Early life adversity drives sex-specific anhedonia and meningeal immune gene expression through mast cell activation.

Exposure to early life adversity (ELA) in the form of physical and/or psychological abuse or neglect increases the risk of developing psychiatric and inflammatory disorders later in life. It has been hypothesized that exposure to ELA results in persistent, low grade inflammation that leads to increased disease susceptibility by amplifying the crosstalk between stress-processing brain networks and the immune system, but the mechanisms remain largely unexplored. The meninges, a layer of three overlapping membranes that surround the central nervous system (CNS)- dura mater, arachnoid, and piamater - possess unique features that allow them to play a key role in coordinating immune trafficking between the brain and the peripheral immune system. These include a network of lymphatic vessels that carry cerebrospinal fluid from the brain to the deep cervical lymph nodes, fenestrated blood vessels that allow the passage of molecules from blood to the CNS, and a rich population of resident mast cells, master regulators of the immune system. Using a mouse model of ELA consisting of neonatal maternal separation plus early weaning (NMSEW), we sought to explore the effects of ELA on sucrose preference behavior, dura mater expression of inflammatory markers and mast cell histology in adult male and female C57Bl/6 mice. We found that NMSEW alone does not affect sucrose preference behavior in males or females, but it increases the dura mater expression of the genes coding for mast cell protease CMA1 (cma1) and the inflammatory cytokine TNF alpha (tnf alpha) in females. When NMSEW is combined with an adult mild stress (that does not affect behavior or gene expression in NH animals) females show reduced sucrose preference and even greater increases in meningeal cma1 levels. Interestingly, systemic administration of the mast cell stabilizer Ketotifen before exposure to adult stress prevents both, reduction in sucrose preference an increases in cma1 expression in NMSEW females, but facilitates stress-induced sucrose anhedonia in NMSEW males and NH females. Finally, histological analyses showed that, compared to males, females have increased baseline activation levels of mast cells located in the transverse sinus of the dura mater, where the meningeal lymphatics run along, and that, in males and females exposed to adult stress, NMSEW increases the number of mast cells in the interparietal region of the dura mater and the levels of mast cell activation in the sagittal sinus regions of the dura mater. Together, our results indicate that ELA induces long-term meningeal immune gene changes and heightened sensitivity to adult stress-induced behavioral and meningeal immune responses and that these effects could mediated via mast cells.

Sternotomy Approach to the Anterior Cervicothoracic Spine.

The anterior cervicothoracic spine is a challenging region to approach given the various vascular, osseous, nervous, and articular structures, which prevent adequate exposure. This region is susceptible to lesions ranging from tumors, degenerative disease, infectious processes, and traumatic fractures. Our objective was to critically evaluate the sternotomy approach in spine surgery to give the technical implications of its usage. The safety and efficacy of the transsternal approach are discussed as well as the advantages, disadvantages, indications, and contraindications. The transsternal approach is the most direct access to pathologies in the upper anterior cervicothoracic spine and enables the spine surgeon to gain direct exposure to the cervicothoracic junction for ideal visualization. Anatomical considerations must be kept in mind while performing a sternotomy to prevent complications such as denervation or bleeding. This technique is useful for the armamentarium of spinal surgeons.

An investigation of craniocervical stability post-condylectomy.

BACKGROUND: Occipital condylectomy is often necessary to gain surgical access to various neurological pathologies. As the lateral limit of the craniovertebral junction (CVJ), partial condylectomy can lead to iatrogenic craniocervical instability. What was once considered an inoperable location is now the target of various complex neurosurgical procedures such as tumor resection and aneurysm clipping. METHODS: In this study, we will review the anatomical structure of the CVJ and provide the first comprehensive assessment of studies investigating craniovertebral stability following condylectomy with the transcondylar surgical approaches. Furthermore, we discuss future considerations that must be evaluated to optimize the chances of preserving craniocervical stability postcondylectomy. RESULTS: The current findings postulate upward of 75% of the occipital condyle can be resected without significantly affecting mobility of the CVJ. The current findings have only examined overall dimensions and have not established a significant correlation into how the shape of the occipital condyles can affect mobility. Occipitocervical fusion should only be considered after 50% condyle resection. In terms of indicators of anatomical stability, components of range of motion (ROM) such as the neutral zone (NZ) and the elastic zone (EZ) have been discussed as potential measures of craniocervical mobility. These components differ by the sense that the NZ has little ligament tension, whereas the EZ does represent ROM where ligaments experience tension. NZ is a more sensitive indicator of instability when measuring for instability postcondylectomy. CONCLUSION: Various transcondylar approaches have been developed to access this region including extreme-lateral and far-lateral condylectomy, with hopes of preserving as much of the condyle as possible and maintaining postoperative craniocervical stability.

Oncologic causes of oculopalatal tremors: neurophysiology and treatment.

Oculopalatal tremor (OPT) is an acquired pathology characterized by continuous and rhythmical soft palatal movements combined with pendular nystagmus. Aside from vascular lesions, oncological masses affecting the dentatorubro-olivary pathway can impair brainstem and/or cerebellar pathways, manifesting as dyssynchronous movement. In this review, we delve into the neurophysiology of OPT along with oncological causes and treatment options based on the most recent clinical trial data. This literature review includes medication treatment data from clinical trials enrolling individuals with features of OPT, including acquired pendular nystagmus (APN). Trials were deemed eligible for inclusion in this review if one or more participants had symptoms determined by the trial authors to be caused by OPT. Trials investigating the treatment of APN secondary to a separate cause, such as multiple sclerosis, were excluded from this review. Several early treatments failed to demonstrate a benefit for patients with APN due to OPT. Trials of anticholinergic agents were largely ineffective and poorly tolerated. Botulinum toxin A demonstrated improvement in APN symptoms. Most recently, trials including memantine and gabapentin have demonstrated success with attenuation of APN. Surgical modalities such as DBS have yet to show improvement, though with only a single case report as evidence. Oculopalatal tremor is a unique manifestation of posterior fossa tumors disrupting the Guillain-Mollaret triangle. Symptom control through medication management has had limited success attributed to poor response and medication intolerance. Surgical modalities like DBS may have an emerging role in OPT treatment by targeting dyssynchronous activity in the dentatorubro-olivary pathway.

Neuroimmunology of depression.

Depression is one of the leading causes of disability worldwide and a major contributor to the global burden of disease, yet the cellular and molecular etiology of depression remain largely unknown. Major Depressive Disorder (MDD) is associated with a variety of chronic physical inflammatory and autoimmune disorders, and mood disorders may act synergistically with other medical disorders to worsen patient outcomes. Here, we outline the neuroimmune complement, explore the evidence for altered immune system function in MDD, and present some of the potential mechanisms by which immune cells and molecules may drive the onset and course of MDD. These include pro-inflammatory signaling, alterations in the hypothalamic-pituitary-adrenal axis, dysregulation of the serotonergic and noradrenergic neurotransmitter systems, neuroinflammation, and meningeal immune dysfunction. Finally, we discuss the interactions between current antidepressants and the immune system and propose the possibility of immunomodulatory drugs as potential novel antidepressant treatments.

Stereoelectroencephalography versus Subdural Electrode Implantation to Determine Whether Patients with Drug-resistant Epilepsy Are Candidates for Epilepsy Surgery.

Epilepsy is a chronic condition that affects about 50 million individuals worldwide. While its challenges are profound, there are increasing instances where antiepileptic drugs (AEDs) fail to provide relief to epileptic manifestations. For these pharmacoresistant cases, epilepsy surgery often is an effective route for treatment. However, the complexity and challenges associated with presurgical evaluations have prevented more widespread utilization of epilepsy surgery in pharmacoresistant cases. While preliminary work-ups and non-invasive diagnostic imaging have allowed for limited identification of the epileptogenic zone (EZ), there is yet to be an established pre-determined algorithm for surgical evaluation of patients with epilepsy. However, two modalities are currently being used for localization of the EZ and in determining candidates for surgery: stereoelectroencephalography (SEEG) and subdural electrodes (SDEs). SDE has been used in the United States for decades; however, SEEG now provides a less invasive option for mapping brain regions. We seek to address which intracranial monitoring technique is superior. Through a review of the outcomes of various clinical studies, SEEG was found to have greater safety and efficiency benefits than SDE, such as lower morbidity rates, lower prevalence of neurological deficits, and shorter recovery times. Moreover, SEEG was also found to have further functional benefits by allowing for deeper targeting of cerebral tissue along with bilateral hemispheric monitoring. This has led to increased rates of seizure freedom and control among SEEG patients. Nevertheless, further studies on the limitations and advancements of SEEG and SDE are still required to provide a more comprehensive understanding regarding their application.

Venous sinus stenting for intractable pulsatile tinnitus: A review of indications and outcomes.

BACKGROUND: Pulsatile tinnitus presents as a unique variation of tinnitus in which a conscious perception of the heartbeat is localized to the ears in either unilateral or bilateral fashion. The sensation is typically caused by an increase in turbulent blood flow in the affected ear, in most cases, due to a structural abnormality of the venous sinuses - the most common of which being stenosis. Herein, we discuss the etiology of pulsatile tinnitus followed by indications for treatment of various pathologies which have been successfully treated with venous sinus stenting and have led to resolution of auditory symptoms. METHODS: The authors queried PubMed database using combinations of the keywords "venous sinus stenting," "endovascular treatment," and "pulsatile tinnitus" to identify relevant studies published in English after 2001 and before December 1, 2020 and verified selected. RESULTS: Our results corroborate those published in prior reviews reporting a high rate of pulsatile tinnitus resolution with venous sinus stenting. CONCLUSION: The success of venous sinus stenting is clinically relevant as an effective treatment option for patients suffering from pulsatile tinnitus. Future applications and studies are needed and are currently being developed to further demonstrate the effectiveness of stents in the treatment of pulsatile tinnitus.

Cerebrolysin for stroke, neurodegeneration, and traumatic brain injury: review of the literature and outcomes.

Cerebrolysin therapy has the potential to significantly aid in the treatment of a wide variety of debilitating neurological diseases including ischemic strokes, neurodegenerative disorders, and traumatic brain injuries. Although Cerebrolysin is not approved for use in the USA, it is used clinically in over 50 countries worldwide. In this review, we focus on outlining the role that Cerebrolysin has in stimulating the molecular signaling pathways that are critical for neurological regeneration and support. An extensive evaluation of these signaling pathways reveals that Cerebrolysin has the potential to intervene in a diverse array of pathophysiological causes of neurological diseases. In the clinical setting, Cerebrolysin is generally safe for human use and has provided functional improvement when used as an adjunct treatment. However, our literature review revealed inconsistent results, as several clinical studies suggested that Cerebrolysin treatment has minor clinical relevance and did not have significant advantages over a placebo. In conclusion, we found that Cerebrolysin therapy can potentially play a major role in the treatment of many neurological diseases. Nevertheless, there remains much to be elucidated about the efficacy of this treatment for specific neurological conditions, and more robust clinical data is needed to reach a consensus and properly define the therapeutic role of Cerebrolysin.

Diffusion tensor imaging of the spinal cord status post trauma.

BACKGROUND: Since its development in 1994, diffusion tensor imaging (DTI) has been successfully used to assess structural and functional changes to neurological tissue within the central nervous system. Namely, DTI is a noninvasive magnetic resonance imaging (MRI)-based technique that uses anisotropic diffusion to visualize and estimate the organization of white matter in neuronal tissue. It has been used to study various spinal pathologies including neoplastic diseases, degenerative myelopathy, demyelinating diseases, and infections involving the spinal cord. However, due to technical uncertainties and experimental limitations, DTI has rarely been clinically applied to assess trauma-related spinal pathologies. METHODS: An extensive review of the published literature on DTI was performed utilizing PubMed, OVID Medline, and EMBASE journals. Terms used for the search included DTI and spine trauma. RESULTS: The search yielded full text English language-related articles regarding DTIs application, limitations, and functional outcomes secondary to spinal trauma. CONCLUSION: DTI relies on anisotropy in CNS tissues to determine the spatial orientation of surrounding axon tracts and define anatomical boundaries. Diffusion along three principle axes is used to calculate the following four DTI indices; fractional anisotropy, apparent diffusion coefficient (ADC), longitudinal ADC, and transverse ADC. Using DTI as a diagnostic tool status, post spine trauma has proven useful in examining the morphological and physiological extent of spinal lesions beyond conventional MRI. Experimental studies are now utilizing DTI to analyze the severity of spinal cord trauma during the hyperacute phase and may potentially be used to providing additional diagnostic information for improved treatment efficiency (e.g., as shown during the stem cell therapy trials).

Emerging role of viral vectors for circuit-specific gene interrogation and manipulation in rodent brain.

Over the past half century, novel tools have allowed the characterization of myriad molecular underpinnings of neural phenomena including synaptic function, neurogenesis and neurodegeneration, membrane excitability, and neurogenetics/epigenetics. More recently, transgenic mice have made possible cell type-specific explorations of these phenomena and have provided critical models of many neurological and psychiatric diseases. However, it has become clear that many critical areas of study require tools allowing the study and manipulation of individual neural circuits within the brain, and viral vectors have come to the forefront in driving these circuit-specific studies. Here, we present a surface-level review of the general classes of viral vectors used for study of the brain, along with their suitability for circuit-specific studies. We then cover in detail a new long-lasting, retrograde expressing form of herpes simplex virus termed LT-HSV that has become highly useful in circuit-based studies. We detail some of its current uses and propose a variety of future uses for this critical new tool, including circuit-based transgene overexpression, gene editing, and gene expression profiling.