Behavior Change Approaches in Digital Technology-Based Physical Rehabilitation Interventions Following Stroke: Scoping Review.

BACKGROUND: Digital health technologies (DHTs) are increasingly used in physical stroke rehabilitation to support individuals in successfully engaging with the frequent, intensive, and lengthy activities required to optimize recovery. Despite this, little is known about behavior change within these interventions. OBJECTIVE: This scoping review aimed to identify if and how behavior change approaches (ie, theories, models, frameworks, and techniques to influence behavior) are incorporated within physical stroke rehabilitation interventions that include a DHT. METHODS: Databases (Embase, MEDLINE, PsycINFO, CINAHL, Cochrane Library, and AMED) were searched using keywords relating to behavior change, DHT, physical rehabilitation, and stroke. The results were independently screened by 2 reviewers. Sources were included if they reported a completed primary research study in which a behavior change approach could be identified within a physical stroke rehabilitation intervention that included a DHT. Data, including the study design, DHT used, and behavior change approaches, were charted. Specific behavior change techniques were coded to the behavior change technique taxonomy version 1 (BCTTv1). RESULTS: From a total of 1973 identified sources, 103 (5%) studies were included for data charting. The most common reason for exclusion at full-text screening was the absence of an explicit approach to behavior change (165/245, 67%). Almost half (45/103, 44%) of the included studies were described as pilot or feasibility studies. Virtual reality was the most frequently identified DHT type (58/103, 56%), and almost two-thirds (65/103, 63%) of studies focused on upper limb rehabilitation. Only a limited number of studies (18/103, 17%) included a theory, model, or framework for behavior change. The most frequently used BCTTv1 clusters were feedback and monitoring (88/103, 85%), reward and threat (56/103, 54%), goals and planning (33/103, 32%), and shaping knowledge (33/103, 32%). Relationships between feedback and monitoring and reward and threat were identified using a relationship map, with prominent use of both of these clusters in interventions that included virtual reality. CONCLUSIONS: Despite an assumption that DHTs can promote engagement in rehabilitation, this scoping review demonstrates that very few studies of physical stroke rehabilitation that include a DHT overtly used any form of behavior change approach. From those studies that did consider behavior change, most did not report a robust underpinning theory. Future development and research need to explicitly articulate how including DHTs within an intervention may support the behavior change required for optimal engagement in physical rehabilitation following stroke, as well as establish their effectiveness. This understanding is likely to support the realization of the transformative potential of DHTs in stroke rehabilitation.

Functional and molecular changes in the nucleus accumbens of MK-801-sensitized rats.

Behavioural sensitization is a putative mechanism in the pathophysiology of drug addiction and neuropsychiatric disorders such as schizophrenia. In rodents, drug-induced behavioural sensitization has been described for several different drug classes. The N-methyl-D-aspartate receptor antagonist MK-801 can inhibit sensitization to other drugs of abuse. However, MK-801 also produces behavioural sensitization to its own hyperlocomotor inducing effects, suggesting that MK-801 sensitization has a distinctive mechanism of action. The aim of this study was to carry out a functional and molecular analysis of the nucleus accumbens (NAc) of adult male Sprague-Dawley rats sensitized to MK-801 (seven daily injections of 0.25 mg/kg, 5 days of withdrawal and subsequent 0.25 mg/kg challenge), or following acute MK-801 (0.25 mg/kg), or naive rats as controls. Locomotor activity was the primary measure of sensitization. Ex-vivo slice electrophysiology showed a decrease in the excitatory synaptic strength in the NAc of rats sensitized to MK-801 compared with acute MK-801 treatment or naive controls. An LC-MS/MS SWATH proteomics approach showed that proteins altered by MK-801 sensitization were predominantly related to functions including calcium and glutamate signalling, and mitochondrial dysfunction. These results shed some light on neural changes in the NAc after sensitization to MK-801. This model could prove useful for studying the role of N-methyl-D-aspartate receptors in the pathophysiology of drug addiction and schizophrenia.

High-fidelity dendritic sodium spike generation in human layer 2/3 neocortical pyramidal neurons.

Dendritic spikes function as cardinal components of rodent neocortical circuit computations. Recently, the biophysical properties of human pyramidal neurons (PNs) have been reported to be divergent, raising the question of whether dendritic spikes have homologous roles in the human neocortex. To directly address this, we made electrical recordings from the soma and apical dendrites of human and rat layer 2/3 PNs of the temporal cortex. In both species, dendritic excitatory input led to the initiation of sodium-channel-mediated dendritic spikes. Dendritic sodium spikes could be generated across a wide input range, exhibited a similar frequency range of activation, and forward-propagated with high-fidelity to implement stereotyped computations in human and rat PNs. However, the physical expansion and complexification of the apical dendritic trees of human PNs allowed the enriched expression of dendritic spike generation. The computational capacity of human PNs is therefore enhanced by the widespread implementation of a conserved dendritic integration mechanism.

Strength training for people with multiple sclerosis and the current recommendations.

Recent guidelines recommend strength and conditioning training for patients with multiple sclerosis (MS). This article evaluates and summarises four systematic reviews examining strength training for people with MS and examines if these reviews substantiate these current guidelines.

Home-based exercise for people living with frailty and chronic kidney disease: A mixed-methods pilot randomised controlled trial.

BACKGROUND: Frailty is associated with adverse health outcomes in people with chronic kidney disease (CKD). Evidence supporting targeted interventions is needed. This pilot randomised controlled trial (RCT) aimed to inform the design of a definitive RCT evaluating the effectiveness of a home-based exercise intervention for pre-frail and frail older adults with CKD. METHODS: Participants were recruited from nephrology outpatient clinics to this two-arm parallel group mixed-methods pilot RCT. Inclusion criteria were: ≥65 years old; CKD G3b-5; and Clinical Frailty Scale score ≥4. Participants categorised as pre-frail or frail using the Frailty Phenotype were randomised to a 12-week progressive multi-component home-based exercise programme or usual care. Primary outcome measures included eligibility, recruitment, adherence, outcome measure completion and participant attrition rate. Semi-structured interviews were conducted with participants to explore trial and intervention acceptability. RESULTS: Six hundred and sixty-five patients had an eligibility assessment with 217 (33%; 95% CI 29, 36) eligible. Thirty-five (16%; 95% CI 12, 22) participants were recruited. Six were categorised as robust and withdrawn prior to randomisation. Fifteen participants were randomised to exercise and 14 to usual care. Eleven (73%; 95% CI 45, 91) participants completed ≥2 exercise sessions/week. Retained participants completed all outcome measures (n = 21; 100%; 95% CI 81, 100). Eight (28%; 95% CI 13, 47) participants were withdrawn. Fifteen participated in interviews. Decision to participate/withdraw was influenced by perceived risk of exercise worsening symptoms. Participant perceived benefits included improved fitness, balance, strength, well-being, energy levels and confidence. CONCLUSIONS: This pilot RCT demonstrates that progression to definitive RCT is possible provided recruitment and retention challenges are addressed. It has also provided preliminary evidence that home-based exercise may be beneficial for people living with frailty and CKD. TRIAL REGISTRATION: ISRCTN87708989; https://clinicaltrials.gov/.

Diversity of interneurons in the lateral and basal amygdala.

The basolateral amygdala (BLA) is a temporal lobe structure that contributes to a host of behaviors. In particular, it is a central player in learning about aversive events and thus assigning emotional valence to sensory events. It is a cortical-like structure and contains glutamatergic pyramidal neurons and GABAergic interneurons. It is divided into the lateral (LA) and basal (BA) nuclei that have distinct cell types and connections. Interneurons in the BLA are a heterogenous population, some of which have been implicated in specific functional roles. Here we use optogenetics and slice electrophysiology to investigate the innervation, postsynaptic receptor stoichiometry, and plasticity of excitatory inputs onto interneurons within the BLA. Interneurons were divided into six groups based on their discharge properties, each of which received input from the auditory thalamus (AT) and auditory cortex (AC). Auditory innervation was concentrated in the LA, and optogenetic stimulation evoked robust synaptic responses in nearly all interneurons, drove many cells to threshold, and evoked disynaptic inhibition in most interneurons. Auditory input to the BA was sparse, innervated fewer interneurons, and evoked smaller synaptic responses. Biophysically, the subunit composition and distribution of AMPAR and NMDAR also differed between the two nuclei, with fewer BA IN expressing calcium permeable AMPAR, and a higher proportion expressing GluN2B-containing NMDAR. Finally, unlike LA interneurons, LTP could not be induced in the BA. These findings show that interneurons in the LA and BA are physiologically distinct populations and suggest they may have differing roles during associative learning.

Fear conditioning and the basolateral amygdala.

Fear is a response to impending threat that prepares a subject to make appropriate defensive responses, whether to freeze, fight, or flee to safety. The neural circuits that underpin how subjects learn about cues that signal threat, and make defensive responses, have been studied using Pavlovian fear conditioning in laboratory rodents as well as humans. These studies have established the amygdala as a key player in the circuits that process fear and led to a model where fear learning results from long-term potentiation of inputs that convey information about the conditioned stimulus to the amygdala. In this review, we describe the circuits in the basolateral amygdala that mediate fear learning and its expression as the conditioned response. We argue that while the evidence linking synaptic plasticity in the basolateral amygdala to fear learning is strong, there is still no mechanism that fully explains the changes that underpin fear conditioning.

The EX-FRAIL CKD trial: a study protocol for a pilot randomised controlled trial of a home-based EXercise programme for pre-frail and FRAIL, older adults with Chronic Kidney Disease.

INTRODUCTION: Frailty is highly prevalent in adults with chronic kidney disease (CKD) and is associated with adverse health outcomes including falls, poorer health-related quality of life (HRQOL), hospitalisation and mortality. Low physical activity and muscle wasting are important contributors to physical frailty in adults with CKD. Exercise training may improve physical function and frailty status leading to associated improvements in health outcomes, including HRQOL. The EX-FRAIL CKD trial aims to inform the design of a definitive randomised controlled trial (RCT) that investigates the effectiveness of a progressive, multicomponent home-based exercise programme in prefrail and frail older adults with CKD. METHODS AND ANALYSIS: The EX-FRAIL CKD trial is a two-arm parallel group pilot RCT. Participants categorised as prefrail or frail, following Frailty Phenotype (FP) assessment, will be randomised to receive exercise or usual care. Participants randomised to the intervention arm will receive a tailored 12-week exercise programme, which includes weekly telephone calls to advise on exercise progression. Primary feasibility outcome measures include rate of recruitment, intervention adherence, outcome measure completion and participant attrition. Semistructured interviews with a purposively selected group of participants will inform the feasibility of the randomisation procedures, outcome measures and intervention. Secondary outcome measures include physical function (walking speed and Short Physical Performance Battery), frailty status (FP), fall concern (Falls Efficacy Scale-International tool), activities of daily living (Barthel Index), symptom burden (Palliative care Outcome Scale-Symptoms RENAL) and HRQOL (Short Form-12v2). ETHICS AND DISSEMINATION: Ethical approval was granted by a National Health Service (NHS) Regional Ethics Committee and the NHS Health Research Authority. The study team aims to publish findings in a peer-reviewed journal and presents the results at relevant national and international conferences. A summary of findings will be provided to participants, a local kidney patient charity and the funding body. TRIAL REGISTRATION NUMBER: ISRCTN87708989.

1,25-Dihydroxyvitamin D modulates L-type voltage-gated calcium channels in a subset of neurons in the developing mouse prefrontal cortex.

Schizophrenia has been associated with a range of genetic and environmental risk factors. Here we explored a link between two risk factors that converge on a shared neurobiological pathway. Recent genome-wide association studies (GWAS) have identified risk variants in genes that code for L-type voltage-gated calcium channels (L-VGCCs), while epidemiological studies have found an increased risk of schizophrenia in those with neonatal vitamin D deficiency. The active form of vitamin D (1,25(OH)2D) is a secosteroid that rapidly modulates L-VGCCs via non-genomic mechanisms in a range of peripheral tissues, though its non-genomic effects within the brain remain largely unexplored. Here we used calcium imaging, electrophysiology and molecular biology to determine whether 1,25(OH)2D non-genomically modulated L-VGCCs in the developing prefrontal cortex, a region widely implicated in schizophrenia pathophysiology. Wide-field Ca2+ imaging revealed that physiological concentrations of 1,25(OH)2D rapidly enhanced activity-dependent somatic Ca2+ levels in a small subset of neurons in the developing PFC, termed vitamin D-responsive neurons (VDRNs). Somatic nucleated patch recordings revealed a rapid, 1,25(OH)2D-evoked increase in high-voltage-activated (HVA) Ca2+ currents. Enhanced activity-dependent Ca2+ levels were mediated by L-VGCC but not associated with any changes to Cacna1c (L-VGCC pore-forming subunit) mRNA expression. Since L-VGCC activity is critical to healthy neurodevelopment, these data suggest that suboptimal concentrations of 1,25(OH)2D could alter brain maturation through modulation of L-VGCC signalling and as such may provide a parsimonious link between epidemiologic and genetic risk factors for schizophrenia.

The association between neonatal vitamin D status and risk of schizophrenia.

Clues from the epidemiology of schizophrenia, such as the increased risk in those born in winter/spring, have led to the hypothesis that prenatal vitamin D deficiency may increase the risk of later schizophrenia. We wish to explore this hypothesis in a large Danish case-control study (n = 2602). The concentration of 25 hydroxyvitamin D (25OHD) was assessed from neonatal dried blood samples. Incidence rate ratios (IRR) were calculated when examined for quintiles of 25OHD concentration. In addition, we examined statistical models that combined 25OHD concentration and the schizophrenia polygenic risk score (PRS) in a sample that combined the new sample with a previous study (total n = 3464; samples assayed and genotyped between 2008-2013). Compared to the reference (fourth) quintile, those in the lowest quintile (<20.4 nmol/L) had a significantly increased risk of schizophrenia (IRR = 1.44, 95%CI: 1.12-1.85). None of the other quintile comparisons were significantly different. There was no significant interaction between 25OHD and the PRS. Neonatal vitamin D deficiency was associated with an increased risk for schizophrenia in later life. These findings could have important public health implications related to the primary prevention of schizophrenia.

Vitamin D and the brain: Genomic and non-genomic actions.

1,25(OH)2D3 (vitamin D) is well-recognized as a neurosteroid that modulates multiple brain functions. A growing body of evidence indicates that vitamin D plays a pivotal role in brain development, neurotransmission, neuroprotection and immunomodulation. However, the precise molecular mechanisms by which vitamin D exerts these functions in the brain are still unclear. Vitamin D signalling occurs via the vitamin D receptor (VDR), a zinc-finger protein in the nuclear receptor superfamily. Like other nuclear steroids, vitamin D has both genomic and non-genomic actions. The transcriptional activity of vitamin D occurs via the nuclear VDR. Its faster, non-genomic actions can occur when the VDR is distributed outside the nucleus. The VDR is present in the developing and adult brain where it mediates the effects of vitamin D on brain development and function. The purpose of this review is to summarise the in vitro and in vivo work that has been conducted to characterise the genomic and non-genomic actions of vitamin D in the brain. Additionally we link these processes to functional neurochemical and behavioural outcomes. Elucidation of the precise molecular mechanisms underpinning vitamin D signalling in the brain may prove useful in understanding the role this steroid plays in brain ontogeny and function.

G-Protein-Coupled Inwardly Rectifying Potassium (GIRK) Channel Activation by the p75 Neurotrophin Receptor Is Required for Amyloid ß Toxicity.

Alzheimer's disease is characterized by cognitive decline, neuronal degeneration, and the accumulation of amyloid-beta (Aß). Although, the neurotoxic Aß peptide is widely believed to trigger neuronal dysfunction and degeneration in Alzheimer's disease, the mechanism by which this occurs is poorly defined. Here we describe a novel, Aß-triggered apoptotic pathway in which Aß treatment leads to the upregulation of G-protein activated inwardly rectifying potassium (GIRK/Kir3) channels, causing potassium efflux from neurons and Aß-mediated apoptosis. Although, GIRK channel activity is required for Aß-induced neuronal degeneration, we show that it is not sufficient, with coincident signaling by the p75 neurotrophin receptor (p75NTR) also required for potassium efflux and cell death. Our results identify a novel role for GIRK channels in mediating apoptosis, and provide a previously missing mechanistic link between the excitotoxicity of Aß and its ability to trigger cell death pathways, such as that mediated by p75NTR. We propose that this death-signaling pathway contributes to the dysfunction of neurons in Alzheimer's disease and is responsible for their eventual degeneration.

Prefrontal and Auditory Input to Intercalated Neurons of the Amygdala.

The basolateral amygdala (BLA) and prefrontal cortex (PFC) are partners in fear learning and extinction. Intercalated (ITC) cells are inhibitory neurons that surround the BLA. Lateral ITC (lITC) neurons provide feed-forward inhibition to BLA principal neurons, whereas medial ITC (mITC) neurons form an inhibitory interface between the BLA and central amygdala (CeA). Notably, infralimbic prefrontal (IL) input to mITC neurons is thought to play a key role in fear extinction. Here, using targeted optogenetic stimulation, we show that lITC neurons receive auditory input from cortical and thalamic regions. IL inputs innervate principal neurons in the BLA but not mITC neurons. These results suggest that (1) these neurons may play a more central role in fear learning as both lITCs and mITCs receive auditory input and that (2) mITC neurons cannot be driven directly by the IL, and their role in fear extinction is likely mediated via the BLA.

Vitamin D and the brain: key questions for future research.

Over the last decade a convergent body of evidence has emerged from epidemiology, animal experiments and clinical trials which links low vitamin D status with a range of adverse neuropsychiatric outcomes. This research demonstrates that the timing of exposure to low vitamin D influences the nature of brain phenotypes, as exposures during gestation versus adulthood result in different phenotypes. With respect to early life exposures, there is robust evidence from rodent experiments indicating that transient developmental vitamin D (DVD) deficiency is associated with changes in brain structure, neurochemistry, gene and protein expression and behavior. In particular, DVD deficiency is associated with alterations in the dopaminergic neurotransmitter systems. In contrast, recently published animal experiments indicate that adult vitamin D (AVD) deficiency is associated with more subtle neurochemical and behavioral phenotypes. This paper explores key issues that need to be addressed in future research. There is a need to define the timing and duration of the 'critical window' during which low vitamin D status is associated with differential and adverse brain outcomes. We discuss the role for 'two-hit hypotheses', which propose that adult vitamin D deficiency leaves the brain more vulnerable to secondary adverse exposures, and thus may exacerbate disease progression. Finally, we explore the evidence implicating a role for vitamin D in rapid, non-genomic mechanisms that may involve L-type calcium channels and brain function. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.