From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease.

Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.

Mindfulness-based therapy for insomnia for older adults with sleep difficulties: a randomized clinical trial.

OBJECTIVE: Poor sleep is a modifiable risk factor for multiple disorders. Frontline treatments (e.g. cognitive-behavioral therapy for insomnia) have limitations, prompting a search for alternative approaches. Here, we compare manualized Mindfulness-Based Therapy for Insomnia (MBTI) with a Sleep Hygiene, Education, and Exercise Program (SHEEP) in improving subjective and objective sleep outcomes in older adults. METHODS: We conducted a single-site, parallel-arm trial, with blinded assessments collected at baseline, post-intervention and 6-months follow-up. We randomized 127 participants aged 50-80, with a Pittsburgh Sleep Quality Index (PSQI) score ⩾5, to either MBTI (n = 65) or SHEEP (n = 62), both 2 hr weekly group sessions lasting 8 weeks. Primary outcomes included PSQI and Insomnia Severity Index, and actigraphy- and polysomnography-measured sleep onset latency (SOL) and wake after sleep onset (WASO). RESULTS: Intention-to-treat analysis showed reductions in insomnia severity in both groups [MBTI: Cohen's effect size d = -1.27, 95% confidence interval (CI) -1.61 to -0.89; SHEEP: d = -0.69, 95% CI -0.96 to -0.43], with significantly greater improvement in MBTI. Sleep quality improved equivalently in both groups (MBTI: d = -1.19; SHEEP: d = -1.02). No significant interaction effects were observed in objective sleep measures. However, only MBTI had reduced WASOactigraphy (MBTI: d = -0.30; SHEEP: d = 0.02), SOLactigraphy (MBTI: d = -0.25; SHEEP: d = -0.09), and WASOPSG (MBTI: d = -0.26; SHEEP (d = -0.18). There was no change in SOLPSG. No participants withdrew because of adverse effects. CONCLUSIONS: MBTI is effective at improving subjective and objective sleep quality in older adults, and could be a valid alternative for persons who have failed or do not have access to standard frontline therapies.

Neural representations of haptic object size in the human brain revealed by multivoxel fMRI patterns.

The brain must interpret sensory input from diverse receptor systems to estimate object properties. Much has been learned about the brain mechanisms behind these processes in vision, but our understanding of haptic perception remains less clear. Here we examined haptic judgments of object size, which require integrating multiple cutaneous and proprioceptive afferent signals, as a model problem. To identify candidate human brain regions that support this process, participants (n = 16) in an event-related functional MRI experiment grasped objects to categorize them as one of four sizes. Object sizes were calibrated psychophysically to be equally distinct for each participant. We applied representational similarity logic to whole brain, multivoxel searchlight analyses to identify brain regions that exhibit size-relevant voxelwise activity patterns. Of particular interest was to identify regions for which more similar sizes produce more similar patterns of activity, which constitutes evidence of a metric size code. Regions of the intraparietal sulcus and the lateral prefrontal cortex met this criterion, both within hands and across hands. We suggest that these regions compute representations of haptic size that abstract over the specific peripheral afferent signals generated in a grasp. Results of a matched visual size task, performed by the same participants and analyzed in the same fashion, identified similar regions, indicating that these representations may be partly modality general. We consider these results with respect to perspectives on magnitude estimation in general and to computational views on perceptual signal integration.NEW & NOTEWORTHY Our understanding of the neural basis of haptics (perceiving the world through touch) remains incomplete. We used functional MRI to study human haptic judgments of object size, which require integrating multiple afferent signals. Multivoxel pattern analyses identified intraparietal and prefrontal regions that encode size haptically in a metric and hand-invariant fashion. Effector-independent haptic size estimates are useful on their own and in combination with other sensory estimates for a variety of perceptual and motor tasks.

Preparatory Activity in Posterior Temporal Cortex Causally Contributes to Object Detection in Scenes.

Theories of visual selective attention propose that top-down preparatory attention signals mediate the selection of task-relevant information in cluttered scenes. Neuroimaging and electrophysiology studies have provided correlative evidence for this hypothesis, finding increased activity in target-selective neural populations in visual cortex in the period between a search cue and target onset. In this study, we used online TMS to test whether preparatory neural activity in visual cortex is causally involved in naturalistic object detection. In two experiments, participants detected the presence of object categories (cars, people) in a diverse set of photographs of real-world scenes. TMS was applied over a region in posterior temporal cortex identified by fMRI as carrying category-specific preparatory activity patterns. Results showed that TMS applied over posterior temporal cortex before scene onset (-200 and -100 msec) impaired the detection of object categories in subsequently presented scenes, relative to vertex and early visual cortex stimulation. This effect was specific to category level detection and was related to the type of attentional template participants adopted, with the strongest effects observed in participants adopting category level templates. These results provide evidence for a causal role of preparatory attention in mediating the detection of objects in cluttered daily-life environments.

Occipital transcranial magnetic stimulation has an activity-dependent suppressive effect.

The effects of transcranial magnetic stimulation (TMS) vary depending on the brain state at the stimulation moment. Four mechanisms have been proposed to underlie these effects: (1) virtual lesion--TMS suppresses neural signals; (2) preferential activation of less active neurons--TMS drives up activity in the stimulated area, but active neurons are saturating; (3) noise generation--TMS adds random neuronal activity, and its effect interacts with stimulus intensity; and (4) noise generation--TMS adds random neuronal activity, and its effect depends on TMS intensity. Here we explore these hypotheses by investigating the effects of TMS on early visual cortex by assessing the contrast response function while varying the adaptation state of the observers. We tested human participants in an orientation discrimination task, in which performance is contingent upon contrast sensitivity. Before each trial, neuronal activation of visual cortex was altered through contrast adaptation to two flickering gratings. In a factorial design, with or without adaptation, a single TMS pulse was delivered simultaneously with targets of varying contrast. Adaptation decreased contrast sensitivity. The effect of TMS on performance was state dependent: TMS decreased contrast sensitivity in the absence of adaptation but increased it after adaptation. None of the proposed mechanisms can account for the results in their entirety, in particular, for the facilitatory effect at intermediate to high contrasts after adaptation. We propose an alternative hypothesis: TMS effects are activity dependent, so that TMS suppresses the most active neurons and thereby changes the balance between excitation and inhibition.

Mindfulness-based therapy improves brain functional network reconfiguration efficiency.

Mindfulness-based interventions are showing increasing promise as a treatment for psychological disorders, with improvements in cognition and emotion regulation after intervention. Understanding the changes in functional brain activity and neural plasticity that underlie these benefits from mindfulness interventions is thus of interest in current neuroimaging research. Previous studies have found functional brain changes during resting and task states to be associated with mindfulness both cross-sectionally and longitudinally, particularly in the executive control, default mode and salience networks. However, limited research has combined information from rest and task to study mindfulness-related functional changes in the brain, particularly in the context of intervention studies with active controls. Recent work has found that the reconfiguration efficiency of brain activity patterns between rest and task states is behaviorally relevant in healthy young adults. Thus, we applied this measure to investigate how mindfulness intervention changed functional reconfiguration between rest and a breath-counting task in elderly participants with self-reported sleep difficulties. Improving on previous longitudinal designs, we compared the intervention effects of a mindfulness-based therapy to an active control (sleep hygiene) intervention. We found that mindfulness intervention improved self-reported mindfulness measures and brain functional reconfiguration efficiency in the executive control, default mode and salience networks, though the brain and behavioral changes were not associated with each other. Our findings suggest that neuroplasticity may be induced through regular mindfulness practice, thus bringing the intrinsic functional configuration in participants' brains closer to a state required for mindful awareness.

Organisational models supported by technology for the management of diabetic disease and its complications in a diabetic clinic setting: study protocol for a randomised controlled trial targeting type 2 diabetes individuals with non-ideal glycaemic values (Telemechron study).

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a non-communicable disease representing one of the most serious public health challenges of the twenty-first century. Its incidence continues to rise in both developed and developing countries, causing the death of 1.5 million people every year. The use of technology (e.g. smartphone application-App) in the health field has progressively increased as it has been proved to be effective in helping individuals manage their long-term diseases. Therefore, it has the potential to reduce the use of health service and its related costs. The objective of this study is to evaluate the impact of using a digital platform called "TreC Diabete" embedded into a novel organisational asset targeting poorly controlled T2DM individuals in the Autonomous Province of Trento (PAT), Italy. METHODS: This trial was designed as a multi-centre, open-label, randomised, superiority study with two parallel groups and a 1:1 allocation ratio. Individuals regularly attending outpatient diabetes clinics, providing informed consent, are randomised to be prescribed TreC Diabete platform as part of their personalised care plan. Healthcare staff members will remotely assess the data shared by the participants through the App by using a dedicated online medical dashboard. The primary end-point is the evaluation of the Hb1Ac level at 12-month post-randomisation. Data will be analysed on an intention-to-treat (ITT) basis. DISCUSSION: This trial is the first conducted in the PAT area for the use of an App specifically designed for individuals with poorly controlled T2DM. If the effects of introducing this specific App within a new organisational asset are positive, the digital platform will represent a possible way for people diagnosed with T2DM to better manage their health in the future. Results will be disseminated through conferences and peer-reviewed journals once the study is completed. TRIAL REGISTRATION: ClinicalTrials.gov NCT05629221. Registered on November 29, 2022, prior start of inclusion.

Effects of ulotaront on brain circuits of reward, working memory, and emotion processing in healthy volunteers with high or low schizotypy.

Ulotaront, a trace amine-associated receptor 1 (TAAR1) and serotonin 5-HT1A receptor agonist without antagonist activity at dopamine D2 or the serotonin 5-HT2A receptors, has demonstrated efficacy in the treatment of schizophrenia. Here we report the phase 1 translational studies that profiled the effect of ulotaront on brain responses to reward, working memory, and resting state connectivity (RSC) in individuals with low or high schizotypy (LS or HS). Participants were randomized to placebo (n = 32), ulotaront (50 mg; n = 30), or the D2 receptor antagonist amisulpride (400 mg; n = 34) 2 h prior to functional magnetic resonance imaging (fMRI) of blood oxygen level-dependent (BOLD) responses to task performance. Ulotaront increased subjective drowsiness, but reaction times were impaired by less than 10% and did not correlate with BOLD responses. In the Monetary Incentive Delay task (reward processing), ulotaront significantly modulated striatal responses to incentive cues, induced medial orbitofrontal responses, and prevented insula activation seen in HS subjects. In the N-Back working memory task, ulotaront modulated BOLD signals in brain regions associated with cognitive impairment in schizophrenia. Ulotaront did not show antidepressant-like biases in an emotion processing task. HS had significantly reduced connectivity in default, salience, and executive networks compared to LS participants and both drugs reduced this difference. Although performance impairment may have weakened or contributed to the fMRI findings, the profile of ulotaront on BOLD activations elicited by reward, memory, and resting state is compatible with an indirect modulation of dopaminergic function as indicated by preclinical studies. This phase 1 study supported the subsequent clinical proof of concept trial in people with schizophrenia.Clinical trial registration: Registry# and URL: ClinicalTrials.gov NCT01972711, https://clinicaltrials.gov/ct2/show/NCT01972711.

Dissociable changes in sleep architecture with mindfulness and sleep hygiene intervention in older adults: Secondary and exploratory analysis of polysomnography data from the Mindfulness Sleep Therapy (MIST) trial.

OBJECTIVES: We conducted a secondary analysis of the Mindfulness Sleep Therapy study, a randomized controlled trial testing Mindfulness-Based Therapy for Insomnia (MBTI) against a sleep hygiene education and exercise program (SHEEP). We investigated whether the interventions led to changes in sleep macroarchitecture (N2, N3 and REM), and microarchitecture (sleep fragmentation, slow wave activity, spectral band power) measured by ambulatory polysomnography (PSG). METHODS: 48 MBTI and 46 SHEEP participants provided usable PSG and subjective sleep quality data both pre- and post intervention. The interventions consisted of 8 weekly 2-hour group sessions, and daily practice. PSG data were staged according to the American Academy of Sleep Medicine criteria by 2 technicians blind to time point and condition. Repeated-measures ANOVA and permutation analysis were used to test for differences over time and between the interventions. RESULTS: Self-reported sleep quality improved in both study groups. We observed significant increases in N2 in MBTI but not SHEEP (p = .045), and significant increases in N3 in SHEEP but not MBTI (p = .012). No significant differences over time or between group were observed in N1, REM, or sleep fragmentation. Higher frequency non-REM EEG power decreased in SHEEP but not MBTI. Slow wave activity and slow wave activity dissipation did not differ over time or between groups. Among all variables, significant time by group interactions were observed in only N3 and non-REM alpha power. CONCLUSIONS: MBTI and sleep hygiene education had different effects on sleep macro and microarchitecture, suggesting that the underlying mechanisms of mindfulness training in improving sleep quality may differ from traditional interventions.

Digital Technologies and the Role of Health Care Professionals: Scoping Review Exploring Nurses' Skills in the Digital Era and in the Light of the COVID-19 Pandemic.

BACKGROUND: The nursing role significantly changed following reforms in the nurse training process. Nowadays, nurses are increasingly trained to promote and improve the quality of clinical practice and to provide support in the assistance of patients and communities. Opportunities and threats are emerging as a consequence of the introduction of new disruptive technologies in public health, which requires the health care staff to develop new digital skills. OBJECTIVE: The aim of this paper is to review and define the role of nurses and the skills they are asked to master in terms of new methodological approaches and digital knowledge in a continuously evolving health care scenario that relies increasingly more on technology and digital solutions. METHODS: This scoping review was conducted using a thematic summary of previous studies. Authors collected publications through a cross-database search (PubMed, Web of Science, Google Scholar) related to new telemedicine approaches impacting the nurses' role, considering the time span of 2011-2021 and therefore including experiences and publications related to the first phase of the COVID-19 pandemic. RESULTS: The assessment was completed between April and July 2021. After a cross-database search, authors reviewed a selection of 60 studies. The results obtained were organized into 5 emerging macro areas: (1) leadership (nurses are expected to show leadership capabilities when introducing new technologies in health care practices, considering their pivotal role in coordinating various professional figures and the patient), (2) soft skills (new communication skills, adaptiveness, and problem solving are needed to adapt the interaction to the level of digital skills and digital knowledge of the patient), (3) training (specific subjects need to be added to nursing training to boost the adoption of new communication and technological skills, enabling health care professionals to largely and effectively use new digital tools), (4) remote management of COVID-19 or chronic patients during the pandemic (a role that has proved to be fundamental is the community and family nurse and health care systems are adopting novel assistance models to support patients at home and to enable decentralization of services from hospitals to the territory), and (5) management of interpersonal relationships with patients through telemedicine (a person-centered approach with an open and sensitive attitude seems to be even more important in the framework of telemedicine where a face-to-face session is not possible and therefore nonverbal indicators are more problematic to be noticed). CONCLUSIONS: Further advancing nurses' readiness in adopting telemedicine requires an integrated approach, including combination of technical knowledge, management abilities, soft skills, and communication skills. This scoping review provides a wide-ranging and general-albeit valuable-starting point to identify these core competences and better understand their implications in terms of present and future health care professionals' roles.

Left occipitotemporal cortex contributes to the discrimination of tool-associated hand actions: fMRI and TMS evidence.

Functional neuroimaging studies have implicated the left lateral occipitotemporal cortex (LOTC) in both tool and hand perception but the functional role of this region is not fully known. Here, by using a task manipulation, we tested whether tool-/hand-selective LOTC contributes to the discrimination of tool-associated hand actions. Participants viewed briefly presented pictures of kitchen and garage tools while they performed one of two tasks: in the action task, they judged whether the tool is associated with a hand rotation action (e.g., screwdriver) or a hand squeeze action (e.g., garlic press), while in the location task they judged whether the tool is typically found in the kitchen (e.g., garlic press) or in the garage (e.g., screwdriver). Both tasks were performed on the same stimulus set and were matched for difficulty. Contrasting fMRI responses between these tasks showed stronger activity during the action task than the location task in both tool- and hand-selective LOTC regions, which closely overlapped. No differences were found in nearby object- and motion-selective control regions. Importantly, these findings were confirmed by a TMS study, which showed that effective TMS over the tool-/hand-selective LOTC region significantly slowed responses for tool action discriminations relative to tool location discriminations, with no such difference during sham TMS. We conclude that left LOTC contributes to the discrimination of tool-associated hand actions.