To the Editor: We appreciate the positive comments1 about our updated decompressive craniectomy chapter for the Guidelines for the Management of Severe Traumatic Brain InjuryFourth Edition2,3 as well as the recently published algorithms for the treatment of severe traumatic brain injury (TBI).4,5 We also share the author's concern that neurosurgeons’ focus on cellular and molecular pathology of neurotrauma is decreasing. A generation ago neurosurgeons were significant contributors to basic science efforts aimed at improving our understanding of cellular and molecular pathomechanisms which follow central nervous system (CNS) injury as well as efforts to develop therapies. For a variety of reasons, neurosurgeons are currently contributing less to the basic science of neurotrauma than in the past. We believe that neurosurgeons well-versed in cellular and molecular mechanisms of secondary injury/CNS injury are likely to be more attentive to the secondary insults noted at the bedside like hypoxia and hypotension, which occur at the level of the organism. Guidelines have led to substantial improvements in patient outcomes6 from TBI despite a relative lack of literature from which to draw. Unfortunately, however, a safe and effective therapeutic directly targeting the neural injury remains to be translated. Diverse research efforts remain justified and hope remains that new approaches may find success where historic efforts did not. There seem to be some fundamental flaws in the TBI research conducted to date which have contributed to the lack of progress. Trials have failed to sufficiently account for the heterogeneity of TBI patients either with enrollment criteria or with analytic methods, and this, undoubtedly, left historical TBI trials grossly underpowered.7 Cerebral autoregulatory principles remain insufficiently accounted for in patient treatment at most institutions. Moreover, it is interesting to consider that Lundberg's demonstration of increased blood volume during plateau waves8 (which accords with Rosner's vasodilatory and vasocontriction cascades9) disproves at least a strict interpretation of the Kellie-Monro Doctrine. Additionally, cortical spreading depressions/depolarizations seem an important contributor to TBI pathophysiology, but we are just beginning to understand this phenomenon.10 The pathophysiology of delayed dementias after TBI—dementia pugilistica, “Alzheimer's Disease,” and chronic traumatic encephalopathy—remains unclear.11 Once these and other fundamental aspects of TBI care are better understood and accounted for, translational TBI studies are more likely to bear fruit. Funding This study did not receive any funding or financial support. Disclosures The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.