Stress exposure is a key risk factor for the developmentof depressive-like conditions. However, despite the higher incidence of Major Depressive Disorder in the female population, classical stress-based experimental paradigms have primarily focused on males. In the present study, we used the well-established chronic mild stress (CMS) paradigm to investigate the development of anhedonia, a cardinal symptom of affective disorders, in the female animals and we also studied the potential effect of the antipsychotic drug lurasidone in normalizing the alterations brought about by stress exposure. We found that three weeks of CMS exposure produced a significant reduction of sucrose intake in 50% of the animals (vulnerable, CMS-V), whereas the others were resilient (CMS-R). The development of an anhedonic phenotype in CMS-V was associated with a significant elevation of different immune markers, such as Complement C3 and C4, and inflammatory cytokines, including INFß and Il1ß in dorsal and ventral hippocampus. Interestingly, sub-chronic treatment with the antipsychotic drug lurasidone was able to revert the anhedonic phenotype while normalizing most of the molecular alterations found in rats vulnerable to CMS exposure. This study extends the ability of lurasidone to normalize the anhedonic phenotype in CMS rats also to females. Moreover, we provide novel evidence on lurasidone's potential effectiveness in treating mental disorders characterized by immune-inflammatory dysfunction.

Anhedonia, a transdiagnostic symptom prevalent in depressive and psychotic disorders, poses a significant challenge for pharmacological intervention due to its association with impaired motivation. Understanding how psychotropic drugs can modulate this pathological domain and elucidating the molecular mechanisms underlying such effects are crucial endeavors in psychiatric research. In this study, we aimed to investigate the pro-motivational properties of lurasidone in a rat (Sprague Dawley males) model of anhedonia and to unravel the interplay between lurasidone and the brain regions critical for reward processing. Exposure to unpredictable chronic stress (UCS) led to a marked reduction in motivation, a deficit that was restored by lurasidone treatment at 3 mg/kg, but not at 10 mg/kg. Interestingly, the stress-induced decrease in reactivity to negative stimuli was reversed by both doses of lurasidone. At the molecular level, stressed animals exhibited reduced expression of neuroplastic markers, that was increased following lurasidone administration. Furthermore, UCS exposure impaired the activation of the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) in response to hedonic stimuli, an effect amended by lurasidone treatment. Additionally, lurasidone restored the impaired phosphorylation of DARPP-32, a key regulator of dopamine signaling, in mPFC and NAc of UCS rats exposed to a hedonic stimulus.These findings underscore the potential of lurasidone in improving various psychopathological domains, like impaired motivation and emotional reactivity, core elements contributing to the disability associated with mental disorders. These effects highlight the therapeutic potential of lurasidone in addressing the intricate behavioral and neurochemical alterations associated with anhedonia and related mood disorders.

Introduction: The cerebellum harbors a variety of different functions, ranging from motor to cognitive and linguistic skills. This complex functional landscape is founded on an intricate and specific architecture of intracerebellar white matter fibers surrounding the dentate nucleus, which is extremely difficult to visualize with modern imaging techniques. Though, surgeons may greatly benefit from detailed knowledge of this anatomy. Historic studies have proved how anatomic dissections allow an accurate study of intracerebellar white matter bundles, providing essential information about the relations between dentatenucleus, cerebellar cortex and cerebellar peduncles. Throughout the centuries, the concept of dentate capsule, the so called Fleece of Stilling, has been demonstrated by multiple Authors but has been neglected in recent times.Materials and Methods: An extensive historical literature research was conducted through multiple digital libraries, searching for complete digitalized works of selected historical anatomists, with the specific goal of reconstructing the evolution of knowledge relative to intracerebellar white matter architecture from the second half of the XVIIIth century to recent years. Key Authors have been selected and their original works were studied and reviewed.Results: Essays and atlases from Malacarne, Vicq d’Azyr, Reil, Meckel, Arnold, Stilling, Cajal, Dejerine and Jakob were collected. Their anatomic descriptions and illustrations were discussed and detailed, demonstrating their discoveries about intracerebellar white matter anatomy.Conclusion: Information deriving from studies performed by the major anatomists of the past highlights pivotal anatomical information. Integration of this knowledge with modern imaging technologies may have an important surgical impact.

Background Although invasiveness is one of the major determinants of the poor glioblastoma (GBM) outcome, the mechanisms of GBM invasion are only partially understood. Among the intrinsic and environmental processes promoting cell-to-cell interaction processes, eventually driving GBM invasion, we focused on the pro-invasive role played by extracellular vesicles (EVs), a heterogeneous group of cell-released membranous structures containing various bioactive cargoes, which can be transferred from donor to recipient cells.Methods Extracellular vesicles isolated from patient-derived GBM cell lines and surgical aspirates were assessed for their pro-migratory competence by spheroid migration assays, calcium imaging, and PYK2/FAK phosphorylation. Brain invasiveness was investigated in human cortical organoids-based assembloids and in vivo orthotopic xenografts. Extracellular vesicles' molecular features were specified by multiplex bead-based flow cytometry.Results Results unveil a self-sustaining mechanism triggering migration through autocrine release and engagement of a specific population of EVs of large size (L-EVs), isolated from either patient-derived cell lines or surgical aspirates. Large size-EVs act through modulation of calcium transients via Connexin 43-Gap Junctions (Cx43-GJ) and phospho-activation of PYK2. Preincubation with blocking antibodies targeting Cx43 hemichannels demonstrated a dose-dependent inhibition of the L-EV-mediated GBM migration. By exploiting patients' surgical aspirates, we show that only L-EVs deriving from tumoral cells, and not those with immune origin, promote tumor migration, impacting more prominently the tumoral cells with mesenchymal subtype.Conclusions We demonstrate that L-EVs released by GBM cells, but not by the immune cells of the tumor microenvironment, represent a relevant and unique autocrine pro-migratory input for the tumor.

The transport of fluids and substances within the brain parenchyma (i.e. interstitial transport) is fundamental to maintaining brain health and delivering treatments for neurological disorders. However, accurately predicting these transport processes has remained a formidable challenge due to the intricate and dynamic nature of the brain's microenvironment. Here, we report a novel, fully validated bottom-up mechanistic framework that bridges advanced mathematical modelling, ultra-high-resolution imaging, and biomechanical testing to achieve precise, in vivo predictions of interstitial transport. Using this approach, we accurately modelled the transport of MRI tracers in living sheep brains, offering unprecedented insights into the interplay between fluid dynamics and tissue properties. This platform is a transformative step forward, with the potential to revolutionise drug delivery strategies not only in the brain but also in cancer therapy and other soft biological systems. By addressing limitations in modelling complex transport in soft tissue, our work establishes a significant tool with profound implications for biomedical engineering and translational medicine. ### Competing Interest Statement The authors have declared no competing interest.

Consumer-grade RGB-D imaging for intraoperative orthopedic tissue tracking is a promising method with high translational potential. Unlike bone-mounted tracking devices, markerless tracking can reduce operating time and complexity. However, its use has been limited to cadaveric studies. This paper introduces the first real-world clinical RGB-D dataset for spine surgery and develops SpineAlign, a system for capturing deformation between preoperative and intraoperative spine states. We also present an intraoperative segmentation network trained on this data and introduce CorrespondNet, a multi-task framework for predicting key regions for registration in both intraoperative and preoperative scenes.

Antenatal depression, affecting 10–20% of pregnancies worldwide, represents a major public health concern due to its association with maternal suicide, obstetric complications, and long-term neurodevelopmental and psychiatric vulnerability in offspring. Despite its prevalence and impact, the neurobiological mechanisms by which maternal mood disturbance shapes offspring brain development remain poorly understood. To address this, we employed a social-isolation rearing (SIR) paradigm in female C57BL/6N mice spanning preconception, gestation, and lactation. Adult offspring were evaluated using established assays of anxiety-like behavior, high-resolution ex vivo structural magnetic resonance imaging, and thalamic bulk RNA sequencing. Offspring of SIR dams exhibited consistent anxiety phenotypes across multiple behavioral tests. Neuroimaging revealed thalamic and striatal hypotrophy together with expansion of gustatory/visceral and visual cortices. Multivariate partial least-squares modelling identified thalamostriatal reductions as the principal latent factor associated with behavioral variance, whereas cortical hypertrophy covaried with exploratory drive. Transcriptomic analysis demonstrated extensive, sex-divergent reprogramming: males showed enrichment of pathways regulating protein synthesis and synaptic organization, while females exhibited alterations related to neuronal plasticity and myelin development. These findings establish preconceptional SIR as a translational model of maternal depression, identify the thalamus as a key locus of intergenerational vulnerability, and provide integrated imaging and molecular markers that may inform mechanistic studies and preventive interventions for offspring exposed to maternal mood disorders.

Exposure to prenatal stress (PNS) has the potential to elicit multiple neurobiological alterations and increase the susceptibility to psychiatric disorders. Moreover, gestational stress may sensitize the brain toward an altered response to subsequent challenges. Here, we investigated the effects of PNS in rats and assessed whether these animals exhibit an altered brain responsiveness to an acute stress (AS) during adolescence. From gestational day 14 until delivery, Sprague Dawley dams were exposed to PNS or left undisturbed. During adolescence (PND38 to PND41), offspring were tested in the social interaction and splash test. At PND44 half of the animals were exposed to 5 min of forced swim stress. Males and Females exposed to PNS showed reduced sociability and increased anhedonic-like behavior. At the molecular level, exposure of adolescent rats to AS produced increased activation of the amygdala and ventral and dorsal hippocampus. Regarding the prefrontal cortex (PFC), we observed a pronounced activation in PNS males exposed to AS. Cell-type specific transcriptional analyses revealed a significant imbalance in the activation of PFC excitatory and inhibitory neurons in PNS males and females exposed to AS. Furthermore, stressed males exhibited disrupted HPA-axis function, while females showed impairments in the modulation of antioxidant genes. Our study shows that PNS induces emotional dysregulation and alters the responsiveness of the PFC to an acute stressor. Moreover, the disruption of excitatory and inhibitory balance during adolescence could influence the ability to respond to challenging events that may contribute to precipitate a full-blown pathologic condition.

Background Petroclival meningiomas are challenging tumors. Several skull base approaches have been proposed in the last decades, with variable rates of postoperative morbidity and extent of resection. Methods We herein reported the step-by-step microsurgical resection of a large petroclival meningioma through an extended retrosigmoid approach. Detailed surgical technique has been accompanied by a 2D operative video. Conclusion The extended retrosigmoid approach allowed for a safe gross total resection of the tumor, as confirmed by the postoperative MRI. The patient did not experience any new postoperative deficit, despite a transient diplopia, and was discharged on postoperative day 7.

The development of new antipsychotics with pro-cognitive properties and less side effects represents a priority in schizophrenia drug research. In this study, we present for the first time a preclinical exploration of the effects of the promising natural atypical antipsychotic Methyl-2-Amino-3- Methoxybenzoate (MAM), a brain-penetrable protoalkaloid from the seed of the plant Nigella damascena. Using animal models related to hyperdopaminergic activity, namely the pharmacogenetic apomorphine (D2/D1 receptor agonist)-susceptible (APO-SUS) rat model and pharmacologically induced mouse and rat models of schizophrenia, we found that MAM reduced gnawing stereotypy and climbing behaviours induced by dopaminergic agents. This predicts antipsychotic activity. In line, MAM antagonized apomorphine-induced c-Fos and NPAS4 mRNA levels in post-mortem brain nucleus accumbens and dorsolateral striatum of APO-SUS rats. Furthermore, phencyclidine (PCP, an NMDA receptor antagonist) and 2,5-Dimethoxy-4-iodoamphetamine (DOI, a 5HT2A/2C receptor agonist) induced prepulse inhibition deficits, reflecting the positive symptoms of schizophrenia, which were rescued by treatment with MAM and atypical antipsychotics alike. Post-mortem brain immunostaining revealed that MAM blocked the strong activation of both PCP- and DOI-induced c-Fos immunoreactivity in a number of cortical areas. Finally, during a 28-day subchronic treatment regime, MAM did not induce weight gain, hyperglycemia, hyperlipidemia or hepato- and nephrotoxic effects, side effects known to be induced by atypical antipsychotics. MAM also did not show any cataleptic effects. In conclusion, its brain penetrability, the apparent absence of preclinical side effects, and its ability to antagonize positive and cognitive symptoms associated with schizophrenia make MAM an exciting new antipsychotic drug that deserves clinical testing.

Exposure to adverse conditions early in life represents an important risk factor for the development of psychiatric disorders. Adverse perinatal events are indeed associated with profound changes in the progeny, which often become manifest during adolescence. In our studies, we employed the prenatal stress model (PNS) in rats to investigate the behavioral and molecular alterations that develop because of this adverse experience in adolescent rats, also considering sex differences. Pregnant rats were exposed to the prenatal stress (PNS) paradigm from gestational day 14 to birth, while control dams were left undisturbed. During adolescence male and female offspring were exposed to a battery of behavioral tests before sacrifice. We found that PNS exposure produces emotional dysregulation, including anhedonia, anxiety and reduced sociability, in the majority (70%) of male and female adolescent offspring, although 30% of PNS animals were resilient. At the molecular level, we found that such behavioral patterns were associated with selective changes in the expression of activity-dependent genes as well as of immune-related mechanisms in different brain regions including amygdala, dorsal and ventral hippocampus, which are known play a key role in emotional regulation. Moreover, adolescent PNS rats show different responsiveness to an acute stress, suggesting altered ability to cope under a challenging condition. Conclusions - The characterization of the neurobiological mechanisms contributing to resilience or vulnerability to early life stress will be instrumental to identify mechanisms that may be targeted by therapeutic approaches to counteract specific pathologic domains of mental disorders.

A considerable proportion of patients with schizophrenia perform below population norms on standardized neuropsychological tests, and the performance of those performing within normal range is lower than predicted based on parental education. Cognitive impairment predates the onset of psychosis, is observed during symptom remission and in non-affected first-degree relatives of patients. At the present time, cognitive deficits are regarded as key features of schizophrenia, important determinants of poor psychosocial outcome and targets for both pharmacological and non-pharmacological treatment strategies. A group of eight key opinion leaders reviewed and discussed latest advances in scientific research and current good clinical practices on assessment, management, and treatment of CIAS. In the present paper they summarize the current evidence, identify main gaps between current knowledge and mental health services clinical practice, and provide practical recommendations to reduce the gap.

Background: Congenital craniovertebral junction anomalies (CCVJAs) encompass a diverse range of conditions characterized by distorted anatomy and significant variation in the pathways of neurovascular structures. This study aims to assess the safety and feasibility of tailoring posterior fixation for CCVJAs through intraoperative CT-based navigation. Methods: An in-depth retrospective analysis was conducted on eight patients diagnosed with CCVJAs (excluding Arnold-Chiari malformation). These patients underwent posterior fixation/arthrodesis facilitated by intraoperative CT-based navigation. The analysis included an examination of the fixation strategies, complication rates, length of stay, post-operative complications, and success of arthrodesis. Additionally, a comprehensive literature review was undertaken to contextualize and compare our findings. Results: Patients undergoing CVJ posterior fixation with intraoperative CT-based navigation exhibited a flawless record, devoid of complications related to the damage to neurovascular structures, as well as any instances of screw misposition, pullout, or breakage (0 out of 36 total screws). Furthermore, the entire cohort demonstrated a 100% arthrodesis rate. None of the patients required treatment with an occipital plate. Conclusions: The incorporation of intraoperative CT-based navigation proves to be an invaluable asset in executing CVJ posterior fixation within the context of CCVJAs. This technology facilitates the customization of posterior constructs, a crucial adaptation required to navigate the anatomical challenges posed by these anomalies. The secure placement of screws into the occipital condyles, made possible by navigation, has proven highly effective in achieving CVJ fixation, obviating the need for an occipital plate. This technological leap represents a significant advancement, enhancing the safety, precision, and overall outcomes for patients undergoing this surgical procedure, while concurrently reducing the necessity for more invasive and morbid interventions.

BACKGROUND: Degenerative cervical myelopathy (DCM) is a leading cause of nontraumatic spinal cord injury. Surgery aims to arrest neurological decline and improve conditions, but controversies surround risks and benefits in elderly patients, outcomes in mild myelopathy, and the risk of adjacent segment disease (ASD). METHODS: Retrospective data of patients who underwent anterior cervical discectomy and fusion for DCM in our hospital were collected. Patients were stratified by preoperative modified Japanese Orthopaedic Association (mJOA) (mild, moderate, severe) and age (under 70, over 70). Clinical outcomes, complications, and ASD rate were analyzed. We evaluated the relationship between mJOA recovery rate and the risk of complications and various preoperative parameters. RESULTS: Five hundred seven consecutive patients were included in the study, with a mean follow-up of 43.52 months (12e71). Improvement in all outcome variables was observed in mild, moderate, and severe myelopathy categories, with elderly patients showing a lower improvement. Except for age, no other variable correlated with mJOA recovery rate. We observed 45 complications (11.1% of patients), with 14 in the U70 group and 31 in the O70 group (P P value < 0.001). Age, Charlson comorbidity index, and ASA score were found to be predictors of complications. Fourteen patients (2.8% of total), mean age 54.2, developed radiological and clinical ASD. Most had cranial-level ASD with Pfirmann grade double dagger 2 before index surgery. CONCLUSIONS: Most myelopathic patients improve after anterior cervical discectomy and fusion. Elderly patients show a lower improvement and higher complication rates than their younger counterparts. ASD rates are low, and younger patients with preexisting cranial level alterations are more susceptible.

Exposure to early-in-life adversities represents one of the most relevant conditions linked to the etiology of mental disorders, characterized by emotional dysregulation. It is thought that changes in stress mediators or immune mechanisms during critical time windows may lead to structural and functional alterations in different brain circuits that underlie the manifestation of specific psychopathologic domains. The present symposium will summarize authoritatively recent advances in the functional mechanisms contributing to the etiology as well as to the manifestation of psychiatric disorders, with a specific focus on stress and immune dysfunction. The symposium will unfold upon the discussion of preclinical and clinical studies addressing different aspects related to psychiatric disorders. Prof. M.A. Riva (University of Milan, Italy) will show how exposure to prenatal stress (PNS) in rodents produces emotional dysregulation, characterized by reduced sociability and anxiety-like behavior in a percentage of adolescent offspring, whereas others appear to be resilient. Such vulnerability to PNS is associated with differences in the activity state of specific brain regions and with changes in the expression of immune and glucocorticoid- related markers. Along this line, Dr. A. Vernon (Kings College London, UK) will show that mouse offspring exposed to maternal immune activation could also be stratified into susceptible or resilient for multiple behavioral dysfunctions and that the neural correlates of susceptibility and resilience to MIA are best described using multivariate analysis of both neuroanatomical and behavioral data. More specifically, multivariate maps associated anxiety-like, social, cognitive, and sensorimotor gating deficits with volumes of multiple prefrontal and limbic grey matter regions and volumes of major white matter tracts. At the clinical level, childhood trauma has been linked with both stress-related disorders and auto-immune disorders, suggesting that inflammation represents both a mechanism and a target for the treatment of these disorders. With this regard, Dr. L. De Picker (University of Antwerp, Belgium) will discuss the endocrine and immunological pathways that are implicated in patients with childhood trauma and how they can result in increased vulnerability for mental disorders. Last, considering that stress and metabolic disturbances are thought to contribute to increased inflammation and effects on the brain and behavior in patients with depression and other psychiatric illnesses, Dr. J. Felger (Emory University, Atlanta, USA) will present new and published data showing relationships between stress and biomarkers of metabolic dysfunction, especially those related to lipid metabolism, and improvement in symptoms of anhedonia and deficits in reward circuit function in response to inflammation-targeted treatments in depression.

OBJECTIVE:Surgery is the mainstay of treatment for low-grade glioma (LGG)-related epilepsy. However, the goal of achieving both oncological radical resection and seizure freedom can be challenging. PET with [11C]methionine (MET) has been recently introduced in clinical practice for the management of patients with LGGs, not only to monitor the response to treatments, but also as a preoperative tool to define the metabolic tumor extent and to predict tumor grading, type, and prognosis. Still, its role in defining tumor-related epilepsy and postoperative seizure outcomes is limited. The aim of this preliminary study was to investigate the role of MET PET in defining preoperative seizure characteristics and short-term postoperative seizure control in a cohort of patients with newly diagnosed temporal lobe low-grade gliomas (tLGGs).METHODS:Patients with newly diagnosed and histologically proven temporal lobe grade 2/3 gliomas (2021 WHO CNS tumor classification) who underwent resection at the authors' institution between July 2011 and March 2021 were included in this retrospective study. MET PET images were acquired, fused with MRI scans, and qualitatively and semiquantitatively analyzed. Any eventual PET/MRI involvement of the temporomesial area, seizure characteristics, and 1-year seizure outcomes were reported.RESULTS:A total of 52 patients with tLGGs met the inclusion criteria. MET PET was positive in 41 (79%) patients, with a median metabolic tumor volume of 14.56 cm3 (interquartile range [IQR] 6.5-28.2 cm3). The median maximum and mean tumor-to-background ratio (TBRmax, TBRmean) were 2.24 (IQR 1.58-2.86) and 1.53 (IQR 1.37-1.70), respectively. The metabolic tumor volume was found to be related to the presence of seizures at disease onset, but only in noncodeleted tumors (p = 0.014). Regarding patients with uncontrolled seizures at surgery, only the temporomesial area PET involvement showed a statistical correlation both in the univariate (p = 0.058) and in the multivariate analysis (p = 0.030). At 1-year follow-up, seizure control was correlated with MET PET-derived semiquantitative data. Particularly, higher TBRmax (p = 0.0192) and TBRmean (p = 0.0128) values were statistically related to uncontrolled seizures 1 year after surgery.CONCLUSIONS:This preliminary study suggests that MET PET may be used as a preoperative tool to define seizure characteristics and outcomes in patients with tLGGs. These findings need to be further validated in larger series with longer epileptological follow-ups.

Gliomas present a complex challenge in neuro-oncology, often accompanied by the debilitating complication of epilepsy. Understanding the biological interaction and common pathways between gliomagenesis and epileptogenesis is crucial for improving the current understanding of tumorigenesis and also for developing effective management strategies. Shared genetic and molecular mechanisms, such as IDH mutations and dysregulated glutamate signaling, contribute to both tumor progression and seizure development. Targeting these pathways, such as through direct inhibition of mutant IDH enzymes or modulation of glutamate receptors, holds promise for improving patient outcomes. Additionally, advancements in surgical techniques, like supratotal resection guided by connectomics, offer opportunities for maximally safe tumor resection and enhanced seizure control. Advanced imaging modalities further aid in identifying epileptogenic foci and tailoring treatment approaches based on the tumor’s metabolic characteristics. This review aims to explore the complex interplay between gliomagenesis, epileptogenesis, and neural circuit remodeling, offering insights into shared molecular pathways and innovative treatment strategies to improve outcomes for patients with gliomas and associated epilepsy.