Diagnosis of lung cancer following emergency admission: Examining care pathways, clinical outcomes, and advanced NSCLC treatment in an Italian cancer Center.

Background: Lung cancer patients diagnosed following emergency admission often present with advanced disease and poor performance status, leading to suboptimal treatment options and outcomes. This study aimed to investigate the clinical and molecular characteristics, treatment initiation, and survival outcomes of these patients. Methods: We retrospectively analyzed data from 124 patients diagnosed with lung cancer following emergency admission at a single institution. Clinical characteristics, results of molecular analyses for therapeutic purpose, systemic treatment initiation, and survival outcomes were assessed. Correlations between patients' characteristics and treatment initiation were analyzed. Results: Median age at admission was 73 years, and 79.0 % had at least one comorbidity. Most patients (87.1 %) were admitted due to cancer-related symptoms. Molecular analyses were performed in 89.5 % of advanced non-small cell lung cancer (NSCLC) cases. In this subgroup, two-thirds (66.2 %) received first-line therapy. Median overall survival (OS) was 3.9 months for the entire cohort, and 2.9 months for patients with metastatic lung cancer. Among patients with advanced NSCLC, OS was significantly longer for those with actionable oncogenic drivers and those who received first-line therapy. Improvement of performance status during hospitalization resulted in increased probability of receiving first-line systemic therapy. Discussion: Patients diagnosed with lung cancer following emergency admission demonstrated poor survival outcomes. Treatment initiation, particularly for patients with actionable oncogenic drivers, was associated with longer OS. These findings highlight the need for proactive medical approaches, including improving access to molecular diagnostics and targeted treatments, to optimize outcomes in this patient population.

Advancing Translational Research Using NIMH Research Domain Criteria and Computational Methods.

The NIMH Research Domain Criteria (RDoC) can aid in the translation of integrative neuroscience. We argue that the RDoC framework, with its emphasis on integration across units of analysis, leveraged with computational approaches, can organize intermediary treatment targets and clinical outcomes, augmenting the translational stream.

Explainable Artificial Intelligence for Neuroscience: Behavioral Neurostimulation.

The use of Artificial Intelligence and machine learning in basic research and clinical neuroscience is increasing. AI methods enable the interpretation of large multimodal datasets that can provide unbiased insights into the fundamental principles of brain function, potentially paving the way for earlier and more accurate detection of brain disorders and better informed intervention protocols. Despite AI's ability to create accurate predictions and classifications, in most cases it lacks the ability to provide a mechanistic understanding of how inputs and outputs relate to each other. Explainable Artificial Intelligence (XAI) is a new set of techniques that attempts to provide such an understanding, here we report on some of these practical approaches. We discuss the potential value of XAI to the field of neurostimulation for both basic scientific inquiry and therapeutic purposes, as well as, outstanding questions and obstacles to the success of the XAI approach.

Removal of area CA3 from hippocampal slices induces postsynaptic plasticity at Schaffer collateral synapses that normalizes CA1 pyramidal cell discharge.

Neural networks that undergo acute insults display remarkable reorganization. This injury related plasticity is thought to permit recovery of function in the face of damage that cannot be reversed. Previously, an increase in the transmission strength at Schaffer collateral to CA1 pyramidal cell synapses was observed after long-term activity reduction in organotypic hippocampal slices. Here we report that, following acute preparation of adult rat hippocampal slices and surgical removal of area CA3, input to area CA1 was reduced and Schaffer collateral synapses underwent functional strengthening. This increase in synaptic strength was limited to Schaffer collateral inputs (no alteration to temporoammonic synapses) and acted to normalize postsynaptic discharge, supporting a homeostatic or compensatory response. Short-term plasticity was not altered, but an increase in immunohistochemical labeling of GluA1 subunits was observed in the stratum radiatum (but not stratum moleculare), suggesting increased numbers of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and a postsynaptic locus of expression. Combined, these data support the idea that, in response to the reduction in presynaptic activity caused by removal of area CA3, Schaffer collateral synapses undergo a relatively rapid increase in functional efficacy likely supported by insertion of more AMPARs, which maintains postsynaptic excitability in CA1 pyramidal neurons. This novel fast compensatory plasticity exhibits properties that would allow it to maintain optimal network activity levels in the hippocampus, a brain structure lauded for its ongoing experience-dependent malleability.

Post-Inhibitory Rebound Spikes in Rat Medial Entorhinal Layer II/III Principal Cells: In Vivo, In Vitro, and Computational Modeling Characterization.

Medial entorhinal cortex Layer-II stellate cells (mEC-LII-SCs) primarily interact via inhibitory interneurons. This suggests the presence of alternative mechanisms other than excitatory synaptic inputs for triggering action potentials (APs) in stellate cells during spatial navigation. Our intracellular recordings show that the hyperpolarization-activated cation current (Ih) allows post-inhibitory-rebound spikes (PIRS) in mEC-LII-SCs. In vivo, strong inhibitory-post-synaptic potentials immediately preceded most APs shortening their delay and enhancing excitability. In vitro experiments showed that inhibition initiated spikes more effectively than excitation and that more dorsal mEC-LII-SCs produced faster and more synchronous spikes. In contrast, PIRS in Layer-II/III pyramidal cells were harder to evoke, voltage-independent, and slower in dorsal mEC. In computational simulations, mEC-LII-SCs morphology and Ih homeostatically regulated the dorso-ventral differences in PIRS timing and most dendrites generated PIRS with a narrow range of stimulus amplitudes. These results suggest inhibitory inputs could mediate the emergence of grid cell firing in a neuronal network.

Distinct Functional Groups Emerge from the Intrinsic Properties of Molecularly Identified Entorhinal Interneurons and Principal Cells.

Inhibitory interneurons are an important source of synaptic inputs that may contribute to network mechanisms for coding of spatial location by entorhinal cortex (EC). The intrinsic properties of inhibitory interneurons in the EC of the mouse are mostly undescribed. Intrinsic properties were recorded from known cell types, such as, stellate and pyramidal cells and 6 classes of molecularly identified interneurons (regulator of calcineurin 2, somatostatin, serotonin receptor 3a, neuropeptide Y neurogliaform (NGF), neuropeptide Y non-NGF, and vasoactive intestinal protein) in acute brain slices. We report a broad physiological diversity between and within cell classes. We also found differences in the ability to produce postinhibitory rebound spikes and in the frequency and amplitude of incoming EPSPs. To understand the source of this intrinsic variability we applied hierarchical cluster analysis to functionally classify neurons. These analyses revealed physiologically derived cell types in EC that mostly corresponded to the lines identified by biomarkers with a few unexpected and important differences. Finally, we reduced the complex multidimensional space of intrinsic properties to the most salient five that predicted the cellular biomolecular identity with 81.4% accuracy. These results provide a framework for the classification of functional subtypes of cortical neurons by their intrinsic membrane properties.

Rebound spiking in layer II medial entorhinal cortex stellate cells: Possible mechanism of grid cell function.

Rebound spiking properties of medial entorhinal cortex (mEC) stellate cells induced by inhibition may underlie their functional properties in awake behaving rats, including the temporal phase separation of distinct grid cells and differences in grid cell firing properties. We investigated rebound spiking properties using whole cell patch recording in entorhinal slices, holding cells near spiking threshold and delivering sinusoidal inputs, superimposed with realistic inhibitory synaptic inputs to test the capacity of cells to selectively respond to specific phases of inhibitory input. Stellate cells showed a specific phase range of hyperpolarizing inputs that elicited spiking, but non-stellate cells did not show phase specificity. In both cell types, the phase range of spiking output occurred between the peak and subsequent descending zero crossing of the sinusoid. The phases of inhibitory inputs that induced spikes shifted earlier as the baseline sinusoid frequency increased, while spiking output shifted to later phases. Increases in magnitude of the inhibitory inputs shifted the spiking output to earlier phases. Pharmacological blockade of h-current abolished the phase selectivity of hyperpolarizing inputs eliciting spikes. A network computational model using cells possessing similar rebound properties as found in vitro produces spatially periodic firing properties resembling grid cell firing when a simulated animal moves along a linear track. These results suggest that the ability of mEC stellate cells to fire rebound spikes in response to a specific range of phases of inhibition could support complex attractor dynamics that provide completion and separation to maintain spiking activity of specific grid cell populations.

Distinct and synergistic feedforward inhibition of pyramidal cells by basket and bistratified interneurons.

Feedforward inhibition (FFI) enables pyramidal cells in area CA1 of the hippocampus (CA1PCs) to remain easily excitable while faithfully representing a broad range of excitatory inputs without quickly saturating. Despite the cortical ubiquity of FFI, its specific function is not completely understood. FFI in CA1PCs is mediated by two physiologically and morphologically distinct GABAergic interneurons: fast-spiking, perisomatic-targeting basket cells and regular-spiking, dendritic-targeting bistratified cells. These two FFI pathways might create layer-specific computational sub-domains within the same CA1PC, but teasing apart their specific contributions remains experimentally challenging. We implemented a biophysically realistic model of CA1PCs using 40 digitally reconstructed morphologies and constraining synaptic numbers, locations, amplitude, and kinetics with available experimental data. First, we validated the model by reproducing the known combined basket and bistratified FFI of CA1PCs at the population level. We then analyzed how the two interneuron types independently affected the CA1PC spike probability and timing as a function of inhibitory strength. Separate FFI by basket and bistratified respectively modulated CA1PC threshold and gain. Concomitant FFI by both interneuron types synergistically extended the dynamic range of CA1PCs by buffering their spiking response to excitatory stimulation. These results suggest testable hypotheses on the precise effects of GABAergic diversity on cortical computation.

Functional impact of dendritic branch-point morphology.

Cortical pyramidal cells store multiple features of complex synaptic input in individual dendritic branches and independently regulate the coupling between dendritic and somatic spikes. Branch points in apical trees exhibit wide ranges of sizes and shapes, and the large diameter ratio between trunk and oblique dendrites exacerbates impedance mismatch. The morphological diversity of dendritic bifurcations could thus locally tune neuronal excitability and signal integration. However, these aspects have never been investigated. Here, we first quantified the morphological variability of branch points from two-photon images of rat CA1 pyramidal neurons. We then investigated the geometrical features affecting spike initiation, propagation, and timing with a computational model validated by glutamate uncaging experiments. The results suggest that even subtle membrane readjustments at branch points could drastically alter the ability of synaptic input to generate, propagate, and time action potentials.

Passive and active shaping of unitary responses from associational/commissural and perforant path synapses in hippocampal CA3 pyramidal cells.

Although associational/commissural (A/C) and perforant path (PP) inputs to CA3b pyramidal cells play a central role in hippocampal mnemonic functions, the active and passive processes that shape A/C and PP AMPA and NMDA receptor-mediated unitary EPSP/EPSC (AMPA and NMDA uEPSP/uEPSC) have not been fully characterized yet. Here we find no differences in somatic amplitude between A/C and PP for either AMPA or NMDA uEPSPs. However, larger AMPA uEPSCs were evoked from proximal than from distal A/C or PP. Given the space-clamp constraints in CA3 pyramidal cells, these voltage clamp data suggest that the location-independence of A/C and PP AMPA uEPSP amplitudes is achieved in part through the activation of voltage dependent conductances at or near the soma. Moreover, similarity in uEPSC amplitudes for distal A/C and PP points to the additional participation of unclamped active conductances. Indeed, the pharmacological blockade of voltage-dependent conductances eliminates the location-independence of these inputs. In contrast, the location-independence of A/C and PP NMDA uEPSP/uEPSC amplitudes is maintained across all conditions indicating that propagation is not affected by active membrane processes. The location-independence for A/C uEPSP amplitudes may be relevant in the recruitment of CA3 pyramidal cells by other CA3 pyramidal cells. These data also suggest that PP excitation represents a significant input to CA3 pyramidal cells. Implication of the passive data on local synaptic properties is further investigated in the companion paper with a detailed computational model.

Feed-forward inhibition as a buffer of the neuronal input-output relation.

Neuronal processing depends on the input-output (I/O) relation between the frequency of synaptic stimulation and the resultant axonal firing rate. The all-or-none properties of spike generation and active membrane mechanisms can make the neuronal I/O relation very steep. The ensuing nearly bimodal behavior may severely limit information coding, as minimal input fluctuations within the expected natural variability could cause neuronal output to jump between quiescence and maximum firing rate. Here, using biophysically and anatomically realistic computational models of individual neurons, we demonstrate that feed-forward inhibition, a ubiquitous mechanism in which inhibitory interneurons and their target cells are activated by the same excitatory input, can change a steeply sigmoid I/O curve into a double-sigmoid typical of buffer systems. The addition of an intermediate plateau stabilizes the spiking response over a broad dynamic range of input frequency, ensuring robust integration of noisy synaptic signals. Both the buffered firing rate and its input firing range can be independently and extensively modulated by biologically plausible changes in the weight and number of excitatory synapses on the feed-forward interneuron. By providing a soft switch between essentially digital and analog rate-code, this continuous control of the circuit I/O could dramatically increase the computational power of neuronal integration.

Selective white matter involvement in a patient with late onset Krabbe disease: MR, MR spectroscopy, and diffusion tensor study.

The most frequent type of Krabbe disease has an infantile onset. Unusual slowly progressive adult forms have also been described. We described a different involvement of white matter tracts where magnetic resonance signal alterations were evident in a case of a patient affected by late-onset form of disease.

Computational models of neuronal biophysics and the characterization of potential neuropharmacological targets.

The identification and characterization of potential pharmacological targets in neurology and psychiatry is a fundamental problem at the intersection between medicinal chemistry and the neurosciences. Exciting new techniques in proteomics and genomics have fostered rapid progress, opening numerous questions as to the functional consequences of ligand binding at the systems level. Psycho- and neuro-active drugs typically work in nerve cells by affecting one or more aspects of electrophysiological activity. Thus, an integrated understanding of neuropharmacological agents requires bridging the gap between their molecular mechanisms and the biophysical determinants of neuronal function. Computational neuroscience and bioinformatics can play a major role in this functional connection. Robust quantitative models exist describing all major active membrane properties under endogenous and exogenous chemical control. These include voltage-dependent ionic channels (sodium, potassium, calcium, etc.), synaptic receptor channels (e.g. glutamatergic, GABAergic, cholinergic), and G protein coupled signaling pathways (protein kinases, phosphatases, and other enzymatic cascades). This brief review of neuromolecular medicine from the computational perspective provides compelling examples of how simulations can elucidate, explain, and predict the effect of chemical agonists, antagonists, and modulators in the nervous system.

Fiber density index, fractional anisotropy, adc and clinical motor findings in the white matter of patients with glioblastoma.

Whether fractional anisotropy (FA), apparent diffusion coefficient (ADC), and fiber density index (FDi) values differ in the white matter close to glioblastomas of both symptomatic and asymptomatic patients was investigated. Twenty patients with glioblastomas underwent magnetic resonance imaging study. The FDi, FA and ADC values were calculated in areas of white matter in close proximity to the tumor (perWM) and encompassing fibers of cortico-spinal tract and in the contralateral normal-appearing white matter (nWM). The clinical compromise of the cortico-spinal tract was graded using Brunnstrom's criteria. FA and FDi were significantly decreased and ADC increased in perWM compared with the contralateral. Mean FDi, FA, and ADC values comparing perWM and nWM in symptomatic patients showed similar differences. Comparing the perWM of symptomatic and asymptomatic patients, mean FDi and ADC values were lower in symptomatic patients than in asymptomatic ones. A positive correlation was found between the clinical score (CS) and, separately, FDi, FA and ADC per WM values. In a multiple stepwise regression among the same factors, only the ADC of perWM values showed a positive correlation with the CS. An increased ADC plays a major role in reducing the number of fibers (reduced FDi) in symptomatic patients.

Prognostic relevance of the postoperative evolution of intramedullary spinal cord changes in signal intensity on magnetic resonance imaging after anterior decompression for cervical spondylotic myelopathy.

OBJECT: Areas of intramedullary signal intensity changes (hypointensity on T1-weighted magnetic resonance [MR] images and hyperintensity on T2-weighted MR images) in patients with cervical spondylotic myelopathy (CSM) have been described by several investigators. The role of postoperative evolution of these alterations is still not well known. METHODS: A total of 47 patients underwent MR imaging before and at the end of the surgical procedure (intraoperative MR imaging [iMRI]) for cervical spine decompression and fusion using an anterior approach. Imaging was performed with a 1.5-tesla scanner integrated with the operative room (BrainSuite). Patients were followed clinically and evaluated using the Japanese Orthopaedic Association (JOA) and Nurick scales and also underwent MR imaging 3 and 6 months after surgery. RESULTS: Preoperative MR imaging showed an alteration (from the normal) of the intramedullary signal in 37 (78.7%) of 47 cases. In 23 cases, signal changes were altered on both T1- and T2-weighted images, and in 14 cases only on T2-weighted images. In 12 (52.2%) of the 23 cases, regression of hyperintensity on T2-weighted imaging was observed postoperatively. In 4 (17.4%) of these 23 cases, regression of hyperintensity was observed during the iMRI at the end of surgery. Residual compression on postoperative iMRI was not detected in any patients. A nonsignificant correlation was observed between postoperative expansion of the transverse diameter of the spinal cord at the level of maximal compression and the postoperative JOA score and Nurick grade. A statistically significant correlation was observed between the surgical result and the length of a patient's clinical history. A significant correlation was also observed according to the preoperative presence of intramedullary signal alteration. The best results were found in patients without spinal cord changes of signal, acceptable results were observed in the presence of changes on T2-weighted imaging only, and the worst results were observed in patients with spinal cord signal changes on both Tl- and T2-weighted imaging. Finally, a statistically significant correlation was observed between patients with postoperative spinal cord signal change regression and better outcomes. CONCLUSIONS: Intramedullary spinal cord changes in signal intensity in patients with CSM can be reversible (hyperintensity on T2-weighted imaging) or nonreversible (hypointensity on T1-weighted imaging). The regression of areas of hyperintensity on T2-weighted imaging is associated with a better prognosis, whereas the T1-weighted hypointensity is an expression of irreversible damage and, therefore, the worst prognosis. The preliminary experience with this patient series appears to exclude a relationship between the time of signal intensity recovery and outcome of CSM.

Signal propagation in oblique dendrites of CA1 pyramidal cells.

The electrophysiological properties of the oblique branches of CA1 pyramidal neurons are largely unknown and very difficult to investigate experimentally. These relatively thin dendrites make up the majority of the apical tree surface area and constitute the main target of Schaffer collateral axons from CA3. Their electrogenic properties might have an important role in defining the computational functions of CA1 neurons. It is thus important to determine if and to what extent the back- and forward propagation of action potentials (AP) in these dendrites could be modulated by local properties such as morphology or active conductances. In the first detailed study of signal propagation in the full extent of CA1 oblique dendrites, we used 27 reconstructed three-dimensional morphologies and different distributions of the A-type K(+) conductance (K(A)), to investigate their electrophysiological properties by computational modeling. We found that the local K(A) distribution had a major role in modulating action potential back propagation, whereas the forward propagation of dendritic spikes originating in the obliques was mainly affected by local morphological properties. In both cases, signal processing in any given oblique was effectively independent of the rest of the neuron and, by and large, of the distance from the soma. Moreover, the density of K(A) in oblique dendrites affected spike conduction in the main shaft. Thus the anatomical variability of CA1 pyramidal cells and their local distribution of voltage-gated channels may suit a powerful functional compartmentalization of the apical tree.

Role of contrast-enhanced MR venography in the preoperative evaluation of parasagittal meningiomas.

Parasagittal meningiomas (PSM) may pose a difficult surgical challenge since venous patency and collateral anastomoses have to be clearly defined for correct surgical planning. The aim of this study was to assess the diagnostic value of contrast-enhanced (CE) magnetic resonance venography (MRV) in the preoperative evaluation of venous infiltration and collateral venous anastomoses in patients with PSM. CE-MRV was compared with phase-contrast (PC) magnetic resonance (MR) angiography, conventional angiography (when available), and surgery as a reference. Twenty-three patients undergoing surgery for meningiomas located adjacent to the superior sagittal sinus were prospectively evaluated. All the patients underwent both conventional MR examination and MRV. This was performed by means of PC and CE techniques. Both sets of angiograms (CE and PC) were evaluated by two expert neuroradiologists to assess (1) patency of the sinus (patent/occluded), (2) the extent of occlusion (in centimeters), and (3) the number of collateral anastomoses close to the insertion of the meningioma. Eight patients underwent digital subtraction angiography (DSA). All patients were operated on, and intraoperative findings were taken as the gold standard to evaluate the diagnostic value of MRA techniques. PC-MRV showed a flow void inside the sinus compatible with its occlusion in 15 cases, whereas CE-MRV showed the sinus to be occluded in five cases. CE-MRV data were confirmed by surgery, showing five patients to have an occlusion of the superior sagittal sinus. The PC-MRV sensitivity was thus 100% with a specificity of 50%. In those cases in which both MRV techniques documented occlusion of the sinus, the extent of occlusion was overestimated by PC compared with CE and surgery. CE-MRV depicted 87% of collateral venous anastomoses close to the meningioma as subsequently confirmed by surgery, while PC showed 58%. In the preoperative planning for patients with meningiomas located close to a venous sinus, CE-MRV provides additional and more reliable information concerning venous infiltration and the presence of collateral anastomoses compared with PC sequences.