Cryoneurolysis versus radiofrequency ablation outcome on pain experience in chronic low back pain (COPE): a single-blinded randomised controlled trial.

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.

Examining the Duration of Carryover Effect in Patients With Chronic Pain Treated With Spinal Cord Stimulation (EChO Study): An Open, Interventional, Investigator-Initiated, International Multicenter Study.

OBJECTIVES: Spinal cord stimulation (SCS) is a surgical treatment for severe, chronic, neuropathic pain. It is based on one to two lead(s) implanted in the epidural space, stimulating the dorsal column. It has long been assumed that when deactivating SCS, there is a variable interval before the patient perceives the return of the pain, a phenomenon often termed echo or carryover effect. Although the carryover effect has been problematized as a source of error in crossover studies, no experimental investigation of the effect has been published. This open, prospective, international multicenter study aimed to systematically document, quantify, and investigate the carryover effect in SCS. MATERIALS AND METHODS: Eligible patients with a beneficial effect from their SCS treatment were instructed to deactivate their SCS device in a home setting and to reactivate it when their pain returned. The primary outcome was duration of carryover time defined as the time interval from deactivation to reactivation. Central clinical parameters (age, sex, indication for SCS, SCS treatment details, pain score) were registered and correlated with carryover time using nonparametric tests (Mann-Whitney/Kruskal-Wallis) for categorical data and linear regression for continuous data. RESULTS: In total, 158 patients were included in the analyses. A median carryover time of five hours was found (interquartile range 2.5;21 hours). Back pain as primary indication for SCS, high-frequency stimulation, and higher pain score at the time of deactivation were correlated with longer carryover time. CONCLUSIONS: This study confirms the existence of the carryover effect and indicates a remarkably high degree of interindividual variation. The results suggest that the magnitude of carryover may be correlated to the nature of the pain condition and possibly stimulation paradigms. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT03386058.

A fast transition: A case study of patients' experiences during the diagnostic and surgical treatment phase of an accelerated brain cancer pathway.

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.

The HortONS study. Treatment of chronic cluster headache with transcutaneous electrical nerve stimulation and occipital nerve stimulation: study protocol for a prospective, investigator-initiated, double-blinded, randomized, placebo-controlled trial.

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).

Treatment of chronic cluster headache with burst and tonic occipital nerve stimulation: A case series.

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.

Virtual Reality Treatment of Severe Neuropathic Pain in an Adolescent Child: A Case Report.

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.

Combined In Vivo Microdialysis and PET Studies to Validate [11C]Yohimbine Binding as a Marker of Noradrenaline Release.

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 [11C]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 [11C]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. [11C]yohimbine volumes of distribution (VT) were obtained using the Logan kinetic model. Both challenges induced a significant decrease in yohimbine VT, 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 VT. These data suggest that [11C]yohimbine can be used to evaluate acute variations in synaptic noradrenaline concentrations after pharmacological challenges.

Associating Compositional, Nutritional and Techno-Functional Characteristics of Faba Bean (Vicia faba L.) Protein Isolates and Their Production Side-Streams with Potential Food Applications.

Faba beans (Vicia faba L.) show exciting prospects as a sustainable source of protein and fibre, with the potential to transition to a more sustainable food production. This study reveals the compositional, nutritional and techno-functional characteristics of two protein isolates from faba beans (Vicia faba L.), a high-starch fraction and a high-fibre side-stream. During the analysis of those four ingredients, particular attention was paid to the isolates' protein profile and the side-streams' carbohydrate composition. The isoelectric precipitated protein isolate 1 showed a protein content of 72.64 ± 0.31% DM. It exhibited low solubility but superior digestibility and high foam stability. High foaming capacity and low protein digestibility were observed for protein isolate 2, with a protein content of 71.37 ± 0.93% DM. This fraction was highly soluble and consisted primarily of low molecular weight proteins. The high-starch fraction contained 83.87 ± 3.07% DM starch, of which about 66% was resistant starch. Over 65% of the high-fibre fraction was insoluble dietary fibre. The findings of this study provide a detailed understanding of different production fractions of faba beans, which is of great value for future product development.

Burst Spinal Cord Stimulation in Pregnancy: First Clinical Experiences.

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.

Spinal cord stimulation therapy for patients with Parkinson's disease and gait problems (STEP-PD): study protocol for an exploratory, double-blind, randomised, placebo-controlled feasibility trial.

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 18F-deoxyglucose and 18FEOBV 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.

An fMRI-compatible system for targeted electrical stimulation.

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.

Spontaneous partial recovery of striatal dopaminergic uptake despite nigral cell loss in asymptomatic MPTP-lesioned female minipigs.

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 (+)-⍺-[11C]-dihydrotetrabenazine ([11C]-DTBZ) and [18F]-dihydroxyphenylalanine ([18F]-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 [11C]-DTBZ and [18F]-FDOPA uptake post-MPTP with partial spontaneous recovery of [18F]-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.

Comparison of Spinal Cord Stimulation Outcomes Between Preoperative Opioid Users and Nonusers: A Cohort Study of 467 Patients.

OBJECTIVES: Spinal cord stimulation (SCS) is a surgical treatment modality reserved for a subset of patients with neuropathic pain in which conventional pharmacologic treatment has proven insufficient. Previous studies have suggested a possible negative relationship between opioid use at referral and subsequent success of SCS therapy. The aim of this cohort study was to investigate whether preoperative opioid use was associated with inferior SCS outcomes. MATERIALS AND METHODS: Data were obtained from the Danish Neurizon Neuromodulation Database and comprised preoperative registrations of analgesic use, postoperative Patients' Global Impression of Change (PGIC) ratings, pre- and postoperative pain intensity scores (Numeric Rating Scale), and detailed surgical data. Patients were dichotomized according to preoperative opioid use (users vs nonusers) with subsequent assessment of the latest PGIC rating, reduction in pain intensity, and current treatment status (implanted/explanted). In addition, daily preoperative opioid dosages were quantified in oral morphine equivalents (OME) and correlated to the treatment outcomes. RESULTS: A total of 467 patients were included; 296 consumed opioids before SCS implantation (median 80 OME/d). Preoperative opioid use was not associated with the latest PGIC rating, reduction in pain intensity (30% or 50%), or risk of undergoing explantation (median follow-up = 3.0 years). Likewise, preoperative median OME per day of opioid users was not correlated with any of the defined outcomes. CONCLUSIONS: Preoperative opioid usage did not predict the outcome of SCS therapy in a large cohort of patients permanently implanted with an SCS system. The results do not support withholding otherwise well-indicated SCS therapy in patients with chronic neuropathic pain conditions based merely on preoperative opioid usage.

Non-ablative doses of focal ionizing radiation alters function of central neural circuits.

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.

Interventions to improve gait in Parkinson's disease: a systematic review of randomized controlled trials and network meta-analysis.

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).

Anterograde Tracing From the Göttingen Minipig Motor and Prefrontal Cortex Displays a Topographic Subthalamic and Striatal Axonal Termination Pattern Comparable to Previous Findings in Primates.

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.

Anatomy and histology of the Göttingen minipig adenohypophysis with special emphasis on the polypeptide hormones: GH, PRL, and ACTH.

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.