies (10 Hz and 25 Hz) and intensities (3 mA and 5 mA) during phasic stimulation (3 s) with time-synchronous recording of pupil dilation in younger adults. Specifically, phasic real taVNS and higher intensity led to increased pupil dilation, which is consistent with phasic invasive VNS studies in animals. The results also suggest that the influence of intensity on pupil dilation may be stronger than that of frequency. However, there was an attenuation of taVNS-induced pupil dilation when differences in perception of sensations were considered. Specifically, pupil dilation during phasic stimulation increased with perceived stimulation intensity. The extent to which the effect of taVNS induces pupil dilation and the involvement of sensory perception in the stimulation process are discussed here and require more extensive research. Additionally, it is crucial to strive for comparable stimulation sensations during systematic parameter testing in order to investigate possible effects of phasic taVNS on pupil dilation in more detail.

Functional locus coeruleus imaging to investigate an ageing noradrenergic system.

The locus coeruleus (LC), our main source of norepinephrine (NE) in the brain, declines with age and is a potential epicentre of protein pathologies in neurodegenerative diseases (ND). In vivo measurements of LC integrity and function are potentially important biomarkers for healthy ageing and early ND onset. In the present study, high-resolution functional MRI (fMRI), a reversal reinforcement learning task, and dedicated post-processing approaches were used to visualise age differences in LC function (N = 50). Increased LC responses were observed during emotionally and task-related salient events, with subsequent accelerations and decelerations in reaction times, respectively, indicating context-specific adaptive engagement of the LC. Moreover, older adults exhibited increased LC activation compared to younger adults, indicating possible compensatory overactivation of a structurally declining LC in ageing. Our study shows that assessment of LC function is a promising biomarker of cognitive aging.

It is the locus coeruleus! Or is it?: a proposition for analyses and reporting standards for structural and functional magnetic resonance imaging of the noradrenergic locus coeruleus.

The noradrenergic locus coeruleus (LC) is one of the protein pathology epicenters in neurodegenerative diseases. In contrast to PET (positron emission tomography), MRI (magnetic resonance imaging) offers the spatial resolution necessary to investigate the 3-4 mm wide and 1.5 cm long LC. However, standard data postprocessing is often too spatially imprecise to allow investigating the structure and function of the LC at the group level. Our analysis pipeline uses a combination of existing toolboxes (SPM12, ANTs, FSL, FreeSurfer), and is tailored towards achieving suitable spatial precision in the brainstem area. Its effectiveness is demonstrated using 2 datasets comprising both younger and older adults. We also suggest quality assessment procedures which allow to quantify the spatial precision obtained. Spatial deviations below 2.5 mm in the LC area are achieved, which is superior to current standard approaches. Relevant for ageing and clinical researchers interested in brainstem imaging, we provide a tool for more reliable analyses of structural and functional LC imaging data which can be also adapted for investigating other nuclei of the brainstem.

Disrupted memory inhibition in dementia of Alzheimer's type.

Cognitive inhibition has been suggested to deteriorate in Alzheimer's disease. While numerous studies with different experimental paradigms found evidence on impaired inhibition in attention and memory, evidence in favour of intact memory inhibition has been reported with regard to the phenomenon of retrieval-induced forgetting (Moulin et al., 2002). Here, we adapted the previously used paradigm in order to reduce the contribution of non-inhibitory processes and examined whether retrieval-induced forgetting could still be observed in a sample of participants with diagnosed Alzheimer's disease. In contrast to the previous finding, we found that retrieval-induced forgetting only occurred in an age-matched control group. These results suggest that inhibitory deficits in Alzheimer's disease also generalize to memory inhibition that resolves interference occurring during retrieval, whereas effects of retrieval-induced forgetting may still occur when non-inhibitory causes, such as, blocking by previously retrieved content, are not precluded.

Current challenges in reliably targeting the noradrenergic locus coeruleus using transcutaneous auricular vagus nerve stimulation (taVNS).

Transcutaneous auricular vagus nerve stimulation (taVNS), as a non-invasive brain stimulation technique may influence the locus coeruleus-norepinephrine system (LC-NE system) via modulation of the Vagus Nerve (VN) which projects to the LC. Few human studies exist examining the effects of taVNS on the LC-NE system and studies to date assessing the ability of taVNS to target the LC yield heterogeneous results. The aim of this review is to present an overview of the current challenges in assessing effects of taVNS on LC function and how translational approaches spanning animal and human research can help in this regard. A particular emphasis of the review discusses how the effects of taVNS may be influenced by changes in structure and function of the LC-NE system across the human lifespan and in disease.

International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020).

Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice.