Abstract Multifunctional agents with limited motor resources must decide what actions will best ensure their survival. Moreover, given that in an unpredictable world things don't always work out, ...considerable advantage is to be gained by learning from experience – instrumental behaviour that maximises reward and minimises punishment. In this review we will argue that the re-entrant looped architecture of the basal ganglia represents biological solutions to these fundamental behavioural problems of selection and reinforcement. A potential solution to the selection problem is provided for by selective disinhibition within the parallel loop architecture that connects the basal ganglia with external neural structures. The relay points within these loops permit the signals of a particular channel to be modified by external influences. In part, these influences have the capacity to modify overall selections so that the probability of re-selecting reinforced behaviours in the future is altered. This is the basic process of instrumental learning, which we suggest decomposes into two sub-problems for the agent: (i) learning which external events it causes to happen and learning precisely what it is doing that is causal; and (ii) having determined agency and discovered novel action-outcome routines, how best to exploit this knowledge to maximise future reward acquisitions. Considerations of connectional architecture and signal timing suggest that the short-latency, sensory-evoked dopamine response, which can modulate the re-entrant loop structure within the basal ganglia, is ideally suited to reinforce the determination of agency and the discovery of novel actions. Alternatively, recent studies showing that presence or absence of reward can selectively modulate the magnitude of signals in structures providing input signals to the basal ganglia, offer an alternative mechanism for biasing selection within the re-entrant loop architecture. We suggest that this mechanism may be better suited to ensure the prioritisation of inputs associated with reward. This article is part of a Special Issue entitled: Function and Dysfunction of the Basal Ganglia.
Abstract Background/Objectives Interhemispheric inhibition in the brain plays a dynamic role in the production of voluntary unimanual actions. In stroke, the interhemispheric imbalance model predicts ...the presence of asymmetry in interhemispheric inhibition, with excessive inhibition from the contralesional hemisphere limiting maximal recovery. Stimulation methods to reduce this asymmetry in the brain may be promising as a stroke therapy, however determining how to best measure and modulate interhemispheric inhibition and who is likely to benefit, remain important questions. Methods This review addresses current understanding of interhemispheric inhibition in the healthy and stroke lesioned brain. We present a review of studies that have measured interhemispheric inhibition using different paradigms in the clinic, as well as results from recent animal studies investigating stimulation methods to target abnormal inhibition after stroke. Main findings/Discussion The degree to which asymmetric interhemispheric inhibition impacts on stroke recovery is controversial, and we consider sources of variation between studies which may contribute to this debate. We suggest that interhemispheric inhibition is not static following stroke in terms of the movement phase in which it is aberrantly engaged. Instead it may be dynamically increased onto perilesional areas during early movement, thus impairing motor initiation. Hence, its effect on stroke recovery may differ between studies depending on the technique and movement phase of eliciting the measurement. Finally, we propose how modulating excitability in the brain through more specific targeting of neural elements underlying interhemispheric inhibition via stimulation type, location and intensity may raise the ceiling of recovery following stroke and enhance functional return.
Dental caries is a highly prevalent diet-related disease and is a major public health problem. A goal of modern dentistry is to manage non-cavitated caries lesions non-invasively through ...remineralization in an attempt to prevent disease progression and improve aesthetics, strength, and function. Remineralization is defined as the process whereby calcium and phosphate ions are supplied from a source external to the tooth to promote ion deposition into crystal voids in demineralized enamel, to produce net mineral gain. Recently, a range of novel calcium-phosphate-based remineralization delivery systems has been developed for clinical application. These delivery systems include crystalline, unstabilized amorphous, or stabilized amorphous formulations of calcium phosphate. These systems are reviewed, and the technology with the most scientific evidence to support its clinical use is the remineralizing system utilizing casein phosphopeptides to stabilize and deliver bioavailable calcium, phosphate, and fluoride ions. The recent clinical evidence for this technology is presented and the mechanism of action discussed. Biomimetic approaches to stabilization of bioavailable calcium, phosphate, and fluoride ions and the localization of these ions to non-cavitated caries lesions for controlled remineralization show promise for the non-invasive management of dental caries.
Dopamine-dependent long-term plasticity is believed to be a cellular mechanism underlying reinforcement learning. In response to reward and reward-predicting cues, phasic dopamine activity ...potentiates the efficacy of corticostriatal synapses on spiny projection neurons (SPNs). Since phasic dopamine activity also encodes other behavioural variables, it is unclear how postsynaptic neurons identify which dopamine event is to induce long-term plasticity. Additionally, it is unknown how phasic dopamine released from arborised axons can potentiate targeted striatal synapses through volume transmission. To examine these questions we manipulated striatal cholinergic interneurons (ChIs) and dopamine neurons independently in two distinct in vivo paradigms. We report that long-term potentiation (LTP) at corticostriatal synapses with SPNs is dependent on the coincidence of pauses in ChIs and phasic dopamine activation, critically accompanied by SPN depolarisation. Thus, the ChI pause defines the time window for phasic dopamine to induce plasticity, while depolarisation of SPNs constrains the synapses eligible for plasticity.
Powerful winds driven by active galactic nuclei are often thought to affect the evolution of both supermassive black holes and their host galaxies, quenching star formation and explaining the close ...relationship between black holes and galaxies. Recent observations of large-scale molecular outflows in ultraluminous infrared galaxies support this quasar-feedback idea, because they directly trace the gas from which stars form. Theoretical models suggest that these outflows originate as energy-conserving flows driven by fast accretion-disk winds. Proposed connections between large-scale molecular outflows and accretion-disk activity in ultraluminous galaxies were incomplete because no accretion-disk wind had been detected. Conversely, studies of powerful accretion-disk winds have until now focused only on X-ray observations of local Seyfert galaxies and a few higher-redshift quasars. Here we report observations of a powerful accretion-disk wind with a mildly relativistic velocity (a quarter that of light) in the X-ray spectrum of IRAS F11119+3257, a nearby (redshift 0.189) optically classified type 1 ultraluminous infrared galaxy hosting a powerful molecular outflow. The active galactic nucleus is responsible for about 80 per cent of the emission, with a quasar-like luminosity of 1.5 × 10(46) ergs per second. The energetics of these two types of wide-angle outflows is consistent with the energy-conserving mechanism that is the basis of the quasar feedback in active galactic nuclei that lack powerful radio jets (such jets are an alternative way to drive molecular outflows).
The existence of ionized X-ray absorbing layers of gas along the line of sight to the nuclei
of Seyfert galaxies is a well established observational fact. This material is systematically
outflowing ...and shows a large range in parameters. However, its actual nature and dynamics
are still not clear. In order to gain insights into these important issues we performed a literature
search for papers reporting the parameters of the soft X-ray warm absorbers (WAs) in 35 type
1 Seyferts and compared their properties to those of the ultra-fast outflows (UFOs) detected in
the same sample. The fraction of sources with WAs is >60 per cent, consistent with previous
studies. The fraction of sources with UFOs is >34 per cent, >67 per cent of which also
show WAs. The large dynamic range obtained when considering all the absorbers together,
spanning several orders of magnitude in ionization, column, velocity and distance allows us,
for the first time, to investigate general relations among them. In particular, we find significant
correlations indicating that the closer the absorber is to the central black hole, the higher the
ionization, column, outflow velocity and consequently the mechanical power. In all the cases,
the absorbers continuously populate the whole parameter space, with the WAs and the UFOs
lying always at the two ends of the distribution. These evidence strongly suggest that these
absorbers, often considered of different types, could actually represent parts of a single large-scale
stratified outflow observed at different locations from the black hole. The UFOs are likely
launched from the inner accretion disc and the WAs at larger distances, such as the outer disc
and/or torus. We argue that the observed parameters and correlations are, to date, consistent
with both radiation pressure through Compton scattering and magnetohydrodynamic processes
contributing to the outflow acceleration, the latter playing a major role. Most of the absorbers,
especially the UFOs, show a sufficiently high mechanical power (at least approx 0.5 per cent of the
bolometric luminosity) to provide a significant contribution to active galactic nuclei (AGN)
feedback and thus to the evolution of the host galaxy. In this regard, we find possible evidence
for the interaction of the AGN wind with the surrounding environment on large scales.
Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) slows the progression of caries and remineralizes enamel subsurface lesions. The aim of this study was to determine the ability of CPP-ACP ...to increase the incorporation of fluoride into plaque and to promote enamel remineralization in situ. Randomized, double-blind, cross-over studies involved mouthrinses and dentifrices containing CPP-ACP and fluoride. The mouthrinses were used for 60 sec, three times/day for 5 days, and supragingival plaque was collected and analyzed for F. The dentifrices were rinsed as a water slurry for 60 sec four times/day for 14 days in an in situ model. The addition of 2% CPP-ACP to the 450-ppm-F mouthrinse significantly increased the incorporation of fluoride into plaque. The dentifrice containing 2% CPP-ACP produced a level of remineralization similar to that achieved with a dentifrice containing 2800 ppm F. The dentifrice containing 2% CPP-ACP plus 1100 ppm F was superior to all other formulations.
Abstract The tonically active neurons (TANs) are a population of neurons scattered sparsely throughout the striatum that show intriguing patterns of firing activity during reinforcement learning. ...Following repeated pairings of a neutral stimulus with a primary reward, TANs develop a transient cessation of firing activity in response to the stimulus, termed the “conditioned pause response.” In tasks where specific cues are arranged to signal the probability of particular outcomes, the pause response to both cue and outcome may differ in ways that suggest the involvement of different inputs to the same neuron. Here we review the cellular properties of cholinergic interneurons and describe the response to their afferents in terms of inducing TAN-like pauses in tonic firing. Recent work has shown that thalamostriatal inputs to cholinergic neurons transiently suppress firing activity via dopamine release. Because these pauses are initiated by subcortical pathways with limited sensory processing abilities, we propose that they are an ideal correlate for the pauses observed in TANs in response to cues signaling trial initiation. On the other hand, pauses that accompany outcome presentation contain higher-level information, including an apparent sensitivity to reward prediction error. Thus, these pauses may be mediated by cortical inputs to cholinergic interneurons. Although there is evidence linking cholinergic pauses to synaptic plasticity, much remains to be discovered about the effect of this relatively sparse but influential population on the striatal learning system. This article is part of a Special Issue entitled: Function and Dysfunction of the Basal Ganglia.
Summary
Background
The ‘treat to target’ paradigm improves outcomes and reduces costs in chronic disease management but is not yet established in psoriasis.
Objectives
To identify treatment targets ...in psoriasis using two common measures of disease activity: Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA).
Methods
Data from a multicentre longitudinal U.K. cohort of patients with psoriasis receiving systemic or biologic therapies (British Association of Dermatologists Biologics and Immunomodulators Register, BADBIR) were used to identify absolute PASI thresholds for 90% (PASI 90) and 75% (PASI 75) improvements in baseline disease activity, using receiver operating characteristic curves. The relationship between PGA (clear, almost clear, mild, moderate, moderate–severe, severe) and PASI (range 0–72) was described, and the concordance between absolute and relative definitions of response was determined. The same approach was used to establish treatment response and eligibility definitions based on PGA.
Results
Data from 13 422 patients were available (58% male, 91% white ethnicity, mean age 44·9 years), including over 23 000 longitudinal PASI and PGA scores. An absolute PASI ≤ 2 was concordant with PASI 90 and an absolute PASI ≤ 4 was concordant with PASI 75 in 90% and 88% of cases, respectively. These findings were robust to subgroups of timing of assessment, baseline disease severity and treatment modality. PASI and PGA were strongly correlated (Spearman's rank correlation coefficient 0·92). The median PASI increased from 0 (interquartile range 0–0, range 0–23) to 19 (interquartile range 15–25, range 0–64) for PGA clear to severe, respectively. PGA clear/almost clear was concordant with PASI ≤ 2 in 90% of cases, and PGA moderate–severe severe was concordant with the National Institute for Health and Care Excellence PASI eligibility criteria for biologics in 81% of cases.
Conclusions
An absolute PASI ≤ 2 and PGA clear/almost clear represent relevant disease end points to inform treat‐to‐target management strategies in psoriasis.
What's already known about this topic?
The most commonly used relative disease activity measure in psoriasis is ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90); however, it has several limitations including dependency on a baseline severity assessment.
Defining an absolute target disease activity end point in psoriasis has the potential to improve patient outcomes and reduce costs, as demonstrated by treat‐to‐target approaches in other chronic diseases such as hypertension and diabetes.
The Physician's Global Assessment (PGA) is a popular alternative measure of psoriasis severity in daily practice; however, its utility has not been formally assessed with respect to PASI.
What does this study add?
An absolute PASI ≤ 2 corresponds with PASI 90 response and is a relevant disease end point for treat‐to‐target approaches in psoriasis.
There is a strong correlation between PASI and PGA.
PGA moderate–severe/severe may serve as an alternative eligibility criterion for biologics to PASI‐based definitions, and PGA clear/almost clear is an appropriate alternative absolute treatment end point.
What are the clinical implications of this work?
Absolute PASI ≤ 2 and PGA clear/almost clear represent relevant disease end points to inform treat‐to‐target management strategies in psoriasis.
Linked Editorial: Takeshita. Br J Dermatol 2020; 182:1075–1076.
Cholinergic interneurons have emerged as one of the key players controlling network functions in the striatum. Extracellularly recorded cholinergic interneurons acquire characteristic responses to ...sensory stimuli during reward-related learning, including a pause and subsequent rebound in spiking. However, the precise underlying cellular mechanisms have remained elusive. Here, we review recent advances in our understanding of the regulation of cholinergic interneuron activity. We discuss evidence of mechanisms that have been proposed to underlie sensory responses, including antagonistic actions by dopamine, recurrent inhibition via local interneurons, and an intrinsically generated membrane hyperpolarization in response to excitatory inputs. The review highlights outstanding questions and concludes with a model of the sensory responses and their downstream effects through dynamic acetylcholine receptor activation.
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