Volumetric microscopy of cerebral arteries with a miniaturized optical coherence tomography imaging probe.

Endovascular interventions are increasingly becoming the preferred approach for treating strokes and cerebral artery diseases. These procedures rely on sophisticated angiographical imaging guidance, which encounters challenges because of limited contrast and spatial resolution. Achieving a more precise visualization of the underlying arterial pathology and neurovascular implants is crucial for accurate procedural decision-making. In a human study involving 32 patients, we introduced the clinical application of a miniaturized endovascular neuro optical coherence tomography (nOCT) imaging probe. This technology was designed to navigate the tortuous paths of the cerebrovascular circulation and to offer high-resolution imaging in situ. The nOCT probe is compatible with standard neurovascular microcatheters, integrating with the procedural workflow used in clinical routine. Equipped with a miniaturized optical fiber and a distal lens, the probe illuminates the tissue and collects the backscattered, near-infrared light. While rotating the fiber and the lens at high speed, the probe is rapidly retracted, creating a spiral-shaped light pattern to comprehensively capture the arterial wall and implanted devices. Using nOCT, we demonstrated volumetric microscopy of cerebral arteries in patients undergoing endovascular procedures. We imaged the anterior and posterior circulation of the brain, including distal segments of the internal carotid and middle-cerebral arteries, as well as the vertebral, basilar, and posterior cerebral arteries. We captured a broad spectrum of neurovascular pathologies, such as brain aneurysms, ischemic stroke, arterial stenoses, dissections, and intracranial atherosclerotic disease. nOCT offered artifact-free, high-resolution visualizations of intracranial artery pathology and neurovascular devices.

Bilateral mechanical rotational vertebral artery occlusion.

Rotational vertebral artery occlusion, or bow hunter's stroke, is reversible, positional symptomatic vertebrobasilar ischemia. The typical mechanism of action is obstruction of a dominant vertebral artery with contralateral head rotation in the setting of baseline ipsilateral vertebral artery stenosis or occlusion. Here we present a rare case of mechanical occlusion of bilateral patent vertebral arteries manifesting as near syncope with rightward head rotation. Diagnostic cerebral angiography showed dynamic right C5 vertebral occlusion and left C2 vertebral occlusion. The patient underwent right C4/5 transverse process decompression. Postoperative angiogram showed patent flow through the right vertebral artery in neutral position and with head turn with resultant resolution of symptoms.

Preadmission beta-blockers are associated with decreased incidence of neurogenic stunned myocardium in aneurysmal subarachnoid hemorrhage.

BACKGROUND: Neurogenic stunned myocardium (NSM) is a frequent complication of aneurysmal subarachnoid hemorrhage (aSAH), with a significant impact on disease course. The presumed cause is catecholamine surge at the time of aneurysm rupture. Beta-blockers, which reduce the impact of the catecholamine surge, may decrease the risk of developing NSM. METHODS: A chart review of 234 consecutive patients admitted to the Oregon Health and Science University Neurosurgery service between March 6, 2008 and June 23, 2010 with a diagnosis of aneurysmal SAH was performed. This group was further subdivided by patients who received echocardiograms on admission, by gender, and by the prehospital administration of ß-blockers. RESULTS: One hundred thirty of 234 patients had echocardiograms on or shortly after admission, and 18 of these developed NSM (13.8%). None of the 22 patients taking prehospital ß-blockers developed NSM. Using the Fisher exact test to compare the 2 groups, patients who were administered prehospital ß-blockers were significantly less likely to develop stunning compared to those who were not (P = .04). After correcting for other variables using multiple logistic regression analysis, the previous use of ß-blockers was still found to be significantly associated with a decreased incidence of NSM after SAH (P = .049). There was no significant difference in hospital length of stay, peribleed stroke, vasospasm, or death. Of the 18 patients with stunning, 15 were women, 5 of whom were on estrogen supplementation. The mean peak troponin elevation of women who developed NSM on estrogen supplementation was significantly higher than for those who were not (mean peak troponin 9.97 ± 2.01 mg/dL; P < .001). CONCLUSION: Prehospital ß-blockers are associated with decreased risk of developing NSM in patients with aSAH. Estrogen may play an additional role in shaping the degree of NSM in women.

Transvenous Embolization for Cerebrospinal Fluid-Venous Fistula. A Case Series from a Single Community-Academic Center.

BACKGROUND: Transvenous embolization is a new treatment for spinal cerebrospinal fluid (CSF)-venous fistula, with only 1 reported large case series from the center that invented this technique. METHODS: We report the clinical and radiographic data of 5 consecutive patients who were diagnosed with CSF-venous fistula at a single community-academic medical center and were treated with transvenous embolization. All patients provided consent for this report. Institutional review board approval was not required because of the retrospective nature of this study describing standards of care. RESULTS: Five patients, 3 men and 2 women, with a median age of 57 years, were diagnosed between March and December 2021with spontaneous intracranial hypotension (SIH) as a result of CSF-venous fistula. Two patients were originally referred for middle meningeal artery embolization for chronic subdural hematoma. All fistulae were in the thoracic spine at a single level in 3 patients, 2 levels in 1 patient, and multiple levels in 1 patient. Transvenous embolization was technically successful in all cases, with no significant complications. Four patients (80%) had complete or near-complete resolution of clinical symptoms and returned to baseline function and employment status. One patient (20%) has had a remitting relapsing course. Posttreatment brain magnetic resonance imaging showed resolution of spontaneous intracranial hypotension findings in 4 patients (80%) and minimal changes in 1 patient (20%), who had significant clinical improvement. CONCLUSIONS: Transvenous embolization for the treatment of CSF-venous fistula is feasible and seems effective in the short-term. The results reported by the previous case series can be reproduced in other centers with available expertise and adherence to published diagnostic and treatment protocols.

Spontaneous chronic subdural hematoma due to cerebral cortical artery rupture: First case report and review of pertinent literature.

INTRODUCTION: Chronic subdural hematoma (CSDH) is generally attributed to pathological changes in the dural arterial system, which has led to growing utilization of middle meningeal artery (MMA) embolization in CSDH treatment. There are no case reports of CSDH due to cerebral cortical artery perforation. METHOD: We report a case of spontaneous CSDH caused by cortical artery rupture that was identified on digital subtraction angiography and could be visualized on computed tomographic angiography (CTA). We also present a brief review of the pertinent literature. RESULT: A 56-year-old man presented with daily headache for three weeks with no history of trauma. Neurologic exam was normal except for subtle left pronator drift. A computed tomography scan of the head showed a right CSDH with a midline shift. CTA was suspicious for a dilated vein in the subdural collection. Catheter cerebral angiogram demonstrated contrast extravasation from a small cortical branch of the middle cerebral artery with no aneurysm, arterial dissection, or vascular malformation. In retrospect, CTA findings represented contrast extravasation, not a dilated vein. Burr-hole mini-craniotomy was performed, and the hematoma was evacuated. The patient had complete clinical and radiographic recovery. CONCLUSION: Ruptured cerebral cortical artery can cause CSDH. In atypical cases of CSDH, careful evaluation of selective internal carotid artery angiography is advised to look for alternative pathologies prior to proceeding with MMA embolization. CTA images may demonstrate active extravasation from a small cortical artery.

Education Research: Challenges Faced by Neurology Trainees in a Neuro-Intervention Career Track.

OBJECTIVE: The widespread adoption of endovascular therapy (EVT) for emergent large vessel occlusion has led to increased nationwide demand for neurointerventionalists, heightened interest among neurology residents to pursue neurointervention as a career, and increased importance of neurointervention exposure for all neurologists who care for patients with acute ischemic stroke. Exposure to neurointervention and its career path are not well-defined for neurology trainees. METHODS: The Society for Vascular and Interventional Neurology (SVIN) Education Committee conducted a multicenter electronic survey directed towards neurology residents and vascular neurology (VN), neurocritical care (NCC), and neurointervention fellows in June 2018. A total of 250 programs were invited to participate; 76 trainees completed the survey. RESULTS: Respondents self-identified as 22% postgraduate year (PGY)2, 40% PGY3/4, 30% VN fellows, and 8% neurointervention or NCC fellows. Eighty-seven percent of trainees had more than 2 months exposure to VN during residency, 41% to NCC, and only 3% to neurointervention. Sixty-eight percent of respondents had no exposure to neurointervention during residency. Whereas 72% believed that a background in neurology was good preparation for neurointervention, only 41% agreed that fellowship training pathway in neurointervention is well-structured for neurology residents when compared to other subspecialties. CONCLUSION: In this survey, respondents identified lack of exposure to neurointervention and a well-defined training pathway as obstacles towards pursuing neurointervention as a career. These obstacles must be addressed for the continued development of neurointervention as a subspecialty of neurology.

Global Impact of COVID-19 on Stroke Care and IV Thrombolysis.

OBJECTIVE: To measure the global impact of COVID-19 pandemic on volumes of IV thrombolysis (IVT), IVT transfers, and stroke hospitalizations over 4 months at the height of the pandemic (March 1 to June 30, 2020) compared with 2 control 4-month periods. METHODS: We conducted a cross-sectional, observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers. Diagnoses were identified by their ICD-10 codes or classifications in stroke databases. RESULTS: There were 91,373 stroke admissions in the 4 months immediately before compared to 80,894 admissions during the pandemic months, representing an 11.5% (95% confidence interval [CI] -11.7 to -11.3, p < 0.0001) decline. There were 13,334 IVT therapies in the 4 months preceding compared to 11,570 procedures during the pandemic, representing a 13.2% (95% CI -13.8 to -12.7, p < 0.0001) drop. Interfacility IVT transfers decreased from 1,337 to 1,178, or an 11.9% decrease (95% CI -13.7 to -10.3, p = 0.001). Recovery of stroke hospitalization volume (9.5%, 95% CI 9.2-9.8, p < 0.0001) was noted over the 2 later (May, June) vs the 2 earlier (March, April) pandemic months. There was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was noted in 3.3% (1,722/52,026) of all stroke admissions. CONCLUSIONS: The COVID-19 pandemic was associated with a global decline in the volume of stroke hospitalizations, IVT, and interfacility IVT transfers. Primary stroke centers and centers with higher COVID-19 inpatient volumes experienced steeper declines. Recovery of stroke hospitalization was noted in the later pandemic months.

First Pass Recanalization Rates of Solitaire vs Trevo vs Primary Aspiration: The Kaiser Southern California Experience.

CONTEXT: New stroke thrombectomy devices have significantly improved recanalization rates in patients with large vessel occlusion. The first pass effect, or complete or near complete recanalization after a single pass of a device, is associated with better outcome. However, it remains unclear whether one technique is superior to the others at first pass recanalization. OBJECTIVE: The successful recanalization rates of three common techniques: 1) Stent-retriever with the Solitaire or 2) Trevo device, or 3) primary aspiration (PA) with a distal aspiration catheter, were compared across three Kaiser Permanente Southern California Medical Centers over a 5-year period. DESIGN: Retrospective review of cases between October 2013 and May 2018. MAIN OUTCOME MEASURE: Successful recanalization after a single pass of a device. RESULTS: Forty-five percent of Solitaire thrombectomies resulted in first pass success, compared with 31% of Trevo and 39% of PA, not statistically significant (p = 0.26). Adjusted for age, gender, and National Institutes of Health Stroke Scale score, the odds of successful recanalization were 1.90 ± 0.72 (CI 0.90-3.99, p = 0.09) for Solitaire compared with Trevo, and 1.41 ± 0.50 (CI 0.70-2.84, p = 0.33) for aspiration compared with Trevo. CONCLUSION: In this multi-center cohort, there was no statistical difference in successful first pass recanalization between Solitaire, Trevo, and PA. However, there was a trend towards improved efficacy with the Solitaire device compared to Trevo (OR 1.90, p = 0.09). Additional data are needed to determine the conditions under which design differences may favor one technique over another.

Long-term retreatment rates of cerebral aneurysms in a population-level cohort.

BACKGROUND: The likelihood of retreatment in patients undergoing procedures for cerebral aneurysms (CAs) has an important role in deciding the optimal treatment type. Existing determinations of retreatment rates, particularly for unruptured CAs, may not represent current clinical practice. OBJECTIVE: To use population-level data to examine a large cohort of patients with treated CAs over a 10-year period to estimate retreatment rates for both ruptured and unruptured CAs and explore the effect of changing treatment practices. METHODS: We used administrative data from all non-federal hospitalizations in California (2005-2011) and Florida (2005-2014) and identified patients with treated CAs. Surgical clipping (SC) and endovascular treatments (ETs) were defined by corresponding procedure codes and an accompanying code for ruptured or unruptured CA. Retreatment was defined as subsequent SC or ET. RESULTS: Among 19 482 patients with treated CAs, ET was performed in 12 007 (62%) patients and SC in 7475 (38%). 9279 (48%) patients underwent treatment for unruptured CAs and 10203 (52%) for ruptured. Retreatment after 90 days occurred in 1624 (8.3%) patients (11.2% vs 3.7%, ET vs SC). Retreatment rates for SC were greater in unruptured than in ruptured aneurysms (4.6% vs 3.1%), but the opposite was true for ET (10.6% vs 11.8%). 85% of retreatments were within 2 years of the index treatment. Retreatment was associated with age (OR=0.99, 95% CI 0.98 to 0.99), female sex (OR=1.5, 95% CI 1.3 to 1.7), Hispanic versus white race (OR=0.86, 95% CI 0.75 to 0.98), and ET versus SC (OR=3.25, 95% CI 2.85 to 3.71). The adjusted 2-year retreatment rate decreased from 2005 to 2012 for patients with unruptured CAs treated with ET (11% to 8%). CONCLUSIONS: Retreatment rates for CAs treated with ET were greater than those for SC. However, for patients with unruptured CAs treated with ET, we identify a continuous decline in retreatment rate over the past decade.

Unique roles of SK and Kv4.2 potassium channels in dendritic integration.

Focal activation of glutamate receptors in distal dendrites of hippocampal pyramidal cells triggers voltage-dependent Ca(2+) channel-mediated plateau potentials that are confined to the stimulated dendrite. We examined the role of dendritic K(+) conductances in determining the amplitude, duration, and spatial compartmentalization of plateau potentials. Manipulations that blocked SK-type Ca(2+)-activated K(+) channels, including apamin and BAPTA dialysis, increased the duration of plateau potentials without affecting their amplitude or compartmentalization. Manipulations that blocked Kv4.2 A-type K(+) channels, including a dominant-negative Kv4.2 construct and 4-aminopyridine, increased the amplitude of plateau potentials by allowing them to recruit neighboring dendrites. Prolongation of plateau potentials or block of Kv4.2 channels at branch points facilitated the ability of dendritic excitation to trigger fast action potentials. SK channels thus underlie repolarization of dendritic plateau potentials, whereas Kv4.2 channels confine these potentials to single dendritic branches, and both act in concert to regulate synaptic integration.

Regional Contributions to Poststroke Disability in Endovascular Therapy.

BACKGROUND AND PURPOSE: The relative contribution of each Alberta Stroke Program Early CT Score (ASPECTS) region to poststroke disability likely varies across regions. Determining the relative weights of each ASPECTS region may improve patient selection for endovascular stroke therapy (EST). METHODS: In the combined Solitaire Flow Restoration with the Intention for Thrombectomy (SWIFT), Solitaire Flow Restoration Thrombectomy for Acute Revascularization (STAR), and Solitaire Flow Restoration with the Intention for Thrombectomy as Primary Endovascular Treatment (SWIFT PRIME) databases, we identified patients treated with the Solitaire stent retriever. Using 24-h CT scan, a multivariate ordinal regression was used to determine the relative contribution of each ASPECTS region to clinical outcome separately in each hemisphere. The coefficients from the regression were used to create a weighted ASPECTS (wASPECTS), which was compared with the original ASPECTS to predict 90-day modified Rankin Scale disability outcomes in an independent validation cohort. RESULTS: Among 342 patients treated with EST, the average age was 67 years, 57% were female, and the median National Institutes of Health Stroke Scale (NIHSS) score was 17 (IQR 13-20). The median ASPECTS at presentation was 8 (IQR 7-10). The most commonly involved ASPECTS regions on 24-h CT were the lentiform nuclei (70%), insula (55%), and caudate (52%). In multivariate analysis, preservation of M6 (ß = 9.7) and M4 (ß = 4.4) regions in the right hemisphere was most strongly predictive of good outcome. For the left hemisphere, M6 (ß = 5.5), M5 (ß = 4.1), and M3 (ß = 3.1) generated the greatest parameter estimates, though they did not reach statistical significance. A wASPECTS incorporating all 20 parameter estimates resulted in improved discrimination against the original ASPECTS in the independent cohort (C-statistic 0.78 vs. 0.67, right hemisphere). CONCLUSIONS: For both right and left hemisphere, preservation of the high cortical regions was more strongly associated with improved outcomes compared to the deep regions. Our findings support taking into consideration the location and relative weightings of the involved ASPECTS regions when evaluating a patient for EST.

Feasibility and utility of an integrated medical imaging and informatics smartphone system for management of acute stroke.

Background Rapid dissemination and coordination of clinical and imaging data among multidisciplinary team members are essential for optimal acute stroke care. Aim To characterize the feasibility and utility of the Synapse Emergency Room mobile (Synapse ERm) informatics system. Methods We implemented the Synapse ERm system for integration of clinical data, computerized tomography, magnetic resonance, and catheter angiographic imaging, and real-time stroke team communications, in consecutive acute neurovascular patients at a Comprehensive Stroke Center. Results From May 2014 to October 2014, the Synapse ERm application was used by 33 stroke team members in 84 Code Stroke alerts. Patient age was 69.6 (±17.1), with 41.5% female. Final diagnosis was: ischemic stroke 64.6%, transient ischemic attack 7.3%, intracerebral hemorrhage 6.1%, and cerebrovascular-mimic 22.0%. Each patient Synapse ERm record was viewed by a median of 10 (interquartile range 6-18) times by a median of 3 (interquartile range 2-4) team members. The most used feature was computerized tomography, magnetic resonance, and catheter angiography image display. In-app tweet team, communications were sent by median 1 (interquartile range 0-1, range 0-13) users per case and viewed by median 1 (interquartile range 0-3, range 0-44) team members. Use of the system was associated with rapid treatment times, faster than national guidelines, including median door-to-needle 51.0 min (interquartile range 40.5-69.5) and median door-to-groin 94.5 min (interquartile range 85.5-121.3). In user surveys, the mobile information platform was judged easy to employ in 91% (95% confidence interval 65%-99%) of uses and of added help in stroke management in 50% (95% confidence interval 22%-78%). Conclusion The Synapse ERm mobile platform for stroke team distribution and integration of clinical and imaging data was feasible to implement, showed high ease of use, and moderate perceived added utility in therapeutic management.

Sudden neurologic deficit.

Clinicians treating sudden neurologic deficit are being faced with an increasing number of available imaging modalities. In this chapter we discuss a general approach to acute neuroimaging and weigh the considerations that determine which modality or modalities should be utilized.

Timing of deep vein thrombosis formation after aneurysmal subarachnoid hemorrhage.

OBJECT: Deep vein thrombosis (DVT) is a common complication of aneurysmal subarachnoid hemorrhage (aSAH). The time period of greatest risk for developing DVT after aSAH is not currently known. aSAH induces a prothrombotic state, which may contribute to DVT formation. Using repeated ultrasound screening, the hypothesis that patients would be at greatest risk for developing DVT in the subacute post-rupture period was tested. METHODS: One hundred ninety-eight patients with aSAH admitted to the Oregon Health & Science University Neurosciences Intensive Care Unit between April 2008 and March 2012 were included in a retrospective analysis. Ultrasound screening was performed every 5.2 ± 3.3 days between admission and discharge. The chi-square test was used to compare DVT incidence during different time periods of interest. Patient baseline characteristics as well as stroke severity and hospital complications were evaluated in univariate and multivariate analyses. RESULTS: Forty-two (21%) of 198 patients were diagnosed with DVT, and 3 (2%) of 198 patients were symptomatic. Twenty-nine (69%) of the 42 cases of DVT were first detected between Days 3 and 14, compared with 3 cases (7%) detected between Days 0 and 3 and 10 cases (24%) detected after Day 14 (p < 0.05). The postrupture 5-day window of highest risk for DVT development was between Days 5 and 9 (40%, p < 0.05). In the multivariate analysis, length of hospital stay and use of mechanical prophylaxis alone were significantly associated with DVT formation. CONCLUSIONS: DVT formation most commonly occurs in the first 2 weeks following aSAH, with detection in this cohort peaking between Days 5 and 9. Chemoprophylaxis is associated with a significantly lower incidence of DVT.

To Tube or Not to Tube? The Role of Intubation during Stroke Thrombectomy.

In the 10 years since the FDA first cleared the use of endovascular devices for the treatment of acute stroke, definitive evidence that such therapy improves outcomes remains lacking. The decision to intubate patients undergoing stroke thrombectomy impacts multiple variables that may influence outcomes after stroke. Three main areas where intubation may deleteriously affect acute stroke management include the introduction of delays in revascularization, fluctuations in peri-procedural blood pressure, and hypocapnia, resulting in cerebral vasoconstriction. In this mini-review, we discuss the evidence supporting these limitations of intubation during stroke thrombectomy and encourage neurohospitalists, neurocritical care specialists, and neurointerventionalists to carefully consider the decision to intubate during thrombectomy and provide strategies to avoid potential complications associated with its use in acute stroke.

Dendritic hold and read: a gated mechanism for short term information storage and retrieval.

Two contrasting theories have been proposed to explain the mechanistic basis of short term memory. One theory posits that short term memory is represented by persistent neural activity supported by reverberating feedback networks. An alternate, more recent theory posits that short term memory can be supported by feedforward networks. While feedback driven memory can be implemented by well described mechanisms of synaptic plasticity, little is known of possible molecular and cellular mechanisms that can implement feedforward driven memory. Here we report such a mechanism in which the memory trace exists in the form of glutamate-bound but Mg(2+)-blocked NMDA receptors on the thin terminal dendrites of CA1 pyramidal neurons. Because glutamate dissociates from subsets of NMDA receptors very slowly, excitatory synaptic transmission can leave a silent residual trace that outlasts the electrical activity by hundreds of milliseconds. Read-out of the memory trace is possible if a critical level of these bound-but-blocked receptors accumulates on a dendritic branch that will allow these quasi-stable receptors to sustain a regenerative depolarization when triggered by an independent gating signal. This process is referred to here as dendritic hold and read (DHR). Because the read-out of the input is not dependent on repetition of the input and information flows in a single-pass manner, DHR can potentially support a feedforward memory architecture.

Lipid rescue of massive verapamil overdose: a case report.

INTRODUCTION: Massive intentional verapamil overdose is a toxic ingestion which can cause multiorgan system failure and has no currently known antidote. CASE PRESENTATION: The patient is a 41-year-old Caucasian woman who ingested 19.2 g of sustained release verapamil in a suicide attempt. Our patient became hypotensive requiring three high-dose vasopressors to maintain arterial pressure. She also developed acute respiratory failure, bradycardic ventricular rhythm necessitating continuous transvenous pacing, and anuric renal failure. Our patient was treated with intravenous calcium, bicarbonate, hyperinsulinemic euglycemic therapy and continuous venovenous hemodialysis without success. On the fourth day after hospital admission continuous intravenous lipid therapy was initiated. Within three hours of beginning lipid therapy, our patient's vasopressor requirement decreased by half. Within 24 hours, she was on minimal vasopressor support and regained an underlying junctional rhythm. After three days of lipid infusion, she no longer required inotropic agents to maintain blood pressure or pacing to maintain stable hemodynamics. CONCLUSIONS: Intravenous fat emulsion therapy may be an effective antidote for massive verapamil toxicity.

Patterned photostimulation with digital micromirror devices to investigate dendritic integration across branch points.

Light is a versatile and precise means to control neuronal excitability. The recent introduction of light sensitive effectors such as channel-rhodopsin and caged neurotransmitters have led to interests in developing better means to control patterns of light in space and time that are useful for experimental neuroscience. One conventional strategy, employed in confocal and 2-photon microscopy, is to focus light to a diffraction limited spot and then scan that single spot sequentially over the region of interest. This approach becomes problematic if large areas have to be stimulated within a brief time window, a problem more applicable to photostimulation than for imaging. An alternate strategy is to project the complete spatial pattern on the target with the aid of a digital micromirror device (DMD). The DMD approach is appealing because the hardware components are relatively inexpensive and is supported by commercial interests. Because such a system is not available for upright microscopes, we will discuss the critical issues in the construction and operations of such a DMD system. Even though we will be primarily describing the construction of the system for UV photolysis, the modifications for building the much simpler visible light system for optogenetic experiments will also be provided. The UV photolysis system was used to carryout experiments to study a fundamental question in neuroscience, how are spatially distributed inputs integrated across distal dendritic branch points. The results suggest that integration can be non-linear across branch points and the supralinearity is largely mediated by NMDA receptors.