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β-band peak in local field potentials as a marker of clinical improvement in Parkinson's Disease after Deep Brain Stimulation
Although locating the stimulation contact in Deep Brain Stimulation (DBS) requires a sub-mm-precision, it remains a trial-and-error, patient-specific procedure that is usually the main cause of post-operational side-effects. In this work, we used microelectrode recordings from Parkinson's disease (PD) patients, acquired at the Neurosurgery Clinic, Evangelismos Hospital, Athens, Greece, to relate the β-band peak, a known neurophysiological signature of the sensorimotor pathways with the clinical outcome of DBS, as assessed by an expert neurologist after a follow-up of at least 1 year. By combining recordings from 5 microelectrodes, we estimated a summed β-band amplitude peak, per recording depth. We suggest that the maximum aggregate β-band peak is related to the stimulation target. We verified our method in 6 patients that responded well in a bilateral DBS treatment (average increase of Unified Parkinson's Disease Rating scale by 32.6 ± 5.4). In 7 out of 12 hemispheres, the distance between the stimulation depth and that of the maximum β-band peak was 0 and for the rest cases that distance was smaller than 2 mm which is a typical effective radius of a stimulation point. Our method needs to be further supported by data acquired from patients with good and poor clinical responses after DBS. © Springer International Publishing Switzerland 2014.
Brain stimulation boosts perceptual learning by altering sensory GABAergic plasticity and functional connectivity
AbstractInterpreting cluttered scenes —a key skill for successfully interacting with our environment— relies on our ability to select relevant sensory signals while filtering out noise. Training is known to improve our ability to make these perceptual judgements by altering local processing in sensory brain areas. Yet, the brain-wide network mechanisms that mediate our ability for perceptual learning remain largely unknown. Here, we combine transcranial direct current stimulation (tDCS) with multi-modal brain measures to modulate cortical excitability during training on a signal-in-noise task (i.e. detection of visual patterns in noise) and test directly the link between processing in visual cortex and its interactions with decision-related areas (i.e. posterior parietal cortex). We test whether brain stimulation alters inhibitory processing in visual cortex, as measured by magnetic resonance spectroscopy (MRS) of GABA and functional connectivity between visual and posterior parietal cortex, as measured by resting state functional magnetic resonance imaging (rs-fMRI). We show that anodal tDCS during training results in faster learning and decreased GABA+ during training, before these changes occur for training without stimulation (i.e. sham). Further, anodal tDCS decreases occipito-parietal interactions and time-varying connectivity across the visual cortex. Our findings demonstrate that tDCS boosts learning by accelerating visual GABAergic plasticity and altering interactions between visual and decision-related areas, suggesting that training optimises gain control mechanisms (i.e. GABAergic inhibition) and functional inter-areal interactions to support perceptual learning.
Learning to optimize perceptual decisions through suppressive interactions in the human brain
AbstractTranslating noisy sensory signals to perceptual decisions is critical for successful interactions in complex environments. Learning is known to improve perceptual judgments by filtering external noise and task-irrelevant information. Yet, little is known about the brain mechanisms that mediate learning-dependent suppression. Here, we employ ultra-high field magnetic resonance spectroscopy of GABA to test whether suppressive processing in decision-related and visual areas facilitates perceptual judgments during training. We demonstrate that parietal GABA relates to suppression of task-irrelevant information, while learning-dependent changes in visual GABA relate to enhanced performance in target detection and feature discrimination tasks. Combining GABA measurements with functional brain connectivity demonstrates that training on a target detection task involves local connectivity and disinhibition of visual cortex, while training on a feature discrimination task involves inter-cortical interactions that relate to suppressive visual processing. Our findings provide evidence that learning optimizes perceptual decisions through suppressive interactions in decision-related networks.
Where functional MRI stops, metabolism starts.
Combining techniques that track blood oxygenation and biochemicals during neuronal activity reveals how the brain computes perceived and unperceived stimuli.
Peripheral blood DNA methylation and neuroanatomical responses to HDACi treatment that rescues neurological deficits in a Kabuki syndrome mouse model.
BACKGROUND: Recent findings from studies of mouse models of Mendelian disorders of epigenetic machinery strongly support the potential for postnatal therapies to improve neurobehavioral and cognitive deficits. As several of these therapies move into human clinical trials, the search for biomarkers of treatment efficacy is a priority. A potential postnatal treatment of Kabuki syndrome type 1 (KS1), caused by pathogenic variants in KMT2D encoding a histone-lysine methyltransferase, has emerged using a mouse model of KS1 (Kmt2d+/βGeo). In this mouse model, hippocampal memory deficits are ameliorated following treatment with the histone deacetylase inhibitor (HDACi), AR-42. Here, we investigate the effect of both Kmt2d+/βGeo genotype and AR-42 treatment on neuroanatomy and on DNA methylation (DNAm) in peripheral blood. While peripheral blood may not be considered a "primary tissue" with respect to understanding the pathophysiology of neurodevelopmental disorders, it has the potential to serve as an accessible biomarker of disease- and treatment-related changes in the brain. METHODS: Half of the KS1 and wildtype mice were treated with 14 days of AR-42. Following treatment, fixed brain samples were imaged using MRI to calculate regional volumes. Blood was assayed for genome-wide DNAm at over 285,000 CpG sites using the Illumina Infinium Mouse Methylation array. DNAm patterns and brain volumes were analyzed in the four groups of animals: wildtype untreated, wildtype AR-42 treated, KS1 untreated and KS1 AR-42 treated. RESULTS: We defined a DNAm signature in the blood of KS1 mice, that overlapped with the human KS1 DNAm signature. We also found a striking 10% decrease in total brain volume in untreated KS1 mice compared to untreated wildtype, which correlated with DNAm levels in a subset KS1 signature sites, suggesting that disease severity may be reflected in blood DNAm. Treatment with AR-42 ameliorated DNAm aberrations in KS1 mice at a small number of signature sites. CONCLUSIONS: As this treatment impacts both neurological deficits and blood DNAm in mice, future KS clinical trials in humans could be used to assess blood DNAm as an early biomarker of therapeutic efficacy.
Reliability of the global cortical atrophy visual rating scale applied to computed tomography versus magnetic resonance imaging scans in acute stroke.
IntroductionResearch using magnetic resonance imaging (MRI) suggests regional cerebral atrophy measures (e.g., frontal lobe, temporal lobe) may predict post-stroke outcomes. Clinical CT scans have excellent potential for use in research but it is unclear whether regional atrophy measures from CT are reliable compared to MRI reference standards.MethodsWe used the Global Cortical Atrophy (GCA) scale to investigate reliability of atrophy measures on CT versus MRI scans from stroke patients originally recruited to the Oxford Cognitive Screening programme. Two raters provided standardised visual ratings at two timepoints. Weighted Kappa statistics assessed the reliability of regional atrophy scores. Spearman's correlation and a two-way repeated measures ANOVA assessed the reliability of the total score.ResultsOn clinically acquired neuroimaging from 98 stroke patients (mean/SD age = 70.97/11.99, 42 female, 84 ischaemic stroke), regional GCA scores on CT versus MRI showed fair to almost perfect intra-rater agreement (κ = .50-.87), substantial to almost perfect intra-rater agreement on CT (κ = .67-.88), and moderate to almost perfect intra-rater reliability on MRI (κ = .50-.89). Regional GCA scores showed mostly moderate to substantial inter-rater reliability on both CT and MRI (κ = .43-.69), except the temporal horns and parieto-occipital region. There was a strong correlation between total GCA scores on CT and MRI (r (96) = .87-.88, p ConclusionsThese results support the use of cerebral atrophy measures from CT in clinical research, as visual ratings showed generally good agreement between CT and MRI, between raters, and between timepoints.
Characterization of neurocognitive deficits in patients with post-COVID-19 syndrome: persistence, patients' complaints, and clinical predictors.
IntroductionCognitive symptoms persisting beyond 3 months following COVID-19 present a considerable disease burden. We aimed to establish a domain-specific cognitive profile of post-COVID-19 syndrome (PCS). We examined the deficits' persistence, relationships with subjective cognitive complaints, and clinical variables, to identify the most relevant cognitive deficits and their predictors.MethodsThis cross-sectional study examined cognitive performance and patient-reported and clinical predictors of cognitive deficits in PCS patients (n = 282) and socio-demographically comparable healthy controls (n = 52).ResultsOn the Oxford Cognitive Screen-Plus, the patient group scored significantly lower in delayed verbal memory, attention, and executive functioning than the healthy group. In each affected domain, 10 to 20% of patients performed more than 1.5 SD below the control mean. Delayed memory was particularly affected, with a small effect of hospitalization and age. Attention scores were predicted by hospitalization and fatigue.DiscussionThus, PCS is associated with long-term cognitive dysfunction, particularly in delayed memory, attention, and executive functioning. Memory deficits seem to be of particular relevance to patients' experience of subjective impairment. Hospitalization, fatigue, and age seem to predict cognitive deficits, while time since infection, depression, and pre-existing conditions do not.
The association of insomnia with long COVID: An international collaborative study (ICOSS-II).
OBJECTIVE: There is evidence of a strong association between insomnia and COVID-19, yet few studies have examined the relationship between insomnia and long COVID. This study aimed to investigate whether COVID-19 patients with pre-pandemic insomnia have a greater risk of developing long COVID and whether long COVID is in turn associated with higher incident rates of insomnia symptoms after infection. METHODS: Data were collected cross-sectionally (May-Dec 2021) as part of an international collaborative study involving participants from 16 countries. A total of 2311 participants (18-99 years old) with COVID-19 provided valid responses to a web-based survey about sleep, insomnia, and health-related variables. Log-binomial regression was used to assess bidirectional associations between insomnia and long COVID. Analyses were adjusted for age, sex, and health conditions, including sleep apnea, attention and memory problems, chronic fatigue, depression, and anxiety. RESULTS: COVID-19 patients with pre-pandemic insomnia showed a higher risk of developing long COVID than those without pre-pandemic insomnia (70.8% vs 51.4%; adjusted relative risk [RR]: 1.33, 95% confidence interval [CI]: 1.07-1.65). Among COVID-19 cases without pre-pandemic insomnia, the rates of incident insomnia symptoms after infection were 24.1% for short COVID cases and 60.6% for long COVID cases (p
Fine Tuning of Phosphorothioate Inclusion in 2'-O-Methyl Oligonucleotides Contributes to Specific Cell Targeting for Splice-Switching Modulation.
Splice-switching antisense oligonucleotide- (SSO-) mediated correction of framedisrupting mutation-containing premessenger RNA (mRNA) transcripts using exon skipping is a highly promising treatment method for muscular diseases such as Duchenne muscular dystrophy (DMD). Phosphorothioate (PS) chemistry, a commonly used oligonucleotide modification, has been shown to increase the stability of and improve the pharmacokinetics of SSOs. However, the effect of PS inclusion in 2'-O-methyl SSOs (2OMe) on cellular uptake and splice switching is less well-understood. At present, we demonstrate that the modification of PS facilitates the uptake of 2OMe in H2k-mdx myoblasts. Furthermore, we found a dependency of SSO nuclear accumulation and high splice-switching activity on PS inclusion in 2OMe (2OMePS), as tested in various reporter cell lines carrying pLuc/705. Increased exon-inclusion activity was observed in muscle, neuronal, liver, and bone cell lineages via both the gymnotic uptake and lipofection of 2OMePS. Using the photoactivatable ribonucleoside-enhanced crosslinking and a subsequent proteomic approach, we identified several 2OMePS-binding proteins, which are likely to play a role in the trafficking of 2OMePS to the nucleus. Ablation of one of them, Ncl by small-interfering RNA (siRNA) enhanced 2OMePS uptake in C2C12 myoblasts and upregulated luciferase RNA splicing in the HeLa Luc/705 reporter cell line. Overall, we demonstrate that PS inclusion increases nuclear delivery and splice switching in muscle, neuronal, liver, and bone cell lineages and that the modulation of 2OMePS-binding partners may improve SSO delivery.
A role for pathogenic autoantibodies in small fiber neuropathy?
The immune system has a role in neuropathic pain which includes autoimmune mechanisms (e.g., autoantibodies). Clinical studies have identified a number of conditions where neuropathic pain is common and that are associated with autoantibodies targeting antigens within the nervous system. Interestingly sensory symptoms can be relieved with immunotherapies or plasma exchange, suggesting that pain in these patients is antibody-mediated. Recent preclinical studies have directly addressed this. For example, passive transfer of CASPR2 autoantibodies from patients cause increased pain sensitivity and enhanced sensory neuron excitability in mice confirming pathogenicity and demonstrating that patient autoantibodies are a mechanism to cause neuropathic pain. Small fiber neuropathy (SFN) exclusively affects small sensory fibers (typically nociceptors) and is characterized by severe neuropathic pain. Known causes include diabetes, B12 deficiency and rare variants in sodium channel genes, although around 50% of cases are idiopathic. SFN is associated with autoimmune conditions such as Sjorgen’s syndrome, Sarcoidosis and Celiac disease and immunotherapy in the form of Intravenous immunoglobulin (IVIG) has proved an effective treatment. Autoantibodies have been identified and, in some cases, passive transfer of SFN patient IgG in mice can recapitulate neuropathic pain-like behavior. Here we will discuss clinical and preclinical data relating to the idea that pathogenic autoantibodies contribute to SNF. We discuss putative pathogenic antibodies, cellular targets and the molecular mechanisms by which they cause sensory neuron damage and the development of neuropathic pain. Finally, we will comment on future directions which may provide further insights into the mechanisms underlying SFN in patients.
Changes in sleep and the prevalence of probable insomnia in undergraduate university students over the course of the COVID-19 pandemic: findings from the U-Flourish cohort study.
BACKGROUND: Sleep problems associated with poor mental health and academic outcomes may have been exacerbated by the COVID-19 pandemic. AIMS: To describe sleep in undergraduate students during the COVID-19 pandemic. METHOD: This longitudinal analysis included data from 9523 students over 4 years (2018-2022), associated with different pandemic phases. Students completed a biannual survey assessing risk factors, mental health symptoms and lifestyle, using validated measures. Sleep was assessed with the Sleep Condition Indicator (SCI-8). Propensity weights and multivariable log-binomial regressions were used to compare sleep in four successive first-year cohorts. Linear mixed-effects models were used to examine changes in sleep over academic semesters and years. RESULTS: There was an overall decrease in average SCI-8 scores, indicating worsening sleep across academic years (average change -0.42 per year; P-trend < 0.001), and an increase in probable insomnia at university entry (range 18.1-29.7%; P-trend < 0.001) before and up to the peak of the pandemic. Sleep improved somewhat in autumn 2021, when restrictions loosened. Students commonly reported daytime sleep problems, including mood, energy, relationships (36-48%) and concentration, productivity, and daytime sleepiness (54-66%). There was a consistent pattern of worsening sleep over the academic year. Probable insomnia was associated with increased cannabis use and passive screen time, and reduced recreation and exercise. CONCLUSIONS: Sleep difficulties are common and persistent in students, were amplified by the pandemic and worsen over the academic year. Given the importance of sleep for well-being and academic success, a preventive focus on sleep hygiene, healthy lifestyle and low-intensity sleep interventions seems justified.
Dynamic modulation of subthalamic nucleus activity facilitates adaptive behavior.
Adapting actions to changing goals and environments is central to intelligent behavior. There is evidence that the basal ganglia play a crucial role in reinforcing or adapting actions depending on their outcome. However, the corresponding electrophysiological correlates in the basal ganglia and the extent to which these causally contribute to action adaptation in humans is unclear. Here, we recorded electrophysiological activity and applied bursts of electrical stimulation to the subthalamic nucleus, a core area of the basal ganglia, in 16 patients with Parkinson's disease (PD) on medication using temporarily externalized deep brain stimulation (DBS) electrodes. Patients as well as 16 age- and gender-matched healthy participants attempted to produce forces as close as possible to a target force to collect a maximum number of points. The target force changed over trials without being explicitly shown on the screen so that participants had to infer target force based on the feedback they received after each movement. Patients and healthy participants were able to adapt their force according to the feedback they received (P < 0.001). At the neural level, decreases in subthalamic beta (13 to 30 Hz) activity reflected poorer outcomes and stronger action adaptation in 2 distinct time windows (Pcluster-corrected < 0.05). Stimulation of the subthalamic nucleus reduced beta activity and led to stronger action adaptation if applied within the time windows when subthalamic activity reflected action outcomes and adaptation (Pcluster-corrected < 0.05). The more the stimulation volume was connected to motor cortex, the stronger was this behavioral effect (Pcorrected = 0.037). These results suggest that dynamic modulation of the subthalamic nucleus and interconnected cortical areas facilitates adaptive behavior.