Publications

@article{ong_association_2025,

title = {Association of Dynamic Trajectories of Time-Series Data and Life-Threatening Mass Effect in Large Middle Cerebral Artery Stroke},

author = {Charlene J. Ong and Qiuxi Huang and Ivy So Yeon Kim and Jack E. Pohlmann and Stefanos Chatzidakis and Benjamin Brush and Yihan Zhang and Yili Du and Leigh Ann Malinger and Emelia J. Benjamin and Josée Dupuis and David M. Greer and Stelios M. Smirnakis and Ludovic Trinquart},

doi = {10.1007/s12028-024-02036-9},

issn = {1556-0961},

year  = {2025},

date = {2025-02-01},

journal = {Neurocritical Care},

volume = {42},

number = {1},

pages = {77–89},

abstract = {BACKGROUND: Life-threatening, space-occupying mass effect due to cerebral edema and/or hemorrhagic transformation is an early complication of patients with middle cerebral artery stroke. Little is known about longitudinal trajectories of laboratory and vital signs leading up to radiographic and clinical deterioration related to this mass effect. 

METHODS: We curated a retrospective data set of 635 patients with large middle cerebral artery stroke totaling 95,463 data points for 10 longitudinal covariates and 40 time-independent covariates. We assessed trajectories of the 10 longitudinal variables during the 72 h preceding three outcomes representative of life-threatening mass effect: midline shift ≥ 5 mm, pineal gland shift (PGS) > 4 mm, and decompressive hemicraniectomy (DHC). We used a "backward-looking" trajectory approach. Patients were aligned based on outcome occurrence time and the trajectory of each variable was assessed before that outcome by accounting for cases and noncases, adjusting for confounders. We evaluated longitudinal trajectories with Cox proportional time-dependent regression. 

RESULTS: Of 635 patients, 49.0% were female, and the mean age was 69 years. Thirty five percent of patients had midline shift ≥ 5 mm, 24.3% of patients had PGS > 4 mm, and 10.7% of patients underwent DHC. Backward-looking trajectories showed mild increases in white blood cell count (10-11 K/UL within 72 h), temperature (up to half a degree within 24 h), and sodium levels (1-3 mEq/L within 24 h) before the three outcomes of interest. We also observed a decrease in heart rate (75-65 beats per minute) 24 h before DHC. We found a significant association between increased white blood cell count with PGS > 4 mm (hazard ratio 1.05, p value 0.007). 

CONCLUSIONS: Longitudinal profiling adjusted for confounders demonstrated that white blood cell count, temperature, and sodium levels appear to increase before radiographic and clinical indicators of space-occupying mass effect. These findings will inform the development of multivariable dynamic risk models to aid prediction of life-threatening, space-occupying mass effect.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{du_quantitative_2025,

title = {Quantitative Pupillometry Predicts Neurologic Deterioration in Patients with Large Middle Cerebral Artery Stroke},

author = {Yili Du and Jack E. Pohlmann and Stefanos Chatzidakis and Benjamin Brush and Leigh Ann Malinger and Rebecca A. Stafford and Anna M. Cervantes-Arslanian and Emelia J. Benjamin and Emily J. Gilmore and Josée Dupuis and David M. Greer and Stelios M. Smirnakis and Shariq Mohammed and Charlene J. Ong},

doi = {10.1002/ana.27178},

issn = {1531-8249},

year  = {2025},

date = {2025-01-01},

journal = {Annals of Neurology},

abstract = {OBJECTIVE: This study assesses whether longitudinal quantitative pupillometry predicts neurological deterioration after large middle cerebral artery (MCA) stroke and determines how early changes are detectable. 

METHODS: This prospective, single-center observational cohort study included patients with large MCA stroke admitted to Boston Medical Center's intensive care unit (2019-2024). Associations between time-to-neurologic deterioration and quantitative pupillometry, including Neurological Pupil Index (NPi), were assessed using Cox proportional hazards models with time-dependent covariates adjusted for age, sex, and Alberta Stroke Program Early CT Score. Models using dilation velocity were compared with partial likelihood ratio tests. Pupillometric changes over 2-h intervals in the 12 h preceding deterioration were analyzed with linear mixed-effects modeling and Tukey's test. Matched referents (age, sex, stroke side, follow-up duration) were used for comparison. Optimal thresholds were identified using the Youden Index. RESULTS: Among 71 patients (mean age 66.5 years; 59.2% women), 32 (45.1%) experienced deterioration. A 1-unit decrease in NPi was associated with a higher hazard of deterioration (hazard ratio 2.46; 95% confidence interval 1.68-3.61). Dilation velocity improved model performance compared to NPi alone. NPi was significantly lower at 0-2 h (3.81 vs. 4.38},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{stafford_follow-up_2024,

title = {Follow-up ASPECTS improves prediction of potentially lethal malignant edema in patients with large middle cerebral artery stroke},

author = {Rebecca A. Stafford and Stefanos Chatzidakis and Ivy So Yeon Kim and Yihan Zhang and Andriani Rina and Benjamin Brush and Asim Mian and Mohamad Abdalkader and David M. Greer and Stelios M. Smirnakis and Steven K. Feske and Josée Dupuis and Charlene J. Ong},

doi = {10.1136/jnis-2023-021145},

issn = {1759-8486},

year  = {2024},

date = {2024-12-01},

journal = {Journal of Neurointerventional Surgery},

volume = {17},

number = {e1},

pages = {e83–e86},

abstract = {BACKGROUND: Recent studies have shown that follow-up head CT is a strong predictor of functional outcomes in patients with middle cerebral artery stroke and mechanical thrombectomy. We sought to determine whether total and/or regional follow-up Alberta Stroke Program Early CT Score (ASPECTSfu) are associated with important clinical outcomes during hospitalization and improve the performance of clinical prediction models of potentially lethal malignant edema (PLME). 

METHODS: We conducted a retrospective study of patients at three medical centers in a major North American metropolitan area with baseline and follow-up head CTs after large middle cerebral artery stroke between 2006 and 2022. We used multivariable logistic regression to test the association of total and regional ASPECTSfu with PLME (cerebral edema related death or surgery), adjusting for total baseline ASPECTS, age, sex, admission glucose, tissue plasminogen activator, and mechanical thrombectomy. We compared existing clinical risk models with and without total or regional ASPECTSfu using area under the curve. 

RESULTS: In our 560 patient cohort, lower total ASPECTSfu was significantly associated with higher odds of PLME when adjusting for confounders (OR 1.69, 95% CI 1.49 to 2.0), and improved model discrimination compared with existing models and models using baseline ASPECTS. Deep territory involvement (OR 2.46, 95% CI 1.53 to 4.01) and anterior territory involvement (OR 3.23, 95% CI 1.88 to 5.71) were significantly associated with PLME. 

CONCLUSIONS: Lower ASPECTSfu and certain locations on regional ASPECTSfu, including deep and anterior areas, were significantly associated with PLME. Including ASPECTSfu information improved discrimination of established edema prediction models and could be used immediately to help facilitate clinical management decisions and prognostication.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{phillips_helmet_2024,

title = {HELMET: A Hybrid Machine Learning Framework for Real-Time Prediction of Edema Trajectory in Large Middle Cerebral Artery Stroke},

author = {Ethan Phillips and Odhran O'Donoghue and Yumeng Zhang and Panos Tsimpos and Leigh Ann Mallinger and Stefanos Chatzidakis and Jack E. Pohlmann and Yili Du and Ivy So Yeon Kim and Jonathan J. Song and Benjamin Brush and Stelios M. Smirnakis and Charlene J. Ong and Agni Orfanoudaki},

doi = {10.1101/2024.11.13.24317229},

year  = {2024},

date = {2024-11-01},

journal = {medRxiv: The Preprint Server for Health Sciences},

pages = {2024.11.13.24317229},

abstract = {Malignant cerebral edema occurs when brain swelling displaces and compresses vital midline structures within the first week of a large middle cerebral artery stroke. Early interventions such as hyperosmolar therapy or surgical decompression may reverse secondary injury but must be administered judiciously. To optimize treatment and reduce secondary damage, clinicians need strategies to frequently and quantitatively assess the trajectory of edema using updated, relevant information. However, existing risk assessment tools are limited by the absence of structured records capturing the evolution of edema and typically estimate risk at a single time point early in the admission, therefore failing to account for changes in variables over the following hours or days. To address this, we developed and validated dynamic machine learning models capable of accurately predicting the severity of midline structure displacement, an established indicator of malignant edema, in real-time. Our models can provide updated estimations as frequently as every hour, using data from structured time-varying patient records, radiographic text, and human-curated neurological characteristics. Our work resulted in two novel multi-class classification models, collectively named Hybrid Ensemble Learning Models for Edema Trajectory (HELMET), predicting the progression of midline shift over 8-hour (HELMET-8) and 24-hour windows (HELMET-24), respectively. HELMET combines transformer-based large language models with supervised ensemble learning, demonstrating the value of merging human expertise and multimodal health records in developing clinical risk scores. Both models were trained on a retrospective cohort of 15,696 observations from 623 patients hospitalized with large middle cerebral artery ischemic stroke and were externally validated using 3,713 observations from 60 patients at a separate hospital system. Our HELMET models are accurate and generalize effectively to diverse populations, achieving a cross-validated mean area under the receiver operating characteristic score of 96.6% in the derivation cohort and 92.5% in the external validation cohort. Moreover, our approach provides a framework for developing hybrid risk prediction models that integrate both human-extracted and algorithm-derived multi-modal inputs. Our work enables accurate estimation of complex, dynamic, and highly specific clinical targets, such as midline shift, in real-time, even when relevant structured information is limited in electronic health record databases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pohlmann_association_2024,

title = {Association of large core middle cerebral artery stroke and hemorrhagic transformation with hospitalization outcomes},

author = {Jack E. Pohlmann and Ivy So Yeon Kim and Benjamin Brush and Krishna M. Sambhu and Lucas Conti and Hanife Saglam and Katie Milos and Lillian Yu and Michael F. M. Cronin and Oluwafemi O. Balogun and Stefanos Chatzidakis and Yihan Zhang and Ludovic Trinquart and Qiuxi Huang and Stelios M. Smirnakis and Emelia J. Benjamin and Josée Dupuis and David M. Greer and Charlene J. Ong},

doi = {10.1038/s41598-024-60635-0},

issn = {2045-2322},

year  = {2024},

date = {2024-05-01},

journal = {Scientific Reports},

volume = {14},

number = {1},

pages = {10008},

abstract = {Historically, investigators have not differentiated between patients with and without hemorrhagic transformation (HT) in large core ischemic stroke at risk for life-threatening mass effect (LTME) from cerebral edema. Our objective was to determine whether LTME occurs faster in those with HT compared to those without. We conducted a two-center retrospective study of patients with ≥ 1/2 MCA territory infarct between 2006 and 2021. We tested the association of time-to-LTME and HT subtype (parenchymal, petechial) using Cox regression, controlling for age, mean arterial pressure, glucose, tissue plasminogen activator, mechanical thrombectomy, National Institute of Health Stroke Scale, antiplatelets, anticoagulation, temperature, and stroke side. Secondary and exploratory outcomes included mass effect-related death, all-cause death, disposition, and decompressive hemicraniectomy. Of 840 patients, 358 (42.6%) had no HT, 403 (48.0%) patients had petechial HT, and 79 (9.4%) patients had parenchymal HT. LTME occurred in 317 (37.7%) and 100 (11.9%) had mass effect-related deaths. Parenchymal (HR 8.24, 95% CI 5.46-12.42, p < 0.01) and petechial HT (HR 2.47, 95% CI 1.92-3.17, p < 0.01) were significantly associated with time-to-LTME and mass effect-related death. Understanding different risk factors and sequelae of mass effect with and without HT is critical for informed clinical decisions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{papadopouli_brain_2024,

title = {Brain orchestra under spontaneous conditions: Identifying communication modules from the functional architecture of area V1},

author = {Maria Papadopouli and Ioannis Smyrnakis and Emmanouil Koniotakis and Mario-Alexios Savaglio and Christina Brozi and Eleftheria Psilou and Ganna Palagina and Stelios M. Smirnakis},

doi = {10.1101/2024.02.29.582364},

issn = {2692-8205},

year  = {2024},

date = {2024-04-01},

journal = {bioRxiv: The Preprint Server for Biology},

pages = {2024.02.29.582364},

abstract = {We used two-photon imaging to record from granular and supragranular layers in mouse primary visual cortex (V1) under spontaneous conditions and applied an extension of the spike time tiling coefficient (STTC; introduced by Cutts and Eglen) to map functional connectivity architecture within and across layers. We made several observations: Approximately, 19-34% of neuronal pairs within 300 μm of each other exhibit statistically significant functional connections, compared to textasciitilde10% at distances of 1mm or more. As expected, neuronal pairs with similar tuning functions exhibit a significant, though relatively small, increase in the fraction of functional inter-neuronal correlations. In contrast, internal state as reflected by pupillary diameter or aggregate neuronal activity appears to play a much stronger role in determining inter-neuronal correlation distributions and topography. Overall, inter-neuronal correlations appear to be slightly more prominent in L4. The first-order functionally connected (i.e., direct) neighbors of neurons determine the hub structure of the V1 microcircuit. L4 exhibits a nearly flat degree of connectivity distribution, extending to higher values than seen in supragranular layers, whose distribution drops exponentially. In all layers, functional connectivity exhibits small-world characteristics and network robustness. The probability of firing of L2/3 pyramidal neurons can be predicted as a function of the aggregate activity in their first-order functionally connected partners within L4, which represent their putative input group. The functional form of this prediction conforms well to a ReLU function, reaching up to firing probability one in some neurons. Interestingly, the properties of L2/3 pyramidal neurons differ based on the size of their L4 functional connectivity group. Specifically, L2/3 neurons with small layer-4 degrees of connectivity appear to be more sensitive to the firing of their L4 functional connectivity partners, suggesting they may be more effective at transmitting synchronous activity downstream from L4. They also appear to fire largely independently from each other, compared to neurons with high layer-4 degrees of connectivity, and are less modulated by changes in pupil size and aggregate population dynamics. Information transmission is best viewed as occurring from neuronal ensembles in L4 to neuronal ensembles in L2/3. Under spontaneous conditions, we were able to identify such candidate neuronal ensembles, which exhibit high sensitivity, precision, and specificity for L4 to L2/3 information transmission. In sum, functional connectivity analysis under spontaneous activity conditions reveals a modular neuronal ensemble architecture within and across granular and supragranular layers of mouse primary visual cortex. Furthermore, modules with different degrees of connectivity appear to obey different rules of engagement and communication across the V1 columnar circuit.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{song_later_2024,

title = {Later Midline Shift Is Associated with Better Outcomes after Large Middle Cerebral Artery Stroke},

author = {Jonathan J. Song and Rebecca A. Stafford and Jack E. Pohlmann and Ivy So Yeon Kim and Maanyatha Cheekati and Sydney Dennison and Benjamin Brush and Stefanos Chatzidakis and Qiuxi Huang and Stelios M. Smirnakis and Emily J. Gilmore and Shariq Mohammed and Mohamad Abdalkader and Emelia J. Benjamin and Josée Dupuis and David M. Greer and Charlene J. Ong},

doi = {10.21203/rs.3.rs-4189278/v1},

issn = {2693-5015},

year  = {2024},

date = {2024-04-01},

journal = {Research Square},

pages = {rs.3.rs–4189278},

abstract = {BACKGROUND/OBJECTIVE: Space occupying cerebral edema is the most feared early complication after large ischemic stroke, occurring in up to 30% of patients with middle cerebral artery (MCA) occlusion, and is reported to peak 2-4 days after injury. Little is known about the factors and outcomes associated with peak edema timing, especially when it occurs after 96 hours. We aimed to characterize differences between patients who experienced maximum midline shift (MLS) or decompressive hemicraniectomy (DHC) in the acute (<48 hours), average (48-96 hours), and subacute (>96 hours) groups and determine whether patients with subacute peak edema timing have improved discharge dispositions. 

METHODS: We performed a two-center, retrospective study of patients with ≥1/2 MCA territory infarct and MLS. We constructed a multivariable model to test the association of subacute peak edema and favorable discharge disposition, adjusting for age, admission Alberta Stroke Program Early CT Score (ASPECTS), National Institute of Health Stroke Scale (NIHSS), acute thrombolytic intervention, cerebral atrophy, maximum MLS, parenchymal hemorrhagic transformation, DHC, and osmotic therapy receipt. 

RESULTS: Of 321 eligible patients with MLS, 32%, 36%, and 32% experienced acute, average, and subacute peak edema. Subacute peak edema was significantly associated with higher odds of favorable discharge than non-subacute swelling, adjusting for confounders (aOR, 1.85; 95% CI, 1.05-3.31). 

CONCLUSIONS: Subacute peak edema after large MCA stroke is associated with better discharge disposition compared to earlier peak edema courses. Understanding how the timing of cerebral edema affects risk of unfavorable discharge has important implications for treatment decisions and prognostication.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{koutsioumpa_dural_2024,

title = {Dural arteriovenous fistula of the craniocervical junction},

author = {Charalampia Koutsioumpa and Dave Ho and Cory Siegel and Nirav Patel and Stelios M. Smirnakis and Viken Babikian},

doi = {10.1136/pn-2023-003912},

issn = {1474-7766},

year  = {2024},

date = {2024-03-01},

journal = {Practical Neurology},

volume = {24},

number = {2},

pages = {148–151},

abstract = {Dural arteriovenous (AV) fistulas of the craniocervical junction can be challenging to diagnose. We describe a 70-year-old man with subacute progressive myelopathy whose MR scan of cervical spine showed serpiginous dorsal vessels, suggesting a dural AV fistula. However, a detailed diagnostic angiogram was normal, prompting additional work-up and a wider differential, which was non-revealing. His symptoms progressed over months, but the evolution of the lesion characteristics on repeat spinal imaging still suggested a dural AV fistula. Repeat angiogram identified an infratentorial dural AV fistula arising from the meningohypophyseal artery. He improved following retrosigmoid craniotomy and clipping. Initial angiography does not always demonstrate a dural AV fistula; if there is clinical and radiographic evolution, repeat angiography might identify a fistula with a rare arterial feeder.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{tobochnik_glioma_2024,

title = {Glioma genetic profiles associated with electrophysiologic hyperexcitability},

author = {Steven Tobochnik and Maria Kristina C. Dorotan and Hia S. Ghosh and Emily Lapinskas and Jayne Vogelzang and David A. Reardon and Keith L. Ligon and Wenya Linda Bi and Stelios M. Smirnakis and Jong Woo Lee},

doi = {10.1093/neuonc/noad176},

issn = {1523-5866},

year  = {2024},

date = {2024-02-01},

journal = {Neuro-Oncology},

volume = {26},

number = {2},

pages = {323–334},

abstract = {BACKGROUND: Distinct genetic alterations determine glioma aggressiveness, however, the diversity of somatic mutations contributing to peritumoral hyperexcitability and seizures over the course of the disease is uncertain. This study aimed to identify tumor somatic mutation profiles associated with clinically significant hyperexcitability. METHODS: A single center cohort of adults with WHO grades 1-4 glioma and targeted exome sequencing (n = 1716) was analyzed and cross-referenced with a validated EEG database to identify the subset of individuals who underwent continuous EEG monitoring (n = 206). Hyperexcitability was defined by the presence of lateralized periodic discharges and/or electrographic seizures. Cross-validated discriminant analysis models trained exclusively on recurrent somatic mutations were used to identify variants associated with hyperexcitability. 

RESULTS: The distribution of WHO grades and tumor mutational burdens were similar between patients with and without hyperexcitability. Discriminant analysis models classified the presence or absence of EEG hyperexcitability with an overall accuracy of 70.9%, regardless of IDH1 R132H inclusion. Predictive variants included nonsense mutations in ATRX and TP53, indel mutations in RBBP8 and CREBBP, and nonsynonymous missense mutations with predicted damaging consequences in EGFR, KRAS, PIK3CA, TP53, and USP28. This profile improved estimates of hyperexcitability in a multivariate analysis controlling for age, sex, tumor location, integrated pathologic diagnosis, recurrence status, and preoperative epilepsy. Predicted somatic mutation variants were over-represented in patients with hyperexcitability compared to individuals without hyperexcitability and those who did not undergo continuous EEG. 

CONCLUSION: These findings implicate diverse glioma somatic mutations in cancer genes associated with peritumoral hyperexcitability. Tumor genetic profiling may facilitate glioma-related epilepsy prognostication and management.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{bogatova_tug–peace_2024,

title = {Tug-of-Peace: Visual Rivalry and Atypical Visual Motion Processing in MECP2 Duplication Syndrome of Autism},

author = {Daria Bogatova and Stelios M. Smirnakis and Ganna Palagina},

doi = {10.1523/ENEURO.0102-23.2023},

issn = {2373-2822},

year  = {2024},

date = {2024-01-01},

journal = {eNeuro},

volume = {11},

number = {1},

pages = {ENEURO.0102–23.2023},

abstract = {Extracting common patterns of neural circuit computations in the autism spectrum and confirming them as a cause of specific core traits of autism is the first step toward identifying cell-level and circuit-level targets for effective clinical intervention. Studies in humans with autism have identified functional links and common anatomic substrates between core restricted behavioral repertoire, cognitive rigidity, and overstability of visual percepts during visual rivalry. To study these processes with single-cell precision and comprehensive neuronal population coverage, we developed the visual bistable perception paradigm for mice based on ambiguous moving plaid patterns consisting of two transparent gratings drifting at an angle of 120°. This results in spontaneous reversals of the perception between local component motion (plaid perceived as two separate moving grating components) and integrated global pattern motion (plaid perceived as a fused moving texture). This robust paradigm does not depend on the explicit report of the mouse, since the direction of the optokinetic nystagmus (OKN) is used to infer the dominant percept. Using this paradigm, we found that the rate of perceptual reversals between global and local motion interpretations is reduced in the methyl-CpG-binding protein 2 duplication syndrome (MECP2-ds) mouse model of autism. Moreover, the stability of local motion percepts is greatly increased in MECP2-ds mice at the expense of global motion percepts. Thus, our model reproduces a subclass of the core features in human autism (reduced rate of visual rivalry and atypical perception of visual motion). This further offers a well-controlled approach for dissecting neuronal circuits underlying these core features.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{petousakis_modeling_2023,

title = {Modeling apical and basal tree contribution to orientation selectivity in a mouse primary visual cortex layer 2/3 pyramidal cell},

author = {Konstantinos-Evangelos Petousakis and Jiyoung Park and Athanasia Papoutsi and Stelios M. Smirnakis and Panayiota Poirazi},

doi = {10.7554/eLife.91627},

issn = {2050-084X},

year  = {2023},

date = {2023-12-01},

journal = {eLife},

volume = {12},

pages = {e91627},

abstract = {Pyramidal neurons, a mainstay of cortical regions, receive a plethora of inputs from various areas onto their morphologically distinct apical and basal trees. Both trees differentially contribute to the somatic response, defining distinct anatomical and possibly functional sub-units. To elucidate the contribution of each tree to the encoding of visual stimuli at the somatic level, we modeled the response pattern of a mouse L2/3 V1 pyramidal neuron to orientation tuned synaptic input. Towards this goal, we used a morphologically detailed computational model of a single cell that replicates electrophysiological and two-photon imaging data. Our simulations predict a synergistic effect of apical and basal trees on somatic action potential generation: basal tree activity, in the form of either depolarization or dendritic spiking, is necessary for producing somatic activity, despite the fact that most somatic spikes are heavily driven by apical dendritic spikes. This model provides evidence for synergistic computations taking place in the basal and apical trees of the L2/3 V1 neuron along with mechanistic explanations for tree-specific contributions and emphasizes the potential role of predictive and attentional feedback input in these cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{ong_dynamic_2023,

title = {Dynamic trajectories of life-threatening mass effect in patients with large middle cerebral artery stroke},

author = {Charlene J. Ong and Qiuxi Huang and Ivy So Yeon Kim and Jack E. Pohlmann and Stefanos Chatzidakis and Benjamin Brush and Yihan Zhang and Yili Du and Leigh Ann Mallinger and Emelia J. Benjamin and Josée Dupuis and David M. Greer and Stelios M. Smirnakis and Ludovic Trinquart},

doi = {10.21203/rs.3.rs-3594179/v1},

issn = {2693-5015},

year  = {2023},

date = {2023-11-01},

journal = {Research Square},

pages = {rs.3.rs–3594179},

abstract = {BACKGROUND: Life-threatening, space-occupying mass effect due to cerebral edema and/or hemorrhagic transformation is an early complication of patients with middle cerebral artery (MCA) stroke. Little is known about longitudinal trajectories of laboratory and vital signs leading up to radiographic and clinical deterioration related to this mass effect. 

METHODS: We curated a granular retrospective dataset of 635 patients with large middle cerebral artery (MCA) stroke totaling 108,547 data points for repeated measurements of 10 covariates, and 40 time-independent covariates. We assessed longitudinal trajectories of the 10 longitudinal variables during the 72 hours preceding three outcomes representative of life-threatening mass effect: midline shift (MLS) ≥5mm, pineal gland shift (PGS) >4mm, and decompressive hemicraniectomy (DHC). We used a "backward looking" trajectory approach. Patients were aligned according to the time of outcome occurrence and the trajectory of each variable was assessed prior to that outcome by accounting for both cases and non-cases. 

RESULTS: Of 635 patients, 49% were female, and mean age was 69 years. Thirty five percent of patients had MLS ≥ 5mm, 24.1% had PGS >4mm, and DHC occurred in 10.7%. For the three outcomes of interest, backward-looking trajectories showed mild increases in white blood cell count (10 up to 11 K/UL within 72 hours), temperature (up to half a degree within 24 hours), and sodium (1-3 mEq/L within 24 hours) leading up to outcomes. We also observed a decrease in heart rate (75 - 65 beats per minute) 24 hours prior to DHC. 

CONCLUSIONS: Univariable longitudinal profiling showed that temperature, white blood cell count, and sodium increase prior to radiographic and clinical indicators of space-occupying mass effect. These findings will inform development of multivariable dynamic risk models to aid prediction of life-threatening space-occupying mass effect.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{ash_increased_2022,

title = {Increased Reliability of Visually-Evoked Activity in Area V1 of the MECP2-Duplication Mouse Model of Autism},

author = {Ryan T. Ash and Ganna Palagina and Jose A. Fernandez-Leon and Jiyoung Park and Rob Seilheimer and Sangkyun Lee and Jasdeep Sabharwal and Fredy Reyes and Jing Wang and Dylan Lu and Muhammad Sarfraz and Emmanouil Froudarakis and Andreas S. Tolias and Samuel M. Wu and Stelios M. Smirnakis},

doi = {10.1523/JNEUROSCI.0654-22.2022},

issn = {1529-2401},

year  = {2022},

date = {2022-08-01},

journal = {The Journal of Neuroscience: The Official Journal of the Society for Neuroscience},

volume = {42},

number = {33},

pages = {6469–6482},

abstract = {Atypical sensory processing is now thought to be a core feature of the autism spectrum. Influential theories have proposed that both increased and decreased neural response reliability within sensory systems could underlie altered sensory processing in autism. Here, we report evidence for abnormally increased reliability of visual-evoked responses in layer 2/3 neurons of adult male and female primary visual cortex in the MECP2-duplication syndrome animal model of autism. Increased response reliability was due in part to decreased response amplitude, decreased fluctuations in endogenous activity, and an abnormal decoupling of visual-evoked activity from endogenous activity. Similar to what was observed neuronally, the optokinetic reflex occurred more reliably at low contrasts in mutant mice compared with controls. Retinal responses did not explain our observations. These data suggest that the circuit mechanisms for combining sensory-evoked and endogenous signal and noise processes may be altered in this form of syndromic autism.SIGNIFICANCE STATEMENT Atypical sensory processing is now thought to be a core feature of the autism spectrum. Influential theories have proposed that both increased and decreased neural response reliability within sensory systems could underlie altered sensory processing in autism. Here, we report evidence for abnormally increased reliability of visual-evoked responses in primary visual cortex of the animal model for MECP2-duplication syndrome, a high-penetrance single-gene cause of autism. Visual-evoked activity was abnormally decoupled from endogenous activity in mutant mice, suggesting in line with the influential "hypo-priors" theory of autism that sensory priors embedded in endogenous activity may have less influence on perception in autism.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{miller_natural_2022,

title = {Natural Language Processing of Radiology Reports to Detect Complications of Ischemic Stroke},

author = {Matthew I. Miller and Agni Orfanoudaki and Michael F. M. Cronin and Hanife Saglam and Ivy So Yeon Kim and Oluwafemi O. Balogun and Maria Tzalidi and Kyriakos Vasilopoulos and Georgia Fanaropoulou and Nina M. Fanaropoulou and Jack Kalin and Meghan R. Hutch and Brenton R. Prescott and Benjamin Brush and Emelia J. Benjamin and Min Shin and Asim Mian and David M. Greer and Stelios M. Smirnakis and Charlene J. Ong},

doi = {10.1007/s12028-022-01513-3},

issn = {1556-0961},

year  = {2022},

date = {2022-08-01},

journal = {Neurocritical Care},

volume = {37},

number = {Suppl 2},

pages = {291–302},

abstract = {BACKGROUND: Abstraction of critical data from unstructured radiologic reports using natural language processing (NLP) is a powerful tool to automate the detection of important clinical features and enhance research efforts. We present a set of NLP approaches to identify critical findings in patients with acute ischemic stroke from radiology reports of computed tomography (CT) and magnetic resonance imaging (MRI). 

METHODS: We trained machine learning classifiers to identify categorical outcomes of edema, midline shift (MLS), hemorrhagic transformation, and parenchymal hematoma, as well as rule-based systems (RBS) to identify intraventricular hemorrhage (IVH) and continuous MLS measurements within CT/MRI reports. Using a derivation cohort of 2289 reports from 550 individuals with acute middle cerebral artery territory ischemic strokes, we externally validated our models on reports from a separate institution as well as from patients with ischemic strokes in any vascular territory. RESULTS: In all data sets, a deep neural network with pretrained biomedical word embeddings (BioClinicalBERT) achieved the highest discrimination performance for binary prediction of edema (area under precision recall curve [AUPRC] > 0.94), MLS (AUPRC > 0.98), hemorrhagic conversion (AUPRC > 0.89), and parenchymal hematoma (AUPRC > 0.76). BioClinicalBERT outperformed lasso regression (p < 0.001) for all outcomes except parenchymal hematoma (p = 0.755). Tailored RBS for IVH and continuous MLS outperformed BioClinicalBERT (p < 0.001) and linear regression, respectively (p < 0.001). 

CONCLUSIONS: Our study demonstrates robust performance and external validity of a core NLP tool kit for identifying both categorical and continuous outcomes of ischemic stroke from unstructured radiographic text data. Medically tailored NLP methods have multiple important big data applications, including scalable electronic phenotyping, augmentation of clinical risk prediction models, and facilitation of automatic alert systems in the hospital setting.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{bhere_target_2022,

title = {Target receptor identification and subsequent treatment of resected brain tumors with encapsulated and engineered allogeneic stem cells},

author = {Deepak Bhere and Sung Hugh Choi and Pim Donk and David Hope and Kiki Gortzak and Amina Kunnummal and Jasneet Khalsa and Esther Revai Lechtich and Clemens Reinshagen and Victoria Leon and Nabil Nissar and Wenya Linda Bi and Cheng Feng and Hongbin Li and Yu Shrike Zhang and Steven H. Liang and Neil Vasdev and Walid Ibn Essayed and Pablo Valdes Quevedo and Alexandra Golby and Naima Banouni and Ganna Palagina and Reza Abdi and Brian Fury and Stelios M. Smirnakis and Alarice Lowe and Brock Reeve and Arthur Hiller and E. Antonio Chiocca and Glenn Prestwich and Hiroaki Wakimoto and Gerhard Bauer and Khalid Shah},

doi = {10.1038/s41467-022-30558-3},

issn = {2041-1723},

year  = {2022},

date = {2022-05-01},

journal = {Nature Communications},

volume = {13},

number = {1},

pages = {2810},

abstract = {Cellular therapies offer a promising therapeutic strategy for the highly malignant brain tumor, glioblastoma (GBM). However, their clinical translation is limited by the lack of effective target identification and stringent testing in pre-clinical models that replicate standard treatment in GBM patients. In this study, we show the detection of cell surface death receptor (DR) target on CD146-enriched circulating tumor cells (CTC) captured from the blood of mice bearing GBM and patients diagnosed with GBM. Next, we developed allogeneic "off-the-shelf" clinical-grade bifunctional mesenchymal stem cells (MSCBif) expressing DR-targeted ligand and a safety kill switch. We show that biodegradable hydrogel encapsulated MSCBif (EnMSCBif) has a profound therapeutic efficacy in mice bearing patient-derived invasive, primary and recurrent GBM tumors following surgical resection. Activation of the kill switch enhances the efficacy of MSCBif and results in their elimination post-tumor treatment which can be tracked by positron emission tomography (PET) imaging. This study establishes a foundation towards a clinical trial of EnMSCBif in primary and recurrent GBM patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{chan_dexmedetomidine_2022,

title = {Dexmedetomidine and Other Analgosedatives Alter Pupil Characteristics in Critically Ill Patients},

author = {Wang Pong Chan and Brenton R. Prescott and Megan E. Barra and David Y. Chung and Ivy So Yeon Kim and Hanife Saglam and Meghan R. Hutch and Min Shin and Sahar F. Zafar and Emelia J. Benjamin and Stelios M. Smirnakis and Josée Dupuis and David M. Greer and Charlene J. Ong},

doi = {10.1097/CCE.0000000000000691},

issn = {2639-8028},

year  = {2022},

date = {2022-05-01},

journal = {Critical Care Explorations},

volume = {4},

number = {5},

pages = {e0691},

abstract = {In critically ill patients with neurologic disease, pupil examination abnormalities can signify evolving intracranial pathology. Analgesic and sedative medications (analgosedatives) target pupillary pathways, but it remains unknown how analgosedatives alter pupil findings in the clinical care setting. We assessed dexmedetomidine and other analgosedative associations with pupil reactivity and size in a heterogeneous cohort of critically ill patients with acute intracranial pathology. 

DESIGN: Retrospective cohort study. 

SETTING: Two neurologic ICUs between 2016 and 2018. 

PATIENTS: Critically ill adult patients with pupil measurements within 60 minutes of analgosedative administration. Patients with a history of intrinsic retinal pathology, extracranial injury, inaccessible brain imaging, or no Glasgow Coma Scale (GCS) data were excluded. 

INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used mixed-effects linear regression accounting for intrapatient correlations and adjusting for sex, age, GCS score, radiographic mass effect, medication confounders, and ambient light. We tested the association between an initiation or increased IV infusion of dexmedetomidine and pupil reactivity (Neurologic Pupil Index [NPi]) and resting pupil size (mm) obtained using NeurOptics NPi-200 (NeurOptics, Irvine, CA) pupillometer. Of our 221 patients with 9,897 pupil observations (median age, 60 [interquartile range, 50-68]; 59% male), 37 patients (166 pupil observations) were exposed to dexmedetomidine. Dexmedetomidine was associated with higher average NPi (β = 0.18 per 1 unit increase in rank-normalized NPi ± 0.04; p < 0.001) and smaller pupil size (β = -0.25 ± 0.05; p < 0.001). Exploratory analyses revealed that acetaminophen was associated with higher average NPi (β = 0.04 ± 0.02; p = 0.02) and that most IV infusion analgosedatives including propofol, fentanyl, and midazolam were associated with smaller pupil size. 

CONCLUSIONS: Dexmedetomidine is associated with higher pupil reactivity (high NPi) and smaller pupil size in a cohort of critically ill patients with neurologic injury. Familiarity with expected pupil changes following analgosedative administration is important for accurate interpretation of pupil examination findings, facilitating optimal management of patients with acute intracranial pathology.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{prescott_anisocoria_2022,

title = {Anisocoria and Poor Pupil Reactivity by Quantitative Pupillometry in Patients With Intracranial Pathology},

author = {Brenton R. Prescott and Hanife Saglam and Jonathan A. Duskin and Matthew I. Miller and Arnav S. Thakur and Eesha A. Gholap and Meghan R. Hutch and Stelios M. Smirnakis and Sahar F. Zafar and Josée Dupuis and Emelia J. Benjamin and David M. Greer and Charlene J. Ong},

doi = {10.1097/CCM.0000000000005272},

issn = {1530-0293},

year  = {2022},

date = {2022-02-01},

journal = {Critical Care Medicine},

volume = {50},

number = {2},

pages = {e143–e153},

abstract = {OBJECTIVES: To describe the prevalence and associated risk factors of new onset anisocoria (new pupil size difference of at least 1 mm) and its subtypes: new onset anisocoria accompanied by abnormal and normal pupil reactivities in patients with acute neurologic injuries. 

DESIGN: We tested the association of patients who experienced new onset anisocoria subtypes with degree of midline shift using linear regression. We further explored differences between quantitative pupil characteristics associated with first-time new onset anisocoria and nonnew onset anisocoria at preceding observations using mixed effects logistic regression, adjusting for possible confounders. 

SETTING: All quantitative pupil observations were collected at two neuro-ICUs by nursing staff as standard of care. 

PATIENTS: We conducted a retrospective two-center study of adult patients with intracranial pathology in the ICU with at least a 24-hour stay and three or more quantitative pupil measurements between 2016 and 2018. MEASUREMENTS AND MAIN RESULTS: We studied 221 patients (mean age 58, 41% women). Sixty-three percent experienced new onset anisocoria. New onset anisocoria accompanied by objective evidence of abnormal pupil reactivity occurring at any point during hospitalization was significantly associated with maximum midline shift (β = 2.27 per mm; p = 0.01). The occurrence of new onset anisocoria accompanied by objective evidence of normal pupil reactivity was inversely associated with death (odds ratio, 0.34; 95% CI, 0.16-0.71; p = 0.01) in adjusted analyses. Subclinical continuous pupil size difference distinguished first-time new onset anisocoria from nonnew onset anisocoria in up to four preceding pupil observations (or up to 8 hr prior). Minimum pupil reactivity between eyes also distinguished new onset anisocoria accompanied by objective evidence of abnormal pupil reactivity from new onset anisocoria accompanied by objective evidence of normal pupil reactivity prior to first-time new onset anisocoria occurrence. 

CONCLUSIONS: New onset anisocoria occurs in over 60% of patients with neurologic emergencies. Pupil reactivity may be an important distinguishing characteristic of clinically relevant new onset anisocoria phenotypes. New onset anisocoria accompanied by objective evidence of abnormal pupil reactivity was associated with midline shift, and new onset anisocoria accompanied by objective evidence of normal pupil reactivity had an inverse relationship with death. Distinct quantitative pupil characteristics precede new onset anisocoria occurrence and may allow for earlier prediction of neurologic decline. Further work is needed to determine whether quantitative pupillometry sensitively/specifically predicts clinically relevant anisocoria, enabling possible earlier treatments.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{keliris_macaque_2022,

title = {Macaque Area V2/V3 Reorganization Following Homonymous Retinal Lesions},

author = {Georgios A. Keliris and Yibin Shao and Michael C. Schmid and Mark A. Augath and Nikos K. Logothetis and Stelios M. Smirnakis},

doi = {10.3389/fnins.2022.757091},

issn = {1662-4548},

year  = {2022},

date = {2022-01-01},

journal = {Frontiers in Neuroscience},

volume = {16},

pages = {757091},

abstract = {In the adult visual system, topographic reorganization of the primary visual cortex (V1) after retinal lesions has been extensively investigated. In contrast, the plasticity of higher order extrastriate areas following retinal lesions is less well studied. Here, we used fMRI to study reorganization of visual areas V2/V3 following the induction of permanent, binocular, homonymous retinal lesions in 4 adult macaque monkeys. We found that the great majority of voxels that did not show visual modulation on the day of the lesion in the V2/V3 lesion projection zone (LPZ) demonstrated significant visual modulations 2 weeks later, and the mean modulation strength remained approximately stable thereafter for the duration of our observations (4-5 months). The distribution of eccentricities of visually modulated voxels inside the V2/V3 LPZ spanned a wider range post-lesion than pre-lesion, suggesting that neurons inside the LPZ reorganize by receiving input either from the foveal or the peripheral border of the LPZ, depending on proximity. Overall, we conclude that area V2/V3 of adult rhesus macaques displays a significant capacity for topographic reorganization following retinal lesions markedly exceeding the corresponding capacity of area V1.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{kim_quantitative_2022,

title = {Quantitative pupillometry and radiographic markers of intracranial midline shift: A pilot study},

author = {Ivy So Yeon Kim and Oluwafemi O. Balogun and Brenton R. Prescott and Hanife Saglam and DaiWai M. Olson and Kinley Speir and Sonja E. Stutzman and Nathan Schneider and Veronica Aguilera and Bethany L. Lussier and Stelios M. Smirnakis and Josée Dupuis and Asim Mian and David M. Greer and Charlene J. Ong},

doi = {10.3389/fneur.2022.1046548},

issn = {1664-2295},

year  = {2022},

date = {2022-01-01},

journal = {Frontiers in Neurology},

volume = {13},

pages = {1046548},

abstract = {BACKGROUND: Asymmetric pupil reactivity or size can be early clinical indicators of midbrain compression due to supratentorial ischemic stroke or primary intraparenchymal hemorrhage (IPH). Radiographic midline shift is associated with worse functional outcomes and life-saving interventions. Better understanding of quantitative pupil characteristics would be a non-invasive, safe, and cost-effective way to improve identification of life-threatening mass effect and resource utilization of emergent radiographic imaging. We aimed to better characterize the association between midline shift at various anatomic levels and quantitative pupil characteristics. 

METHODS: We conducted a multicenter retrospective study of brain CT images within 75 min of a quantitative pupil observation from patients admitted to Neuro-ICUs between 2016 and 2020 with large (>1/3 of the middle cerebral artery territory) acute supratentorial ischemic stroke or primary IPH > 30 mm3. For each image, we measured midline shift at the septum pellucidum (MLS-SP), pineal gland shift (PGS), the ratio of the ipsilateral to contralateral midbrain width (IMW/CMW), and other exploratory markers of radiographic shift/compression. Pupil reactivity was measured using an automated infrared pupillometer (NeurOptics®, Inc.), specifically the proprietary algorithm for Neurological Pupil Index® (NPi). We used rank-normalization and linear mixed-effects models, stratified by diagnosis and hemorrhagic conversion, to test associations of radiographic markers of shift and asymmetric pupil reactivity (Diff NPi), adjusting for age, lesion volume, Glasgow Coma Scale, and osmotic medications. RESULTS: Of 53 patients with 74 CT images, 26 (49.1%) were female, and median age was 67 years. MLS-SP and PGS were greater in patients with IPH, compared to patients with ischemic stroke (6.2 v. 4.0 mm, 5.6 v. 3.4 mm, respectively). We found no significant associations between pupil reactivity and the radiographic markers of shift when adjusting for confounders. However, we found potentially relevant relationships between MLS-SP and Diff NPi in our IPH cohort (β = 0.11, SE 0.04},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{rina_visual_2022,

title = {Visual Motion Coherence Responses in Human Visual Cortex},

author = {Andriani Rina and Amalia Papanikolaou and Xiaopeng Zong and Dorina T. Papageorgiou and Georgios A. Keliris and Stelios M. Smirnakis},

doi = {10.3389/fnins.2022.719250},

issn = {1662-4548},

year  = {2022},

date = {2022-01-01},

journal = {Frontiers in Neuroscience},

volume = {16},

pages = {719250},

abstract = {Random dot kinematograms (RDKs) have recently been used to train subjects with cortical scotomas to perform direction of motion discrimination, partially restoring visual motion perception. To study the recovery of visual perception, it is important to understand how visual areas in normal subjects and subjects with cortical scotomas respond to RDK stimuli. Studies in normal subjects have shown that blood oxygen level-dependent (BOLD) responses in human area hV5/MT+ increase monotonically with coherence, in general agreement with electrophysiology studies in primates. However, RDK responses in prior studies were obtained while the subject was performing fixation, not a motion discrimination condition. Furthermore, BOLD responses were gauged against a baseline condition of uniform illumination or static dots, potentially decreasing the specificity of responses for the spatial integration of local motion signals (motion coherence). Here, we revisit this question starting from a baseline RDK condition of no coherence, thereby isolating the component of BOLD response due specifically to the spatial integration of local motion signals. In agreement with prior studies, we found that responses in the area hV5/MT+ of healthy subjects were monotonically increasing when subjects fixated without performing a motion discrimination task. In contrast, when subjects were performing an RDK direction of motion discrimination task, responses in the area hV5/MT+ remained flat, changing minimally, if at all, as a function of motion coherence. A similar pattern of responses was seen in the area hV5/MT+ of subjects with dense cortical scotomas performing direction of motion discrimination for RDKs presented inside the scotoma. Passive RDK presentation within the scotoma elicited no significant hV5/MT+ responses. These observations shed further light on how visual cortex responses behave as a function of motion coherence, helping to prepare the ground for future studies using these methods to study visual system recovery after injury.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{tehovnik_visuomotor_2021,

title = {Visuomotor control in mice and primates},

author = {Edward J. Tehovnik and Emmanouil Froudarakis and F. Scala and Stelios M. Smirnakis and S. S. Patel and Andreas S. Tolias},

doi = {10.1016/j.neubiorev.2021.08.009},

issn = {1873-7528},

year  = {2021},

date = {2021-11-01},

journal = {Neuroscience and Biobehavioral Reviews},

volume = {130},

pages = {185–200},

abstract = {We conduct a comparative evaluation of the visual systems from the retina to the muscles of the mouse and the macaque monkey noting the differences and similarities between these two species. The topics covered include (1) visual-field overlap, (2) visual spatial resolution, (3) V1 cortical point-image [i.e., V1 tissue dedicated to analyzing a unit receptive field], (4) object versus motion encoding, (5) oculomotor range, (6) eye, head, and body movement coordination, and (7) neocortical and cerebellar function. We also discuss blindsight in rodents and primates which provides insights on how the neocortex mediates conscious vision in these species. This review is timely because the field of visuomotor neurophysiology is expanding beyond the macaque monkey to include the mouse; there is therefore a need for a comparative analysis between these two species on how the brain generates visuomotor responses.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{yue_motor_2021,

title = {Motor training improves coordination and anxiety in symptomatic Mecp2-null mice despite impaired functional connectivity within the motor circuit},

author = {Yuanlei Yue and Pan Xu and Zhichao Liu and Xiaoqian Sun and Juntao Su and Hongfei Du and Lingling Chen and Ryan T. Ash and Stelios M. Smirnakis and Rahul Simha and Linda Kusner and Chen Zeng and Hui Lu},

doi = {10.1126/sciadv.abf7467},

issn = {2375-2548},

year  = {2021},

date = {2021-10-01},

journal = {Science Advances},

volume = {7},

number = {43},

pages = {eabf7467},

abstract = {Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by loss of function of the X-linked methyl-CpG–binding protein 2 (MECP2). Several case studies report that gross motor function can be improved in children with RTT through treadmill walking, but whether the MeCP2-deficient motor circuit can support actual motor learning remains unclear. We used two-photon calcium imaging to simultaneously observe layer (L) 2/3 and L5a excitatory neuronal activity in the motor cortex (M1) while mice adapted to changing speeds on a computerized running wheel. Despite circuit hypoactivity and weakened functional connectivity across L2/3 and L5a, the Mecp2-null circuit’s firing pattern evolved with improved performance over 2 weeks. Moreover, trained mice became less anxious and lived 20% longer than untrained mice. Because motor deficits and anxiety are core symptoms of RTT, which is not diagnosed until well after symptom onset, these results underscore the benefit of motor learning.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{sreekrishnan_subcortical_2021,

title = {Subcortical Sparing Associated with Ambulatory Independence after Hemicraniectomy for Malignant Infarction},

author = {Anirudh Sreekrishnan and Charlene J. Ong and Rahul Mahajan and Brenton R. Prescott and Stelios M. Smirnakis and Matthew B. Bevers and Steven K. Feske and Samuel B. Snider},

doi = {10.1016/j.jstrokecerebrovasdis.2021.105850},

issn = {1532-8511},

year  = {2021},

date = {2021-08-01},

journal = {Journal of Stroke and Cerebrovascular Diseases: The Official Journal of National Stroke Association},

volume = {30},

number = {8},

pages = {105850},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{ash_excessive_2021,

title = {Excessive Formation and Stabilization of Dendritic Spine Clusters in the MECP2-Duplication Syndrome Mouse Model of Autism},

author = {Ryan T. Ash and Jiyoung Park and Bernhard Suter and Huda Y. Zoghbi and Stelios M. Smirnakis},

doi = {10.1523/ENEURO.0282-20.2020},

issn = {2373-2822},

year  = {2021},

date = {2021-01-01},

journal = {eNeuro},

volume = {8},

number = {1},

pages = {ENEURO.0282–20.2020},

abstract = {Autism-associated genetic mutations may perturb the balance between stability and plasticity of synaptic connections in the brain. Here, we report an increase in the formation and stabilization of dendritic spines in the cerebral cortex of the mouse model of MECP2-duplication syndrome, a high-penetrance form of syndromic autism. Increased stabilization is mediated entirely by spines that form cooperatively in 10-μm clusters and is observable across multiple cortical areas both spontaneously and following motor training. Excessive stability of dendritic spine clusters could contribute to behavioral rigidity and other phenotypes in syndromic autism.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{ash_inhibition_2021,

title = {Inhibition of Elevated Ras-MAPK Signaling Normalizes Enhanced Motor Learning and Excessive Clustered Dendritic Spine Stabilization in the MECP2-Duplication Syndrome Mouse Model of Autism},

author = {Ryan T. Ash and Shelly Alexandra Buffington and Jiyoung Park and Bernhard Suter and Mauro Costa-Mattioli and Huda Y. Zoghbi and Stelios M. Smirnakis},

doi = {10.1523/ENEURO.0056-21.2021},

issn = {2373-2822},

year  = {2021},

date = {2021-01-01},

journal = {eNeuro},

volume = {8},

number = {4},

pages = {ENEURO.0056–21.2021},

abstract = {The inflexible repetitive behaviors and "insistence on sameness" seen in autism imply a defect in neural processes controlling the balance between stability and plasticity of synaptic connections in the brain. It has been proposed that abnormalities in the Ras-ERK/MAPK pathway, a key plasticity-related cell signaling pathway known to drive consolidation of clustered synaptic connections, underlie altered learning phenotypes in autism. However, a link between altered Ras-ERK signaling and clustered dendritic spine plasticity has yet to be explored in an autism animal model in vivo The formation and stabilization of dendritic spine clusters is abnormally increased in the MECP2-duplication syndrome mouse model of syndromic autism, suggesting that ERK signaling may be increased. Here, we show that the Ras-ERK pathway is indeed hyperactive following motor training in MECP2-duplication mouse motor cortex. Pharmacological inhibition of ERK signaling normalizes the excessive clustered spine stabilization and enhanced motor learning behavior in MECP2-duplication mice. We conclude that hyperactive ERK signaling may contribute to abnormal clustered dendritic spine consolidation and motor learning in this model of syndromic autism.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{sun_blood_2020,

title = {Blood Pressure Thresholds During Endovascular Therapy in Ischemic Stroke},

author = {Zhuyi Elizabeth Sun and Stelios M. Smirnakis and Steven K. Feske},

doi = {10.1001/jamaneurol.2020.3816},

issn = {2168-6157},

year  = {2020},

date = {2020-12-01},

journal = {JAMA neurology},

volume = {77},

number = {12},

pages = {1578–1579},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{izzy_characteristics_2020,

title = {Characteristics and Outcomes of Latinx Patients With COVID-19 in Comparison With Other Ethnic and Racial Groups},

author = {Saef Izzy and Zabreen Tahir and David J. Cote and Ali Al Jarrah and Matthew Blake Roberts and Sarah Turbett and Aran Kadar and Stelios M. Smirnakis and Steven K. Feske and Ross Zafonte and Jay A. Fishman and Joseph El Khoury},

doi = {10.1093/ofid/ofaa401},

issn = {2328-8957},

year  = {2020},

date = {2020-10-01},

journal = {Open Forum Infectious Diseases},

volume = {7},

number = {10},

pages = {ofaa401},

abstract = {BACKGROUND: There is a limited understanding of the impact of coronavirus disease 2019 (COVID-19) on the Latinx population. We hypothesized that Latinx patients would be more likely to be hospitalized and admitted to the intensive care unit (ICU) than White patients. 

METHODS: We analyzed all patients with COVID-19 in 12 Massachusetts hospitals between February 1 and April 14, 2020. We examined the association between race, ethnicity, age, reported comorbidities, and hospitalization and ICU admission using multivariable regression. 

RESULTS: Of 5190 COVID-19 patients, 29% were hospitalized; 33% required the ICU, and 4.3% died. Forty-six percent of patients were White, 25% Latinx, 14% African American, and 3% Asian American. Ethnicity and race were significantly associated with hospitalization. More Latinx and African American patients in the younger age groups were hospitalized than whites. Latinxs and African Americans disproportionally required the ICU, with 39% of hospitalized Latinx patients requiring the ICU compared with 33% of African Americans, 24% of Asian Americans, and 30% of Whites (P < .007). Within each ethnic and racial group, age and male gender were independently predictive of hospitalization. Previously reported preexisting comorbidities contributed to the need for hospitalization in all racial and ethnic groups (P < .05). However, the observed disparities were less likely related to reported comorbidities, with Latinx and African American patients being admitted at twice the rate of Whites, regardless of such comorbidities. 

CONCLUSIONS: Latinx and African American patients with COVID-19 have higher rates of hospitalization and ICU admission than White patients. The etiologies of such disparities are likely multifactorial and cannot be explained only by reported comorbidities.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{ong_machine_2020,

title = {Machine learning and natural language processing methods to identify ischemic stroke, acuity and location from radiology reports},

author = {Charlene J. Ong and Agni Orfanoudaki and Rebecca Zhang and Francois Pierre M. Caprasse and Meghan R. Hutch and Liang Ma and Darian Fard and Oluwafemi O. Balogun and Matthew I. Miller and Margaret Minnig and Hanife Saglam and Brenton R. Prescott and David M. Greer and Stelios M. Smirnakis and Dimitris Bertsimas},

doi = {10.1371/journal.pone.0234908},

issn = {1932-6203},

year  = {2020},

date = {2020-01-01},

journal = {PloS One},

volume = {15},

number = {6},

pages = {e0234908},

abstract = {Accurate, automated extraction of clinical stroke information from unstructured text has several important applications. ICD-9/10 codes can misclassify ischemic stroke events and do not distinguish acuity or location. Expeditious, accurate data extraction could provide considerable improvement in identifying stroke in large datasets, triaging critical clinical reports, and quality improvement efforts. In this study, we developed and report a comprehensive framework studying the performance of simple and complex stroke-specific Natural Language Processing (NLP) and Machine Learning (ML) methods to determine presence, location, and acuity of ischemic stroke from radiographic text. We collected 60,564 Computed Tomography and Magnetic Resonance Imaging Radiology reports from 17,864 patients from two large academic medical centers. We used standard techniques to featurize unstructured text and developed neurovascular specific word GloVe embeddings. We trained various binary classification algorithms to identify stroke presence, location, and acuity using 75% of 1,359 expert-labeled reports. We validated our methods internally on the remaining 25% of reports and externally on 500 radiology reports from an entirely separate academic institution. In our internal population, GloVe word embeddings paired with deep learning (Recurrent Neural Networks) had the best discrimination of all methods for our three tasks (AUCs of 0.96, 0.98, 0.93 respectively). Simpler NLP approaches (Bag of Words) performed best with interpretable algorithms (Logistic Regression) for identifying ischemic stroke (AUC of 0.95), MCA location (AUC 0.96), and acuity (AUC of 0.90). Similarly, GloVe and Recurrent Neural Networks (AUC 0.92, 0.89, 0.93) generalized better in our external test set than BOW and Logistic Regression for stroke presence, location and acuity, respectively (AUC 0.89, 0.86, 0.80). Our study demonstrates a comprehensive assessment of NLP techniques for unstructured radiographic text. Our findings are suggestive that NLP/ML methods can be used to discriminate stroke features from large data cohorts for both clinical and research-related investigations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{park_contribution_2019,

title = {Contribution of apical and basal dendrites to orientation encoding in mouse V1 L2/3 pyramidal neurons},

author = {Jiyoung Park and Athanasia Papoutsi and Ryan T. Ash and Miguel A. Marin and Panayiota Poirazi and Stelios M. Smirnakis},

doi = {10.1038/s41467-019-13029-0},

issn = {2041-1723},

year  = {2019},

date = {2019-11-01},

journal = {Nature Communications},

volume = {10},

number = {1},

pages = {5372},

abstract = {Pyramidal neurons integrate synaptic inputs from basal and apical dendrites to generate stimulus-specific responses. It has been proposed that feed-forward inputs to basal dendrites drive a neuron's stimulus preference, while feedback inputs to apical dendrites sharpen selectivity. However, how a neuron's dendritic domains relate to its functional selectivity has not been demonstrated experimentally. We performed 2-photon dendritic micro-dissection on layer-2/3 pyramidal neurons in mouse primary visual cortex. We found that removing the apical dendritic tuft did not alter orientation-tuning. Furthermore, orientation-tuning curves were remarkably robust to the removal of basal dendrites: ablation of 2 basal dendrites was needed to cause a small shift in orientation preference, without significantly altering tuning width. Computational modeling corroborated our results and put limits on how orientation preferences among basal dendrites differ in order to reproduce the post-ablation data. In conclusion, neuronal orientation-tuning appears remarkably robust to loss of dendritic input.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{froudarakis_visual_2019,

title = {The Visual Cortex in Context},

author = {Emmanouil Froudarakis and Paul G. Fahey and Jacob Reimer and Stelios M. Smirnakis and Edward J. Tehovnik and Andreas S. Tolias},

doi = {10.1146/annurev-vision-091517-034407},

issn = {2374-4650},

year  = {2019},

date = {2019-09-01},

journal = {Annual Review of Vision Science},

volume = {5},

pages = {317–339},

abstract = {In this article, we review the anatomical inputs and outputs to the mouse primary visual cortex, area V1. Our survey of data from the Allen Institute Mouse Connectivity project indicates that mouse V1 is highly interconnected with both cortical and subcortical brain areas. This pattern of innervation allows for computations that depend on the state of the animal and on behavioral goals, which contrasts with simple feedforward, hierarchical models of visual processing. Thus, to have an accurate description of the function of V1 during mouse behavior, its involvement with the rest of the brain circuitry has to be considered. Finally, it remains an open question whether the primary visual cortex of higher mammals displays the same degree of sensorimotor integration in the early visual system.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{palagina_inhibitory_2019,

title = {Inhibitory Units: An Organizing Nidus for Feature-Selective SubNetworks in Area V1},

author = {Ganna Palagina and Jochen F. Meyer and Stelios M. Smirnakis},

doi = {10.1523/JNEUROSCI.2275-18.2019},

issn = {1529-2401},

year  = {2019},

date = {2019-06-01},

journal = {The Journal of Neuroscience: The Official Journal of the Society for Neuroscience},

volume = {39},

number = {25},

pages = {4931–4944},

abstract = {Neuronal circuits often display small-world network architecture characterized by neuronal cliques of dense local connectivity communicating with each other through a limited number of cells that participate in multiple cliques. The principles by which such cliques organize to encode information remain poorly understood. Similarly tuned pyramidal cells that preferentially target each other may form multicellular encoding units performing distinct computational tasks. The existence of such units can reflect upon both spontaneous and stimulus-driven population events.We applied two-photon calcium imaging to study spontaneous population bursts in layer 2/3 of area V1 in male C57BL/6 mice. To identify potential small-world cliques, we searched for pyramidal cells whose calcium events had a consistent temporal relationship with the events of local inhibitory interneurons. This was guided by the intuition that groups of neurons whose synchronous firing represents a temporally coherent computational unit should be inhibited together. Pyramidal members of these interneuron-centered clusters on average displayed stronger functional connectivity between each other than with nonmember pyramidal neurons. The structure of the clusters evolved during postnatal development: cluster size and overlap between clusters decreased with developmental maturation. Pyramidal neurons in a cluster showed higher than chance tuning function similarity between each other and with the linked interneuron. Thus, spontaneous population events in V1 are shaped by small-world subnetworks of pyramidal neurons that share functional properties and work as a coherent unit with a local interneuron. These interneuron-pyramidal cell partnerships may represent a fundamental neocortical unit of computation at the population level.SIGNIFICANCE STATEMENT Neuronal circuit in layer 2/3 of mouse area V1 possesses small-world network architecture, where cliques of densely interconnected neurons ("small worlds") communicate via restricted number of hub cells. We show that: (1) in mouse V1 individual small-world cliques preferably incorporate pyramidal neurons with similar visual feature tuning, and (2) ongoing population activity of such pyramidal neuron clique is temporally linked to the activity of the local interneuron sharing its feature tuning with the clique members. Functional grouping of similarly tuned interneurons and pyramidal cells into cliques may ensure that ensembles of functionally alike pyramidal cells recruited during perceptual tasks and spontaneous activity are also turned off together as a unit, with interneurons serving as organizers of linked pyramidal ensemble activity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{papanikolaou_organization_2019,

title = {Organization of area hV5/MT+ in subjects with homonymous visual field defects},

author = {Amalia Papanikolaou and Georgios A. Keliris and Dorina T. Papageorgiou and Ulrich Schiefer and Nikos K. Logothetis and Stelios M. Smirnakis},

doi = {10.1016/j.neuroimage.2018.03.062},

issn = {1095-9572},

year  = {2019},

date = {2019-04-01},

journal = {NeuroImage},

volume = {190},

pages = {254–268},

abstract = {Damage to the primary visual cortex (V1) leads to a visual field loss (scotoma) in the retinotopically corresponding part of the visual field. Nonetheless, a small amount of residual visual sensitivity persists within the blind field. This residual capacity has been linked to activity observed in the middle temporal area complex (V5/MT+). However, it remains unknown whether the organization of hV5/MT+ changes following early visual cortical lesions. We studied the organization of area hV5/MT+ of five patients with dense homonymous defects in a quadrant of the visual field as a result of partial V1+ or optic radiation lesions. To do so, we developed a new method, which models the boundaries of population receptive fields directly from the BOLD signal of each voxel in the visual cortex. We found responses in hV5/MT+ arising inside the scotoma for all patients and identified two possible sources of activation: 1) responses might originate from partially lesioned parts of area V1 corresponding to the scotoma, and 2) responses can also originate independent of area V1 input suggesting the existence of functional V1-bypassing pathways. Apparently, visually driven activity observed in hV5/MT+ is not sufficient to mediate conscious vision. More surprisingly, visually driven activity in corresponding regions of V1 and early extrastriate areas including hV5/MT+ did not guarantee visual perception in the group of patients with post-geniculate lesions that we examined. This suggests that the fine coordination of visual activity patterns across visual areas may be an important determinant of whether visual perception persists following visual cortical lesions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{keliris_estimating_2019,

title = {Estimating average single-neuron visual receptive field sizes by fMRI},

author = {Georgios A. Keliris and Qinglin Li and Amalia Papanikolaou and Nikos K. Logothetis and Stelios M. Smirnakis},

doi = {10.1073/pnas.1809612116},

issn = {1091-6490},

year  = {2019},

date = {2019-03-01},

journal = {Proceedings of the National Academy of Sciences of the United States of America},

volume = {116},

number = {13},

pages = {6425–6434},

abstract = {The noninvasive estimation of neuronal receptive field (RF) properties in vivo allows a detailed understanding of brain organization as well as its plasticity by longitudinal following of potential changes. Visual RFs measured invasively by electrophysiology in animal models have traditionally provided a great extent of our current knowledge about the visual brain and its disorders. Voxel-based estimates of population RF (pRF) by functional magnetic resonance imaging (fMRI) in humans revolutionized the field and have been used extensively in numerous studies. However, current methods cannot estimate single-neuron RF sizes as they reflect large populations of neurons with individual RF scatter. Here, we introduce an approach to estimate RF size using spatial frequency selectivity to checkerboard patterns. This method allowed us to obtain noninvasive, average single-neuron RF estimates over a large portion of human early visual cortex. These estimates were significantly smaller compared with prior pRF methods. Furthermore, fMRI and electrophysiology experiments in nonhuman primates demonstrated an exceptionally good match, validating the approach.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{lee_internal_2019,

title = {Internal Gain Modulations, But Not Changes in Stimulus Contrast, Preserve the Neural Code},

author = {Sangkyun Lee and Jiyoung Park and Stelios M. Smirnakis},

doi = {10.1523/JNEUROSCI.2012-18.2019},

issn = {1529-2401},

year  = {2019},

date = {2019-02-01},

journal = {The Journal of Neuroscience: The Official Journal of the Society for Neuroscience},

volume = {39},

number = {9},

pages = {1671–1687},

abstract = {Neurons in primary visual cortex are strongly modulated both by stimulus contrast and by fluctuations of internal inputs. An important question is whether the population code is preserved under these conditions. Changes in stimulus contrast are thought to leave the population code invariant, whereas the effect of internal gain modulations remains unknown. To address these questions we studied how the direction-of-motion of oriented gratings is encoded in layer 2/3 primary visual cortex of mouse (with C57BL/6 background, of either sex). We found that, because contrast gain responses across cells are heterogeneous, a change in contrast alters the information distribution profile across cells leading to a violation of contrast invariance. Remarkably, internal input fluctuations that cause commensurate firing rate modulations at the single-cell level result in more homogeneous gain responses, respecting population code invariance. These observations argue that the brain strives to maintain the stability of the neural code in the face of fluctuating internal inputs.SIGNIFICANCE STATEMENT Neuronal responses are modulated both by stimulus contrast and by the spontaneous fluctuation of internal inputs. It is not well understood how these different types of input impact the population code. Specifically, it is important to understand whether the neural code stays invariant in the face of significant internal input modulations. Here, we show that changes in stimulus contrast lead to different optimal population codes, whereas spontaneous internal input fluctuations leave the population code invariant. This is because spontaneous internal input fluctuations modulate the gain of neuronal responses more homogeneously across cells compared to changes in stimulus contrast.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{solomon_fatal_2018,

title = {Fatal Powassan Encephalitis (Deer Tick Virus, Lineage II) in a Patient With Fever and Orchitis Receiving Rituximab},

author = {Isaac H. Solomon and Kristyn M. Spera and Sophia L. Ryan and Jeffrey Helgager and Juliana Andrici and Sherif R. Zaki and Henrikas Vaitkevicius and Kristoffer E. Leon and Michael R. Wilson and Joseph L. DeRisi and Sophia Koo and Stelios M. Smirnakis and Umberto De Girolami},

doi = {10.1001/jamaneurol.2018.0132},

issn = {2168-6157},

year  = {2018},

date = {2018-06-01},

journal = {JAMA neurology},

volume = {75},

number = {6},

pages = {746–750},

abstract = {IMPORTANCE: Powassan virus is a rare but increasingly recognized cause of severe neurological disease. 

OBJECTIVE: To highlight the diagnostic challenges and neuropathological findings in a fatal case of Powassan encephalitis caused by deer tick virus (lineage II) in a patient with follicular lymphoma receiving rituximab, with nonspecific anti-GAD65 antibodies, who was initially seen with fever and orchiepididymitis. 

DESIGN, SETTING, AND PARTICIPANTS: Comparison of clinical, radiological, histological, and laboratory findings, including immunohistochemistry, real-time polymerase chain reaction, antibody detection, and unbiased sequencing assays, in a single case report (first seen in December 2016) at an academic medical center. 

EXPOSURE: Infection with Powassan virus. 

MAIN OUTCOMES AND MEASURES: Results of individual assays compared retrospectively. 

RESULTS: In a 63-year-old man with fatal Powassan encephalitis, serum and cerebrospinal fluid IgM antibodies were not detected via standard methods, likely because of rituximab exposure. Neuropathological findings were extensive, including diffuse leptomeningeal and parenchymal lymphohistiocytic infiltration, microglial proliferation, marked neuronal loss, and white matter microinfarctions most severely involving the cerebellum, thalamus, and basal ganglia. Diagnosis was made after death by 3 independent methods, including demonstration of Powassan virus antigen in brain biopsy and autopsy tissue, detection of viral RNA in serum and cerebrospinal fluid by targeted real-time polymerase chain reaction, and detection of viral RNA in cerebrospinal fluid by unbiased sequencing. Extensive testing for other etiologies yielded negative results, including mumps virus owing to prodromal orchiepididymitis. Low-titer anti-GAD65 antibodies identified in serum, suggestive of limbic encephalitis, were not detected in cerebrospinal fluid. 

CONCLUSIONS AND RELEVANCE: Owing to the rarity of Powassan encephalitis, a high degree of suspicion is required to make the diagnosis, particularly in an immunocompromised patient, in whom antibody-based assays may be falsely negative. Unbiased sequencing assays have the potential to detect uncommon infectious agents and may prove useful in similar scenarios.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{meyer_asynchronous_2018,

title = {Asynchronous suppression of visual cortex during absence seizures in stargazer mice},

author = {Jochen F. Meyer and Atul Maheshwari and Jeffrey Noebels and Stelios M. Smirnakis},

doi = {10.1038/s41467-018-04349-8},

issn = {2041-1723},

year  = {2018},

date = {2018-05-01},

journal = {Nature Communications},

volume = {9},

number = {1},

pages = {1938},

abstract = {Absence epilepsy is a common childhood disorder featuring frequent cortical spike-wave seizures with a loss of awareness and behavior. Using the calcium indicator GCaMP6 with in vivo 2-photon cellular microscopy and simultaneous electrocorticography, we examined the collective activity profiles of individual neurons and surrounding neuropil across all layers in V1 during spike-wave seizure activity over prolonged periods in stargazer mice. We show that most (textasciitilde80%) neurons in all cortical layers reduce their activity during seizures, whereas a smaller pool activates or remains neutral. Unexpectedly, ictal participation of identified single-unit activity is not fixed, but fluctuates on a flexible time scale from seizure to seizure. Pairwise correlation analysis of calcium activity reveals a surprising lack of synchrony among neurons and neuropil patches in all layers during seizures. Our results demonstrate asynchronous suppression of visual cortex during absence seizures, with potential implications for understanding cortical network function during EEG states of reduced awareness.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{ash_increased_2018,

title = {Increased Axonal Bouton Stability during Learning in the Mouse Model of MECP2 Duplication Syndrome},

author = {Ryan T. Ash and Paul G. Fahey and Jiyoung Park and Huda Y. Zoghbi and Stelios M. Smirnakis},

doi = {10.1523/ENEURO.0056-17.2018},

issn = {2373-2822},

year  = {2018},

date = {2018-01-01},

journal = {eNeuro},

volume = {5},

number = {3},

pages = {ENEURO.0056–17.2018},

abstract = {MECP2 duplication syndrome is an X-linked form of syndromic autism caused by genomic duplication of the region encoding methyl-CpG-binding protein 2 (MECP2). Mice overexpressing MECP2 demonstrate social impairment, behavioral inflexibility, and altered patterns of learning and memory. Previous work showed abnormally increased stability of dendritic spines formed during motor training in the apical tuft of primary motor cortex (area M1) corticospinal neurons in the MECP2 duplication mouse model. In the current study, we measure the structural plasticity of axonal boutons in layer 5 pyramidal neuron projections to layer 1 of area M1 during motor training. In wild-type littermate control mice, we find that during rotarod training the bouton formation rate changes minimally, if at all, while the bouton elimination rate more than doubles. Notably, the observed upregulation in bouton elimination with training is absent in MECP2 duplication mice. This result provides further evidence of an imbalance between structural stability and plasticity in this form of syndromic autism. Furthermore, the observation that axonal bouton elimination more than doubles with motor training in wild-type animals contrasts with the increase of dendritic spine consolidation observed in corticospinal neurons at the same layer. This dissociation suggests that different area M1 microcircuits may manifest different patterns of structural synaptic plasticity during motor training.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{meyer_effect_2018,

title = {The Effect of Single Pyramidal Neuron Firing Within Layer 2/3 and Layer 4 in Mouse V1},

author = {Jochen F. Meyer and Peyman Golshani and Stelios M. Smirnakis},

doi = {10.3389/fncir.2018.00029},

issn = {1662-5110},

year  = {2018},

date = {2018-01-01},

journal = {Frontiers in Neural Circuits},

volume = {12},

pages = {29},

abstract = {The influence of cortical cell spiking activity on nearby cells has been studied extensively in vitro. Less is known, however, about the impact of single cell firing on local cortical networks in vivo. In a pioneering study, Kwan and Dan (Kwan and Dan, 2012) reported that in mouse layer 2/3 (L2/3), under anesthesia, stimulating a single pyramidal cell recruits textasciitilde2.1% of neighboring units. Here we employ two-photon calcium imaging in layer 2/3 of mouse V1, in conjunction with single-cell patch clamp stimulation in layer 2/3 or layer 4, to probe, in both the awake and lightly anesthetized states, how (i) activating single L2/3 pyramidal neurons recruits neighboring units within L2/3 and from layer 4 (L4) to L2/3, and whether (ii) activating single pyramidal neurons changes population activity in local circuit. To do this, it was essential to develop an algorithm capable of quantifying how sensitive the calcium signal is at detecting effectively recruited units ("followers"). This algorithm allowed us to estimate the chance of detecting a follower as a function of the probability that an epoch of stimulation elicits one extra action potential (AP) in the follower cell. Using this approach, we found only a small fraction (<0.75%) of L2/3 cells to be significantly activated within a radius of textasciitilde200 μm from a stimulated neighboring L2/3 pyramidal cell. This fraction did not change significantly in the awake vs. the lightly anesthetized state, nor when stimulating L2/3 vs. underlying L4 pyramidal neurons. These numbers are in general agreement with, though lower than, the percentage of neighboring cells (2.1% pyramidal cells and interneurons combined) reported by Kwan and Dan to be activated upon stimulating single L2/3 pyramidal neurons under anesthesia (Kwan and Dan, 2012). Interestingly, despite the small number of individual units found to be reliably driven, we did observe a modest but significant elevation in aggregate population responses compared to sham stimulation. This underscores the distributed impact that single cell stimulation has on neighboring microcircuit responses, revealing only a small minority of relatively strongly connected partners. 

ONE SENTENCE SUMMARY: Patch-clamp stimulation in conjunction with 2-photon imaging shows that activating single layer-2/3 or layer-4 pyramidal neurons produces few (<1% of local units) reliable single-cell followers in L2/3 of mouse area V1, either under light anesthesia or in quiet wakefulness: instead, single cell stimulation was found to elevate aggregate population activity in a weak but highly distributed fashion.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{troullinou_dictionary_2017,

title = {Dictionary Learning for Spontaneous Neural Activity Modeling},

author = {Eirini Troullinou and Grigorios Tsagkatakis and Ganna Palagina and Maria Papadopouli and Stelios M. Smirnakis and Panagiotis Tsakalides},

doi = {10.23919/EUSIPCO.2017.8081475},

issn = {2219-5491},

year  = {2017},

date = {2017-01-01},

journal = {Proceedings of the ... European Signal Processing Conference (EUSIPCO). EUSIPCO (Conference)},

volume = {2017},

pages = {1579–1583},

abstract = {Modeling the activity of an ensemble of neurons can provide critical insights into the workings of the brain. In this work we examine if learning based signal modeling can contribute to a high quality modeling of neuronal signal data. To that end, we employ the sparse coding and dictionary learning schemes for capturing the behavior of neuronal responses into a small number of representative prototypical signals. Performance is measured by the reconstruction quality of clean and noisy test signals, which serves as an indicator of the generalization and discrimination capabilities of the learned dictionaries. To validate the merits of the proposed approach, a novel dataset of the actual recordings from 183 neurons from the primary visual cortex of a mouse in early postnatal development was developed and investigated. The results demonstrate that high quality modeling of testing data can be achieved from a small number of training examples and that the learned dictionaries exhibit significant specificity when introducing noise.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{smyrnakis_radar_2017,

title = {RADAR: A novel fast-screening method for reading difficulties with special focus on dyslexia},

author = {Ioannis Smyrnakis and Vassilios Andreadakis and Vassilios Selimis and Michail Kalaitzakis and Theodora Bachourou and Georgios Kaloutsakis and George D. Kymionis and Stelios M. Smirnakis and Ioannis M. Aslanides},

doi = {10.1371/journal.pone.0182597},

issn = {1932-6203},

year  = {2017},

date = {2017-01-01},

journal = {PloS One},

volume = {12},

number = {8},

pages = {e0182597},

abstract = {Dyslexia is a developmental learning disorder of single word reading accuracy and/or fluency, with compelling research directed towards understanding the contributions of the visual system. While dyslexia is not an oculomotor disease, readers with dyslexia have shown different eye movements than typically developing students during text reading. Readers with dyslexia exhibit longer and more frequent fixations, shorter saccade lengths, more backward refixations than typical readers. Furthermore, readers with dyslexia are known to have difficulty in reading long words, lower skipping rate of short words, and high gaze duration on many words. It is an open question whether it is possible to harness these distinctive oculomotor scanning patterns observed during reading in order to develop a screening tool that can reliably identify struggling readers, who may be candidates for dyslexia. Here, we introduce a novel, fast, objective, non-invasive method, named Rapid Assessment of Difficulties and Abnormalities in Reading (RADAR) that screens for features associated with the aberrant visual scanning of reading text seen in dyslexia. Eye tracking parameter measurements that are stable under retest and have high discriminative power, as indicated by their ROC (receiver operating characteristic) curves, were obtained during silent text reading. These parameters were combined to derive a total reading score (TRS) that can reliably separate readers with dyslexia from typical readers. We tested TRS in a group of school-age children ranging from 8.5 to 12.5 years of age. TRS achieved 94.2% correct classification of children tested. Specifically, 35 out of 37 control (specificity 94.6%) and 30 out of 32 readers with dyslexia (sensitivity 93.8%) were classified correctly using RADAR, under a circular validation condition (see section Results/Total Reading Score) where the individual evaluated was not included in the test construction group. In conclusion, RADAR is a novel, automated, fast and reliable way to identify children at high risk of dyslexia that is amenable to large-scale screening. Moreover, analysis of eye movement parameters obtained with RADAR during reading will likely be useful for implementing individualized treatment strategies and for monitoring objectively the success of chosen interventions. We envision that it will be possible to use RADAR as a sensitive, objective, and quantitative first pass screen to identify individuals with reading disorders that manifest with abnormal oculomotor reading strategies, like dyslexia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{lee_visually_2017,

title = {Visually Driven Neuropil Activity and Information Encoding in Mouse Primary Visual Cortex},

author = {Sangkyun Lee and Jochen F. Meyer and Jiyoung Park and Stelios M. Smirnakis},

doi = {10.3389/fncir.2017.00050},

issn = {1662-5110},

year  = {2017},

date = {2017-01-01},

journal = {Frontiers in Neural Circuits},

volume = {11},

pages = {50},

abstract = {Cortical neuropil modulations recorded by calcium imaging reflect the activity of large aggregates of axo-dendritic processes and synaptic compartments from a large number of neurons. The organization of this activity impacts neuronal firing but is not well understood. Here we used in vivo 2-photon imaging with Oregon Green Bapta (OGB) and GCaMP6s to study neuropil visual responses to moving gratings in layer 2/3 of mouse area V1. We found neuropil responses to be strongly modulated and more reliable than neighboring somatic activity. Furthermore, stimulus independent modulations in neuropil activity, i.e., noise correlations, were highly coherent across the cortical surface, up to distances of at least 200 μm. Pairwise neuropil-to-neuropil-patch noise correlation strength was much higher than cell-to-cell noise correlation strength and depended strongly on brain state, decreasing in quiet wakefulness relative to light anesthesia. The profile of neuropil noise correlation strength decreased gently with distance, dropping by textasciitilde11% at a distance of 200 μm. This was comparatively slower than the profile of cell-to-cell noise correlations, which dropped by textasciitilde23% at 200 μm. Interestingly, in spite of the "salt & pepper" organization of orientation and direction encoding across mouse V1 neurons, populations of neuropil patches, even of moderately large size (radius textasciitilde100 μm), showed high accuracy for discriminating perpendicularly moving gratings. This was commensurate to the accuracy of corresponding cell populations. The dynamic, stimulus dependent, nature of neuropil activity further underscores the need to carefully separate neuropil from cell soma activity in contemporary imaging studies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{palagina_complex_2017,

title = {Complex Visual Motion Representation in Mouse Area V1},

author = {Ganna Palagina and Jochen F. Meyer and Stelios M. Smirnakis},

doi = {10.1523/JNEUROSCI.0997-16.2017},

issn = {1529-2401},

year  = {2017},

date = {2017-01-01},

journal = {The Journal of Neuroscience: The Official Journal of the Society for Neuroscience},

volume = {37},

number = {1},

pages = {164–183},

abstract = {Rodent visual cortex has a hierarchical architecture similar to that of higher mammals (Coogan and Burkhalter, 1993; Marshel et al., 2011; Wang et al., 2012). Although notable differences exist between the species in terms or receptive field sizes and orientation map organization (Dräger, 1975; Gattass et al., 1987; Van den Bergh et al., 2010), mouse V1 is thought to respond to local orientation and visual motion elements rather than to global patterns of motion, similar to V1 in higher mammals (Niell and Stryker, 2008; Bonin et al., 2011). However, recent results are inconclusive: some argue mouse V1 is analogous to monkey V1 (Juavinett and Callaway, 2015); others argue that it displays complex motion responses (Muir et al., 2015). We used type I plaids formed by the additive superposition of moving gratings (Adelson and Movshon, 1982; Movshon et al., 1985; Albright and Stoner, 1995) to investigate this question. We show that mouse V1 contains a considerably smaller fraction of component-motion-selective neurons (∼17% vs ∼84%), and a larger fraction of pattern-motion-selective neurons (∼10% vs <1.3%) compared with primate/cat V1. The direction of optokinetic nystagmus correlates with visual perception in higher mammals (Fox et al., 1975; Logothetis and Schall, 1990; Wei and Sun, 1998; Watanabe, 1999; Naber et al., 2011). Measurement of optokinetic responses to plaid stimuli revealed that mice demonstrate bistable perception, sometimes tracking individual stimulus components and others the global pattern of motion. Moreover, bistable optokinetic responses cannot be entirely attributed to subcortical circuitry as V1 lesions alter the fraction of responses occurring along pattern versus component motion. These observations suggest that area V1 input contributes to complex motion perception in the mouse. 

SIGNIFICANCE STATEMENT: Area V1 in the mouse is hierarchically similar but not necessarily identical to area V1 in cats and primates. Here we demonstrate that area V1 neurons process complex motion plaid stimuli differently in mice versus in cats or primates. Specifically, a smaller proportion of mouse V1 cells are sensitive to component motion, and a larger proportion to pattern motion than are found in area V1 of cats/primates. Furthermore, we demonstrate for the first time that mice exhibit bistable visual perception of plaid stimuli, and that this depends, at least in part, on area V1 input. Finally, we suggest that the relative proportion of component-motion-selective responses to pattern-motion-selective responses in mouse V1 may bias visual perception, as evidenced by changes in the direction of elicited optokinetic responses.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{smirnakis_probing_2016,

title = {Probing Human Visual Deficits with Functional Magnetic Resonance Imaging},

author = {Stelios M. Smirnakis},

doi = {10.1146/annurev-vision-111815-114535},

issn = {2374-4650},

year  = {2016},

date = {2016-10-01},

journal = {Annual Review of Vision Science},

volume = {2},

pages = {171–195},

abstract = {Much remains to be understood about visual system malfunction following injury. The resulting deficits range from dense, visual field scotomas to mild dysfunction of visual perception. Despite the predictive value of anatomical localization studies, much patient-to-patient variability remains regarding (a) perceptual abilities following injury and (b) the capacity of individual patients for visual rehabilitation. Visual field perimetry is used to characterize the visual field deficits that result from visual system injury. However, standard perimetry mapping does not always precisely correspond to underlying anatomical or functional deficits. Functional magnetic resonance imaging can be used to probe the function of surviving visual circuits, allowing us to classify better how the pattern of injury relates to residual visual perception. Identifying pathways that are potentially modifiable by training may guide the development of improved strategies for visual rehabilitation. This review discusses primary visual cortex lesions, which cause dense contralateral scotomas.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{lu_loss_2016,

title = {Loss and Gain of MeCP2 Cause Similar Hippocampal Circuit Dysfunction that Is Rescued by Deep Brain Stimulation in a Rett Syndrome Mouse Model},

author = {Hui Lu and Ryan T. Ash and Lingjie He and Sara E. Kee and Wei Wang and Dinghui Yu and Shuang Hao and Xiangling Meng and Kerstin Ure and Aya Ito-Ishida and Bin Tang and Yaling Sun and Daoyun Ji and Jianrong Tang and Benjamin R. Arenkiel and Stelios M. Smirnakis and Huda Y. Zoghbi},

doi = {10.1016/j.neuron.2016.07.018},

issn = {1097-4199},

year  = {2016},

date = {2016-08-01},

journal = {Neuron},

volume = {91},

number = {4},

pages = {739–747},

abstract = {Loss- and gain-of-function mutations in methyl-CpG-binding protein 2 (MECP2) underlie two distinct neurological syndromes with strikingly similar features, but the synaptic and circuit-level changes mediating these shared features are undefined. Here we report three novel signs of neural circuit dysfunction in three mouse models of MECP2 disorders (constitutive Mecp2 null, mosaic Mecp2(+/-), and MECP2 duplication): abnormally elevated synchrony in the firing activity of hippocampal CA1 pyramidal neurons, an impaired homeostatic response to perturbations of excitatory-inhibitory balance, and decreased excitatory synaptic response in inhibitory neurons. Conditional mutagenesis studies revealed that MeCP2 dysfunction in excitatory neurons mediated elevated synchrony at baseline, while MeCP2 dysfunction in inhibitory neurons increased susceptibility to hypersynchronization in response to perturbations. Chronic forniceal deep brain stimulation (DBS), recently shown to rescue hippocampus-dependent learning and memory in Mecp2(+/-) (Rett) mice, also rescued all three features of hippocampal circuit dysfunction in these mice.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{papanikolaou_nonlinear_2015,

title = {Nonlinear population receptive field changes in human area V5/MT+ of healthy subjects with simulated visual field scotomas},

author = {Amalia Papanikolaou and Georgios A. Keliris and Sangkyun Lee and Nikos K. Logothetis and Stelios M. Smirnakis},

doi = {10.1016/j.neuroimage.2015.06.085},

issn = {1095-9572},

year  = {2015},

date = {2015-10-01},

journal = {NeuroImage},

volume = {120},

pages = {176–190},

abstract = {There is extensive controversy over whether the adult visual cortex is able to reorganize following visual field loss (scotoma) as a result of retinal or cortical lesions. Functional magnetic resonance imaging (fMRI) methods provide a useful tool to study the aggregate receptive field properties and assess the capacity of the human visual cortex to reorganize following injury. However, these methods are prone to biases near the boundaries of the scotoma. Retinotopic changes resembling reorganization have been observed in the early visual cortex of normal subjects when the visual stimulus is masked to simulate retinal or cortical scotomas. It is not known how the receptive fields of higher visual areas, like hV5/MT+, are affected by partial stimulus deprivation. We measured population receptive field (pRF) responses in human area V5/MT+ of 5 healthy participants under full stimulation and compared them with responses obtained from the same area while masking the left superior quadrant of the visual field ("artificial scotoma" or AS). We found that pRF estimations in area hV5/MT+ are nonlinearly affected by the AS. Specifically, pRF centers shift towards the AS, while the pRF amplitude increases and the pRF size decreases near the AS border. The observed pRF changes do not reflect reorganization but reveal important properties of normal visual processing under different test-stimulus conditions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{bershad_multidisciplinary_2015,

title = {Multidisciplinary protocol for rapid head computed tomography turnaround time in acute stroke patients},

author = {Eric M. Bershad and Chethan P. Venkatasubba Rao and Kevin Dat Vuong and Janine Mazabob and Gerard Brown and Suzan L. Styron and Thuy Nguyen and Elizabeth Delledera and Stelios M. Smirnakis and Christos Lazaridis and Alexandros L. Georgiadis and Marilyn Mokracek and Timothy J. Seipel and John J. Nisbet and Visveshwar Baskaran and Andrew H. Chang and Patrick Stewart and Jose I. Suarez},

doi = {10.1016/j.jstrokecerebrovasdis.2015.01.029},

issn = {1532-8511},

year  = {2015},

date = {2015-06-01},

journal = {Journal of Stroke and Cerebrovascular Diseases: The Official Journal of National Stroke Association},

volume = {24},

number = {6},

pages = {1256–1261},

abstract = {BACKGROUND: The door-to-computed tomography (CT) head reporting time is an essential step to determining eligibility for thrombolysis in acute stroke patients, but the specific components of the process have not been reported in detail. 

METHODS: We performed a retrospective cross-sectional analysis of the prospectively collected Get-With-The-Guidelines database in our comprehensive stroke center to evaluate the effect of a structured multidisciplinary protocol on head CT times in acute stroke patients under consideration for thrombolysis. RESULTS: The median CT turnaround time in the first 6-month period was 27 (interquartile range [IQR], 27) and decreased in all subsequent periods after implementation of a formal protocol to 18 (IQR, 12; range, 17-20 minutes; P < .0001 for all pairwise comparisons). The median CT turnaround time was 18 (IQR, 12) versus 20 (IQR, 14) minutes for patients with admission diagnosis of stroke (n = 1123) versus nonstroke (n = 685; P < .0001), respectively. 

CONCLUSIONS: A structured multidisciplinary protocol for obtaining acute stroke protocol head CT scan was associated with reduced CT turnaround time over the study period. Prospective studies should be done to determine if implementation in other stroke centers confirms the effectiveness of our protocol.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{olson_global_2015,

title = {Global monitoring in the neurocritical care unit},

author = {DaiWai M. Olson and W. Andrew Kofke and Kristine O'Phelan and Puneet K. Gupta and Stephen A. Figueroa and Stelios M. Smirnakis and Peter D. Leroux and Jose I. Suarez and Second Neurocritical Care Research Conference Investigators},

doi = {10.1007/s12028-015-0132-y},

issn = {1556-0961},

year  = {2015},

date = {2015-06-01},

journal = {Neurocritical Care},

volume = {22},

number = {3},

pages = {337–347},

abstract = {Effective methods of monitoring the status of patients with neurological injuries began with non-invasive observations and evolved during the past several decades to include more invasive monitoring tools and physiologic measures. The monitoring paradigm continues to evolve, this time back toward the use of less invasive tools. In parallel, the science of monitoring began with the global assessment of the patient's neurological condition, evolved to focus on regional monitoring techniques, and with the advent of enhanced computing capabilities is now moving back to focus on global monitoring. The purpose of this session of the Second Neurocritical Care Research Conference was to collaboratively develop a comprehensive understanding of the state of the science for global brain monitoring and to identify research priorities for intracranial pressure monitoring, neuroimaging, and neuro-electrophysiology monitoring.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{lee_topographical_2015,

title = {Topographical estimation of visual population receptive fields by FMRI},

author = {Sangkyun Lee and Amalia Papanikolaou and Georgios A. Keliris and Stelios M. Smirnakis},

doi = {10.3791/51811},

issn = {1940-087X},

year  = {2015},

date = {2015-02-01},

journal = {Journal of Visualized Experiments: JoVE},

number = {96},

pages = {51811},

abstract = {Visual cortex is retinotopically organized so that neighboring populations of cells map to neighboring parts of the visual field. Functional magnetic resonance imaging allows us to estimate voxel-based population receptive fields (pRF), i.e., the part of the visual field that activates the cells within each voxel. Prior, direct, pRF estimation methods(1) suffer from certain limitations: 1) the pRF model is chosen a-priori and may not fully capture the actual pRF shape, and 2) pRF centers are prone to mislocalization near the border of the stimulus space. Here a new topographical pRF estimation method(2) is proposed that largely circumvents these limitations. A linear model is used to predict the Blood Oxygen Level-Dependent (BOLD) signal by convolving the linear response of the pRF to the visual stimulus with the canonical hemodynamic response function. PRF topography is represented as a weight vector whose components represent the strength of the aggregate response of voxel neurons to stimuli presented at different visual field locations. The resulting linear equations can be solved for the pRF weight vector using ridge regression(3), yielding the pRF topography. A pRF model that is matched to the estimated topography can then be chosen post-hoc, thereby improving the estimates of pRF parameters such as pRF-center location, pRF orientation, size, etc. Having the pRF topography available also allows the visual verification of pRF parameter estimates allowing the extraction of various pRF properties without having to make a-priori assumptions about the pRF structure. This approach promises to be particularly useful for investigating the pRF organization of patients with disorders of the visual system.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{um_dynamic_2014,

title = {Dynamic control of excitatory synapse development by a Rac1 GEF/GAP regulatory complex},

author = {Kyongmi Um and Sanyong Niu and Joseph G. Duman and Jinxuan X. Cheng and Yen-Kuei Tu and Brandon Schwechter and Feng Liu and Laura Hiles and Anjana S. Narayanan and Ryan T. Ash and Shalaka Mulherkar and Kannan Alpadi and Stelios M. Smirnakis and Kimberley F. Tolias},

doi = {10.1016/j.devcel.2014.05.011},

issn = {1878-1551},

year  = {2014},

date = {2014-06-01},

journal = {Developmental Cell},

volume = {29},

number = {6},

pages = {701–715},

abstract = {The small GTPase Rac1 orchestrates actin-dependent remodeling essential for numerous cellular processes including synapse development. While precise spatiotemporal regulation of Rac1 is necessary for its function, little is known about the mechanisms that enable Rac1 activators (GEFs) and inhibitors (GAPs) to act in concert to regulate Rac1 signaling. Here, we identify a regulatory complex composed of a Rac-GEF (Tiam1) and a Rac-GAP (Bcr) that cooperate to control excitatory synapse development. Disruption of Bcr function within this complex increases Rac1 activity and dendritic spine remodeling, resulting in excessive synaptic growth that is rescued by Tiam1 inhibition. Notably, EphB receptors utilize the Tiam1-Bcr complex to control synaptogenesis. Following EphB activation, Tiam1 induces Rac1-dependent spine formation, whereas Bcr prevents Rac1-mediated receptor internalization, promoting spine growth over retraction. The finding that a Rac-specific GEF/GAP complex is required to maintain optimal levels of Rac1 signaling provides an important insight into the regulation of small GTPases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{ecker_state_2014,

title = {State dependence of noise correlations in macaque primary visual cortex},

author = {Alexander S. Ecker and Philipp Berens and R. James Cotton and Manivannan Subramaniyan and George H. Denfield and Cathryn R. Cadwell and Stelios M. Smirnakis and Matthias Bethge and Andreas S. Tolias},

doi = {10.1016/j.neuron.2014.02.006},

issn = {1097-4199},

year  = {2014},

date = {2014-04-01},

urldate = {2014-04-01},

journal = {Neuron},

volume = {82},

number = {1},

pages = {235–248},

abstract = {Shared, trial-to-trial variability in neuronal populations has a strong impact on the accuracy of information processing in the brain. Estimates of the level of such noise correlations are diverse, ranging from 0.01 to 0.4, with little consensus on which factors account for these differences. Here we addressed one important factor that varied across studies, asking how anesthesia affects the population activity structure in macaque primary visual cortex. We found that under opioid anesthesia, activity was dominated by strong coordinated fluctuations on a timescale of 1-2 Hz, which were mostly absent in awake, fixating monkeys. Accounting for these global fluctuations markedly reduced correlations under anesthesia, matching those observed during wakefulness and reconciling earlier studies conducted under anesthesia and in awake animals. Our results show that internal signals, such as brain state transitions under anesthesia, can induce noise correlations but can also be estimated and accounted for based on neuronal population activity.},

keywords = {key},

pubstate = {published},

tppubtype = {article}

}