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Frontiers in Immunology 2023Encephalitis is a devastating neurologic disorder with high morbidity and mortality. Autoimmune causes are roughly as common as infectious ones. N-methyl-D-aspartic acid...
BACKGROUND AND OBJECTIVES
Encephalitis is a devastating neurologic disorder with high morbidity and mortality. Autoimmune causes are roughly as common as infectious ones. N-methyl-D-aspartic acid receptor (NMDAR) encephalitis (NMDARE), characterized by serum and/or spinal fluid NMDAR antibodies, is the most common form of autoimmune encephalitis (AE). A translational rodent NMDARE model would allow for pathophysiologic studies of AE, leading to advances in the diagnosis and treatment of this debilitating neuropsychiatric disorder. The main objective of this work was to identify optimal active immunization conditions for NMDARE in mice.
METHODS
Female C57BL/6J mice aged 8 weeks old were injected subcutaneously with an emulsion of complete Freund's adjuvant, killed and dessicated , and a 30 amino acid peptide flanking the NMDAR GluN1 subunit N368/G369 residue targeted by NMDARE patients' antibodies. Three different induction methods were examined using subcutaneous injection of the peptide emulsion mixture into mice in 1) the ventral surface, 2) the dorsal surface, or 3) the dorsal surface with reimmunization at 4 and 8 weeks (boosted). Mice were bled biweekly and sacrificed at 2, 4, 6, 8, and 14 weeks. Serum and CSF NMDAR antibody titer, mouse behavior, hippocampal cell surface and postsynaptic NMDAR cluster density, and brain immune cell entry and cytokine content were examined.
RESULTS
All immunized mice produced serum and CSF NMDAR antibodies, which peaked at 6 weeks in the serum and at 6 (ventral and dorsal boosted) or 8 weeks (dorsal unboosted) post-immunization in the CSF, and demonstrated decreased hippocampal NMDAR cluster density by 6 weeks post-immunization. In contrast to dorsally-immunized mice, ventrally-induced mice displayed a translationally-relevant phenotype including memory deficits and depressive behavior, changes in cerebral cytokines, and entry of T-cells into the brain at the 4-week timepoint. A similar phenotype of memory dysfunction and anxiety was seen in dorsally-immunized mice only when they were serially boosted, which also resulted in higher antibody titers.
DISCUSSION
Our study revealed induction method-dependent differences in active immunization mouse models of NMDARE disease. A novel ventrally-induced NMDARE model demonstrated characteristics of AE earlier compared to dorsally-induced animals and is likely suitable for most short-term studies. However, boosting and improving the durability of the immune response might be preferred in prolonged longitudinal studies.
Topics: Mice; Female; Animals; Emulsions; Mice, Inbred C57BL; Encephalitis; Antibodies; Receptors, N-Methyl-D-Aspartate; Vaccination; Disease Models, Animal; Autoimmune Diseases of the Nervous System
PubMed: 37520559
DOI: 10.3389/fimmu.2023.1177672 -
AJNR. American Journal of Neuroradiology May 2022Dorsal root ganglion MR imaging (MR gangliography) is increasingly gaining clinical-scientific relevance. However, dorsal root ganglion morphometry by MR imaging is...
BACKGROUND AND PURPOSE
Dorsal root ganglion MR imaging (MR gangliography) is increasingly gaining clinical-scientific relevance. However, dorsal root ganglion morphometry by MR imaging is typically performed under the assumption of ellipsoid geometry, which remains to be validated.
MATERIALS AND METHODS
Sixty-four healthy volunteers (37 [57.8%] men; mean age, 31.5 [SD, 8.3] years) underwent MR gangliography of the bilateral L4-S2 levels (3D-T2WI TSE spectral attenuated inversion recovery-sampling perfection with application-optimized contrasts by using different flip angle evolution, isotropic voxels = 1.1 mm³, TE = 301 ms). Ground truth dorsal root ganglion volumes were bilaterally determined for 96 dorsal root ganglia (derivation cohort) by expert manual 3D segmentation by 3 independent raters. These ground truth dorsal root ganglion volumes were then compared with geometric ellipsoid dorsal root ganglion approximations as commonly practiced for dorsal root ganglion morphometry. On the basis of the deviations from ellipsoid geometry, improved volume estimation could be derived and was finally applied to a large human validation cohort (510 dorsal root ganglia).
RESULTS
Commonly used equations of ellipsoid geometry underestimate true dorsal root ganglion volume by large degrees (factor = 0.42-0.63). Ground truth segmentation enabled substantially optimizing dorsal root ganglion geometric approximation using its principal axes lengths by deriving the dorsal root ganglion volume term of [Formula: see text]. Using this optimization, the mean volumes of 510 lumbosacral healthy dorsal root ganglia were as follows: L4: 211.3 (SD, 52.5) mm³, L5: 290.7 (SD, 90.9) mm³, S1: 384.2 (SD, 145.0) mm³, and S2: 192.4 (SD, 52.6) mm³. Dorsal root ganglion volume increased from L4 to S1 and decreased from S1 to S2 (< .001). Dorsal root ganglion volume correlated with subject height ( = . 22, < .001) and was higher in men (< .001).
CONCLUSIONS
Dorsal root ganglion volumetry by measuring its principal geometric axes on MR gangliography can be substantially optimized. By means of this optimization, dorsal root ganglion volume distribution was estimated in a large healthy cohort for the clinically most relevant lumbosacral levels, L4-S2.
Topics: Adult; Female; Ganglia, Spinal; Humans; Magnetic Resonance Imaging; Male
PubMed: 35450855
DOI: 10.3174/ajnr.A7487 -
Brain, Behavior and Evolution 2022Comparative neurobiologists have long wondered when and how the dorsal pallium (e.g., mammalian neocortex) evolved. For the last 50 years, the most widely accepted... (Review)
Review
Comparative neurobiologists have long wondered when and how the dorsal pallium (e.g., mammalian neocortex) evolved. For the last 50 years, the most widely accepted answer has been that this structure was already present in the earliest vertebrates and, therefore, homologous between the major vertebrate lineages. One challenge for this hypothesis is that the olfactory bulbs project throughout most of the pallium in the most basal vertebrate lineages (notably lampreys, hagfishes, and lungfishes) but do not project to the putative dorsal pallia in teleosts, cartilaginous fishes, and amniotes (i.e., reptiles, birds, and mammals). To make sense of these data, one may hypothesize that a dorsal pallium existed in the earliest vertebrates and received extensive olfactory input, which was subsequently lost in several lineages. However, the dorsal pallium is notoriously difficult to delineate in many vertebrates, and its homology between the various lineages is often based on little more than its topology. Therefore, we suspect that dorsal pallia evolved independently in teleosts, cartilaginous fishes, and amniotes. We further hypothesize that the emergence of these dorsal pallia was accompanied by the phylogenetic restriction of olfactory projections to the pallium and the expansion of inputs from other sensory modalities. We do not deny that the earliest vertebrates may have possessed nonolfactory sensory inputs to some parts of the pallium, but such projections alone do not define a dorsal pallium.
Topics: Animals; Biological Evolution; Fishes; Mammals; Neocortex; Phylogeny; Reptiles; Vertebrates
PubMed: 34175847
DOI: 10.1159/000516563 -
JBJS Essential Surgical Techniques 2023The all-dorsal scapholunate reconstruction technique is indicated for the treatment of scapholunate injuries in cases in which the carpus is reducible and there is no...
BACKGROUND
The all-dorsal scapholunate reconstruction technique is indicated for the treatment of scapholunate injuries in cases in which the carpus is reducible and there is no arthrosis present. The goal of this procedure is to reconstruct the torn dorsal portion of the scapholunate ligament in order to stabilize the scaphoid and lunate.
DESCRIPTION
A standard dorsal approach to the wrist, extending from the third metacarpal distally to the distal radioulnar joint, is utilized. The extensor pollicis longus is transposed and retracted radially, and the second and fourth extensor compartments are retracted ulnarly. A Berger ligament-sparing capsulotomy is utilized to visualize the carpus. Volarly, an extended open carpal tunnel release is also utilized to relieve any median nerve compression and to aid in reduction. The contents of the carpal tunnel can be retracted radially, allowing for visualization of the carpal bones. Joystick pins are placed in order to reduce the scaphoid and lunate. Reduction is held provisionally by clamping the pins until 4 pins can be placed across the carpal bones. For scapholunate reconstruction, 3 holes are made: in the lunate, proximal scaphoid, and distal scaphoid. Suture tape is then utilized to hold the scaphoid and lunate in their proper position. The dorsal wrist capsule and extensor retinaculum are repaired during closure. The pins are cut near the skin and are removed in 8 to 12 weeks.
ALTERNATIVES
Several other methods of scapholunate reconstruction have been described, including capsulodesis, tenodesis, and bone-tissue-bone repairs. Additionally, in patients who are poor candidates for scapholunate reconstruction, wrist-salvage procedures can be utilized as the primary treatment.
RATIONALE
Scapholunate reconstruction has the advantage of preserving the native physiologic motion of the wrist, in contrast to the many different wrist-salvage procedures that include arthrodesis or arthroplasty. Avoiding arthrodesis is specifically advantageous in patients who have not yet developed arthrosis of the wrist bones.
EXPECTED OUTCOMES
Outcomes of scapholunate reconstruction vary widely; however, there is a nearly universal decrease in range of motion and strength of the wrist. Wrist range of motion is typically 55% to 75% of the contralateral side, and grip strength is typically approximately 65% of the contralateral side. In a prior study, 50% to 60% of patients whose work involved physical labor were able to return to their same level of full-time work. Disabilities of the Arm, Shoulder and Hand scores average between 24 and 30. Specific patients at risk for inferior outcomes are those with delayed surgical treatment, poor carpal alignment following reduction, or open injuries.
IMPORTANT TIPS
Patients are counseled preoperatively regarding the likelihood of permanent wrist stiffness and the possibility of scapholunate diastasis even in the setting of technically successful repair.Traction and dorsally directed pressure on the lunate through an extended carpal tunnel incision can aid in reduction of the lunate.The joystick pin position in the dorsal scaphoid is angulated from distal to proximal and that in the lunate is angulated from proximal to distal in order to help correct flexion of the scaphoid and extension of the lunate by clamping together the Kirschner wires. Modifying the distance of the clamp from the carpus can allow precision in the degree of scapholunate angle fixation.Intercarpal Kirschner wire fixation of the scapholunate, lunotriquetral, and midcarpal joints (scaphocapitate and triquetrohamate) is best performed with 0.062-in (1.6-mm) Kirschner wires. The insertion angle is best visualized when the Kirschner wire is introduced from inside the incision through the skin, "inside out," in order to best envision the trajectory on the dorsal carpus and define the starting point on the bone. The Kirschner wire is then advanced through the carpus from outside-in at a slightly more volarly translated (but not angulated) position. The Kirschner wires are then cut beneath the skin at a depth that will allow them to be retrieved but will not cause them to become exposed once swelling decreases.The wrist is generally immobilized until the pins are removed at 3 months postoperatively.
ACRONYMS AND ABBREVIATIONS
ROM = range of motionK-wire = Kirschner wireDASH = Disabilities of the Arm, Shoulder and HandDISI = dorsal intercarpal ligament instability.
PubMed: 38357468
DOI: 10.2106/JBJS.ST.23.00031 -
Brain, Behavior, and Immunity Jul 2023Peripheral injury during the early postnatal period alters the somatosensory system, leading to behavioural hyperalgesia upon re-injury in adulthood. Spinal microglia...
Peripheral injury during the early postnatal period alters the somatosensory system, leading to behavioural hyperalgesia upon re-injury in adulthood. Spinal microglia have been implicated as the cellular mediators of this phenomenon, but the mechanism is unclear. We hypothesised that neonatal injury (1) alters microglial phagocytosis of synapses in the dorsal horn leading to long-term structural changes in neurons, and/or (2) trains microglia, leading to a stronger microglial response after re-injury in adulthood. Using hindpaw surgical incision as a model we showed that microglial density and phagocytosis increased in the dorsal horn region innervated by the hindpaw. Dorsal horn microglia increased engulfment of synapses following injury, with a preference for those expressing the vesicular GABA transporter VGAT and primary afferent A-fibre terminals in neonates. This led to a long-term reduction of VGAT density in the dorsal horn and reduced microglial phagocytosis of VGLUT2 terminals. We also saw an increase in apoptosis following neonatal injury, which was not limited to the dorsal horn suggesting that larger circuit wide changes are happening. In adults, hindpaw incision increased microglial engulfment of predominantly VGAT synapses but did not alter the engulfment of A-fibres. This engulfment was not affected by prior neonatal injury, suggesting that microglial phagocytosis was not trained. These results highlight microglial phagocytosis in the dorsal horn as an important physiological response towards peripheral injury with potential long-term consequences and reveals differences in microglial responses between neonates and adults.
Topics: Rats; Animals; Infant, Newborn; Humans; Microglia; Rats, Sprague-Dawley; Reinjuries; Spinal Cord Dorsal Horn; Hyperalgesia; Spinal Cord; Posterior Horn Cells
PubMed: 37037363
DOI: 10.1016/j.bbi.2023.04.001 -
Cerebral Cortex Communications 2023Despite their anatomical and functional distinctions, there is growing evidence that the dorsal and ventral visual pathways interact to support object recognition....
Despite their anatomical and functional distinctions, there is growing evidence that the dorsal and ventral visual pathways interact to support object recognition. However, the exact nature of these interactions remains poorly understood. Is the presence of identity-relevant object information in the dorsal pathway simply a byproduct of ventral input? Or, might the dorsal pathway be a source of input to the ventral pathway for object recognition? In the current study, we used high-density EEG-a technique with high temporal precision and spatial resolution sufficient to distinguish parietal and temporal lobes-to characterise the dynamics of dorsal and ventral pathways during object viewing. Using multivariate analyses, we found that category decoding in the dorsal pathway preceded that in the ventral pathway. Importantly, the dorsal pathway predicted the multivariate responses of the ventral pathway in a time-dependent manner, rather than the other way around. Together, these findings suggest that the dorsal pathway is a critical source of input to the ventral pathway for object recognition.
PubMed: 36726794
DOI: 10.1093/texcom/tgad003 -
Ugeskrift For Laeger Nov 2020In this review, we discuss mucoid cysts, which are common benign cysts, most often located dorsally or laterally to the distal interphalangeal joint. The origin of the... (Review)
Review
In this review, we discuss mucoid cysts, which are common benign cysts, most often located dorsally or laterally to the distal interphalangeal joint. The origin of the cyst is suggested to be similar to that of a ganglion, or to be a degeneration of dermis, and it is often linked to osteoarthritis. Two types of mucoid cysts seem to exist, probably needing different treatment. A cyst is usually asymptomatic and needs no treatment, but limited joint movement, pain and nail deformity may occur. In the latter case, conservative or surgical treatment is asked for. If a cyst is atypical, pathology is needed.
Topics: Fingers; Ganglion Cysts; Humans; Nail Diseases; Osteoarthritis
PubMed: 33215593
DOI: No ID Found -
Frontiers in Cellular Neuroscience 2022Spinal interneurons located in the dorsal horn induce primary afferent depolarization (PAD) controlling the excitability of the afferent's terminals. Following...
Spinal interneurons located in the dorsal horn induce primary afferent depolarization (PAD) controlling the excitability of the afferent's terminals. Following inflammation, PAD may reach firing threshold contributing to maintain inflammation and pain. Our aim was to study the collective behavior of dorsal horn neurons, its relation to backfiring of primary afferents and the effects of a peripheral inflammation in this system. Experiments were performed on slices of spinal cord obtained from naïve adult mice or mice that had suffered an inflammatory pretreatment. Simultaneous recordings from groups of dorsal horn neurons and primary afferents were obtained and machine-learning methodology was used to analyze effective connectivity between them. Dorsal horn recordings showed grouping of spontaneous action potentials from different neurons in "population bursts." These occurred at irregular intervals and were formed by action potentials from all classes of neurons recorded. Compared to naïve, population bursts from treated animals concentrated more action potentials, had a faster onset and a slower decay. Population bursts were disrupted by perfusion of picrotoxin and held a strong temporal correlation with backfiring of afferents. Effective connectivity analysis allowed pinpointing specific neurons holding pre- or post-synaptic relation to the afferents. Many of these neurons had an irregular fast bursting pattern of spontaneous firing. We conclude that population bursts contain action potentials from neurons presynaptic to the afferents which are likely to control their excitability. Peripheral inflammation may enhance synchrony in these neurons, increasing the chance of triggering action potentials in primary afferents and contributing toward central sensitization.
PubMed: 36212688
DOI: 10.3389/fncel.2022.1004956 -
Frontiers in Neural Circuits 2020Somatosensation encompasses a variety of essential modalities including touch, pressure, proprioception, temperature, pain, and itch. These peripheral sensations are... (Review)
Review
Somatosensation encompasses a variety of essential modalities including touch, pressure, proprioception, temperature, pain, and itch. These peripheral sensations are crucial for all types of behaviors, ranging from social interaction to danger avoidance. Somatosensory information is transmitted from primary afferent fibers in the periphery into the central nervous system the dorsal horn of the spinal cord. The dorsal horn functions as an intermediary processing center for this information, comprising a complex network of excitatory and inhibitory interneurons as well as projection neurons that transmit the processed somatosensory information from the spinal cord to the brain. It is now known that there can be dysfunction within this spinal cord circuitry in pathological pain conditions and that these perturbations contribute to the development and maintenance of pathological pain. However, the complex and heterogeneous network of the spinal dorsal horn has hampered efforts to further elucidate its role in somatosensory processing. Emerging optical techniques promise to illuminate the underlying organization and function of the dorsal horn and provide insights into the role of spinal cord sensory processing in shaping the behavioral response to somatosensory input that we ultimately observe. This review article will focus on recent advances in optogenetics and fluorescence imaging techniques in the spinal cord, encompassing findings from both and preparations. We will also discuss the current limitations and difficulties of employing these techniques to interrogate the spinal cord and current practices and approaches to overcome these challenges.
Topics: Animals; Humans; Interneurons; Nerve Net; Optogenetics; Sensation; Somatosensory Cortex; Spinal Cord Dorsal Horn
PubMed: 32595458
DOI: 10.3389/fncir.2020.00031