The effect of target-related and target-irrelevant novel stimuli on response behaviour.

Novel events catch our attention, which can influence performance of a task. Whether this attentional capture by novelty benefits or impairs performance depends on several factors, such as the relevance of the stimulus, task requirements, and the timing of the event. Additionally, it has been argued that novel stimuli can hold intrinsic reward value, which may directly affect approach motivation, similar to positive valence stimuli. This link between novelty and approach/avoid behaviour has not been investigated directly. Here, we investigated whether stimulus novelty interacts with response behaviour in an approach/avoidance task, and whether these effects depend on the task relevance of novelty and stimulus timing. In experiment 1, participants gave an approach or avoid response dependent on a shape (diamond or square) presented at different stimulus onset asynchronies (SOA) following a novel or familiar scene (target-irrelevant novelty). In experiment 2, participants had to approach or avoid a novel or familiar image depending on the content (indoor/outdoor; target-related novelty). A shape was presented at different SOA. Results of a linear mixed model showed novelty-induced performance costs as demonstrated by longer RT and lower accuracy when novelty was target-relevant, likely due to attentional lingering at novel images. When images were target-irrelevant, approach but not avoid responses were faster for familiar versus novel images at 200 ms SOA only. Thus, novelty had a differentially pronounced detrimental effect on performance. These observations confirm that processing of novel stimuli generally depends on stimulus relevance, and tentatively suggests that differential processing of novel and familiar images is intensified by motivated approach behaviour.

Motor cortical excitability and pre-supplementary motor area neurochemistry in healthy adults with substantia nigra hyperechogenicity.

Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50-70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n = 14; 61 ± 7 yrs) or abnormally enlarged (hyperechogenic; n = 9; 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN- and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p = .005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10-12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease.

COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms.

SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. SARS-CoV-2 infection is necessary but not sufficient for development of clinical COVID-19 disease. Currently, there are no approved pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain obscure. We have investigated several plausible hypotheses for famotidine activity including antiviral and host-mediated mechanisms of action. We propose that the principal mechanism of action of famotidine for relieving COVID-19 symptoms involves on-target histamine receptor H2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release. Based on these findings and associated hypothesis, new COVID-19 multi-drug treatment strategies based on repurposing well-characterized drugs are being developed and clinically tested, and many of these drugs are available worldwide in inexpensive generic oral forms suitable for both outpatient and inpatient treatment of COVID-19 disease.

COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms.

SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. Currently, there are no pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain obscure. We explore several plausible avenues of activity including antiviral and host-mediated actions. We propose that the principal famotidine mechanism of action for COVID-19 involves on-target histamine receptor H2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release.

Mind-wandering in Parkinson's disease hallucinations reflects primary visual and default network coupling.

Visual hallucinations are an underappreciated symptom affecting the majority of patients during the natural history of Parkinson's disease. Little is known about other forms of abstract and internally generated cognition - such as mind-wandering - in this population, but emerging evidence suggests that an interplay between the brain's primary visual and default networks might play a crucial role in both internally generated imagery and hallucinations. Here, we explored the association between mind-wandering and visual hallucinations in Parkinson's disease, and their relationship with brain network coupling. We administered a validated thought-sampling task to 38 Parkinson's disease patients (18 with hallucinations; 20 without) and 40 controls, to test the hypothesis that individuals with hallucinations experience an increased frequency of mind-wandering. Group differences in the association between mind-wandering frequency and brain network coupling were also examined using resting state functional magnetic resonance imaging. Our results showed that patients with hallucinations exhibited significantly higher mind-wandering frequencies compared to non-hallucinators, who in turn had reduced levels of mind-wandering relative to controls. At the level of brain networks, inter-network connectivity and seed-to-voxel analyses identified that increased mind-wandering in the hallucinating versus non-hallucinating group was associated with greater coupling between the primary visual cortex and dorsal default network. Taken together, our results suggest a relative preservation of mind-wandering in Parkinson's disease patients who experience visual hallucinations, which is associated with increased visual cortex-default network coupling. We propose that the preservation of florid abstract and internally generated cognition in the context of the Parkinson's disease can contribute to visual hallucinations, whereas healthy individuals experience only the vivid images of the mind's eye. These findings refine current models of visual hallucinations by identifying a specific cognitive phenomenon and neural substrate consistent with the top-down influences over perception that have been implicated in hallucinations across neuropsychiatric disorders.

Twelve tips for developing and implementing curriculum in dedicated 'collaborative classrooms'.

Many health professional schools may be investing time and resources on dedicated educational spaces intended to promote collaborative learning. Alone, innovative physical space or technologies are not sufficient to ensure success in this. Lesson plans informed by collaborative praxis, individual motivation, faculty development, learner feedback, and team interactions also play a necessary and substantial role. We have used faculty observations, quantitative and qualitative student evaluation data, and the existing educational literature to provide twelve tips on leveraging curricular content, activity setup, physical space, learner behavior, and faculty facilitation to make the most of collaborative learning spaces.

Melatonin for rapid eye movement sleep behavior disorder in Parkinson's disease: A randomised controlled trial.

BACKGROUND: Melatonin may reduce REM-sleep behavior disorder (RBD) symptoms in Parkinson's disease (PD), though robust clinical trials are lacking. OBJECTIVE: To assess the efficacy of prolonged-release (PR) melatonin for RBD in PD. METHODS: Randomized, double-blind, placebo-controlled, parallel-group trial with an 8-week intervention and 4-week observation pre- and postintervention (ACTRN12613000648729). Thirty PD patients with rapid eye movement sleep behavior disorder were randomized to 4 mg of prolonged-release melatonin (Circadin) or matched placebo, ingested orally once-daily before bedtime. Primary outcome was the aggregate of rapid eye movement sleep behavior disorder incidents averaged over weeks 5 to 8 of treatment captured by a weekly diary. Data were included in a mixed-model analysis of variance (n = 15 per group). RESULTS: No differences between groups at the primary endpoint (3.4 events/week melatonin vs. 3.6 placebo; difference, 0.2; 95% confidence interval = -3.2 to 3.6; P = 0.92). Adverse events included mild headaches, fatigue, and morning sleepiness (n = 4 melatonin; n = 5 placebo). CONCLUSION: Prolonged-release melatonin 4 mg did not reduce rapid eye movement sleep behavior disorder in PD. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Perturbation of Nuclear Hormone Receptors by Endocrine Disrupting Chemicals: Mechanisms and Pathological Consequences of Exposure.

Much of the early work on Nuclear Hormone Receptors (NHRs) focused on their essential roles as mediators of sex steroid hormone signaling in reproductive development and function, and thyroid hormone-dependent formation of the central nervous system. However, as NHRs display tissue-specific distributions and activities, it is not surprising that they are involved and vital in numerous aspects of human development and essential for homeostasis of all organ systems. Much attention has recently been focused on the role of NHRs in energy balance, metabolism, and lipid homeostasis. Dysregulation of NHR function has been implicated in numerous pathologies including cancers, metabolic obesity and syndrome, Type II diabetes mellitus, cardiovascular disease, hyperlipidemia, male and female infertility and other reproductive disorders. This review will discuss the dysregulation of NHR function by environmental endocrine disrupting chemicals (EDCs), and the associated pathological consequences of exposure in numerous tissues and organ systems, as revealed by experimental, clinical, and epidemiological studies.

Subtle gait and balance impairments occur in idiopathic rapid eye movement sleep behavior disorder.

BACKGROUND: Although motor abnormalities have been flagged as potentially the most sensitive and specific clinical features for predicting the future progression to Parkinson's disease, little work has been done to characterize gait and balance impairments in idiopathic rapid eye movement sleep behavior disorder (iRBD). OBJECTIVE: The objective of this study was to quantitatively determine any static balance as well as gait impairments across the 5 independent domains of gait in polysomnography-confirmed iRBD patients using normal, fast-paced, and dual-task walking conditions. METHODS: A total of 38 participants (24 iRBD, 14 healthy controls) completed the following 5 different walking trials across a pressure sensor carpet: (1) normal pace, (2) fast pace, (3) while counting backward from 100 by 1s, (4) while naming as many animals as possible, (5) while subtracting 7s from 100. RESULTS: Although no gait differences were found between the groups during normal walking, there were significant differences between groups under the fast-paced and dual-task gait conditions. Specifically, in response to the dual tasking, healthy controls widened their step width without changing step width variability, whereas iRBD patients did not widen their step width but, rather, significantly increased their step width variability. Similarly, changes between the groups were observed during fast-paced walking wherein the iRBD patients demonstrated greater step length asymmetry when compared with controls. CONCLUSIONS: This study demonstrates that iRBD patients have subtle gait impairments, which likely reflect early progressive degeneration in brainstem regions that regulate both REM sleep and gait coordination. Such gait assessments may be useful as a diagnostic preclinical screening tool for future fulminant gait abnormalities for trials of disease-preventive agents. © 2019 International Parkinson and Movement Disorder Society.

10Kin1day: A Bottom-Up Neuroimaging Initiative.

We organized 10Kin1day, a pop-up scientific event with the goal to bring together neuroimaging groups from around the world to jointly analyze 10,000+ existing MRI connectivity datasets during a 3-day workshop. In this report, we describe the motivation and principles of 10Kin1day, together with a public release of 8,000+ MRI connectome maps of the human brain.

Changes in structural network topology correlate with severity of hallucinatory behavior in Parkinson's disease.

Inefficient integration between bottom-up visual input and higher order visual processing regions is implicated in visual hallucinations in Parkinson's disease (PD). Here, we investigated white matter contributions to this perceptual imbalance hypothesis. Twenty-nine PD patients were assessed for hallucinatory behavior. Hallucination severity was correlated to connectivity strength of the network using the network-based statistic approach. The results showed that hallucination severity was associated with reduced connectivity within a subnetwork that included the majority of the diverse club. This network showed overall greater between-module scores compared with nodes not associated with hallucination severity. Reduced between-module connectivity in the lateral occipital cortex, insula, and pars orbitalis and decreased within-module connectivity in the prefrontal, somatosensory, and primary visual cortices were associated with hallucination severity. Conversely, hallucination severity was associated with increased between- and within-module connectivity in the orbitofrontal and temporal cortex, as well as regions comprising the dorsal attentional and default mode network. These results suggest that hallucination severity is associated with marked alterations in structural network topology with changes in participation along the perceptual hierarchy. This may result in the inefficient transfer of information that gives rise to hallucinations in PD.

The Role of Dietary Phytoestrogens and the Nuclear Receptor PPARγ in Adipogenesis: An in Vitro Study.

BACKGROUND: Phytoestrogens, naturally occurring plant chemicals, have long been thought to confer beneficial effects on human cardiovascular and metabolic health. However, recent epidemiological studies, have yielded conflicting outcomes, in which phytoestrogen consumption was both positively and negatively correlated with adiposity. Interestingly, several dietary phytoestrogens are known to stimulate or inhibit the activity of the peroxisome proliferator-activated receptor gamma (PPARγ), a key physiological regulator of adipogenesis. OBJECTIVE: The objective of this study was to test the hypothesis that the pro- or anti-adipogenic activity of phytoestrogen chemicals is related to the ability to activate PPARγ in adipocytes. METHODS: The effects of resveratrol and the soy isoflavones genistein and daidzein on adipogenesis were examined in cell-based assays using the 3T3-L1 cell model. In parallel, ligand-mediated alterations in PPARγ target gene expression were measured by quantitative polymerase chain reaction. The agonist/antagonist activities of phytoestrogens on PPARγ were further assessed by quantifying their ability to affect recruitment of transcriptional cofactors to the receptor. RESULTS: Resveratrol displayed significant anti-adipogenic activities as exhibited by the ability to antagonize PPARγ-dependent adipocyte differentiation, down-regulate genes involved in lipid metabolism, block cofactor recruitment to PPARγ, and antagonize the effects of the PPARγ agonist rosiglitazone. In contrast, genistein and daidzein functioned as PPARγ agonists while also displaying pro-adipogenic activities. CONCLUSIONS: These data provide biological evidence that the pro- or anti-obesity effects of phytoestrogens are related to their relative agonist/antagonist activity on PPARγ. Thus, PPARγ-activation assays may enable the screening of dietary components and identification of agents with adipogenic activities. https://doi.org/10.1289/EHP3444.

Neural Correlates of Cognitive Impairment in Parkinson's Disease: A Review of Structural MRI Findings.

Cognitive impairment is one of the most salient non-motor symptoms of Parkinson's disease (PD). Cognitive decline poses a significant burden on the patient as well as the caregiver and a better understanding of the underlying pathological processes will aid in directing disease-specific treatment. In recent years, significant progress in the understanding of the underlying mechanisms of cognition in PD has been made using neuroimaging modalities. In this review, we will discuss the evidence for gray matter atrophy and cortical thinning, diffusivity changes and white matter hyperintensities in dementia, mild cognitive impairment and in several cognitive domains. Structural MRI studies have revealed considerable changes in gray and white matter in PD patients with cognitive dysfunction, showing marked atrophy and diffusivity changes in patients with dementia. The neural substrates of mild cognitive impairment in PD are more variable, perhaps reflecting a heterogeneous cohort with patients showing deficits in various cognitive domains. This review further highlights the potential areas of future research avenues in cognitive impairment in PD.

The interactive effect of valence and context on reversal learning in individuals with Parkinson's disease.

Cognitive deficits in Parkinson's disease (PD) have increasingly been recognized over the last decade and reversal learning in particular has received a great deal of attention. In a classical reversal-learning paradigm, participants learn to associate various stimuli with specific responses (i.e. A →Positive; B→ Negative), and subsequently learn to associate the same stimuli with opposite outcomes (i.e., A→Negative; B→ Positive). Prior studies have revealed that medicated PD patients have a selective impairment with learning from negative, but not positive, outcomes, even when both reward- and punishment-related stimuli were equally relevant. The aim of the present study was to further understand this impairment by applying a novel reversal-learning paradigm, which enables the differentiation between positive/negative and cue/context reversal impairments. Twenty-seven medicated PD patients and twenty-nine healthy individuals matched for age, gender and education completed the cue-context reversal learning paradigm. The results revealed no significant differences in context reversal learning between individuals with PD and healthy controls. However, in cue reversal learning, healthy controls were significantly better at performing positive-to-negative reversal trials compared to individuals with PD, while individuals with PD were significantly better in negative-to-positive reversal trials compared to healthy controls. As such, the present study distinguishes between different types of reversal learning and suggests that different neural circuits are responsible for context and cue learning. These results improve our understanding of the possible effects of dopaminergic medications and may have important clinical implications.

Evidence for subtypes of freezing of gait in Parkinson's disease.

BACKGROUND: The purpose of this study is to identify and characterize subtypes of freezing of gait by using a novel questionnaire designed to delineate freezing patterns based on self-reported and behavioral gait assessment. METHODS: A total of 41 Parkinson's patients with freezing completed the Characterizing Freezing of Gait questionnaire that identifies situations that exacerbate freezing. This instrument underwent examination for construct validity and internal consistency, after which a data-driven clustering approach was employed to identify distinct patterns amongst individual responses. Behavioral freezing assessments in both dopaminergic states were compared across 3 identified subgroups. RESULTS: This novel questionnaire demonstrated construct validity (severity scores correlated with percentage of time frozen; r = 0.54) and internal consistency (Cronbach's α = .937), and thus demonstrated promising utility for identifying patterns of freezing that are independently related to motor, anxiety, and attentional impairments. CONCLUSIONS: Patients with freezing may be dissociable based on underlying neurobiological underpinnings that would have significant implications for targeting future treatments. © 2018 International Parkinson and Movement Disorder Society.

Cognitive training for freezing of gait in Parkinson's disease: a randomized controlled trial.

The pathophysiological mechanism of freezing of gait (FoG) has been linked to executive dysfunction. Cognitive training (CT) is a non-pharmacological intervention which has been shown to improve executive functioning in Parkinson's disease (PD). This study aimed to explore whether targeted CT can reduce the severity of FoG in PD. Patients with PD who self-reported FoG and were free from dementia were randomly allocated to receive either a CT intervention or an active control. Both groups were clinician-facilitated and conducted twice-weekly for seven weeks. The primary outcome was percentage of time spent frozen during a Timed Up and Go task, assessed both on and off dopaminergic medications. Secondary outcomes included multiple neuropsychological and psychosocial measures. A full analysis was first conducted on all participants randomized, followed by a sample of interest including only those who had objective FoG at baseline, and completed the intervention. Sixty-five patients were randomized into the study. The sample of interest included 20 in the CT group and 18 in the active control group. The primary outcome of percentage time spent frozen during a gait task was significantly improved in the CT group compared to active controls in the on-state. There were no differences in the off-state. Patients who received CT also demonstrated improved processing speed and reduced daytime sleepiness compared to those in the active control. The findings suggest that CT can reduce the severity of FoG in the on-state, however replication in a larger sample is required.

Alterations in white matter network topology contribute to freezing of gait in Parkinson's disease.

Freezing of gait (FOG) is a common symptom in advanced Parkinson's disease (PD). Despite current advances, the neural mechanisms underpinning this disturbance remain poorly understood. To this end, we investigated the structural organisation of the white matter connectome in PD freezers and PD non-freezers. We hypothesized that freezers would show an altered network architecture, which could hinder the effective information processing that characterizes the disorder. Twenty-six freezers and twenty-four well-matched non-freezers were included in this study. Using diffusion tensor imaging, we investigated the modularity and integration of the regional connectome by calculating the module degree z score and the participation coefficient, respectively. Compared to non-freezers, freezers demonstrated lower participation coefficients in the right caudate, thalamus, and hippocampus, as well as within superior frontal and parietal cortical regions. Importantly, several of these nodes were found within the brain's 'rich club'. Furthermore, group differences in module degree z scores within cortical frontal and sensory processing areas were found. Together, our results suggest that changes in the structural network topology contribute to the manifestation of FOG in PD, specifically due to a lack of structural integration between key information processing hubs of the brain.

The functional network signature of heterogeneity in freezing of gait.

Freezing of gait is a complex, heterogeneous, and highly variable phenomenon whose pathophysiology and neural signature remains enigmatic. Evidence suggests that freezing is associated with impairments across cognitive, motor and affective domains; however, most research to date has focused on investigating one axis of freezing of gait in isolation. This has led to inconsistent findings and a range of different pathophysiological models of freezing of gait, due in large part to the tendency for studies to investigate freezing of gait as a homogeneous entity. To investigate the neural mechanisms of this heterogeneity, we used an established virtual reality paradigm to elicit freezing behaviour in 41 Parkinson's disease patients with freezing of gait and examined individual differences in the component processes (i.e. cognitive, motor and affective function) that underlie freezing of gait in conjunction with task-based functional MRI. First, we combined three unique components of the freezing phenotype: impaired set-shifting ability, step time variability, and self-reported anxiety and depression in a principal components analysis to estimate the severity of freezing behaviour with a multivariate approach. By combining these measures, we were then able to interrogate the pattern of task-based functional connectivity associated with freezing (compared to normal foot tapping) in a sub-cohort of 20 participants who experienced sufficient amounts of freezing during task functional MRI. Specifically, we used the first principal component from our behavioural analysis to classify patterns of functional connectivity into those that were associated with: (i) increased severity; (ii) increased compensation; or (iii) those that were independent of freezing severity. Coupling between the cognitive and limbic networks was associated with 'worse freezing severity', whereas anti-coupling between the putamen and the cognitive and limbic networks was related to 'increased compensation'. Additionally, anti-coupling between cognitive cortical regions and the caudate nucleus were 'independent of freezing severity' and thus may represent common neural underpinnings of freezing that are unaffected by heterogenous factors. Finally, we related these connectivity patterns to each of the individual components (cognitive, motor, affective) in turn, thus exposing latent heterogeneity in the freezing phenotype, while also identifying critical functional network signatures that may represent potential targets for novel therapeutic intervention. In conclusion, our findings provide confirmatory evidence for systems-level impairments in the pathophysiology of freezing of gait and further advance our understanding of the whole-brain deficits that mediate symptom expression in Parkinson's disease.