External assessment of preoperative scores for predicting outcome after microvascular decompression for trigeminal neuralgia.

OBJECTIVE: Recently, two scoring systems have been developed for predicting pain-free outcomes after microvascular decompression (MVD). Evaluation of these scores on large external datasets has been limited. In this study, the authors aimed to evaluate the performance of published MVD scoring systems in predicting pain-free outcome. METHODS: A total of 458 patients who underwent MVD for trigeminal neuralgia (TN) between 2007 and 2020 and had at least 6 months of follow-up were included in this study. Hardaway and Panczykowski scores were retrospectively computed for each patient and compared with postoperative pain recurrence and pain-free duration. RESULTS: The mean ± SD area under the receiver operating characteristic curve for predicting any pain recurrence after MVD was 0.567 ± 0.081 using the Hardaway score and 0.546 ± 0.085 using the Panczykowski score. On log-rank tests and Kaplan-Meier analysis, the patients with Hardaway scores of 0-2 had significantly shorter pain-free survival times after MVD than did those with a score of 3. Patients with a Panczykowski score of 1 had a significantly shorter pain-free duration after surgery compared with both patients with scores of 2-3 and patients with scores of 4-5. Patients with Panczykowski scores of 2-3 also had significantly shorter pain-free duration compared with patients with scores of 4-5. CONCLUSIONS: Both the Hardaway and Panczykowski scores may be useful for predicting postoperative pain-free duration in TN patients, and their utility may be greatest when scores are clustered. Continued refinement of both scoring systems will help to improve our ability to predict patient outcomes after MVD.

Hemoglobin Drop is Associated with Early Post-operative Stroke Following Revascularization Surgery for Moyamoya Disease.

BACKGROUND: Postoperative stroke is a potentially devastating neurological complication following surgical revascularization for Moyamoya disease. We sought to evaluate whether peri-operative hemoglobin levels were associated with the risk of early post-operative stroke following revascularization surgery in adult Moyamoya patients. METHODS: Adult patients having revascularization surgeries for Moyamoya disease between 1999-2022 were identified through single institutional retrospective review. Logistic regression analysis was used to test for the association between hemoglobin drop and early postoperative stroke. RESULTS: In all, 106 revascularization surgeries were included in the study. A stroke occurred within 7 days after surgery in 9.4% of cases. There were no significant associations between the occurrence of an early postoperative stroke and patient age, gender, or race. Mean postoperative hemoglobin drop was greater in patients who suffered an early postoperative stroke compared with patients who did not (2.3±1.1 g/dL vs. 1.3±1.1 g/dL, respectively; P=0.034). Patients who experienced a hemoglobin drop post-operatively had 2.03 times greater odds (95% confidence interval, 1.06-4.23; P=0.040) of having a stroke than those whose hemoglobin levels were stable. Early postoperative stroke was also associated with an increase in length of hospital stay (P<0.001), discharge to a rehabilitation facility (P=0.014), and worse modified Rankin scale at 1 month (P=0.001). CONCLUSION: This study found a significant association between hemoglobin drop and early postoperative stroke following revascularization surgery in adult patients with Moyamoya disease. Based on our findings, it may be prudent to avoid hemoglobin drops in Moyamoya patients undergoing surgical revascularization.

Preoperative Opioid Use and Postoperative Outcomes in Patients Undergoing Microvascular Decompression for Trigeminal Neuralgia.

BACKGROUND AND OBJECTIVES: The prescription of opioid analgesics for trigeminal neuralgia (TN) is controversial, and their effect on postoperative outcomes for patients with TN undergoing microvascular decompression (MVD) has not been reported. We aimed to describe the relationship between preoperative opioid use and postoperative outcomes in patients with TN undergoing MVD. METHODS: We reviewed the records of 920 patients with TN at our institution who underwent an MVD between 2007 and 2020. Patients were sorted into 2 groups based on preoperative opioid usage. Demographic information, comorbidities, characteristics of TN, preoperative medications, pain and numbness outcomes, and recurrence data were recorded and compared between groups. Multivariate ordinal regression, Kaplan-Meier survival analysis, and Cox proportional hazards were used to assess differences in pain outcomes between groups. RESULTS: One hundred and forty-five (15.8%) patients in this study used opioids preoperatively. Patients who used opioids preoperatively were younger (P = .04), were more likely to have a smoking history (P < .001), experienced greater pain in modified Barrow Neurological Institute pain score at final follow-up (P = .001), and were more likely to experience pain recurrence (P = .01). In addition, patients who used opioids preoperatively were more likely to also have been prescribed TN medications including muscle relaxants and antidepressants preoperatively (P < .001 and P < .001, respectively). On multivariate regression, opioid use was an independent risk factor for greater postoperative pain at final follow-up (P = .006) after controlling for variables including female sex and age. Opioid use was associated with shorter time to pain recurrence on Kaplan-Meier analysis (P = .005) and was associated with increased risk for recurrence on Cox proportional hazards regression (P = .008). CONCLUSION: Preoperative opioid use in the setting of TN is associated with worse pain outcomes and increased risk for pain recurrence after MVD. These results indicate that opioids should be prescribed cautiously for TN and that worse post-MVD outcomes may occur in patients using opioids preoperatively.

Hypothermia is Associated with Improved Neurological Outcomes After Mechanical Thrombectomy.

BACKGROUND: Acute ischemic stroke (AIS) is the second leading cause of death globally. Mechanical thrombectomy (MT) has improved patient prognosis but expedient treatment is still necessary to minimize anoxic injury. Lower intraoperative body temperature decreases cerebral oxygen demand, but the role of hypothermia in treatment of AIS with MT is unclear. METHODS: We retrospectively reviewed patients undergoing MT for AIS from 2014 to 2020 at our institution. Patient demographics, comorbidities, intraoperative parameters, and outcomes were collected. Maximum body temperature was extracted from minute-by-minute anesthesia readings, and patients with maximal temperature below 36°C were considered hypothermic. Risk factors were assessed by χ2 and multivariate ordinal regression. RESULTS: Of 68 patients, 27 (40%) were hypothermic. There was no significant association of hypothermia with patient age, comorbidities, time since last known well, number of passes intraoperatively, favorable revascularization, tissue plasminogen activator use, and immediate postoperative complications. Hypothermic patients exhibited better neurologic outcome at 3-month follow-up (P = 0.02). On multivariate ordinal regression, lower maximum intraoperative body temperature was associated with improved 3-month outcomes (P < 0.001), when adjusting for other factors influencing neurological outcomes. Other significant protective factors included younger age (P = 0.03), better revascularization (P = 0.03), and conscious sedation (P = 0.02). CONCLUSIONS: Lower intraoperative body temperature during MT was independently associated with improved neurological outcome in this single center retrospective series. These results may help guide clinicians in employing therapeutic hypothermia during MT to improve long-term neurologic outcomes from AIS, although larger studies are needed.

Application of Sequential Thresholding-Based Automated Reconstruction of the Trigeminal Nerve in Trigeminal Neuralgia.

OBJECTIVE: High-resolution magnetic resonance imaging (MRI) of the trigeminal nerve is indispensable for workup of trigeminal neuralgia (TN) before microvascular decompression; however, the evaluation is often subjective and prone to variability. We aim to develop and assess sequential thresholding-based automated reconstruction of the trigeminal nerve (STAR-TN) as an algorithm for segmenting the trigeminal nerve and contacting structures that will allow for a structured method for assessing neurovascular conflict. METHODS: A total of 42 patients with TN who underwent high-resolution MRI before microvascular decompression in 2022 were included in our study. Segmentation of the trigeminal nerve and contacting structures was performed on preoperative MRI scans using STAR-TN. The segmentations were then evaluated for neurovascular conflict and compared to the preoperative radiology and operative notes. Geometric features, including the area of contact and distance to conflict, were extracted. RESULTS: Of the 42 patients, 32 (76.2%) were found to show neurovascular conflict based solely on their STAR-TN segmentations and 10 (23.8%) were found to not show neurovascular conflict. Compared with the intraoperative findings, this resulted in a sensitivity of 78.0% and specificity of 100%. In contrast, assessments of neurovascular conflict by radiologists using only 2-dimensional MRI views had a sensitivity of 68.3% and specificity of 100%. Of the 32 patients with neurovascular conflict, 29 (90.9%) had conflict within the root entry zone. Overall, the patients had a median area of contact of 10.66 mm2. CONCLUSIONS: STAR-TN allows for 3-dimensional visualization and identification of neurovascular conflict with improved sensitivity compared with neuroradiologist assessments from MRI slices.

The influence of prior percutaneous rhizotomy on outcomes following microvascular decompression for trigeminal neuralgia.

OBJECTIVE: Microvascular decompression (MVD) is an effective intervention in patients with trigeminal neuralgia (TN). How prior rhizotomy can impact long-term pain outcomes following MVD is not well understood. In this study, the authors sought to compare pain outcomes in patients who had undergone primary MVD versus those who had undergone secondary MVD after a single or multiple rhizotomies. METHODS: The authors retrospectively reviewed the data on all patients who had undergone MVD at their institution from 2007 to 2020. Patients were included in the study if they had undergone primary MVD or if their surgical history was notable for past rhizotomy. Barrow Neurological Institute (BNI) pain scores were assigned at preoperative and final follow-up appointments. Perioperative complications were noted for each patient, and evidence of pain recurrence was recorded as well. A history of rhizotomy as well as other variables that might influence TN pain recurrence were evaluated using a Cox proportional hazards model. The impact of prior rhizotomy on TN pain recurrence following MVD was further assessed using Kaplan-Meier survival analysis. RESULTS: Of 1044 patients reviewed, 947 met the study inclusion criteria. Of these, 796 patients had undergone primary MVD, 84 had a history of a single rhizotomy before MVD, and 67 had a history of ≥ 2 rhizotomies prior to MVD. Patients in the single rhizotomy and multiple rhizotomies cohorts exhibited a greater frequency of preoperative numbness (p < 0.001), higher preoperative BNI pain scores (p < 0.005), and higher rates of postoperative numbness (p = 0.04). However, final follow-up BNI pain scores were not significantly different between the primary MVD and prior rhizotomy groups (p = 0.34). Cox proportional hazards analysis revealed that younger age, multiple sclerosis, and female sex independently predicted an increased risk of pain recurrence following MVD. Neither a history of a single prior rhizotomy nor a history of multiple prior rhizotomies independently increased the risk of pain recurrence. Furthermore, Kaplan-Meier analysis of pain-free survival among the 3 groups revealed no relationship between a history of prior rhizotomy and pain recurrence following MVD (p = 0.57). CONCLUSIONS: Percutaneous rhizotomy does not complicate outcomes following subsequent MVD for TN pain. However, patients undergoing rhizotomy before MVD may have an increased risk of postoperative facial numbness compared to that in patients undergoing primary MVD.

A Case Series of Stereotactic Radiosurgery First for Trigeminal Neuralgia: A History of Stereotactic Radiosurgery Does Not Complicate Microvascular Decompression.

BACKGROUND AND OBJECTIVES: The influence of prior stereotactic radiosurgery (SRS) on outcomes of subsequent microvascular decompression (MVD) for patients with trigeminal neuralgia (TN) is not well understood. To directly compare pain outcomes in patients undergoing primary MVD vs those undergoing MVD with a history of 1 prior SRS procedure. METHODS: We retrospectively reviewed all patients undergoing MVD at our institution from 2007 to 2020. Patients were included if they underwent primary MVD or had a history of SRS alone before MVD. Barrow Neurological Institute (BNI) pain scores were assigned at preoperative and immediate postoperative time points and at every follow-up appointment. Evidence of pain recurrence was recorded and compared via Kaplan-Meier analysis. Multivariate Cox proportional hazards regression was used to identify factors associated with worse pain outcomes. RESULTS: Of patients reviewed, 833 met our inclusion criteria. Thirty-seven patients were in the SRS alone before MVD group, and 796 patients were in the primary MVD group. Both groups demonstrated similar preoperative and immediate postoperative BNI pain scores. There were no significant differences between average BNI at final follow-up between the groups. Multiple sclerosis (hazard ratio (HR) = 1.95), age (HR = 0.99), and female sex (HR = 1.43) independently predicted increased likelihood of pain recurrence on Cox proportional hazards analysis. SRS alone before MVD did not predict increased likelihood of pain recurrence. Furthermore, Kaplan-Meier survival analysis demonstrated no relationship between a history of SRS alone and pain recurrence after MVD ( P = .58). CONCLUSION: SRS is an effective intervention for TN that may not worsen outcomes for subsequent MVD in patients with TN.

Preoperative Characteristics and Postoperative Pain Outcomes in Trigeminal Neuralgia With Concomitant Autoimmune Disease.

BACKGROUND AND OBJECTIVES: Although the association between multiple sclerosis and trigeminal neuralgia (TN) is well established, little is known about TN pain characteristics and postoperative pain outcomes after microvascular decompression (MVD) in patients with TN and other autoimmune diseases. In this study, we aim to describe presenting characteristics and postoperative outcomes in patients with concomitant TN and autoimmune disease who underwent an MVD. METHODS: A retrospective review of all patients who underwent an MVD at our institution between 2007 and 2020 was conducted. The presence and type of autoimmune disease were recorded for each patient. Patient demographics, comorbidities, clinical characteristics, postoperative Barrow Neurological Institute (BNI) pain and numbness scores, and recurrence data were compared between groups. RESULTS: Of the 885 patients with TN identified, 32 (3.6%) were found to have concomitant autoimmune disease. Type 2 TN was more common in the autoimmune cohort ( P = .01). On multivariate analysis, concomitant autoimmune disease, younger age, and female sex were found to be significantly associated with higher postoperative BNI score ( P = .04, <0.001, and <0.001, respectively). In addition, patients with autoimmune disease were more likely to experience significant pain recurrence ( P = .009) and had shorter time to recurrence on Kaplan-Meier analysis ( P = .047), although this relationship was attenuated on multivariate Cox proportional hazards regression. CONCLUSION: Patients with concomitant TN and autoimmune disease were more likely to have Type 2 TN, had worse postoperative BNI pain scores at the final follow-up after MVD, and were more likely to experience recurrent pain than patients with TN alone. These findings may influence postoperative pain management decisions for these patients and support a possible role for neuroinflammation in TN pain.

Outcomes After Microvascular Decompression for Sole Arterial Versus Venous Compression in Trigeminal Neuralgia.

OBJECTIVE: In most cases of trigeminal neuralgia (TN), the trigeminal nerve is compressed by the arterial vasculature. We sought to address the gap in understanding of pain outcomes in patients with sole arterial versus sole venous compression. METHODS: We retrospectively reviewed all patients undergoing microvascular decompression at our institution, identifying patients with either sole arterial or venous compression. We dichotomized patients into arterial or venous groups and obtained demographics and postoperative complications for each case. Barrow Neurological Index (BNI) pain scores were collected preoperatively, postoperatively, and at final follow-up, as well as recurrence of pain. Differences were calculated via χ2 tests t tests, and Mann-Whitney U Tests. Ordinal regression was used to account for variables known to influence TN pain. Kaplan-Meier analysis was used to determine recurrence-free survival. RESULTS: Of 1044 patients, 642 (61.5%) had either sole arterial or venous compression. Of these cases, 472 showed arterial compression and 170 showed sole venous compression. Patients in the venous compression group were significantly younger (P < 0.001). Patients with sole venous compression showed worse preoperative (P = 0.04) and final follow-up (P < 0.001) pain scores. Patients with sole venous compression had significantly higher rate of pain recurrence (P = 0.02) and BNI score at pain recurrence (P = 0.04). On ordinal regression, venous compression was found to independently predict worse BNI pain scores (odds ratio, 1.66; P = 0.003). Kaplan-Meier analysis showed a significant relationship between sole venous compression and increased risk of pain recurrence (P = 0.03). CONCLUSIONS: Patients with TN with sole venous compression show worse pain outcomes after microvascular decompression compared with those with only arterial compression.

Same-day versus staged revascularization of bilateral moyamoya arteriopathy in pediatric patients.

PURPOSE: To compare the outcomes of conducting left and right hemisphere surgical revascularization on the same day versus different days for bilateral pediatric moyamoya arteriopathy patients. METHODS: We retrospectively analyzed mortality, stroke, and transient neurologic event (TNE) rates in North American bilateral pediatric moyamoya arteriopathy patients who underwent bilateral cerebral revascularization. RESULTS: A total of 38 pediatric (≤ 18 years old) patients at our institution underwent bilateral cerebral revascularization for moyamoya arteriopathy. Of these patients, 24 (63.2%) had both operations on the same day and 14 (36.8%) had the two operations on different days. The average length of stay for patients who underwent same-day bilateral revascularization was 6.9 ± 2.0 days and the average length of stay for each operation for patients who underwent staged bilateral revascularization was 4.5 ± 1.4 days, p = 0.001. While there were 7 (14.6%) postoperative strokes in patients who had both hemispheres revascularized on the same day, 0 (0%) strokes occurred in hemispheres after they had been operated on in the staged cohort, p = 0.042. Additionally, the postoperative stroke-free survival time in the ipsilateral hemisphere and TNE-free survival time were significantly longer in patients in the staged revascularization cohort. CONCLUSION: Same-day bilateral revascularization was associated with longer length of stay per operation, higher rate of ipsilateral stroke, and shorter postoperative TNE-free and stroke-free survival time in the revascularized hemisphere.

Timing of Revascularization in Ischemic Moyamoya Disease: Association of Early Versus Delayed Surgery with Perioperative and Long-Term Outcomes.

OBJECTIVE: Patients with nmoyamoya disease (MMD) who present primarily with ischemic stroke are known to have greater rates of perioperative strokes as compared with those who present with nonstroke symptoms. The optimal timing for revascularization for these patients remains unclear. METHODS: From 1994 to 2015, 91 patients with MMD presented with signs and symptoms of an acute ischemic stroke with diffusion restriction correlate on magnetic resonance imaging, and these patients were subdivided into those who underwent early revascularization (<90 days from last stroke), versus those who underwent delayed revascularization (≥90 days after last stroke), based on evidence that most neurological recovery after stroke occurs during the first three months. Perioperative and long-term outcomes were compared between the 2 surgical cohorts. RESULTS: In total, 27 patients underwent early revascularization, and 64 patients underwent delayed revascularization. Patients who underwent early revascularization had a statistically greater rate of perioperative stroke (P = 0.04) and perioperative mortality (P = 0.03), and overall complication rate (P = 0.049). At last follow-up of 5.2 ± 4.3 years, patients who underwent delayed revascularization had a lower mortality rate (P = 0.01) and a lower overall postoperative stroke incidence (P = 0.002). As a function of time, patients with MMD undergoing delayed revascularization had a statistically higher length of stroke-free survival (P = 0.005). CONCLUSIONS: Patients with MMD who present with ischemic stroke are more likely to have perioperative strokes, overall perioperative complications, worse long-term mortality rates, and lower rates of stroke-free survival if revascularization surgery occurred within 90 days of last stroke.

Revascularization of Hemorrhagic Moyamoya Disease in a North American Cohort: The Role of Timing in Perioperative and Long-Term Outcomes.

BACKGROUND: Several East Asian studies have examined the role of revascularization in the context of hemorrhagic moyamoya disease (MMD) and found a decrease in postoperative rehemorrhage rates. To date, no data exist comparing revascularization with conservative management in North American patients with hemorrhagic MMD. OBJECTIVE: To compare the clinical outcomes of conservative management vs surgical revascularization for North American patients with hemorrhagic MMD and investigate the effect of revascularization timing. METHODS: We retrospectively studied the mortality and stroke-free survival of patients with MMD presenting with hemorrhagic stroke between 1994 and 2015. RESULTS: The diagnosis of hemorrhagic MMD was established in 38 patients. Seventeen patients were managed conservatively, and 21 were surgically revascularized. Twelve patients underwent revascularization within 6 months of hemorrhage, and 9 underwent surgery in a delayed fashion. Six conservatively managed patients (35.3%) died within the follow-up period compared with 0 (0%) surgically revascularized patients, P = .004. Conservatively managed patients also experienced an increased number of postoperative strokes, P = .037, and shorter stroke-free survival compared with patients undergoing revascularization, P = .047. On multivariate analysis, increased age, worse baseline modified Rankin score, and conservative management were independently associated with worse neurological outcomes, P < .05. Early revascularization was associated with higher rates of postoperative seizures, P = .033, and wound complications, P = .031, compared with those who underwent delayed surgery. CONCLUSION: Conservative management in a North American patient cohort was associated with greater mortality and worsened neurological outcomes compared with those undergoing revascularization. Early revascularization was associated with higher rates of postoperative seizures and wound complications, although these risks must be balanced against the risk of rehemorrhage.

Trigeminal Neuralgia: Current Approaches and Emerging Interventions.

Trigeminal neuralgia (TN) has been described in the literature as one of the most debilitating presentations of orofacial pain. This review summarizes over 150 years of collective clinical experience in the medical and surgical treatment of TN. Fundamentally, TN remains a clinical diagnosis that must be distinguished from other types of trigeminal neuropathic pain and/or facial pain associated with other neuralgias or headache syndromes. What is increasingly clear is that there is no catch-all medical or surgical intervention that is effective for all patients with trigeminal neuralgia, likely reflective of the fact that TN is likely a heterogenous group of disorders that jointly manifests in facial pain. The first-line treatment for TN remains anticonvulsant medical therapy. Patients who fail this have a range of surgical options available to them. In general, microvascular decompression is a safe and effective procedure with immediate and durable outcomes. Patients who are unable to tolerate general anesthesia or whose medical comorbidities preclude a suboccipital craniectomy may benefit from percutaneous methodologies including glycerol or radiofrequency ablation, or both. For patients with bleeding diathesis due to blood thinning medications who are ineligible for invasive procedures, or for those who are unwilling to undergo open surgical procedures, radiosurgery may be an excellent option-provided the patient understands that maximum pain relief will take on the order of months to achieve. Finally, peripheral neurectomies continue to provide an inexpensive and resource-sparing alternative to pain relief for patients in locations with limited economic and medical resources. Ultimately, elucidation of the molecular mechanisms underlying trigeminal neuralgia will pave the way for novel, more effective and less invasive therapies.

Epidemiology and outcomes of pediatric intracranial aneurysms: comparison with an adult population in a 30-year, prospective database.

OBJECTIVE: Pediatric intracranial aneurysms are rare. Most large series in the last 15 years reported on an average of only 39 patients. The authors sought to report their institutional experience with pediatric intracranial aneurysms from 1991 to 2021 and to compare pediatric patient and aneurysm characteristics with those of a contemporaneous adult cohort. METHODS: Pediatric (≤ 18 years of age) and adult patients with one or more intracranial aneurysms were identified in a prospective database. Standard epidemiological features and outcomes of each pediatric patient were retrospectively recorded. These results were compared with those of adult aneurysm patients managed at a single institution over the same time period. RESULTS: From a total of 4500 patients with 5150 intracranial aneurysms admitted over 30 years, there were 47 children with 53 aneurysms and 4453 adults with 5097 aneurysms; 53.2% of children and 36.4% of adults presented with a subarachnoid hemorrhage (SAH). Pediatric aneurysms were significantly more common in males, more likely giant (≥ 25 mm), and most frequently located in the middle cerebral artery. Overall, 85.1% of the pediatric patients had a modified Rankin Scale score ≤ 2 at the last follow-up (with a mean follow-up of 65.9 months), and the pediatric mortality rate was 10.6%; all 5 patients who died had an SAH. The recurrence rate of treated aneurysms was 6.7% (1/15) in the endovascular group but 0% (0/31) in the microsurgical group. No de novo aneurysms occurred in children (mean follow-up 5.5 years). CONCLUSIONS: Pediatric intracranial aneurysms are significantly different from adult aneurysms in terms of sex, presentation, location, size, and outcomes. Future prospective studies will better characterize long-term aneurysm recurrence, rebleeds, and de novo aneurysm occurrences. The authors currently favor microsurgical over endovascular treatment for pediatric aneurysms.

High-fidelity estimates of spikes and subthreshold waveforms from 1-photon voltage imaging in vivo.

The ability to probe the membrane potential of multiple genetically defined neurons simultaneously would have a profound impact on neuroscience research. Genetically encoded voltage indicators are a promising tool for this purpose, and recent developments have achieved a high signal-to-noise ratio in vivo with 1-photon fluorescence imaging. However, these recordings exhibit several sources of noise and signal extraction remains a challenge. We present an improved signal extraction pipeline, spike-guided penalized matrix decomposition-nonnegative matrix factorization (SGPMD-NMF), which resolves supra- and subthreshold voltages in vivo. The method incorporates biophysical and optical constraints. We validate the pipeline with simultaneous patch-clamp and optical recordings from mouse layer 1 in vivo and with simulated and composite datasets with realistic noise. We demonstrate applications to mouse hippocampus expressing paQuasAr3-s or SomArchon1, mouse cortex expressing SomArchon1 or Voltron, and zebrafish spines expressing zArchon1.

All-Optical Electrophysiology Reveals the Role of Lateral Inhibition in Sensory Processing in Cortical Layer 1.

Cortical layer 1 (L1) interneurons have been proposed as a hub for attentional modulation of underlying cortex, but the transformations that this circuit implements are not known. We combined genetically targeted voltage imaging with optogenetic activation and silencing to study the mechanisms underlying sensory processing in mouse barrel cortex L1. Whisker stimuli evoked precisely timed single spikes in L1 interneurons, followed by strong lateral inhibition. A mild aversive stimulus activated cholinergic inputs and evoked a bimodal distribution of spiking responses in L1. A simple conductance-based model that only contained lateral inhibition within L1 recapitulated the sensory responses and the winner-takes-all cholinergic responses, and the model correctly predicted that the network would function as a spatial and temporal high-pass filter for excitatory inputs. Our results demonstrate that all-optical electrophysiology can reveal basic principles of neural circuit function in vivo and suggest an intuitive picture for how L1 transforms sensory and modulatory inputs. VIDEO ABSTRACT.

Voltage imaging and optogenetics reveal behaviour-dependent changes in hippocampal dynamics.

A technology that simultaneously records membrane potential from multiple neurons in behaving animals will have a transformative effect on neuroscience research1,2. Genetically encoded voltage indicators are a promising tool for these purposes; however, these have so far been limited to single-cell recordings with a marginal signal-to-noise ratio in vivo3-5. Here we developed improved near-infrared voltage indicators, high-speed microscopes and targeted gene expression schemes that enabled simultaneous in vivo recordings of supra- and subthreshold voltage dynamics in multiple neurons in the hippocampus of behaving mice. The reporters revealed subcellular details of back-propagating action potentials and correlations in subthreshold voltage between multiple cells. In combination with stimulation using optogenetics, the reporters revealed changes in neuronal excitability that were dependent on the behavioural state, reflecting the interplay of excitatory and inhibitory synaptic inputs. These tools open the possibility for detailed explorations of network dynamics in the context of behaviour. Fig. 1 PHOTOACTIVATED QUASAR3 (PAQUASAR3) REPORTS NEURONAL ACTIVITY IN VIVO.: a, Schematic of the paQuasAr3 construct. b, Photoactivation by blue light enhanced voltage signals excited by red light in cultured neurons that expressed paQuasAr3 (representative example of n = 4 cells). c, Model of the photocycle of paQuasAr3. d, Confocal images of sparsely expressed paQuasAr3 in brain slices. Scale bars, 50 µm. Representative images, experiments were repeated in n = 3 mice. e, Simultaneous fluorescence and patch-clamp recordings from a neuron expressing paQuasAr3 in acute brain slice. Top, magnification of boxed regions. Schematic shows brain slice, patch pipette and microscope objective. f, Simultaneous fluorescence and patch-clamp recordings of inhibitory post synaptic potentials in an L2-3 neuron induced by electrical stimulation of L5-6 in acute slice. g, Normalized change in fluorescence (ΔF/F) and SNR of optically recorded post-synaptic potentials (PSPs) as a function of the amplitude of the post-synaptic potentials. The voltage sensitivity was ΔF/F = 40 ± 1.7% per 100 mV. The SNR was 0.93 ± 0.07 per 1 mV in a 1-kHz bandwidth (n = 42 post-synaptic potentials from 5 cells, data are mean ± s.d.). Schematic shows brain slice, patch pipette, field stimulation electrodes and microscope objective. h, Optical measurements of paQuasAr3 fluorescence in the CA1 region of the hippocampus (top) and glomerular layer of the olfactory bulb (bottom) of anaesthetized mice (representative traces from n = 7 CA1 cells and n = 13 olfactory bulb cells, n = 3 mice). Schematics show microscope objective and the imaged brain region. i, STA fluorescence from 88 spikes in a CA1 oriens neuron. j, Frames from the STA video showing the delay in the back-propagating action potential in the dendrites relative to the soma. k, Sub-Nyquist fitting of the action potential delay and width shows electrical compartmentalization in the dendrites. Experiments in k-m were repeated in n = 2 cells from n = 2 mice.