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Objective: Occipital Nerve Stimulation (ONS) is increasingly used to treat a range of chronic, refractory headache conditions, most notably chronic cluster headache (CCH). Despite this, there is still no consensus on the optimal implantation technique. Clinical reports and reviews in the field have reported remarkably high complication rates of which several can be directly related to the surgical approach. We here describe a comprehensive and detailed surgical approach used at Aarhus University Hospital, Denmark, aiming to improve paresthesia coverage and minimize complications., Methods: The implantation procedure described here is performed with a sleep-awake anesthetic regimen in a lateral position using anatomical landmarks and perioperative testing based on patient feedback. A single lead is subcutaneously implanted from behind the ear and across the back of the head, and the implantable pulse generator (IPG) is placed below the right clavicle., Results: From March 2018 to June 2024, 45 CCH patients were implanted using this approach and followed up for a total of 86.3 patient years. A total of 22 adverse events (AEs) occurred in 17 patients, with nine AEs requiring revision surgery. Notably, no instances of lead migration, lead breakage, or muscle/neck stiffness were observed. Temporary occipital dysesthesia was the most frequent non-surgical AE, resolving spontaneously within weeks. The rate of serious adverse events (SAEs) was one per 9.6 patient years. Six patients had the ONS system explanted due to lack of efficacy., Conclusions: The surgical approach described here in detail offers several advantages, with a favorable complication profile, satisfactory paresthesia coverage, and good perioperative patient comfort. Advances in the surgical technique are vital to both patients and healthcare providers, and we believe this approach is a valuable contribution toward improved patient outcomes and procedural efficiency., (© 2024 World Institute of Pain.)

Background: Chronic cluster headache (CCH) is an excruciatingly painful condition that can be difficult to treat sufficiently with the available medical treatment options. The greater occipital nerves (GON) are of major interest in treating CCH, and various invasive treatment modalities, such as stimulating or blocking the nerves, have been applied. Because the terminal segment of the GON has a superficial course, the nerve is also accessible for non-invasive transcutaneous stimulation. Transcutaneous electrical nerve stimulation (TENS) has been suggested as a treatment for different chronic headaches, but evidence of the efficacy in patients with CCH is scarce. Additionally, no consensus exists on the optimal placement of the transcutaneous stimulation electrodes or the treatment usage pattern., Methods: In this explorative open-label clinical study, 36 patients with CCH were treated with TENS of the GON for 8-12 consecutive weeks between August 2021 and October 2023 as a separate part of the study protocol for a trial on stimulation of the GON (Clinicaltrials.gov identifier: NCT05023460). After a baseline period, TENS was used primarily as a preventive treatment, stimulating for 30 min twice daily at a minimum. The primary outcome was a change in attack frequency and safety with TENS treatment. Secondary outcomes were change in attack duration and pain intensity on the numeric rating scale, abortive treatments, and the Patient Global Impression of Change (PGIC) with TENS treatment. The change in attack frequency, duration, pain intensity, and use of abortive treatment was analyzed by comparing the baseline data with 4-weekly data from TENS treatment. The study aimed to systematically investigate the effect of TENS of the GON as a preventive treatment for CCH., Results: Weekly attack frequency decreased from a median of 15.7 (95% confidence interval [CI] 11.2-22.1) at baseline to 11.0 (95% CI 7.4-16.4) with TENS. In all, 13 of the 36 (36%) patients had a minimum 30% reduction in attack frequency. In the group of 30% responders, the number of weekly attacks decreased from 15.8 (95% CI 9.8-24.5) at baseline to 5.8 (95% CI 3.3-10.5) attacks with TENS. Five patients became entirely or nearly attack-free. For the entire cohort, attack duration and pain intensity were also significantly reduced with TENS. The use of oxygen was reduced by 42%, and triptan injections decreased by 55%. Overall, 15 (42%) patients reported a clinically important improvement with TENS treatment, rated on the PGIC scale. The 100 Hz stimulation programs were preferred over 10 Hz. No serious adverse events were registered., Conclusion: Transcutaneous electrical nerve stimulation of the GON significantly reduced the frequency, intensity, and duration of weekly headache attacks in patients with severe CCH. Not all patients benefitted from TENS, but the treatment responders had a substantial improvement in their cluster headache. TENS treatment was well-tolerated with little or no side effects and could be a relevant supplement to conventional preventive treatment. A standard TENS apparatus is low cost, making the treatment accessible to most patients. This paper includes a detailed, comprehensive description of our clinical application of the therapy., (© 2024 American Headache Society.)

Background: There has been an increased focus on patient involvement in health care worldwide, with studies showing that involving patients in their treatment and care is associated with positive outcomes. However, there is a dearth of knowledge about inpatient preferences and experiences of involvement in neurosurgery in Scandinavian countries. This study aimed to identify inpatients' preferences regarding their involvement in their treatment and the extent to which they experienced being involved in their treatment and care during admission., Methods: A questionnaire survey was administered in a neurosurgical department. Patients' preferences and experiences regarding their involvement in their treatment and care were assessed using a validated questionnaire., Results: One hundred patients were enrolled in the study. Eighty-two percent of them preferred sharing responsibility for their treatment with their doctor; 16% preferred leaving their treatment decisions entirely up to the doctor; and 2 percent preferred making the final decision about their treatment independently. The average participation score for information, communication, and participation was 4.08, suggesting that the patients experienced a high level of involvement in their care and treatment. Thirty patients reported preferences for changes during admission, while 25 suggested ideas for improvement., Conclusions: The patients mostly preferred shared decision-making about their treatment during hospitalization and generally reported high involvement in their treatment and care. The results showed a desire for improved information sharing and dialog among healthcare professionals, patients, and relatives., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The subgenual gyrus is a promising target for deep brain stimulation (DBS) against depression. However, to optimize this treatment modality, we need translational animal models., Aim: To describe the anatomy and connectivity of the Göttingen minipig subgenual area (sgC)., Materials and Methods: The frontal pole of 5 minipigs was cryosectioned into 40 μm coronal and horizontal sections and stained with Nissl and NeuN-immunohistochemistry to visualize cytoarchitecture and cortical lamination. Eight animals were unilaterally stereotaxically injected in the sgC with anterograde (BDA) and retrograde (FluoroGold) tracers to reveal the sgC connectivity., Results: In homology with human nomenclature (Brodmann 1909), the minipig sgC can be subdivided into three distinct areas named area 25 (BA25), area 33 (BA33), and indusium griseum (IG). BA25 is a thin agranular cortex, approximately 1 mm thick. Characteristically, perpendicular to the pial surface, cell-poor cortical columns separate the otherwise cell-rich cortex of layer II, III and V. In layer V the cells are of similar size as seen in layer III, while layer VI contains more widely dispersed neurons. BA33 is less differentiated than BA25. Accordingly, the cortex is thinner and displays a complete lack of laminar differentiation due to diffusely arranged small, lightly stained neurons. It abuts the IG, which is a neuron-dense band of heavily stained small neurons separating BA33 directly from the corpus callosum and the posteriorly located septal nuclear area. Due to the limited area size and nearby location to the lateral ventricle and longitudinal cerebral fissure, only 3/8 animals received sgC injections with an antero- and retrograde tracer mixture. Retrograde tracing was seen primarily to the neighbouring ipsilateral ventral- and mPFC areas with some contralateral labelling as well. Prominent projections were furthermore observed from the ipsilateral insula, the medial aspect of the amygdala and the hippocampal formation, diencephalon and the brainstem ventral tegmental area. Anterograde tracing revealed prominent projections to the neighbouring medial prefrontal, mPFC and cingulate cortex, while moderate staining was noted in the hippocampus and adjoining piriform cortex., Conclusion: The minipig sgC displays a cytoarchitectonic pattern and connectivity like the human and may be well suited for further translational studies on BA25-DBS against depression., (© 2024. The Author(s).)

Background: Patients receiving a brain cancer diagnosis may face cognitive decline and a poor prognosis. In addition, they suffer from a high symptom burden in a complex cancer pathway. The aim of this study was to investigate the early hospital experiences of brain tumour patients during the diagnostic and surgical treatment phase., Methods: A descriptive longitudinal single-case study design was used, and data were analysed via systematic text condensation., Results: The patients' experiences of being diagnosed with and treated for brain cancer were interpreted in terms of the central theme: a fast transition into an unknown journey. This theme consisted of the following subthemes: emotionally overwhelmed, putting life on hold and an unfamiliar dependency., Conclusions: Patients diagnosed with brain cancer struggle with overwhelming emotions due to this sudden life-threatening diagnosis, their fear of brain surgery and their progressing dependence. Patients did not voice their feelings, fears or needs, so these may easily be overlooked and unmet. A proactive and continuous care approach throughout the diagnostic phase is needed to support these patients., (© 2024 Nordic College of Caring Science.)

Objective: A comparison of cryoneurolysis or radio frequency (RF) with placebo in patients with facetogenic chronic low back pain (LBP) for patient global impression of change (PGIC), pain intensity, function and quality of life, with 1-year follow-up., Design: Single-centre, single-blinded placebo-controlled randomised controlled trial., Setting: Single-centre study., Participants: Inclusion from March 2020 to September 2022: consenting adults over 18 years of age, LBP>3 months, average Numeric Rating Scale LBP≥4 average last 14 days and a positive response to a diagnostic medial branch block ( > 50% pain reduction after 60 min)., Interventions: 120 patients were block randomised 1:1:1 to cryoneurolysis, RF or placebo of the medial branch nerves. Physical therapy was added after 4 weeks for all groups., Main Outcome Measures: Primary outcome was PGIC 4 weeks after the intervention. Secondary outcomes included pain intensity (Numeric Rating Scale, NRS), quality of life (Short Form 36, EQ-5D-5L), disability (Oswestry Disability Index), depression (Major Depression Inventory) and catastrophising (Pain Catastrophising Scale). Outcomes were measured at 4 weeks, 3, 6 and 12 months., Results: There was no statistically significant difference in PGIC at 4 weeks between cryoneurolysis and placebo (risk ratio (RR) 2; 95% CI 0.75 to 5.33, p=0.17) and RF and placebo (RR 1.6; 95% CI 0.57 to 4.49, p=0.37), except PGIC for cryoneurolysis at 6-month follow-up (RR 5.1; 95% CI 1.20 to 22.03, p=0.03). No statistically significant differences were found in secondary follow-up endpoints., Conclusions: Denervation of the medial branch nerve by either cryoneurolysis or RF compared with placebo did not demonstrate significant improvement in PGIC, pain intensity, function and quality of life in patients with facetogenic chronic LBP at short-term or long-term follow-up., Trial Registration Number: NCT04786145., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Chronic cluster headache (CCH) is a debilitating primary headache disorder. Occipital nerve stimulation (ONS) has shown the potential to reduce attack frequency, but the occipital paresthesia evoked by conventional (tonic) stimulation challenges a blinded comparison of active stimulation and placebo. Burst ONS offers paresthesia-free stimulation, enabling a blinded, placebo-controlled study. Identification of a feasible preoperative test would help select the best candidates for implantation. This study aims to explore ONS as a preventive treatment for CCH, comparing burst stimulation to tonic stimulation and placebo, and possibly identifying a potential preoperative predictor., Methods: An investigator-initiated, double-blinded, randomized, placebo-controlled trial is conducted, including 40 patients with CCH. Eligible patients complete a trial with the following elements: I) four weeks of baseline observation, II) 12 weeks of transcutaneous electrical nerve stimulation (TENS) of the occipital nerves, III) implantation of a full ONS system followed by 2 week grace period, IV) 12 weeks of blinded trial with 1:1 randomization to either placebo (deactivated ONS system) or burst (paresthesia-free) stimulation, and V) 12 weeks of tonic stimulation. The primary outcomes are the reduction in headache attack frequency with TENS and ONS and treatment safety. Secondary outcomes are treatment efficacy of burst versus tonic ONS, the feasibility of TENS as a predictor for ONS outcome, reduction in headache pain intensity (numeric rating scale), reduction in background headache, the patient's impression of change (PGIC), health-related quality of life (EuroQoL-5D), self-reported sleep quality, and symptoms of anxiety and depression (Hospital Anxiety and Depression Scale, HADS). Data on headache attack characteristics are registered weekly. Data on patient-reported outcomes are assessed after each trial phase., Discussion: The study design allows a comparison between burst ONS and placebo in refractory CCH and enables a comparison of the efficacy of burst and tonic ONS. It will provide information about the effect of burst ONS and explore whether the addition of this stimulation paradigm may improve stimulation protocols. TENS is evaluated as a feasible preoperative screening tool for ONS outcomes by comparing the effect of attack prevention of TENS and tonic ONS., Trial Registration: The study is registered at Clinicaltrials.gov (trial registration number NCT05023460, registration date 07-27-2023)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objectives and Background: Chronic cluster headache (CCH) is a rare but severely debilitating primary headache condition. A growing amount of evidence suggests that occipital nerve stimulation (ONS) can offer effective treatment in patients with severe CCH for whom conventional medical therapy does not have a sufficient effect. The paresthesia evoked by conventional (tonic) stimulation can be bothersome and may thus limit therapy. Burst ONS produces paresthesia-free stimulation, but the amount of evidence on the efficacy of burst ONS as a treatment for intractable CCH is scarce., Methods: In this case series, we report 15 patients with CCH treated with ONS at Aarhus University Hospital, Denmark, from 2013 to 2020. Nine of these received burst stimulation either as primary treatment or as a supplement to tonic stimulation. The results were assessed in terms of the frequency of headache attacks per week and their intensity on the Numeric Rating Scale, as well as the Patient Global Impression of Change (PGIC) with ONS treatment., Results: At a median (range) follow-up of 38 (16-96) months, 12 of the 15 patients (80%) reported a reduction in attack frequency of ≥50% (a reduction from a median of 35 to 1 attack/week, p < 0.001). Seven of these patients were treated with burst ONS. A significant reduction was also seen in maximum pain intensity. Overall, 10 patients stated a clinically important improvement in their headache condition following ONS treatment, rated on the PGIC scale. A total of 16 adverse events (nine of which were in the same patient) were registered., Conclusion: Occipital nerve stimulation significantly reduced the number of weekly headache attacks and their intensity. Burst ONS seems to function well alone or as a supplement to conventional tonic ONS as a preventive treatment for CCH; however, larger prospective studies are needed to determine whether the effect can be confirmed and whether the efficacy of the two stimulation paradigms is even., (© 2023 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

We describe virtual reality (VR) used as an effective intervention to treat severe chronic neuropathic pain in an otherwise healthy adolescent boy. The patient presented with severe pain and allodynia in the right foot after calcaneus extension surgery. Multiple medical and psychological interventions were unsuccessful over 3 years, with the pain leading the patient to drop out of school. VR gaming intervention provided the patient with significant pain relief and substantial improvement in functionality. This case report details the VR intervention and its effect on the patient's severe, medically refractory pain syndrome., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Anesthesia Research Society.)

The noradrenaline system attracts attention for its role in mood disorders and neurodegenerative diseases but the lack of well-validated methods impairs our understanding when assessing its function and release in vivo. This study combines simultaneous positron emission tomography (PET) and microdialysis to explore if [ 11 C]yohimbine, a selective antagonist radioligand of the α2 adrenoceptors, may be used to assess in vivo changes in synaptic noradrenaline during acute pharmacological challenges. Anesthetised Göttingen minipigs were positioned in a head holder in a PET/CT device. Microdialysis probes were placed in the thalamus, striatum and cortex and dialysis samples were collected every 10 min. Three 90 min [ 11 C]yohimbine scans were acquired: at baseline and at two timepoints after the administration of amphetamine (1-10 mg/kg), a non-specific releaser of dopamine and noradrenaline, or nisoxetine (1 mg/kg), a specific noradrenaline transporter inhibitor. [ 11 C]yohimbine volumes of distribution (V T ) were obtained using the Logan kinetic model. Both challenges induced a significant decrease in yohimbine V T , with time courses reflecting their different mechanisms of action. Dialysis samples revealed a significant increase in noradrenaline extracellular concentrations after challenge and an inverse correlation with changes in yohimbine V T . These data suggest that [ 11 C]yohimbine can be used to evaluate acute variations in synaptic noradrenaline concentrations after pharmacological challenges.

Objectives: Spinal cord stimulation (SCS) is a treatment for chronic neuropathic pain. It is based on the delivery of electric impulses to the spinal cord, traditionally in a regular square-wave pattern ("tonic" stimulation) and, more recently, in a rhythmic train-of-five "BurstDR" pattern. The safety of active SCS therapy in pregnancy is not established, and recommendations are based on limited casuistic evidence. We present in this study clinical data on a case series of six women treated with burst SCS during pregnancy. In addition, we present the ultrasonographic flow measurements of fetal and uteroplacental blood flow in a pregnant patient., Materials and Methods: Patients were included if they had been implanted with a full SCS system at Aarhus University Hospital, Denmark, between 2006 and 2020 and received active burst SCS stimulation during a pregnancy. Telephone interviews were conducted, including details on SCS therapy, medication, pregnancy course and outcome, and health status of the offspring. In one patient, the uteroplacental and fetal blood flow was assessed in gestational week 29 by Doppler flow measurements performed during both ON and OFF phases of the SCS system., Results: Six patients were included with a total of 11 pregnancies. Three pregnancies ended in miscarriages, all in the same patient who had preexisting significant risk factors for miscarriage. Eight resulted in a live-born child with normal birth weight for gestational age; seven were born at term, and one was born late preterm, in gestational week 36. Ultrasonographic Doppler flow, measured in one patient, was normal and did not reveal any immediate changes between burst SCS ON and OFF. Seven children were reported healthy with normal neurodevelopment and one physically healthy but with developmental delays., Conclusions: The data presented in this study add to the accumulating evidence of the safety of SCS in pregnancy., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflict of Interest The authors declare no conflict of interests.

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.)

Introduction: Disabling gait symptoms, especially freezing of gait (FoG), represents a milestone in the progression of Parkinson's disease (PD). This systematic review and network meta-analysis assessed and ranked interventions according to their effectiveness in treating gait symptoms in people with PD across four different groups of gait measures., Methods: A systematic search was carried out across PubMed, EMBASE, PubMed Central (PMC), and Cochrane Central Library from January 2000 to April 2021. All interventions, or combinations, were included. The primary outcome was changes in objective gait measures, before and after intervention. Outcome measures in the included studies were stratified into four different types of gait outcome measures; dynamic gait, fitness, balance, and freezing of gait. For the statistical analysis, five direct head-to-head comparisons of interventions, as well as indirect comparisons were performed. Corresponding forest plots ranking the interventions were generated., Results: The search returned 6288 articles. From these, 148 articles could be included. Of the four different groups of measurement, three were consistent, meaning that there was agreement between direct and indirect evidence. The groups with consistent evidence were dynamic gait, fitness, and freezing of gait. For dynamic gait measures, treatments with the largest observed effect were Aquatic Therapy with dual task exercising (SMD 1.99 [- 1.00; 4.98]) and strength and balance training (SMD 1.95 [- 0.20; 4.11]). For measures of fitness, treatments with the largest observed effects were aquatic therapy (SMD 3.41 [2.11; 4.71] and high-frequency repetitive transcranial magnetic stimulation (SMD 2.51 [1.48; 3.55]). For FoG measures, none of the included interventions yielded significant results., Conclusion: Some interventions can ameliorate gait impairment in people with PD. No recommendations on a superior intervention can be made. None of the studied interventions proved to be efficacious in the treatment of FoG. PROSPERO (registration ID CRD42021264076)., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: 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., New Method: 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., Results: 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., Comparisons With Existing Method: 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., Conclusions: 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., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

The Göttingen minipig is a large animal with a gyrencephalic brain that expresses -complex behavior, making it an attractive model for Parkinson's disease research. Here, we investigate the temporal evolution of presynaptic dopaminergic function for 14 months after injections of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the minipig using a multi-tracer longitudinal positron emission tomography (PET) design. We injected seven sedated minipigs with 1-2 mg/kg of MPTP, and two with saline, three times a week over four weeks. We monitored behavioral deficits using a validated motor scale and walking mat. Brains were imaged with (+)-⍺-[ 11 C]-dihydrotetrabenazine ([ 11 C]-DTBZ) and [ 18 F]-dihydroxyphenylalanine ([ 18 F]-FDOPA) PET at baseline and 1, 3, 10 and 14 months after MPTP injection, and immunohistochemistry was used to assess nigral cell loss. The minipigs showed mild bradykinesia and impaired coordination at early timepoints after MPTP. PET revealed decreases of striatal [ 11 C]-DTBZ and [ 18 F]-FDOPA uptake post-MPTP with partial spontaneous recovery of [ 18 F]-FDOPA after 10 months. Postmortem analysis estimated an MPTP-induced nigral loss of 57% tyrosine hydroxylase+ and 43% Nissl-stained cells. Normal motor function despite substantial damage to the dopaminergic system is consistent with prodromal Parkinson's disease, and offers an opportunity for testing disease-modifying therapies. However, partial spontaneous recovery of dopamine terminal function must be taken into account in future studies., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Modulation of pathological neural circuit activity in the brain with a minimum of complications is an area of intense interest., Objective: The goal of the study was to alter neurons' physiological states without apparent damage of cellular integrity using stereotactic radiosurgery (SRS)., Methods: We treated a 7.5 mm-diameter target on the visual cortex of Göttingen minipigs with doses of 40, 60, 80, and 100 Gy. Six months post-irradiation, the pigs were implanted with a 9 mm-wide, eight-shank multi-electrode probe, which spanned the radiation focus as well as the low-exposure neighboring areas., Results: Doses of 40 Gy led to an increase of spontaneous firing rate, six months post-irradiation, while doses of 60 Gy and greater were associated with a decrease. Subjecting the animals to visual stimuli resulted in typical visual evoked potentials (VEP). At 40 Gy, a significant reduction of the P1 peak time, indicative of higher network excitability was observed. At 80 Gy, P1 peak time was not affected, while a minor reduction at 60 Gy was seen. No distance-dependent effects on spontaneous firing rate, or on VEP were observed. Post-mortem histology revealed no evidence of necrosis at doses below 60 Gy. In an in vitro assay comprising of iPS-derived human neuron-astrocyte co-cultures, we found a higher vulnerability of inhibitory neurons than excitatory neurons with respect to radiation, which might provide the cellular mechanism of the disinhibitory effect observed in vivo., Conclusion: We provide initial evidence for a rather circuit-wide, long-lasting disinhibitory effect of low sub-ablative doses of SRS., Competing Interests: Declaration of competing interest GW, WC, PR, CJ, MBS, and JRA are employees of, and own stock in Zap Surgical Systems, Inc, a company that has patents in the field of stereotactic radiosurgery and neuromodulation. TP, JYH and CN are employees of NeuCyte, Inc. The above listed interests did not have influence on the results of the experiments. Other authors declare that they have no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Steinmüller, Bjarkam, Orlowski, Sørensen and Glud.)

Background: Complex regional pain syndrome (CRPS) is a debilitating pain condition often resistant to standard treatment modalities. In these cases, spinal cord stimulation (SCS) can be an option, but the effect on CRPS remains disputed. We aimed to assess the long-term effect of SCS on CRPS., Methods: We retrospectively analysed 51 CRPS patients implanted with an SCS system at the University Hospitals in Aarhus or Odense, Denmark, with a median follow-up time of 4.4 years. Primary outcomes were pain intensity on a numeric rating scale (NRS) and the Patients' Global Impression of Change (PGIC). Secondary outcomes were patient satisfaction, work status, consumption of pain medication, the Major Depression Inventory (MDI), Pain Catastrophizing Scale (PCS) and quality of life (QoL) measured using the Short-Form Health Survey (SF-36). For each outcome measure, baseline data were compared to the latest collected data point., Results: A significant pain relief was found with a mean reduction in NRS score of 2.4 (95% CI: 1.7-3.0, p < 0.0001). 68.8% reported 'much improved' or 'very much improved' on the PGIC scale. 87.5% would choose SCS again for the same outcome. A significant beneficial impact was found on MDI score, PCS, SF-36 summary scores and consumption of tricyclic antidepressants, antiepileptic drugs and opioids. No statistical effect was found on work status., Conclusion: Pain intensity, depression, pain catastrophizing, pain medication use and QoL were significantly improved after SCS implantation, with high patient satisfaction rates in CRPS patients. This study supports the continued use of SCS in the treatment of severe CRPS., Significance: This study presents detailed data from a large, well-characterized cohort of Danish CRPS patients treated with SCS, analyzing several outcome measures. The results serve to document SCS as an effective treatment for severe CRPS and expands the cumulative level of evidence in favor of its use. Additionally, analysis of preoperative patient characteristics suggests that SCS treatment should not be withheld in patients with a high degree of psychological distress or high consumption of analgesics., (© 2021 European Pain Federation - EFIC®.)

Background: OptimalTTF-2 is a randomized, comparative, multi-center, investigator-initiated, interventional study aiming to test skull remodeling surgery in combination with Tumor Treating Fields therapy (TTFields) and best physicians choice medical oncological therapy for first recurrence in glioblastoma patients. OptimalTTF-2 is a phase 2 trial initiated in November 2020. Skull remodeling surgery consists of five burrholes, each 15 mm in diameter, directly over the tumor resection cavity. Preclinical research indicates that this procedure enhances the effect of Tumor Treating Fields considerably. We recently concluded a phase 1 safety/feasibility trial that indicated improved overall survival and no additional toxicity. This phase 2 trial aims to validate the efficacy of the proposed intervention., Methods: The trial is designed as a comparative, 1:1 randomized, minimax two-stage phase 2 with an expected 70 patients to a maximum sample size of 84 patients. After 12-months follow-up of the first 52 patients, an interim futility analysis will be performed. The two trial arms will consist of either a) TTFields therapy combined with best physicians choice oncological treatment (control arm) or b) skull remodeling surgery, TTFields therapy and best practice oncology (interventional arm). Major eligibility criteria include age ≥ 18 years, 1st recurrence of supratentorial glioblastoma, Karnofsky performance score ≥ 70, focal tumor, and lack of significant co-morbidity. Study design aims to detect a 20% increase in overall survival after 12 months (OS12), assuming OS12 = 40% in the control group and OS12 = 60% in the intervention group. Secondary endpoints include hazard rate ratio of overall survival and progression-free survival, objective tumor response rate, quality of life, KPS, steroid dose, and toxicity. Toxicity, objective tumor response rate, and QoL will be assessed every 3rd month. Endpoint data will be collected at the end of the trial, including the occurrence of suspected unexpected serious adverse reactions (SUSARs), unacceptable serious adverse events (SAEs), withdrawal of consent, or loss-to-follow-up., Discussion: New treatment modalities are highly needed for first recurrence glioblastoma. Our proposed treatment modality of skull remodeling surgery, Tumor Treating Fields, and best practice medical oncological therapy may increase overall survival significantly., Trial Registration: ClinicalTrials.gov Identifier: NCT0422399 , registered 13. January 2020., (© 2021. The Author(s).)

The pituitary is involved in the regulation of endocrine homeostasis. Therefore, animal models of pituitary disease based on a thorough knowledge of pituitary anatomy are of great importance. Accordingly, we aimed to perform a qualitative and quantitative description of polypeptide hormone secreting cellular components of the Göttingen minipig adenohypophysis using immunohistochemistry and stereology. Estimates of the total number of cells immune-stained for adrenocorticotrophic hormone (ACTH), prolactin (PRL), and growth hormone (GH) were obtained with the optical fractionator technique using Stereo Investigator software. Moreover, 3D reconstructions of cell distribution were made. We estimated that the normal minipig adenohypophysis contains, on average, 5.6 million GH, 3.5 million PRL, and 2.4 million ACTH producing cells. The ACTH producing cells were widely distributed, while the PRL and GH producing cells were located in clusters in the central and lateral regions of the adenohypophysis. The morphology of the hormone producing cells also differs. We visualized a clear difference in the numerical density of hormone producing cells throughout the adenohypophysis. The relative proportions of the cells analyzed in our experiment are comparable to those observed in humans, primates, and rodents; however, the distribution of cells differs among species. The distribution of GH cells in the minipig is similar to that in humans, while the PRL and ACTH cell distributions differ. The volume of the pituitary is slightly smaller than that of humans. These data provide a framework for future large animal experimentation on pituitary function in health and disease., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Dorsal root ganglion (DRG) stimulation is a novel treatment of chronic neuropathic pain and has been shown to be efficacious across several case reports and randomized trials. However, long-term follow-up is limited, as are reports of complication rates. This study presents efficacy and complications for patients treated with DRG stimulation., Materials and Methods: We performed an observational, multicenter cohort study of all patients in Denmark implanted with FDA-approved DRG stimulation systems to treat chronic, neuropathic pain between 2014 and 2018. Follow-up period was one to three years., Results: Forty-three patients underwent trial DRG stimulation; 33 were subsequently fully implanted. Pain location: 58% lower extremity; 21% upper extremity; 21% thoracic/abdominal. At the end of the observation period, 58% of fully implanted patients were still implanted; 42% had fully functional systems. In these patients, average Numerical Rating Scale (NRS)-score of pain was reduced from 6.8 to 3.5 (p = 0.00049) and worst NRS-score was reduced from 8.6 to 6.0 (p = 0.0039) at 12 months follow-up. Pain Catastrophizing Score was reduced from 32 to 15 (p = 0.0039). Thirteen patients experienced complications related to defect leads (39% of implanted systems). In four patients (12%), lead removal left fragments in the root canal due to lead fracture, and three patients suffered permanent nerve damage during attempts to replace broken leads., Conclusions: This study suggests a significant, clinically relevant effect of DRG stimulation on neuropathic pain, but also demonstrates substantial problems with maintenance and revision of currently available systems. Consequently, treatment with equipment marketed specifically for DRG stimulation is currently paused in Denmark., (© 2020 International Neuromodulation Society.)

Background: Low-back pain, including facet joint pain, accounts for up to 20 % of all sick leaves in DenmarkA proposed treatment option is cryoneurolysis. This study aims to investigate the effect of cryoneurolysis in lumbar facet joint pain syndrome., Methods: A single-center randomized controlled trial (RCT) is performed including 120 participants with chronic facet joint pain syndrome, referred to the Department of Neurosurgery, Aarhus University Hospital. Eligible patients receive a diagnostic anesthetic block, where a reduction of pain intensity ≥ 50 % on a numerical rating scale (NRS) is required to be enrolled. Participants are randomized into three groups to undergo either one treatment of cryoneurolysis, radiofrequency ablation or placebo. Fluoroscopy and sensory stimulation is used to identify the intended target nerve prior to administrating the above-mentioned treatments. All groups receive physiotherapy for 6 weeks, starting 4 weeks after treatment. The primary outcome is the patients' impression of change in pain after intervention (Patient Global Impression of Change (PGIC)) at 4 weeks follow-up, prior to physiotherapy. Secondary outcomes are a reduction in low-back pain intensity (numeric rating scale) and quality of life (EQ-5D, SF-36) and level of function (Oswestry Disability Index), psychological perception of pain (Pain Catastrophizing Scale) and depression status (Major Depression Inventory). Data will be assessed at baseline (T0), randomization (T1), day one (T2), 4 weeks (T3), 3 (T4), 6 (T5) and 12 months (T6)., Discussion: This study will provide information on the effectiveness of cryoneurolysis vs. the effectiveness of radiofrequency ablation or placebo for patients with facet joint pain, and help to establish whether cryoneurolysis should be implemented in clinical practice for this patient population., Trial Registration: The trial is approved by the ethical committee of Central Jutland Denmark with registration number 1-10-72-27-19 and the Danish Data Protection Agency with registration number 666,852. The study is registered at Clinicaltrial.gov with the ID number NCT04786145 .

Synapses in the cerebral cortex constantly change and this dynamic property regulated by the action of neuromodulators such as dopamine (DA), is essential for reward learning and memory. DA modulates spike-timing-dependent plasticity (STDP), a cellular model of learning and memory, in juvenile rodent cortical neurons. However, it is unknown whether this neuromodulation also occurs at excitatory synapses of cortical neurons in mature adult mice or in humans. Cortical layer V pyramidal neurons were recorded with whole cell patch clamp electrophysiology and an extracellular stimulating electrode was used to induce STDP. DA was either bath-applied or optogenetically released in slices from mice. Classical STDP induction protocols triggered non-hebbian excitatory synaptic depression in the mouse or no plasticity at human cortical synapses. DA reverted long term synaptic depression to baseline in mouse via dopamine 2 type receptors or elicited long term synaptic potentiation in human cortical synapses. Furthermore, when DA was applied during an STDP protocol it depressed presynaptic inhibition in the mouse but not in the human cortex. Thus, DA modulates excitatory synaptic plasticity differently in human vs. mouse cortex. The data strengthens the importance of DA in gating cognition in humans, and may inform on therapeutic interventions to recover brain function from diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Louth, Jørgensen, Korshoej, Sørensen and Capogna.)

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., Competing Interests: MBS and JRA are employees of Zap Surgical Systems, Inc., that funded this study, own stock, and have patents in the field of stereotactic radiosurgery without affecting the trial’s outcome. AD, QF, VG, and JM were employees of Triangle BioSystems International as a division of Harvard Bioscience Inc., however, did not have any influence on the result of the experiments. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zaer, Deshmukh, Orlowski, Fan, Prouvot, Glud, Jensen, Worm, Lukacova, Mikkelsen, Fitting, Adler, Schneider, Jensen, Fu, Go, Morizio, Sørensen and Stroh.)

Objective: Spinal cord stimulation (SCS) is an important treatment modality used to treat chronic neuropathic pain. However, reported success rates of 26%-70% entail an increased focus on patient selection. An area of core interest is psychological evaluation, often using scales such as the Pain Catastrophizing Scale (PCS). The aim of this study was to assess the relation between baseline PCS scores obtained before implantation and SCS outcomes defined as (1) Rating on Patients' Global Impression of Change scale (PGIC), (2) Pain relief on the Numeric Rating Scale (NRS), (3) Cessation of pain medication, and (4) Risk of permanent explantation., Materials and Methods: Using records from the Neurizon Neuromodulation Database, we performed a multicenter open cohort study of 259 permanently implanted SCS patients. Follow-up ranged from six months to nine years (median = three years). For each of the defined SCS outcomes, patients were grouped according to their latest follow-up registration. Subsequently, we used a one-way ANOVA and exact t-tests to compare mean baseline PCS scores between groups., Results: No difference in mean baseline PCS scores was found between PGIC groups. Baseline PCS scores was not associated with the probability of obtaining 30% or 50% pain relief on latest registration. Baseline PCS scores of patients able to cease all usage of tricyclic antidepressants, antiepileptics, or opioids during SCS treatment did not differ from baseline scores of continuous users. We found no association between baseline PCS scores and risk of permanent explantation., Conclusion: This study did not demonstrate any associations between baseline PCS scores and SCS outcomes., (© 2020 International Neuromodulation Society.)

The tsunami effect of the COVID-19 pandemic is affecting many aspects of scientific activities. Multidisciplinary experimental studies with international collaborators are hindered by the closing of the national borders, logistic issues due to lockdown, quarantine restrictions, and social distancing requirements. The full impact of this crisis on science is not clear yet, but the above-mentioned issues have most certainly restrained academic research activities. Sharing innovative solutions between researchers is in high demand in this situation. The aim of this paper is to share our successful practice of using web-based communication and remote control software for real-time long-distance control of brain stimulation. This solution may guide and encourage researchers to cope with restrictions and has the potential to help expanding international collaborations by lowering travel time and costs., (Copyright © 2020 Zaer, Fan, Orlowski, Glud, Andersen, Schneider, Adler, Stroh and Sørensen.)

Stereotactic radiosurgery (SRS) has proven an effective tool for the treatment of brain tumors, arteriovenous malformation, and functional conditions. However, radiation-induced therapeutic effect in viable cells in functional SRS is also suggested. Evaluation of the proposed modulatory effect of irradiation on neuronal activity without causing cellular death requires the knowledge of radiation dose tolerance at very small tissue volume. Therefore, we aimed to establish a porcine model to study the effects of ultra-high radiosurgical doses in small volumes of the brain. Five minipigs received focal stereotactic radiosurgery with single large doses of 40-100 Gy to 5-7.5 mm fields in the left primary motor cortex and the right subcortical white matter, and one animal remained as unirradiated control. The animals were followed-up with serial MRI, PET scans, and histology 6 months post-radiation. We observed a dose-dependent relation of the histological and MRI changes at 6 months post-radiation. The necrotic lesions were seen in the grey matter at 100 Gy and in white matter at 60 Gy. Furthermore, small volume radiosurgery at different dose levels induced vascular, as well as neuronal cell changes and glial cell remodeling.

Background: Preclinical studies suggest that skull remodeling surgery (SR-surgery) increases the dose of tumor treating fields (TTFields) in glioblastoma (GBM) and prevents wasteful current shunting through the skin. SR-surgery introduces minor skull defects to focus the cancer-inhibiting currents toward the tumor and increase the treatment dose. This study aimed to test the safety and feasibility of this concept in a phase I setting., Methods: Fifteen adult patients with the first recurrence of GBM were treated with personalized SR-surgery, TTFields, and physician's choice oncological therapy. The primary endpoint was toxicity and secondary endpoints included standard efficacy outcomes., Results: SR-surgery resulted in a mean skull defect area of 10.6 cm 2 producing a median TTFields enhancement of 32% (range 25-59%). The median TTFields treatment duration was 6.8 months and the median compliance rate 90%. Patients received either bevacizumab, bevacizumab/irinotecan, or temozolomide rechallenge. We observed 71 adverse events (AEs) of grades 1 (52%), 2 (35%), and 3 (13%). There were no grade 4 or 5 AEs or intervention-related serious AEs. Six patients experienced minor TTFields-induced skin rash. The median progression-free survival (PFS) was 4.6 months and the PFS rate at 6 months was 36%. The median overall survival (OS) was 15.5 months and the OS rate at 12 months was 55%., Conclusions: TTFields therapy combined with SR-surgery and medical oncological treatment is safe and nontoxic and holds the potential to improve the outcome for GBM patients through focal dose enhancement in the tumor., (© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: No PET radioligand has yet demonstrated the capacity to map glutamate N-methyl-d-aspartate receptor ion channel (NMDAR-IC) function. [ 18 F]GE-179 binds to the phencyclidine (PCP) site in open NMDAR-ICs and potentially provides a use-dependent PET biomarker of these ion channels., Objective: To show [ 18 F]GE-179 PET can detect increased NMDAR-IC activation during electrical deep brain stimulation (DBS) of pig hippocampus., Methods: Six minipigs had an electrode implanted into their right hippocampus. They then had a baseline [ 18 F]GE-179 PET scan with DBS turned off followed by a second scan with DBS turned on. Brain [ 18 F]GE-179 uptake at baseline and then during DBS was measured with PET. Cerebral blood flow (CBF) was measured with [ 15 O]H 2 O PET at baseline and during DBS and parametric CBF images were generated to evaluate DBS induced CBF changes. Functional effects of injecting the PCP blocker MK-801 were also evaluated. Electrode positions were later histologically verified., Results: DBS induced a 47.75% global increase in brain [ 18 F]GE-179 uptake (p = 0.048) compared to baseline. Global CBF was unchanged by hippocampal DBS. [ 18 F]GE-179 PET detected a 5% higher uptake in the implanted compared with the non-implanted temporo-parietal cortex at baseline (p = 0.012) and during stimulation (p = 0.022). Administration of MK-801 before DBS failed to block [ 18 F]GE-179 uptake during stimulation., Conclusion: PET detected an increase in global brain [ 18 F]GE-179 uptake during unilateral hippocampal DBS while CBF remained unchanged. These findings support that [ 18 F]GE-179 PET provides a use-dependent marker of abnormal NMDAR-IC activation., Competing Interests: Declaration of competing interest GE Healthcare supported the study by supplying the precursor for [(18)F]GE-179. DJB is a consultant for Biogen and has been a consultant for GE Healthcare, Plexxikon, and GenePod. These funders had no role in the study design, data analyses, data interpretation or writing of the article., (Copyright © 2020. Published by Elsevier Inc.)

Complex regional pain syndrome (CRPS) can be a debilitating, persistent, and treatment-resistant pain condition. This report presents a case of severe CRPS affecting multiple limbs, resistant to standard treatment modalities. Treatment with spinal cord stimulation (SCS) had an initial good effect. Nevertheless, the CRPS continued to progress, eventually affecting all 4 extremities. A lead fracture resulted in a rapidly developing recurrence of CRPS in the patient's arm, necessitating amputation. SCS may be an effective modality for treatment of severe CRPS. However, mechanical problems should always be considered when an SCS-implanted patient experiences rapid symptom progression or abrupt cessation of stimulation.

The limbic system encompasses a collection of brain areas primarily involved in higher cognitive and emotional processing. Altered function in the limbic circuitry may play a major role in various psychiatric disorders. This study aims to provide a high-quality ex vivo diffusion-weighted MRI (DWI) tractographic overview of the Göttingen minipig limbic system pathways, which are currently not well described. This may facilitate future translational large animal studies. The study used previously obtained post-mortem DWI scans in 3 female Göttingen minipigs aging 11-15 months. The tractography performed on the DWI data set was made using a probabilistic algorithm, and regions of interest (ROIs) were defined in accordance with a histological atlas. The investigated pathways included the fornix, mammillothalamic tract, stria terminalis, stria medullaris, habenulo-interpeduncular tract, and cingulum. All the investigated limbic connections could be visualized with a high detail yielding a comprehensive three-dimensional overview, which was emphasized by the inclusion of video material. The minipig limbic system pathways displayed using tractography closely resembled what was previously described in both human studies and neuronal tracing studies from other mammalian species. We encountered well-known inherent methodological challenges of tractography, e.g., partial volume effects and complex white matter regions, which may have contributed to derouted false-positive streamlines and the failure to visualize some of the minor limbic pathway ramifications. This underlines the importance of preexisting anatomical knowledge. Conclusively, we have, for the first time, provided an overview and substantial insight of the Göttingen minipig limbic system.

Tumor treating fields (TTFields) is a new non-invasive approach to cancer treatment. TTFields is low-intensity (1-5 V/m), intermediate frequency (150-200 kHz) alternating electric fields delivered locally to the tumour to selectively kill dividing cells and disrupt cancer growth. TTFields has proven safe and effective for newly diagnosed glioblastoma and is currently being tried for multiple other tumours. This review presents an introduction to TTFields, covering the main indications, the application method, the mechanism of action, the clinical results and the perspectives for implementation in Danish cancer treatment.

[This corrects the article DOI: 10.1016/j.heliyon.2019.e01363.].

Objectives: In spinal cord stimulation (SCS), the electrical stimulation of the spinal cord with an implanted lead evokes a tingling peripheral sensation known as paresthesias. Newer stimulation paradigms allow paresthesia-free treatment, but during the implantation of the lead, paresthesias must cover the painful area to achieve optimal treatment effect. The localization of the evoked paresthesias can be difficult to accurately describe for the patient, and furthermore depends on a complex and only partially predictable set of parameters that includes the anatomical localization and the programming of the electrical field. We aimed to optimize SCS implantation procedures by devising a way to aid the patient in making useful descriptions of the evoked paresthesias, then to visually convey the full set of information-anatomical position of the lead, programming parameters, and evoked paresthesias-directly to the implanting physician., Materials and Methods: To aid the patient in making accurate descriptions of the evoked paresthesia, we use an app dedicated to creating pain drawings on a tablet. We used Chromecast and Apple TV to project the information from the pain drawing tablet and the programming device to two monitors placed in the implanter's field of vision, right next to the fluoroscopy monitor., Results: The three monitors combined provide a direct visual representation of the dynamic dataset used during SCS implantation: Position, Programming, and Paresthesias, essentially creating the equivalent of the dashboard of a car., Conclusions: We present an Implanter's Integrated Information (I3) system; a simple, inexpensive solution for gathering, integrating, and conveying the complex set of information necessary for a successful SCS procedure., (© 2018 International Neuromodulation Society.)

Background: The high mortality and morbidity after SAH is partly due to DCI, which is traditionally ascribed to development of angiographic vasospasms. This relation has been challenged, and capillary flow disturbances are proposed as another mechanism contributing to brain damage after SAH., Objective: To investigate capillary flow changes 4 days following experimental SAH., Methods: SAH was induced by endovascular perforation of circle of Willis. We used TPM to evaluate blood flow characteristics. Cortical capillary diameters were investigated by both TPM and histology., Results: We found elevated CTH and MTT of blood in SAH mice compared to sham animals. We observed capillaries with stagnant RBCs, and capillaries with increased RBC LD in the SAH group, suggesting severe blood maldistribution among cortical capillaries. Favoring that these capillary flow changes were primary to upstream vasoconstrictions, TPM showed no significant differences in arteriolar diameter between groups, while histological examination showed reduced capillary diameter in SAH group., Conclusion: Our study shows profound subacute hypoperfusion and capillary flow disturbances in a mouse SAH model and suggests that these changes are the result of changes in capillary function, rather than upstream vasospasm., (© 2019 John Wiley & Sons Ltd.)

Background: The cytoarchitecture of the Göttingen minipig telencephalon has recently been elucidated in the published article (Bjarkam et al., 2017). The aim of the current paper is to describe how such data can be presented in an online histological atlas of the Gottingen minipig brain and how this atlas was constructed., Methods: Two sets of histological sections were used. One set was photographed in high resolution and labelled, the other set in low resolution (resized first set) was used for reference on the computer screen. The two sets of microphotographs enable, using the freely available JQuery Image Zoom Plugin, the subsequent construction of a simple HTML-based atlas web page with a "virtual microscope like" style, which allowed magnifying of the base image (low-resolution image) up to the maximum resolution of the high-resolution image. In addition, we describe how the established histological atlas can be accompanied by a set of similar T1-weighted MRI pictures., Results and Conclusion: Histological and MRI pictures are presented in atlas form on www.cense.dk/minipig&#95;atlas/index.html. The described pipeline represent a cheap and freely available way to present histological images, in online virtual microscopic atlas form, and may thus be of general interest to anyone who would like to present histological data accordingly.

Tumor treating fields (TTFields) are increasingly used to treat newly diagnosed and recurrent glioblastoma (GBM). Recently, the authors proposed a new and comprehensive method for efficacy estimation based on singular value decomposition of the sequential field distributions. The method accounts for all efficacy parameters known to affect anti-cancer efficacy of TTFields, i.e. intensity, exposure time, and spatial field correlation. In this paper, we describe a further development, which enables individual optimization of the TTFields activation cycle. The method calculates the optimal device settings to obtain a desired average field intensity in the tumor, while minimizing unwanted field correlation. Finite element (FE) methods were used to estimate the electrical field distribution in the head. The computational head model was based on MRI data from a GBM patient. Sequential field vectors were post-processed using singular value decomposition. A linear transformation was applied to the resulting field matrix to reduce fractional anisotropy (FA) of the principal field components in the tumor. Results were computed for four realistic transducer array layouts. The optimization method significantly reduced FA and maintained the average field intensity in the tumor. The algorithm produced linear gain factors to be applied to the transducer array pairs producing the sequential fields. FA minimization was associated with an increase in total current delivered through the head during a activation cycle. Minimized FA can be obtained for an unchanged total current level, albeit with a reduction in average field intensity. We present an algorithm for optimization of the TTFields activation cycle settings. The method can be used to minimize the spatial correlation between sequential TTFields, while adjusting the total current level and mean field intensity to a desired level. Future studies are needed to validate clinical impact and assess sensitivity towards model parameters.

Aim and Clinical Rationale for the Study: Spontaneous intracerebral haemorrhage (sICH) is an acute life-threatening injury and constitutes 10-15% of first-ever stroke cases. The Surgical Trials in Intracerebral Haematoma studies (STICH and STICH II) represent the two foremost studies in the field, however, with arguable shortcomings. To find more accurate criteria, we aimed to correlate the preoperative neurological and neuroimaging findings with the clinical outcome of operated patients., Materials and Methods: In this retrospective study, sICH patients were recruited from the Central Denmark Region from 2010 to 2016. We evaluated the patients' medical records regarding preoperative Glasgow Coma Scale (GCS) 6 months and one year after surgery, focal neurological defects, thrombolytic treatment, pupil status, and haemorrhage localization visualized by neuroimaging. The patients' clinical outcome was assessed using the Glasgow Outcome Scale (GOS)., Results: Based on logistic multiple linear analysis, age, basal ganglia haemorrhage and mass effect had significant effect on the mortality rate. Besides, age, basal ganglia haemorrhage, intra ventricular haemorrhage and pupil difference had significant correlation with good outcome (GOS>3)., Conclusions and Clinical Implications: Neurosurgical treatment of the sICH patients is indicated only if age and potentially improved morbidity is carefully evaluated considering the STICH and this study; otherwise, we will just increase the health care burden with a number of extremely care-dependent patients., (Copyright © 2018 Polish Neurological Society. Published by Elsevier Sp. z o.o. All rights reserved.)

Impairment of the ubiquitin proteasome system has been implicated in Parkinson's disease. We used positron emission tomography to investigate longitudinal effects of chronic intracerebroventricular exposure to the proteasome inhibitor lactacystin on monoaminergic projections and neuroinflammation. Göttingen minipigs were implanted in the cisterna magna with a catheter connected to a subcutaneous injection port. Minipigs were imaged at baseline and after cumulative doses of 200 and 400 μg lactacystin, respectively. Main radioligands included [ 11 C]-DTBZ (vesicular monoamine transporter type 2) and [ 11 C]-yohimbine (α2-adrenoceptor). [ 11 C]-DASB (serotonin transporter) and [ 11 C]-PK11195 (activated microglia) became available later in the study and we present their results in a smaller subset of animals for information purposes only. Striatal [ 11 C]-DTBZ binding potentials decreased significantly by 16% after 200 μg compared to baseline, but the decrease was not sustained after 400 μg (n = 6). [ 11 C]-yohimbine volume of distribution increased by 18-25% in the pons, grey matter and the thalamus after 200 μg, which persisted at 400 μg (n = 6). In the later subset of minipigs, we observed decreased [ 11 C]-DASB (n = 5) and increased [ 11 C]-PK11195 (n = 3) uptake after 200 μg. These changes may mimic monoaminergic changes and compensatory responses in early Parkinson's disease.

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., (© 2018 Anatomical Society.)

Background: Pigs and minipigs are increasingly used as non-primate large animal models for preclinical research on nervous system disorders resulting in motor dysfunction. Knowledge of the minipig pyramidal tract is therefore essential to support such models., Aim and Methods: This study used 5 female Göttingen minipigs aging 11-15 months. The Göttingen minipig corticospinal tract was investigated, in the same animals, with in vivo neuronal tracing and with postmortem diffusion weighted MRI tractography to provide a thorough insight in the encephalic distribution of this primary motor pathway and its decussation at the craniocervical junction., Results: The two methods similarly outlined the course of the pyramidal tract from its origin in the motor cortex down through the internal capsule to the craniocervical junction, where both methods displayed an axonal crossover at the pyramid decussation. The degree of crossover was quantified with unbiased stereology, where 81-93% of the traced corticospinal fibers crossed to the contralateral spinal cord. Accordingly, in the upper cervical spinal cord the corticospinal tract is primarily distributed in the contralateral lateral funiculus and in close relation to the gray matter, wherein some direct terminations on large ventral column gray matter neurons could be identified., Discussion: The combination of neuronal tracing and tractography exploited the strengths of the respective methods to gain a better understanding of the encephalic distribution and craniocervical decussation of the Göttingen minipig corticospinal tract. Moreover, a quantification of the crossing fibers was obtained from the tracing data, which was not possible with tractography. Our data indicate that the porcine corticospinal system is quite lateralized down to the investigated upper cervical levels. However, further elucidation of this point will require a full examination of the corticospinal tracing pattern into the caudal spinal cord combined with an analysis of the direct versus indirect termination pattern on the lower motor neurons., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Tumor treating fields (TTFields) is a new modality used for the treatment of glioblastoma. It is based on antineoplastic low-intensity electric fields induced by two pairs of electrode arrays placed on the patient's scalp. The layout of the arrays greatly impacts the intensity (dose) of TTFields in the pathology. The present study systematically characterizes the impact of array position on the TTFields distribution calculated in a realistic human head model using finite element methods. We investigate systematic rotations of arrays around a central craniocaudal axis of the head and identify optimal layouts for a large range of (nineteen) different frontoparietal tumor positions. In addition, we present comprehensive graphical representations and animations to support the users' understanding of TTFields. For most tumors, we identified two optimal array positions. These positions varied with the translation of the tumor in the anterior-posterior direction but not in the left-right direction. The two optimal directions were oriented approximately orthogonally and when combining two pairs of orthogonal arrays, equivalent to clinical TTFields therapy, we correspondingly found a single optimum position. In most cases, an oblique layout with the fields oriented at forty-five degrees to the sagittal plane was superior to the commonly used anterior-posterior and left-right combinations of arrays. The oblique configuration may be used as an effective and viable configuration for most frontoparietal tumors. Our results may be applied to assist clinical decision-making in various challenging situations associated with TTFields. This includes situations in which circumstances, such as therapy-induced skin rash, scar tissue or shunt therapy, etc., require layouts alternative to the prescribed. More accurate distributions should, however, be based on patient-specific models. Future work is needed to assess the robustness of the presented results towards variations in conductivity., Competing Interests: Anders Rosendal Korshoej has received funding from Novocure Ltd. to support the clinical trial 'Enhancing Optune Therapy with Targeted Craniotomy' (clinicaltrials.gov identifier NCT02893137). The remaining authors have no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Aims and Objectives: To identify and describe patients' experiences and care needs throughout the diagnostic phase of an integrated brain cancer pathway., Background: A malignant brain tumour is a devastating diagnosis, which may cause psychical symptoms and cognitive deficits. Studies have shown that the shock of the diagnosis, combined with the multiple symptoms, affects patients' ability to understand information and express needs of care and support. Unmet needs have been reported within this group of patients; however, the experiences and care needs of patients going through the diagnostic phase of a standardised integrated brain cancer pathway have not previously been explored., Design: A case study design was used to provide detailed information of the complex needs of patients being diagnosed with a malignant brain tumour., Methods: Research interviews and direct participant observation of four patients during hospital admission, brain surgery and discharge were conducted in a Danish university hospital. Systematic text condensation was used to analyse the data material., Results: Four major themes were identified: information needs, balancing hope and reality while trying to perceive the unknown reality of brain cancer, not knowing what to expect and participants' perceptions of the relationship with the healthcare providers. The analysis revealed that participants were in risk of having unmet information needs and that contextual factors seemed to cause fragmented care that led to feelings of uncertainty and loss of control., Conclusions: Brain tumour patients have complex care needs and experience a particular state of vulnerability during the diagnostic phase. Through personal relationships based on trust with skilled healthcare providers, participants experienced an existential recognition and alleviation of emotional distress., Relevance to Clinical Practice: Patients receiving a brain tumour diagnosis experience unmet care needs in several areas during their hospital stay. There is a need for interventions from healthcare providers., (© 2018 John Wiley & Sons Ltd.)

Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra leading to slowness and stiffness of limb movement with rest tremor. Using ubiquitin proteasome system inhibitors, rodent models have shown nigrostriatal degeneration and motor impairment. We translated this model to the Göttingen minipig by administering lactacystin into the medial forebrain bundle (MFB). Minipigs underwent positron emission tomography (PET) imaging with (+)-α-[ 11 C]dihydrotetrabenazine ([ 11 C]DTBZ), a marker of vesicular monoamine transporter 2 availability, at baseline and three weeks after the unilateral administration of 100 μg lactacystin into the MFB. Compared to their baseline values, minipigs injected with lactacystin showed on average a 36% decrease in ipsilateral striatal binding potential corresponding to impaired presynaptic dopamine terminals. Behaviourally, minipigs displayed asymmetrical motor disability with spontaneous rotations in one of the animals. Immunoreactivity for tyrosine hydroxylase (TH) and HLA-DR-positive microglia confirmed asymmetrical reduction in nigral TH-positive neurons with an inflammatory response in the lactacystin-injected minipigs. In conclusion, direct injection of lactacystin into the MFB of minipigs provides a model of PD with reduced dopamine neurotransmission, TH-positive neuron reduction, microglial activation and behavioural deficits. This large animal model could be useful in studies of symptomatic and neuroprotective therapies with translatability to human PD., (Copyright © 2018 Elsevier Inc. All rights reserved.)