Longer Latency Research Articles

Diagnostic value of EEG after a first unprovoked seizure in adults – A population-based study

ObjectiveElectroencephalography (EEG) is a standard investigation after a first unprovoked seizure but the diagnostic value in adults remains unclear. Our objective was to investigate the diagnostic value of EEG after a first unprovoked seizure in a population-based cohort in Gothenburg, Sweden. MethodsThis retrospective population-based study included adult patients referred by a neurologist for EEG after a first unprovoked seizure from August 2016 - December 2019 in the greater Gothenburg catchment area. In total 520 patients were included and followed in medical records for a median of 4.42 years (range 0.33–6.93). Primary outcome measures were epileptiform activity. Medical records were reviewed for the influence of EEG on clinical management. The frequency of epileptiform activity was calculated and compared in different subgroup analyses. ResultsEEGs were recorded after a median of 70 days from the seizure. In total, 7.7 % had epileptiform activity, and 27.9 % had pathological slowing on their EEG. Seizure recurrence occurred in 33.7 % (29.6–37.8). Epileptiform activity predicted seizure recurrence with a recurrence risk of 82.5 % (70.7–94.3). The sensitivity of epileptiform activity was only 19.2 % (13.6–25.9) but the specificity was 98.0 % (95.9–99.2) and the relative risk of recurrence in presence of such activity was 2.8 (2.3–3.5). The EEG findings resulted in an alteration of diagnosis and/or medication in 4.4 % of the patients. Factors associated with epileptiform activity on EEG were younger age, EEG including sleep recording, generalized onset seizure, shorter time from seizure to EEG and longer duration of EEG recording. SignificanceThe yield of EEG recorded with a longer latency after a first unprovoked seizure in adults was low. However, epileptiform activity highly predicted seizure recurrence and our results suggest that epileptiform activity on EEG could be explored further as a biomarker for defining epilepsy already after a first seizure.

High frequency post-pause word choices and task-dependent speech behavior characterize connected speech in individuals with mild cognitive impairment.

Alzheimer's disease (AD) is characterized by progressive cognitive decline, including impairments in speech production and fluency. Mild cognitive impairment (MCI), a prodrome of AD, has also been linked with changes in speech behavior but to a more subtle degree. This study aimed to investigate whether speech behavior immediately following both filled and unfilled pauses (post-pause speech behavior) differs between individuals with MCI and healthy controls (HCs), and how these differences are influenced by the cognitive demands of various speech tasks. Transcribed speech samples were analyzed from both groups across different tasks, including immediate and delayed narrative recall, picture descriptions, and free responses. Key metrics including lexical and syntactic complexity, lexical frequency and diversity, and part of speech usage, both overall and post-pause, were examined. Significant differences in pause usage were observed between groups, with a higher incidence and longer latencies following these pauses in the MCI group. Lexical frequency following filled pauses was higher among MCI participants in the free response task but not in other tasks, potentially due to the relative cognitive load of the tasks. The immediate recall task was most useful at differentiating between groups. Predictive analyses utilizing random forest classifiers demonstrated high specificity in using speech behavior metrics to differentiate between MCI and HCs. Speech behavior following pauses differs between MCI participants and healthy controls, with these differences being influenced by the cognitive demands of the speech tasks. These post-pause speech metrics can be easily integrated into existing speech analysis paradigms.

Abstract 4136745: How do sleep quality and heart failure symptoms impact functional status among patients with heart failure?

Background: Patients with heart failure (HF) frequently experience poor sleep quality and multiple HF symptoms, both of which are linked to diminished functional status. Poor sleep quality can manifest as prolonged latency, short duration, low efficiency, or difficulty staying asleep. HF symptoms encompass different dimensions: presence, frequency, severity, and distress of HF symptoms. Different dimensions of sleep quality and HF symptoms may uniquely influence functional status, necessitating tailored interventions, yet how individual dimensions of sleep quality and HF symptoms impact functional status remains unexplored. Research Question: how do individual dimensions of sleep quality and HF symptoms impact functional status in patients with HF? Methods: We studied 197 adults with HF (male: 66%, age: 62±11 yrs). The Pittsburgh Sleep Quality Index was used to assess seven dimensions of sleep quality: subjective sleep quality, latency, duration, efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction over the last month. Four dimensions (i.e., presence, frequency, severity, distress) of 7 HF symptoms (e.g., shortness of breath, fatigue, swelling) were assessed using the Symptom Status Questionnaire-HF. Functional status was measured using the Duke Activity Status Index. Correlations and two multiple linear regression models (1 st model: 7 dimensions of sleep quality on functional status, and 2 nd model: 4 dimensions of HF symptoms on functional status) were conducted for data analysis. Results: Worse subjective sleep quality, longer latency, more sleep disturbances, use of sleeping medications, and higher levels of daytime dysfunction were correlated with poor functional status. All four dimensions of HF symptoms were negatively correlated with functional status. In the 1 st multiple linear regression model, more sleep disturbances (B=-3.91, p =.006) and higher daytime dysfunction (B=-5.70, p <.001) were predictive of poor functional status (model R 2 =0.23, p <.001). In the 2 nd multiple linear regression model, only higher frequency of HF symptoms (B=-.70, p =.022) predicted poor functional status (model R 2 =0.34, p <.001). Conclusion: Increased sleep disturbances, daytime dysfunction, and frequency of HF symptoms were associated with poorer functional status in patients with HF. These findings underscore the importance of developing tailored interventions to address individual sleep problems and HF symptoms to improve functional status.

Recurrent Aphthous Stomatitis and Sleep Quality Factors: A Comprehensive Analysis.

Due to the unclear etiology of recurrent aphthous stomatitis (RAS), a painful and distressing condition with a high prevalence, the researchers have hypothesized a connection between sleep quality and RAS. The cross-sectional study enrolled 10,138 Fasa Cohort Study participants aged 35-70 years. Various sleep quality factors were calculated and categorized based on the Pittsburgh Sleep Questionnaire. Among 9030 subjects finally included with RAS prevalence of 20.2%, adjusted logistic regression showed significant odds ratios (ORs) in subjects who sleep < 5 h (OR = 1.44, 95%CI 1.25, 1.66), have sleep latencies of more than 60 min (OR = 1.37, 95%CI 1.11, 1.69), have sleep efficiencies of 65%-75% (OR = 1.55, 95%CI 1.21, 1.98), or regularly go to bed after 11 p.m. (OR = 1.23, 95%CI 1.11, 1.37). Subgroup analyses indicated no significant associations between RAS and various sleep factors in individuals who worked night shifts, and stronger associations were observed in men than women. The study found a significant positive association between RAS and sleep quality factors such as shorter duration, lower efficiency, longer latency, later bedtime, and regular sleeping pill use. Establishing early and sufficient sleep and addressing sleep onset disturbances by adhering to sleep hygiene principles should be prioritized in individuals with RAS.

V1 neurons are tuned to perceptual borders in natural scenes

The visual system needs to identify perceptually relevant borders to segment complex natural scenes. The primary visual cortex (V1) is thought to extract local borders, and higher visual areas are thought to identify the perceptually relevant borders between objects and the background. To test this conjecture, we used natural images that had been annotated by human observers who marked the perceptually relevant borders. We assessed the effect of perceptual relevance on V1 responses using human neuroimaging, macaque electrophysiology, and computational modeling. We report that perceptually relevant borders elicit stronger responses in the early visual cortex than irrelevant ones, even if simple features, such as contrast and the energy of oriented filters, are matched. Moreover, V1 neurons discriminate perceptually relevant borders surprisingly fast, during the early feedforward-driven activity at a latency of ~50 ms, indicating that they are tuned to the features that characterize them. We also revealed a delayed, contextual effect that enhances the V1 responses that are elicited by perceptually relevant borders at a longer latency. Our results reveal multiple mechanisms that allow V1 neurons to infer the layout of objects in natural images.

Radiotherapy and increased risk of second primary cancers in breast cancer survivors: An epidemiological and large cohort study

BackgroundRadiotherapy (RT) for breast cancer (BC) may raise the risk of second primary cancers (SPCs), a relationship inadequately studied. MethodsWe analyzed 248268 female BC patients from 9 SEER registries, 1988–2018, identifying SPCs >5 years after initial treatment, comparing SPC risks between RT and non-RT cohorts using Fine-Gray and Poisson regressions. ResultsOf all participants, 55.4 % received surgery and RT. The RT group had a higher SPC incidence, with excess incidence significantly dropped from 6.9 % in 1990 to 0.2 % in 2012. The 30-year SPC incidence was 24.69 % in the RT cohort and 18.11 % in the NRT cohort. RT increased the risk of SPCs(HR, 1.29 [95%CI,1.26–1.33]; P < 0.001), BC(HR, 1.58[1.52–1.64]; P < 0.001), cancer of respiratory system(HR, 1.21[1.13–1.30]; P = 0.013), skin cancer(HR, 1.26[1.10–1.44]; P < 0.001), leukemia(HR, 1.30[1.11–1.54]; P = 0.001), soft tissue cancer(HR, 1.78[1.34–2.37]; P < 0.001), and eye & orbit cancer(HR, 2.21[1.02–4.80]; P = 0.044), except for reducing the risk of multiple myeloma (HR 0.76). Notably, RT-related risks(RR) for BC declined with increasing age and the year of BC diagnosed, increased with longer latency, but the dynamic RR for cancer of respiratory system presented the almost opposite trends. The RT cohort had higher standardized incidence ratios for SPCs compared to both the NRT cohort and the general population overall. Although 15-year overall survival for SPCs was similar between RT and NRT cohorts, SPC presence significantly lowered 30-year survival from 35.64 % to 23.90 %. ConclusionsRT might increase susceptibility to SPC in breast, respiratory system, skin, soft tissue, eye and orbit, and leukemia in BC survivors. Efforts should be made to timely diagnose SPCs based on their specific patterns to improve patient's quality of life.

Age-related Electrophysical Correlates of Cross-modal Attention Switching.

The human experience demands seamless attentional switches between sensory modalities. Aging raises questions about how declines in auditory and visual processing affect cross-modal attention switching. This study used a cued cross-modal attention-switching paradigm where visual and auditory stimuli were simultaneously presented on either spatially congruent or incongruent sides. A modality cue indicated the target modality, requiring a spatially left versus right key-press response. EEG recordings were collected during task performance. We investigated whether the mixing costs (decreased performance for repetition trials in a mixed task compared with a single task) and switch costs (decreased performance for a switch of target modality compared with a repetition) in cross-modal attention-switching paradigms would exhibit similarities in terms of behavioral performance and the ERP components to those observed in the traditional unimodal attention-switching paradigms. Specifically, we focused on the ERP components: cue-locked P3 (mixing/switch-related increased positivity), target-locked P3 (mixing/switch-related decreased positivity), and target-locked lateralized readiness potential (mixing/switch-related longer latency). In addition, we assessed how aging impacts cross-modal attention-switching performance. Results revealed that older adults exhibited more pronounced mixing and switch costs than younger adults, especially when visual and auditory stimuli were presented on incongruent sides. ERP findings showed increased cue-locked P3 amplitude, prolonged cue-locked P3 latency, decreased target-locked P3 amplitude, prolonged target-locked P3 latency in association with switch costs, and prolonged onset latency of the target-locked lateralized readiness potential in association with the mixing costs. Age-related effects were significant only for cue-locked P3 amplitude, cue-locked P3 latency (switch-related), and target-locked P3 latency (switch-related). These findings suggest that the larger mixing costs and switch costs in older adults were because of the inefficient use of modality cues to update a representation of the relevant task sets and required more processing time for evaluating and categorizing the target.

High frequency post-pause word choices and task-dependent speech behavior characterize connected speech in individuals with mild cognitive impairment.

Alzheimer's disease (AD) is characterized by progressive cognitive decline, including impairments in speech production and fluency. Mild cognitive impairment (MCI), a prodrome of AD, has also been linked with changes in speech behavior but to a more subtle degree. This study aimed to investigate whether speech behavior immediately following both filled and unfilled pauses (post-pause speech behavior) differs between individuals with MCI and healthy controls (HCs), and how these differences are influenced by the cognitive demands of various speech tasks. Transcribed speech samples were analyzed from both groups across different tasks, including immediate and delayed narrative recall, picture descriptions, and free responses. Key metrics including lexical and syntactic complexity, lexical frequency and diversity, and part of speech usage, both overall and post-pause, were examined. Significant differences in pause usage were observed between groups, with a higher incidence and longer latencies following these pauses in the MCI group. Lexical frequency following filled pauses was higher among MCI participants in the free response task but not in other tasks, potentially due to the relative cognitive load of the tasks. The immediate recall task was most useful at differentiating between groups. Predictive analyses utilizing random forest classifiers demonstrated high specificity in using speech behavior metrics to differentiate between MCI and HCs. Speech behavior following pauses differs between MCI participants and healthy controls, with these differences being influenced by the cognitive demands of the speech tasks. These post-pause speech metrics can be easily integrated into existing speech analysis paradigms.

The Importance of Timing—An Expert Evaluation on Latencies for Voice Assistants

In a driving simulator study, six experts interacted with an in-vehicle voice assistant (VA) and rated different latencies. The results suggest that in order to maintain drivers’ satisfaction with the interaction, in-vehicle VAs should have a latency of no more than 5 s. A slight delay of 1.5 s was rated best while shorter latencies caused highest variance amongst experts—indicating that the fastest response may not necessarily be the most desirable. Satisfaction may also depend on the complexity of the use case as experts showed higher tolerance toward longer latencies in the navigation-domain. Furthermore, our results raise thought-provoking insights about the importance of considering human expectations and preferences in the design of in-vehicle VAs. Despite technological advancements, humans might still expect a natural delay, similar to that in a human-human interaction. These findings emphasize the need to balance using cutting-edge technology with the desire for familiar interactions.

LGI1 encephalitis: potentially complement-activating anti-LGI1-IgG subclasses 1/2/3 are associated with the development of hippocampal sclerosis

Two-thirds of published patients with anti-leucine rich, glioma inactivated 1 (LGI1) encephalitis develop hippocampal sclerosis (HS). It is likely that this contributes to residual cognitive long-term deficits and the risk of epilepsy. Almost all patients harbor anti-LGI1-immunoglobulin G-(IgG-) subclass 4, which is considered a “benign”, non-destructive subclass. In contrast, neuropathological case studies have suggested that the classical complement cascade may contribute to mediotemporal cell death in patients with LGI1 antibodies. IgG subclasses 1, 2, or 3 are required to initiate this cascade. We hypothesized that patients with these anti-LGI1-IgG1/2/3 in addition to IgG4 have a higher risk of developing HS than patients with anti-LGI1-IgG4 alone. We retrospectively assessed all anti-LGI1 encephalitis patients from this center with anti-LGI1-IgG-subclass information and follow-up MRI available. Nine out of 20 patients had developed HS (45%). Volumetric FreeSurfer analysis confirmed the visual HS diagnoses. HS and a lower hippocampal volume were associated with anti-LGI1-IgG1/2/3. All six patients with this IgG subclass status developed HS. There was no association with older or younger age at onset, female sex, longer latency from disease onset to start of immunotherapy, less intense immunotherapy, higher serum titers of LGI1 antibodies, LGI1 antibodies in CSF or higher LGI1-specific antibody indices. There was no association between anti-LGI1-IgG1/2/3 status and neuropsychological performance, epilepsy, or general neurological performance. This confirms our hypothesis that anti-LGI1-IgG1/2/3 in serum puts patients at risk of developing HS. If these findings can be confirmed and clinically corroborated, patients with anti-LGI1-IgG1/2/3 might become candidates for anti-complement-directed immunological treatments.

Neurons of Macaque Frontal Eye Field Signal Reward-Related Surprise.

The frontal eye field (FEF) plays a well-established role in the control of visual attention. The strength of an FEF neuron's response to a visual stimulus presented in its receptive field is enhanced if the stimulus captures spatial attention by virtue of its salience. A stimulus can be rendered salient by cognitive factors as well as by physical attributes. These include surprise. The aim of the present experiment was to determine whether surprise-induced salience would result in enhanced visual-response strength in the FEF. Toward this end, we monitored neuronal activity in two male monkeys while presenting first a visual cue predicting with high probability that the reward delivered at the end of the trial would be good or bad (large or small) and then a visual cue announcing the size of the impending reward with certainty. The second cue usually confirmed but occasionally violated the expectation set up by the first cue. Neurons responded more strongly to the second cue when it violated than when it confirmed expectation. The increase in the firing rate was accompanied by a decrease in spike-count correlation as expected from capture of attention. Although both good surprise and bad surprise induced enhanced firing, the effects appeared to arise from distinct mechanisms as indicated by the fact that the bad-surprise signal appeared at a longer latency than the good-surprise signal and by the fact that the strength of the two signals varied independently across neurons.

Secondary Multiple Evanescent White Dot Syndrome Following Blunt Trauma.

To report a case of secondary unilateral MEWDS following blunt trauma to the eye. Observational case report of one patient. A 25-year-old male initially presented after being hit in the left eye with a football, with visual acuity of 20/50, traumatic iritis, commotio retinae, vitreous hemorrhage, and a large pigment epithelial detachment in the superior macula. He was lost to follow-up for two years before presenting with a sudden decrease in vision. On exam, best corrected VA (BCVA) was counting fingers and clinical exam demonstrated fibrosis in the superior macula, small white lesions around the optic disc and throughout the posterior pole, and ellipsoid zone disruption on OCT. Given the clinical appearance, a diagnosis of Multiple Evanescent White Dot Syndrome was made and the decision was made to observe. Two months later, without treatment, BCVA improved to 20/20, and there was resolution of the white lesions in the posterior pole as well as improved continuity of the ellipsoid zone on OCT. We describe a case of Multiple Evanescent White Dot Syndrome two years after blunt trauma to the eye; a far longer latency than previously reported cases of MEWDS secondary to blunt trauma.

RSVP-based BCI for inconspicuous targets: detection, localization, and modulation of attention

Objective.While brain-computer interface (BCI) based on rapid serial visual presentation (RSVP) is widely used in target detection, patterns of event-related potential (ERP), as well as the performance on detecting inconspicuous targets remain unknown. Moreover, participant-screening methods to excluded 'BCI-blind' users are still lacking.Approach.A RSVP paradigm was designed with targets of varied concealment, size, and location. ERPs (e.g. P300 and N2pc) and target detection accuracy were compared among these conditions. The relationship between participants' attention scores and target detection accuracy was also analyzed to test attention level as a criterion for participant screening.Main results.Statistical analysis showed that the conditions of target concealment and size significantly influenced ERP. In particular, ERP for inconspicuous targets, such as concealed and small targets, exhibited lower amplitudes and longer latencies. In consistent, the accuracy of detection in inconspicuous condition was significantly lower than that of conspicuous condition. In addition, a significant association was found between attention scores and target detection accuracy for camouflaged targets.Significance.The study was the first to address ERP features among multiple dimensions of concealment, size, and location. The conclusion provided insights into the relationship between ERP decoding and properties of targets. In addition, the association between attention scores and detection accuracy implied a promising method in screening well-behaved participants for camouflaged target detection.

Environmental complexity impacts anxiety in broiler chickens depending on genetic strain and body weight

The objective was to assess the impact of environmental complexity on affective state (anxiety) in fast- and slow-growing broilers (Gallus gallus domesticus) as they gain weight. Six hundred fast-growing broilers (Ross 708; “fast-growers”) and 600 slow-growing broilers (Hubbard Redbro Mini; “slow-growers”) were raised in 24 pens with simple (standard; SE) or complex (permanent and temporary enrichments; CE) environments. Six birds/pen underwent the attention bias test on day 23 (fast-growers only), 28–29, 35–36, 42–43, and 56–57 (slow-growers only), with individuals only tested once (n = 576). Proportion of birds feeding, time spent vigilant and latencies to eat and step were recorded. Greater vigilance and longer latencies indicate more anxiety. Slow-growers fed more (p = 0.001), were less vigilant (p = 0.003), and stepped sooner than fast-growers (p = 0.007). For both strains, likelihood of feeding was unrelated to weight in SE, but decreased with increasing weight in CE (p = 0.048). Birds in CE stepped sooner than birds in SE (p = 0.030). Vigilance increased with body weight (p = 0.024). These results indicate that affective state (anxiety) can change as birds gain weight, depending on environmental complexity and genetic strain. Overall, slow-growers showed reduced anxiety compared to fast-growers, across housing treatments or weights.

Lysine Methyltransferase 2D Regulates Immune Response and Metastasis in Head and Neck Cancer.

The most frequently altered epigenetic modifier in head and neck squamous carcinoma (HNSC) is the histone methyltransferase KMT2D. KMT2D catalyzes methylation of histone H3K4 resulting in open chromatin and the activation of target genes. Tumor-associated macrophages (TAMs) promote cancer growth by causing T lymphocyte exhaustion. C-C motif chemokine ligand 2 (CCL2) is a potent TAM chemotactic factor. In HNSC, TAMs have been associated with unfavorable patient outcomes and metastasis. The aim of this study was to determine the role of KMT2D in HNSC using genetically engineered in vivo models. KMT2D protein expression was correlated with lymph node metastasis in human HNSC using immunohistochemistry. Genetically engineered KMT2D and CCL2 knockout models of HNSC were created in vivo. HNSC was characterized using qRT-PCR, histopathology, and immunohistochemistry/immunofluorescence microscopy. We also analyzed the effects of KMT2D expression on the proliferation and migration of human HNSC lines. The regulation of the CCL2 gene by KMT2D was characterized using chromatin immunoprecipitation-sequencing assay of transposase accessible chromatin-sequencing, and chromatin conformation capture-sequencing. Human HNSC cases with high KMT2D expression exhibited significantly increased lymph node metastasis. Reduced KMT2D expression in our genetically engineered model correlated with reduced lymph node metastasis, longer latency, and slow tumor growth. CCL2 expression was decreased in KMT2D deficient HNSC, which correlated with a reduced TAM gene expression signature. Genomic experiments demonstrated that KMT2D directly targeted the CCL2 gene. A new genetically engineered in vivo model of CCL2-null HNSC was created, recapitulating the KMT2D deficient phenotype and showing a decreased T lymphocyte exhaustion signature. KMT2D regulates CCL2-mediated immune response and metastasis in HNSC.

Study on the influence of food emulsion components on its lubrication characteristics and smooth perception

Due to the increasing risk of obesity and cardiovascular diseases caused by high-fat diets, low-fat foods have become a priority demand for consumers’ health. However, the smoothness perception and scientific assessment methods of the existing low-fat foods should be improved. In this study, three food emulsions were prepared, and their lubrication characteristics, sensory evaluation of smoothness, and electroencephalogram (EEG) signals were assessed to preliminarily investigate the effects of food emulsion components on their above characteristics. The results showed that fat substitute (FSU) and fat could significantly reduce coefficient of friction (CoF) of the food emulsions, with average CoF reduced by 28% and 63% compared to the original food emulsions. In addition, fat-enriched food emulsions continued to exhibit excellent lubrication characteristics after adding artificial saliva, with an average CoF reduced by 31.1% compared to that of the food emulsions without artificial saliva. Both FSU and fat improved the smoothness of food emulsions, and the lubricating properties of fat were more pronounced, with fat-enriched food emulsion which could provide a substantial improvement in smoothness compared to the fat-free food emulsion. Comparison of subjects’ EEG signals revealed that food emulsion with lower CoF and higher smoothness triggered higher P3 amplitudes and longer latencies. These findings provide better insights into the scientific evaluation of food texture and the development of low-fat foods.

The combined treatment with ketogenic diet and metformin slows tumor growth in two mouse models of triple negative breast cancer

BackgroundMany tumors contain hypoxic microenvironments caused by inefficient tumor vascularization. Hypoxic tumors have been shown to resist conventional cancer therapies. Hypoxic cancer cells rely on glucose to meet their energetic and anabolic needs to fuel uncontrolled proliferation and metastasis. This glucose dependency is linked to a metabolic shift in response to hypoxic conditions.MethodsTo leverage the glucose dependency of hypoxic tumor cells, we assessed the effects of a mild reduction in systemic glucose by controlling both dietary carbohydrates with a ketogenic diet and endogenous glucose production by using metformin on two mouse models of triple-negative breast cancer (TNBC).ResultsHere, we showed that animals with TNBC treated with the combination regimen of ketogenic diet and metformin (a) had their tumor burden lowered by two-thirds, (b) displayed 38% slower tumor growth, and (c) showed 36% longer latency, compared to the animals treated with a ketogenic diet or metformin alone. As a result, lowering systemic glucose by this combined dietary and pharmacologic approach improved overall survival in our mouse TNBC models by 31 days, approximately equivalent to 3 years of life extension in human terms.ConclusionThis preclinical study demonstrates that reducing systemic glucose by combining a ketogenic diet and metformin significantly inhibits tumor proliferation and increases overall survival. Our findings suggest a possible treatment for a broad range of hypoxic and glycolytic tumor types that can augment existing treatment options to improve patient outcomes.

Exploratory assessment of the effect of systemic administration of soluble glycoprotein 130 on cognitive performance and chemokine levels in a mouse model of experimental traumatic brain injury

Uncontrolled neuroinflammation mediates traumatic brain injury (TBI) pathology and impairs recovery. Interleukin-6 (IL-6), a pleiotropic inflammatory regulator, is associated with poor clinical TBI outcomes. IL-6 operates via classical-signaling through membrane-bound IL-6 receptor (IL-6R) and trans-signaling through soluble IL-6 receptor (s)IL-6R. IL-6 trans-signaling specifically contributes to neuropathology, making it a potential precision therapeutic TBI target. Soluble glycoprotein 130 (sgp130) prevents IL-6 trans-signaling, sparing classical signaling, thus is a possible treatment. Mice received either controlled cortical impact (CCI) (6.0 ± 0.2 m/s; 2 mm; 50-60ms) or sham procedures. Vehicle (VEH) or sgp130-Fc was subcutaneously administered to sham (VEH or 1 µg) and CCI (VEH, 0.25 µg or 1 µg) mice on days 1, 4, 7, 10 and 13 post-surgery to assess effects on cognition [Morris Water Maze (MWM)] and ipsilateral hemisphere IL-6 related biomarkers (day 21 post-surgery). CCI + sgp130-Fc groups (0.25 µg and 1 µg) were combined for analysis given similar behavior/biomarker outcomes. CCI + VEH mice had longer latencies and path lengths to the platform and increased peripheral zone time versus Sham + VEH and Sham + sgp130-Fc mice, suggesting injury-induced impairments in learning and anxiety. CCI + sgp130-Fc mice had shorter platform latencies and path lengths and had decreased peripheral zone time, indicating a therapeutic benefit of sgp130-Fc after injury on learning and anxiety. Interestingly, Sham + sgp130-Fc mice had shorter platform latencies, path lengths and peripheral zone times than Sham + VEH mice, suggesting a beneficial effect of sgp130-Fc, independent of injury. CCI + VEH mice had increased brain IL-6 and decreased sgp130 levels versus Sham + VEH and Sham + sgp130-Fc mice. There was no treatment effect on IL-6, sIL6-R or sgp130 in Sham + VEH versus Sham + sgp130-Fc mice. There was also no treatment effect on IL-6 in CCI + VEH versus CCI + sgp130-Fc mice. However, CCI + sgp130-Fc mice had increased sIL-6R and sgp130 versus CCI + VEH mice, demonstrating sgp130-Fc treatment effects on brain biomarkers. Inflammatory chemokines (MIP-1β, IP-10, MIG) were increased in CCI + VEH mice versus Sham + VEH and Sham + sgp130-Fc mice. However, CCI + sgp130-Fc mice had decreased chemokine levels versus CCI + VEH mice. IL-6 positively correlated, while sgp130 negatively correlated, with chemokine levels. Overall, we found that systemic sgp130-Fc treatment after CCI improved learning, decreased anxiety and reduced CCI-induced brain chemokines. Future studies will explore sex-specific dosing and treatment mechanisms for sgp130-Fc therapy.

Breath-by-breath Analysis of a Rat Model of Pompe Disease Exposes Deficits in High-frequency Behaviors

Pompe disease (PD) is caused by a loss of function of the enzyme acid-α-glucosidase (GAA) leading to glycogen accumulation, neuromuscular dysfunction, and breathing failure. Here, we characterized longitudinal changes in breathing of GAA null ( Gaa−/−) rats on a breath-by-breath basis using a novel respiratory event detection algorithm. Adult Pompe (n = 5) and Sprague Dawley (n = 5) rats were implanted with chronic diaphragm EMG electrodes. Once a month from 4-10 months of age, full body plethysmography with concurrent EMG was used to record respiratory waveforms under room air and hypoxia. Waveforms were analyzed by the Adjustable Baselines Respiratory Analysis Program (ABRAP) algorithm. An adaptive threshold identified “respiratory events” defined as crossings of a threshold set between the recent maxima and minima of the waveform. After event identification, a range of waveform characteristics are calculated and tagged to that event. Averages of each characteristic were taken for all events and then analyzed based on respiratory rate in breaths/minute (bpm): low (&lt;120 bpm, ‘quiet breathing’), medium (between 120 and 240 bpm) and high (&gt;240 bpm, ‘high frequency sniffng’). In room air, Pompe rats had a lower breathing rate than wildtype rats by month 10 (173 vs 285 bpm, standard error of the difference (SE of diff.) 37, p=0.03). This decrease in frequency was driven by the high rate events as there were no differences in the mean rate of low rate events at month 10 (80 vs 83 bpm, SE of diff. 3) while the frequency of high rate events was significantly lower by 9 months (mo 9: 393 vs 440 bpm, SE of diff. 16, p=0.04, mo 10: 383 vs 440 bpm, SE of diff. 17, p=0.008). Not only was the breathing frequency of high-rate events impaired in Pompe rats, but there was a trend towards decrease in the proportion of events falling in the high rate category indicating less time spent in high rate breathing behaviors (mo 4: 52 vs 59%, SE of diff. 6, mo 10: 25 vs 52%, SE of diff. 9) with a concomitant increase in the proportion of low frequency events. Additionally, there was a main effect of genotype on the latency between diaphragm activation and onset of inspiratory flow during hypoxia with Pompe rats having a longer latency across all months and frequency bands. This difference was most pronounced in the medium (44 vs 29 ms, SE of diff. 4 ms, p=0.003) frequency events. Active expiration was impaired in Pompe animals with peak post-event airflow (maximum positive pressure reached before the next inspiratory effort) blunted across all months. This effect was pronounced in the high frequency events (0.16 mL vs 0.24 mL, SE of diff. 0.01, p=0.0001). These deficits in high frequency events are consistent with progressive neuromuscular diaphragm weakness. We conclude that comprehensive analyses of all respiratory events over extended recording periods enables detection of altered breathing behaviors that may be missed when assessing only short periods of quiet breathing. In turn, this may help uncover a respiratory signature of disease progression in Pompe disease or other neuromuscular conditions. 2R01HD052682-11A1 (DDF, BJB), T32HL134621 (AM), R01HL153102 (ED), SPARC OT2OD023854 (ED), Craig H. Neilsen Pilot Grant (ED). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Impaired Cortical Tracking of Speech in Children with Developmental Language Disorder.

In developmental language disorder (DLD), learning to comprehend and express oneself with spoken language is impaired, but the reason for this remains unknown. Using millisecond-scale magnetoencephalography recordings combined with machine learning models, we investigated whether the possible neural basis of this disruption lies in poor cortical tracking of speech. The stimuli were common spoken Finnish words (e.g., dog, car, hammer) and sounds with corresponding meanings (e.g., dog bark, car engine, hammering). In both children with DLD (10 boys and 7 girls) and typically developing (TD) control children (14 boys and 3 girls), aged 10-15 years, the cortical activation to spoken words was best modeled as time-locked to the unfolding speech input at ∼100 ms latency between sound and cortical activation. Amplitude envelope (amplitude changes) and spectrogram (detailed time-varying spectral content) of the spoken words, but not other sounds, were very successfully decoded based on time-locked brain responses in bilateral temporal areas; based on the cortical responses, the models could tell at ∼75-85% accuracy which of the two sounds had been presented to the participant. However, the cortical representation of the amplitude envelope information was poorer in children with DLD compared with TD children at longer latencies (at ∼200-300 ms lag). We interpret this effect as reflecting poorer retention of acoustic-phonetic information in short-term memory. This impaired tracking could potentially affect the processing and learning of words as well as continuous speech. The present results offer an explanation for the problems in language comprehension and acquisition in DLD.