Search results
Found 21004 matches for
Tim Behrens is among the laureates and finalists of the 2018 Blavatnik Awards for Young Scientists in the United Kingdom, announced today by the Blavatnik Family Foundation and the New York Academy of Sciences.
Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes
Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G>A and CNGB3:c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing—a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.
Comparative neuroimaging of sex differences in human and mouse brain anatomy.
In vivo neuroimaging studies have established several reproducible volumetric sex differences in the human brain, but the causes of such differences are hard to parse. While mouse models are useful for understanding the cellular and mechanistic bases of sex-specific brain development, there have been no attempts to formally compare human and mouse neuroanatomical sex differences to ascertain how well they translate. Addressing this question would shed critical light on the use of the mouse as a translational model for sex differences in the human brain and provide insights into the degree to which sex differences in brain volume are conserved across mammals. Here, we use structural magnetic resonance imaging to conduct the first comparative neuroimaging study of sex-specific neuroanatomy of the human and mouse brain. In line with previous findings, we observe that in humans, males have significantly larger and more variable total brain volume; these sex differences are not mirrored in mice. After controlling for total brain volume, we observe modest cross-species congruence in the volumetric effect size of sex across 60 homologous regions (r=0.30). This cross-species congruence is greater in the cortex (r=0.33) than non-cortex (r=0.16). By incorporating regional measures of gene expression in both species, we reveal that cortical regions with greater cross-species congruence in volumetric sex differences also show greater cross-species congruence in the expression profile of 2835 homologous genes. This phenomenon differentiates primary sensory regions with high congruence of sex effects and gene expression from limbic cortices where congruence in both these features was weaker between species. These findings help identify aspects of sex-biased brain anatomy present in mice that are retained, lost, or inverted in humans. More broadly, our work provides an empirical basis for targeting mechanistic studies of sex-specific brain development in mice to brain regions that best echo sex-specific brain development in humans.
Multi-night cortico-basal recordings reveal mechanisms of NREM slow-wave suppression and spontaneous awakenings in Parkinson’s disease
AbstractSleep disturbance is a prevalent and disabling comorbidity in Parkinson’s disease (PD). We performed multi-night (n = 57) at-home intracranial recordings from electrocorticography and subcortical electrodes using sensing-enabled Deep Brain Stimulation (DBS), paired with portable polysomnography in four PD participants and one with cervical dystonia (clinical trial: NCT03582891). Cortico-basal activity in delta increased and in beta decreased during NREM (N2 + N3) versus wakefulness in PD. DBS caused further elevation in cortical delta and decrease in alpha and low-beta compared to DBS OFF state. Our primary outcome demonstrated an inverse interaction between subcortical beta and cortical slow-wave during NREM. Our secondary outcome revealed subcortical beta increases prior to spontaneous awakenings in PD. We classified NREM vs. wakefulness with high accuracy in both traditional (30 s: 92.6 ± 1.7%) and rapid (5 s: 88.3 ± 2.1%) data epochs of intracranial signals. Our findings elucidate sleep neurophysiology and impacts of DBS on sleep in PD informing adaptive DBS for sleep dysfunction.
Cortical signatures of sleep are altered following effective deep brain stimulation for depression
AbstractDeep brain stimulation (DBS) of the subcallosal cingulate cortex (SCC) is an experimental therapy for treatment-resistant depression (TRD). Chronic SCC DBS leads to long-term changes in the electrophysiological dynamics measured from local field potential (LFP) during wakefulness, but it is unclear how it impacts sleep-related brain activity. This is a crucial gap in knowledge, given the link between depression and sleep disturbances, and an emerging interest in the interaction between DBS, sleep, and circadian rhythms. We therefore sought to characterize changes in electrophysiological markers of sleep associated with DBS treatment for depression. We analyzed key electrophysiological signatures of sleep—slow-wave activity (SWA, 0.5–4.5 Hz) and sleep spindles—in LFPs recorded from the SCC of 9 patients who responded to DBS for TRD. This allowed us to compare the electrophysiological changes before and after 24 weeks of therapeutically effective SCC DBS. SWA power was highly correlated between hemispheres, consistent with a global sleep state. Furthermore, SWA occurred earlier in the night after chronic DBS and had a more prominent peak. While we found no evidence for changes to slow-wave power or stability, we found an increase in the density of sleep spindles. Our results represent a first-of-its-kind report on long-term electrophysiological markers of sleep recorded from the SCC in patients with TRD, and provides evidence of earlier NREM sleep and increased sleep spindle activity following clinically effective DBS treatment. Future work is needed to establish the causal relationship between long-term DBS and the neural mechanisms underlying sleep.
Bioelectronic Zeitgebers: targeted neuromodulation to re-establish circadian rhythms.
Existing neurostimulation systems implanted for the treatment of neurodegenerative disorders generally deliver invariable therapy parameters, regardless of phase of the sleep/wake cycle. However, there is considerable evidence that brain activity in these conditions varies according to this cycle, with discrete patterns of dysfunction linked to loss of circadian rhythmicity, worse clinical outcomes and impaired patient quality of life. We present a targeted concept of circadian neuromodulation using a novel device platform. This system utilises stimulation of circuits important in sleep and wake regulation, delivering bioelectronic cues (Zeitgebers) aimed at entraining rhythms to more physiological patterns in a personalised and fully configurable manner. Preliminary evidence from its first use in a clinical trial setting, with brainstem arousal circuits as a surgical target, further supports its promising impact on sleep/wake pathology. Data included in this paper highlight its versatility and effectiveness on two different patient phenotypes. In addition to exploring acute and long-term electrophysiological and behavioural effects, we also discuss current caveats and future feature improvements of our proposed system, as well as its potential applicability in modifying disease progression in future therapies.
Multimodal neuroimaging correlates of physical-cognitive covariation in Chilean adolescents. The Cogni-Action Project.
Health-related behaviours have been related to brain structural features. In developing settings, such as Latin America, high social inequality has been inversely associated with several health-related behaviours affecting brain development. Understanding the relationship between health behaviours and brain structure in such settings is particularly important during adolescence when critical habits are acquired and ingrained. In this cross-sectional study, we carry out a multimodal analysis identifying a brain region associated with health-related behaviours (i.e., adiposity, fitness, sleep problems and others) and cognitive/academic performance, independent of socioeconomic status in a large sample of Chilean adolescents. Our findings suggest that the relationship between health behaviours and cognitive/academic performance involves a particular brain phenotype that could play a mediator role. These findings fill a significant gap in the literature, which has largely focused on developed countries and raise the possibility of promoting healthy behaviours in adolescence as a means to influence brain structure and thereby cognitive/academic achievement, independently of socioeconomic factors. By highlighting the potential impact on brain structure and cognitive/academic achievement, policymakers could design interventions that are more effective in reducing health disparities in developing countries.
A Prospective, Observational, Noninterventional Clinical Study of Participants With Choroideremia: The NIGHT Study.
PURPOSE: The NIGHT study aimed to assess the natural history of choroideremia (CHM), an X-linked inherited chorioretinal degenerative disease leading to blindness, and determine which outcomes would be the most sensitive for monitoring disease progression. DESIGN: A prospective, observational, multicenter cohort study. METHODS: Males aged ≥18 years with genetically confirmed CHM, visible active disease within the macular region, and best-corrected visual acuity (BCVA) ≥34 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at baseline were assessed for 20 months. The primary outcome was the change in BCVA over time at Months 4, 8, 12, 16, and 20. A range of functional and anatomical secondary outcome measures were assessed up to Month 12, including retinal sensitivity, central ellipsoid zone (EZ) area, and total area of fundus autofluorescence (FAF). Additional ocular assessments for safety were performed. RESULTS: A total of 220 participants completed the study. The mean BCVA was stable over 20 months. Most participants (81.4% in the worse eye and 77.8% in the better eye) had change from baseline > -5 ETDRS letters at Month 20. Interocular symmetry was low overall. Reductions from baseline to Month 12 were observed (worse eye, better eye) for retinal sensitivity (functional outcome; -0.68 dB, -0.48 dB), central EZ area (anatomical outcome; -0.276 mm2, -0.290 mm2), and total area of FAF (anatomical outcome; -0.605 mm2, -0.533 mm2). No assessment-related serious adverse events occurred. CONCLUSIONS: Retinal sensitivity, central EZ area, and total area of FAF are more sensitive than BCVA in measuring the natural progression of CHM.
Optical Coherence Tomography Feature of Retinoschisis in CRB1-Associated Maculopathy
This case report describes 2 individuals with hyperreflective columns in the outer nuclear layer observed on optical coherence tomography and possible implications for CRB1-associated maculopathy.
Reliability of a clinical sensory test battery in patients with spine‐related leg and arm pain
AbstractBackgroundThe current standard to evaluate the presence of somatosensory dysfunctions is quantitative sensory testing, but its clinical utility remains limited. Low‐cost and time‐efficient clinical sensory testing (CST) batteries have thus been developed. Recent studies show moderate to substantial reliability in populations with neuropathic pain. This study evaluates the inter‐ and intra‐tester reliability of people with spine‐related leg and arm pain, representing mixed pain mechanisms.MethodsFifty‐three patients with spine‐related leg (n = 41) and arm pain (n = 12) attended three CST sessions. The CST battery consisted of eleven tests, determining loss and gain of sensory nerve function. CST was performed by the same investigator twice and by an additional investigator to determine inter‐ and intra‐tester reliability. Fleiss' (inter‐tester) and Cohen's (intra‐tester) kappa were calculated for dichotomized and intraclass correlation coefficients (ICC) for continuous outcomes.ResultsFleiss' kappa varied among modalities from fair to substantial (κ = 0.23–0.66). Cold, warm, and vibration detection thresholds and cold and pressure pain thresholds reached kappa >0.4 (moderate to substantial reliability). Cohen's kappa ranged from moderate to substantial (κ = 0.45–0.66). The reliability of the windup ratio was poor (ICC <0.18).ConclusionCST modalities with moderate to substantial inter‐tester reliability could be of benefit as a screening tool. The moderate to substantial intra‐tester reliability for all sensory modalities (except windup ratio) supports their potential use in clinical practice and research to monitor somatosensory changes over time in patients with spine‐related limb pain of mixed pain mechanisms.SignificanceWe already know that most modalities of clinical sensory test (CST) batteries achieve moderate to substantial inter‐ and intra‐tester reliability in populations with neuropathic pain.This study evaluates the reliability of a CST battery in populations with mixed pain mechanisms. We found inter‐tester reliability varied from poor to substantial for sensory modalities, questioning the value of some CST modalities. The CST battery showed moderate to substantial intra‐tester reliability, suggesting its usefulness to monitor sensory changes over time in this cohort.
GABA and Glutamate in hMT+ Link to Individual Differences in Residual Visual Function After Occipital Stroke
BACKGROUND: Damage to the primary visual cortex following an occipital stroke causes loss of conscious vision in the contralateral hemifield. Yet, some patients retain the ability to detect moving visual stimuli within their blind field. The present study asked whether such individual differences in blind field perception following loss of primary visual cortex could be explained by the concentration of neurotransmitters γ-aminobutyric acid (GABA) and glutamate or activity of the visual motion processing, human middle temporal complex (hMT+). METHODS: We used magnetic resonance imaging in 19 patients with chronic occipital stroke to measure the concentration of neurotransmitters GABA and glutamate (proton magnetic resonance spectroscopy) and functional activity in hMT+ (functional magnetic resonance imaging). We also tested each participant on a 2-interval forced choice detection task using high-contrast, moving Gabor patches. We then measured and assessed the strength of relationships between participants’ residual vision in their blind field and in vivo neurotransmitter concentrations, as well as visually evoked functional magnetic resonance imaging activity in their hMT+. Levels of GABA and glutamate were also measured in a sensorimotor region, which served as a control. RESULTS: Magnetic resonance spectroscopy-derived GABA and glutamate concentrations in hMT+ (but not sensorimotor cortex) strongly predicted blind-field visual detection abilities. Performance was inversely related to levels of both inhibitory and excitatory neurotransmitters in hMT+ but, surprisingly, did not correlate with visually evoked blood oxygenation level–dependent signal change in this motion-sensitive region. CONCLUSIONS: Levels of GABA and glutamate in hMT+ appear to provide superior information about motion detection capabilities inside perimetrically defined blind fields compared to blood oxygenation level–dependent signal changes—in essence, serving as biomarkers for the quality of residual visual processing in the blind-field. Whether they also reflect a potential for successful rehabilitation of visual function remains to be determined.
Recommended Changes to Standard of Care for Monitoring of Cortically Blind Fields
Global incidence of stroke has risen 70% in the last 30 years, affecting approximately 25% of adults throughout the course of their lives. Up to 60% of stroke survivors will suffer visual impairments, which significantly reduce quality of life and independence. Despite the high prevalence, patients are hugely underserved by the medical and research communities. Clinical care is variable throughout the United States and United Kingdom, with only 57% of patients receiving visual field assessments and 61% stating their need for support has not been fully met. Additionally, unlike stroke survivors with motor or language deficits, those with vision loss are rarely offered visual rehabilitation. This is despite recent research into the efficacy of visual training and the propensity for the visual deficit to worsen in the absence of an intervention. This article reviews common gaps in patient care and proposes policy changes to increase awareness of the condition, foster clinical and scientific advances in treatment, and enhance patient outcomes.