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To review the prevalence of depression among adolescents and young adults after moderate to severe TBI. A systematic literature search was conducted on literature published up to December 2018 in PubMed, EMBASE, Cochrane and PsychInfo. A systematic review of the identified literature was based on PRISMA guidelines. Risk of Bias was evaluated based on the aspects of Risk of Bias assessment described by the Agency of Health Research and Quality. Seven studies were deemed eligible and information on the prevalence of depression among adolescents and young adults (age 13–35) after moderate to severe TBI was extracted. Depression was assessed at 12 months (n = 2), >12 months (n = 2) or at varying times (n = 3) after TBI. The identified studies reported a prevalence proportion of depression from 1.6% to 60%. The Risk of Bias assessment showed a range of study quality with the selection of subjects and analysis of attrition being problematic. Although literature is sparse and of varying quality, depression was found to be common among adolescents and young adults with moderate to severe TBI which implies a need to focus on depression in the rehabilitation process and calls for further research. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) can, when used with appropriate radioligands, non-invasively generate temporal and spatial information about acute changes in brain neurotransmitter systems. We for the first time evaluate the novel 5-HT2A receptor agonist PET radioligand, [11C]Cimbi-36, for its sensitivity to detect changes in endogenous cerebral 5-HT levels, as induced by different pharmacological challenges. To enable a direct translation of PET imaging data to changes in brain 5-HT levels, we calibrated the [11C]Cimbi-36 PET signal in the pig brain by simultaneous measurements of extracellular 5-HT levels with microdialysis and [11C]Cimbi-36 PET after various acute interventions (saline, citalopram, citalopram + pindolol, fenfluramine). In a subset of pigs, para-chlorophenylalanine pretreatment was given to deplete cerebral 5-HT. The interventions increased the cerebral extracellular 5-HT levels to 2–11 times baseline, with fenfluramine being the most potent pharmacological enhancer of 5-HT release, and induced a varying degree of decline in [11C]Cimbi-36 binding in the brain, consistent with the occupancy competition model. The observed correlation between changes in the extracellular 5-HT level in the pig brain and the 5-HT2A receptor occupancy indicates that [11C]Cimbi-36 binding is sensitive to changes in endogenous 5-HT levels, although only detectable with PET when the 5-HT release is sufficiently high. [ABSTRACT FROM AUTHOR]

Nucleus accumbens (NAcc) has been implicated in several psychiatric disorders such as treatment resistant depression (TRD), and obsessive-compulsive disorder (OCD), and has been an ongoing experimental target for deep brain stimulation (DBS) in both rats and humans. In order to translate basic scientific results from rodents to the human setting a large animal model is needed to thoroughly study the effect of such therapeutic interventions. The aim of the study was, accordingly, to describe the basic anatomy of the Göttingen minipig NAcc and its retrograde connections. Tracing was carried out by MRI-guided stereotactic unilateral fluorogold injections in the NAcc of Göttingen minipigs. After 2 weeks the brains were sectioned and subsequently stained with Nissl-, autometallographic (AMG) development of myelin, and DARPP-32 and calbindin immunohistochemistry. The minipig NAcc was divided in a central core and an outer medial, ventral and lateral shell. We confirmed the NAcc to be a large and well-segregated structure toward its medial, ventral and lateral borders. The fluorogold tracing revealed inputs to NAcc from the medial parts of the prefrontal cortex, BA 25 (subgenual cortex), insula bilaterally, amygdala, the CA1-region of hippocampus, entorhinal cortex, subiculum, paraventricular and anterior parts of thalamus, dorsomedial parts of hypothalamus, substantia nigra, ventral tegmental area (VTA), the retrorubral field and the dorsal and median raphe nuclei. In conclusion the Göttingen minipig NAcc is a large ventral striatal structure that can be divided into a core and shell with prominent afferent connections from several subrhinal and infra-/prelimbic brain areas. [ABSTRACT FROM AUTHOR]

Dogs with Canine Cognitive Dysfunction (CCD) accumulate amyloid beta (Aβ) in the brain. As the cognitive decline and neuropathology of these old dogs share features with Alzheimer's disease (AD), the relation between Aβ and cognitive decline in animal models of cognitive decline is of interest to the understanding of AD. However, the sensitivity of the biomarker Pittsburgh Compound B (PiB) to the presence of Aβ in humans and in other mammalian species is in doubt. To test the sensitivity and assess the distribution of Aβ in dog brain, we mapped the brains of dogs with signs of CCD (nD16) and a control group (nD4) of healthy dogs with radioactively labeled PiB ([11C]PiB). Structural magnetic resonance imaging brain scans were obtained from each dog. Tracer washout analysis yielded parametric maps of PiB retention in brain. In the CCD group, dogs had significant retention of [11C]PiB in the cerebellum, compared to the cerebral cortex. Retention in the cerebellum is at variance with evidence from brains of humans with AD. To confirm the lack of sensitivity, we stained two dog brains with the immunohistochemical marker 6E10, which is sensitive to the presence of both Aβ and Aβ precursor protein (AβPP). The 6E10 stain revealed intracellular material positive for Aβ or AβPP, or both, in Purkinje cells. The brains of the two groups of dogs did not have significantly different patterns of [11C]PiB binding, suggesting that the material detected with 6E10 is AβPP rather than Aβ. As the comparison with the histological images revealed no correlation between the [11C]PiB and Aβ and AβPP deposits in post-mortem brain, the marked intracellular staining implies intracellular involvement of amyloid processing in the dog brain. We conclude that PET maps of [11C]PiB retention in brain of dogs with CCD fundamentally differ from the images obtained in most humans with AD. [ABSTRACT FROM AUTHOR]

Abstract: Estimation of spine number and spine density by manual counting under the assumption that all dendrite protrusions equal spines are often used in studies on neuroplasticity occurring during health, brain diseases, and different experimental paradigms. Manual spine counting is, however, time consuming and biased by inter-observer variation. We present accordingly a quick, reproducible and simple non-stereological semi-automatic spine density estimation method based on the irregularity of the dendrite surface. Using the freeware ImageJ program, microphotographs of Golgi impregnated hippocampal dendrites derived from a previously performed study on the impact of chronic restrained stress were binarized, skeletonized, and the skeleton endings assumed to represent spine positions were counted and the spine densities calculated. The results based on 754 dendrite fragments were compared to manual spine counting of the same dendrite fragments using the Bland–Altman method. The results from both methods were correlated (r =0.79, p <0.0001), The semi-automatic counting method gave a statistically higher (approx. 4%) spine density number, but both counting methods showed similar significant differences between the groups in the CA1 area, and no differences between the groups in the CA3 area. In conclusion, the presented semi-automatic spine density estimation method yields consistently a higher spine density number than manual counting resulting in similar significance between groups. The proposed method may therefore be a reproducible time saving and useful non-stereological approach to spine counting in neuroplasticity studies requiring analysis of hundreds of dendrites. [Copyright &y& Elsevier]

Chronic stress has detrimental effects on physiology, learning and memory and is involved in the development of anxiety and depressive disorders. Besides changes in synaptic formation and neurogenesis, chronic stress also induces dendritic remodeling in the hippocampus, amygdala and the prefrontal cortex. Investigations of dendritic remodeling during development and treatment of stress are currently limited by the invasive nature of histological and stereological methods. Here we show that high field diffusion-weighted MRI combined with quantitative biophysical modeling of the hippocampal dendritic loss in 21 day restraint stressed rats highly correlates with former histological findings. Our study strongly indicates that diffusion-weighted MRI is sensitive to regional dendritic loss and thus a promising candidate for non-invasive studies of dendritic plasticity in chronic stress and stress-related disorders. [ABSTRACT FROM AUTHOR]

Background: A new intracerebral microinjection instrument (IMI) allowing multiple electrophysiologically guided microvolume injections from a single proximal injection path in rats has been adapted to clinical use by coupling the IMI to an FHC microTargeting Manual Drive, designed to be used with standard stereotactic frame-based systems and FHC frameless microTargeting Platforms. Methods: The function and safety of the device was tested by conducting bilateral electrophysiologically guided microinjections of fluorescent microspheres in the substantia nigra of 4 Göttingen minipigs. Results: The device was easy to handle and enabled accurate electrophysiologically guided targeting of the substantia nigra with minimal local tissue damage. Conclusion: The IMI is suitable for clinical use and may prove useful for various stereotactic procedures that require high levels of precision and/or three-dimensional distribution of therapeutics within the brain. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: We present a stereotaxic procedure enabling MRI-guided isocentric stereotaxy in pigs. The procedure is based on the Leksell stereotaxic arch principle, and a stereotaxic localizer box with an incorporated fiducial marking system (sideplates) defining a stereotaxic space similar to the clinical Leksell system. The obtained MRIs can be imported for 3D-reconstruction and coordinate calculation in the clinical stereotaxic software planning system (Leksell SurgiPlan, Elekta AB, Sweden). After MRI the sideplates are replaced by a modified Leksell arch accommodating clinical standard manipulators for isocentric placement of DBS-electrodes, neural tracers and therapeutics in the calculated target coordinates. The mechanical accuracy of the device was within 0.3–0.5mm. Stereotaxic MRIs were imported to the stereotaxic software planning system with a mean error of 0.4–0.5mm and a max error of 0.8–0.9mm. Application accuracy measured on a phantom and on inserted skull markers in nine pigs was within 1mm in all planes. The intracerebral application accuracy found after placement of 10 manganese trajectories within the full extent of the intracerebral stereotaxic space in two minipigs was equally randomly distributed and within 0.7±0.4; 0.5±0.4; and 0.7±0.3mm in the X, Y, and Z plane. Injection of neural tracers in the subgenual gyrus of three minipigs and placement of encapsulated gene-modified cells in four minipigs confirmed the accuracy and functionality of the described procedure. We conclude that the devised technique and instrumentation enable high-precision stereotaxic procedures in pigs that may benefit future large animal neuroscience research and outline the technical considerations for a similar stereotaxic methodology in other animals. [Copyright &y& Elsevier]

Abstract: The authors present an easily applicable deep brain stimulation (DBS) electrode anchoring technique for use in human and experimental animals. The anchoring technique combines the use of fibrin glue, a two-component surgical adhesive (BioGlue®), a protective electrode covering, and a titanium microplate. The BioGlue® (CryoLife International, Inc., Kennesaw, GA, USA) hinders unwanted electrode movement during the electrode fixation step and seals the burr hole, while the protective electrode covering protects the electrode under the titanium microplate which keeps the electrode in a permanent position. The described technique further has the advantage of being cosmetically acceptable to the human patient, and furthermore it perfectly adapts to the smaller and irregular-shaped skull in experimental animals. The described technique has clinically been used to implant DBS-electrodes in the subthalamic nucleus for Parkinson disease and is the preferred DBS-electrode anchoring technique for our experimental DBS-studies in the Göttingen minipig. [Copyright &y& Elsevier]

Background: Digital pain mapping allows for remote and ecological momentary assessment in patients over multiple time points spanning days to months. Frequent ecological assessments may reveal tendencies and fluctuations more clearly and provide insights into the trajectory of a patient's pain.Objective: The primary aim of this study is to remotely map and track the intensity and distribution of pain and discomfort (eg, burning, aching, and tingling) in patients with nonmalignant spinal referred pain over 12 weeks using a web-based app for digital pain mapping. The secondary aim is to explore the barriers of use by determining the differences in clinical and user characteristics between patients with good (regular users) and poor (nonregular users) reporting compliance.Methods: Patients (N=91; n=53 women) with spinal referred pain were recruited using web-based and traditional in-house strategies. Patients were asked to submit weekly digital pain reports for 12 weeks. Each pain report consisted of digital pain drawings on a pseudo-three-dimensional body chart and pain intensity ratings. The pain drawings captured the distribution of pain and discomfort (pain quality descriptors) expressed as the total extent and location. Differences in weekly pain reports were explored using the total extent (pixels), current and usual pain intensity ratings, frequency of quality descriptor selection, and Jaccard similarity index. Validated e-questionnaires were completed at baseline to determine the patients' characteristics (adapted Danish National Spine Register), disability (Oswestry Disability Index and Neck Disability Index), and pain catastrophizing (Pain Catastrophizing Scale) profiles. Barriers of use were assessed at 6 weeks using a health care-related usability and acceptance e-questionnaire and a self-developed technology-specific e-questionnaire to assess the accessibility and ease of access of the pain mapping app. Associations between total extent, pain intensity, disability, and catastrophizing were explored to further understand pain. Differences between regular and nonregular users were assessed to understand the pain mapping app reporting compliance.Results: Fluctuations were identified in pain reports for total extent and pain intensity ratings (P<.001). However, quality descriptor selection (P=.99) and pain drawing (P=.49), compared using the Jaccard index, were similar over time. Interestingly, current pain intensity was greater than usual pain intensity (P<.001), suggesting that the timing of pain reporting coincided with a more intense pain experience than usual. Usability and acceptance were similar between regular and nonregular users. Regular users were younger (P<.001) and reported a larger total extent of pain than nonregular users (P<.001).Conclusions: This is the first study to examine digital reports of pain intensity and distribution in patients with nonmalignant spinal referred pain remotely for a sustained period and barriers of use and compliance using a digital pain mapping app. Differences in age, pain distribution, and current pain intensity may influence reporting behavior and compliance. [ABSTRACT FROM AUTHOR]

Abstract: The microscopic organization of the Göttingen minipig (sus scrofa) hypothalamus was studied using Nissl stain, acetylcholinesterase histochemistry, and immunohistochemical staining for calretinin, tyrosin hydroxylase, oxytocin, vasopressin, and orexin A. Mediolaterally the minipig hypothalamus can be divided into three cytoarchitectonic distinct longitudinal zones. The periventricular longitudinal zone comprises the supraoptic, paraventricular, median preoptic, anteroventral periventricular, suprachiasmatic and arcuate nuclei. The medial longitudinal zone includes the prominent medial preoptic, ventromedial, dorsomedial and medial mammillary nuclei. Together with the anterior hypothalamic area, they can be further divided into distinct subregions. The dorsal and posterior hypothalamic areas and the retromammillary and lateral mammillary nuclei are cyto- and chemoarchitectonically distinct but cannot be further divided into subregions. The cell sparse, fiber rich lateral longitudinal zone comprises the lateral preoptic and lateral hypothalamic area as well as the perifornical, lateral tuberal and tuberomammillary nuclei. The findings presented here indicate that the cyto- and chemoarchitecture of the Göttingen minipig hypothalamus is comparable to that of rat, landrace pig, monkey, and human and that the Göttingen minipig may be well suited for future, non-primate, large mammal, hypothalamic research. [Copyright &y& Elsevier]

Highlights • The Göttingen minipig corticospinal system has features similar to humans. • The crossover of corticospinal fibers was quantified with stereology to 81–93%. • The corticospinal tract was found to project caudally into the spinal cord. • Tractography and neuronal tracing displayed a similar corticospinal anatomy. Abstract 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. [ABSTRACT FROM AUTHOR]

Summary: Balancing trophic and apoptotic cues is critical for development and regeneration of neuronal circuits. Here we identify SorCS2 as a proneurotrophin (proNT) receptor, mediating both trophic and apoptotic signals in conjunction with p75NTR. CNS neurons, but not glia, express SorCS2 as a single-chain protein that is essential for proBDNF-induced growth cone collapse in developing dopaminergic processes. SorCS2- or p75NTR-deficient in mice caused reduced dopamine levels and metabolism and dopaminergic hyperinnervation of the frontal cortex. Accordingly, both knockout models displayed a paradoxical behavioral response to amphetamine reminiscent of ADHD. Contrary, in PNS glia, but not in neurons, proteolytic processing produced a two-chain SorCS2 isoform that mediated proNT-dependent Schwann cell apoptosis. Sciatic nerve injury triggered generation of two-chain SorCS2 in p75NTR-positive dying Schwann cells, with apoptosis being profoundly attenuated in Sorcs2 −/− mice. In conclusion, we have demonstrated that two-chain processing of SorCS2 enables neurons and glia to respond differently to proneurotrophins. [Copyright &y& Elsevier]

Abstract: Background: Deep brain stimulation (DBS) in experimental animals has promoted new indications and refined existing treatments. Implantation of downscaled clinical DBS leads directly compatible with commercially available implantable pulse generators can however be challenging. Accordingly, we have developed a lead implantation device (LID) and technique for minimally invasive implantation of experimental multicontact DBS leads in large research animals. Materials and methods: The LID carries a small-diameter biocompatible polyimide guide tube which is first used for inserting the stimulating end of the lead and then implanted subcutaneously with the rest of the lead. The functionality of the device was tested by implanting 2 different designs of experimental DBS leads in 12 Göttingen minipigs for up to 12 weeks. The brains were histologically analyzed in order to assess implantation accuracy and local tissue reaction. Results and conclusions: The LID was easy to handle and capable of accurate stereotaxic implantation of downscaled experimental DBS leads in the predetermined target brain structures with minimal surrounding tissue reaction. The device may benefit future large animal DBS research as it allows for precise implantation of DBS leads and may have implications for further refinement of clinical DBS leads. [Copyright &y& Elsevier]

Nerve growth factor (NGF) prevents cholinergic degeneration in Alzheimer's disease (AD) and improves memory in AD animal models. In humans, the safe delivery of therapeutic doses of NGF is challenging. For clinical use, we have therefore developed an encapsulated cell (EC) biodelivery device, capable of local delivery of NGF. The clinical device, named NsG0202, houses an NGF-secreting cell line (NGC-0295), which is derived from a human retinal pigment epithelial (RPE) cell line, stably genetically modified to secrete NGF. Bioactivity and correct processing of NGF was confirmed in vitro. NsG0202 devices were implanted in the basal forebrain of Göttingen minipigs and the function and retrievability were evaluated after 7 weeks, 6 and 12 months. All devices were implanted and retrieved without associated complications. They were physically intact and contained a high number of viable and NGF-producing NGC-0295 cells after explantation. Increased NGF levels were detected in tissue surrounding the devices. The implants were well tolerated as determined by histopathological brain tissue analysis, blood analysis, and general health status of the pigs. The NsG0202 device represents a promising approach for treating the cognitive decline in AD patients. [ABSTRACT FROM AUTHOR]

Pigs have become increasingly popular in large-animal translational neuroscience research as an economically and ethically feasible substitute to non-human primates. The large brain size of the pig allows the use of conventional clinical brain imagers and the direct use and testing of neurosurgical procedures and equipment from the human clinic. Further macroscopic and histological analysis, however, requires postmortem exposure of the pig central nervous system (CNS) and subsequent brain removal. This is not an easy task, as the pig CNS is encapsulated by a thick, bony skull and spinal column. The goal of this paper and instructional video is to describe how to expose and remove the postmortem pig brain and the pituitary gland in an intact state, suitable for subsequent macroscopic and histological analysis.

Positron emission tomography (PET) can, when used with appropriate radioligands, non-invasively generate temporal and spatial information about acute changes in brain neurotransmitter systems. We for the first time evaluate the novel 5-HT 2A receptor agonist PET radioligand, [ 11 C]Cimbi-36, for its sensitivity to detect changes in endogenous cerebral 5-HT levels, as induced by different pharmacological challenges. To enable a direct translation of PET imaging data to changes in brain 5-HT levels, we calibrated the [ 11 C]Cimbi-36 PET signal in the pig brain by simultaneous measurements of extracellular 5-HT levels with microdialysis and [ 11 C]Cimbi-36 PET after various acute interventions (saline, citalopram, citalopram + pindolol, fenfluramine). In a subset of pigs, para-chlorophenylalanine pretreatment was given to deplete cerebral 5-HT. The interventions increased the cerebral extracellular 5-HT levels to 2-11 times baseline, with fenfluramine being the most potent pharmacological enhancer of 5-HT release, and induced a varying degree of decline in [ 11 C]Cimbi-36 binding in the brain, consistent with the occupancy competition model. The observed correlation between changes in the extracellular 5-HT level in the pig brain and the 5-HT 2A receptor occupancy indicates that [ 11 C]Cimbi-36 binding is sensitive to changes in endogenous 5-HT levels, although only detectable with PET when the 5-HT release is sufficiently high.

The emergence of the Göttingen minipig in research of topics such as neuroscience, toxicology, diabetes, obesity, and experimental surgery reflects the close resemblance of these animals to human anatomy and physiology (1-6).The size of the Göttingen minipig permits the use of surgical equipment and advanced imaging modalities similar to those used in humans (6-8). The aim of this instructional video is to increase the awareness on the value of minipigs in biomedical research, by demonstrating how to perform tracheal intubation, transurethral bladder catheterization, femoral artery and vein catheterization, as well as transcardial perfusion. Endotracheal Intubation should be performed whenever a minipig undergoes general anesthesia, because it maintains a patent airway, permits assisted ventilation and protects the airways from aspirates. Transurethral bladder catheterization can provide useful information about about hydration state as well as renal and cardiovascular function during long surgical procedures. Furthermore, urinary catheterization can prevent contamination of delicate medico-technical equipment and painful bladder extension which may harm the animal and unnecessarily influence the experiment due to increased vagal tone and altered physiological parameters. Arterial and venous catheterization is useful for obtaining repeated blood samples and monitoring various physiological parameters. Catheterization of femoral vessels is preferable to catheterization of the neck vessels for ease of access, when performing experiments involving frame-based stereotaxic neurosurgery and brain imaging. When performing vessel catheterization in survival studies, strict aseptic technique must be employed to avoid infections(6). Transcardial perfusion is the most effective fixation method, and yields preeminent results when preparing minipig organs for histology and histochemistry(2,9). For more information about anesthesia, surgery and experimental techniques in swine in general we refer to Swindle 2007. Supplementary information about premedication and induction of anesthesia, assisted ventilation, analgesia, pre- and postoperative care of Göttingen minipigs are available via the internet at http://www.minipigs.com(10). For extensive information about porcine anatomy we refer to Nickel et al. Vol. 1-5(11).

The authors present an easily applicable deep brain stimulation (DBS) electrode anchoring technique for use in human and experimental animals. The anchoring technique combines the use of fibrin glue, a two-component surgical adhesive (BioGlue), a protective electrode covering, and a titanium microplate. The BioGlue (CryoLife International, Inc., Kennesaw, GA, USA) hinders unwanted electrode movement during the electrode fixation step and seals the burr hole, while the protective electrode covering protects the electrode under the titanium microplate which keeps the electrode in a permanent position. The described technique further has the advantage of being cosmetically acceptable to the human patient, and furthermore it perfectly adapts to the smaller and irregular-shaped skull in experimental animals. The described technique has clinically been used to implant DBS-electrodes in the subthalamic nucleus for Parkinson disease and is the preferred DBS-electrode anchoring technique for our experimental DBS-studies in the Göttingen minipig.