Brain Sites Research Articles

RADT-28. THE ROLE OF CRANIAL RE-IRRADIATION IN EGFR MUTANT LUNG CANCER PATIENTS WITH BRAIN METASTASES

Abstract INTRODUCTION Re-irradiation with stereotactic radiosurgery (SRS) or whole-brain radiotherapy (WBRT) may be used for treating recurrent brain metastases. Here, we are reporting on the rate of cranial re-irradiation based on our institutional experience in patients with mutated Epidermal Growth Factor Receptor Non-Small Cell Lung Cancer (mEGFR-NSCLC). METHODS This is a retrospective review of patients from three NYP-WCM hospitals with brain metastases treated with radiotherapy and Tyrosine Kinase Inhibitors (TKIs) from December 2012 to May 2023. RESULTS Ninety-eight patients (60.5%) out of 162 with brain metastases from mEGFR-NSCLC were treated with radiation. Twenty-seven patients (27.5%) were treated with WBRT. Among 71 patients treated with SRS, 10 (14.1%) patients underwent surgical resection of the dominant brain lesion followed by fractioned SRS (FSRS) to the surgical bed. Sixty-one (85.9%) patients received SRS for intact brain lesions ranging from single fraction 16-20Gy to FSRT with 24Gy –30Gy in 3-5 fractions based on the size and eloquence of the brain site of the brain metastasis. In the SRS group, fifteen (21.1%) patients required at least one more course of cranial irradiation. The mean duration of local intracranial control between the first and the second course of radiation was 19.6 months [range from 2.0- 56.7 months], while from the start of TKI to the first intracranial failure was 11.3 months [0.8m-45.3 months]. In the WBRT group, two patients (7.4%) were treated with another course of WBRT 20Gy in 5 fractions. These two patients started TKI simultaneously with their first course of WBRT; the mean duration of intracranial local control was 12.8 months [range from 11.6-14.1 months]. Both patients suffered significant cognitive declines. CONCLUSION In the Tyrosine Kinase Inhibitor era, patients with brain metastases from mEGFR-NSCLC have protracted progression-free survival. Multiple courses of cranial re-irradiation may be needed. Stereotactic radiotherapy should be preferred for the best results in preserving cognitive functions.

Altered resting-state functional connectivity in a thalamo-cortico-cerebellar network in patients with schizophrenia

The diagnosis of schizophrenia is associated with a complex psychopathology related to disrupted brain circuitry causing a failure in coordinating information across brain sites with no consensus regarding the mechanisms. Although schizophrenia is well-studied, the great majority of studies investigated pre-selected ROIs or Seed-based connectivity. Whole brain ROI-wise studies that consider all ROIs available simultaneously are lacking. This technique helps understand large- and local-scale dynamics of information exchange across the whole brain. We investigated ROI-wise whole brain networks in 35 participants diagnosed with schizophrenia and 41 control participants. To unveil dysfunctions in brain subnetworks and to characterize network topology, we applied a statistical tool specially developed for network comparison called network-based statistic and graph theory. We observed a hyperconnected thalamo-cortico-cerebellar subnetwork in participants with schizophrenia; nodal analysis revealed higher number of thalamic connections. Our results suggest disruptions at the local level of the subnetwork rather than globally spread across the brain and driven by hyperconnectivity. Importantly, this subnetwork emerged from an exploratory analysis directly comparing ROI-wise whole brain network. This fact makes it an important contribution to the field as additional evidence, demonstrating the high reliability of malfunction in the local thalamo-cortico-cerebellar network.

Cellular Profile of Subfornical Organ Insulin Receptors in Mice.

Brain insulin receptor signaling is strongly implicated in cardiovascular and metabolic physiological regulation. In particular, we recently demonstrated that insulin receptors within the subfornical organ (SFO) play a tonic role in cardiovascular and metabolic regulation in mice. The SFO is a forebrain sensory circumventricular organ that regulates cardiometabolic homeostasis due to its direct exposure to the circulation and thus its ability to sense circulating factors, such as insulin. Previous work has demonstrated broad distribution of insulin receptor-expressing cells throughout the entire SFO, indirectly indicating insulin receptor expression in multiple cell types. Based on this, we sought to determine the cellular phenotypes that express insulin receptors within the SFO by combining immunohistochemistry with genetically modified reporter mouse models. Interestingly, SFO neurons, including both excitatory and inhibitory types, were the dominant cell site for insulin receptor expression, although a weak degree of insulin receptor expression was also detected in astrocytes. Moreover, SFO angiotensin type 1a receptor neurons also expressed insulin receptors. Collectively, these anatomical findings indicate the existence of potentially complex cellular networks within the SFO through which insulin signaling can influence physiology and further point to the SFO as a possible brain site for crosstalk between angiotensin-II and insulin.

Characterizing the clinical, radiological and serological features of children diagnosed with neuromyelitis optica spectrum disorder at pediatric neurology unit

Background. Neuromyelitis optica spectrum disorder is a rare autoimmune disease with a chronic inflammatory demyelinating characteristics that affects the central nervous. The aim of the study is to characterize the clinical, serological and radiological features of neuromyelitis optica disease in a sample of children from Iraq. Methods. A cross-sectional descriptive study has been carried out in the period from August 2019 to September 2020, in pediatric neurology ward in Children Welfare Teaching Hospital, Baghdad. In 12 retrospectively gathered cases, the medical registration of the ward was assessed. A total of 13 patients, aged 3-16 years were included. Results. Among the patients, girls represented 61.5% (8), and the females: males ration was (1.6:1). The patients' ages ranged from 3 to 16 years (mean 9.3 ± 4.02 years). All patients younger than 6 years were AQP-ve, in contrast to 15.3% in those older than 6 years. Negative AQP patients equally distributed between males and females. While females predominated in those with AQP positive status (5,71.4%). Weakness of the limbs and sphincteric disturbance were the first two common clinical features in both AQP positive and negative patients. The three most common brain sites insulted were deep white matter (10, 76.9%), periaqueductal area (5, 38.4%), and brainstem (4, 30.7%). All patients showed long spinal lesions, affecting predominantly the cervico-thoracic (61.53%). Conclusion. The demographic characteristics of the present cohort were comparative to that reported in the literature. Transverse myelitis phenotype was the most common and consistent one. Vomiting was more common in AQP +ve patients.

Exploring Brain Activity in Different Mental Cognitive Workloads

Objective: Understanding neural mechanisms underlying cognitive workload is crucial for advancing our knowledge of human cognition and mental processes. In this study, we utilized electroencephalography (EEG) analysis to investigate brain activity associated with varying mental cognitive workloads from a psychological perspective. Method: We employed a publicly accessible EEG dataset consisting of a cohort of 36 healthy volunteers (75% female), aged 18 to 26 years, while the participants were at rest or engaged in an arithmetic task to explore mental cognitive workload. After preprocessing to reduce noise and various artifacts and to obtain a clean signal for every subject, functional connectivity and complexity features were calculated from EEGs through the coherence and permutation entropy algorithms, respectively. Then, repeated measures analysis of variance (ANOVA) was conducted to assess the differences in complexity and connectivity measures across various brain regions between the rest and task states. Results: Brain sites showed significant within-subject effects, and the interaction between states and channels was significant for connectivity values (F = 3.68, P = 0.034). Post hoc comparisons indicated that FP1-F7, FP1-F8 and FP1-Fz connectivity were significantly lower during the task state compared to the rest state (P < 0.05). Moreover, F4-P3, F4-P4, FP1-O1, FP2-O2, F3-O1, F4-O1, F8-O1, C4-O1, F3-O2, F4-O2, F7-O2, F8-O2, Fz-O1, Fz-O2, Cz-O1 and Fz-P4 connectivity were significantly higher during the arithmetic task state (P < 0.05). Furthermore, brain sites showed significant within-subject effects and the interaction between states and channels was significant for entropy values (F = 3.50, P = 0.041). Post hoc comparisons indicated that the permutation entropy was significantly higher in the FP1, T3, T4, P4 and Pz channels during the arithmetic task compared to the rest state (P < 0.05). Conclusion: During arithmetic tasks, the increased connectivity in the frontoparietal and frontooccipital networks and heightened complexity in the prefrontal, temporal and parietal lobes reflect the collaborative engagement of brain areas specialized in numerical processing, attention, working memory, cognitive control, and visual-spatial cognition. These changes in connectivity and complexity facilitate the integration of multiple cognitive processes essential for effective arithmetic problem-solving.

Controlling spatial optical illuminations in optogenetics using an angled optical fiber tip

The advent of optogenetic tools has revolutionized neuroscience research through its spatiotemporally precise activation of specific neurons by illuminating light on opsin-expressing neurons. A long-standing challenge of in vivo optogenetics remains in delivering light to multiple brain sites simultaneously and maintaining high spatial resolution. Optical fiber-based technologies have been proposed to address these challenges. This work presents the fabrication and characterization of an innovative angled optical fiber probe based on a double-sided angled tip (DSAT) structure. A custom griding setup was used for the reproducible fabrication of a smooth DSAT probe. The designed probe enables precise spatial control of light propagation in brain tissue in which DSAT at angled tip 55° achieving a maximum lateral illumination position of ± 420 μm away from the optical axis and a peak irradiance of 478.5 mW/mm2, using a 5 mW of 473 nm laser light. Also, the designed DAST probe was simulated based on ray tracing method and obtained the practical tip angle to evaluate the propagation of light rays emitted from the DSAT at various input optical angles ranging from 0° to 12.5° to predict their irradiance and positions in the modelled tissue. The results indicate the probe generates two elliptical rings each containing two spots with higher optical concentration. Consequently, this device provides four optical spots with irradiance peaks that enable simultaneous illumination of four different locations in the brain tissue. Obtained experiment results are in good agreement with simulation results which can be used for multipoint illumination of brain tissue in optogenetics applications.

Parkinson's disease is characterized by vitamin B6-dependent inflammatory kynurenine pathway dysfunction.

Parkinson's disease (PD) is a complex multisystem disorder clinically characterized by motor, non-motor, and premotor manifestations. Pathologically, PD involves neuronal loss in the substantia nigra, striatal dopamine deficiency, and accumulation of intracellular inclusions containing aggregates of α-synuclein. Recent studies demonstrate that PD is associated with dysregulated metabolic flux through the kynurenine pathway (KP), in which tryptophan is converted to kynurenine (KYN), and KYN is subsequently metabolized to neuroactive compounds quinolinic acid (QA) and kynurenic acid (KA). This multicenter study used highly sensitive liquid chromatography-tandem mass-spectrometry to compare blood and cerebral spinal fluid (CSF) KP metabolites between 158 unimpaired older adults and 177 participants with PD. Results indicate that increased neuroexcitatory QA/KA ratio in both plasma and CSF of PD participants associated with peripheral and cerebral inflammation and vitamin B6 deficiency. Furthermore, increased QA tracked with CSF tau and severity of both motor and non-motor PD clinical dysfunction. Importantly, plasma and CSF kynurenine metabolites classified PD participants with a high degree of accuracy (AUC = 0.897). Finally, analysis of metabolite data revealed subgroups with distinct KP profiles, and these were subsequently found to display distinct PD clinical features. Together, these data further support the hypothesis that the KP serves as a site of brain and periphery crosstalk, integrating B-vitamin status, inflammation and metabolism to ultimately influence PD clinical manifestation.

Abstract P212: Microinjection of the novel angiotensin, alamandine-(1-5) into insular cortex, increase blood pressure

It is well known that the renin-angiotensin system plays a critical role in cardiovascular control and hydro-electrolyte homeostasis. At least in some circumstances Alamandine (Ala) and Angiotensin-(1-7) can have selective actions such as reported in the insular córtex (IC). Hydrolysis of Angiotensin-(1-7) by angiotensin converting enzyme (ACE) can form the heptapeptide Angiotensin-(1-5) and recently our group demonstrated that hydrolysis of Ala by ACE can form Ala-(1-5). In this study we aimed to evaluate the cardiovascular effects produced by microinjection of Ala-(1-5) and Angiotensin-(1-5) into the rostral region of the posterior IC. Urethane (1.4g/kg) anesthetized rats were instrumented for measurement of mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA). Unilateral microinjection of vehicle (0,9% NaCl, 100nL, n=4), Ala (40pmol/100nl, n=7), Ala-(1-5) (400pmol/100nl, n=7) or Angiotensin-(1-5) (400pmol/100nl, n=5) were made into IC (+1.5mm rostral to the bregma). At the baseline, there was no difference between the groups (Vehicle: 85±2 mmHg and 388±5bpm, Ala: 83±9mmHg and 389±10bpm, Ala-(1–5): 91±6mmHg and 386±7bpm or Ang-(1-5): 96±9mmHg and 375±6bpm). Vehicle microinjection was performed as a control for nonspecific effects (ΔMAP:2±1mmHg, ΔHR:4±2bpm, ΔRSNA:3±1%). Ala microinjection into IC, confirmed our previous data showing a long-lasting (18±3min) increase in MAP (Δ=14±2mmHg), and this effect was associated with a significant increase in HR (Δ=32±4bpm) and in RSNA (Δ=36±6%). These responses were elicited immediately after Ala microinjection. When compared with vehicle and, very different from what was observed with Ala, microinjection of Ala-(1–5) evoked a significant increase in blood pressure without altering RSNA or HR (ΔMAP:22±2mmHg, ΔHR:-1±3bpm, ΔRSNA:1±3%). Differently from Ala evoked responses, the effects of Ala-(1–5) had a shorter duration (5.88±1.9min) without delay to beginning the effects. On other hand, microinjection of Angiotensin-(1-5) did not elicited autonomic and cardiovascular effects (ΔMAP:-1±3mmHg, ΔHR:-2±2bpm, ΔRSNA:2±3%). In conclusion, these data showed that the IC is a brain site that has unique effects of Ala (increase in MAP, HR and RSNA) and Ala-(1-5) (increase in MAP only) contrasting with the essentially absent effects of Angiotensin-(1-7) and Angiotensin-(1-5). These findings will contribute to extend our understanding of the brain renin-angiotensin system.

Contributions of neuroimaging in central poststroke pain: a review.

Central neuropathic poststroke pain (CNPSP) affects up to 12% of patients with stroke in general and up to 18% of patients with sensory deficits. This pain syndrome is often incapacitating and refractory to treatment. Brain computed tomography and magnetic resonance imaging (MRI) are widely used methods in the evaluation of CNPSP. The present study aims to review the role of neuroimaging methods in CNPSP. We performed a literature review of the main clinical aspects of CNPSP and the contribution of neuroimaging methods to study its pathophysiology, commonly damaged brain sites, and possible differential diagnoses. Lastly, we briefly mention how neuroimaging can contribute to the non-pharmacological CNPSP treatment. Additionally, we used a series of MRI from our institution to illustrate this review. Imaging has been used to explain CNPSP pathogenesis based on spinothalamic pathway damage and connectome dysfunction. Imaging locations associated with CNPSP include the brainstem (mainly the dorsolateral medulla), thalamus (especially the ventral posterolateral/ventral posteromedial nuclei), cortical areas such as the posterior insula and the parietal operculum, and, more recently, the thalamocortical white matter in the posterior limb of the internal capsule. Imaging also brings the prospect of helping search for new targets for non-pharmacological treatments for CNPSP. Other neuropathic pain causes identified by imaging include syringomyelia, multiple sclerosis, and herniated intervertebral disc. Imaging is a valuable tool in the complimentary evaluation of CNPSP patients in clinical and research scenarios.

Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging.

The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It is produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia and other anomalies. Importantly, it is associated with chronic pathologies (often age-related) that have an inflammatory component. This includes atherosclerosis, diabetes and Alzheimer's disease. Its mode of action in these diseases is not well understood, but it inhibits or regulates multiple major pathways. Klotho has a membrane form and a soluble form (s-Klotho). Cytosolic Klotho is postulated but not well characterized. s-Klotho has endocrine properties that are incompletely elucidated. It binds to the FGF receptor 1c (FGFR1c) that is widely expressed (including endothelial cells). It also attaches to soluble FGF23, and FGF23/Klotho binds to FGFRs. Thus, s-Klotho might be a roaming FGF23 coreceptor, but it has other functions. Notably, Klotho (cell-bound or soluble) counteracts inflammation and appears to mitigate related aging (inflammaging). It inhibits NF-κB and the NLRP3 inflammasome. This inflammasome requires priming by NF-κB and produces active IL-1β, membrane pores and cell death (pyroptosis). In accord, Klotho countered inflammation and cell injury induced by toxins, damage-associated molecular patterns (DAMPs), cytokines, and reactive oxygen species (ROS). s-Klotho also blocks the TGF-β receptor and Wnt ligands, which lessens fibrotic disease. Low Klotho is associated with loss of muscle mass (sarcopenia), as occurs in aging and chronic diseases. s-Klotho counters the inhibitory effects of myostatin and TGF-β on muscle, reduces inflammation, and improves muscle repair following injury. The inhibition of TGF-β and other factors may also be protective in diabetic retinopathy and age-related macular degeneration (AMD). This review examines Klotho functions especially as related to inflammation and potential applications.

Neurological Validation of ASD Diagnostic Criteria Using Frontal Alpha and Theta Asymmetry.

Background/Objectives: Diagnosis of Autism Spectrum Disorder (ASD) relies on the observation of difficulties in social communication and interaction, plus the presence of repetitive and restrictive behaviors. The identification of neurological correlates of these symptoms remains a high priority for clinical research, and has the potential to increase the validity of diagnosis of ASD as well as provide greater understanding of how the autistic brain functions. This study focused on two neurological phenomena that have been previously associated with psychiatric disorders (alpha- and theta-wave asymmetry across the frontal region of the brain), and tested for their association with the major diagnostic criteria for ASD. Methods: A total of 41 male autistic youth underwent assessment with the Autism Diagnostic Observation Schedule (ADOS-2) and 3 min of eyes-closed resting EEG to collect alpha- and theta-wave data from right and left frontal brain sites. Results: Different associations were found for theta versus alpha asymmetry and the ADOS-2 subscales, across different brain regions responsible for a varying range of cognitive functions. In general, theta asymmetry was associated with conversation with others, sharing of enjoyment, and making social overtures, whereas alpha asymmetry was linked with making eye contact, reporting events to others, and engaging in reciprocal social communication. Specific brain regions involved are identified, as well as implications for clinical practice. Conclusions: Specific autism symptoms may be associated with selected brain region activity, providing a neurological basis for diagnosis and treatment.

Acoustically targeted measurement of transgene expression in the brain.

Gene expression is a critical component of brain physiology, but monitoring this expression in the living brain represents a major challenge. Here, we introduce a new paradigm called recovery of markers through insonation (REMIS) for noninvasive measurement of gene expression in the brain with cell type, spatial, and temporal specificity. Our approach relies on engineered protein markers that are produced in neurons but exit into the brain's interstitium. When ultrasound is applied to targeted brain regions, it opens the blood-brain barrier and releases these markers into the bloodstream. Once in blood, the markers can be readily detected using biochemical techniques. REMIS can noninvasively confirm gene delivery and measure endogenous signaling in specific brain sites through a simple insonation and a subsequent blood test. REMIS is reliable and demonstrated consistent improvement in recovery of markers from the brain into the blood. Overall, this work establishes a noninvasive, spatially specific method of monitoring gene delivery and endogenous signaling in the brain.

Palatable solution overconsumption in the Cntnap2-/- murine model of autism: a link with oxytocin.

Dysregulated appetite is common in autism spectrum disorder (ASD) and it includes excessive interest in tasty foods. Overconsumption of palatable fluids has been found in the valproic acid-induced ASD rat. Though ASD has a strong genetic component, the link between ASD-related genes and appetite for palatable foods remains elusive. We focused on the CNTNAP2 gene whose deletion in mice recapitulates human ASD symptoms. We investigated whether Cntnap2-/- male mice consume greater amounts of palatable 10% sucrose, 0.1% saccharin, and 4.1% intralipid solutions offered in episodic meals either in a no-choice paradigm or a two-bottle choice test. We examined how sucrose intake affects c-Fos immunoreactivity in feeding-related brain areas. Finally, we determined doses at which intraperitoneal oxytocin decreases sucrose intake in mutants. In the single-bottle tests, Cntnap2-/- mice drank more sucrose, saccharin, and intralipid compared to WTs. Given a choice between two tastants, Cntnap2-/- mice had a higher preference for sucrose than intralipid. While the standard 1 mg/kg oxytocin dose reduced sucrose intake in WTs, a low oxytocin dose (0.1 mg/kg) decreased sucrose intake in Cntnap2-/- mice. Sucrose intake induced a more robust c-Fos response in wild-type (WT) than Cntnap2-/- mice in the reward and hypothalamic sites and it increased the percentage of Fos-immunoreactivity oxytocin neurons in WTs, but not in mutants. We conclude that Cntnap2-/- mice overconsume palatable solutions, especially sucrose, beyond levels seen in WTs. This excessive consumption is associated with blunted c-Fos immunoreactivity in feeding-related brain sites, and it can be reversed by low-dose oxytocin.

Dopaminergic Neurons in Zona Incerta Drives Appetitive Self-Grooming.

Dopaminergic (DA) neurons are known to play a key role in controlling behaviors. While DA neurons in other brain regions are extensively characterized, those in zona incerta (ZITH or A13) receive much less attention and their function remains to be defined. Here it is shown that optogenetic stimulation of these neurons elicited intensive self-grooming behaviors and promoted place preference, which can be enhanced by training but cannot be converted into contextual memory. Interestingly, the same stimulation increased DA release to periaqueductal grey (PAG) neurons and local PAG antagonism of DA action reduced the elicited self-grooming. In addition, A13 neurons increased their activity in response to various external stimuli and during natural self-grooming episodes. Finally, monosynaptic retrograde tracing showed that the paraventricular hypothalamus represents one of the major upstream brain regions to A13 neurons. Taken together, these results reveal that A13 neurons are one of the brain sites that promote appetitive self-grooming involving DA release to the PAG.

Proton spot dose estimation based on positron activity distributions with neural network.

Positron emission tomography (PET) has been investigated for its ability to reconstruct proton-induced positron activity distributions in proton therapy. This technique holds potential for range verification in clinical practice. Recently, deep learning-based dose estimation from positron activity distributions shows promise for in vivo proton dose monitoring and guided proton therapy. This study evaluates the effectiveness of three classical neural network models, recurrent neural network (RNN), U-Net, and Transformer, for proton dose estimating. It also investigates the characteristics of these models, providing valuable insights for selecting the appropriate model in clinical practice. Proton dose calculations for spot beams were simulated using Geant4. Computed tomography (CT) images from four head cases were utilized, with three for training neural networks and the remaining one for testing. The neural networks were trained with one-dimensional (1D) positron activity distributions as inputs and generated 1D dose distributions as outputs. The impact of the number of training samples on the networks was examined, and their dose prediction performance in both homogeneous brain and heterogeneous nasopharynx sites was evaluated. Additionally, the effect of positron activity distribution uncertainty on dose prediction performance was investigated. To quantitatively evaluate the models, mean relative error (MRE) and absolute range error (ARE) were used as evaluation metrics. The U-Net exhibited a notable advantage in range verification with a smaller number of training samples, achieving approximately 75% of AREs below 0.5mm using only 500 training samples. The networks performed better in the homogeneous brain site compared to the heterogeneous nasopharyngeal site. In the homogeneous brain site, all networks exhibited small AREs, with approximately 90% of the AREs below 0.5mm. The Transformer exhibited the best overall dose distribution prediction, with approximately 92% of MREs below 3%. In the heterogeneous nasopharyngeal site, all networks demonstrated acceptable AREs, with approximately 88% of AREs below 3mm. The Transformer maintained the best overall dose distribution prediction, with approximately 85% of MREs below 5%. The performance of all three networks in dose prediction declined as the uncertainty of positron activity distribution increased, and the Transformer consistently outperformed the other networks in all cases. Both the U-Net and the Transformer have certain advantages in the proton dose estimation task. The U-Net proves well suited for range verification with a small training sample size, while the Transformer outperforms others at dose-guided proton therapy.

An atlas of brain-bone sympathetic neural circuits in mice.

There is clear evidence that the sympathetic nervous system (SNS) mediates bone metabolism. Histological studies show abundant SNS innervation of the periosteum and bone marrow-these nerves consist of noradrenergic fibers that immunostain for tyrosine hydroxylase, dopamine beta-hydroxylase, or neuropeptide Y. Nonetheless, the brain sites that send efferent SNS outflow to the bone have not yet been characterized. Using pseudorabies (PRV) viral transneuronal tracing, we report, for the first time, the identification of central SNS outflow sites that innervate bone. We find that the central SNS outflow to bone originates from 87 brain nuclei, sub-nuclei, and regions of six brain divisions, namely the midbrain and pons, hypothalamus, hindbrain medulla, forebrain, cerebral cortex, and thalamus. We also find that certain sites, such as the raphe magnus (RMg) of the medulla and periaqueductal gray (PAG) of the midbrain, display greater degrees of PRV152 infection, suggesting that there is considerable site-specific variation in the levels of central SNS outflow to the bone. This comprehensive compendium illustrating the central coding and control of SNS efferent signals to bone should allow for a greater understanding of the neural regulation of bone metabolism, and importantly and of clinical relevance, mechanisms for central bone pain.

Using camera-guided electrode microdrive navigation for precise 3D targeting of macaque brain sites.

Spatial accuracy in electrophysiological investigations is paramount, as precise localization and reliable access to specific brain regions help the advancement of our understanding of the brain's complex neural activity. Here, we introduce a novel, multi camera-based, frameless neuronavigation technique for precise, 3-dimensional electrode positioning in awake monkeys. The investigation of neural functions in awake primates often requires stable access to the brain with thin and delicate recording electrodes. This is usually realized by implanting a chronic recording chamber onto the skull of the animal that allows direct access to the dura. Most recording and positioning techniques utilize this implanted recording chamber as a holder of the microdrive or to hold a grid. This in turn reduces the degrees of freedom in positioning. To solve this problem, we require innovative, flexible, but precise tools for neuronal recordings. We instead mount the electrode microdrive above the animal on an arch, equipped with a series of translational and rotational micromanipulators, allowing movements in all axes. Here, the positioning is controlled by infrared cameras tracking the location of the microdrive and the monkey, allowing precise and flexible trajectories. To verify the accuracy of this technique, we created iron deposits in the tissue that could be detected by MRI. Our results demonstrate a remarkable precision with the confirmed physical location of these deposits averaging less than 0.5 mm from their planned position. Pilot electrophysiological recordings additionally demonstrate the accuracy and flexibility of this method. Our innovative approach could significantly enhance the accuracy and flexibility of neural recordings, potentially catalyzing further advancements in neuroscientific research.

No Consistent Antidepressant Effects of Deep Brain Stimulation of the Bed Nucleus of the Stria Terminalis.

Applying deep brain stimulation (DBS) to several brain regions has been investigated in attempts to treat highly treatment-resistant depression, with variable results. Our initial pilot data suggested that the bed nucleus of the stria terminalis (BNST) could be a promising therapeutic target. The aim of this study was to gather blinded data exploring the efficacy of applying DBS to the BNST in patients with highly refractory depression. Eight patients with chronic severe treatment-resistant depression underwent DBS to the BNST. A randomised, double-blind crossover study design with fixed stimulation parameters was followed and followed by a period of open-label stimulation. During the double-blind crossover phase, no consistent antidepressant effects were seen with any of the four stimulation parameters applied, and no patients achieved response or remission criteria during the blinded crossover phase or during a subsequent period of three months of blinded stimulation. Stimulation-related side effects, especially agitation, were reported by a number of patients and were reversible with adjustment of the stimulation parameters. The results of this study do not support the application of DBS to the BNST in patients with highly resistant depression or ongoing research utilising stimulation at this brain site. The blocked randomised study design utilising fixed stimulation parameters was poorly tolerated by the participants and does not appear suitable for assessing the efficacy of DBS at this location.

Congenital Disseminated Pyogenic Granuloma: A Case With Numerous Mucocutaneous and Visceral Lesions

Abstract Congenital disseminated pyogenic granuloma (CDPG) is characterized by eruptive disseminated or localized lesions, which may arise spontaneously or secondary to predisposing factors. Even rarer is the occurrence of CDPG with numerous lesions affecting variable organs, which develop during the fetal period. This report describes the case of a 32-week-old fetus presenting with severe hydrocephalus and vascular intracranial and right lung masses on magnetic resonance imaging. Preterm labor occurred at the 32nd week due to preterm premature rupture of membranes, and the newborn died due to cardiac dysfunction within 2 hours postpartum. The subsequent autopsy revealed multiple violaceous to dark red papules, nodules, pedunculated and un-pedunculated mucocutaneous masses, as well as two brain lesions, a lung lesion, a thoracic wall intramuscular mass, and a pyloric mass. Microscopic examination and immunohistochemical evaluation for glucose transporter 1 (GLUT1) confirmed the diagnosis of CDPG. CDPG represents a rare condition with an elusive etiology and limited reports in the literature. Differential diagnosis from multifocal infantile hemangioma, based on GLUT1 negativity of CDPG, is imperative due to differing clinical course and treatment modalities. This report underscores a severe case of CDPG characterized by preterm labor and demise shortly after delivery, notable for its extensive involvement across multiple organs, including the brain, lung, intestine, musculoskeletal system, mucosal, and numerous cutaneous sites.

Abstract PO5-04-07: Characteristics of patients with metastatic HR+/HER2+ breast cancer in a Kaiser Permanente observational multi-site cohort

Abstract Background: Approximately 10% of female breast cancer and 13% of male breast cancer tumors express hormone-receptor positive/human epidermal growth factor receptor 2 positive (HR+/HER2+) molecular subtype. Since HER2+ targeted agents were made available nearly 10 years ago, there has been limited innovation in treatment of patients with HR+/HER2+ metastatic breast cancer (mBC) to improve clinical outcomes. This study aims to characterize the HR+/HER2+ mBC patient population by describing demographic and clinical characteristics and treatment patterns in a racially diverse, insured, population-based cohort. This study includes data from 4 regions of the Kaiser Permanente (KP) health system – Northwest, Northern California, Southern California, and Colorado. Methods: Eligible study patients were adults age > 18 years with HR+/HER2+ invasive breast cancer who were either initially diagnosed with Stage IV disease or were diagnosed at an earlier stage and experienced recurrence with distant metastasis between 6/8/2012 and 12/31/2019 with data collected through 12/31/2021. Select information was extracted from electronic health records (EHR) of eligible patients and combined with manually abstracted data to create the analytic dataset. Breast cancer recurrence was identified by tumor registrars or obtained through a breast cancer recurrence detection algorithm and verified by chart review. Chart reviewers collected data on metastatic sites, disease progression, reasons for stopping systemic therapy medications, and verified use of medications. Preliminary results: During the study period, we identified 492 subjects with HR+/HER2+ mBC. Seven were men and 485 were women. 221 (45%) had de novo Stage IV breast cancer at diagnosis and 271 (55%) had recurrent mBC. Median age at metastatic diagnosis was 59 years for de novo cases and 62 years for recurrent cases. The cohort was racially and ethnically diverse, with 13% Asian subjects (11% de novo, 15% recurrent), 12% Black subjects (10% de novo, 14% recurrent), and 66% White subjects (71% de novo, 63% recurrent). 18% of cases were recorded as Hispanic (19% de novo, 18% recurrent) in the EHR. Major sites of metastases, including bone, liver, lung, brain, and distant lymph nodes, were similar in both the de novo and recurrent groups. Among women (see table below), 28 (6%) received no systemic treatment for their metastatic disease (9% de novo, 3% recurrent). Among women with systemic treatment, 80% received anti-HER2 agents (90% de novo, 73% recurrent). Of women with recurrent mBC who received systemic therapy, 56% had received anti-HER2 therapy in the adjuvant setting. Conclusion: This population-based study of a racially diverse cohort examined EHR-derived data to describe current demographics and treatment patterns for HR+/HER2+ mBC in an insured patient population. Over 90% of women received systemic therapy, and the majority of those received anti-HER2 therapy per current treatment guidelines. Future analyses will focus on clinical outcomes in this cohort with a goal of informing how prognosis can be improved. Table. Citation Format: Sheila Weinmann, Debra Ritzwoller, Marilyn Kwan, Reina Haque, Stella Stergiopoulos, Ashley Cha, Eric Gauthier, Daniel Sapp, John Dickerson, Kathryn Richert-Boe, Weiming Hu, Nikki Carroll, Lie Hong Chen, Valerie Lee, Ravi Zalavadia, Maureen O'Keeffe-Rosetti. Characteristics of patients with metastatic HR+/HER2+ breast cancer in a Kaiser Permanente observational multi-site cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-04-07.