All Publications

  • Boda Bodas and Road Traffic Injuries in Uganda: An Overview of Traffic Safety Trends from 2009 to 2017. International journal of environmental research and public health Vaca, S. D., Feng, A. Y., Ku, S., Jin, M. C., Kakusa, B. W., Ho, A. L., Zhang, M., Fuller, A., Haglund, M. M., Grant, G. 2020; 17 (6)


    INTRODUCTION: Road traffic injuries (RTIs) are an important contributor to the morbidity and mortality of developing countries. In Uganda, motorcycle taxis, known as boda bodas, are responsible for a growing proportion of RTIs. This study seeks to evaluate and comment on traffic safety trends from the past decade.METHODS: Traffic reports from the Ugandan police force (2009 to 2017) were analyzed for RTI characteristics. Furthermore, one month of casualty ward data in 2015 and 2018 was collected from the Mulago National Referral Hospital and reviewed for casualty demographics and trauma type.RESULTS: RTI motorcycle contribution rose steadily from 2009 to 2017 (24.5% to 33.9%). While the total number of crashes dropped from 22,461 to 13,244 between 2010 and 2017, the proportion of fatal RTIs increased from 14.7% to 22.2%. In the casualty ward, RTIs accounted for a greater proportion of patients and traumas in 2018 compared to 2015 (10%/41% and 36%/64%, respectively).CONCLUSIONS: Although RTIs have seen a gross reduction in Uganda, they have become more deadly, with greater motorcycle involvement. Hospital data demonstrate a rising need for trauma and neurosurgical care to manage greater RTI patient burden. Combining RTI prevention and care pathway improvements may mitigate current RTI trends.

    View details for DOI 10.3390/ijerph17062110

    View details for PubMedID 32235768

  • Evaluating Shunt Survival Following Ventriculoperitoneal Shunting with and without Stereotactic Navigation in Previously Shunt-Naïve Patients. World neurosurgery Jin, M. C., Wu, A., Azad, T. D., Feng, A., Prolo, L. M., Veeravagu, A., Grant, G. A., Ratliff, J., Li, G. 2020

    View details for DOI 10.1016/j.wneu.2020.01.138

    View details for PubMedID 31996335

  • Metformin Potential Impact on the Growth of Vestibular Schwannomas. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology Feng, A. Y., Enriquez-Marulanda, A., Kouhi, A., Ali, N. E., Moore, J. M., Vaisbuch, Y. 2020


    Previous work has suggested that metformin may possess antineoplastic properties. This study aims to assess the effect of metformin on the growth of sporadic vestibular schwannomas.A retrospective cohort study was performed on patients presenting with radiologically confirmed vestibular schwannomas to Stanford medical center between January 1990 and October 2018. Patients who received metformin during the follow-up period were included and were compared with the control group who were not receiving metformin. Tumor progression and hearing loss are primary and secondary outcomes, respectively.A total of 149 patients were analyzed, with 42 patients receiving metformin. The mean age at presentation is 69.6 (±11.7) years. There are 69 (46.3%) females and 80 (53.7%) males and there is no significant age difference between the groups. Tumor size at presentation is similar between both groups, 8 mm (4-13) in control group and 7.5 mm (4-14) in metformin group. The average follow-up period is 34.2 months (18.3-57.8) and 30.3 months (13.6-69.8) in the metformin and control cohorts, respectively, and they are not significantly different. No significant differences between both groups were found in final American Academy of Otolaryngology - Head and Neck Surgery hearing outcome or poor audiogram outcome. Metformin users are significantly less likely to present with tumor growth at final follow-up compared with nonmetformin users (28.6 versus 49.5%, respectively; p = 0.02).This preliminary result suggests metformin may reduce vestibular schwannoma tumor growth rate and shows potential promise as a novel chemotherapeutic agent. Further studies are needed to validate this finding.

    View details for DOI 10.1097/MAO.0000000000002545

    View details for PubMedID 31913209

  • Utilization of Novel High-Resolution, MRI-Based Vascular Imaging Modality for Preoperative Stereoelectroencephalography Planning in Children: A Technical Note. Stereotactic and functional neurosurgery Feng, A. Y., Ho, A. L., Kim, L. H., Sussman, E. S., Pendharkar, A. V., Iv, M., Yeom, K. W., Halpern, C. H., Grant, G. A. 2020: 1–7


    Stereoelectroencephalography (SEEG) is a powerful intracranial diagnostic tool that requires accurate imaging for proper electrode trajectory planning to ensure efficacy and maximize patient safety. Computed tomography (CT) angiography and digital subtraction angiography are commonly used, but recent developments in magnetic resonance angiography allow for high-resolution vascular visualization without added risks of radiation. We report on the accuracy of electrode placement under robotic assistance planning utilizing a novel high-resolution magnetic resonance imaging (MRI)-based imaging modality.Sixteen pediatric patients between February 2014 and October 2017 underwent SEEG exploration for epileptogenic zone localization. A gadolinium-enhanced 3D T1-weighted spoiled gradient recalled echo sequence with minimum echo time and repetition time was applied for background parenchymal suppression and vascular enhancement. Electrode placement accuracy was determined by analyzing postoperative CT scans laid over preoperative virtual electrode trajectory paths. Entry point, target point, and closest vessel intersection were measured.For any intersection along the trajectory path, 57 intersected vessels were measured. The mean diameter of an intersected vessel was 1.0343 ± 0.1721 mm, and 21.05% of intersections involved superficial vessels. There were 157 overall intersection + near-miss events. The mean diameter for an involved vessel was 1.0236 ± 0.0928 mm, and superficial vessels were involved in 20.13%. Looking only at final electrode target, 3 intersection events were observed. The mean diameter of an intersected vessel was 1.0125 ± 0.2227 mm. For intersection + near-miss events, 24 were measured. An involved vessel's mean diameter was 1.1028 ± 0.2634 mm. For non-entry point intersections, 45 intersected vessels were measured. The mean diameter for intersected vessels was 0.9526 ± 0.0689 mm. For non-entry point intersections + near misses, 126 events were observed. The mean diameter for involved vessels was 0.9826 ± 0.1008 mm.We believe this novel sequence allows better identification of superficial and deeper subcortical vessels compared to conventional T1-weighted gadolinium-enhanced MRI.

    View details for DOI 10.1159/000503693

    View details for PubMedID 32062664

  • Dual antiplatelet therapy after carotid artery stenting: trends and outcomes in a large national database. Journal of neurointerventional surgery Sussman, E. S., Jin, M., Pendharkar, A. V., Pulli, B., Feng, A., Heit, J. J., Telischak, N. A. 2020


    While dual antiplatelet therapy (dAPT) is standard of care following carotid artery stenting (CAS), the optimal dAPT regimen and duration has not been established.We canvassed a large national database (IBM MarketScan) to identify patients receiving carotid endarterectomy (CEA) or CAS for treatment of ischemic stroke or carotid artery stenosis from 2007 to 2016. We performed univariable and multivariable regression methods to evaluate the impact of covariates on post-CAS stroke-free survival, including post-discharge antiplatelet therapy.A total of 79 084 patients diagnosed with ischemic stroke or carotid stenosis received CEA (71 178; 90.0%) or CAS (7906; 10.0%). After adjusting for covariates, <180 days prescribed post-CAS P2Y12-inhibition was associated with increased risk for stroke (<90 prescribed days HR=1.421, 95% CI 1.038 to 1.946; 90-179 prescribed days HR=1.484, 95% CI 1.045 to 2.106). The incidence of hemorrhagic complications was higher during the period of prescribed P2Y12-inhibition (1.16% per person-month vs 0.49% per person-month after discontinuation, P<0.001). The rate of extracranial hemorrhage was nearly six-fold higher while on dAPT (6.50% per patient-month vs 1.16% per patient-month, P<0.001), and there was a trend towards higher rate of intracranial hemorrhage that did not reach statistical significance (5.09% per patient-month vs 3.69% per patient-month, P=0.0556). Later hemorrhagic events beyond 30 days post-CAS were significantly more likely to be extracranial (P=0.028).Increased duration of post-CAS dAPT is associated with lower rates of readmissions for stroke, and with increased risk of hemorrhagic complications, particularly extracranial hemorrhage. The potential benefit of prolonging dAPT with regard to ischemic complications must be balanced with the corresponding increased risk of predominantly extracranial hemorrhagic complications.

    View details for DOI 10.1136/neurintsurg-2020-016008

    View details for PubMedID 32414894

  • Patterns of Opioid and Benzodiazepine Use in Opioid-Naive Patients with Newly Diagnosed Low Back and Lower Extremity Pain. Journal of general internal medicine Azad, T. D., Zhang, Y., Stienen, M. N., Vail, D., Bentley, J. P., Ho, A. L., Fatemi, P., Herrick, D., Kim, L. H., Feng, A., Varshneya, K., Jin, M., Veeravagu, A., Bhattacharya, J., Desai, M., Lembke, A., Ratliff, J. K. 2019


    BACKGROUND: The morbidity and mortality associated with opioid and benzodiazepine co-prescription is a pressing national concern. Little is known about patterns of opioid and benzodiazepine use in patients with acute low back pain or lower extremity pain.OBJECTIVE: To characterize patterns of opioid and benzodiazepine prescribing among opioid-naive, newly diagnosed low back pain (LBP) or lower extremity pain (LEP) patients and to investigate the relationship between benzodiazepine prescribing and long-term opioid use.DESIGN/SETTING: We performed a retrospective analysis of a commercial database containing claims for more than 75 million enrollees in the USA.PARTICIPANTS: Participants were adult patients newly diagnosed with LBP or LEP between 2008 and 2015 who did not have a red flag diagnosis, had not received an opioid prescription in the 6months prior to diagnosis, and had 12months of continuous enrollment after diagnosis.MAIN OUTCOMES AND MEASURES: Among patients receiving at least one opioid prescription within 12months of diagnosis, we defined discrete patterns of benzodiazepine prescribing-continued use, new use, stopped use, and never use. We tested the association of these prescription patterns with long-term opioid use, defined as six or more fills within 12months.RESULTS: We identified 2,497,653 opioid-naive patients with newly diagnosed LBP or LEP. Between 2008 and 2015, 31.9% and 11.5% of these patients received opioid and benzodiazepine prescriptions, respectively, within 12months of diagnosis. Rates of opioid prescription decreased from 34.8% in 2008 to 27.0% in 2015 (P<0.001); however, prescribing of benzodiazepines only decreased from 11.6% in 2008 to 10.8% in 2015. Patients with continued or new benzodiazepine use consistently used more opioids than patients who never used or stopped using benzodiazepines during the study period (one-way ANOVA, P<0.001). For patients with continued and new benzodiazepine use, the odds ratio of long-term opioid use compared with those never prescribed a benzodiazepine was 2.99 (95% CI, 2.89-3.08) and 2.68 (95% CI, 2.62-2.75), respectively.LIMITATIONS: This study used administrative claims analyses, which rely on accuracy and completeness of diagnostic, procedural, and prescription codes.CONCLUSION: Overall opioid prescribing for low back pain or lower extremity pain decreased substantially during the study period, indicating a shift in management within the medical community. Rates of benzodiazepine prescribing, however, remained at approximately 11%. Concurrent prescriptions of benzodiazepines and opioids after LBP or LEP diagnosis were associated with increased risk of long-term opioid use.

    View details for DOI 10.1007/s11606-019-05549-8

    View details for PubMedID 31720966

  • Expenditures and Health Care Utilization Among Adults With Newly Diagnosed LowBack and Lower Extremity Pain JAMA NETWORK OPEN Kim, L. H., Vail, D., Azad, T. D., Bentley, J. P., Zhang, Y., Ho, A. L., Fatemi, P., Feng, A., Varshneya, K., Desai, M., Veeravagu, A., Ratliff, J. K. 2019; 2 (5)
  • Expenditures and Health Care Utilization Among Adults With Newly Diagnosed Low Back and Lower Extremity Pain. JAMA network open Kim, L. H., Vail, D., Azad, T. D., Bentley, J. P., Zhang, Y., Ho, A. L., Fatemi, P., Feng, A., Varshneya, K., Desai, M., Veeravagu, A., Ratliff, J. K. 2019; 2 (5): e193676


    Low back pain (LBP) with or without lower extremity pain (LEP) is one of the most common reasons for seeking medical care. Previous studies investigating costs in this population targeted patients receiving surgery. Little is known about health care utilization among patients who do not undergo surgery.To assess use of health care resources for LBP and LEP management and analyze associated costs.This cohort study used a retrospective analysis of a commercial database containing inpatient and outpatient data for more than 75 million individuals. Participants were US adults who were newly diagnosed with LBP or LEP between 2008 and 2015, did not have a red-flag diagnosis, and were opiate naive prior to diagnosis. Dates of analysis were October 6, 2018, to March 7, 2019.Newly diagnosed LBP or LEP.The primary outcome was total cost of care within the first 6 and 12 months following diagnosis, stratified by whether patients received spinal surgery. An assessment was performed to determine whether patients who did not undergo surgery received care in accordance with proposed guidelines for conservative LBP and LEP management. Costs resulting from use of different health care services were estimated.A total of 2 498 013 adult patients with a new LBP or LEP diagnosis (median [interquartile range] age, 47 [36-58] years; 1 373 076 [55.0%] female) were identified. More than half (55.7%) received no intervention. Only 1.2% of patients received surgery, but they accounted for 29.3% of total 12-month costs ($784 million). Total costs of care among the 98.8% of patients who did not receive surgery were $1.8 billion. Patients who did not undergo surgery frequently received care that was inconsistent with clinical guidelines for LBP and LEP: 32.3% of these patients received imaging within 30 days of diagnosis and 35.3% received imaging without a trial of physical therapy.The findings suggest that surgery is rare among patients with newly diagnosed LBP and LEP but remains a significant driver of spending. Early imaging in patients who do not undergo surgery was also a major driver of increased health care expenditures. Avoidable costs among patients with typically self-limited conditions result in considerable economic burden to the US health care system.

    View details for PubMedID 31074820

  • Randomized Controlled Trials in Functional Neurosurgery-Association of Device Approval Status and Trial Quality. Neuromodulation : journal of the International Neuromodulation Society Azad, T. D., Feng, A. Y., Mehta, S., Bak, A. B., Johnson, E., Mittal, V., Esparza, R., Veeravagu, A., Halpern, C. H., Grant, G. A. 2019


    Randomized controlled trials (RCTs) have been critical in evaluating the safety and efficacy of functional neurosurgery interventions. Given this, we sought to systematically assess the quality of functional neurosurgery RCTs.We used a database of neurosurgical RCTs (trials published from 1961 to 2016) to identify studies of functional neurosurgical procedures (N = 48). We extracted data on the design and quality of these RCTs and quantified the quality of trials using Jadad scores. We categorized RCTs based on the device approval status at the time of the trial and tested the association of device approval status with trial design and quality parameters.Of the 48 analyzed functional neurosurgery RCTs, the median trial size was 34.5 patients with a median age of 51. The most common indications were Parkinson's disease (N = 20), epilepsy (N = 10), obsessive-compulsive disorder (N = 4), and pain (N = 4). Most trials reported inclusion and exclusion criteria (95.8%), sample size per arm (97.9%), and baseline characteristics of the patients being studied (97.9%). However, reporting of allocation concealment (29.2%), randomization mode (66.7%), and power calculations (54.2%) were markedly less common. We observed that trial quality has improved over time (Spearman r, 0.49). We observed that trials studying devices with humanitarian device exemption (HDE) and experimental indications (EI) tended to be of higher quality than trials of FDA-approved devices (p = 0.011). A key distinguishing quality characteristic was the proportion of HDE and EI trials that were double-blinded, compared to trials of FDA-approved devices (HDE, 83.3%; EI, 69.2%; FDA-approved, 35.3%). Although more than one-third of functional neurosurgery RCTs reported funding from industry, no significant association was identified between funding source and trial quality or outcome.The quality of RCTs in functional neurosurgery has improved over time but reporting of specific metrics such as power calculations and allocation concealment requires further improvement. Device approval status but not funding source was associated with trial quality.

    View details for DOI 10.1111/ner.13083

    View details for PubMedID 31828896

  • Optogenetic Modulation for the Treatment of Traumatic Brain Injury. Stem cells and development Delaney, S. L., Gendreau, J. L., DSouza, M., Feng, A. Y., Ho, A. 2019


    Although research involving traumatic brain injury (TBI) has traditionally focused on the acute clinical manifestations, new studies provide evidence for chronic and progressive neurological sequelae associated with TBI, highlighting the risk of persistent, and sometimes life-long, consequences for affected patients. Several treatment modalities to date have demonstrated efficacy in experimental models. However, there is currently no effective treatment to improve neural structure repair and functional recovery of TBI patients. Optogenetics represents a potential molecular tool for neuromodulation and monitoring cellular activity with unprecedented spatial resolution and millisecond temporal precision. In this review, we discuss the conceptual background and preclinical evidence of optogenetics for neuromodulation, and translational applications for TBI treatment are considered.

    View details for DOI 10.1089/scd.2019.0187

    View details for PubMedID 31559914

  • Graft Materials and Biologics for Spinal Interbody Fusion. Biomedicines D'Souza, M., Macdonald, N. A., Gendreau, J. L., Duddleston, P. J., Feng, A. Y., Ho, A. L. 2019; 7 (4)


    Spinal fusion is the most widely performed procedure in spine surgery. It is the preferred treatment for a wide variety of pathologies including degenerative disc disease, spondylolisthesis, segmental instability, and deformity. Surgeons have the choice of fusing vertebrae by utilizing cages containing autografts, allografts, demineralized bone matrices (DBMs), or graft substitutes such as ceramic scaffolds. Autografts from the iliac spine are the most commonly used as they offer osteogenic, osteoinductive, and osteoconductive capabilities, all while avoiding immune system rejection. Allografts obtained from cadavers and living donors can also be advantageous as they lack the need for graft extraction from the patient. DBMs are acid-extracted organic allografts with osteoinductive properties. Ceramic grafts containing hydroxyapatite can be readily manufactured and are able to provide osteoinductive support while having a long shelf life. Further, bone-morphogenetic proteins (BMPs), mesenchymal stem cells (MSCs), synthetic peptides, and autologous growth factors are currently being optimized to assist in improving vertebral fusion. Genetic therapies utilizing viral transduction are also currently being devised. This review provides an overview of the advantages, disadvantages, and future directions of currently available graft materials. The current literature on growth factors, stem cells, and genetic therapy is also discussed.

    View details for DOI 10.3390/biomedicines7040075

    View details for PubMedID 31561556

  • Robotic-Assisted Spine Surgery: History, Efficacy, Cost, And Future Trends. Robotic surgery (Auckland) D'Souza, M., Gendreau, J., Feng, A., Kim, L. H., Ho, A. L., Veeravagu, A. 2019; 6: 9–23


    Robot-assisted spine surgery has recently emerged as a viable tool to enable less invasive and higher precision surgery. The first-ever spine robot, the SpineAssist (Mazor Robotics Ltd., Caesarea, Israel), gained FDA approval in 2004. With its ability to provide real-time intraoperative navigation and rigid stereotaxy, robotic-assisted surgery has the potential to increase accuracy while decreasing radiation exposure, complication rates, operative time, and recovery time. Currently, robotic assistance is mainly restricted to spinal fusion and instrumentation procedures, but recent studies have demonstrated its use in increasingly complex procedures such as spinal tumor resections and ablations, vertebroplasties, and deformity correction. However, robots do require high initial costs and training, and thus, require justification for their incorporation into common practice. In this review, we discuss the history of spinal robots along as well as currently available systems. We then examine the literature to evaluate accuracy, operative time, complications, radiation exposure, and costs - comparing robotic-assisted to traditional fluoroscopy-assisted freehand approaches. Finally, we consider future applications for robots in spine surgery.

    View details for DOI 10.2147/RSRR.S190720

    View details for PubMedID 31807602

    View details for PubMedCentralID PMC6844237

  • Robot-assisted versus manual navigated stereoelectroencephalography in adult medically-refractory epilepsy patients. Epilepsy research Kim, L. H., Feng, A. Y., Ho, A. L., Parker, J. J., Kumar, K. K., Chen, K. S., Grant, G. A., Henderson, J. M., Halpern, C. H. 2019; 159: 106253


    Stereoelectroencephalography (SEEG) has experienced a recent growth in adoption for epileptogenic zone (EZ) localization. Advances in robotics have the potential to improve the efficiency and safety of this intracranial seizure monitoring method. We present our institutional experience employing robot-assisted SEEG and compare its operative efficiency, seizure reduction outcomes, and direct hospital costs with SEEG performed without robotic assistance using navigated stereotaxy.We retrospectively identified 50 consecutive adult SEEG cases at our institution in this IRB-approved study, of which 25 were navigated with image guidance (hereafter referred to as "navigated") (02/2014-10/2016) and 25 were robot-assisted (09/2016-12/2017). A thorough review of medical/surgical history and operative records with imaging and trajectory plans was done for each patient. Direct inpatient costs related to each technique were compared.Most common seizure etiologies for patients undergoing navigated and robot-assisted SEEG included non-lesional and benign temporal lesions. Despite having a higher mean number of leads-per-patient (10.2 ± 3.5 versus 7.2 ± 2.6, P = 0.002), robot-assisted cases had a significantly shorter mean operative time than navigated cases (125.5±48.5 versus 173.4±84.3 min, P = 0.02). Comparison of robot-assisted cases over the study interval revealed no significant difference in mean operative time (136.4±51.4 min for the first ten cases versus 109.9±75.8 min for the last ten cases, P = 0.25) and estimated operative time-per-lead (13.4±6.0 min for the first ten cases versus 12.9±7.7 min for the last ten cases, P = 0.86). The mean depth, radial, target, and entry point errors for robot-assisted cases were 2.12±1.89, 1.66±1.58, 3.05±2.02 mm, and 1.39 ± 0.75 mm, respectively. The two techniques resulted in equivalent EZ localization rate (navigated 88 %, robot-assisted 96 %, P = 0.30). Common types of epilepsy surgery performed consisted of implantation of responsive neurostimulation (RNS) device (56 %), resection (19.1 %), and laser ablation (23.8 %) for navigated SEEG. For robot-assisted SEEG, either RNS implantation (68.2 %) or laser ablation (22.7 %) were performed or offered. A majority of navigated and robot-assisted patients who underwent epilepsy surgery achieved either Engel Class I (navigated 36.8 %, robot-assisted 31.6 %) or II (navigated 36.8 %, robot-assisted 15.8 %) outcome with no significant difference between the groups (P = 0.14). Direct hospital cost for robot-assisted SEEG was 10 % higher than non-robotic cases.This single-institutional study suggests that robotic assistance can enhance efficiency of SEEG without compromising safety or precision when compared to image guidance only. Adoption of this technique with uniform safety and efficacy over a short period of time is feasible with favorable epilepsy outcomes.

    View details for DOI 10.1016/j.eplepsyres.2019.106253

    View details for PubMedID 31855826

  • Stereoelectroencephalography in children: a review. Neurosurgical focus Ho, A. L., Feng, A. Y., Kim, L. H., Pendharkar, A. V., Sussman, E. S., Halpern, C. H., Grant, G. A. 2018; 45 (3): E7


    Stereoelectroencephalography (SEEG) is an intracranial diagnostic measure that has grown in popularity in the United States as outcomes data have demonstrated its benefits and safety. The main uses of SEEG include 1) exploration of deep cortical/sulcal structures; 2) bilateral recordings; and 3) 3D mapping of epileptogenic zones. While SEEG has gradually been accepted for treatment in adults, there is less consensus on its utility in children. In this literature review, the authors seek to describe the current state of SEEG with a focus on the more recent technology-enabled surgical techniques and demonstrate its efficacy in the pediatric epilepsy population.

    View details for PubMedID 30173607

  • The cannabinoid-1 receptor is abundantly expressed in striatal striosomes and striosome-dendron bouquets of the substantia nigra PLOS ONE Davis, M. I., Crittenden, J. R., Feng, A. Y., Kupferschmidt, D. A., Naydenov, A., Stella, N., Graybiel, A. M., Lovinger, D. M. 2018; 13 (2): e0191436


    Presynaptic cannabinoid-1 receptors (CB1-R) bind endogenous and exogenous cannabinoids to modulate neurotransmitter release. CB1-Rs are expressed throughout the basal ganglia, including striatum and substantia nigra, where they play a role in learning and control of motivated actions. However, the pattern of CB1-R expression across different striatal compartments, microcircuits and efferent targets, and the contribution of different CB1-R-expressing neurons to this pattern, are unclear. We use a combination of conventional techniques and novel genetic models to evaluate CB1-R expression in striosome (patch) and matrix compartments of the striatum, and in nigral targets of striatal medium spiny projection neurons (MSNs). CB1-R protein and mRNA follow a descending dorsolateral-to-ventromedial intensity gradient in the caudal striatum, with elevated expression in striosomes relative to the surrounding matrix. The lateral predominance of striosome CB1-Rs contrasts with that of the classical striosomal marker, the mu opioid receptor (MOR), which is expressed most prominently in rostromedial striosomes. The dorsolateral-to-ventromedial CB1-R gradient is similar to Drd2 dopamine receptor immunoreactivity and opposite to Substance P. This topology of CB1-R expression is maintained downstream in the globus pallidus and substantia nigra. Dense CB1-R-expressing striatonigral fibers extend dorsally within the substantia nigra pars reticulata, and colocalize with bundles of ventrally extending, striosome-targeted, dendrites of dopamine-containing neurons in the substantia nigra pars compacta (striosome-dendron bouquets). Within striatum, CB1-Rs colocalize with fluorescently labeled MSN collaterals within the striosomes. Cre recombinase-mediated deletion of CB1-Rs from cortical projection neurons or MSNs, and MSN-selective reintroduction of CB1-Rs in knockout mice, demonstrate that the principal source of CB1-Rs in dorsolateral striosomes is local MSN collaterals. These data suggest a role for CB1-Rs in caudal dorsolateral striosome collaterals and striosome-dendron bouquet projections to lateral substantia nigra, where they are anatomically poised to mediate presynaptic disinhibition of both striosomal MSNs and midbrain dopamine neurons in response to endocannabinoids and cannabinomimetics.

    View details for DOI 10.1371/journal.pone.0191436

    View details for Web of Science ID 000425604300010

    View details for PubMedID 29466446

    View details for PubMedCentralID PMC5821318