Predicting Functional Dependency in Patients with Disorders of Consciousness: A TBI-Model Systems and TRACK-TBI Study.

OBJECTIVE: It is not currently possible to predict long-term functional dependency in patients with disorders of consciousness (DoC) after traumatic brain injury (TBI). Our objective was to fit and externally validate a prediction model for 1-year dependency in patients with DoC ≥ 2 weeks after TBI. METHODS: We included adults with TBI enrolled in TBI Model Systems (TBI-MS) or Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) studies who were not following commands at rehabilitation admission or 2 weeks post-injury, respectively. We fit a logistic regression model in TBI-MS and validated it in TRACK-TBI. The primary outcome was death or dependency at 1 year post-injury, defined using the Disability Rating Scale. RESULTS: In the TBI-MS Discovery Sample, 1,960 participants (mean age 40 [18] years, 76% male, 68% white) met inclusion criteria, and 406 (27%) were dependent 1 year post-injury. In a TBI-MS held out cohort, the dependency prediction model's area under the receiver operating characteristic curve was 0.79 (95% CI 0.74-0.85), positive predictive value was 53% and negative predictive value was 86%. In the TRACK-TBI external validation (n = 124, age 40 [16] years, 77% male, 81% white), the area under the receiver operating characteristic curve was 0.66 (0.53, 0.79), equivalent to the standard IMPACTcore + CT score (p = 0.8). INTERPRETATION: We developed a 1-year dependency prediction model using the largest existing cohort of patients with DoC after TBI. The sensitivity and negative predictive values were greater than specificity and positive predictive values. Accuracy was diminished in an external sample, but equivalent to the IMPACT model. Further research is needed to improve dependency prediction in patients with DoC after TBI. ANN NEUROL 2023;94:1008-1023.

The biomechanical signature of loss of consciousness: computational modelling of elite athlete head injuries.

Sports related head injuries can cause transient neurological events including loss of consciousness and dystonic posturing. However, it is unknown why head impacts that appear similar produce distinct neurological effects. The biomechanical effect of impacts can be estimated using computational models of strain within the brain. Here, we investigate the strain and strain rates produced by professional American football impacts that led to loss of consciousness, posturing or no neurological signs. We reviewed 1280 National Football League American football games and selected cases where the team's medical personnel made a diagnosis of concussion. Videos were then analysed for signs of neurological events. We identified 20 head impacts that showed clear video signs of loss of consciousness and 21 showing clear abnormal posturing. Forty-one control impacts were selected where there was no observable evidence of neurological signs, resulting in 82 videos of impacts for analysis. Video analysis was used to guide physical reconstructions of these impacts, allowing us to estimate the impact kinematics. These were then used as input to a detailed 3D high-fidelity finite element model of brain injury biomechanics to estimate strain and strain rate within the brain. We tested the hypotheses that impacts producing loss of consciousness would be associated with the highest biomechanical forces, that loss of consciousness would be associated with high forces in brainstem nuclei involved in arousal and that dystonic posturing would be associated with high forces in motor regions. Impacts leading to loss of consciousness compared to controls produced higher head acceleration (linear acceleration; 81.5 g ± 39.8 versus 47.9 ± 21.4; P = 0.004, rotational acceleration; 5.9 krad/s2 ± 2.4 versus 3.5 ± 1.6; P < 0.001) and in voxel-wise analysis produced larger brain deformation in many brain regions, including parts of the brainstem and cerebellum. Dystonic posturing was also associated with higher deformation compared to controls, with brain deformation observed in cortical regions that included the motor cortex. Loss of consciousness was specifically associated with higher strain rates in brainstem regions implicated in maintenance of consciousness, including following correction for the overall severity of impact. These included brainstem nuclei including the locus coeruleus, dorsal raphé and parabrachial complex. The results show that in head impacts producing loss of consciousness, brain deformation is disproportionately seen in brainstem regions containing nuclei involved in arousal, suggesting that head impacts produce loss of consciousness through a biomechanical effect on key brainstem nuclei involved in the maintenance of consciousness.

Clinical and Electroencephalographic Predictors of Seizures and Status Epilepticus in 12,450 Critically Ill Adults: A Retrospective Cohort Study.

OBJECTIVES: Status epilepticus (SE) is associated with significantly higher morbidity and mortality than isolated seizures. Our objective was to identify clinical diagnoses and rhythmic and periodic electroencephalogram patterns (RPPs) associated with SE and seizures. DESIGN: Retrospective cohort study. SETTING: Tertiary-care hospitals. SUBJECTS: Twelve thousand four hundred fifty adult hospitalized patients undergoing continuous electroencephalogram (cEEG) monitoring in selected participating sites in the Critical Care EEG Monitoring Research Consortium database (February 2013 to June 2021). INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: We defined an ordinal outcome in the first 72 hours of cEEG: no seizures, isolated seizures without SE, or SE (with or without isolated seizures). Composite groups included isolated seizures or SE (AnySz) and no seizure or isolated seizures. In this cohort (mean age: 60 ± 17 yr), 1,226 patients (9.8%) had AnySz and 439 patients (3.5%) had SE. In a multivariate model, factors independently associated with SE were cardiac arrest (9.2% with SE; adjusted odds ratio, 8.8 [6.3-12.1]), clinical seizures before cEEG (5.7%; 3.3 [2.5-4.3]), brain neoplasms (3.2%; 1.6 [1.0-2.6]), lateralized periodic discharges (LPDs) (15.4%; 7.3 [5.7-9.4]), brief potentially ictal rhythmic discharges (BIRDs) (22.5%; 3.8 [2.6-5.5]), and generalized periodic discharges (GPDs) (7.2%; 2.4 [1.7-3.3]). All above variables and lateralized rhythmic delta activity (LRDA) were also associated with AnySz. Factors disproportionately increasing odds of SE over isolated seizures were cardiac arrest (7.3 [4.4-12.1]), clinical seizures (1.7 [1.3-2.4]), GPDs (2.3 [1.4-3.5]), and LPDs (1.4 [1.0-1.9]). LRDA had lower odds of SE compared with isolated seizures (0.5 [0.3-0.9]). RPP modifiers did not improve SE prediction beyond RPPs presence/absence ( p = 0.8). CONCLUSIONS: Using the largest existing cEEG database, we identified specific predictors of SE (cardiac arrest, clinical seizures prior to cEEG, brain neoplasms, LPDs, GPDs, and BIRDs) and seizures (all previous and LRDA). These findings could be used to tailor cEEG monitoring for critically ill patients.

Applications of Advanced MRI to Disorders of Consciousness.

Disorder of consciousness (DoC) after severe brain injury presents numerous challenges to clinicians, as the diagnosis, prognosis, and management are often uncertain. Magnetic resonance imaging (MRI) has long been used to evaluate brain structure in patients with DoC. More recently, advances in MRI technology have permitted more detailed investigations of the brain's structural integrity (via diffusion MRI) and function (via functional MRI). A growing literature has begun to show that these advanced forms of MRI may improve our understanding of DoC pathophysiology, facilitate the identification of patient consciousness, and improve the accuracy of clinical prognostication. Here we review the emerging evidence for the application of advanced MRI for patients with DoC.

Transcranial-Doppler-Measured Vasospasm Severity is Associated with Delayed Cerebral Infarction After Subarachnoid Hemorrhage.

BACKGROUND: Angiographic vasospasm after aneurysmal subarachnoid hemorrhage (aSAH) is associated with delayed cerebral ischemia (DCI)-related cerebral infarction (radiological DCI) and worsened neurological outcome. Transcranial Doppler (TCD) measurements of cerebral blood flow velocity are commonly used after aSAH to screen for vasospasm; however, their association with cerebral infarction is not well characterized. We sought to determine whether time-varying TCD-measured vasospasm severity is associated with cerebral infarction and investigate the performance characteristics of different time/severity cutoffs for predicting cerebral infarction. METHODS: We conducted a retrospective single-center cohort study of consecutive adult patients with aSAH with at least one TCD study between 2011 and 2020. The primary outcome was radiological DCI, defined as a cerebral infarction developing at least 2 days after any surgical or endovascular intervention without an alternative cause. Cox proportional hazards models were used to examine associations between time-varying vasospasm severity and radiological DCI. Optimal TCD-based time/severity thresholds for predicting radiological DCI were then determined. RESULTS: Of 262 patients with aSAH who underwent TCD studies, 27 (10%) developed radiological DCI. Patients with radiological DCI had higher modified Fisher scale scores and trended toward earlier onset of vasospasm. Adjusted for age, Hunt and Hess scores, and modified Fisher scale scores, the worst-vessel vasospasm severity was associated with radiological DCI (adjusted hazard ratio 1.7 [95% confidence interval 1.1-2.4]). Vasospasm severity within a specific vessel was associated with risk of delayed infarction in the territory supplied by that vessel. Optimal discrimination of patients with radiological DCI was achieved with thresholds of mild vasospasm on days 4-5 or moderate vasospasm on days 6-9, with negative predictive values greater than 90% and positive predictive values near 20%. CONCLUSIONS: TCD-measured vasospasm severity is associated with radiological DCI after aSAH. An early, mild TCD-based vasospasm severity threshold had a high negative predictive value, supporting its role as a screening tool to identify at-risk patients.

Midline Shift Greater than 3 mm Independently Predicts Outcome After Ischemic Stroke.

BACKGROUND: Cerebral edema is associated with worse outcome after acute stroke; however, the minimum clinically relevant threshold remains unknown. This study aimed to identify the minimal degree of midline shift (MLS) that predicts outcome in a cohort encompassing a broad range of patients with acute stroke. METHODS: Patient-level data from six acute stroke clinical trials were combined with endovascular thrombectomy registries from two academic referral centers, generating a combined cohort of 1977 patients. MLS was extracted from the original trial data or measured on computed tomography or magnetic resonance imaging that was obtained a median of 47.0 h (interquartile range 27.0-75.1 h) after stroke onset. Logistic regression was performed to identify predictors of poor outcome and the minimal clinically relevant MLS threshold. RESULTS: The presence of MLS was a predictor of poor outcome, independent of baseline clinical and demographic factors (adjusted odds ratio 4.46, 95% confidence interval 3.56-5.59, p < 0.001). Examining the full range of MLS values identified, a value of greater than 3 mm was the critical threshold that significantly predicted poor outcome (adjusted odds ratio 3.20 [1.31-7.82], p = 0.011). CONCLUSIONS: These results show that the presence of MLS predicts poor outcome and, specifically, MLS value greater than 3 mm is an important threshold across a variety of clinical settings. These findings may have relevance for the design and interpretation of future trials for antiedema therapies.

Volume replacement is associated with a diminished osmolar effect of mannitol in patients with acute brain injury.

INTRODUCTION: Animal experiments recently demonstrated that replacing urinary loses with crystalloid diminishes the therapeutic effect of mannitol by reducing the increase in osmolality. We aimed to investigate whether this effect is similarly seen in in brain-injured patients by studying the association between total body fluid balance (TBB) and the osmolar response to mannitol. METHODS: We performed a retrospective cohort study of adult patients with acute brain injury between 2015 and 2021 who received ≥ 2 doses of mannitol within 8 hours and no intercurrent concentrated saline solution. We analyzed the association between the change in TBB (∆TBB) and change in osmolality (∆Osm) before and after mannitol in a linear model, both as univariate and after adjustment for common confounding factors. RESULTS: Of 6,145 patients who received mannitol, 155 patients met inclusion criteria (mean age 60 ± 17 years, 48% male, 83% white). The mean total mannitol dose was 2 ± 0.5 g/kg and the mean change in plasma osmolality was 7.9 ± 7.1 mOsm/kg. Each 1 L increase in ∆TBB was associated with a change of -1.1 mOsm/L in ∆Osm (95% CI [-2.2, -0.02], p = 0.045). The magnitude of association was similar to that of total mannitol dose and remained consistent in an adjusted model and after excluding outliers. CONCLUSIONS: In patients with acute brain injury, a positive TBB is associated with a diminished mannitol-induced increase in plasma osmolality. Future prospective studies are needed to confirm these findings and their influence on the therapeutic effect of mannitol.

New Uses for Thromboelastography and Other Forms of Viscoelastic Monitoring in the Emergency Department: A Narrative Review.

Patients frequently visit the emergency department with conditions that place them at risk of worse outcomes when accompanied by coagulopathy. Routine tests of coagulation-prothrombin time, partial thromboplastin time, platelets, and fibrinogen-have shortcomings that limit their use in providing emergency care. One alternative is to investigate coagulation disturbance with viscoelastic monitoring (VEM), a coagulation test that measures the timing and strength of blood clot development in real time. VEM is widely used and studied in cardiac surgery, liver transplant surgery, anesthesia, and trauma. In this article, we review the technique of VEM and the biologic rationale of using it in addition to routine tests of coagulation in emergency clinical situations. Then, we review the evidence (or lack thereof) for using VEM in the diagnosis and treatment of specific conditions. Finally, we describe the limitations of the test and future directions for clinical use and research in emergency medicine.

Therapies to Restore Consciousness in Patients with Severe Brain Injuries: A Gap Analysis and Future Directions.

BACKGROUND/OBJECTIVE: For patients with disorders of consciousness (DoC) and their families, the search for new therapies has been a source of hope and frustration. Almost all clinical trials in patients with DoC have been limited by small sample sizes, lack of placebo groups, and use of heterogeneous outcome measures. As a result, few therapies have strong evidence to support their use; amantadine is the only therapy recommended by current clinical guidelines, specifically for patients with DoC caused by severe traumatic brain injury. To foster and advance development of consciousness-promoting therapies for patients with DoC, the Curing Coma Campaign convened a Coma Science Work Group to perform a gap analysis. METHODS: We consider five classes of therapies: (1) pharmacologic; (2) electromagnetic; (3) mechanical; (4) sensory; and (5) regenerative. For each class of therapy, we summarize the state of the science, identify gaps in knowledge, and suggest future directions for therapy development. RESULTS: Knowledge gaps in all five therapeutic classes can be attributed to the lack of: (1) a unifying conceptual framework for evaluating therapeutic mechanisms of action; (2) large-scale randomized controlled trials; and (3) pharmacodynamic biomarkers that measure subclinical therapeutic effects in early-phase trials. To address these gaps, we propose a precision medicine approach in which clinical trials selectively enroll patients based upon their physiological receptivity to targeted therapies, and therapeutic effects are measured by complementary behavioral, neuroimaging, and electrophysiologic endpoints. CONCLUSIONS: This personalized approach can be realized through rigorous clinical trial design and international collaboration, both of which will be essential for advancing the development of new therapies and ultimately improving the lives of patients with DoC.

MRI in disorders of consciousness.

PURPOSE OF REVIEW: In the study of brain-injured patients with disorders of consciousness (DoC), structural and functional MRI seek to provide insights into the neural correlates of consciousness, identify neurophysiologic signatures of covert consciousness, and identify biomarkers for recovery of consciousness. RECENT FINDINGS: Cortical volume, white matter volume and integrity, and structural connectivity across many grey and white matter regions have been shown to vary with level of awareness in brain-injured patients. Resting-state functional connectivity (rs-FC) within and between canonical cortical networks also correlates with DoC patients' level of awareness. Stimulus-based and motor-imagery fMRI paradigms have identified some behaviorally unresponsive DoC patients with cortical processing and activation patterns that mirror healthy controls. Emerging techniques like dynamic rs-FC have begun to identify temporal trends in brain-wide connectivity that may represent novel neural correlates of consciousness. SUMMARY: Structural and functional MRI will continue to advance our understanding of brain regions supporting human consciousness. Measures of regional and global white matter integrity and rs-FC in particular networks have shown significant improvement over clinical features in identifying acute and chronic DoC patients likely to recover awareness. As they are refined, functional MRI paradigms may additionally provide opportunities for interacting with behaviorally unresponsive patients.

Cortical lesions causing loss of consciousness are anticorrelated with the dorsal brainstem.

Brain lesions can provide unique insight into the neuroanatomical substrate of human consciousness. For example, brainstem lesions causing coma map to a specific region of the tegmentum. Whether specific lesion locations outside the brainstem are associated with loss of consciousness (LOC) remains unclear. Here, we investigate the topography of cortical lesions causing prolonged LOC (N = 16), transient LOC (N = 91), or no LOC (N = 64). Using standard voxel lesion symptom mapping, no focus of brain damage was associated with LOC. Next, we computed the network of brain regions functionally connected to each lesion location using a large normative connectome dataset (N = 1,000). This technique, termed lesion network mapping, can test whether lesions causing LOC map to a connected brain circuit rather than one brain region. Connectivity between cortical lesion locations and an a priori coma-specific region of brainstem tegmentum was an independent predictor of LOC (B = 1.2, p = .004). Connectivity to the dorsal brainstem was the only predictor of LOC in a whole-brain voxel-wise analysis. This relationship was driven by anticorrelation (negative correlation) between lesion locations and the dorsal brainstem. The map of regions anticorrelated to the dorsal brainstem thus defines a distributed brain circuit that, when damaged, is most likely to cause LOC. This circuit showed a slight posterior predominance and had peaks in the bilateral claustrum. Our results suggest that cortical lesions causing LOC map to a connected brain circuit, linking cortical lesions that disrupt consciousness to brainstem sites that maintain arousal.

Personalized Connectome Mapping to Guide Targeted Therapy and Promote Recovery of Consciousness in the Intensive Care Unit.

There are currently no therapies proven to promote early recovery of consciousness in patients with severe brain injuries in the intensive care unit (ICU). For patients whose families face time-sensitive, life-or-death decisions, treatments that promote recovery of consciousness are needed to reduce the likelihood of premature withdrawal of life-sustaining therapy, facilitate autonomous self-expression, and increase access to rehabilitative care. Here, we present the Connectome-based Clinical Trial Platform (CCTP), a new paradigm for developing and testing targeted therapies that promote early recovery of consciousness in the ICU. We report the protocol for STIMPACT (Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness), a CCTP-based trial in which intravenous methylphenidate will be used for targeted stimulation of dopaminergic circuits within the subcortical ascending arousal network (ClinicalTrials.gov NCT03814356). The scientific premise of the CCTP and the STIMPACT trial is that personalized brain network mapping in the ICU can identify patients whose connectomes are amenable to neuromodulation. Phase 1 of the STIMPACT trial is an open-label, safety and dose-finding study in 22 patients with disorders of consciousness caused by acute severe traumatic brain injury. Patients in Phase 1 will receive escalating daily doses (0.5-2.0 mg/kg) of intravenous methylphenidate over a 4-day period and will undergo resting-state functional magnetic resonance imaging and electroencephalography to evaluate the drug's pharmacodynamic properties. The primary outcome measure for Phase 1 relates to safety: the number of drug-related adverse events at each dose. Secondary outcome measures pertain to pharmacokinetics and pharmacodynamics: (1) time to maximal serum concentration; (2) serum half-life; (3) effect of the highest tolerated dose on resting-state functional MRI biomarkers of connectivity; and (4) effect of each dose on EEG biomarkers of cerebral cortical function. Predetermined safety and pharmacodynamic criteria must be fulfilled in Phase 1 to proceed to Phase 2A. Pharmacokinetic data from Phase 1 will also inform the study design of Phase 2A, where we will test the hypothesis that personalized connectome maps predict therapeutic responses to intravenous methylphenidate. Likewise, findings from Phase 2A will inform the design of Phase 2B, where we plan to enroll patients based on their personalized connectome maps. By selecting patients for clinical trials based on a principled, mechanistic assessment of their neuroanatomic potential for a therapeutic response, the CCTP paradigm and the STIMPACT trial have the potential to transform the therapeutic landscape in the ICU and improve outcomes for patients with severe brain injuries.

Corticospinal Tract Injury Estimated From Acute Stroke Imaging Predicts Upper Extremity Motor Recovery After Stroke.

Background and Purpose- Injury to the corticospinal tract (CST) has been shown to have a major effect on upper extremity motor recovery after stroke. This study aimed to examine how well CST injury, measured from neuroimaging acquired during the acute stroke workup, predicts upper extremity motor recovery. Methods- Patients with upper extremity weakness after ischemic stroke were assessed using the upper extremity Fugl-Meyer during the acute stroke hospitalization and again at 3-month follow-up. CST injury was quantified and compared, using 4 different methods, from images obtained as part of the stroke standard-of-care workup. Logistic and linear regression were performed using CST injury to predict ΔFugl-Meyer. Injury to primary motor and premotor cortices were included as potential modifiers of the effect of CST injury on recovery. Results- N=48 patients were enrolled 4.2±2.7 days poststroke and completed 3-month follow-up (median 90-day modified Rankin Scale score, 3; interquartile range, 1.5). CST injury distinguished patients who reached their recovery potential (as predicted from initial impairment) from those who did not, with area under the curve values ranging from 0.70 to 0.8. In addition, CST injury explained ≈20% of the variance in the magnitude of upper extremity recovery, even after controlling for the severity of initial impairment. Results were consistent when comparing 4 different methods of measuring CST injury. Extent of injury to primary motor and premotor cortices did not significantly influence the predictive value that CST injury had for recovery. Conclusions- Structural injury to the CST, as estimated from standard-of-care imaging available during the acute stroke hospitalization, is a robust way to distinguish patients who achieve their predicted recovery potential and explains a significant amount of the variance in poststroke upper extremity motor recovery.

Hemorrhagic and ischemic stroke secondary to herpes simplex virus type 2 meningitis and vasculopathy.

Herpes simplex virus type 2 (HSV-2) meningitis dogmatically is benign and self-limited in the immune competent patient. However, we describe how left untreated HSV-2 meningitis can be complicated by vasculitis and both ischemic and hemorrhagic stroke. We report a 57-year-old woman with lymphocytic meningitis complicated by ischemic stroke and intracerebral hemorrhage in the setting of vasculopathy and HSV-2 DNA detected in CSF successfully treated with acyclovir and corticosteroids. Subsequent angiographic magnetic resonance imaging revealed improvement in the vasculopathy after treatment. This case demonstrates that HSV-2 meningitis may take a less benign course and further provides the first evidence of angiographic improvement in addition to clinical improvement after definitive treatment.

Transcranial Doppler cerebrovascular reactivity: Thresholds for clinical significance in cerebrovascular disease.

BACKGROUND AND PURPOSE: Thresholds for abnormal transcranial Doppler cerebrovascular reactivity (CVR) studies are poorly understood, especially for patients with cerebrovascular disease. Using a real-world cohort with cerebral arterial stenosis, we sought to describe a clinically significant threshold for carbon dioxide reactivity (CO2R) and vasomotor range (VMR). METHODS: CVR studies were performed during conditions of breathing room air normally, breathing 8% carbon dioxide air mixture, and hyperventilation. The mean and standard deviation (SD) of CO2R and VMR were calculated for the unaffected side in patients with unilateral stenosis; a deviation of 2 SDs below the mean was chosen as the threshold for abnormal. Receiver operating characteristic (ROC) curves for both sides for patients with unilateral and bilateral stenosis were evaluated for sensitivity (Sn) and specificity (Sp). RESULTS: A total of 133 consecutive CVR studies were performed on 62 patients with stenosis with mean±SD age 55±16 years. Comorbidities included hypertension (60%), diabetes (15%), stroke (40%), and smoking (35%). In patients with unilateral stenosis, mean±SD CO2R for the unaffected side was 1.86±0.53%, defining abnormal CO2R as <0.80%. Mean±SD CO2R for the affected side was 1.27±0.90%. The CO2R threshold predicted abnormal acetazolamide single-photon emission computed tomography (SPECT) (Sn = .73, Sp = .79), CT/MRI perfusion abnormality (Sn = .42, Sp = .77), infarction on MRI (Sn = .45, Sp = .76), and pressure-dependent exam (Sn = .50, Sp = .76). For the unaffected side, mean±SD VMR was 39.5±15.8%, defining abnormal VMR as <7.9%. For the affected side, mean±SD VMR was 26.5±17.8%. The VMR threshold predicted abnormal acetazolamide SPECT (Sn = .46, Sp = .94), infarction on MRI (Sn = .27, Sp = .94), and pressure-dependent exam (Sn = .31, Sp = .90). CONCLUSIONS: In patients with multiple vascular risk factors, a reasonable threshold for clinically significant abnormal CO2R is <0.80% and VMR is <7.9%. Noninvasive CVR may aid in diagnosing and risk stratifying patients with stenosis.

Longitudinal Lesion Expansion in Chronic Traumatic Brain Injury.

Traumatic brain injury (TBI) is a risk factor for neurodegeneration and cognitive decline, yet the underlying pathophysiologic mechanisms are incompletely understood. This gap in knowledge is in part related to the lack of analytic methods to account for cortical lesions in prior neuroimaging studies. The objective of this study was to develop a lesion detection tool and apply it to an investigation of longitudinal changes in brain structure among individuals with chronic TBI. We identified 24 individuals with chronic moderate-to-severe TBI enrolled in the Late Effects of TBI (LETBI) study who had cortical lesions detected by T1-weighted MRI at two time points. Initial MRI scans were performed more than 1-year post-injury and follow-up scans were performed 3.1 (IQR=1.7) years later. We leveraged FreeSurfer parcellations of T1-weighted MRI volumes and a recently developed super-resolution technique, SynthSR, to identify cortical lesions in this longitudinal dataset. Trained raters received the data in a randomized order and manually corrected the automated lesion segmentation, yielding a final lesion mask for each scan at each timepoint. Lesion volume significantly increased between the two time points with a median volume change of 3.2 (IQR=5.9) mL (p<0.001), and the increases significantly exceeded the possible variance in lesion volume changes due to manual tracing errors (p < 0.001). Lesion volume significantly expanded longitudinally in 23 of 24 subjects, with all FDR corrected p-values ≤ 0.02. Inter-scan duration was not associated with the magnitude of lesion growth. We also demonstrated that the semi-automated tool showed a high level of accuracy compared to "ground truth" manual lesion segmentation. Semi-automated lesion segmentation is feasible in TBI studies and creates opportunities to elucidate mechanisms of post-traumatic neurodegeneration.

Multimodal MRI reveals brainstem connections that sustain wakefulness in human consciousness.

Consciousness is composed of arousal (i.e., wakefulness) and awareness. Substantial progress has been made in mapping the cortical networks that underlie awareness in the human brain, but knowledge about the subcortical networks that sustain arousal in humans is incomplete. Here, we aimed to map the connectivity of a proposed subcortical arousal network that sustains wakefulness in the human brain, analogous to the cortical default mode network (DMN) that has been shown to contribute to awareness. We integrated data from ex vivo diffusion magnetic resonance imaging (MRI) of three human brains, obtained at autopsy from neurologically normal individuals, with immunohistochemical staining of subcortical brain sections. We identified nodes of the proposed default ascending arousal network (dAAN) in the brainstem, hypothalamus, thalamus, and basal forebrain. Deterministic and probabilistic tractography analyses of the ex vivo diffusion MRI data revealed projection, association, and commissural pathways linking dAAN nodes with one another and with DMN nodes. Complementary analyses of in vivo 7-tesla resting-state functional MRI data from the Human Connectome Project identified the dopaminergic ventral tegmental area in the midbrain as a widely connected hub node at the nexus of the subcortical arousal and cortical awareness networks. Our network-based autopsy methods and connectivity data provide a putative neuroanatomic architecture for the integration of arousal and awareness in human consciousness.

Biological constraints limit the use of rapamycin-inducible FKBP12-Inp54p for depleting PIP2 in dorsal root ganglia neurons.

BACKGROUND: Rapamycin-induced translocation systems can be used to manipulate biological processes with precise temporal control. These systems are based on rapamycin-induced dimerization of FK506 Binding Protein 12 (FKBP12) with the FKBP Rapamycin Binding (FRB) domain of mammalian target of rapamycin (mTOR). Here, we sought to adapt a rapamycin-inducible phosphatidylinositol 4,5-bisphosphate (PIP2)-specific phosphatase (Inp54p) system to deplete PIP2 in nociceptive dorsal root ganglia (DRG) neurons. RESULTS: We genetically targeted membrane-tethered CFP-FRBPLF (a destabilized FRB mutant) to the ubiquitously expressed Rosa26 locus, generating a Rosa26-FRBPLF knockin mouse. In a second knockin mouse line, we targeted Venus-FKBP12-Inp54p to the Calcitonin gene-related peptide-alpha (CGRPα) locus. We hypothesized that after intercrossing these mice, rapamycin treatment would induce translocation of Venus-FKBP12-Inp54p to the plasma membrane in CGRP+ DRG neurons. In control experiments with cell lines, rapamycin induced translocation of Venus-FKBP12-Inp54p to the plasma membrane, and subsequent depletion of PIP2, as measured with a PIP2 biosensor. However, rapamycin did not induce translocation of Venus-FKBP12-Inp54p to the plasma membrane in FRBPLF-expressing DRG neurons (in vitro or in vivo). Moreover, rapamycin treatment did not alter PIP2-dependent thermosensation in vivo. Instead, rapamycin treatment stabilized FRBPLF in cultured DRG neurons, suggesting that rapamycin promoted dimerization of FRBPLF with endogenous FKBP12. CONCLUSIONS: Taken together, our data indicate that these knockin mice cannot be used to inducibly deplete PIP2 in DRG neurons. Moreover, our data suggest that high levels of endogenous FKBP12 could compete for binding to FRBPLF, hence limiting the use of rapamycin-inducible systems to cells with low levels of endogenous FKBP12.

Automated detection of axonal damage along white matter tracts in acute severe traumatic brain injury.

New techniques for individualized assessment of white matter integrity are needed to detect traumatic axonal injury (TAI) and predict outcomes in critically ill patients with acute severe traumatic brain injury (TBI). Diffusion MRI tractography has the potential to quantify white matter microstructure in vivo and has been used to characterize tract-specific changes following TBI. However, tractography is not routinely used in the clinical setting to assess the extent of TAI, in part because focal lesions reduce the robustness of automated methods. Here, we propose a pipeline that combines automated tractography reconstructions of 40 white matter tracts with multivariate analysis of along-tract diffusion metrics to assess the presence of TAI in individual patients with acute severe TBI. We used the Mahalanobis distance to identify abnormal white matter tracts in each of 18 patients with acute severe TBI as compared to 33 healthy subjects. In all patients for which a FreeSurfer anatomical segmentation could be obtained (17 of 18 patients), including 13 with focal lesions, the automated pipeline successfully reconstructed a mean of 37.5 ± 2.1 white matter tracts without the need for manual intervention. A mean of 2.5 ± 2.1 tracts resulted in partial or failed reconstructions and needed to be reinitialized upon visual inspection. The pipeline detected at least one abnormal tract in all patients (mean: 9.1 ± 7.9) and accurately discriminated between patients and controls (AUC: 0.91). The number and neuroanatomic location of abnormal tracts varied across patients and levels of consciousness. The premotor, temporal, and parietal sections of the corpus callosum were the most commonly damaged tracts (in 10, 9, and 8 patients, respectively), consistent with prior histopathological studies of TAI. TAI measures were not associated with concurrent behavioral measures of consciousness. In summary, we provide proof-of-principle evidence that an automated tractography pipeline has translational potential to detect and quantify TAI in individual patients with acute severe TBI.