A Hospice Transitions Program for Patients in the Emergency Department.

Importance: Patients often visit the emergency department (ED) near the end of life. Their common disposition is inpatient hospital admission, which can result in a delayed transition to hospice care and, ultimately, an inpatient hospital death that may be misaligned with their goals of care. Objective: To assess the association of hospice use with a novel multidisciplinary hospice program to rapidly identify and enroll eligible patients presenting to the ED near end of life. Design, Setting, and Participants: This pre-post quality improvement study of a novel, multifaceted care transitions program involving a formalized pathway with email alerts, clinician training, hospice vendor expansion, metric creation, and data tracking was conducted at a large, urban tertiary care academic medical center affiliated with a comprehensive cancer center among adult patients presenting to the ED near the end of life. The control period before program launch was from September 1, 2018, to January 31, 2020, and the intervention period after program launch was from August 1, 2021, to December 31, 2022. Main Outcome and Measures: The primary outcome was a transition to hospice without hospital admission and/or hospice admission within 96 hours of the ED visit. Secondary outcomes included length of stay and in-hospital mortality. Results: This study included 270 patients (median age, 74.0 years [IQR, 62.0-85.0 years]; 133 of 270 women [49.3%]) in the control period, and 388 patients (median age, 73.0 years [IQR, 60.0-84.0 years]; 208 of 388 women [53.6%]) in the intervention period, identified as eligible for hospice transition within 96 hours of ED arrival. In the control period, 61 patients (22.6%) achieved the primary outcome compared with 210 patients (54.1%) in the intervention period (P < .001). The intervention was associated with the primary outcome after adjustment for age, race and ethnicity, primary payer, Charlson Comorbidity Index, and presence of a Medical Order for Life-Sustaining Treatment (MOLST) (adjusted odds ratio, 5.02; 95% CI, 3.17-7.94). In addition, the presence of a MOLST was independently associated with hospice transition across all groups (adjusted odds ratio, 1.88; 95% CI, 1.18-2.99). There was no significant difference between the control and intervention periods in inpatient length of stay (median, 2.0 days [IQR, 1.1-3.0 days] vs 1.9 days [IQR, 1.1-3.0 days]; P = .84), but in-hospital mortality was lower in the intervention period (48.5% [188 of 388] vs 64.4% [174 of 270]; P < .001). Conclusions and Relevance: In this quality improvement study, a multidisciplinary program to facilitate ED patient transitions was associated with hospice use. Further investigation is needed to examine the generalizability and sustainability of the program.

Trial of Early Minimally Invasive Removal of Intracerebral Hemorrhage.

BACKGROUND: Trials of surgical evacuation of supratentorial intracerebral hemorrhages have generally shown no functional benefit. Whether early minimally invasive surgical removal would result in better outcomes than medical management is not known. METHODS: In this multicenter, randomized trial involving patients with an acute intracerebral hemorrhage, we assessed surgical removal of the hematoma as compared with medical management. Patients who had a lobar or anterior basal ganglia hemorrhage with a hematoma volume of 30 to 80 ml were assigned, in a 1:1 ratio, within 24 hours after the time that they were last known to be well, to minimally invasive surgical removal of the hematoma plus guideline-based medical management (surgery group) or to guideline-based medical management alone (control group). The primary efficacy end point was the mean score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes, according to patients' assessment) at 180 days, with a prespecified threshold for posterior probability of superiority of 0.975 or higher. The trial included rules for adaptation of enrollment criteria on the basis of hemorrhage location. A primary safety end point was death within 30 days after enrollment. RESULTS: A total of 300 patients were enrolled, of whom 30.7% had anterior basal ganglia hemorrhages and 69.3% had lobar hemorrhages. After 175 patients had been enrolled, an adaptation rule was triggered, and only persons with lobar hemorrhages were enrolled. The mean score on the utility-weighted modified Rankin scale at 180 days was 0.458 in the surgery group and 0.374 in the control group (difference, 0.084; 95% Bayesian credible interval, 0.005 to 0.163; posterior probability of superiority of surgery, 0.981). The mean between-group difference was 0.127 (95% Bayesian credible interval, 0.035 to 0.219) among patients with lobar hemorrhages and -0.013 (95% Bayesian credible interval, -0.147 to 0.116) among those with anterior basal ganglia hemorrhages. The percentage of patients who had died by 30 days was 9.3% in the surgery group and 18.0% in the control group. Five patients (3.3%) in the surgery group had postoperative rebleeding and neurologic deterioration. CONCLUSIONS: Among patients in whom surgery could be performed within 24 hours after an acute intracerebral hemorrhage, minimally invasive hematoma evacuation resulted in better functional outcomes at 180 days than those with guideline-based medical management. The effect of surgery appeared to be attributable to intervention for lobar hemorrhages. (Funded by Nico; ENRICH ClinicalTrials.gov number, NCT02880878.).

Hypoxanthine is a pharmacodynamic marker of ischemic brain edema modified by glibenclamide.

Brain edema after a large stroke causes significant morbidity and mortality. Here, we seek to identify pharmacodynamic markers of edema that are modified by intravenous (i.v.) glibenclamide (glyburide; BIIB093) treatment. Using metabolomic profiling of 399 plasma samples from patients enrolled in the phase 2 Glyburide Advantage in Malignant Edema and Stroke (GAMES)-RP trial, 152 analytes are measured using liquid chromatography-tandem mass spectrometry. Associations with midline shift (MLS) and the matrix metalloproteinase-9 (MMP-9) level that are further modified by glibenclamide treatment are compared with placebo. Hypoxanthine is the only measured metabolite that associates with MLS and MMP-9. In sensitivity analyses, greater hypoxanthine levels also associate with increased net water uptake (NWU), as measured on serial head computed tomography (CT) scans. Finally, we find that treatment with i.v. glibenclamide reduces plasma hypoxanthine levels across all post-treatment time points. Hypoxanthine, which has been previously linked to inflammation, is a biomarker of brain edema and a treatment response marker of i.v. glibenclamide treatment.

Delayed functional independence after thrombectomy: temporal characteristics and predictors.

BACKGROUND: Variability in early neurological improvement after endovascular thrombectomy (EVT) for large vessel occlusion (LVO) stroke is well documented. Understanding the temporal progression of functional independence after EVT, especially delayed functional independence in patients who do not experience early improvement, is essential for prognostication and rehabilitation. OBJECTIVE: To determine the incidence of early and delayed functional independence and identify associated predictors after EVT. METHODS: A retrospective analysis of prospectively collected data on patients undergoing EVT in the setting of anterior circulation LVO was performed. Demographic, clinical, radiological, treatment, and procedural information were analyzed. Incidence and predictors of early functional independence (EFI, modified Rankin Scale (mRS) score 0-2 at discharge) and delayed functional independence (DFI, mRS score 0-2 at 90 days in non-EFI patients) were analyzed. RESULTS: Three hundred and fifty-five patients met the study criteria. 55% were women and mean age was 71±15. Mean National Institutes of Health Stroke Scale (NIHSS) score was 17±6 and median Alberta Stroke Program Early CT Score was 9 (8-10). EFI was observed in 21% (73) of patients. Among non-EFI patients (282), DFI was observed in 30% (85) of patients. Shorter time to treatment (p=0.03), lower 24 hours NIHSS score (p<0.001), and smaller follow-up infarct volume (p=0.003) were independent predictors of EFI. Younger age (p=0.011), lower 24 hours NIHSS score (p=0.001), and absence of parenchymal hemorrhage (PH2; p=0.039) were independent predictors of DFI. CONCLUSION: Approximately one-fifth of patients experience EFI and one-third of non-early improvers experience DFI. Younger age, lower 24 hours NIHSS score, and absence of parenchymal hemorrhage were independent predictors of DFI among non-early improvers. Further studies are required to improve our understanding of DFI.

Osmotherapy for malignant cerebral edema in a phase 2 prospective, double blind, randomized, placebo-controlled study of IV glibenclamide.

BACKGROUND/OBJECTIVE: Malignant edema can be a life-threatening complication of large hemispheric infarction (LHI), and is often treated with osmotherapy. In this exploratory analysis of data from the GAMES-RP study, we hypothesized that patients receiving osmotherapy had symptomatic cerebral edema, and that treatment with intravenous (IV) glibenclamide would modify osmotherapy use as compared with placebo. METHODS: GAMES-RP was a phase 2 multi-center prospective, double blind, randomized, placebo-controlled study in LHI. Patients were randomized to IV glibenclamide (e.g. IV glyburide) or placebo. Cerebral edema therapies included osmotherapy and/or decompressive craniectomy at the discretion of the treating team. Total bolus osmotherapy dosing was quantified by "osmolar load". Radiographic edema was defined by dichotomizing midline shift at 24 h. Clinical changes were defined as any increase in NIHSS1a. RESULTS: Osmotherapy was administered to 40 of the 77 patients at a median of 39 [27-55] h after stroke onset. The median baseline DWI lesion volume was significantly larger in the osmotherapy treated group (167 [146-211] mL v. 139 [112-170] mL; P=0.046). Adjudicated malignant edema (75% v. 16%; P<0.001) was more common in the osmotherapy treated group. There were no differences in the proportion of patients receiving osmotherapy or the median total osmolar load between treatment arms. Most patients (76%) had a decrease in consciousness (NIHSS item 1A ≥1) on the day they began receiving osmotherapy. CONCLUSIONS: In the GAMES-RP trial, osmolar therapies were most often administered in response to clinical symptoms of decreased consciousness. However, the optimal timing of administration and impact on outcome after LHI have yet to be defined.

Interaction between time, ASPECTS, and clinical mismatch.

BACKGROUND: Imaging-based patient selection for neurothrombectomy is reliant on the identification of irreversibly damaged brain tissue (core) and salvageable tissue (penumbra). The DAWN trial used the clinical-core mismatch (CCM) paradigm (clinical deficit out of proportion to infarct volume). We aim to determine the prevalence of CCM in large vessel occlusion (LVO) strokes and study the impact of time and the Alberta Stroke Program Early CT Score (ASPECTS) on the likelihood of mismatch. METHODS: We performed a retrospective observational analysis of internal carotid artery/middle cerebral artery M1 occlusions with available advanced imaging (relative cerebral blood flow/MRI). We used automated software for infarct volume analysis and ASPECTS determination. The prevalence of CCM and the impact of time and ASPECTS were analyzed. RESULT: One hundred and eighty-five LVO strokes were included. Mean age was 71±15 years and median National Institutes of Health Stroke Scale score was 17 (range 12-21). Mean ischemic core volume was 50±69 mL. Within 0-24 hours, CCM was present in 53% and ranged from 63% in 0-3 hours to 25% at 21-24 hours (p=0.03). Prevalence of mismatch reduced 1.6% for every 1 hour increase in time to imaging. CCM prevalence by ASPECTS groups was: ASPECTS 9-10: 77%, ASPECTS 6-8: 65%, ASPECTS 0-5: 13% (p<0.01), with a 6.4% decrement for every 1 point decrease in ASPECTS. The prevalence of mismatch did not diminish over time among ASPECTS groups and higher ASPECTS was an independent predictor of CCM (OR 1.4 (95% CI 1.1 to 1.7), p<0.001). CONCLUSIONS: CCM is present in 57% and 50% of LVO strokes in the 0-6 and 6-24 hour window, respectively. The prevalence of mismatch declines with increasing time (1.6%/hour) and decreasing ASPECTS (6.4%/point). Among ASPECTS groups the prevalence of mismatch does not decline over time. These data support the use of an ASPECTS-based paradigm for late window patient selection.

Intravenous Glibenclamide Reduces Lesional Water Uptake in Large Hemispheric Infarction.

Background and Purpose- Prior studies have shown a linear relationship between computed tomography (CT)-derived radiodensity and water uptake, or brain edema, within stroke lesions. To test the hypothesis that intravenous glibenclamide (glyburide; BIIB093) reduces ischemic brain water uptake, we quantified the lesional net water uptake (NWU) on serial CT scans from patients enrolled in the phase 2 GAMES-RP Trial (Glyburide Advantage in Malignant Edema and Stroke). Methods- This was a post hoc exploratory analysis of the GAMES-RP study. Noncontrast CT scans performed between admission and day 7 (n=264) were analyzed in the GAMES-RP modified intention-to-treat sample. Quantitative change in CT radiodensity (ie, NWU) and midline shift (MLS) was measured. The gray and white matter NWU were also examined separately. Repeated-measures mixed-effects models were used to assess the effect of intravenous glibenclamide on MLS or NWU. Results- A median of 3 CT scans (interquartile range, 2-4) were performed per patient during the first 7 days after stroke. In a repeated-measures regression model, greater NWU was associated with increased MLS (ß=0.23; 95% CI, 0.20-0.26; P<0.001). Treatment with intravenous glibenclamide was associated with reduced NWU (ß=-2.80; 95% CI, -5.07 to -0.53; P=0.016) and reduced MLS (ß=-1.50; 95% CI, -2.71 to -0.28; P=0.016). Treatment with intravenous glibenclamide reduced both gray and white matter water uptake. In mediation analysis, gray matter NWU (ß=0.15; 95% CI, 0.11-0.20; P<0.001) contributed to a greater proportion of MLS mass effect, as compared with white matter NWU (ß=0.08; 95% CI, 0.03-0.13; P=0.001). Conclusions- In this phase 2 post hoc analysis, intravenous glibenclamide reduced both water accumulation and mass effect after large hemispheric infarction. This study demonstrates NWU is a quantitative and modifiable biomarker of ischemic brain edema accumulation. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01794182.

Differential association of subtypes of epileptiform activity with outcome after cardiac arrest.

BACKGROUND: Epileptiform activity is common after cardiac arrest, although intensity of electroencephalographic (EEG) monitoring may affect detection rates. Prior work has grouped these patterns together as "malignant," without considering discrete subtypes. We describe the incidence of distinct patterns in the ictal-interictal spectrum at two centers and their association with outcomes. METHODS: We analyzed a retrospective cohort of comatose post-arrest patients admitted at two academic centers from January 2011 to October 2014. One center uses routine continuous EEG, the other acquires "spot" EEG at the treating physicians' discretion. We reviewed all available EEG data and classified epileptiform patterns. We abstracted antiepileptic drugs (AEDs) administrations from the electronic medical record. We compared apparent incidence of each pattern between centers, and compared outcomes (awakening from coma, survival to discharge, discharge modified Rankin Scale (mRS) 0-2) across EEG patterns and number of AEDs administered. RESULTS: We included 818 patients. Routine continuous EEG was associated with a higher apparent incidence of polyspike burst-suppression (25% vs 13% P < 0.001). Frequency of other epileptiform findings did not differ. Among patients with any epileptiform pattern, only 2/258 (1%, 95%CI 0-3%) were discharged with mRS 0-2, although 24/258 (9%, 95%CI 6-14%) awakened and 36/258 (14%, 95%CI 10-19%) survived. The proportions that awakened and survived decreased in a stepwise manner with progressively worse EEG patterns (range 38% to 2% and 32% to 7%, respectively). Among patients receiving ≥3 AEDs, only 5/80 (6%, 95%CI 2-14%) awakened and 1/80 (1%, 95%CI 0-7%) had a mRS 0-2. CONCLUSION: We found high rates of epileptiform EEG findings, regardless of intensity of EEG monitoring. The association of distinct ictal-interictal EEG findings with outcome was variable.

Effect of IV glyburide on adjudicated edema endpoints in the GAMES-RP Trial.

OBJECTIVE: In this secondary analysis of the Glyburide Advantage in Malignant Edema and Stroke (GAMES-RP) Trial, we report the effect of IV glyburide on adjudicated, edema-related endpoints. METHODS: Blinded adjudicators assigned designations for hemorrhagic transformation, neurologic deterioration, malignant edema, and edema-related death to patients from the GAMES-RP phase II randomized controlled trial of IV glyburide for large hemispheric infarct. Rates of these endpoints were compared between treatment arms in the per-protocol sample. In those participants with malignant edema, the effects of treatment on additional markers of edema and clinical deterioration were examined. RESULTS: In the per-protocol sample, 41 patients received glyburide and 36 received placebo. There was no difference in the frequency of hemorrhagic transformation (n = 24 [58.5%] in IV glyburide vs n = 23 [63.9%] in placebo, p = 0.91) or the incidence of malignant edema (n = 19 [46%] in IV glyburide vs n = 17 [47%] in placebo, p = 0.94). However, treatment with IV glyburide was associated with a reduced proportion of deaths attributed to cerebral edema (n = 1 [2.4%] with IV glyburide vs n = 8 [22.2%] with placebo, p = 0.01). In the subset of patients with malignant edema, those treated with IV glyburide had less midline shift (p < 0.01) and reduced MMP-9 (matrix metalloproteinase 9) levels (p < 0.01). The glyburide treatment group had lower rate of NIH Stroke Scale (NIHSS) increase of ≥4 during the infusion period (n = 7 [37%] in IV glyburide vs n = 12 [71%] in placebo, p = 0.043), and of change in level of alertness (NIHSS subscore 1a; n = 11 [58%] vs n = 15 [94%], p = 0.016). CONCLUSION: IV glyburide was associated with improvements in midline shift, level of alertness, and NIHSS, and there were fewer deaths attributed to edema. Additional studies of IV glyburide in large hemispheric infarction are warranted to corroborate these findings. CLINICALTRIALSGOV IDENTIFIER: NCT01794182. LEVEL OF EVIDENCE: This study provides Class II evidence that for patients with large hemispheric infarction, IV glyburide improves some edema-related endpoints.

Thrombectomy 6-24 hours after stroke in trial ineligible patients.

BACKGROUND AND PURPOSE: The DAWN and DEFUSE-3 trials demonstrated the benefit of endovascular thrombectomy (ET) in late-presenting acute ischemic strokes due to anterior circulation large vessel occlusion (ACLVO). Strict criteria were employed for patient selection. We sought to evaluate the characteristics and outcomes of patients treated outside these trials. METHODS: A retrospective review of acute ischemic stroke admissions to a single comprehensive stroke center was performed during the DAWN trial enrollment period (November 2014 to February 2017) to identify all patients presenting in the 6-24 hour time window. These patients were further investigated for trial eligibility, baseline characteristics, treatment, and outcomes. RESULTS: Approximately 70% (n=142) of the 204 patients presenting 6-24 hours after last known well with NIH Stroke Scale score ≥6 and harboring an ACLVO are DAWN and/or DEFUSE-3 ineligible, most commonly due to large infarct burden (38%). 26% (n=37) of trial ineligible patients with large vessel occlusion strokes received off-label ET and 30% of them achieved functional independence (modified Rankin Scale 0-2) at 90 days. Rates of symptomatic intracranial hemorrhage and mortality were 8% and 24%, respectively CONCLUSION: Trial ineligible patients with large vessel occlusion strokes receiving off-label ET achieved outcomes comparable to DAWN and DEFUSE-3 eligible patients. Patients aged <80 years are most likely to benefit from ET in this subgroup. These data indicate a larger population of patients who can potentially benefit from ET in the expanded time window if more permissive criteria are applied.

Long-Term Outcomes in Patients Aged ≤70 Years With Intravenous Glyburide From the Phase II GAMES-RP Study of Large Hemispheric Infarction: An Exploratory Analysis.

BACKGROUND AND PURPOSE: We aimed to determine whether subjects aged ≤70 years who were treated with intravenous glyburide (RP-1127; BIIB093; glibenclamide) would have better long-term outcomes than those who received placebo. METHODS: GAMES-RP (Glyburide Advantage in Malignant Edema and Stroke-Remedy Pharmaceuticals) was a prospective, double-blind, randomized, placebo-controlled phase 2 clinical trial. Eighty-six participants, aged 18 to 80 years, who presented to 18 centers with large hemispheric infarction (baseline diffusion-weighted imaging volumes, 82-300 cm3) randomized within 10 hours of symptom onset were enrolled. In the current exploratory analysis, we included participants aged ≤70 years treated with intravenous glyburide (n=35) or placebo (n=30) who met per-protocol criteria. Intravenous glyburide or placebo was administered in a 1:1 ratio. We analyzed 90-day and 12-month mortality, functional outcome (modified Rankin Scale, Barthel Index), and quality of life (EuroQol group 5-dimension). Additional outcomes assessed included blood-brain barrier injury (MMP-9 [matrix metalloproteinase 9]) and cerebral edema (brain midline shift). RESULTS: Participants ≤70 years of age treated with intravenous glyburide had lower mortality at all time points (log-rank for survival hazards ratio, 0.34; P=0.04). After adjustment for age, the difference in functional outcome (modified Rankin Scale) demonstrated a trend toward benefit for intravenous glyburide-treated subjects at 90 days (odds ratio, 2.31; P=0.07). Repeated measures analysis at 90 days, 6 months, and 12 months using generalized estimating equations showed a significant treatment effect of intravenous glyburide on the Barthel Index (P=0.03) and EuroQol group 5-dimension (P=0.05). Participants treated with intravenous glyburide had lower plasma levels of MMP-9 (189 versus 376 ng/mL; P<0.001) and decreased midline shift (4.7 versus 9 mm; P<0.001) compared with participants who received placebo. CONCLUSIONS: In this exploratory analysis, participants ≤70 years of age with large hemispheric infarction have improved survival after acute therapy with intravenous glyburide. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01794182.

Early decompressive craniectomy for malignant cerebral infarction: Meta-analysis and clinical decision algorithm.

BACKGROUND: Decompressive craniectomy (DC) is an aggressive life-saving surgical intervention for patients with malignant cerebral infarction (MCI). However, DC remains inconsistently and infrequently utilized, primarily due to enduring concern that increased survival occurs only at the cost of poor functional outcome. Our aim was to clarify the role of DC performed within 48 hours (early DC) for patients with MCI, including patients aged >60 years. METHODS: We performed a meta-analysis of all available randomized controlled trials comparing early DC to best medical care for MCI. Studies were identified through literature searches of electronic databases including PubMed, EMBASE, and Scopus. We employed a Mantel-Haenszel fixed effects model to assess treatment effect on dichotomized modified Rankin Scale (mRS) outcomes at 12 months. RESULTS: A total of 289 patients from 6 randomized controlled trials comparing early DC to best medical care were included. Early DC resulted in an increased rate of excellent outcomes, defined as mRS ≤2 (relative risk [RR] 2.81, 95% confidence interval [CI] 1.01-7.82, p = 0.047), and favorable outcomes, defined as mRS ≤3 (RR 2.06, 95% CI 1.25-3.40, p = 0.005). Early DC also increased the rate of survival with unfavorable outcomes, defined as mRS 4-5 (RR 3.03, 95% CI 1.98-4.65, p < 0.001). CONCLUSIONS: Early DC increases the rate of excellent outcomes, i.e., functional independence, in addition to favorable and unfavorable outcomes; however, these findings must be interpreted within the context of patients' goals of care. We have developed a clinical decision algorithm that incorporates goals of care, which may guide consideration of early DC for MCI in clinical practice.

DeCoN: genome-wide analysis of in vivo transcriptional dynamics during pyramidal neuron fate selection in neocortex.

Neuronal development requires a complex choreography of transcriptional decisions to obtain specific cellular identities. Realizing the ultimate goal of identifying genome-wide signatures that define and drive specific neuronal fates has been hampered by enormous complexity in both time and space during development. Here, we have paired high-throughput purification of pyramidal neuron subclasses with deep profiling of spatiotemporal transcriptional dynamics during corticogenesis to resolve lineage choice decisions. We identified numerous features ranging from spatial and temporal usage of alternative mRNA isoforms and promoters to a host of mRNA genes modulated during fate specification. Notably, we uncovered numerous long noncoding RNAs with restricted temporal and cell-type-specific expression. To facilitate future exploration, we provide an interactive online database to enable multidimensional data mining and dissemination. This multifaceted study generates a powerful resource and informs understanding of the transcriptional regulation underlying pyramidal neuron diversity in the neocortex.

SOX5 controls the sequential generation of distinct corticofugal neuron subtypes.

The molecular mechanisms controlling the development of distinct subtypes of neocortical projection neurons, and CNS neuronal diversity more broadly, are only now emerging. We report that the transcription factor SOX5 controls the sequential generation of distinct corticofugal neuron subtypes by preventing premature emergence of normally later-born corticofugal neurons. SOX5 loss-of-function causes striking overlap of the identities of the three principal sequentially born corticofugal neuron subtypes: subplate neurons, corticothalamic neurons, and subcerebral projection neurons. In Sox5(-/-) cortex, subplate neurons aberrantly develop molecular hallmarks and connectivity of subcerebral projection neurons; corticothalamic neurons are imprecisely differentiated, while differentiation of subcerebral projection neurons is accelerated. Gain-of-function analysis reinforces the critical role of SOX5 in controlling the sequential generation of corticofugal neurons--SOX5 overexpression at late stages of corticogenesis causes re-emergence of neurons with corticofugal features. These data indicate that SOX5 controls the timing of critical fate decisions during corticofugal neuron production and thus subtype-specific differentiation and neocortical neuron diversity.

Fezl is required for the birth and specification of corticospinal motor neurons.

The molecular mechanisms controlling the differentiation of neural progenitors into distinct subtypes of neurons during neocortical development are unknown. Here, we report that Fezl is required for the specification of corticospinal motor neurons and other subcerebral projection neurons, which are absent from Fezl null mutant neocortex. There is neither an increase in cell death in Fezl(-/-) cortex nor abnormalities in migration, indicating that the absence of subcerebral projection neurons is due to a failure in fate specification. In striking contrast, other neuronal populations in the same and other cortical layers are born normally. Overexpression of Fezl results in excess production of subcerebral projection neurons and arrested migration of these neurons in the germinal zone. These data indicate that Fezl plays a central role in the specification of corticospinal motor neurons and other subcerebral projection neurons, controlling early decisions regarding lineage-specific differentiation from neural progenitors.