Disentangling the Effects of Craniotomy and Traumatic Brain Injury in Experimental Models: A Narrative Review

Many widely used open-head models of traumatic brain injury (TBI) require craniotomy before injury, while sham-operated animals undergo surgery without impact and serve as controls. However, sham surgery itself may alter physiological, molecular, and behavioral parameters, complicating interpretation of TBI-specific effects. This narrative review, based on a structured PubMed search, synthesizes studies employing a three-group design to distinguish injury-related changes from those associated with craniotomy and other perioperative procedures. Evidence indicates that sham surgery produces outcome-, region-, and time-dependent effects that are generally milder, more localized, and more transient than TBI. These include neuroinflammatory responses, localized neuronal alterations, temporary sensorimotor and cognitive deficits, nociceptive changes, and shifts in gut microbiota. In contrast, TBI causes more severe abnormalities, including extensive neuronal damage, sustained astrogliosis, microglial activation, neutrophilic infiltration, mitochondrial dysfunction, and long-term dysbiosis. Most electrophysiological parameters are relatively unaffected by sham surgery, although selected changes have been reported. Importantly, differences between naïve and sham animals cannot be attributed exclusively to craniotomy, as anesthesia, analgesia, and surgical technique may contribute. Thus, sham surgery should not be considered a biologically neutral control. Inclusion of both naïve and sham groups is particularly important when distinguishing surgery-associated from injury-specific effects in preclinical studies.