Freezing of gait in Parkinson's disease is a complex, heterogeneous and highly variable phenomenon. Using task-based fMRI, Ehgoetz Martens et al. show that freezing is a systems-level impairment ...characterised by a loss of synchrony between the cortex and striatum, and loss of segregation/specificity between cortico-striatal pathways.
Abstract
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.
Knowledge co-production (KCP) is presented as an effective strategy to inform responses to complex coastal and marine social-ecological challenges. Co-production processes are further posited to ...improve research and decision outcomes in a wide range of problem contexts (e.g., biodiversity conservation, climate change adaptation), for example, by facilitating social learning among diverse actors. As such, KCP processes are increasingly centered in global environment initiatives such as the United Nations Decade of Ocean Science for Sustainable Development. However, KCP is not a panacea, and much uncertainty remains about its emergence and implementation, in particular, the manner in which broader governance contexts determine the interplay of knowledge, power, and decision-making. Three objectives guide our analysis: (1) to interrogate more fully the interplay among social relations of power, knowledge production practices, and the (colonial) governance contexts in which they are embedded; (2) to consider the challenges and limitations of KCP in particular places by drawing attention to key governance themes and their implications for achieving better outcomes; and (3) to work toward a fuller understanding of "deep KCP" that cautions against a tendency to view knowledge processes in coastal and marine governance settings as an instrumental or techno-managerial problem. A qualitative and reflective approach was used to examine multiple dimensions of the interplay of KCP, governance, and power in several marine and coastal contexts, including Canada, New Zealand, and Papua New Guinea. In particular, our analysis highlights the importance of: (1) recognizing diverse motivations that frame co-production processes; (2) the manner in which identities, positionality, and values influence and are influenced by governance contexts; (3) highlighting governance capacity with respect to spatial and temporal constraints; (4) institutional reforms necessary for KCP and the links to governance; and (5) the relationship between knowledge sharing, data sovereignty, and governance. We seek to encourage those involved in or considering co-production initiatives to engage carefully and critically in these processes and make co-production more than a box to tick.
Summary Background Cerebral cavernous malformations (CCMs) are prone to bleeding but the risk of intracranial haemorrhage and focal neurological deficits, and the factors that might predict their ...occurrence, are unclear. We aimed to quantify these risks and investigate whether they are affected by sex and CCM location. Methods We undertook a population-based study using multiple overlapping sources of case ascertainment (including a Scotland-wide collaboration of neurologists, neurosurgeons, stroke physicians, radiologists, and pathologists, as well as searches of registers of hospital discharges and death certificates) to identify definite CCM diagnoses first made in Scottish residents between 1999 and 2003, which study neuroradiologists independently validated. We used multiple sources of prospective follow-up both to identify outcome events (which were assessed by use of brain imaging, by investigators masked to potential predictive factors) and to assess adults' dependence. The primary outcome was a composite of intracranial haemorrhage or focal neurological deficits (not including epileptic seizure) that were definitely or possibly related to CCM. Findings 139 adults had at least one definite CCM and 134 were alive at initial presentation. During 1177 person-years of follow-up (completeness 97%), for intracranial haemorrhage alone the 5-year risk of a first haemorrhage was lower than the risk of recurrent haemorrhage (2·4%, 95% CI 0·0–5·7 vs 29·5%, 4·1–55·0; p<0·0001). For the primary outcome, the 5-year risk of a first event was lower than the risk of recurrence (9·3%, 3·1–15·4 vs 42·4%, 26·8–58·0; p<0·0001). The annual risk of recurrence of the primary outcome declined from 19·8% (95% CI 6·1–33·4) in year 1 to 5·0% (0·0–14·8) in year 5 and was higher for women than men (p=0·01) but not for adults with brainstem CCMs versus CCMs in other locations (p=0·17). Interpretation The risk of recurrent intracranial haemorrhage or focal neurological deficit from a CCM is greater than the risk of a first event, is greater for women than for men, and declines over 5 years. This information can be used in clinical practice, but further work is needed to quantify risks precisely in the long term and to understand why women are at greater risk of recurrence than men. Funding UK Medical Research Council, Chief Scientist Office of the Scottish Government, and UK Stroke Association.
Impairments in motor automaticity cause patients with Parkinson's disease to rely on attentional resources during gait, resulting in greater motor variability and a higher risk of falls. Although ...dopaminergic circuitry is known to play an important role in motor automaticity, little evidence exists on the neural mechanisms underlying the breakdown of locomotor automaticity in Parkinson's disease. This impedes clinical management and is in great part due to mobility restrictions that accompany the neuroimaging of gait. This study therefore utilized a virtual reality gait paradigm in conjunction with functional MRI to investigate the role of dopaminergic medication on lower limb motor automaticity in 23 patients with Parkinson's disease that were measured both on and off dopaminergic medication. Participants either operated foot pedals to navigate a corridor (‘walk’ condition) or watched the screen while a researcher operated the paradigm from outside the scanner (‘watch’ condition), a setting that controlled for the non-motor aspects of the task. Step time variability during walk was used as a surrogate measure for motor automaticity (where higher variability equates to reduced automaticity), and patients demonstrated a predicted increase in step time variability during the dopaminergic “off” state. During the “off” state, subjects showed an increased blood oxygen level-dependent response in the bilateral orbitofrontal cortices (walk>watch). To estimate step time variability, a parametric modulator was designed that allowed for the examination of brain regions associated with periods of decreased automaticity. This analysis showed that patients on dopaminergic medication recruited the cerebellum during periods of increasing variability, whereas patients off medication instead relied upon cortical regions implicated in cognitive control. Finally, a task-based functional connectivity analysis was conducted to examine the manner in which dopamine modulates large-scale network interactions during gait. A main effect of medication was found for functional connectivity within an attentional motor network and a significant condition by medication interaction for functional connectivity was found within the striatum. Furthermore, functional connectivity within the striatum correlated strongly with increasing step time variability during walk in the off state (r=0.616, p=0.002), but not in the on state (r=−0.233, p=0.284). Post-hoc analyses revealed that functional connectivity in the dopamine depleted state within an orbitofrontal-striatal limbic circuit was correlated with worse step time variability (r=0.653, p<0.001). Overall, this study demonstrates that dopamine ameliorates gait automaticity in Parkinson's disease by altering striatal, limbic and cerebellar processing, thereby informing future therapeutic avenues for gait and falls prevention.
•Parkinson's disease patients performed a virtual reality gait task during fMRI.•The role of dopamine on gait automaticity impairments was investigated.•Limbic interference and poor striatal and cerebellar processing impair automaticity.•Dopamine ameliorates gait automaticity impairments in Parkinson's disease.
It has been proposed that aging results from the lifelong accumulation of intracellular damage via reactions with reactive oxygen species (ROS). Metallothioneins are conserved cysteine-rich proteins ...that function as efficient ROS scavengers and may affect longevity. To better understand mechanisms controlling metallothionein expression, the regulatory factors and pathways that controlled cadmium-inducible transcription of the C. elegans metallothionein gene, mtl-1, were identified. The transcription factor ATF-7 was identified in both ethylmethanesulfonate mutagenesis and candidate gene screens. PMK-1 and members of the insulin signaling pathway, PDK-1 and AKT-1/2, were also identified as mtl-1 regulators. Genetic and previous results support a model for the regulation of cadmium-inducible mtl-1 transcription based on the derepression of the constitutively active transcription factor ELT-2. In addition, knockdown of the mammalian homologs of PDK1 and ATF7 in HEK293 cells resulted in changes in metallothionein expression, suggesting that this pathway was evolutionarily conserved. The insulin signaling pathway is known to influence the aging process; however, various factors responsible for affecting the aging phenotype are unknown. Identification of portions of the insulin signaling pathway as regulators of metallothionein expression supports the hypothesis that longevity is affected by the expression of this efficient ROS scavenger.
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.
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 H
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.
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