Ongoing Stimulation Research Articles

Touch Helps Hearing: Evidence From Continuous Audio-Tactile Stimulation.

Identifying target sounds in challenging environments is crucial for daily experiences. It is important to note that it can be enhanced by nonauditory stimuli, for example, through lip-reading in an ongoing conversation. However, how tactile stimuli affect auditory processing is still relatively unclear. Recent studies have shown that brief tactile stimuli can reliably facilitate auditory perception, while studies using longer-lasting audio-tactile stimulation yielded conflicting results. This study aimed to investigate the impact of ongoing pulsating tactile stimulation on basic auditory processing. In experiment 1, the electroencephalogram (EEG) was recorded while 24 participants performed a loudness-discrimination task on a 4-Hz modulated tone-in-noise and received either in-phase, anti-phase, or no 4-Hz electrotactile stimulation above the median nerve. In experiment 2, another 24 participants were presented with the same tactile stimulation as before, but performed a tone-in-noise detection task while their selective auditory attention was manipulated. We found that in-phase tactile stimulation enhanced EEG responses to the tone, whereas anti-phase tactile stimulation suppressed these responses. No corresponding tactile effects on loudness-discrimination performance were observed in experiment 1. Using a yes/no paradigm in experiment 2, we found that in-phase tactile stimulation, but not anti-phase tactile stimulation, improved detection thresholds. Selective attention also improved thresholds but did not modulate the observed benefit from in-phase tactile stimulation. Our study highlights that ongoing in-phase tactile input can enhance basic auditory processing as reflected in scalp EEG and detection thresholds. This might have implications for the development of hearing enhancement technologies and interventions.

Tonic and phasic transcutaneous auricular vagus nerve stimulation (taVNS) both evoke rapid and transient pupil dilation

BackgroundTranscutaneous auricular vagus nerve stimulation (tVNS or taVNS) is a non-invasive method of electrical stimulation of the afferent pathway of the vagus nerve, suggested to drive changes in putative physiological markers of noradrenergic activity, including pupil dilation. ObjectiveHowever, it is unknown whether different taVNS modes can map onto the phasic and tonic modes of noradrenergic activity. The effects of taVNS on pupil dilation in humans are inconsistent, largely due to differences in stimulation protocols. Here, we attempted to address these issues. MethodsWe investigated pupil dilation under phasic (1 s) and tonic (30 s) taVNS, in a pre-registered, single-blind, sham-controlled, within-subject cross-over design, in the absence of a behavioural task. ResultsPhasic taVNS induced a rapid increase in pupil size over baseline, significantly greater than under sham stimulation, which rapidly declined after stimulation offset. Tonic taVNS induced a similarly rapid (and larger than sham) increase in pupil size over baseline, returning to baseline within 5 s, despite the ongoing stimulation. Thus, both active and sham tonic modes closely resembled the phasic effect. There were no differences in tonic baseline pupil size, and no sustained effects of stimulation on tonic baseline pupil size. ConclusionsThese results suggest that both phasic- and tonic-like taVNS under the standard stimulation parameters may modulate primarily the phasic mode of noradrenergic activity, as indexed by evoked pupil dilation, over and above somatosensory effects. This result sheds light on the temporal profile of phasic and tonic stimulation, with implications for their applicability in further research.

Intestinal permeability is associated with aggravated inflammation and myofibroblast accumulation in Graves' orbitopathy: the MicroGO study.

Graves' disease (GD) and Graves' orbitopathy (GO) result from ongoing stimulation of the TSH receptor due to autoantibodies acting as persistent agonists. Orbital pre-adipocytes and fibroblasts also express the TSH receptor, resulting in expanded retro-orbital tissue and causing exophthalmos and limited eye movement. Recent studies have shown that GD/GO patients have a disturbed gut microbiome composition, which has been associated with increased intestinal permeability. This study hypothesizes that enhanced intestinal permeability may aggravate orbital inflammation and, thus, increase myofibroblast differentiation and the degree of fibrosis. Two distinct cohorts of GO patients were studied, one of which was a unique cohort consisting of blood, fecal, and retro-orbital tissue samples. Intestinal permeability was assessed by measuring serum lipopolysaccharide-binding protein (LBP), zonulin, TLR5, and TLR9 ligands. The influx of macrophages and accumulation of T-cells and myofibroblast were quantified in orbital connective tissue. The NanoString immune-oncology RNA targets panel was used to determine the transcriptional profile of active fibrotic areas within orbital sections. GO patients displayed significantly higher LBP serum concentrations than healthy controls. Within the MicroGO cohort, patients with high serum LBP levels also showed higher levels of zonulin and TLR5 and TLR9 ligands in their circulation. The increased intestinal permeability was accompanied by augmented expression of genes marking immune cell infiltration and encoding key proteins for immune cell adhesion, antigen presentation, and cytokine signaling in the orbital tissue. Macrophage influx was positively linked to the extent of T cell influx and fibroblast activation within GO-affected orbital tissues. Moreover, serum LBP levels significantly correlated with the abundance of specific Gram-negative gut bacteria, linking the gut to local orbital inflammation. These results indicate that GO patients have enhanced intestinal permeability. The subsequent translocation of bacterial compounds to the systemic circulation may aggravate inflammatory processes within the orbital tissue and, as a consequence, augment the proportion of activated myofibroblasts, which actively secrete extracellular matrix leading to retro-orbital tissue expansion. These findings warrant further exploration to assess the correlation between specific inflammatory pathways in the orbital tissue and the gut microbiota composition and may pave the way for new microbiota-targeting therapies.

Whole brain network effects of subcallosal cingulate deep brain stimulation for treatment-resistant depression

Ongoing experimental studies of subcallosal cingulate deep brain stimulation (SCC DBS) for treatment-resistant depression (TRD) show a differential timeline of behavioral effects with rapid changes after initial stimulation, and both early and delayed changes over the course of ongoing chronic stimulation. This study examined the longitudinal resting-state regional cerebral blood flow (rCBF) changes in intrinsic connectivity networks (ICNs) with SCC DBS for TRD over 6 months and repeated the same analysis by glucose metabolite changes in a new cohort. A total of twenty-two patients with TRD, 17 [15 O]-water and 5 [18 F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) patients, received SCC DBS and were followed weekly for 7 months. PET scans were collected at 4-time points: baseline, 1-month after surgery, and 1 and 6 months of chronic stimulation. A linear mixed model was conducted to examine the differential trajectory of rCBF changes over time. Post-hoc tests were also examined to assess postoperative, early, and late ICN changes and response-specific effects. SCC DBS had significant time-specific effects in the salience network (SN) and the default mode network (DMN). The rCBF in SN and DMN was decreased after surgery, but responder and non-responders diverged thereafter, with a net increase in DMN activity in responders with chronic stimulation. Additionally, the rCBF in the DMN uniquely correlated with depression severity. The glucose metabolic changes in a second cohort show the same DMN changes. The trajectory of PET changes with SCC DBS is not linear, consistent with the chronology of therapeutic effects. These data provide novel evidence of both an acute reset and ongoing plastic effects in the DMN that may provide future biomarkers to track clinical improvement with ongoing treatment.

Hello from the other side: Robust contralateral interference in tactile detection

Touch is unique among the sensory modalities in that our tactile receptors are spread across the body surface and continuously receive different inputs at the same time. These inputs vary in type, properties, relevance according to current goals, and, of course, location on the body. Sometimes, they must be integrated, and other times set apart and distinguished. Here, we investigate how simultaneous stimulation to different body sites affects tactile cognition. Specifically, we characterized the impact of irrelevant tactile sensations on tactile change detection. To this end, we embedded detection targets amidst ongoing performance, akin to the conditions encountered in everyday life, where we are constantly confronted with new events within ongoing stimuli. In the set of experiments presented here, participants detected a brief intensity change (.04 s) within an ongoing vibrotactile stimulus (1.6 s) that was always presented in a constantly attended location. The intensity change (i.e., the detection target) varied parametrically, from hardly detectable to easily detectable. In half of the trials, irrelevant ongoing stimulation was simultaneously presented to a site across the body midline, but participants were instructed to ignore it. In line with previous bimanual studies employing brief onset targets, we document robust interference on performance due to the irrelevant stimulation at each of the measured body sites (homologous and nonhomologous fingers, and the contralateral ankle). After describing this basic phenomenon, we further examine the conditions under which such interference occurs in three additional tasks. In each task, we honed in on a different aspect of the stimulation protocol (e.g., hand distance, the strength of the irrelevant stimulation, the detection target itself) in order to better understand the principles governing the observed interference effects. Our findings suggest a minimal role for exogenous attentional capture in producing the observed interference effects (Exp. 2), and a principled distribution of attentional resources or sensory integration between body sides (Exps. 3, 4). In our last study (Exp. 4), we presented bilateral tactile targets of varying intensities to both the relevant and irrelevant stimulation sites. We then characterized the degree to which the irrelevant stimulation is also processed. Our results—that participants’ perception of target intensity is always proportional to the combined bilateral signal—suggest that both body sites are equally weighed and processed despite clear instructions to attend only the target site. In light of this observation and participants’ inability to use selection processes to guide their perception, we propose that bilateral tactile inputs are automatically combined, quite possibly early in the hierarchy of somatosensory processing.

The Long-term Outcomes of Sacral Neuromodulation for Fecal Incontinence: A Single Center Experience.

Sacral neuromodulation is an effective treatment for fecal incontinence. This study aimed to assess the long-term outcomes of sacral neuromodulation and establish the outcomes of patients with inactive devices. This is an observational study of patients treated for more than 5 years. A positive outcome was defined as a >50% reduction in fecal incontinence episodes or improvement in a symptom severity score. Data were reviewed from a prospectively managed database. This study was conducted at a single tertiary referral center. Data from 74 patients (72 female) were available at long-term follow up. Bowel diary, St. Mark's incontinence score, and Manchester Health Questionnaire data were prospectively recorded at baseline, after peripheral nerve evaluation, and at last follow-up. Patients were analyzed in cohorts based on time since sacral neuromodulation implantation: Group 1: 5-10 years (n = 20), Group 2: >10 years (n = 35), and Group 3: inactive SNM devices (n = 19). Median St. Mark's incontinence score and Manchester Health Questionnaire improved from baseline to last follow-up in Group 1 (p ≤ 0.05) and Group 2 (p ≤ 0.05), but in Group 3 results returned to baseline levels at last follow-up. Similarly, weekly fecal incontinence episodes improved in both active device groups at last follow-up. However, in Group 3 incontinence episodes were no different from baseline (p = 0.722). Despite active devices, fecal urgency episodes increased at last follow-up after more than 10 years since peripheral nerve evaluation (p ≤ 0.05). Complete continence was reported by 44% of patients, and at least a 50% improvement in 77% with active devices. This study is retrospective with some gaps in the available data at last follow-up. Sacral neuromodulation is an effective treatment for fecal incontinence in the long term, but all outcomes are adversely affected by device inactivity. Therefore, ongoing stimulation is required for continued benefit..

Associations between stimulant use and return to illicit opioid use following initiation onto medication for opioid use disorder.

The aim of this study was to estimate how ongoing stimulant use affects return to illicit opioid use after initiation onto medication for opioid use disorder (MOUD). This was a secondary analysis of pooled data from two clinical trials comparing buprenorphine (BUP-NX) and extended-release naltrexone (XR-NTX). Thirteen opioid treatment programs and HIV clinics across 10 states in the United States from 2014 to 2019 took part in this study. A total of 528 participants who initiated MOUD as part of trial participation were included. Nearly half (49%) were between 30 and 49 years of age, 69% were male and 66% were non-Hispanic White. The primary outcome was first self-reported day of non-prescribed opioid use following MOUD initiation, and the exposure of interest was daily stimulant use (methamphetamine, amphetamines or cocaine). Both were defined using time-line follow-back. Among participants reporting at least 1day of illicit opioid use, we also examined relapse to ongoing use, defined as (1) 7days of continuous opioid use or (2) 4 consecutive weeks with self-reported opioid use, one or more positive urine drug screens (UDS) for opioids or one or more missing UDS. Forty-seven per cent of participants reported stimulant use following MOUD initiation, 58% returned to illicit opioid use and 66% of those relapsed to ongoing use. Stimulant use was strongly associated with increased risk of misusing opioids after MOUD initiation when measured daily [adjusted hazard ratio (aHR) = 9.23, 95% confidence interval (CI) = 6.80-12.50, P < 0.001] and over a 7-day period (aHR = 1.27 for each additional day, CI = 1.18-1.37, P < 0.001). Using stimulants weekly or more often was associated with increased likelihood of relapse to ongoing opioid use compared with less than weekly or no stimulant use (adjusted odds ratio = 2.30, CI = 1.05-5.39, P = 0.044). People initiated on medication for opioid use disorder who subsequently use stimulants appear to be more likely to return to and continue using non-prescribed opioids compared with those without stimulant use. The association appears to be stronger among patients who initiate buprenorphine compared with those who initiate extended-release naltrexone.

Multiple pathways and independent functional pools in insulin granule exocytosis.

In contrast to synaptic vesicle exocytosis, secretory granule exocytosis follows a much longer time course, and thus allows for different prefusion states prior to stimulation. Indeed, total internal reflection fluorescence microscopy in living pancreatic β cells reveals that, prior to stimulation, either visible or invisible granules fuse in parallel during both early (first) and late (second) phases after glucose stimulation. Therefore, fusion occurs not only from granules predocked to the plasma membrane but also from those translocated from the cell interior during ongoing stimulation. Recent findings suggest that such heterogeneous exocytosis is conducted by a specific set of multiple Rab27 effectors that appear to operate on the same granule; namely, exophilin-8, granuphilin, and melanophilin play differential roles in distinct secretory pathways to final fusion. Furthermore, the exocyst, which is known to tether secretory vesicles to the plasma membrane in constitutive exocytosis, cooperatively functions with these Rab27 effectors in regulated exocytosis. In this review, the basic nature of insulin granule exocytosis will be described as a representative example of secretory granule exocytosis, followed by a discussion of the means by which different Rab27 effectors and the exocyst coordinate to regulate the entire exocytic processes in β cells.

TGF-BETA STIMULATES PERIOSTEAL OSTEOGENIC ACTIVITY

Osteoprogenitors on the inner layer of periosteum are the major cellular contributors to appositional bone growth and bone repair by callus formation. Previous work showed that periosteal-derived cells have little or no osteogenic activity under standard in vitro osteogenic culture conditions. This study was conducted to determine what growth factor(s) can activate periosteal osteogenic capacity.This study was conducted with IACUC approval. Periosteum from five equine donors was digested in collagenase for 3-4 hours at 37C. Isolated periosteal cells were maintained in DMEM/10% FBS medium and exposed to PDGF, Prostaglandin E2, BMP-2 and TGF-b3 at a range of concentrations for 72 hours. Changes in osteogenic gene expression (Runx2, OSX and ALP) were measured by qPCR. Periosteal cells were pre-treated with TGF-b3 or maintained in control medium were transferred into basal or osteogenic medium. Osteogenic status was assessed by Alizarin Red staining for mineralized matrix, ALP enzymatic activity and induction of osteogenic genes.PDGF, PgE2 and BMP-2 had little impact on expression of osteogenic markers by periosteal cells. In contrast, TGF-b3 stimulated significant increases in Osterix (over 100-fold) ALP expression (over 70-fold). Pre-treating periosteal cells with TGF-b3 for 72 hours stimulated rapid cell aggregation and aggregate mineralization once cells were transferred to osteogenic medium, while cells not exposed to TGF-b3 exhibited minimal evidence of osteogenic activity.This study indicate that TGF-b signaling is vital for periosteal osteogenic activity. Transient ‘priming’ of periosteal cells through TGF-b exposure was sufficient to activate subsequent osteogenesis without requiring ongoing growth factor stimulation. TGF beta ligands are secreted by many cell types, including periosteal progenitors and osteocytes, providing opportunities for both autocrine and paracrine pathways to regulate periosteal bone formation under homeostatic and reparative conditions.

Continuous theta burst stimulation for drug-resistant epilepsy.

IntroductionRepetitive transcranial magnetic stimulation (rTMS) may have anti-epileptic effects, especially in patients with neocortical lesions. Initial clinical trials demonstrated that the duration of the seizure reducing effect is relatively short-lived. In the context of a chronic condition like epilepsy, theta burst stimulation (TBS) may represent a potential solution in optimizing treatment practicality and durability as it was demonstrated to be associated with longer-lasting after-effects. TBS has been studied extensively in diverse neuropsychiatric conditions, but a therapeutic TBS protocol has not previously been applied in epilepsy patients.Materials and methodsWe performed a prospective open-label pilot study of 4-day accelerated continuous TBS (cTBS) treatment in patients with neocortical drug-resistant epilepsy (DRE). A treatment session consisted of 5 cTBS trains, each comprising 600 pulses presented in 50 Hz triplet bursts every 200 ms, delivered at 10-min intertrain-intervals, targeted over the epileptic focus (EF) using a neuronavigation-guided figure-of-8 coil. Safety and feasibility, and seizure frequency were assessed as primary and secondary endpoints, respectively, over a 4-week baseline period, a 1-week treatment period and a 7-week follow-up period, using adverse event logging, electro-encephalography, cognitive, and psychological questionnaires and a seizure diary kept by the patients and/or caregivers.ResultsSeven subjects (4M:3F; median age 48, interquartile ranges 25) underwent the treatment protocol. Adverse events were reported in all subjects but were mild and transient. No clinical or electrographic seizures were evoked during or immediately following stimulation. No deterioration was found in cognition nor in psycho-emotional well-being following treatment. Treatment burden was acceptable, but seems to depend on clinical effect, duration of ongoing effect and stimulation site. Median weekly seizure frequency and ratio of seizure-free weeks did not change significantly in this small patient cohort.ConclusionWe report the results of the first ever trial of cTBS as a treatment for neocortical DRE. A 4-day accelerated cTBS protocol over the EF appears safe and feasible. Although the design and sample size of this open-label pilot study is unfit to reliably identify a therapeutic effect, results encourage further exploration of cTBS as an anti-epileptic treatment and potential optimization compared to conventional rTMS in a dedicated randomized controlled trial. (clinicaltrials.gov: NCT02635633).

Vagus Nerve Stimulation for Treatment-Resistant Depression: Current Status of This Novel Treatment

Patients with treatment-resistant or difficult-to-treat major depression (TRD/DTD) have limited proven treatment options. Vagus nerve stimulation (VNS), chronic stimulation of the left cervical vagus nerve using an implantable pulse generator, has been demonstrated in numerous clinical trials to effectively treat TRD/DTD. In this review, seminal and ongoing vagus nerve stimulation trials are summarized and compared, and critical clinical findings are discussed. [ Psychiatr Ann. 2022;52(7):272–282.]

A Chronic Condition Disguised as an Acute Event: the Case for Re-thinking Stimulant Overdose Death.

Recent reports indicate that stimulant-related deaths are increasing dramatically. People who die from acute stimulant toxicity have high rates of pre-existing cardiovascular disease (CVD), much of which is undiagnosed. Moreover, people who use stimulants with CVD often remain asymptomatic until presenting to an emergency department with an acute event. Prior research shows that symptoms of stimulant toxicity may occur on a regular basis, and that people who die from stimulant toxicity are older than those who die of opioid toxicity. Taken collectively, the existing evidence suggests that death from acute stimulant toxicity is often an outcome of long-term, cumulative exposure leading to cardiovascular dysfunction rather than acute intoxication. Strategies tailored to the distinct etiology of stimulant overdose are needed. We propose a three-part approach including (1) implementing stimulant use interventions that promote not only abstinence, but also use reduction, (2) treating ongoing stimulant use as a chronic cardiovascular condition, and (3) making stimulant toxicity interventions relevant to the populations most affected, which includes people outside of the traditional health-care system. In short, to reduce stimulant-related fatality, we need to transform our approach in ways that are tailored to address its natural history.

A Predictive Processing Model of Episodic Memory and Time Perception

Human perception and experience of time are strongly influenced by ongoing stimulation, memory of past experiences, and required task context. When paying attention to time, time experience seems to expand; when distracted, it seems to contract. When considering time based on memory, the experience may be different than what is in the moment, exemplified by sayings like "time flies when you're having fun." Experience of time also depends on the content of perceptual experience-rapidly changing or complex perceptual scenes seem longer in duration than less dynamic ones. The complexity of interactions among attention, memory, and perceptual stimulation is a likely reason that an overarching theory of time perception has been difficult to achieve. Here, we introduce a model of perceptual processing and episodic memory that makes use of hierarchical predictive coding, short-term plasticity, spatiotemporal attention, and episodic memory formation and recall, and apply this model to the problem of human time perception. In an experiment with approximately 13,000 human participants, we investigated the effects of memory, cognitive load, and stimulus content on duration reports of dynamic natural scenes up to about 1 minute long. Using our model to generate duration estimates, we compared human and model performance. Model-based estimates replicated key qualitative biases, including differences by cognitive load (attention), scene type (stimulation), and whether the judgment was made based on current or remembered experience (memory). Our work provides a comprehensive model of human time perception and a foundation for exploring the computational basis of episodic memory within a hierarchical predictive coding framework.

Indicators of nonspecific resistance of the organism in patients with destructive forms of erysipelas

Purpose of the study. to evaluate the indicators of nonspecific resistance of the organism in patients with destructive forms of erysipelas.&#x0D; Materials and methods. 114 case histories of patients who were hospitalized in the center of purulent - septic surgery of KNP "City Hospital G3" in Zaporozhye for the period 2019-2020 were analyzed.&#x0D; According to the forms of the disease, patients were distributed as follows: erythematous - 24 (21.0%) - control group; bullous - 28 (24.6%), phlegmonous form - 48 (42.1%), necrotic - 14 (12.3%). Among the latter, 10 patients were aggravated by sepsis. 6 patients died, mortality was 60%.&#x0D; Results. Complementary activity of blood serum in patients with destructive forms of erysipelas in a favorable course of the disease is significantly increased, which is not observed in patients with sepsis. A significant increase in the HCT- test provides information on the degree of functional irritation of peripheral blood neutrophils under the influence of pathogens. But its increase almost 2 times until the moment of clinical recovery indicates the ongoing stimulation of phagocytic cells of peripheral blood, which caused changes in the metabolic profile of cast iron. The decrease in phagocytic activity in patients with sepsis may be due to a defect in the absorption capacity of polymorphonuclear leukocytes, and its progressive decrease, to some extent, may be a marker of adverse disease outcome.&#x0D; Conclusion. The degree of changes in the indicators of nonspecific resistance of the organism makes it possible to assess the reserves of the immune response, to determine the intensity and dynamics of destructive forms of erysipelas.

How Do You Treat Trigeminal Neuralgia in Your Practice?

How Do You Treat Trigeminal Neuralgia in Your Practice?

Meningeal lymphatic drainage promotes T cell responses against Toxoplasma gondii but is dispensable for parasite control in the brain

Abstract Toxoplasma gondii is an intracellular protozoan parasite that causes chronic brain infection in a wide range of mammalian hosts. Animal studies have demonstrated that continuous T cell recruitment to the brain is necessary for parasite control. However, it has remained unclear how T cells outside the central nervous system sense and respond to brain-derived microbial antigen. Here, we test the hypothesis that the newly described meningeal lymphatic system promotes T cell immunity during T. gondii brain infection. We find that chronic brain infection is associated with significant expansion of parasite-specific T cells in the cerebrospinal fluid (CSF)-draining deep cervical lymph nodes. T cell activation at this site is correlated with parasite burden in the brain and peaks during the late stages of chronic infection. Flow cytometric analysis of CSF reveals a population of activated dendritic cells that is not present in the CSF of naïve mice. Mature dendritic cells are also mobilized in the meninges, specifically in areas where CSF protein can be sampled. Disrupting meningeal lymphatic drainage by ligating the collecting vessels leads to impaired T cell responses in the deep cervical lymph nodes. Surprisingly, in spite of reduced T cell activation and IFN-γ production at this site, T cell responses in the brain remain intact, likely due to ongoing antigenic stimulation in lymph nodes that drain non-central nervous system tissue. Overall, we provide evidence that meningeal lymphatic drainage supports robust parasite-specific T cell responses in the deep cervical lymph nodes. Nonetheless, we find that drainage of central nervous system material to this site is dispensable for host-protective T cell responses in the brain. Supported by grants from NIH (5T32AI007496, 5T32GM007267, R01NS091067, R01NS112516, R56NS106028, F30AI154740)

P 2 Effects of deep brain stimulation (DBS) in the entopeduncular nucleus (EPN) in dystonic dtsz hamsters

Introduction: DBS of the globus pallidus internus (GPi; entopeduncular nucleus, EPN, in rodents) has become important for the treatment of generalized dystonia. There is evidence that striatal dysfunctions cause a disturbed thalamocortical inhibition via altered neuronal activity in the GPi/EPN. However, the pathophysiology as well as the mechanisms of DBS are largely unknown, which hampers the detection of drug targets. In our project of the CRC “Electrically active implants” we aim to elucidate mechanisms of DBS in animal models of dystonia. We recently found that short-term (3 h) EPN-DBS with 130 Hz (50 µA, 60 µs) improves paroxysmal dystonia in the dt sz mutant hamster 1 and reduces spontaneous excitatory cortico-striatal activity in brain slices of this model 2 , indicating fast effects in synaptic plasticity. In the present study, we therefore examined whether short-term DBS leads to changes of c-Fos, an immunohistochemical marker of neuronal activity, in EPN-related network regions. Materials & Methods: For immunohistochemistry we used brains of stimulated dt s z hamsters, in which DBS had improved dystonia, as well as sham-stimulated and naïve animals and performed cell counting and fluorescence intensity measurements of c-Fos within the basal ganglia network. In addition, we performed double labeling of c-Fos with GAD67 and with parvalbumin (PV), respectively, in brain slices of the same animals. Results: After DBS vs. sham, c-Fos + around the electrode was increased. Unexpectedly, c-Fos + cells were decreased in deep cerebellar nuclei (DCN) after DBS, but no changes became evident within the whole EPN, habenula, ventromedial thalamus, cortex and striatum. Cell counting of c-Fos activated GAD67 + as well as activated PV + cells showed no differences between the groups in motor cortex and striatum. Conclusion: With regard to recent electrophysiological data, we expected c-Fos changes especially in cortical GABAergic neurons after DBS in dt sz hamsters. The lack of changes within the basal ganglia network could be related to the short duration of stimulation or the time interval between stimulation and c-Fos staining. Ongoing long-term EPN stimulations, now feasible by a new fully implantable stimulator 3 , probably lead to more pronounced effects within the network and will be useful to verify the DCN effects. Funded by the DFG within the Collaborative Research Centre 1270 ELAINE.

Upregulation of Cytotoxic T-cells in pediatric patients with Gaucher disease

Cytotoxic (CD8) T-cells and natural killer (NK) cells have a significant immune function role. The ongoing stimulation of immunity and the excessive release of proinflammatory cytokines observed in pediatric patients with Gaucher disease (GD) can affect immune cells. Few studies have looked at the proportion of cytotoxic CD8 T-cells and their subsets in children with GD. A prospective case–control study was performed involving twenty pediatric patients with type 1 GD and twenty healthy age-matched controls. All patients received regular enzyme replacement therapy (ERT) for at least 6 months before the study. Complete blood count and flow cytometric analyses of CD8 T, Tc1, Tc2, NK, and NK T-cells were performed. GD patients showed significantly increased of CD8 T, Tc1 and significantly decreased NK cells frequencies when compared to healthy controls. However, no significant difference in Tc2 and NK T-cells was found between the studied groups. GD patients on regular ERT have increased CD8+ T-cell frequencies, predominantly Tc1, together with a reduction in NK cells than in healthy controls. These crucial immunological changes may contribute to some extent to the pathogenesis and the progression of GD.

Continued Virus-Specific Antibody-Secreting Cell Production, Avidity Maturation and B Cell Evolution in Patients Hospitalized with COVID-19.

Understanding the development and sustainability of the virus-specific protective immune response to infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remains incomplete with respect to the appearance and disappearance of virus-specific antibody-secreting cells (ASCs) in circulation. Therefore, we performed cross-sectional and longitudinal analyses of peripheral blood mononuclear cells and plasma collected from 55 hospitalized patients up to 4 months after onset of COVID-19 symptoms. Spike (S)- and nucleocapsid (N)-specific IgM and IgG ASCs appeared within 2 weeks accompanied by flow cytometry increases in double negative plasmablasts consistent with a rapid extrafollicular B cell response. Total and virus-specific IgM and IgG ASCs peaked at 3-4 weeks and were still being produced at 3-4 months accompanied by increasing antibody avidity consistent with a slower germinal center B cell response. N-specific ASCs were produced for longer than S-specific ASCs and avidity maturation was greater for antibody to N than S. Patients with more severe disease produced more S-specific IgM and IgG ASCs than those with mild disease and had higher levels of N- and S-specific antibody. Women had more B cells in circulation than men and produced more S-specific IgA and IgG and N-specific IgG ASCs. Flow cytometry analysis of B cell phenotypes showed an increase in circulating B cells at 4-6 weeks with decreased percentages of switched and unswitched memory B cells. These data indicate ongoing antigen-specific stimulation, maturation, and production of ASCs for several months after onset of symptoms in patients hospitalized with COVID-19.

Dorsal column and root stimulation at Aβ-fiber intensity activate superficial dorsal horn glutamatergic and GABAergic populations.

Neurostimulation therapies are frequently used in patients with chronic pain conditions. They emerged from Gate Control Theory (GCT), which posits that Aβ-fiber activation recruits superficial dorsal horn (SDH) inhibitory networks to “close the gate” on nociceptive transmission, resulting in pain relief. However, the efficacy of current therapies is limited, and the underlying circuits remain poorly understood. For example, it remains unknown whether ongoing stimulation of Aβ-fibers is sufficient to drive activity in SDH neurons. We used multiphoton microscopy in spinal cords extracted from mice expressing the genetically encoded calcium indicator GCaMP6s in glutamatergic and GABAergic populations; activity levels were inferred from deconvolved calcium signals using CaImAn software. Sustained Aβ-fiber stimulation at the dorsal columns or dorsal roots drove robust yet transient activation of both SDH populations. Following the initial increase, activity levels decreased below baseline in glutamatergic neurons and were depressed after stimulation ceased in both populations. Surprisingly, only about half of GABAergic neurons responded to Aβ-fiber stimulation. This subset showed elevated activity for the entire duration of stimulation, while non-responders decreased with time. Our findings suggest that Aβ-fiber stimulation initially recruits both excitatory and inhibitory populations but has divergent effects on their activity, providing a foundation for understanding the analgesic effects of neurostimulation devices.Perspective: This article used microscopy to characterize the responses of mouse spinal cord cells to stimulation of non-painful nerve fibers. These findings deepen our understanding of how the spinal cord processes information and provide a foundation for improving pain-relieving therapies.