Faculty Bibliography

Experience shapes the central nervous system throughout life. Structural and functional plasticity confers a remarkable ability on the brain, allowing neural circuits to adequately adapt to dynamic environments. This process can require selective adjustment of many excitatory and inhibitory synapses in an organized manner, in such a way as to enhance representations of behaviorally important sensory stimuli while preserving overall network excitability. The rules and mechanisms that orchestrated these changes across different synapses and throughout neuronal ensembles are beginning to be understood. Here, we review the evidence connecting synaptic plasticity to functional plasticity and perceptual learning, focusing on the roles of various neuromodulatory systems in enabling plasticity of adult neural circuits. However, the challenge remains to appropriately leverage these systems and forms of plasticity to persistently improve perceptual abilities and behavioral performance.

Depression is a salient emotional feature of chronic pain. Depression alters the pain threshold and impairs functional recovery. To date, however, there has been limited understanding of synaptic or circuit mechanisms that regulate depression in the pain state. Here, we demonstrate that depression-like behaviors are induced in a rat model of chronic neuropathic pain. Using this model, we show that chronic pain selectively increases the level of GluA1 subunits of AMPA-type glutamate receptors at the synapses of the nucleus accumbens (NAc), a key component of the brain reward system. We find, in addition, that this increase in GluA1 levels leads to the formation of calcium-permeable AMPA receptors (CPARs). Surprisingly, pharmacologic blockade of these CPARs in the NAc increases depression-like behaviors associated with pain. Consistent with these findings, an AMPA receptor potentiator delivered into the NAc decreases pain-induced depression. These results show that transmission through CPARs in the NAc represents a novel molecular mechanism modulating the depressive symptoms of pain, and thus CPARs may be a promising therapeutic target for the treatment of pain-induced depression. More generally, these findings highlight the role of central glutamate signaling in pain states and define the brain reward system as an important region for the regulation of depressive symptoms of pain.

AIM: To evaluate the relationship between intraoperative blood loss and juvenile nasopharyngeal angiofibroma (JNA) vascular supply and tumour stage in patients who underwent superselective external carotid artery (ECA) embolization. This series is unique in that all embolizations were performed by dedicated paediatric interventional radiologists at a tertiary referral paediatric centre. MATERIALS AND METHODS: Seventeen male patients treated from January 2002 to August 2009 underwent preoperative angiography and embolization using polyvinyl alcohol (PVA) particles. Tumours were graded using three different staging systems based on preoperative imaging and correlated to surgical blood loss. All patients underwent bilateral internal and external carotid angiography, with embolization of ECA tumour supply via microcatheter delivery of PVA particles. Particle size ranged from 150-500 mum with a mean size of 250-355 mum. Surgical resection was performed with either endoscopic or open techniques within 24 h and intraoperative blood loss was reported. RESULTS: Seven lesions were supplied strictly by the ECA circulation and had mean surgical blood loss of 336 ml. Twelve lesions had both ECA and internal carotid artery (ICA) supply and had mean surgical blood loss of 842 ml. The difference in blood loss in these two groups was statistically significant (p = 0.03). There was no case of inadvertent intracranial or ophthalmic embolization. There were statistically significant correlations between estimated surgical blood loss and the Andrews (p = 0.008), Radkowski (p = 0.015), and University of Pittsburgh Medical Center (UPMC; p = 0.015) preoperative tumour staging systems, respectively. CONCLUSION: Preoperative embolization of JNA tumours can be safely performed without neurological complications. The present study identified a statistically significant difference in intraoperative blood loss between those lesions with a purely ECA vascular supply and a combination of ECA and ICA vascular supply. Angiography is helpful in delineating ICA supply and can help guide surgical planning.

BACKGROUND: Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns. METHODS: We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. RESULTS: Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0.0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0.0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p<0.0001). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival after recurrence was significantly longer in patients with group 4 tumours in cohort 1 (p=0.013) than with other subgroups, which was confirmed in cohort 2 (p=0.0075), but not cohort 3 (p=0.70). INTERPRETATION: Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases. FUNDING: Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto.

OBJECTIVE: Neurofibromatosis (NF)-related benign tumors such as plexiform neurofibromas (PN) and vestibular schwannomas (VS) can cause substantial morbidity. Clinical trials directed at these tumors have become available. Due to differences in disease manifestations and the natural history of NF-related tumors, response criteria used for solid cancers (1-dimensional/RECIST [Response Evaluation Criteria in Solid Tumors] and bidimensional/World Health Organization) have limited applicability. No standardized response criteria for benign NF tumors exist. The goal of the Tumor Measurement Working Group of the REiNS (Response Evaluation in Neurofibromatosis and Schwannomatosis) committee is to propose consensus guidelines for the evaluation of imaging response in clinical trials for NF tumors. METHODS: Currently used imaging endpoints, designs of NF clinical trials, and knowledge of the natural history of NF-related tumors, in particular PN and VS, were reviewed. Consensus recommendations for response evaluation for future studies were developed based on this review and the expertise of group members. RESULTS: MRI with volumetric analysis is recommended to sensitively and reproducibly evaluate changes in tumor size in clinical trials. Volumetric analysis requires adherence to specific imaging recommendations. A 20% volume change was chosen to indicate a decrease or increase in tumor size. Use of these criteria in future trials will enable meaningful comparison of results across studies. CONCLUSIONS: The proposed imaging response evaluation guidelines, along with validated clinical outcome measures, will maximize the ability to identify potentially active agents for patients with NF and benign tumors.

OBJECTIVES: To determine which demographic or performance variables are associated with inconsistent use of a second implant in pediatric recipients of sequential bilateral cochlear implants (CIs). METHODS: A retrospective chart review was conducted on pediatric recipients of sequential bilateral CIs. Children were divided into two age groups, 5-9 and 10-17 years of age. For each group, we examined whether inconsistent use of the second implant (CI-2) was associated with a variety of demographic variables, or speech-perception scores. RESULTS: In children aged 5-9 years, inconsistent use of CI-2 was not significantly associated with any demographic variable, but was related to both the word-recognition score with CI-2, and the difference in word-recognition scores between the first implant (CI-1) and CI-2. In children aged 10-17 years, these relationships were not significant due to smaller number of subjects. Finally, CI-2 word-recognition scores across all children were significantly correlated with the age of implantation for both CI-1 and CI-2, and the time between CI-1 and CI-2 surgeries. DISCUSSION: Speech-recognition scores obtained with CI-2, and the extent to which it differs from CI-1, are most closely related with inconsistent use of CI-2 in pediatric sequential implantees. These results are consistent with similar data previously reported by other investigators. While children implanted with CI-2 at a later age generally perform more poorly, most children still use both implants, and benefit from CI-2 even when receiving the implant as an adolescent. CONCLUSION: In pediatric recipients of sequential bilateral CIs, inconsistent use of CI-2 is related to the speech recognition scores with CI-2, and the difference in speech-recognition scores between CI-1 and CI-2. In addition, speech-recognition scores with CI-2 are related to the amount of time between CI-1 and CI-2 surgeries, and the age of implantation for both CI-1 and CI-2.

BACKGROUND: Traditional microscopic and endoscopic transsphenoidal approaches (TSAs) are the most common surgical techniques in pituitary surgery. Examining regional practice patterns in pituitary surgery can provide valuable insights into which surgical strategies are most accessible, effective, and cost-efficient. In this study we investigated regional variations in surgical approaches to pituitary tumors and evaluated evolving practice patterns in pituitary surgery. METHODS: The 2010 Medicare Part B Carrier Summary Database and Medicare Part B National Summary Database from 2003-2010 were examined using pituitary surgery Current Procedure Terminology (CPT) codes 61548 (microscopic transsphenoidal approach), 62165 (endoscopic transsphenoidal approach), and 61546 (transcranial approach). RESULTS: Endoscopic TSAs increased by over 10-fold in the past decade, while usage of microscopic TSAs decreased by 23.3%. Nevertheless, the microscopic approach was still the most common TSA (64.7%) in 2010 compared to the endoscopic approach (35.3%). The microscopic TSA was predominant in the Southern and Western United States (74% and 69%, respectively). In the Northeast and Midwest, the rates of microscopic and endoscopic TSAs were roughly equivalent. However, the rate of endoscopic TSAs was statistically significantly higher (p < 0.05) in the Northeast and Midwest (47% and 45%, respectively) than in the South and West (26% and 31%, respectively). Transcranial approaches continued to decline from 4% to 2% over the last decade. CONCLUSION: Regional disparities in transsphenoidal practice patterns exist in the United States. Although the microscopic approach is still more common overall, there has been an evolving shift toward endoscopic TSAs in the last decade.

ObjectiveTo characterize malpractice litigation regarding obstructive sleep apnea (OSA) and educate physicians on frequently cited factors.Study Design and SettingAnalysis of the Westlaw legal databaseMethodsJury verdict and settlement reports were examined for outcome, awards, patient demographic factors, defendant specialty, and alleged causes of malpracticeResultsOut of 54 identified cases, 33 (61.1%) cases were resolved in favor of defendants, 12 (22.2%) via settlement, and 9 (16.7%) through jury award. Median settlement and jury awards did not significantly differ ($750,000 vs $550,000, P > .50). Age and gender did not affect outcome. Otolaryngologists and anesthesiologists were the most frequently named defendants. Forty-seven cases (87.1%) stemmed from OSA patients who underwent procedures with resultant perioperative adverse events. Common alleged factors included death (48.1%), permanent deficits (42.6%), intraoperative complications (35.2%), requiring additional surgery (25.9%), anoxic brain injury (24.1%), inadequate informed consent (24.1%), inappropriate medication administration (22.2%), and inadequate monitoring (20.4%).ConclusionLitigation related to OSA is frequently associated with perioperative complications more than nonoperative issues such as a failure to diagnose this disorder. Nonetheless, OSA is considerably underdiagnosed, and special attention should be paid to at-risk patients, including close monitoring of their clinical status and the medications they receive. For patients with diagnosed or suspected OSA with planned operative intervention, whether for OSA or an unrelated issue, a comprehensive informed consent process detailing the factors outlined in this analysis is an effective strategy to increase communication and improve the physician-patient relationship, minimize liability, and ultimately improve patient safety.

BACKGROUND: The BRAF V600E (BRAF+) mutation activates the mitogen-activated protein kinase (MAPK/ERK) pathway and may confer an aggressive phenotype in papillary thyroid cancer (PTC). Clinically, the behavior of BRAF+ PTC, however, varies from an indolent to an aggressive course. SPRY2 is a negative feedback regulator of the MAPK/ERK pathway. We hypothesize that the level of SPRY2 expression contributes to MAPK/ERK pathway output and accounts for BRAF+ and clinical heterogeneity. METHODS: A tissue microarray with BRAF-positive PTCs (BRAF+ PTCs) was constructed and analyzed for SPRY2 expression and MAPK/ERK output. Data were studied in the context of clinicopathologic factors to develop a risk stratification system predictive of tumor biology. SPRY2 function was studied by silencing SPRY2 in BRAF+ PTC cells. These cells were treated with MAPK/ERK pathway inhibitors and assessed for growth effects. RESULTS: BRAF+ PTCs with an intact MAPK/ERK feedback pathway do not exhibit lymph node metastases. BRAF+ PTCs with dysregulated feedback pathways have nodal metastasis. When SPRY2 is silenced, the BRAF+ PTC cells are significantly more sensitive to MAPK/ERK inhibition. CONCLUSION: PTC behavior likely is dependent on both the driver of the MAPK/ERK pathway and its regulatory feedback. When the feedback pathway is intact, the tumor phenotype seems to be less aggressive. This observation has direct and important clinical implications and may alter our treatment strategies.

BACKGROUND: BRAF V600E mutation is the most common genetic alteration in papillary thyroid cancer (PTC). We used a mutation-specific antibody for immunohistochemical (IHC) detection of the BRAF V600E mutation and correlated expression with clinicopathologic features. The study was designed to validate the accuracy and determine the clinical importance of IHC detection of the BRAF V600E mutation in PTC. METHODS: Direct sequencing and IHC for BRAF V600E mutation was performed in 37 consecutive patients with PTCs. IHC was scored on an intensity proportion scale. IHC positive tumors were stratified into intensity categories. The categories were assessed for clinicopathologic variables, including age, extrathyroidal extension, lymphovascular invasion, and lymph node metastases. RESULTS: A total of 25 PTCs were BRAF V600E-positive and 12 were BRAF mutation-negative on IHC. The BRAF V600E mutation-specific antibody had a sensitivity of 89% and specificity of 100% for detecting the mutation. Tumors with high-intensity staining were more likely to have extrathyroidal extension. CONCLUSION: IHC is an accurate method for the detection of the BRAF V600E mutation in PTC, and its ability to quantify the mutation expression may serve as a better predictor of tumor behavior than molecular sequencing. It provides a potentially rapid, easily applicable, and economic alternative to current techniques.