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Open research questions in Traumatic Brain Injury and Neurovascular Disturbances

59 unresolved questions extracted from the limitations and future-work sections of 391 Traumatic Brain Injury and Neurovascular Disturbances papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • ImportanceNeuroinflammation is a key component of the response to injury after concussion, but direct links between diffusion MRI metrics and specific plasma inflammatory pathways in human concussion have not been established.

    Diffusion MRI Profiles Map onto Distinct Inflammatory States After Adolescent Concussion: A CARE4Kids Study · 2026 · DOI

  • Future research should address the limitations highlighted, by improving methodological rigour (e. The available evidence was limited and insufficient to support clear conclusions; however, hypotheses regarding structural MRI-derived features, particularly lower hip- pocampal volume, were generated based on their reported involvement across several psychopathologies.

    Transdiagnostic MRI-derived Features of Psychopathology Following Traumatic Brain Injury: A Systematic Review · 2026 · DOI

  • Despite the clinical relevance of this scenario, data on the incidence, management, and outcomes of TBI in anticoagulated mechanical valve patients remain scarce.

    Traumatic brain injury in patients with mechanical heart valves on lifelong anticoagulation: incidence, management, and outcomes of intracranial hemorrhage · 2026 · DOI

  • It was a non-ran- domized, non-controlled analysis of medical records conducted retrospectively, which meant there were no standardized indi- cations for intubation, mechanical ventilation, weaning, extu- bation, or ICU admission and discharge. These findings provide preliminary clinical evidence sup- porting the feasibility of early SPN in patients with TBI when EN alone is insufficient.

    Association of Early Supplemental Parenteral Nutrition with Clinical Outcomes in Patients with Traumatic Brain Injury · 2026 · DOI

  • It was a non-ran- domized, non-controlled analysis of medical records conducted retrospectively, which meant there were no standardized indi- cations for intubation, mechanical ventilation, weaning, extu- bation, or ICU admission and discharge. These findings provide preliminary clinical evidence sup- porting the feasibility of early SPN in patients with TBI when EN alone is insufficient.

    Association of Early Supplemental Parenteral Nutrition with Clinical Outcomes in Patients with Traumatic Brain Injury · 2026 · DOI

  • AM (corresponding author) – conceptualization, design, data collection, clinical assessment, methodology, and manuscript drafting. AA – literature search, data processing, and manuscript revision. TG, NA – data and manuscript revision. MG – data processing. RB – data collection and manuscript revision. Conflicts of interest: The authors declare no conflicts of interest. Financial support: This research did not receive any specific grant from funding agencies in the public, commercial, or nonprofit sectors. Future studies should include invasive ICP monitoring to clarify the relationship between ONSD and true intracranial pressure.

    Role of ultrasound-derived optic nerve sheath diameter in critically ill patients with metabolic encephalopathy: agreement with CT and prognostic implications · 2026 · DOI

  • This study has several important limitations. First, invasive ICP monitoring was not performed; there- fore, ONSD findings cannot be interpreted as valida- tion of actual intracranial pressure. Second, agree- ment between CT-ONSD and US-ONSD represents a comparison between two non-invasive surrogate techniques, and CT itself is not a gold standard for ICP measurement. Romanian JouRnal of neuRology – Volume 25, No. 1, 2026 Romanian JouRnal of neuRology – Volume 25, No. 1, 2026 87 Third, serial US measurements were not available for all patients at later time points due to death or clinical instability, introducing potential survivor- ship and attrition bias. Moreover, repeated measure- ments were analyzed without formal longitudinal mixed-effects modeling, limiting interpretation of temporal associations. Fourth, interobserver and intraobserver reliabili- ty were not formally assessed, as a single experienced operator measured each modality without independ- ent repeated measurements at separate time points. Although averaging two readings per eye may reduce random measurement error, reproducibility across observers or time points cannot be confirmed. Finally, the observational design limits causal in- ference. Important clinical confounders, including ventilation parameters (e.g., PEEP), PaCO2 levels, se- dation depth, osmotherapy, hemodynamic status, and fluid balance, were not controlled for or adjusted in the analysis and may have influenced ONSD meas- urements and their associations with clinical out- comes. tion, and adjustment for hemodynamic variables would help define ONSD’s independent contribution. Larger multicenter studies with longitudinal mode- ling and assessment of inter- and intraobserver relia- bility are needed to improve generalizability. Ethical approval and informed consent: Written informed consent was obtained. The study adhered to ethical guidelines and was ap- proved by the Research Ethics Committee at Mansou- ra Faculty of Medicine. The study was approved by the (IRB Code: MD.24.03.836). The confidentiality of patients’ infor- mation was maintained during all stages of the study. The research design adhered to the ethical principles outlined in the Declaration of Helsinki (1975).

    Role of ultrasound-derived optic nerve sheath diameter in critically ill patients with metabolic encephalopathy: agreement with CT and prognostic implications · 2026 · DOI

  • Although cortical thickness measurement cannot replace established clinical criteria or validated ancillary tests, its inte- gration with CT brain angiography may enhance di- agnostic confidence, especially in cases in which neurological examination is limited or CT brain angi- ography findings are equivocal. Prospective, multicenter studies with standard- ized imaging protocols and automated or semi-au- tomated measurement techniques are warranted to validate these findings and to establish clinically ap- plicable reference thresholds.

    Diagnostic Performance and Reliability of 4-Point CT Brain Angiography and Precentral Gyrus Cortical Thickness in Brain Death Assessment · 2026 · DOI

  • BACKGROUND AND OBJECTIVES: The rapid rise of electric and mechanical bikes and scooters has transformed urban transportation, but their neurosurgical consequences remain underexplored.

    The Fast and the Fragile: Neurosurgical Trauma in the Age of Micromobility · 2026 · DOI

  • SoT, also known as “sinking skin flap syndrome,” is an under-recognized complica- tion following DC, characterized by a spectrum of delayed neurological and physical symptoms that improve after cranioplasty (19).

    Clinical manifestations, progression and treatment of post-traumatic hydrocephalus accompanied by contralateral subdural effusion after decompressive craniectomy: a single-center retrospective study · 2026 · DOI

  • Together, these results may inform targets for early prevention and support further investigation of the causal pathophysiology underlying TBI-related brain cancer mortality.

    Brain Cancer Mortality following Traumatic Brain Injury (TBI): A TBI Model Systems Study · 2026 · DOI

  • The observational nature of the evidence remains the most important limitation. Most studies were retrospective with incomplete adjustment for confounding, although study quality has improved recently with publication of large prospective registries [5, 55]. One report of a randomized trial directly compared early (1–3 months) versus late (6–12 months) titanium-mesh cranioplasty and reported significantly higher BI scores at 30 days in the early group; however, numerical data were unavailable for inclusion in our synthesis. Three ongoing randomized trials may further strengthen the evidence base [34, 42, 59]. High heterogeneity across most analyses also limits inference. The most evident potential source was the wide variability in assessment times after CP, but differences patient selection, outcome definitions, surgical protocols, and reconstructive materials were also likely contributors. The latter may be particularly relevant, as included studies variably used autologous bone, titanium mesh, PMMA, and, in more recent practice, patient-specific implants. These differences may influence complication risk, fit, and perioperative course, and likely contribute to between-study variability even if they could not be formally stratified in the present review. Additional limitations include incomplete availability of primary summary statistics for some studies, imputation of change-score variances, and reliance on MMSE as the dominant cognitive outcome measure, which limits conclusions regarding broader cognitive recovery. 1 3Neurosurgical Review (2026) 49:440 Page 13 of 19 440 1 3Neurosurgical Review (2026) 49:440 440 Page 14 of 19 1 3Neurosurgical Review (2026) 49:440 Fig. 6 Forest plot of post-CP neurological outcome scores in the TBI subgroup, comparing early versus late CP. Effect estimates are presented as standardized mean differences (SMD), with positive values indicating greater scores in the early cranioplasty group. mRS and NIHSS scores inverted, so that positive SMD indicates better function Future research should prioritize well-designed prospective multicenter trials incorporating standardized timing definitions, unified outcome measures, and extended follow-up to evaluate both neurological and quality-of-life outcomes. Integration of perfusion imaging and neurophysiological monitoring could further elucidate mechanisms underlying functional improvement. Development of predictive models incorporating patient-specific factors, such as etiology, defect size, and complication risk, may enable individualized timing strategies. Page 15 of 19 440 Fig. 7 Forest plot comparing change in neurological outcome scores between early and late CP in the TBI subgroup. Effect estimates are presented as standardized mean differences (SMD) of change in scores, with positive values indicating greater improvement in the early CP group. mRS and NIHSS scores inverted, so that positive SMD indicates better function 1 3Neurosurgical Review (2026) 49:440 440 Page 16 of 19 Fig. 8 Forest plot of post-CP neurological outcome scores comparing ultra-early versus later CP. Effect estimates are presented as standardized mean differences (SMD), with positive values indicating greater scores in the ultra-early CP group. mRS scores inverted, so that positive SMD indicates better function Fig. 9 Forest plot comparing change in neurological outcome scores between ultra-early and later. Effect estimates are presented as standardized mean differences (SMD) of change in scores, with positive values indicating greater improvement in the ultra-early CP group.

    Timing of cranioplasty after decompressive craniectomy and neurological recovery: A systematic review and meta-analysis · 2026 · DOI

  • Additional patient 1 3Neurosurgical Review (2026) 49:419 populations should be studied to determine more specific conditions for which ICP monitoring would have the best indication, improving outcomes in patients with TBI.

    The effect of intracranial pressure monitoring on severe traumatic brain injury patients who undergo subdural hematoma evacuation · 2026 · DOI

  • This study has several limitations. First, its retrospective single- center design limits causal inference and raises the possibility of resid- ual confounding despite multivariable adjustment. Second, although onset-to-admission time was available for all patients and was included in sensitivity analyses, the precise timing of each laboratory test relative to injury onset, admission, and clinical interventions may still have varied across patients. Third, the primary AAR exposure was based on median in-hospital AST and ALT values, which may capture the overall biochemical burden during hospitalization rather than a purely baseline biomarker. To address this issue, we performed sensi- tivity analyses using the first available AAR measurement, but pro- spective studies with standardized sampling windows are still needed. Fourth, disease categories used for analysis inevitably simplified clini- cally heterogeneous entities. In particular, hemorrhagic lesions differ in etiology and mechanism, and traumatic and hemorrhagic pheno- types may overlap in real-world practice. Finally, the biological mech- anisms underlying the stronger association of AAR with TBI outcomes remain inferential and were not directly measured. External validation in independent cohorts and integration with dynamic biomarker, imaging, and molecular data will be necessary before AAR can be incorporated into broader prognostic frameworks for neurocriti- cal care.

    Distinct prognostic value of aspartate-to-alanine aminotransferase ratio (AAR) in traumatic brain injury versus hemorrhagic stroke: a cohort study of 1,069 patients · 2026 · DOI

  • Ethics statement This study has several limitations. First, the sample size was modest, and the wide disease-duration range (1–24 months) may have introduced clinical heterogeneity, as biomarker profiles, endocrine status, imaging findings, and cognitive performance can vary across different stages of TBI. Second, although all participating centers followed a common study protocol, residual implementation inter-center differences in testing platforms, details, and clinical practice may still have influenced the results. Third, this study was designed to focus on routine blood and hormonal biomarkers rather than to construct a fully comprehensive clinical model; therefore, some potentially important clinical confounders were not incorporated into the modeling process. In addition, given the limited sample size, the use of multiple machine learning models and a single train-validation split may have affected model stability, and the relatively low validation-set R² values indicate limited predictive performance. Finally, the cross-sectional design precludes causal inference, and the observed associations, including the suggested nonlinear patterns, should be regarded as exploratory. Larger studies with more homogeneous populations longitudinal and more comprehensive clinical adjustment are needed for further validation. The studies involving humans were approved by the ethics committee of China Rehabilitation Research Center. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

    Screening of biomarkers and machine learning prediction in traumatic brain injury · 2026 · DOI

  • The major limitation of the study is the retrospective design, which would have missed cases with hidden PSH-like activity and the effect of recall bias. The scores could have been lower, as subjective components like sweating and posturing would not have been properly evaluated. Apart from this, the study is limited by its reproducibility due to a small sample size (n = 7) and a lack of standardized treatment protocols. The outcome of cases with PSH-AM scores less than 16 was not evaluated. There was no uniform treatment for those cases with a PSH-AM score ≥17, and the analysis was done on a very small number of patients (n = 7). Scores of 8-16 were unevaluated, resulting in missed diagnoses for these patients, which could further affect the generalizability. An audit on the excessive use of drugs, organ supports, changing existing invasive catheters, and investigations during the period of PSH, assuming it to be a seizure or infection, could have further highlighted the hidden cost of underdiagnosis of PSH in the study.

    Paroxysmal Sympathetic Hyperactivity in Non-traumatic Brain Injury: A Retrospective Analysis From the Intensive Care Unit of a Tertiary Care Academic University · 2026 · DOI

  • Further longitudinal studies with a prospective multi-center study design screening for PSH-AM score daily in patients with non-traumatic brain insult in the intensive care unit are needed to evaluate the impact of PSH in such a cohort. While the PSH-AM remains the gold standard, its low specificity in the ICU remains a challenge. Future modifications, such as incorporating automated physiological trending or re-weighting the DLT for non-traumatic etiologies, may enhance its utility in hypoxic and encephalitic populations [3]. The score should be revised for an ICU setting with less reliance on qualitative parameters like excessive sweating. Further clarity on how frequently this condition should be screened for should also be evaluated.

    Paroxysmal Sympathetic Hyperactivity in Non-traumatic Brain Injury: A Retrospective Analysis From the Intensive Care Unit of a Tertiary Care Academic University · 2026 · DOI

  • The acoustic window quality dependency and operator proficiency requirements for TCD limit its applicability in certain geriatric patient populations. Systematic assessment of which patient characteristics (obesity, advanced age, anatomical variations) predict inadequate acoustic windows and development of alternative or supplementary imaging approaches for these populations is lacking.

    Transcranial Doppler ultrasonography in geriatric anesthesia: moving toward personalized brain protection strategies · 2026 · DOI

  • The clinical feasibility and safety of portable and wearable TCD systems for continuous long-term hemodynamic monitoring in post-anesthesia care units, intensive care units, and home-care settings remain untested. Development and validation of compact TCD devices enabling extended perioperative and post-discharge brain protection monitoring in elderly patients across diverse care environments is needed.

    Transcranial Doppler ultrasonography in geriatric anesthesia: moving toward personalized brain protection strategies · 2026 · DOI

  • Standardized multimodal monitoring protocols that formally integrate TCD with electroencephalography, bispectral index, near-infrared spectroscopy, and biomarker analysis to achieve personalized brain-protection strategies in geriatric anesthesia have not been established. Specific procedural guidelines and decision-making algorithms combining these complementary modalities require development and validation.

    Transcranial Doppler ultrasonography in geriatric anesthesia: moving toward personalized brain protection strategies · 2026 · DOI

  • Long-term cognitive outcomes in relation to intraoperative perioperative cerebral perfusion variability and cumulative microembolic load detected by TCD remain uninvestigated. Future research must establish the quantitative relationship between TCD-measured hemodynamic parameters during surgery and postoperative cognitive dysfunction development in geriatric patients over extended follow-up periods.

    Transcranial Doppler ultrasonography in geriatric anesthesia: moving toward personalized brain protection strategies · 2026 · DOI

  • The clinical utility of correlating intraoperative TCD-derived parameters (microembolic load and hypoperfusion duration) with postoperative cerebrospinal fluid and serum biomarkers (neuron-specific enolase, S100B protein) for predicting perioperative brain injury has not been systematically validated. Research integrating these hemodynamic measurements with neuronal injury biomarker concentrations is needed to establish comprehensive risk assessment models.

    Transcranial Doppler ultrasonography in geriatric anesthesia: moving toward personalized brain protection strategies · 2026 · DOI

  • Robotic probe positioning and AI-based waveform analysis for TCD show promise in reducing operator dependence, but current research consists only of feasibility and proof-of-concept studies. Large-scale validation of these robotic and AI-assisted TCD systems across diverse perioperative patient populations, with specific assessment of probe fixation safety, algorithm transparency, and workflow integration, is lacking.

    Transcranial Doppler ultrasonography in geriatric anesthesia: moving toward personalized brain protection strategies · 2026 · DOI

  • Current evidence for TCD in geriatric anesthesia derives predominantly from small-scale observational or retrospective studies. Large, multicenter randomized controlled trials are urgently needed to validate the relationship between specific TCD-derived parameters (mean flow velocity, microembolic signals, pulsatility index) and quantifiable perioperative neurological outcomes in elderly surgical patients.

    Transcranial Doppler ultrasonography in geriatric anesthesia: moving toward personalized brain protection strategies · 2026 · DOI

  • The low and invariable percentages of frames achieving statistical significance for K2 across experimental conditions suggest that squared coherence may have limited discriminative utility in CA characterization; investigation is needed to determine whether alternative coherence thresholding strategies or multivariate coherence measures would improve detection sensitivity in populations with preserved cerebrovascular regulation.

    Accounting for squared coherence marginally improves the discriminative power of frequency domain cerebral autoregulation markers in surgical aortic valve replacement patients · 2026 · DOI

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59 open questions have been extracted from the limitations and future-work passages of 391 Traumatic Brain Injury and Neurovascular Disturbances papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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