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Brain disease has become one of this century's biggest health challenges, urging the development of novel, more effective treatments. To this end, neuromodulation represents an excellent method to modulate the activity of distinct neuronal regions to alleviate disease. Recently, the medical indications for neuromodulation therapy have expanded through the adoption of the idea that neurological disorders emerge from deficits in systems-level structures, such as brain waves and neural topology. Connections between neuronal regions are thought to fluidly form and dissolve again based on the patterns by which neuronal populations synchronize. Akin to a fire that may spread or die out, the brain's activity may similarly hyper-synchronize and ignite, such as seizures, or dwindle out and go stale, as in a state of coma. Remarkably, however, the healthy brain remains hedged in between these extremes in a critical state around which neuronal activity maneuvers local and global operational modes. While it has been suggested that perturbations of this criticality could underlie neuropathologies, such as vegetative states, epilepsy, and schizophrenia, a major translational impact is yet to be made. In this hypothesis article, we dissect recent computational findings demonstrating that a neural network's short- and long-range connections have distinct and tractable roles in sustaining the critical regime. While short-range connections shape the dynamics of neuronal activity, long-range connections determine the scope of the neuronal processes. Thus, to facilitate translational progress, we introduce topological and dynamical system concepts within the framework of criticality and discuss the implications and possibilities for therapeutic neuromodulation guided by topological decompositions. [ABSTRACT FROM AUTHOR]

The human brain contains billions of neurons that flexibly interconnect to support local and global computational spans. As neuronal activity propagates through the neural medium, it approaches a critical state hedged between ordered and disordered system regimes. Recent work demonstrates that this criticality coincides with the small-world topology, a network arrangement that accommodates both local (subcritical) and global (supercritical) system properties. On one hand, operating near criticality is thought to offer several neurocomputational advantages, e.g., high-dynamic range, efficient information capacity, and information transfer fidelity. On the other hand, aberrations from the critical state have been linked to diverse pathologies of the brain, such as post-traumatic epileptiform seizures and disorders of consciousness. Modulation of brain activity, through neuromodulation, presents an attractive mode of treatment to alleviate such neurological disorders, but a tractable neural framework is needed to facilitate clinical progress. Using a variation on the generative small-world model of Watts and Strogatz and Kuramoto's model of coupled oscillators, we show that the topological and dynamical properties of the small-world network are divided into two functional domains based on the range of connectivity, and that these domains play distinct roles in shaping the behavior of the critical state. We demonstrate that short-range network connections shape the dynamics of the system, e.g., its volatility and metastability, whereas long-range connections drive the system state, e.g., a seizure. Together, these findings lend support to combinatorial neuromodulation approaches that synergistically normalize the system dynamic while mobilizing the system state. [ABSTRACT FROM AUTHOR]

Background : Deep brain stimulation (DBS) of the dorsal subthalamic nucleus (STN) is a validated neurosurgical treatment of Parkinson's Disease (PD). To investigate the mechanism of action, including potential DBS induced neuroplasticity, we have previously used a minipig model of Parkinson's Disease, although the basal ganglia circuitry was not elucidated in detail. Aim : To describe the cortical projections from the primary motor cortex (M1) to the basal ganglia and confirm the presence of a cortico-striatal pathway and a hyperdirect pathway to the subthalamic nucleus, respectively, which is known to exist in primates. Materials and Methods : Five female Göttingen minipigs were injected into the primary motor cortex (n = 4) and adjacent prefrontal cortex (n = 1) with the anterograde neuronal tracer, Biotinylated Dextran Amine (BDA). 4 weeks later the animals were sacrificed and the brains cryosectioned into 30 μm thick coronal sections for subsequent microscopic analysis. Results : The hyperdirect axonal connections from the primary motor cortex were seen to terminate in the dorsolateral STN, whereas the axonal projections from the prefrontal cortex terminated medially in the STN. Furthermore, striatal tracing from the motor cortex was especially prominent in the dorsolateral putamen and less so in the dorsolateral caudate nucleus. The prefrontal efferents were concentrated mainly in the caudate nucleus and to a smaller degree in the juxtacapsular dorsal putamen, but they were also found in the nucleus accumbens and ventral prefrontal cortex. Discussion : The organization of the Göttingen minipig basal ganglia circuitry is in accordance with previous descriptions in primates. The existence of a cortico-striatal and hyperdirect basal ganglia pathway in this non-primate, large animal model may accordingly permit further translational studies on STN-DBS induced neuroplasticity of major relevance for future DBS treatments. [ABSTRACT FROM AUTHOR]

Recording and manipulating neuronal ensemble activity is a key requirement in advanced neuromodulatory and behavior studies. Devices capable of both recording and manipulating neuronal activity brain-computer interfaces (BCIs) should ideally operate un-tethered and allow chronic longitudinal manipulations in the freely moving animal. In this study, we designed a new intracortical BCI feasible of telemetric recording and stimulating local gray and white matter of visual neural circuit after irradiation exposure. To increase the translational reliance, we put forward a Göttingen minipig model. The animal was stereotactically irradiated at the level of the visual cortex upon defining the target by a fused cerebral MRI and CT scan. A fully implantable neural telemetry system consisting of a 64 channel intracortical multielectrode array, a telemetry capsule, and an inductive rechargeable battery was then implanted into the visual cortex to record and manipulate local field potentials, and multi-unit activity. We achieved a 3-month stability of the functionality of the un-tethered BCI in terms of telemetric radio-communication, inductive battery charging, and device biocompatibility for 3 months. Finally, we could reliably record the local signature of sub- and suprathreshold neuronal activity in the visual cortex with high bandwidth without complications. The ability to wireless induction charging combined with the entirely implantable design, the rather high recording bandwidth, and the ability to record and stimulate simultaneously put forward a wireless BCI capable of long-term un-tethered real-time communication for causal preclinical circuit-based closed-loop interventions. [ABSTRACT FROM AUTHOR]

Highlights • We evaluated a large animal model for intrathecal delivery and CSF flow. • 11C- labelled PET-tracer was injected via a surgically placed catheter in cisterna magna. • Continuous infusion with artificial cerebrospinal fluid pushed the tracer, while intracranial pressure was monitored. • Reconstruction of the PET/CT scans visualize the distribution of the 11C tracer in the subarachnoid space. Abstract Background Intrathecal (IT) delivery is useful in both basic research and clinical treatments. Here we aim to test a new minimally invasive distribution route to the subarachnoid space (SAS) and the flow of IT administrations. We placed a radioligand into SAS during positron emission tomography (PET) scanning as a proof of concept. New method We injected a 11C-labeled PET-tracer using a surgically placed catheter in the cisterna magna of anesthetized female pigs. The pigs were scanned for 1.5–2 hours in a PET/CT-scanner. The pressure from continuous infusion of artificial CSF (aCSF) promoted distribution of the tracer. The procedure was done under continuous intracranial pressure (ICP) monitoring. The catheter was made accessible both by externalization through the skin and through a subcutaneously placed sterile titanium port connected to the catheter. After image reconstruction, we used PMOD software to assess the tracer distribution throughout SAS. Internalisation of the catheter to a port enables survival studies. Previous studies performing ventriculography have placed a catheter trough brain cortex and parenchyma; such procedures may affect any behavioural or neurological evaluation, and have an increased risk of bleeding per- and post-operatively (Kaiser & Frühauf, 2007). Results The PET-CT visualized tracer was evenly distributed in the SAS. Furthermore, the ICP measurement made it possible to adjust infusion speed within acceptable pressure levels. Conclusion This new method can be useful for testing distribution of PET-tracers, antibiotics, chemotherapeutics and a wide range of other pharmaceuticals targeting the CNS and spinal cord in large animal models, and potentially later in human. [ABSTRACT FROM AUTHOR]

Abstract: The Göttingen minipig is being used increasingly in biomedical research. The anatomical structure of the porcine peripheral nervous system has been extensively characterized, but no equivalent to the dermatome map, which is so valuable in human neurophysiological research, has been created. We characterized the medullar segmental skin and muscle innervations of the minipig hind body, using neurophysiological methodology. Six adult minipigs underwent unilateral laminectomy from L2 to S3, exposing the nerve roots. The skin of the hind part of the body was divided into 36 predefined fields, based on anatomical landmarks for consistent reproducibility. We recorded the evoked potential in each exposed nerve root L2‐S3 for cutaneous stimulation of each skin field, mapping the sensory innervation of the entire hind body. We subsequently recorded the motor response in seven predefined muscles during sequential stimulation of the L2‐S3 nerve roots. We obtained a clear sensory evoked potential in the nerve roots during stimulation of the skin fields, allowing us to map the sensory innervation of the minipig hind body. Neurophysiological data from skin stimulation and muscle recordings enabled us to map the sensory innervation of the Göttingen minipig hind body and provide information about muscular innervation. The skin fields were sensory innervated by more than one root. The muscles each had one dominant root with minor contribution from neighboring roots. This is consistent with experimental data from human studies. [ABSTRACT FROM AUTHOR]

Background Stereotaxic neurosurgery in large animals is used widely in different sophisticated models, where precision is becoming more crucial as desired anatomical target regions are becoming smaller. Individually calculated coordinates are necessary in large animal models with cortical and subcortical anatomical differences. New method We present a convenient method to make an MRI-visible skull fiducial for 3D MRI-based stereotaxic procedures in larger experimental animals. Plastic screws were filled with either copper-sulfate solution or MRI-visible paste from a commercially available cranial head marker. The screw fiducials were inserted in the animal skulls and T1 weighted MRI was performed allowing identification of the inserted skull marker. Results Both types of fiducial markers were clearly visible on the MRÍs. This allows high precision in the stereotaxic space. Comparison with existing method The use of skull bone based fiducial markers gives high precision for both targeting and evaluation of stereotaxic systems. There are no metal artifacts and the fiducial is easily removed after surgery. Conclusion The fiducial marker can be used as a very precise reference point, either for direct targeting or in evaluation of other stereotaxic systems. [ABSTRACT FROM AUTHOR]

Parkinson's disease is characterized by a progressive loss of substantia nigra (SN) dopaminergic neurons and the formation of Lewy bodies containing accumulated alpha‐synuclein (α‐syn). The pathology of Parkinson's disease is associated with neuroinflammatory microglial activation, which may contribute to the ongoing neurodegeneration. This study investigates the in vivo microglial and dopaminergic response to overexpression of α‐syn. We used positron emission tomography (PET) and the 18 kDa translocator protein radioligand, [11C](R)PK11195, to image brain microglial activation and (+)‐α‐[11C]dihydrotetrabenazine ([11C]DTBZ), to measure vesicular monoamine transporter 2 (VMAT2) availability in Göttingen minipigs following injection with recombinant adeno‐associated virus (rAAV) vectors expressing either mutant A53T α‐syn or green fluorescent protein (GFP) into the SN (4 rAAV‐α‐syn, 4 rAAV‐GFP, 5 non‐injected control minipigs). We performed motor symptom assessment and immunohistochemical examination of tyrosine hydroxylase (TH) and transgene expression. Expression of GFP and α‐syn was observed at the SN injection site and in the striatum. We observed no motor symptoms or changes in striatal [11C]DTBZ binding potential in vivo or striatal or SN TH staining in vitro between the groups. The mean [11C](R)PK11195 total volume of distribution was significantly higher in the basal ganglia and cortical areas of the α‐syn group than the control animals. We conclude that mutant α‐syn expression in the SN resulted in microglial activation in multiple sub‐ and cortical regions, while it did not affect TH stains or VMAT2 availability. Our data suggest that microglial activation constitutes an early response to accumulation of α‐syn in the absence of dopamine neuron degeneration. The pathology of Parkinson's disease is associated with alpha‐synuclein overexpression and neuroinflammation. We injected viral vectors expressing human A53T alpha‐synuclein into the midbrain of Göttingen minipigs. Using [11C](R)PK11195, a marker of activated microglia, we observed significantly increased uptake in alpha‐synuclein versus control animals, suggesting that accumulation of alpha‐synuclein may induce neuroinflammation. [ABSTRACT FROM AUTHOR]

• A pressure sensitive gait mat is a useful tool for quantitative motor assessment. • Pressure sensitive gait mats are simple alternatives to camera-sensor based systems. • The gait of minipigs displays symmetry and a slightly frontal center of gravity. • Subtle motor deterioration is detectable after lesions affecting the motor system. • Lesion-compensatory dynamics involve decreased velocity and increased stance time. [ABSTRACT FROM AUTHOR]

Neuromodulation is a rapidly expanding therapeutic option considered within neuropsychiatry, pain and rehabilitation therapy. Combining electrostimulation with feedback from fMRI can provide information about the mechanisms underlying the therapeutic effects, but so far, such studies have been hampered by the lack of technology to conduct safe and accurate experiments. Here we present a system for fMRI compatible electrical stimulation, and the first proof-of-concept neuroimaging data with deep brain stimulation (DBS) in pigs obtained with the device. The system consists of two modules, placed in the control and scanner room, connected by optical fiber. The system also connects to the MRI scanner to timely initiate the stimulation sequence at start of scan. We evaluated the system in four pigs with DBS in the subthalamic nucleus (STN) while we acquired BOLD responses in the STN and neocortex. We found that the system delivered robust electrical stimuli to the implanted electrode in sync with the preprogrammed fMRI sequence. All pigs displayed a DBS-STN induced neocortical BOLD response, but none in the STN. The system solves three major problems related to electric stimuli and fMRI examinations, namely preventing distortion of the fMRI signal, enabling communication that synchronize the experimental conditions, and surmounting the safety hazards caused by interference with the MRI scanner. The fMRI compatible electrical stimulator circumvents previous problems related to electroceuticals and fMRI. The system allows flexible modifications for fMRI designs and stimulation parameters, and can be customized to electroceutical applications beyond DBS. • The system circumvents previous problems related to electroceuticals and fMRI. • Safe and high performance. • Flexible modifications for fMRI designs and stimulation parameters. • Electroceutical applications even beyond deep brain stimulation. [ABSTRACT FROM AUTHOR]

Background: Patients with multiple comorbidities can present as a diagnostic challenge as overlapping symptomatology complicates the discovery of emergent pathology. Symptoms of alcohol misuse or orthostatic hypotension may especially cloud the diagnosis of insidious neurological disease, such as posterior circulation infarct. With a growing elderly population, it is expected that the complex multimorbid patient will represent a growing challenge to prompt stroke detection and treatment., Case Description: Herein, we present a 69-year-old male with a history of alcohol abuse, chronic obstructive pulmonary disease, type 2 diabetes mellitus, paroxysmal atrial fibrillation, and congestive heart disease. The patient arrived at our emergency department with dizziness, ataxia, and diplopia. His symptoms had a sudden onset and gradual exacerbation over a span of 2 days, notably aggravated by standing and walking, but relieved when seated or supine. Notably, a month before admission, the patient had been treated with anti-congestive medications for severe congestive heart failure leading to a weight loss of 55 lbs over period of 2 weeks. The initial differential diagnoses were orthostatism, Wernicke's encephalopathy (WE), and ischemic stroke. Magnetic resonance imaging (MRI) revealed a subacute infarct in the medial longitudinal fasciculus (MLF)., Conclusions: The case underscores the challenge in diagnosing neurological conditions in multimorbid individuals. The combination of various underlying conditions may drastically complicate the diagnosis. Successful diagnosis and treatment necessitates meticulous evaluation of clinical observations, medical history, current medications, and pertinent diagnostic evaluations to effectively narrow down the potential differential diagnoses., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-23-177/coif). The authors have no conflicts of interest to declare., (2024 AME Case Reports. All rights reserved.)

Introduction: Gait difficulties are common in Parkinson's disease (PD) and cause significant disability. These symptoms are often resistant to treatment. Spinal cord stimulation (SCS) has been found to improve gait, including freezing of gait, in a small number of patients with PD. The mechanism of action is unclear, and some patients are non-responders. With this double-blind, placebo-controlled efficacy and feasibility clinical and imaging study, we aim to shed light on the mechanism of action of SCS and collect data to inform development of a scientifically sound clinical trial protocol. We also aim to identify clinical and imaging biomarkers at baseline that could be predictive of a favourable or a negative outcome of SCS and improve patient selection., Methods and Analysis: A total of 14 patients will be assessed with clinical rating scales and gait evaluations at baseline, and at 6 and 12 months after SCS implantation. They will also receive serial 18 F-deoxyglucose and 18 FEOBV PET scans to assess the effects of SCS on cortical/subcortical activity and brain cholinergic function. The first two patients will be included in an open pilot study while the rest will be randomised to receive active treatment or placebo (no stimulation) for 6 months. From this point, the entire cohort will enter an open label active treatment phase for a subsequent 6 months., Ethics and Dissemination: This study was reviewed and approved by the Committee on Health Research Ethics, Central Denmark RM. It is funded by the Danish Council for Independent Research. Independent of outcome, the results will be published in peer-reviewed journals and presented at national and international conferences., Trial Registration Number: NCT05110053; ClinicalTrials.gov Identifier., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Chronic neuropathic pain is often very difficult to treat effectively and constitutes a significant burden on both the affected patients and society. Invasive neuromodulation, electrical stimulation of specific nerve structures with implanted electrodes, can be a viable treatment option for patients suffering from severe, chronic neuropathic pain where conventional treatment has not provided sufficient pain relief. Careful patient selection is vital. This paper provides an overview of the treatment field in Denmark.

Introduction: Endoscopic third ventriculostomy (ETV) is becoming an increasingly widespread treatment for hydrocephalus, but research is primarily based on paediatric populations. In 2009, Kulkarni et al created the ETV Success score to predict the outcome of ETV in children. The purpose of this study is to create a prognostic model to predict the success of ETV for adult patients with hydrocephalus. The ability to predict who will benefit from an ETV will allow better primary patient selection both for ETV and shunting. This would reduce additional second procedures due to primary treatment failure. A success score specific for adults could also be used as a communication tool to provide better information and guidance to patients., Methods and Analysis: The study will adhere to the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis reporting guidelines and conducted as a retrospective chart review of all patients≥18 years of age treated with ETV at the participating centres between 1 January 2010 and 31 December 2018. Data collection is conducted locally in a standardised database. Univariate analysis will be used to identify several strong predictors to be included in a multivariate logistic regression model. The model will be validated using K-fold cross validation. Discrimination will be assessed using area under the receiver operating characteristic curve (AUROC) and calibration with calibration belt plots., Ethics and Dissemination: The study is approved by appropriate ethics or patient safety boards in all participating countries., Trial Registration Number: NCT04773938; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The discovery and application of induced pluripotent stem cells (iPSCs) provide a novel treatment modality for diseases, which remain incurable. Particularly, in the treatment of neurodegenerative diseases such as Parkinson's disease (PD), iPSC‑technology holds an interesting prospect for replacement therapy. Currently, the prognostic improvement of PD is limited and relies on symptomatic treatment. However, the symptomatic dopamine‑replacement therapies lose their long‑duration responses, and novel regenerative treatment modalities are needed. Animal models have provided valuable information and identified pathogenic mechanisms underlying PD but the lack of models that recapitulate the complex pathophysiology of the disease postpones further development of novel therapeutics. This review summarizes the possible uses of iPSCs in PD and discusses the future investigations needed for iPSCs as a possible treatment of PD patients.

A 60-year-old male patient with a large infected cranial apex lesion was admitted with lethargy and mental status changes. The patient underwent evaluation with imaging studies, a skin biopsy, cultures with microscopy and a diagnostic burr hole. MRI and positron emission tomography/CT scan revealed a squamous cell carcinoma with ingrowth in the midline of the brain and subdural empyema infected with Streptococcus anginosus and Staphylococcus aureus High dose intravenous antibiotic treatment was initiated and the patient subsequently underwent a surgical resection of the carcinoma with a 1 cm margin of surrounding skin and skull. The defect was reconstructed using a titanium plate and a free microvascular lattisimus dorsi muscle flap then covered with a split skin graft.The patient received 37 radiation therapy sessions (66 GY) as adjuvant therapy.Intensive neurorehabilitation slowly improved an initial paraparesis. The 7-month follow-up revealed a satisfactory cosmetic result and residual gait impairment secondary to central nervous system invasion., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The aim was to establish a non-primate large animal PD model by lentiviral vector mediated mutant alpha-synuclein overexpression in the substantia nigra. Lentivirus encoding A53T alpha-synuclein (6 x 2.5 μl) was stereotaxically injected into the substantia nigra of six adult female Göttingen minipigs. Contralateral control injections encoding enhanced green fluorescent protein (EGFP) were performed. Gait-analysis was performed pre- and postoperatively. PCR of the transgenes and immunohistochemical staining against alpha-synuclein, EGFP, GFAP and TH was performed after 20 weeks. Gait analysis revealed a significant increase in step length and height, and a decrease in the double stand phase. PCR verified the mesencephalic presence of transgenes. IHC analysis showed alpha-synuclein expression in nigral neurons, around the injection tract and in related nigrostriatal projections. The alpha-synuclein positive neurons appeared swollen and vacuolated, in contrast to the EGFP-injected control side. To transduct all nigrostriatal cells with few microinjections, wider dissemination of the transgene must be achieved.