Pneumocephalus with Inverted Papilloma in the Frontoethmoidal Sinus: Case Report and Literature Review.

Here, we describe the unique case of a pneumocephalus originating from an inverted papilloma (IP) in the frontoethmoidal sinus. A 71-year-old man with diabetes presented with headaches and altered consciousness. Imaging revealed the pneumocephalus together with bone destruction in the left frontal sinus. He underwent simultaneous endoscopic endonasal and transcranial surgery using an ORBEYE exoscope. Pathological diagnosis of the tumor confirmed IP. Post-surgery, the pneumocephalus was significantly resolved and the squamous cell carcinoma antigen level, which had been elevated, decreased. This case underscores the importance of a multidisciplinary approach and innovative surgical methods in treating complex sinonasal pathologies.

A Pediatric Case of Cauda Equina Dermoid Cyst Resected by Minimally Invasive Unilateral Hemilaminectomy.

A 3-year-old boy had difficulty sitting up and walking for several months. Magnetic resonance imaging (MRI) revealed an intradural tumor at the L3-4 level. The tumor was successfully resected by unilateral hemilaminectomy and diagnosed as dermoid cyst. The patient had an uneventful postoperative course without pain, and MRI found no recurrence after surgery. A small bone defect remained that might be favorably reconstructed with autologous and artificial bone. Hemilaminectomy allowed us to resect the cauda equina dermoid cyst with minimal invasiveness. Pediatric patients require follow-up as they are more likely to experience spinal deformity or instability after surgery.

Cell encapsulation enhances antidepressant effect of the mesenchymal stem cells and counteracts depressive-like behavior of treatment-resistant depressed rats.

Despite the advances in pharmacological therapies, only the half of depressed patients respond to currently available treatment. Thus, the need for further investigation and development of effective therapies, especially those designed for treatment-resistant depression, has been sorely needed. Although antidepressant effects of mesenchymal stem cells (MSCs) have been reported, the potential benefit of this cell therapy on treatment-resistant depression is unknown. Cell encapsulation may enhance the survival rate of grafted cells, but the therapeutic effects and mechanisms mediating encapsulation of MSCs remain unexplored. Here, we showed that encapsulation enhanced the antidepressant effects of MSCs by attenuating depressive-like behavior of Wistar Kyoto (WKY) rats, which are considered as a promising animal model of treatment-resistant depression. The implantation of encapsulated MSCs (eMSCs) into the lateral ventricle counteracted depressive-like behavior and enhanced the endogenous neurogenesis in the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus, whereas the implantation of MSCs without encapsulation or the implantation of eMSCs into the striatum did not show such ameliorative effects. eMSCs displayed robust and stable secretion of vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor, fibroblast growth factor-2, and ciliary neurotrophic factor (CNTF), and the implantation of eMSCs into the lateral ventricle activated relevant pathways associated with these growth factors. Additionally, eMSCs upregulated intrinsic expression of VEGF and CNTF and their receptors. This study suggests that the implantation of eMSCs into the lateral ventricle exerted antidepressant effects likely acting via neurogenic pathways, supporting their utility for depression treatment.

Electrical Stimulation Enhances Migratory Ability of Transplanted Bone Marrow Stromal Cells in a Rodent Ischemic Stroke Model.

BACKGROUND/AIMS: Bone marrow stromal cells (BMSCs) transplantation is an important strategy for the treatment of ischemic stroke. Currently, there are no effective methods to guide BMSCs toward the targeted site. In this study, we investigated the effect of electrical stimulation on BMSCs migration in an ischemic model of rats. METHODS: Adult male Wistar rats weighing 200 to 250 g received right middle cerebral artery occlusion (MCAO) for 90 minutes. BMSCs (2.5×105 cells/ 4 µl PBS) were stereotaxically injected into the left corpus callosum at 1 day after MCAO. After BMSCs injection, a plate electrode with a diameter of 3 mm connected to an implantable electrical stimulator was placed on the right frontal epidural space and a counter electrode was placed in the extra-cranial space. Electrical stimulation at preset current (100 µA) and frequency (100 Hz) was performed for two weeks. Behavioral tests were performed at 1, 4, 8, and 15 days after MCAO using the modified Neurological Severity Score (mNSS) and cylinder test. Rats were euthanized at 15 days after MCAO for evaluation of infarction area and the migration distance and area of BMSCs found in the brain tissue. After evaluating cell migration, we proceeded to explore the mechanisms guiding these observations. MCAO rats without BMSCs transplantation were stimulated with same current and frequency. At 1 and 2 weeks after MCAO, rats were euthanized to evaluate stromal cell-derived factor 1 alpha (SDF-1α) level of brain tissues in the bilateral cortex and striatum. RESULTS: Behavioral tests at 4, 8, and 15 days after MCAO revealed that stimulation group displayed significant amelioration in mNSS and cylinder test compared to control group (p<0.05). Similarly, the infarction areas of stroke rats in stimulation group were significantly decreased compared to control group (p<0.05). Migration distance and area of transplanted BMSCs were significantly longer and wider respectively in stimulation group. An increased concentration gradient of SDF-1α in stimulation group accompanied this enhanced migration of transplanted cells. CONCLUSIONS: These results suggest that electrical stimulation enhances migratory ability of transplanted BMSCs in ischemic stroke model of rats. If we can direct the implanted BMSCs to the site of interest, it may lead to a greater therapeutic effect.

Peritoneal catheter knot formation in ventriculoperitoneal shunting: an intraoperative artificial phenomenon?

BACKGROUND: Peritoneal catheter knot formation is a rare complication associated with ventriculoperitoneal shunting. In most reports, the knot formation was also considered to be the cause of shunt malfunction. DISCUSSION: In this study, we demonstrate the possible misinterpretation of peritoneal catheter knot formation in ventriculoperitoneal shunting. We found a knot in the peritoneal catheter intraoperatively, while no knot was noted on the abdominal X-ray taken 1 day prior to the operation. Our findings indicate that the knot had actually formed intraoperatively. This case suggests that we should not immediately conclude that a knot is the cause of shunt malfunction in such an operation.

Spinal Extradural Arachnoid Cyst: Significance of Intrathecal Infusion after Fistula Closure.

The spinal extradural arachnoid cyst is a rare entity. Obtaining the correct diagnosis and detecting the fistula location are critical for providing effective treatment. A 41-year-old man had numbness in the soles of his feet for 2 years with accompanying gait disturbance, and a defecation disorder. Computed tomography myelography performed at another hospital revealed an epidural arachnoid cyst from Th11 to L2. He received a subarachnoid-cyst shunt at the rostral part of the cyst. However, his symptoms worsened and he was admitted to our hospital. Neuroradiological investigations revealed the correct location of the fistula at the level of Th12. We performed partial removal of the cyst wall with fistula closure via right hemilaminectomy of Th11 and 12. The complete closure of the fistula was confirmed by intrathecal infusion of artificial cerebrospinal fluid through the shunt tube. The shunt tube was removed with the sutures. The patient's symptoms improved, although numbness remained in his bilateral heels. There has been no recurrence in 15 months since the surgery. Fistula closure may work as a balanced therapeutic strategy for spinal extradural arachnoid cyst, and intrathecal cerebrospinal fluid infusion is useful for the confirmation of complete fistula closure.

Hypertensive Cerebral Hemorrhage in a Patient with Turner Syndrome Caused by Deletion in the Short Arm of the X Chromosome.

Turner syndrome is a chromosomal disorder usually caused by complete deletion of an X chromosome, with deletion in the short arm of the X chromosome being a rare cause of the condition. Patients with Turner syndrome commonly develop hypertension, and associated vascular complications such as aortic dissection or cerebral hemorrhage have been reported. Cerebral hemorrhage in Turner syndrome is a rare complication, and only a few reports have been published. In these reports, all patients have XO karyotypes or a mosaic type as the cause of Turner syndrome, while no other Turner syndrome types have been documented. In this report, we present for the first time a patient with Turner syndrome caused by deletion in the short arm of the X chromosome who experienced hypertensive hemorrhage as a late complication.

Stenting for Internal Carotid Artery Stenosis Associated with Persistent Primitive Hypoglossal Artery Using Proximal Flow Blockade and Distal Protection System: A Technical Case Report and Literature Review.

We report a very rare case of internal carotid artery (ICA) stenosis associated with persistent primitive hypoglossal artery (PPHA) treated by stenting using a proximal flow blockade and distal filter protection system. A 77-year-old man with a medical history of repeated cerebral infarction was referred to our hospital for treatment of progressive ICA stenosis. Cerebral angiography revealed that the degree of stenosis was 50% and the PPHA branched just distal to the stenosis at the C2 vertebral level. Black-blood magnetic resonance imaging indicated vulnerable plaque. The stenosis was at a high location, so carotid artery stenting was employed. Under the proximal flow blockade system with occlusion of the external and common carotid artery, distal filter protection was placed in the ICA to prevent distal embolization. A self-expanding stent was successfully deployed and the patient was discharged without any neurological deficits. In stenting for the ICA stenosis associated with PPHA, the combination of a proximal flow blockade and distal protection system is reasonable and safe.

Trigeminal neuralgia caused by a persistent primitive trigeminal artery: preoperative three-dimensional multifusion imaging and computational fluid dynamics analysis. Illustrative case.

BACKGROUND: Trigeminal neuralgia (TN) is caused by trigeminal nerve compression by colliding vessels. Preoperative three-dimensional (3D) multifusion images are useful for surgical simulations. Moreover, computational fluid dynamics (CFD) analysis of colliding vessels may be useful for hemodynamic evaluation at the site of neurovascular contact (NVC). OBSERVATIONS: A 71-year-old woman had TN due to compression of the trigeminal nerve by the superior cerebellar artery (SCA) fused with the persistent primitive trigeminal artery (PTA). Preoperative 3D multifusion simulation images of silent magnetic resonance (MR) angiography and MR cisternography depicted the NVC, including the trigeminal nerve, SCA, and PTA. CFD analysis revealed the hemodynamic condition of the NVC, including the SCA and PTA. The wall shear stress magnitude (WSSm) at the NVC showed a local elevation due to flow confluence from the SCA and PTA. High WSSm was observed in the NVC. LESSONS: Preoperative simulation images of MR angiography and MR cisternography may depict the NVC. CFD analysis can provide the hemodynamic condition at the NVC.

Occipital condyle fracture caused by minor head trauma.

Background: Occipital condyle fractures (OCF) are commonly identified in patients suffering from severe craniocerebral trauma. Here, we present a 57-year-old male whose computed tomography (CT)-documented atlanto-occipital dislocation (AOD), due to just minor trauma was successfully managed with bracing alone. Case Description: A 57-year-old male presented with the right upper neck pain following a motor vehicle accident. The screening cervical CT scan revealed a fracture of the right occipital condyle, while the subsequent dynamic X-rays showed no instability or AOD. The patient was treated with a hard cervical collar, and over the next 6 months, remained asymptomatic. The 6-month repeat craniocervical CT scan additionally confirmed spontaneous fusion at the fracture site. Conclusion: Patients who have sustained even mild craniocervical trauma may develop AOD attributed to an OCF. It is critical to screen these patients early with CT and X-ray studies so they can be successfully managed with bracing alone, and avoid the need for surgery to address the delayed onset of instability.

A Case of Pseudoaneurysm of the Superficial Temporal Artery Causing a Massive Subcutaneous Hematoma after Craniotomy.

We present a case of a ruptured pseudoaneurysm of the superficial temporal artery (STA) after surgery for intracranial hemorrhage. To our knowledge, only three similar cases have been reported. A 47-year-old man underwent left frontal craniotomy for a left frontal subcortical hematoma. The left STA was not identified during the surgery, and no STA bleeding was observed. The postoperative course was uneventful for 20 days, until the patient experienced a left-side headache and noticed a subcutaneous mass. The mass increase in size within 1 hour and arterial hemorrhage was observed through a tear in the wound. Findings on subsequent contrast computed tomography were consistent with a ruptured pseudoaneurysm arising from the left STA. Emergency evacuation of the hematoma and STA ligation were performed. Pathological findings were consistent with a pseudoaneurysm. STA pseudoaneurysms occasionally grow rapidly and can cause massive hematoma. Surgeons should carefully monitor for evidence of a pseudoaneurysm after craniotomy, even in the absence of intraoperative bleeding from the STA.

Surgical Outcomes of Full-Endoscopic Lumbar Discectomy in the Early Adoption Phase.

Background We adopted full-endoscopic lumbar discectomy (FELD) in 2019 with the assistance of the Japanese Society for Minimally Invasive and Endoscopic Techniques of Spinal Neurosurgery (JASMETS). This study analyzed short-term outcomes in our initial FELD cases and compared them with microdiscectomy cases performed during the same period. Methods FELD was performed in 21 patients over a period of 2 years and 6 months (15 men and 6 women; mean age, 57.0±17.0 years). The transforaminal approach was performed in 8 patients, the posterolateral approach in 3, and the interlaminar approach in 10. During the same period, microdiscectomy was performed in 30 patients. Japanese Orthopaedic Association (JOA) and visual analog scale (VAS) scores, operation time, blood loss volume, complications, and incidence of lumbar disc herniation recurrence were compared between the groups. Results Preoperative VAS and JOA scores did not significantly differ between the FELD and microdiscectomy groups. JOA and VAS scores significantly improved in both groups after surgery. Operation time and incidence of recurrence rate did not differ. Conclusion Spine surgeons who adopt FELD can achieve good surgical outcomes similar to those of microdiscectomy, even in the early period. Participation in JASMETS seminars and training and proctoring by a certified endoscopic spine surgeon were instrumental in our experience.

Transplantation of modified human bone marrow-derived stromal cells affords therapeutic effects on cerebral ischemia in rats.

AIMS: SB623 cells are human bone marrow stromal cells transfected with Notch1 intracellular domain. In this study, we examined potential regenerative mechanisms underlying stereotaxic transplantation of SB623 cells in rats with experimental acute ischemic stroke. METHODS: We prepared control group, empty capsule (EC) group, SB623 cell group (SB623), and encapsulated SB623 cell (eSB623) group. Transient middle cerebral artery occlusion (MCAO) was performed on day 0, and 24 h after MCAO, stroke rats received transplantation into the envisioned ischemic penumbra. Modified neurological severity score (mNSS) was evaluated, and histological evaluations were performed. RESULTS: In the mNSS, SB623 and eSB623 groups showed significant improvement compared to the other groups. Histological analysis revealed that the infarction area in SB623 and eSB623 groups was reduced. In the eSB623 group, robust cell viability and neurogenesis were detected in the subventricular zone that increased significantly compared to all other groups. CONCLUSION: SB623 cells with or without encapsulation showed therapeutic effects on ischemic stroke. Encapsulated SB623 cells showed enhanced neurogenesis and increased viability inside the capsules. This study reveals the mechanism of secretory function of transplanted SB623 cells, but not cell-cell interaction as primarily mediating the cells' functional benefits in ischemic stroke.

Cauda equina syndrome due to lumbar disc herniation and ossification of the yellow ligament.

BACKGROUND: Patients with lumbar disc herniation at a level with significant stenosis due to ossification of the yellow ligament (OYL) may rarely present with rapid neurological deterioration warranting emergent surgery. CASE DESCRIPTION: A 40-year-old female developed an acute cauda equina syndrome (CES) attributed to an acute lumbar disc herniation and to marked canal stenosis due to OYL. As the patient underwent a 9 h delayed removal of the ossified ligament and discectomy, she sustained only minimal recovery. CONCLUSION: Patients diagnosed with acute lumbar disc herniation and severe stenosis due to OYL who present with acute CES warrant emergent surgical decompression to avoid permanent postoperative neurological sequelae.

Spinal Surgery after Bilateral Subthalamic Stimulation for Patients with Parkinson's Disease: A Retrospective Outcome Analysis of Pain and Functional Control.

Parkinson's disease (PD) patients often suffer from spinal diseases requiring surgeries, although the risk of complications is high. There are few reports on outcomes after spinal surgery for PD patients with deep brain stimulation (DBS). The objective of this study was to explore the data on spinal surgery for PD patients with precedent DBS. We evaluated 24 consecutive PD patients with 28 spinal surgeries from 2007 to 2017 who received at least a 2-year follow-up. The characteristics and outcomes of PD patients after spinal surgery were compared to those of 156 non-PD patients with degenerative spinal diseases treated in 2013-2017. Then, the characteristics, outcomes, and spinal alignment of PD patients receiving DBS were analyzed in degenerative spinal/lumbar diseases. The mean age at the time of spinal surgery was 68 years. The Hoehn and Yahr score regarding PD was stage 1 for 8 patients, stage 2 for 2 patients, stage 3 for 8 patients, stage 4 for 10 patients, and stage 5 for 0 patient. The median preoperative L-DOPA equivalent daily dose was 410 mg. Thirteen patients (46%) received precedent subthalamic nucleus (STN) DBS. Lumbar lesions with pain were common, and operation and anesthesia times were long in PD patients. Pain and functional improvement of PD patients persisted for 2 years after surgery with a higher complication rate than for non-PD patients. PD patients with STN DBS maintained better lumbar lordosis for 2 years after spinal surgery. STN DBS significantly maintained spinal alignment with subsequent pain and functional amelioration 2 years after surgery. The outcomes of spinal surgery for PD patients might be favorably affected by thorough treatment for PD including DBS.

Spinal Cord Diffuse Midline Glioma, H3K27M- mutant Effectively Treated with Bevacizumab: A Report of Two Cases.

"Diffuse midline glioma (DMG), H3K27M-mutant" was newly classified in the revised World Health Organization (WHO) 2016 classification of central nervous system tumors. Spinal cord DMG, H3K27M-mutant is relatively rare, with poor prognosis, and there are no effective treatment protocols. In this study, we report two cases of spinal cord DMG, H3K27M-mutant treated with bevacizumab. The two patients were women in their 40s who initially presented with sensory impairment. MRI showed spinal intramedullary tumors, and each patient underwent laminectomy/laminoplasty and biopsy of the tumors. Histological examination initially suggested low-grade astrocytoma in case 1 and glioblastoma in case 2. Upon further immunohistochemical examination in case 1 and molecular examination in case 2, however, both cases were diagnosed as DMG, H3K27M-mutant. Case 1 was treated with radiation therapy and temozolomide (TMZ) chemotherapy, which induced a transient improvement of symptoms; 3 months after surgery, however, the patient's symptoms rapidly deteriorated. MRI showed tumor enlargement with edema to the medulla. Triweekly administration of bevacizumab improved her symptoms for the following 12 months. Case 2 was treated with bevacizumab from the beginning because of acute deterioration of breathing. After bevacizumab administration, both cases showed tumor regression on MRI and drastic improvement of symptoms within a few days. Although spinal cord DMG, H3K27M-mutant has an aggressive clinical course and poor prognosis, bevacizumab administration may offer the significant clinical benefit of alleviating edema, which improves patient's capacity for activities of daily life.

Vagus Nerve Stimulation with Mild Stimulation Intensity Exerts Anti-Inflammatory and Neuroprotective Effects in Parkinson's Disease Model Rats.

BACKGROUND: The major surgical treatment for Parkinson's disease (PD) is deep brain stimulation (DBS), but a less invasive treatment is desired. Vagus nerve stimulation (VNS) is a relatively safe treatment without cerebral invasiveness. In this study, we developed a wireless controllable electrical stimulator to examine the efficacy of VNS on PD model rats. METHODS: Adult female Sprague-Dawley rats underwent placement of a cuff-type electrode and stimulator on the vagus nerve. Following which, 6-hydroxydopamine (6-OHDA) was administered into the left striatum to prepare a PD model. VNS was started immediately after 6-OHDA administration and continued for 14 days. We evaluated the therapeutic effects of VNS with behavioral and immunohistochemical outcome assays under different stimulation intensity (0.1, 0.25, 0.5 and 1 mA). RESULTS: VNS with 0.25-0.5 mA intensity remarkably improved behavioral impairment, preserved dopamine neurons, reduced inflammatory glial cells, and increased noradrenergic neurons. On the other hand, VNS with 0.1 mA and 1 mA intensity did not display significant therapeutic efficacy. CONCLUSIONS: VNS with 0.25-0.5 mA intensity has anti-inflammatory and neuroprotective effects on PD model rats induced by 6-OHDA administration. In addition, we were able to confirm the practicality and effectiveness of the new experimental device.

Long-Term Continuous Cervical Spinal Cord Stimulation Exerts Neuroprotective Effects in Experimental Parkinson's Disease.

BACKGROUND: Spinal cord stimulation (SCS) exerts neuroprotective effects in animal models of Parkinson's disease (PD). Conventional stimulation techniques entail limited stimulation time and restricted movement of animals, warranting the need for optimizing the SCS regimen to address the progressive nature of the disease and to improve its clinical translation to PD patients. OBJECTIVE: Recognizing the limitations of conventional stimulation, we now investigated the effects of continuous SCS in freely moving parkinsonian rats. METHODS: We developed a small device that could deliver continuous SCS. At the start of the experiment, thirty female Sprague-Dawley rats received the dopamine (DA)-depleting neurotoxin, 6-hydroxydopamine, into the right striatum. The SCS device was fixed below the shoulder area of the back of the animal, and a line from this device was passed under the skin to an electrode that was then implanted epidurally over the dorsal column. The rats were divided into three groups: control, 8-h stimulation, and 24-h stimulation, and behaviorally tested then euthanized for immunohistochemical analysis. RESULTS: The 8- and 24-h stimulation groups displayed significant behavioral improvement compared to the control group. Both SCS-stimulated groups exhibited significantly preserved tyrosine hydroxylase (TH)-positive fibers and neurons in the striatum and substantia nigra pars compacta (SNc), respectively, compared to the control group. Notably, the 24-h stimulation group showed significantly pronounced preservation of the striatal TH-positive fibers compared to the 8-h stimulation group. Moreover, the 24-h group demonstrated significantly reduced number of microglia in the striatum and SNc and increased laminin-positive area of the cerebral cortex compared to the control group. CONCLUSIONS: This study demonstrated the behavioral and histological benefits of continuous SCS in a time-dependent manner in freely moving PD animals, possibly mediated by anti-inflammatory and angiogenic mechanisms.

SF-36 scores predict postoperative delirium after surgery for cervical spondylotic myelopathy.

OBJECTIVECervical spondylotic myelopathy (CSM) is one of the most common causes of spinal cord dysfunction. Surgery for CSM is generally effective, but postoperative delirium is a potential complication. Although there have been some studies that investigated postoperative delirium after spine surgery, no useful tool for identifying high-risk patients has been established, and it is unknown if 36-Item Short Form Health Survey (SF-36) scores can predict postoperative delirium. The objective of this study was to evaluate the correlation between preoperative SF-36 scores and postoperative delirium after surgery for CSM.METHODSSixty-seven patients who underwent surgery for CSM at the authors' institution were enrolled in this study. Medical records of these patients were retrospectively reviewed. Patient background, preoperative laboratory data, preoperative SF-36 scores, the preoperative Japanese Orthopaedic Association (JOA) score for the evaluation of cervical myelopathy, and perioperative factors were selected as potential risk factors for postoperative delirium. These factors were evaluated using univariable and multivariable logistic regression analysis.RESULTSTen patients were diagnosed with postoperative delirium. Univariable analysis revealed that the physical functioning score (p = 0.01), general health perception score (p < 0.01), and vitality score (p < 0.01) of the SF-36 were significantly lower in patients with postoperative delirium than in those without. The total number of medications was significantly higher in the delirium group compared with the no-delirium group (p = 0.02). In contrast, there were no significant differences between the delirium group and the no-delirium group in cervical JOA scores (p = 0.20). Multivariable analysis revealed that a low general health perception score was an independent risk factor for postoperative delirium (p = 0.02; odds ratio 0.810, 95% confidence interval 0.684-0.960).CONCLUSIONSSome of the SF-36 scores were significantly lower in patients with postoperative delirium than in those without. In particular, the general health perception score was independently correlated with postoperative delirium. SF-36 scores could help identify patients at high risk for postoperative delirium and aid in the development of prevention strategies.

Lithium counteracts depressive behavior and augments the treatment effect of selective serotonin reuptake inhibitor in treatment-resistant depressed rats.

Wistar Kyoto (WKY) rats are a useful animal model of treatment-resistant depression. Lithium is effective for treating recurrent mood disorders or treatment-resistant depression, and lithium augmentation treatment is also useful for treatment-resistant depression. However, the treatment effect of lithium on the depressive behavior of WKY rats remains poorly understood, and whether lithium augments the treatment effect of antidepressants in WKY rats is also unknown. In this study, we evaluated the treatment effect of lithium in WKY rats. We also sought to determine if lithium treatment augments the treatment effect of fluoxetine. Lithium was administered for 15 consecutive days and fluoxetine was administered 23.5, 5, and 1 h before the forced swim test (FST) day 2, based on previous studies. Lithium treatment counteracted depressive behavior in the FST and increased hippocampal neurogenesis. Additionally, co-administration of lithium and fluoxetine augmented the treatment effect observed in the FST and in hippocampal neurogenesis in WKY rats, although fluoxetine monotherapy showed no treatment effect. Lithium prevented an increase in body weight, similar to its effect in human patients. These results are consistent with those of lithium augmentation treatment for human patients with treatment-resistant depression. They suggest that WKY rats are a promising animal model for treatment-resistant depression. However, lithium treatment has various side effects. A new treatment with the same anti-depressive effect as fluoxetine + lithium treatment and fewer side effects compared with lithium would be desirable for patients with treatment-resistant depression.