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Understanding the mechanisms regulating root development under drought conditions is an important question for plant biology and world agriculture. We examine the effect of osmotic stress on abscisic acid (ABA), cytokinin and ethylene responses and how they mediate auxin transport, distribution and root growth through effects on PIN proteins. We integrate experimental data to construct hormonal crosstalk networks to formulate a systems view of root growth regulation by multiple hormones. Experimental analysis shows: that ABA-dependent and ABA-independent stress responses increase under osmotic stress, but cytokinin responses are only slightly reduced; inhibition of root growth under osmotic stress does not require ethylene signalling, but auxin can rescue root growth and meristem size; osmotic stress modulates auxin transporter levels and localization, reducing root auxin concentrations; PIN1 levels are reduced under stress in an ABA-dependent manner, overriding ethylene effects; and the interplay among ABA, ethylene, cytokinin and auxin is tissue-specific, as evidenced by differential responses of PIN1 and PIN2 to osmotic stress. Combining experimental analysis with network construction reveals that ABA regulates root growth under osmotic stress conditions via an interacting hormonal network with cytokinin, ethylene and auxin.

Frontotemporal dementia (FTD) and Progressive Supranuclear Palsy (PSP) have distinct molecular pathologies, with Tau and TDP43 aggregation, and distinct patterns of regional brain atrophy. However, they share the synaptotoxicity of protein aggregation, and neurotransmitter loss (including GABA), which contribute to clinical and neurophysiological similarities. Defining the relationships between synaptic loss, network physiology and cognition builds bridges between preclinical and clinical studies, and facilitates early phase trials. We quantified the effect of behavioural variant frontotemporal dementia (±parkinsonism) and progressive supranuclear palsy (Richardson's syndrome, and PSP-F), and controls with Magnetoencephalography (resting state, mismatch task, and motor control task); 11-C-UCBJ PET estimation of synaptic density; 3T T1w and fMRI. Participants with bvFTD showed severe synaptic loss compared to controls which correlated strongly with baseline cognitive function (ACE-r r∼0.8, p<0.001). Participants with PSP showed severe synaptic loss, which progressed over 12 months; the degree of synaptic loss over prefrontal cortex correlated with functional decline (PSPRS, r∼0.47, p<0.03. In both PSP and FTD, synaptic loss was more severe and widespread than cortical atrophy; prefrontal/ACC atrophy was significant in PSP, but less than in bvFTD. Synaptic loss correlated with the loss of weighted dress of fMRI-based cortical network measures. On MEG, deviant-versus-repeat tones evoked the frontotemporal peak 160-200ms and induced loss of beta-power (∼20Hz) during this window. Both bvFTD and PSP reduced/abolished the effect of deviant stimuli on prefrontal beta power, and this reduction in beta-power correlated with clinical severity, as FRS (in bvFTD) and PSPRS (in PSP). Inversion of the MEG response to biophysically informed dynamic causal models accurately explained the causes of the evoked response (r>0.9). Bayesian Model Comparison and second level parametric empirical Bayes analysis with UCBJ priors indicated the effect of bvFTD and PSP was attributable to loss of synapses from superficial cortical layers. MEG, PET and MRI are each well tolerated by people with PSP/bvFTD. These methods indicate severe and progressive synaptic loss, more than atrophy, with resulting behaviourally-relevant changes in prefrontal network beta-power and connectivity. Biophysical modelling confirms in vivo the post mortem observation of superficial cortical vulnerability to PSP/bvFTD.

Accurate identification of brain function is necessary to understand the neurobiology of cognitive ageing, and thereby promote well-being across the lifespan. A common tool used to investigate neurocognitive ageing is functional magnetic resonance imaging (fMRI). However, although fMRI data are often interpreted in terms of neuronal activity, the blood oxygenation level-dependent (BOLD) signal measured by fMRI includes contributions of both vascular and neuronal factors, which change differentially with age. While some studies investigate vascular ageing factors, the results of these studies are not well known within the field of neurocognitive ageing and therefore vascular confounds in neurocognitive fMRI studies are common. Despite over 10 000 BOLD-fMRI papers on ageing, fewer than 20 have applied techniques to correct for vascular effects. However, neurovascular ageing is not only a confound in fMRI, but an important feature in its own right, to be assessed alongside measures of neuronal ageing. We review current approaches to dissociate neuronal and vascular components of BOLD-fMRI of regional activity and functional connectivity. We highlight emerging evidence that vascular mechanisms in the brain do not simply control blood flow to support the metabolic needs of neurons, but form complex neurovascular interactions that influence neuronal function in health and disease. This article is part of the theme issue ‘Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity’.

Although commonly known as movement disorders, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) may present with changes in speech and language alongside or even before motor symptoms. The differential diagnosis of these two disorders can be challenging, especially in the early stages. Here we review their impact on speech and language. We discuss the neurobiological and clinical-phenomenological overlap of PSP and CBS with each other, and with other disorders including non-fluent agrammatic primary progressive aphasia and primary progressive apraxia of speech. Because language impairment is often an early and persistent problem in CBS and PSP, there is a need for improved methods for language screening in primary and secondary care, and more detailed language assessments in tertiary healthcare settings. Improved language assessment may aid differential diagnosis as well as inform clinical management decisions.

•We performed meta-analyses on fMRI/PET studies of human intentional decision.•Intentional choices activate a brain network maximal in the medial frontal cortex.•Four types of intentional decision paradigms are identified in the literature.•Intentional decisions rely on regions with distinct cognitive and computational roles. Brain-imaging research on intentional decision-making often employs a “free-choice” paradigm, in which participants choose among options with identical values or outcomes. Although the medial prefrontal cortex has commonly been associated with choices, there is no consensus on the wider network that underlies diverse intentional decisions and behaviours. Our systematic literature search identified 35 fMRI/PET experiments using various free-choice paradigms, with appropriate control conditions using external instructions. An Activation Likelihood Estimate (ALE) meta-analysis showed that, compared with external instructions, intentional decisions consistently activate the medial and dorsolateral prefrontal cortex, the left insula and the inferior parietal lobule. We then categorized the studies into four different types according to their experimental designs: reactive motor intention, perceptual intention, inhibitory intention, and cognitive intention. We conducted conjunction and contrast meta-analyses to identify consistent and selective spatial convergence of brain activation within each specific category of intentional decision. Finally, we used meta-analytic decoding to probe cognitive processes underlying free choices. Our findings suggest that the neurocognitive process underlying intentional decision incorporates anatomically separated components subserving distinct cognitive and computational roles.

To design effective therapies for neurodegenerative diseases, it is critical to understand the processes that trigger protein aggregation in sequential brain regions as the disease progresses. Aggregates formed in many neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are capable of seeding, leading to the proposal to regard them all as prion‐like. We here argue that the utility of this classification is limited; the terms protein misfolding and aggregation‐related diseases describe the general class of diseases, and the connotation of prion‐like that the spreading of infectious prions is the rate‐limiting process narrows the view of possible mechanisms. Instead, we suggest four factors along which to compare different diseases and model systems, providing a clearer basis to consider the different ways in which pathology can spread, account for factors beyond the aggregating protein, such as declining protein homeostasis with age, and understand the differences between model systems and human disease. Highlights Four aspects by which to classify neurodegenerative diseases are proposed. Aggregates in health and inflammation are important factors. Prion‐like spreading classification is not sufficient to capture the necessary nuance. Different diseases and model systems are dominated by different aspects.

Over the last two decades, inhibitory control has featured prominently in accounts of how humans and other organisms regulate their behaviour and thought. Previous work on how the brain stops actions and thoughts, however, has emphasised distinct prefrontal regions supporting these functions, suggesting domain-specific mechanisms. Here we show that stopping actions and thoughts recruits common regions in the right dorsolateral and ventrolateral prefrontal cortex to suppress diverse content, via dynamic targeting. Within each region, classifiers trained to distinguish action-stopping from action-execution also identify when people are suppressing their thoughts (and vice versa). Effective connectivity analysis reveals that both prefrontal regions contribute to action and thought stopping by targeting the motor cortex or the hippocampus, depending on the goal, to suppress their task-specific activity. These findings support the existence of a domain-general system that underlies inhibitory control and establish Dynamic Targeting as a mechanism enabling this ability. The authors use fMRI to show that the ability to stop unwanted actions and thoughts arises from a common stopping mechanism that flexibly inhibits activity in diverse, content-specific brain areas.

IntroductionAssociations between cerebral small vessel disease (SVD) and inflammation have been largely examined using peripheral blood markers of inflammation, with few studies measuring inflammation within the brain. We investigated the cross-sectional relationship between SVD and in vivo neuroinflammation using [11C]PK11195 positron emission tomography (PET) imaging.MethodsForty-two participants were recruited (according to NIA-AA guidelines, 14 healthy controls, 14 mild Alzheimer’s disease, 14 amyloid-positive mild cognitive impairment). Neuroinflammation was assessed using [11C]PK11195 PET imaging, a marker of microglial activation. To quantify SVD, we assessed white matter hyperintensities (WMH), enlarged perivascular spaces, cerebral microbleeds and lacunes. Composite scores were calculated for global SVD burden, and SVD subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). General linear models examined associations between SVD and [11C]PK11195, adjusting for sex, age, education, cognition, scan interval, and corrected for multiple comparisons via false discovery rate (FDR). Dominance analysis directly compared the relative importance of hypertensive arteriopathy and CAA scores as predictors of [11C]PK11195.ResultsGlobal [11C]PK11195 binding was associated with SVD markers, particularly in regions typical of hypertensive arteriopathy: deep microbleeds (β=0.63, F(1,35)=35.24, p<0.001), deep WMH (β=0.59, t=4.91, p<0.001). In dominance analysis, hypertensive arteriopathy score outperformed CAA in predicting [11C]PK11195 binding globally and in 28 out of 37 regions of interest, especially the medial temporal lobe (β=0.66–0.76, t=3.90–5.58, FDR-corrected p (pFDR)=<0.001–0.002) and orbitofrontal cortex (β=0.51–0.57, t=3.53–4.30, pFDR=0.001–0.004).ConclusionMicroglial activation is associated with SVD, particularly with the hypertensive arteriopathy subtype of SVD. Although further research is needed to determine causality, our study suggests that targeting neuroinflammation might represent a novel therapeutic strategy for SVD.

Cognitive problems are a major factor determining quality of life of patients with Parkinson's disease. These include deficits in inhibitory control, ranging from subclinical alterations in decision-making to severe impulse control disorders. Based on preclinical studies, we proposed that Parkinson's disease does not cause a unified disorder of inhibitory control, but rather a set of impulsivity factors with distinct psychological profiles, anatomy and pharmacology. We assessed a broad set of measures of the cognitive, behavioural and temperamental/trait aspects of impulsivity. Sixty adults, including 30 idiopathic Parkinson's disease patients (Hoehn and Yahr stage I-III) and 30 healthy controls, completed a neuropsychological battery, objective behavioural measures and self-report questionnaires. Univariate analyses of variance confirmed group differences in nine out of eleven metrics. We then used factor analysis (principal components method) to identify the structure of impulsivity in Parkinson's disease. Four principal factors were identified, consistent with four different mechanisms of impulsivity, explaining 60% of variance. The factors were related to (1) tests of response conflict, interference and self assessment of impulsive behaviours on the Barrett Impulsivity Scale, (2) tests of motor inhibitory control, and the self-report behavioural approach system, (3) time estimation and delay aversion, and (4) reflection in hypothetical scenarios including temporal discounting. The different test profiles of these four factors were consistent with human and comparative studies of the pharmacology and functional anatomy of impulsivity. Relationships between each factor and clinical and demographic features were examined by regression against factor loadings. Levodopa dose equivalent was associated only with factors (2) and (3). The results confirm that impulsivity is common in Parkinson's disease, even in the absence of impulse control disorders, and that it is not a unitary phenomenon. A better understanding of the structure of impulsivity in Parkinson's disease will support more evidence-based and effective strategies to treat impulsivity.