Later Midline Shift Is Associated with Better Outcomes after Large Middle Cerebral Artery Stroke.

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.

Association of large core middle cerebral artery stroke and hemorrhagic transformation with hospitalization outcomes.

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.

Brain orchestra under spontaneous conditions: Identifying communication modules from the functional architecture of area V1.

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 ~10% 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.

Tug-of-Peace: Visual Rivalry and Atypical Visual Motion Processing in MECP2 Duplication Syndrome of Autism.

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.

Dural arteriovenous fistula of the craniocervical junction.

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.

Glioma genetic profiles associated with electrophysiologic hyperexcitability.

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.

Modeling apical and basal tree contribution to orientation selectivity in a mouse primary visual cortex layer 2/3 pyramidal cell.

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.

Dynamic trajectories of life-threatening mass effect in patients with large middle cerebral artery stroke.

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.

Follow-up ASPECTS improves prediction of potentially lethal malignant edema in patients with large middle cerebral artery stroke.

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.

Glioma genetic profiles associated with electrophysiologic hyperexcitability.

Distinct genetic alterations determine glioma aggressiveness, however the diversity of somatic mutations contributing to peritumoral hyperexcitability and seizures is uncertain. In a large cohort of patients with sequenced gliomas (n=1716), we used discriminant analysis models to identify somatic mutation variants associated with electrographic hyperexcitability in a subset with continuous EEG recording (n=206). Overall tumor mutational burdens were similar between patients with and without hyperexcitability. A cross-validated model trained exclusively on somatic mutations classified the presence or absence of hyperexcitability with an overall accuracy of 70.9%, and improved estimates of hyperexcitability and anti-seizure medication failure in multivariate analysis incorporating traditional demographic factors and tumor molecular classifications. Somatic mutation variants of interest were also over-represented in patients with hyperexcitability compared to internal and external reference cohorts. These findings implicate diverse mutations in cancer genes associated with the development of hyperexcitability and response to treatment.

Quantitative pupillometry and radiographic markers of intracranial midline shift: A pilot study.

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 (ß = 0.11, SE 0.04, P = 0.01), and PGS and Diff NPi in the ischemic stroke cohort (ß = 0.16, SE 0.09, P = 0.07). Conclusion: We found the relationship between midline shift and asymmetric pupil reactivity may differ between IPH and ischemic stroke. Our study may serve as necessary preliminary data to guide further prospective investigation into how clinical manifestations of radiographic midline shift differ by diagnosis and proximity to the midbrain.

Increased Reliability of Visually-Evoked Activity in Area V1 of the MECP2-Duplication Mouse Model of Autism.

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.

Dexmedetomidine and Other Analgosedatives Alter Pupil Characteristics in Critically Ill Patients.

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 (ß = 0.18 per 1 unit increase in rank-normalized NPi ± 0.04; p < 0.001) and smaller pupil size (ß = -0.25 ± 0.05; p < 0.001). Exploratory analyses revealed that acetaminophen was associated with higher average NPi (ß = 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.

Target receptor identification and subsequent treatment of resected brain tumors with encapsulated and engineered allogeneic stem cells.

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.

Natural Language Processing of Radiology Reports to Detect Complications of Ischemic Stroke.

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.

Visual Motion Coherence Responses in Human Visual Cortex.

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.

Macaque Area V2/V3 Reorganization Following Homonymous Retinal Lesions.

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.

Anisocoria and Poor Pupil Reactivity by Quantitative Pupillometry in Patients With Intracranial Pathology.

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 (ß = 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.

Motor training improves coordination and anxiety in symptomatic Mecp2-null mice despite impaired functional connectivity within the motor circuit.

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by loss of function of the X-linked methyl-CpG­binding 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.

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.

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.