Liquid-biopsy proteomics combined with AI identifies cellular drivers of eye aging and disease in vivo.

Single-cell analysis in living humans is essential for understanding disease mechanisms, but it is impractical in non-regenerative organs, such as the eye and brain, because tissue biopsies would cause serious damage. We resolve this problem by integrating proteomics of liquid biopsies with single-cell transcriptomics from all known ocular cell types to trace the cellular origin of 5,953 proteins detected in the aqueous humor. We identified hundreds of cell-specific protein markers, including for individual retinal cell types. Surprisingly, our results reveal that retinal degeneration occurs in Parkinson's disease, and the cells driving diabetic retinopathy switch with disease stage. Finally, we developed artificial intelligence (AI) models to assess individual cellular aging and found that many eye diseases not associated with chronological age undergo accelerated molecular aging of disease-specific cell types. Our approach, which can be applied to other organ systems, has the potential to transform molecular diagnostics and prognostics while uncovering new cellular disease and aging mechanisms.

STAT3 signaling induced by the IL-6 family of cytokines modulates angiogenesis.

Aberrant angiogenesis is a hallmark of cardiovascular and retinal neovascular disease. The STAT3 signaling pathway represents a potential pharmacological target for these diseases due to its impact on angiogenesis. Surprisingly, some STAT3 activators, such as the IL-6 cytokine family member oncostatin M (OSM), enhance angiogenesis, whereas others, such as ciliary neurotropic factor (CNTF), reduce it. This study aimed to clarify these conflicting effects. In contrast to the anti-angiogenic cytokine CNTF, the pro-angiogenic cytokine OSM was able to activate intracellular signaling pathways beyond the STAT3 pathway, including the ERK and AKT pathways. These differences translated into transcriptomic and metabolic shifts. siRNA-mediated STAT3 knockdown experiments showed a decrease in VEGF-induced endothelial migration and sprouting, enhancing the pro-angiogenic drive of OSM and switching the CNTF response from anti-angiogenic to pro-angiogenic. These effects correlated with a transcriptomic shift representing enhanced STAT1 and ERK activity following STAT3 knockdown, including a compensatory prolonged phosphorylated STAT1 activity. In conclusion, the angiogenic effect of STAT3 appears to be determined by cytokine-induced STAT3 specificity and simultaneous activity of other intracellular signaling pathways, whereas the STAT3 pathway, predominantly recognized for its pro-angiogenic phenotypes, reveals novel anti-angiogenic potential.

Recommendations for empowering early career researchers to improve research culture and practice.

Early career researchers (ECRs) are important stakeholders leading efforts to catalyze systemic change in research culture and practice. Here, we summarize the outputs from a virtual unconventional conference (unconference), which brought together 54 invited experts from 20 countries with extensive experience in ECR initiatives designed to improve the culture and practice of science. Together, we drafted 2 sets of recommendations for (1) ECRs directly involved in initiatives or activities to change research culture and practice; and (2) stakeholders who wish to support ECRs in these efforts. Importantly, these points apply to ECRs working to promote change on a systemic level, not only those improving aspects of their own work. In both sets of recommendations, we underline the importance of incentivizing and providing time and resources for systems-level science improvement activities, including ECRs in organizational decision-making processes, and working to dismantle structural barriers to participation for marginalized groups. We further highlight obstacles that ECRs face when working to promote reform, as well as proposed solutions and examples of current best practices. The abstract and recommendations for stakeholders are available in Dutch, German, Greek (abstract only), Italian, Japanese, Polish, Portuguese, Spanish, and Serbian.

Motor network gamma oscillations in chronic home recordings predict dyskinesia in Parkinson's disease.

In Parkinson's disease, imbalances between 'antikinetic' and 'prokinetic' patterns of neuronal oscillatory activity are related to motor dysfunction. Invasive brain recordings from the motor network have suggested that medical or surgical therapy can promote a prokinetic state by inducing narrowband gamma rhythms (65-90 Hz). Excessive narrowband gamma in the motor cortex promotes dyskinesia in rodent models, but the relationship between narrowband gamma and dyskinesia in humans has not been well established. To assess this relationship, we used a sensing-enabled deep brain stimulator system, attached to both motor cortex and basal ganglia (subthalamic or pallidal) leads, paired with wearable devices that continuously tracked motor signs in the contralateral upper limbs. We recorded 984 h of multisite field potentials in 30 hemispheres of 16 subjects with Parkinson's disease (2/16 female, mean age 57 ± 12 years) while at home on usual antiparkinsonian medications. Recordings were done 2-4 weeks after implantation, prior to starting therapeutic stimulation. Narrowband gamma was detected in the precentral gyrus, subthalamic nucleus or both structures on at least one side of 92% of subjects with a clinical history of dyskinesia. Narrowband gamma was not detected in the globus pallidus. Narrowband gamma spectral power in both structures co-fluctuated similarly with contralateral wearable dyskinesia scores (mean correlation coefficient of ρ = 0.48 with a range of 0.12-0.82 for cortex, ρ = 0.53 with a range of 0.5-0.77 for subthalamic nucleus). Stratification analysis showed the correlations were not driven by outlier values, and narrowband gamma could distinguish 'on' periods with dyskinesia from 'on' periods without dyskinesia. Time lag comparisons confirmed that gamma oscillations herald dyskinesia onset without a time lag in either structure when using 2-min epochs. A linear model incorporating the three oscillatory bands (beta, theta/alpha and narrowband gamma) increased the predictive power of dyskinesia for several subject hemispheres. We further identified spectrally distinct oscillations in the low gamma range (40-60 Hz) in three subjects, but the relationship of low gamma oscillations to dyskinesia was variable. Our findings support the hypothesis that excessive oscillatory activity at 65-90 Hz in the motor network tracks with dyskinesia similarly across both structures, without a detectable time lag. This rhythm may serve as a promising control signal for closed-loop deep brain stimulation using either cortical or subthalamic detection.

Dopamine and deep brain stimulation accelerate the neural dynamics of volitional action in Parkinson's disease.

The ability to initiate volitional action is fundamental to human behaviour. Loss of dopaminergic neurons in Parkinson's disease is associated with impaired action initiation, also termed akinesia. Both dopamine and subthalamic deep brain stimulation (DBS) can alleviate akinesia, but the underlying mechanisms are unknown. An important question is whether dopamine and DBS facilitate de novo build-up of neural dynamics for motor execution or accelerate existing cortical movement initiation signals through shared modulatory circuit effects. Answering these questions can provide the foundation for new closed-loop neurotherapies with adaptive DBS, but the objectification of neural processing delays prior to performance of volitional action remains a significant challenge. To overcome this challenge, we studied readiness potentials and trained brain signal decoders on invasive neurophysiology signals in 25 DBS patients (12 female) with Parkinson's disease during performance of self-initiated movements. Combined sensorimotor cortex electrocorticography (ECoG) and subthalamic local field potential (LFP) recordings were performed OFF therapy (N = 22), ON dopaminergic medication (N = 18) and ON subthalamic deep brain stimulation (N = 8). This allowed us to compare their therapeutic effects on neural latencies between the earliest cortical representation of movement intention as decoded by linear discriminant analysis classifiers and onset of muscle activation recorded with electromyography (EMG). In the hypodopaminergic OFF state, we observed long latencies between motor intention and motor execution for readiness potentials and machine learning classifications. Both, dopamine and DBS significantly shortened these latencies, hinting towards a shared therapeutic mechanism for alleviation of akinesia. To investigate this further, we analysed directional cortico-subthalamic oscillatory communication with multivariate granger causality. Strikingly, we found that both therapies independently shifted cortico-subthalamic oscillatory information flow from antikinetic beta (13-35 Hz) to prokinetic theta (4-10 Hz) rhythms, which was correlated with latencies in motor execution. Our study reveals a shared brain network modulation pattern of dopamine and DBS that may underlie the acceleration of neural dynamics for augmentation of movement initiation in Parkinson's disease. Instead of producing or increasing preparatory brain signals, both therapies modulate oscillatory communication. These insights provide a link between the pathophysiology of akinesia and its' therapeutic alleviation with oscillatory network changes in other non-motor and motor domains, e.g. related to hyperkinesia or effort and reward perception. In the future, our study may inspire the development of clinical brain computer interfaces based on brain signal decoders to provide temporally precise support for action initiation in patients with brain disorders.

Liquid Biopsy Proteomics in Ophthalmology.

Minimally invasive liquid biopsies from the eye capture locally enriched fluids that contain thousands of proteins from highly specialized ocular cell types, presenting a promising alternative to solid tissue biopsies. The advantages of liquid biopsies include sampling the eye without causing irreversible functional damage, potentially better reflecting tissue heterogeneity, collecting samples in an outpatient setting, monitoring therapeutic response with sequential sampling, and even allowing examination of disease mechanisms at the cell level in living humans, an approach that we refer to as TEMPO (Tracing Expression of Multiple Protein Origins). Liquid biopsy proteomics has the potential to transform molecular diagnostics and prognostics and to assess disease mechanisms and personalized therapeutic strategies in individual patients. This review addresses opportunities, challenges, and future directions of high-resolution liquid biopsy proteomics in ophthalmology, with particular emphasis on the large-scale collection of high-quality samples, cutting edge proteomics technology, and artificial intelligence-supported data analysis.

Dopaminergic reinforcement in the motor system: Implications for Parkinson's disease and deep brain stimulation.

Millions of people suffer from dopamine-related disorders spanning disturbances in movement, cognition and emotion. These changes are often attributed to changes in striatal dopamine function. Thus, understanding how dopamine signalling in the striatum and basal ganglia shapes human behaviour is fundamental to advancing the treatment of affected patients. Dopaminergic neurons innervate large-scale brain networks, and accordingly, many different roles for dopamine signals have been proposed, such as invigoration of movement and tracking of reward contingencies. The canonical circuit architecture of cortico-striatal loops sparks the question, of whether dopamine signals in the basal ganglia serve an overarching computational principle. Such a holistic understanding of dopamine functioning could provide new insights into symptom generation in psychiatry to neurology. Here, we review the perspective that dopamine could bidirectionally control neural population dynamics, increasing or decreasing their strength and likelihood to reoccur in the future, a process previously termed neural reinforcement. We outline how the basal ganglia pathways could drive strengthening and weakening of circuit dynamics and discuss the implication of this hypothesis on the understanding of motor signs of Parkinson's disease (PD), the most frequent dopaminergic disorder. We propose that loss of dopamine in PD may lead to a pathological brain state where repetition of neural activity leads to weakening and instability, possibly explanatory for the fact that movement in PD deteriorates with repetition. Finally, we speculate on how therapeutic interventions such as deep brain stimulation may be able to reinstate reinforcement signals and thereby improve treatment strategies for PD in the future.

Redefining the ontogeny of hyalocytes as yolk sac-derived tissue-resident macrophages of the vitreous body.

BACKGROUND: The eye is a highly specialized sensory organ which encompasses the retina as a part of the central nervous system, but also non-neural compartments such as the transparent vitreous body ensuring stability of the eye globe and a clear optical axis. Hyalocytes are the tissue-resident macrophages of the vitreous body and are considered to play pivotal roles in health and diseases of the vitreoretinal interface, such as proliferative vitreoretinopathy or diabetic retinopathy. However, in contrast to other ocular macrophages, their embryonic origin as well as the extent to which these myeloid cells might be replenished by circulating monocytes remains elusive. RESULTS: In this study, we combine transgenic reporter mice, embryonic and adult fate mapping approaches as well as parabiosis experiments with multicolor immunofluorescence labeling and confocal laser-scanning microscopy to comprehensively characterize the murine hyalocyte population throughout development and in adulthood. We found that murine hyalocytes express numerous well-known myeloid cell markers, but concomitantly display a distinct immunophenotype that sets them apart from retinal microglia. Embryonic pulse labeling revealed a yolk sac-derived origin of murine hyalocytes, whose precursors seed the developing eye prenatally. Finally, postnatal labeling and parabiosis established the longevity of hyalocytes which rely on Colony Stimulating Factor 1 Receptor (CSF1R) signaling for their maintenance, independent of blood-derived monocytes. CONCLUSION: Our study identifies hyalocytes as long-living progeny of the yolk sac hematopoiesis and highlights their role as integral members of the innate immune system of the eye. As a consequence of their longevity, immunosenescence processes may culminate in hyalocyte dysfunction, thereby contributing to the development of vitreoretinal diseases. Therefore, myeloid cell-targeted therapies that convey their effects through the modification of hyalocyte properties may represent an interesting approach to alleviate the burden imposed by diseases of the vitreoretinal interface.

Contribution of basal ganglia activity to REM sleep disorder in Parkinson's disease.

BACKGROUND: Rapid eye movement (REM) sleep behaviour disorder (RBD) is one of the most common sleep problems and represents a key prodromal marker in Parkinson's disease (PD). It remains unclear whether and how basal ganglia nuclei, structures that are directly involved in the pathology of PD, are implicated in the occurrence of RBD. METHOD: Here, in parallel with whole-night video polysomnography, we recorded local field potentials from two major basal ganglia structures, the globus pallidus internus and subthalamic nucleus, in two cohorts of patients with PD who had varied severity of RBD. Basal ganglia oscillatory patterns during RBD and REM sleep without atonia were analysed and compared with another age-matched cohort of patients with dystonia that served as controls. RESULTS: We found that beta power in both basal ganglia nuclei was specifically elevated during REM sleep without atonia in patients with PD, but not in dystonia. Basal ganglia beta power during REM sleep positively correlated with the extent of atonia loss, with beta elevation preceding the activation of chin electromyogram activities by ~200 ms. The connectivity between basal ganglia beta power and chin muscular activities during REM sleep was significantly correlated with the clinical severity of RBD in PD. CONCLUSIONS: These findings support that basal ganglia activities are associated with if not directly contribute to the occurrence of RBD in PD. Our study expands the understanding of the role basal ganglia played in RBD and may foster improved therapies for RBD by interrupting the basal ganglia-muscular communication during REM sleep in PD.

Rapid Compensation for Noisy Voluntary Movements in Adults with Primary Tic Disorders.

BACKGROUND: It has been proposed that tics and premonitory urges in primary tic disorders (PTD), like Tourette syndrome, are a manifestation of sensorimotor noise. However, patients with tics show no obvious movement imprecision in everyday life. One reason could be that patients have strategies to compensate for noise that disrupts performance (ie, noise that is task-relevant). OBJECTIVES: Our goal was to unmask effects of elevated sensorimotor noise on the variability of voluntary movements in patients with PTD. METHODS: We tested 30 adult patients with PTD (23 male) and 30 matched controls in a reaching task designed to unmask latent noise. Subjects reached to targets whose shape allowed for variability either in movement direction or extent. This enabled us to decompose variability into task-relevant versus less task-relevant components, where the latter should be less affected by compensatory strategies than the former. In alternating blocks, the task-relevant target dimension switched, allowing us to explore the temporal dynamics with which participants adjusted movement variability to changes in task demands. RESULTS: Both groups accurately reached to targets, and adjusted movement precision based on target shape. However, when task-relevant dimensions of the target changed, patients initially produced movements that were more variable than controls, before regaining precision after several reaches. This effect persisted across repeated changes in the task-relevant dimension across the experiment, and therefore did not reflect an effect of novelty, or differences in learning. CONCLUSIONS: Our results suggest that patients with PTD generate noisier voluntary movements compared with controls, but rapidly compensate according to current task demands. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neurophysiological mechanisms of deep brain stimulation across spatiotemporal resolutions.

Deep brain stimulation is a neuromodulatory treatment for managing the symptoms of Parkinson's disease and other neurological and psychiatric disorders. Electrodes are chronically implanted in disease-relevant brain regions and pulsatile electrical stimulation delivery is intended to restore neurocircuit function. However, the widespread interest in the application and expansion of this clinical therapy has preceded an overarching understanding of the neurocircuit alterations invoked by deep brain stimulation. Over the years, various forms of neurophysiological evidence have emerged which demonstrate changes to brain activity across spatiotemporal resolutions; from single neuron, to local field potential, to brain-wide cortical network effects. Though fruitful, such studies have often led to debate about a singular putative mechanism. In this Update we aim to produce an integrative account of complementary instead of mutually exclusive neurophysiological effects to derive a generalizable concept of the mechanisms of deep brain stimulation. In particular, we offer a critical review of the most common historical competing theories, an updated discussion on recent literature from animal and human neurophysiological studies, and a synthesis of synaptic and network effects of deep brain stimulation across scales of observation, including micro-, meso- and macroscale circuit alterations.

Pallidal activities during sleep and sleep decoding in dystonia, Huntington's, and Parkinson's disease.

BACKGROUND: Sleep disturbances are highly prevalent in movement disorders, potentially due to the malfunctioning of basal ganglia structures. Pallidal deep brain stimulation (DBS) has been widely used for multiple movement disorders and been reported to improve sleep. We aimed to investigate the oscillatory pattern of pallidum during sleep and explore whether pallidal activities can be utilized to differentiate sleep stages, which could pave the way for sleep-aware adaptive DBS. METHODS: We directly recorded over 500 h of pallidal local field potentials during sleep from 39 subjects with movement disorders (20 dystonia, 8 Huntington's disease, and 11 Parkinson's disease). Pallidal spectrum and cortical-pallidal coherence were computed and compared across sleep stages. Machine learning approaches were utilized to build sleep decoders for different diseases to classify sleep stages through pallidal oscillatory features. Decoding accuracy was further associated with the spatial localization of the pallidum. RESULTS: Pallidal power spectra and cortical-pallidal coherence were significantly modulated by sleep-stage transitions in three movement disorders. Differences in sleep-related activities between diseases were identified in non-rapid eye movement (NREM) and REM sleep. Machine learning models using pallidal oscillatory features can decode sleep-wake states with over 90% accuracy. Decoding accuracies were higher in recording sites within the internus-pallidum than the external-pallidum, and can be precited using structural (P < 0.0001) and functional (P < 0.0001) whole-brain neuroimaging connectomics. CONCLUSION: Our findings revealed strong sleep-stage dependent distinctions in pallidal oscillations in multiple movement disorders. Pallidal oscillatory features were sufficient for sleep stage decoding. These data may facilitate the development of adaptive DBS systems targeting sleep problems that have broad translational prospects.

Adaptive Deep Brain Stimulation: From Experimental Evidence Toward Practical Implementation.

Closed-loop adaptive deep brain stimulation (aDBS) can deliver individualized therapy at an unprecedented temporal precision for neurological disorders. This has the potential to lead to a breakthrough in neurotechnology, but the translation to clinical practice remains a significant challenge. Via bidirectional implantable brain-computer-interfaces that have become commercially available, aDBS can now sense and selectively modulate pathophysiological brain circuit activity. Pilot studies investigating different aDBS control strategies showed promising results, but the short experimental study designs have not yet supported individualized analyses of patient-specific factors in biomarker and therapeutic response dynamics. Notwithstanding the clear theoretical advantages of a patient-tailored approach, these new stimulation possibilities open a vast and mostly unexplored parameter space, leading to practical hurdles in the implementation and development of clinical trials. Therefore, a thorough understanding of the neurophysiological and neurotechnological aspects related to aDBS is crucial to develop evidence-based treatment regimens for clinical practice. Therapeutic success of aDBS will depend on the integrated development of strategies for feedback signal identification, artifact mitigation, signal processing, and control policy adjustment, for precise stimulation delivery tailored to individual patients. The present review introduces the reader to the neurophysiological foundation of aDBS for Parkinson's disease (PD) and other network disorders, explains currently available aDBS control policies, and highlights practical pitfalls and difficulties to be addressed in the upcoming years. Finally, it highlights the importance of interdisciplinary clinical neurotechnological research within and across DBS centers, toward an individualized patient-centered approach to invasive brain stimulation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Christmas-Related Reduction in Beta Activity in Parkinson's Disease.

BACKGROUND: Subthalamic nucleus (STN) beta (13 - 35 Hz) activity is a biomarker reflecting motor state in Parkinson's disease (PD). Adaptive deep brain stimulation (DBS) aims to use beta activity for therapeutic adjustments, but many aspects of beta activity in real-life situations are unknown. OBJECTIVE: The aim was to investigate Christmas-related influences on beta activity in PD. METHODS: Differences in Christmas Day to nonfestive daily averages in chronic biomarker recordings in 4 PD patients with a sensing-enabled STN DBS implant were retrospectively analyzed. Sweet-spot and whole-brain network connectomic analyses were performed. RESULTS: Beta activity was significantly reduced on Christmas Eve in all patients (4.00-9.00 p.m.: -12.30 ± 10.78%, P = 0.015). A sweet spot in the dorsolateral STN connected recording sites to motor, premotor, and supplementary motor cortices. CONCLUSIONS: We demonstrate that festive events can reduce beta biomarker activity. We conclude that circadian and holiday-related changes should be considered when tailoring adaptive DBS algorithms to patient demands. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cortical phase-amplitude coupling is key to the occurrence and treatment of freezing of gait.

Freezing of gait is a debilitating symptom in advanced Parkinson's disease and responds heterogeneously to treatments such as deep brain stimulation. Recent studies indicated that cortical dysfunction is involved in the development of freezing, while evidence depicting the specific role of the primary motor cortex in the multi-circuit pathology of freezing is lacking. Since abnormal beta-gamma phase-amplitude coupling recorded from the primary motor cortex in patients with Parkinson's disease indicates parkinsonian state and responses to therapeutic deep brain stimulation, we hypothesized this metric might reveal unique information on understanding and improving therapy for freezing of gait. Here, we directly recorded potentials in the primary motor cortex using subdural electrocorticography and synchronously captured gait freezing using optoelectronic motion-tracking systems in 16 freely-walking patients with Parkinson's disease who received subthalamic nucleus deep brain stimulation surgery. Overall, we recorded 451 timed up-and-go walking trials and quantified 7073 s of stable walking and 3384 s of gait freezing in conditions of on/off-stimulation and with/without dual-tasking. We found that (i) high beta-gamma phase-amplitude coupling in the primary motor cortex was detected in freezing trials (i.e. walking trials that contained freezing), but not non-freezing trials, and the high coupling in freezing trials was not caused by dual-tasking or the lack of movement; (ii) non-freezing episodes within freezing trials also demonstrated abnormally high couplings, which predicted freezing severity; (iii) deep brain stimulation of subthalamic nucleus reduced these abnormal couplings and simultaneously improved freezing; and (iv) in trials that were at similar coupling levels, stimulation trials still demonstrated lower freezing severity than no-stimulation trials. These findings suggest that elevated phase-amplitude coupling in the primary motor cortex indicates higher probabilities of freezing. Therapeutic deep brain stimulation alleviates freezing by both decoupling cortical oscillations and enhancing cortical resistance to abnormal coupling. We formalized these findings to a novel 'bandwidth model,' which specifies the role of cortical dysfunction, cognitive burden and therapeutic stimulation on the emergence of freezing. By targeting key elements in the model, we may develop next-generation deep brain stimulation approaches for freezing of gait.

The Human Eye Transcriptome Atlas: A searchable comparative transcriptome database for healthy and diseased human eye tissue.

The applications of deep sequencing technologies in life science research and clinical diagnostics have increased rapidly over the last decade. Although fast algorithms for data processing exist, intuitive, portable solutions for data analysis are still rare. For this purpose, we developed a web-based transcriptome database, which provides a platform-independent, intuitive solution to easily explore and compare ocular gene expression of 100 diseased and healthy human tissue samples from 15 different tissue types collected at the Eye Center of the University of Freiburg. To ensure comparability of expression between different tissues, reads were normalized across all 100 samples. Differentially expressed genes were calculated between each tissue type to determine tissue-specific genes. Unsupervised analysis of all 100 samples revealed an accurate clustering according to different tissue types and a high tissue specificity by analyzing known tissue-specific marker genes. Bioinformatic cell type deconvolution using xCell provided detailed insights into the cellular profiles of each tissue type. Several new tissue-specific marker genes were identified. These genes were involved in tissue- or disease-specific processes, such as myelination for the optic nerve, visual perception for retina, keratinocyte differentiation for conjunctival carcinoma, as well as endothelial cell migration for choroidal neovascularization membranes. The results are accessible at the Human Eye Transcriptome Atlas website at https://www.eye-transcriptome.com. In summary, this searchable transcriptome database enables easy exploration of ocular gene expression in healthy and diseased human ocular tissues without bioinformatics expertise. Thus, it provides rapid access to detailed insights into the molecular mechanisms of various ocular tissues and diseases, as well as the rapid retrieval of potential new diagnostic and therapeutic targets.

Functional connectivity maps of theta/alpha and beta coherence within the subthalamic nucleus region.

The subthalamic nucleus (STN) is a primary target for deep brain stimulation in Parkinson's disease (PD). Although small in size, the STN is commonly partitioned into sensorimotor, cognitive/associative, and limbic subregions based on its structural connectivity profile to cortical areas. We investigated whether such a regional specialization is also supported by functional connectivity between local field potential recordings and simultaneous magnetoencephalography. Using a novel data set of 21 PD patients, we replicated previously reported cortico-STN coherence networks in the theta/alpha and beta frequency ranges, and looked for the spatial distribution of these networks within the STN region. Although theta/alpha and beta coherence peaks were both observed in on-medication recordings from electrode contacts at several locations within and around the STN, sites with theta/alpha coherence peaks were situated at significantly more inferior MNI coordinates than beta coherence peaks. Sites with only theta/alpha coherence peaks, i.e. without distinct beta coherence, were mostly located near the border of sensorimotor and cognitive/associative subregions as defined by a tractography-based atlas of the STN. Peak coherence values were largely unaltered by the medication state of the subject, however, theta/alpha peaks were more often identified in recordings obtained after administration of dopaminergic medication. Our findings suggest the existence of a frequency-specific topography of cortico-STN coherence within the STN, albeit with considerable spatial overlap between functional networks. Consequently, optimization of deep brain stimulation targeting might remain a trade-off between alleviating motor symptoms and avoiding adverse neuropsychiatric side effects.

Low-frequency oscillations link frontal and parietal cortex with subthalamic nucleus in conflicts.

Low-frequency oscillations (LFOs, 28 Hz) in the subthalamic nucleus(STN) are known to reflect cognitive conflict. However, it is unclear if LFOs mediate communication and functional interactions among regions implicated in conflict processing, such as the motor cortex (M1), premotor cortex (PMC), and superior parietal lobule (SPL). To investigate the potential contribution of LFOs to cognitive conflict mediation, we recorded M1, PMC, and SPL activities by right subdural electrocorticography (ECoG) simultaneously with bilateral STN local field potentials (LFPs) by deep brain stimulation electrodes in 13 patients with Parkinson's disease who performed the arrow version of the Eriksen flanker task. Elevated cue-related LFO activity was observed across patients during task trials, with the earliest onset in PMC and SPL. At cue onset, LFO power exhibited a significantly greater increase or a trend of a greater increase in the PMC, M1, and STN, and less increase in the SPL during high-conflict (incongruent) trials than in low-conflict (congruent) trials. The local LFO power increases in PMC, SPL, and right STN were correlated with response time, supporting the notion that these structures are critical hubs for cognitive conflict processing. This power increase was accompanied by increased functional connectivity between the PMC and right STN, which was correlated with response time across subjects. Finally, ipsilateral PMC-STN Granger causality was enhanced during high-conflict trials, with direction from STN to PMC. Our study indicates that LFOs link the frontal and parietal cortex with STN during conflicts, and the ipsilateral PMC-STN connection is specifically involved in this cognitive conflict processing.

Subretinal fibrosis in neovascular age-related macular degeneration: current concepts, therapeutic avenues, and future perspectives.

Age-related macular degeneration (AMD) is a progressive, degenerative disease of the human retina which in its most aggressive form is associated with the formation of macular neovascularization (MNV) and subretinal fibrosis leading to irreversible blindness. MNVs contain blood vessels as well as infiltrating immune cells, myofibroblasts, and excessive amounts of extracellular matrix proteins such as collagens, fibronectin, and laminin which disrupts retinal function and triggers neurodegeneration. In the mammalian retina, damaged neurons cannot be replaced by tissue regeneration, and subretinal MNV and fibrosis persist and thus fuel degeneration and visual loss. This review provides an overview of subretinal fibrosis in neovascular AMD, by summarizing its clinical manifestations, exploring the current understanding of the underlying cellular and molecular mechanisms and discussing potential therapeutic approaches to inhibit subretinal fibrosis in the future.

Subthalamic stimulation impairs stopping of ongoing movements.

The subthalamic nucleus is part of a global stopping network that also includes the presupplementary motor area and inferior frontal gyrus of the right hemisphere. In Parkinson's disease, subthalamic deep brain stimulation improves movement initiation and velocity, but its effect on stopping of ongoing movement is unknown. Here, we examine the relation between movement stopping and connectivity of stimulation volumes to the stopping network. Stop and go times were collected in 17 patients with Parkinson's disease on and off subthalamic stimulation during visually cued initiation and termination of continuous, rotational movements. Deep brain stimulation contacts were localized; the stimulation volume computed and connectivity profiles estimated using an openly available, normative structural connectome. Subthalamic stimulation significantly increased stop times, which correlated with the connectivity of the stimulation volume to presupplementary motor area and inferior frontal gyrus of the right hemisphere. The robustness of this finding was validated using three separate analysis streams: voxel-wise whole-brain connectivity, region of interest connectivity and a tract-centred method. Our study sheds light on the role of the fronto-subthalamic inhibitory triangle in stopping of ongoing movements and may inspire circuit based adaptive stimulation strategies for control of stopping impairment, possibly reflected in stimulation-induced dyskinesia.