9,888 research outputs found
A review of combined neuromodulation and physical therapy interventions for enhanced neurorehabilitation
Rehabilitation approaches for individuals with neurologic conditions have increasingly shifted toward promoting neuroplasticity for enhanced recovery and restoration of function. This review focuses on exercise strategies and non-invasive neuromodulation techniques that target neuroplasticity, including transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), and peripheral nerve stimulation (PNS). We have chosen to focus on non-invasive neuromodulation techniques due to their greater potential for integration into routine clinical practice. We explore and discuss the application of these interventional strategies in four neurological conditions that are frequently encountered in rehabilitation settings: Parkinsonās Disease (PD), Traumatic Brain Injury (TBI), stroke, and Spinal Cord Injury (SCI). Additionally, we discuss the potential benefits of combining non-invasive neuromodulation with rehabilitation, which has shown promise in accelerating recovery. Our review identifies studies that demonstrate enhanced recovery through combined exercise and non-invasive neuromodulation in the selected patient populations. We primarily focus on the motor aspects of rehabilitation, but also briefly address non-motor impacts of these conditions. Additionally, we identify the gaps in current literature and barriers to implementation of combined approaches into clinical practice. We highlight areas needing further research and suggest avenues for future investigation, aiming to enhance the personalization of the unique neuroplastic responses associated with each condition. This review serves as a resource for rehabilitation professionals and researchers seeking a comprehensive understanding of neuroplastic exercise interventions and non-invasive neuromodulation techniques tailored for specific diseases and diagnoses
Studying the interplay between ageing and Parkinson's disease using the zebrafish model
Parkinsonās disease (PD) is a neurodegenerative disorder characterised by the loss of dopaminergic neurons in the substantia nigra. Ageing is the major risk factor for developing PD but the interplay between ageing and PD remains elusive.
To investigate the effect of ageing on PD-relevant pathological mechanisms, zebrafish mutant lines harbouring mutations in ageing-associated genes (klotho-/-, sirt1-/-, satb1a-/-, satb1b-/- and satb1a-/-;satb1b-/-) were generated, using CRISPR/Cas9 gene editing. Likewise, a chemical model for SIRT1 deficiency was utilised.
klotho-/- zebrafish displayed an accelerated ageing phenotype at 3mpf and reduced survival to 6mpf. Dopaminergic neuron number, MPP+ susceptibility and microglial number were unaffected in klotho-/- larvae. NAD+ levels were decreased in 6mpf klotho-/- brains. However, ATP levels and DNA damage were unaffected. sirt1-/- zebrafish did not display a phenotype through adulthood. il-1Ī² and il-6 were not upregulated in sirt1-/- larvae, and chemical inhibition of sirt1 did not increase microglial number. cdkn1a, il-1Ī² and il-6 were not upregulated in satb1a-/- and satb1b-/- larvae. Dopaminergic neuron number and MPP+ susceptibility were unaffected in satb1a-/- larvae. However, satb1b-/- larvae demonstrated a moderate decrease in dopaminergic neuron number but equal susceptibility to MPP+ as satb1b+/+ larvae. Adult satb1a-/- but not adult satb1b-/- zebrafish were emaciated. satb1a-/-;satb1b-/- zebrafish did not display a phenotype through adulthood.
Transgenic zebrafish expressing human wildtype Ī±-Synuclein (Tg(eno2:hsa.SNCA-ires-EGFP)) were crossed with klotho-/- and sirt1-/- zebrafish, and treated with a sirt1-specific inhibitor. Neither genetic cross affected survival. The klotho mutation did not increase microglial number in Tg(eno2:hsa.SNCA-ires-EGFP) larvae. Likewise, sirt1 inhibition did not induce motor impairment or cell death in Tg(eno2:hsa.SNCA-ires-EGFP) larvae.
In conclusion, the suitability of zebrafish for studying ageing remains elusive, as only 1 ageing-associated mutant line displayed accelerated ageing. However, zebrafish remain an effective model for studying PD-relevant pathological mechanisms due to the availability of CRISPR/Cas9 gene editing, neuropathological and neurobehavioral tools
Overcoming drug resistance: targeting the BCL-2 family and the long non-coding RNA HCP5 in medulloblastoma and colorectal cancer
Colorectal cancer (CRC) is one of the most common cancers in the UK and medulloblastoma is a common cancer found in children. While there has been a progressive improvement in treatment outcomes, success has been marred by drug resistance and severe side effects. Therefore, this project focused on two aspects of chemotherapeutic drug resistance, the first using the antimitotic agent vincristine in combination with inhibitors of the anti-apoptotic Bcl-2 family proteins, while the second investigated the role of the long non-coding RNA (lncRNA), HCP5 in the resistance of cells to genotoxic agents. In the first part, three medulloblastoma cell lines (DAOY, MB03, ONS76) were analysed for the expression of Bcl-xL and ONS76 cells found to have the highest level of this anti-apoptotic protein. Subsequent results indicated that Bcl-xL encourages mitotic slippage and stemness and that knockdown of Bcl-xL in the high expressing ONS76 cells, reduces these and sensitizes the cells to the anti-mitotic agent vincristine. Thus, pharmacological inhibition of Bcl-xL should sensitize medulloblastoma cells to low doses of vincristine. Regarding the lncRNA HCP5, results showed that HCP5 was generally more highly expressed in a panel of CRC cell lines than the three medulloblastoma cell lines, corroborating data from an in-silico analysis for the corresponding tumours. One function of HCP5 is to translocate the multifunctional YB-1 protein from the cytoplasm to the nucleus where it carries out many of its functions. Knockdown of HCP5 followed by immunofluorescence indicated a reduction in the amount of YB-1 in the nucleus, confirming this function. Subsequently, HCP5 silencing sensitized all cell lines tested to the DNA damaging agents, cisplatin, oxaliplatin and tert-butyl hydroperoxide and also resulted in an increase in double-strand breaks as determined by H2AX formation. Finally, fluorescence activated cell sorting using Annexin V and propidium iodide confirmed a decrease in cell viability in HCP5 knockdown cells following treatment with genotoxic agents and that this was mirrored by an increased apoptotic fraction. Together, these studies indicate the possibilities of using novel therapeutics to increase the functionality of existing treatments to combat acquired drug resistance in cancer patients
ACOUSTIC SPEECH MARKERS FOR TRACKING CHANGES IN HYPOKINETIC DYSARTHRIA ASSOCIATED WITH PARKINSONāS DISEASE
Previous research has identified certain overarching features of hypokinetic dysarthria
associated with Parkinsonās Disease and found it manifests differently between
individuals. Acoustic analysis has often been used to find correlates of perceptual
features for differential diagnosis. However, acoustic parameters that are robust for
differential diagnosis may not be sensitive to tracking speech changes. Previous
longitudinal studies have had limited sample sizes or variable lengths between data
collection. This study focused on using acoustic correlates of perceptual features to
identify acoustic markers able to track speech changes in people with Parkinsonās
Disease (PwPD) over six months. The thesis presents how this study has addressed
limitations of previous studies to make a novel contribution to current knowledge.
Speech data was collected from 63 PwPD and 47 control speakers using an online
podcast software at two time points, six months apart (T1 and T2). Recordings of a
standard reading passage, minimal pairs, sustained phonation, and spontaneous speech
were collected. Perceptual severity ratings were given by two speech and language
therapists for T1 and T2, and acoustic parameters of voice, articulation and prosody
were investigated. Two analyses were conducted: a) to identify which acoustic
parameters can track perceptual speech changes over time and b) to identify which
acoustic parameters can track changes in speech intelligibility over time. An additional
attempt was made to identify if these parameters showed group differences for
differential diagnosis between PwPD and control speakers at T1 and T2.
Results showed that specific acoustic parameters in voice quality, articulation and
prosody could differentiate between PwPD and controls, or detect speech changes
between T1 and T2, but not both factors. However, specific acoustic parameters within
articulation could detect significant group and speech change differences across T1 and
T2. The thesis discusses these results, their implications, and the potential for future
studies
TERT promoter mutation and H3K27me3 trimethylation loss as focal molecular markers in meningioma aggressiveness
Biomarkers to identify high-grade meningiomas have finally been added to the recent 2021 edition of the World Health Organization (WHO) grading scheme. Among them, are the well-known telomerase reverse transcriptase promoter (TERTp) mutation and the recently emerged epigenetic marker, trimethylation of lysine 27 of histone 3 (H3K27me3). Although the presence of TERTp is now associated with WHO grade 3 meningiomas and the loss of trimethylation of H3K27me3 is implicated with potentially worse prognosis, the question remains as to their ability to predict an event rather than an observed association. Furthermore, the standards for H3K27me3 immunohistochemistry (IHC) in meningiomas have not been set and have led to inconsistencies in reporting. To address these critical clinical concerns, I set out to investigate the prevalence of TERTp mutations in a cohort of suspected high-risk meningiomas through Sanger sequencing. I also conducted a meta-analysis of all H3K27me3 publications to qualify the current assessment of H3K27me3 trimethylation loss as a predictor of tumor aggressiveness. Due to complications with the quality of purified DNA from FFPE tissue, I was unable to obtain satisfactory sequencing results to assess the prevalence of TERTp mutation in my cohort. I did, however, develop an optimized DNA purification protocol for FFPE tissues for future research purposes. The pooled data on H3K27me3 did confirm a significant association between the loss of H3K27me3 trimethylation and more aggressive tumors (p5 years old resulted in significantly higher rates of H3K27me3 loss, implying tissue age and quality had a significant effect on the staining for H3K27me3 loss in meningiomas. Although H3K27me3 is associated substantially with meningiomas of more aggressive nature and thus a higher likelihood of recurrence, several criteria must be met first to standardize the process to ensure accuracy in reporting and ease of implementation into standard clinical workups
Cerebellum and neurodevelopmental disorders: RORĪ± is a unifying force
Errors of cerebellar development are increasingly acknowledged as risk factors for neuro-developmental disorders (NDDs), such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and schizophrenia. Evidence has been assembled from cerebellar abnormalities in autistic patients, as well as a range of genetic mutations identified in human patients that affect the cerebellar circuit, particularly Purkinje cells, and are associated with deficits of motor function, learning and social behavior; traits that are commonly associated with autism and schizophrenia. However, NDDs, such as ASD and schizophrenia, also include systemic abnormalities, e.g., chronic inflammation, abnormal circadian rhythms etc., which cannot be explained by lesions that only affect the cerebellum. Here we bring together phenotypic, circuit and structural evidence supporting the contribution of cerebellar dysfunction in NDDs and propose that the transcription factor Retinoid-related Orphan Receptor alpha (RORĪ±) provides the missing link underlying both cerebellar and systemic abnormalities observed in NDDs. We present the role of RORĪ± in cerebellar development and how the abnormalities that occur due to RORĪ± deficiency could explain NDD symptoms. We then focus on how RORĪ± is linked to NDDs, particularly ASD and schizophrenia, and how its diverse extra-cerebral actions can explain the systemic components of these diseases. Finally, we discuss how RORĪ±-deficiency is likely a driving force for NDDs through its induction of cerebellar developmental defects, which in turn affect downstream targets, and its regulation of extracerebral systems, such as inflammation, circadian rhythms, and sexual dimorphism
Vascular contributions to the neurobiological effects of prenatal alcohol exposure
Background: Fetal alcohol spectrum disorders (FASD) are often characterized as a cluster of brain-based disabilities. Though cardiovascular effects of prenatal alcohol exposure (PAE) have been documented, the vascular deficits due to PAE are less understood, but may contribute substantially to the severity of neurobehavioral presentation and health outcomes in persons with FASD.Methods: We conducted a systematic review of research articles curated in PubMed to assess the strength of the research on vascular effects of PAE. 40 pertinent papers were selected, covering studies in both human populations and animal models.Results: Studies in human populations identified cardiac defects, and defects in vasculature, including increased tortuosity, defects in basement membranes, capillary basal hyperplasia, endarteritis, and disorganized and diminished cerebral vasculature due to PAE. Preclinical studies showed that PAE rapidly and persistently results in vasodilation of large afferent cerebral arteries, but to vasoconstriction of smaller cerebral arteries and microvasculature. Moreover, PAE continues to affect cerebral blood flow into middle-age. Human and animal studies also indicate that ocular vascular parameters may have diagnostic and predictive value. A number of intervening mechanisms were identified, including increased autophagy, inflammation and deficits in mitochondria. Studies in animals identified persistent changes in blood flow and vascular density associated with endocannabinoid, prostacyclin and nitric oxide signaling, as well as calcium mobilization.Conclusion: Although the brain has been a particular focus of studies on PAE, the cardiovascular system is equally affected. Studies in human populations, though constrained by small sample sizes, did link pathology in major blood vessels and tissue vasculature, including brain vasculature, to PAE. Animal studies highlighted molecular mechanisms that may be useful therapeutic targets. Collectively, these studies suggest that vascular pathology is a possible contributing factor to neurobehavioral and health problems across a lifespan in persons with a diagnosis of FASD. Furthermore, ocular vasculature may serve as a biomarker for neurovascular health in FASD
Tau positron emission tomography in tauopathies: A narrative review
Aggregation of misfolded tau in the brain is a major pathological feature common in various neurodegenerative disorders known as tauopathies, including Alzheimerās disease, progressive supranuclear palsy, corticobasal syndrome, and dementia with Lewy bodies. Tauopathies are collection of diseases with varied overlapping symptoms and complicated manifestations. Consequently, it is crucial to be able to assess tau deposits in vivo. Over the past decade, tau-specific radioligands for positron emission tomography (PET) have been developed and tested, including first-generation compounds (e.g., 18F-THK5317, 18F-THK5351, 18F-AV1451, and 11C-PBB3) and second-generation compounds (18F-MK-6240, 18F-RO-948, and 18F-PI-2620). With the recent advances of tau PET tracers, assessing the pattern of tau deposition in vivo is possible. These methods will allow accurate diagnosis of tauopathies and monitoring of disease progression. In this mini review, we summarize current findings from studies using tau PET tracers regarding neuropathological characteristics, clinical implications, and potential applications of tau PET. We also discuss methodological considerations for appropriate use of these technologies and discuss what has been learned from these findings
- ā¦