Directed differentiation of human induced pluripotent stem cells into midbrain / 南方医科大学学报

OBJECTIVE@#To establish an efficient protocol for directed differentiation of human induced pluripotent stem cells (hiPSCs) into functional midbrain dopaminergic progenitor cells (DAPs) in vitro.@*METHODS@#hiPSCs were induced to differentiate into DAPs in two developmental stages. In the first stage (the first 13 days), hiPSCs were induced into intermediate cells morphologically similar to primitive neuroepithelial cells (NECs) in neural induction medium containing a combination of small molecule compounds. In the second stage, the intermediate cells were further induced in neural differentiation medium until day 28 to obtain DAPs. After CM-DiI staining, the induced DAPs were stereotactically transplanted into the right medial forebrain bundle (MFB) of rat models of Parkinson's disease (PD). Eight weeks after transplantation, the motor behaviors of PD rats was evaluated. Immunofluorescence assay of brain sections of the rats was performed at 2 weeks after transplantation to observe the survival, migration and differentiation of the transplanted cells in the host brain microenvironment.@*RESULTS@#hiPSCs passaged stably on Matrigel showed a normal diploid karyotype, expressed the pluripotency markers OCT4, SOX2, and Nanog, and were positive for alkaline phosphatase. The primitive neuroepithelial cells obtained on day 13 formed dense cell colonies in the form of neural rosettes and expressed the neuroepithelial markers (SOX2, Nestin, and PAX6, 91.3%-92.8%). The DAPs on day 28 highly expressed the specific markers (TH, FOXA2, LMX1A and NURR1, 93.3-96.7%). In rat models of PD, the hiPSCs-DAPs survived and differentiated into TH+, FOXA2+ and Tuj1+ neurons at 2 weeks after transplantation. Eight weeks after transplantation, the motor function of PD rats was significantly improved as shown by water maze test (P < 0.0001) and apomorphine-induced rotation test (P < 0.0001) compared with rats receiving vehicle injection.@*CONCLUSION@#HiPSCs can be effectively induced to differentiate into DAPs capable of differentiating into functional neurons both in vivo and in vitro. In rat models of PD, the transplanted hiPSCs-DAPs can survive for more than 8 weeks in the MFB and differentiate into multiple functional neurocytes to ameliorate neurological deficits of the rats, suggesting the potential value of hiPSCs-DAPs transplantation for treatment of neurological diseases.

Wernekink Commissure Syndrome With Hallucinations and Involuntary Groping:Report of One Case / 中国医学科学院学报

Wernekink commissure syndrome is a rare midbrain syndrome with bilateral cerebellar dysfunction,eye movement disorder,and palatal myoclonus.Few cases of this syndrome have been reported in China,let alone those combined with hallucinations and involuntary groping.This paper reports the diagnosis and treatment of a case of Wernekink commissure syndrome with hallucinations and involuntary groping,aiming to enrich the knowledge about this disease for clinicians.

An Anterior Cingulate Cortex-to-Midbrain Projection Controls Chronic Itch in Mice / 神经科学通报·英文版

Itch is an unpleasant sensation that provokes the desire to scratch. While acute itch serves as a protective system to warn the body of external irritating agents, chronic itch is a debilitating but poorly-treated clinical disease leading to repetitive scratching and skin lesions. However, the neural mechanisms underlying the pathophysiology of chronic itch remain mysterious. Here, we identified a cell type-dependent role of the anterior cingulate cortex (ACC) in controlling chronic itch-related excessive scratching behaviors in mice. Moreover, we delineated a neural circuit originating from excitatory neurons of the ACC to the ventral tegmental area (VTA) that was critically involved in chronic itch. Furthermore, we demonstrate that the ACC→VTA circuit also selectively modulated histaminergic acute itch. Finally, the ACC neurons were shown to predominantly innervate the non-dopaminergic neurons of the VTA. Taken together, our findings uncover a cortex-midbrain circuit for chronic itch-evoked scratching behaviors and shed novel insights on therapeutic intervention.

Sarcoma de Ewing mesencefálico: reporte de caso / Mesencephalic Ewing sarcoma: Case report

El sarcoma de Ewing es una neoplasia de origen más frecuentemente óseo; otras localizaciones son excepcionales. En el caso de las presentaciones primarias intracraneales, resulta imprescindible descartar que se trate de un secundarismo así como también de otros tumores neuroectodérmicos que puedan requerir distintos abordajes diagnósticos y terapéuticos. Se presenta a una paciente de 14 años que consultó por ptosis palpebral de ojo izquierdo asociado a diplopía de 2 meses de evolución; los estudios por imágenes mostraron una lesión tumoral extraaxial situada a nivel de la cisterna interpeduncular. Se realizó la exéresis completa, con diagnóstico anatomopatológico de sarcoma de Ewing de ubicación mesencefálica

Ewing's sarcoma is a malignant neoplasm mainly occurring in the bone, with other locations being exceptional. In the case of primary intracranial presentations, it is essential to rule out metastatic lesions as well as other neuroectodermal tumors that may require different diagnostic and therapeutic approaches. We present a 14-year-old patient who consulted for upper eyelid ptosis of left eye associated with a 2-month history of diplopia, with imaging evidence of extra-axial tumor lesion, located at the level of the interpeduncular cistern. Complete excision was performed, with a pathological diagnosis of Ewing's sarcoma of midbrain location.

Autophagy inhibitor 3-methyladenine could not modulate rotenone neurotoxicity in primary mesencephalic cell culture / El inhibidor de la autofagia 3-metiladenina no logra modular la neurotoxicidad de la rotenona en el cultivo primario de células mesencefálicas

Dysregulated autophagy, whether excessive or downregulated, has been thought to be associated with neurodegenerative disorders including Parkinson's disease. Accordingly, the present study was carried out to investigate whether 3-methyladenine, an autophagy inhibitor, can modulate the effects of rotenone on dopaminergic neurons in primary mesencephalic cell culture. Cultures were prepared from embryonic mouse mesencephala at gestation day 14. Four groups of cultures were treated on the 10th DIV for 48 h as follows: the first was kept as an untreated control, the second was treated with 3-methyladenine alone (1, 10, 100, 200 mM), the third was treated with 20 nM rotenone and the fourth was co-treated with 20 nM rotenone and 3-methyladenine (1, 10, 100, 200 mM). On the 12th DIV, cultured cells were stained immunohistochemically against tyrosine hydroxylase and culture media were used to measure the levels of lactate dehydrogenase. 3methyladenine had no effects on both the survival of dopaminergic neurons and the release of lactate dehydrogenase. Rotenone significantly decreased the number of dopaminergic neurons and increased the levels of lactate dehydrogenase in the culture media. When cultures concomitantly treated with 3-methyladenine and rotenone, 3-methyladenine had no effect against rotenone-induced dopaminergic cell damage and lactate dehydrogenase release into the culture medium. In conclusion, the autophagy inhibitor 3-methyladenine could not modulate rotenone-induced dopaminergic cell damage in primary mesencephalic cell culture.

Se estima que la autofagia desregulada, ya sea excesiva o con baja regulación, está asociada con trastornos neurodegenerativos, incluyendo la enfermedad de Parkinson. En consecuencia, el se realizó este estudio para investigar si la 3metiladenina, un inhibidor de la autofagia,puede modular los efectos de la rotenona en las neuronas dopaminérgicas en el cultivo primario de células mesencefálicas. Los cultivos se prepararon a partir de mesencéfalo de ratón embrionario el día 14 de gestación. Cuatro grupos de cultivos se trataron en el 10º DIV durante 48 h de la siguiente manera: el primer grupo se mantuvo como un control no tratado, el segundo se trató con 3-metiladenina sola (1, 10, 100, 200 mM), el tercer grupo se trató con rotenona 20 nM y el cuarto se trató conjuntamente con rotenona 20 nM y 3-metiladenina (1, 10, 100, 200 mM). En el 12º DIV; las células cultivadas fueron tratadas mediante tinción inmunohistoquímica en tirosina hidroxilasa y se usaron medios de cultivo para medir los niveles de lactato deshidrogenasa. La 3-metiladenina no tuvo efectos tanto en la supervivencia de las neuronas dopaminérgicas como en la liberación de lactato deshidrogenasa. La rotenona disminuyó significativamente el número de neuronas dopaminérgicas y se observó un aumento de los niveles de lactato deshidrogenasa en los medios de cultivo. Cuando los cultivos tratados concomitantemente con 3-metiladenina y rotenona, la 3metiladenina no tuvo efecto contra el daño celular dopaminérgico inducido por la rotenona y la liberación de lactato deshidrogenasa en el medio de cultivo. En conclusión, el inhibidor de la autofagia 3-metiladenina no moduló el daño celular dopaminérgico inducido por la rotenona en el cultivo celular mesencefálico primario.

A Cortical Substrate for Square-Wave Jerks in Progressive Supranuclear Palsy

Utilización de las zonas de entrada seguras para el abordaje de lesiones intrínsecas de tronco cerebral en adultos / Use of safe entry zones for the approach of intrinsic brainstem lesions in adults

Introducción: Las "zonas de entrada seguras" (ZES) al tronco cerebral describen accesos destinados a preservar estructuras críticas. La mayoría de las publicaciones son descripciones anatómicas; existiendo pocas sobre su aplicación. En este escenario, nuestro trabajo puede sumar información para el manejo quirúrgico en casos seleccionados. Material y Métodos: De una serie de 13 pacientes, se presentan 9 que no eran candidatos para biopsia estereotáctica y recibieron microcirugía. Las localizaciones fueron: mesencéfalo (3), tectum (1), protuberancia (2) y bulbo (3). Cinco pacientes tuvieron KPS => 70; y 4, KPS <70. Diferentes ZES fueron utilizadas según la topografía lesional. El grado de resección se basó en la biopsia intraoperatoria y el monitoreo neurofisiológico. Resultados: Los hallazgos patológicos fueron: astrocitoma pilocítico (1), glioma de bajo grado (1), hemangioblastoma (1), subependimoma (1), disgerminoma (1), y lesiones pseudotumorales (3 cavernomas y 1 pseudotumor inflamatorio). El grado de resección fue completo (4), subtotal (3), y biopsia fue considerada suficiente en (2). Un paciente falleció en el postoperatorio. Discusión: Las lesiones del tronco cerebral son infrecuentes en adultos. Las controversias surgen cuando se balancean los beneficios de obtener diagnóstico histopatológico y los riesgos potenciales de procedimientos invasivos. La amplia variedad de hallazgos en esta localización exige una precisa definición histopatológica, que no solamente determinará la terapéutica adecuada, sino que advierte sobre las consecuencias potencialmente catastróficas de los tratamientos empíricos. Las ZES ofrecen un acceso posible y seguro, aunque es más realista considerarlas como áreas para abordar lesiones intrínsecas con baja morbilidad más que como zonas completamente seguras

Introduction: The "safe entry zones" (SEZ) to the brainstem are special entrances described to preserve critical structures. Most publications correspond to anatomic research; few papers report their application in surgery. In this scenario, our report could add information to the surgical management in selected cases. Material and Methods: Out of a series of 13 patients, 9 were non-candidates for stereotactic biopsy and received microsurgery. Localizations of the lesions were: mesencephalus (3), tectal plate (1), pons (2) and medulla oblongata (3). Five patients had KPS => 70; 4, KPS <70. Different SEZ were used according to lesional topography. The extent of resection were based on the frozen pathology findings and neurophysiological monitoring. Results: A variety of pathological findings were found: low-grade glioma (1); pilocytic astrocytoma (1); hemangioblastoma (1); subependimoma (1); disgerminoma (1); pseudotumoral lesions (cavernomas 3 and inflammatory pseudotumor 1). The extent of resection was complete (4), subtotal (3), and biopsy was considered sufficient in 2 cases. One patient died 96-hours-postoperative due to brainstem edema. Discussion: Brainstem structural lesions are uncommon in adults. Controversies arise regarding the need of histologic diagnosis, weighing benefits of a reliable diagnosis and the potential disadvantages of the invasive procedures. The accurate histopathological definition could not only determine an adequate therapy, but also can prevent the disastrous consequences of empiric treatments. The SEZ provides a feasible and safe access, although it is more realistic to consider them as areas to approach intrinsec lesions with less morbidity than to consider them as completely safe entrances

Comparative morphology and histology of the brain in Chinese toad ( Bufo gargarizans ) and chinese fire-billed newt ( Cynops orientalis ) / Morfología e histología comparada del cerebro en el sapo chino ( Bufo gargarizans ) y el tritón vientre de fuego chino ( Cynops orientalis )

The morphological and histological structure of the brains of Bufo gargarizans and Cynops orientalis were observed by anatomy and light microscopy. The results show that the brains of Bufo gargarizans and Cynops orientalis are divided into 5 parts which include the telencephalon, diencephalon, mesencephalon, cerebellum and medulla oblongata. The telencephalon consists of the olfactory bulb and the cerebral hemisphere. The olfactory bulb is developed that has two pairs of olfactory nerve. Bufo gargarizan has a symmetrical oval hemisphere optic lobes; Cynops orientalis only has a spherical optic lobe. The cerebellum is situated behind the optic lobe and closely connected with the myelencephalon. In this paper, the morphological and histological differences between the two species are discussed. The proportion of cerebral hemisphere is gradually increasing, which correlated with a progressive increase in the number of neuronal cell classes, and reflected in behavior complexity.

La estructura morfológica e histológica de los cerebros de Bufo gargarizans y Cynops orientalis se observó mediante anatomía y microscopía óptica. Los resultados muestran que los cerebros de Bufo gargarizans y Cynops orientalis se dividen en 5 partes, que incluyen el telencéfalo, diencéfalo, mesencéfalo, cerebelo y mielencéfalo. El telencéfalo consiste en bulbo olfatorio y hemisferio cerebral. El bulbo olfatorio tiene dos pares de nervios olfatorios. Los lóbulos ópticos de Bufo gargarizans son ovalados y simétricos en ambos hemisferios cerebrales; Cynops orientalis tiene solo un lóbulo óptico esférico. El cerebelo está situado detrás del lóbulo óptico y está estrechamente conectado con el mielencéfalo. En este trabajo, se discuten las diferencias morfológicas e histológicas entre las dos especies. El tamaño del hemisferio cerebral aumenta gradualmente, lo que se correlaciona con un aumento progresivo de células neuronales en los núcleos, reflejándose en la complejidad del comportamiento.

Mesencephalotomy, How I Do It: Analysis of 34 Cases

The present paper aims to demystify the use of rostral mesencephalic reticulotomy (mesencephalotomy) in the treatment of chronic pain in cancer patients. A retrospective review of the medical records from the Central Pain and Stereotaxy Department of the A. C. Camargo Cancer Center, São Paulo, state of São Paulo, Brazil, between 2005 and 2012, was performed. Surgical indication was restricted to patients with cancer pain refractory to etiological and symptomatic treatments, > 2 months of expected survival, preserved cognition, and absence of coagulation disorders, of systemic infection, and of intracranial hypertension. We have selected 34 patients, with an average follow-up of 9.4 months, an average age of 54.3 years-old, and an average follow-up time until death of 6.4 months. Lung cancer was themost frequent diagnosis. Satisfactory and immediate pain relief was achieved in 91% of the cases, and 83% of these patients had no relapses. Among the complications, ocular movement disorder was the most frequent, but often transient. Permanent disturbances occurred in 8.8% of the cases (diplopia, rubral tremor, and paresthesia). Compared to the pharmacological treatment, mesencephalotomy was economically feasible, more effective, and improved quality of life. According to the data presented, it can be concluded that mesencephalotomy is a viable procedure for cancer pain control in selected cases.

Hemicorea como presentación clínica de hemorragia mesencefálica / Hemichorea as clinical presentation of hemorrhagic ictus

Paciente masculino, hipertenso con inicio súbito de trastornos de movimientos hipercineticos, involuntarios, continuos e irregulares, de la cabeza y hemicuerpo izquierdo. Cursó con afectación de diversos segmentos corporales, principalmente la porción distal de las extremidades, que disminuyen significativamente durante el sueño y se exacerban con emociones, stress o alta concentración. Este trastorno puede tener múltiples causas: genéticas, degenerativas, cerebrovasculares, metabólicas, endocrinas, tóxicas y medicamentosas; en este caso no hay historia de consumo de tóxicos o medicamentos, ni tampoco, datos de causas metabólicas como hiper o hipoglicemia, hipercalcemia significativa o hipernatremia o hiponatremia, entre otras. Se descartó la etiología degenerativa por el curso agudo de la enfermedad. Las imágenes tomográficas fueron compatibles con hemorragia mesencefálica, lo cual motiva esta presentación por lo infrecuente de los trastornos del movimiento involuntario tras un ictus, aunque está descrita en la bibliografía(AU)

We describe a male patient, with hypertension, who consulted for sudden onset of continuous hemichoreic movements of the head and left side of the body. These movements diminished during the sleep and exacerbated with emotions, stress or alertness. Usually this clinical presentation can be due to genetic, degenerative, cerebrovascular events, metabolic causes, medications, toxic substances and several electrolytic disturbances. None of the later were found in this patient, and degenerative origin was not an option due to the sudden onset of his symptoms. The brain cat-scan showed a mesencephalic hemorrhage, which is infrequent with this clinical presentation(AU)

Use of neuron-specific enolase to predict mild brain injury in motorcycle crash patients with maxillofacial fractures: A pilot study / 中华创伤杂志(英文版)

PURPOSE@#Mild traumatic brain injury (TBI) is common but accurate diagnosis and its clinical consequences have been a problem. Maxillofacial trauma does have an association with TBI. Neuron-specific enolase (NSE) has been developed to evaluate neuronal damage. The objective of this study was to investigate the accuracy of NSE serum levels to detect mild brain injury of patients with sustained maxillofacial fractures during motor vehicle accidents.@*METHODS@#Blood samples were drawn from 40 healthy people (control group) and 48 trauma patients who had sustained isolated maxillofacial fractures and mild brain injury in motor vehicle accidents. Brain injuries were graded by Glasgow Coma Scale. In the trauma group, correlations between the NSE serum value and different facial fracture sites were also assessed.@*RESULTS@#The NSE serum level (mean ± SD, ng/ml) in the 48 patients with maxillofacial fractures and mild TBI was 13.12 ± 9.68, significantly higher than that measured in the healthy control group (7.72 ± 1.82, p < 0.001). The mean NSE serum level (ng/ml) in the lower part of the facial skeleton (15.44 with SD 15.34) was higher than that in the upper facial part (12.42 with SD 7.68); and the mean NSE level (ng/ml) in the middle-and lower part (11.97 with SD 5.63) was higher than in the middle part (7.88 with SD 2.64).@*CONCLUSION@#An increase in NSE serum levels can be observed in patients sustained maxillofacial fractures and mild brain injury.

Parkinson's Disease: The Emerging Role of Gut Dysbiosis, Antibiotics, Probiotics, and Fecal Microbiota Transplantation

The role of the microbiome in health and human disease has emerged at the forefront of medicine in the 21st century. Over the last 2 decades evidence has emerged to suggest that inflammation-derived oxidative damage and cytokine induced toxicity may play a significant role in the neuronal damage associated with Parkinson's disease (PD). Presence of pro-inflammatory cytokines and T cell infiltration has been observed in the brain parenchyma of patients with PD. Furthermore, evidence for inflammatory changes has been reported in the enteric nervous system, the vagus nerve branches and glial cells. The presence of α-synuclein deposits in the post-mortem brain biopsy in patients with PD has further substantiated the role of inflammation in PD. It has been suggested that the α-synuclein misfolding might begin in the gut and spread “prion like” via the vagus nerve into lower brainstem and ultimately to the midbrain; this is known as the Braak hypothesis. It is noteworthy that the presence of gastrointestinal symptoms (constipation, dysphagia, and hypersalivation), altered gut microbiota and leaky gut have been observed in PD patients several years prior to the clinical onset of the disease. These clinical observations have been supported by in vitro studies in mice as well, demonstrating the role of genetic (α-synuclein overexpression) and environmental (gut dysbiosis) factors in the pathogenesis of PD. The restoration of the gut microbiome in patients with PD may alter the clinical progression of PD and this alteration can be accomplished by carefully designed studies using customized probiotics and fecal microbiota transplantation.

Increased Signal in the Superior Cerebellar Peduncle of Patients with Progressive Supranuclear Palsy

OBJECTIVE: The provisional diagnosis of progressive supranuclear palsy (PSP) depends on a combination of typical clinical features and specific MRI findings, such as atrophy of the tegmentum in the midbrain. Atrophy of the superior cerebellar peduncle (SCP) distinguishes PSP from other types of parkinsonism. Histological factors affect the conventional fluid-attenuated inversion recovery (FLAIR) signals, such as the extent of neuronal loss and gliosis. METHODS: We investigated patients with PSP to verify the percentage of patients with various PSP phenotypes presenting a high signal intensity in the SCP. Three interviewers, who were not informed about the clinical data, visually inspected the presence or absence of a high signal intensity in the SCP on the FLAIR images. We measured the pixel value in the SCP of each patient. Clinical characteristics were evaluated using the Mann-Whitney test, followed by the χ² test. RESULTS: Ten of the 51 patients with PSP showed a high signal intensity in the SCP on FLAIR MRI. Higher pixel values were observed within the SCP of patients with a high signal intensity in the SCP than in patients without a high signal intensity (p < 0.001). The sensitivity and specificity of the high signal intensity in the SCP of patients with PSP was 19.6% and 100%, respectively. This finding was more frequently observed in patients with PSP with Richardson's syndrome (PSP-RS) (25.7%) than other phenotypes (6.2%). CONCLUSION: The high signal intensity in the SCP on FLAIR MRI might be an effective diagnostic tool for PSP-RS.

The roles of habenula and related neural circuits in neuropsychiatric diseases / 浙江大学学报·医学版

The habenula is a small and bilateral nucleus above dorsal thalamus, which contains several different types of neurons. The habenula has extensive connections with the forebrain, septum and monoaminergic nuclei in the midbrain and brainstem. Habenula is known as an 'anti-reward' nucleus, which can be activated by aversive stimulus and negative reward prediction errors. Accumulating researchs have implicated that the habenula is involved in several behaviors crucial to survival. Meanwhile, the roles of the habenula in neuropsychiatric diseases have received increasing attention. This review summaries the studies regarding the roles of habenula and the related circuits in neuropathic pain, depression, drug addiction and schizophrenia, and discusses the possibility to use the habenula as a treatment target.

Clinical Factors Associated with Videofluoroscopic Swallowing Study Findings in Stroke Patients / 대한연하장애학회지

OBJECTIVE: To examine the clinical factors and brain lesion locations related to the patterns of dysphagia in stroke patients in a rehabilitation hospital. METHODS: The medical records of 116 stroke patients who underwent a videofluoroscopic swallowing study (VFSS) between January 2010 and January 2015 in a rehabilitation hospital were reviewed retrospectively. The swallowing-related parameters were assessed using a VFSS. The brain lesion locations were classified as the cortex, basal ganglia, thalamus, midbrain, pons, medulla, cerebellum, and others (subarachnoid or intraventricular hemorrhage). The ambulation ability was assessed using functional ambulation categories (FACs). The independence in the activities of daily living and the degree of cognitive impairment were assessed using the Korean versions of the modified Barthel index (K-MBI) and Mini-Mental State Examination (K-MMSE), respectively. After adjusting for the potential confounding factors in multivariate analysis, the odds ratios and confidence intervals of the stroke brain lesions were calculated and the clinical factors for predicting the VFSS findings were determined. RESULTS: Among the 116 patients, 35 (27%) had an impaired oral stage and 58 (50%) had aspiration. The impaired oral stage was associated significantly with the onset time, basal ganglia stroke, dietary and fluid intake methods at the time of the VFSS, symptoms of dysphagia, FACs, K-MBI, and K-MMSE. Aspiration was correlated with a pontine stroke, methods of dietary and fluid intakes at the time of the VFSS, symptoms of dysphagia, FACs, and K-MBI. Multivariate analysis showed that the pontine stroke and methods of dietary and fluid intake at the time of VFSS predicted aspiration after adjusting for the potential confounding factors. In subgroup analysis of the diet type, the liquid and semisolid aspirations were correlated with the dietary and fluid intake methods and pontine stroke, respectively. CONCLUSION: Patients with a pons lesion stroke, who are on a modified diet (fluid thickening and tube feeding), have higher risks of aspiration. This provides evidence for precise clinical reasoning in this specific patient group.

Three-Dimensional Analysis of Mouse Habenula Subnuclei Reveals Reduced Volume and Gene Expression in the Lipopolysaccharide-mediated Depression Model

The habenula (Hb) is small but important brain structure, anatomically and functionally links the forebrain with the midbrain to modulate various neuropsychiatric functions associated with drug addiction and emotion-associated dysfunctions. Several reports suggested that the dysfunction of Hb-related functions affected the Hb structurally and functionally. However, the technical limitation has awaited the solid conclusion of whether Hb change due to depression is likely to occur in certain subnuclei of the Hb. To probe this possibility, we developed 3-dimensional reconstruction methods for the high-resolution volumetric analysis of Hb and the mRNA levels at the given volume in normal or lipopolysaccharide (LPS)-mediated mouse model of depression. Notably, we discovered that the volume reduction was prominent in medial Hb but not in lateral Hb after LPS treatments. On the other hand, the RNA expression levels of known Hb regional markers such as Tac1 (dorsal part of medial Hb), ChAT (ventral part of medial Hb), and Tacr1 (medial and lateral Hb) were all decreased in all Hb subnuclei in LPS-injected mice. Accordingly, accurate volumetry with marker labeling was not feasible. Collectively, these established 3D analyses of mouse Hb successfully and precisely determine the volume-based changes of small brain structure, which should be applicable in a wider range of mouse models or pathological specimens.

Combination of In Vivo ¹²³IFP-CIT SPECT and Microdialysis Reveals an Antipsychotic Drug Haloperidol-induced Synaptic Dopamine Availability in the Rat Midbrain and Striatum

Synaptic dopamine (DA) is mainly regulated by the presynaptic DA transporter (DAT). Single-photon emission computerized tomography (SPECT) with the DAT radiotracer [¹²³I]FP-CIT assesses changes in synaptic DA availability when endogenous DA displaces [¹²³I]FP-CIT or competes for DAT. Here, we investigated the effects of haloperidol (HAL) and clozapine (CLZ) on [¹²³I]FP-CIT binding in the rat striatum and midbrain to assess the utility of [¹²³I]FP-CIT SPECT to quantify changes in synaptic DA availability. Rats underwent [¹²³I]FP-CIT SPECT after intraperitoneal administration of normal saline (vehicle), HAL (1 and 7 mg/kg), CLZ (10 and 54 mg/kg) and bupropion (BUP, a DAT blocker, 20 and 100 mg/kg). In the striatum and midbrain, percent differences in the nondisplaceable binding potential (BP(ND)) of [¹²³I]FP-CIT compared to the vehicle were calculated for the various drugs and doses. In another experiment, changes in endogenous striatal DA concentration were measured by in vivo microdialysis under the conditions used in the SPECT study. BUP dose-dependently occupied DAT at considerable levels. Compared to the vehicle, HAL decreased [¹²³I]FP-CIT BP(ND) in the striatum (−25.29% and −2.27% for 1 and 7 mg/kg, respectively) and to a greater degree in the midbrain (−58.74% and −49.64% for 1 and 7 mg/kg, respectively), whereas the CLZ-treated group showed a decrease in the midbrain (−38.60% and −40.38% for 10 and 54 mg/kg, respectively) but an increase in the striatum (18.85% and 38.64% for 10 and 54 mg/kg, respectively). Antipsychotic-induced changes in endogenous striatal DA concentrations varied across drugs and doses. The data demonstrate that [¹²³I]FP-CIT SPECT may be a useful preclinical technique for detecting increases in synaptic DA availability in the midbrain and striatum in response to HAL, with results comparable to those of in vivo microdialysis.

Ramsay Hunt Syndrome Complicated by Meningoencephalitis and Radiologic findings: a Rare Case Report

Ramsay Hunt syndrome with the complication of encephalitis or meningoencephalitis is rarely reported and uncommon in immunocompetent patients. The radiological manifestations of such cases usually involve the cerebellum and brainstem or exhibit the absence of any abnormality. We report a case of a 78-year-old immunocompetent man hospitalized with Ramsay Hunt syndrome, who later developed meningoencephalitis. The cerebrospinal fluid-study excluded other causes of meningoencephalitis, and the clinical diagnosis indicated varicella zoster virus meningoencephalitis. Magnetic resonance imaging revealed increased signal intensities in the bilateral temporal lobe, midbrain, and pons on T2-weighted imaging, and T2 fluid attenuated inversion recovery and contralateral asymmetric pachymeningeal enhancement. Contrast-enhanced T1-weighted imaging revealed ipsilateral facial nerve enhancement.

Promising Neuroimaging Biomarkers in Depression

The neuroimaging has been applied in the study of pathophysiology in major depressive disorder (MDD). In this review article, several kinds of methodologies of neuroimaging would be discussed to summarize the promising biomarkers in MDD. For the magnetic resonance imaging (MRI) and magnetoencephalography field, the literature review showed the potentially promising roles of frontal lobes, such as anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC). In addition, the limbic regions, such as hippocampus and amygdala, might be the potentially promising biomarkers for MDD. The structures and functions of ACC, DLPFC, OFC, amygdala and hippocampus might be confirmed as the biomarkers for the prediction of antidepressant treatment responses and for the pathophysiology of MDD. The functions of cognitive control and emotion regulation of these regions might be crucial for the establishment of biomarkers. The near-infrared spectroscopy studies demonstrated that blood flow in the frontal lobe, such as the DLPFC and OFC, might be the biomarkers for the field of near-infrared spectroscopy. The electroencephalography also supported the promising role of frontal regions, such as the ACC, DLPFC and OFC in the biomarker exploration, especially for the sleep electroencephalogram to detect biomarkers in MDD. The positron emission tomography (PET) and single-photon emission computed tomography (SPECT) in MDD demonstrated the promising biomarkers for the frontal and limbic regions, such as ACC, DLPFC and amygdala. However, additional findings in brainstem and midbrain were also found in PET and SPECT. The promising neuroimaging biomarkers of MDD seemed focused in the fronto-limbic regions.