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Stefano Signoretti, Roberto Vagnozzi, Barbara Tavazzi and Giuseppe Lazzarino

Although numerous studies have been carried out to investigate the pathophysiology of mild traumatic brain injury (mTBI), there are still no standard criteria for the diagnosis and treatment of this peculiar condition. The dominant theory that diffuse axonal injury is the main neuropathological process behind mTBI is being revealed as weak at best or inconclusive, given the current literature and the fact that neuronal injury inherent to mTBI improves, with few lasting clinical sequelae in the vast majority of patients.

Clinical and experimental evidence suggests that such a course, rather than being due to cell death, is based on temporal neuronal dysfunction, the inevitable consequence of complex biochemical and neurochemical cascade mechanisms directly and immediately triggered by the traumatic insult.

This report is an attempt to summarize data from a long series of experiments conducted in the authors' laboratories and published during the past 12 years, together with an extensive analysis of the available literature, focused on understanding the biochemical damage produced by an mTBI.

The overall clinical implications, as well as the metabolic nature of the post-mTBI brain vulnerability, are discussed. Finally, the application of proton MR spectroscopy as a possible tool to monitor the full recovery of brain metabolic functions is emphasized.

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Anthony Marmarou, Stefano Signoretti, Panos P. Fatouros, Gina Portella, Gunes A. Aygok and M. Ross Bullock


The edema associated with brain swelling after traumatic brain injury (TBI) has been thought to be vasogenic in origin, but the results of previous laboratory studies by the authors have shown that a cellular form of edema is mainly responsible for brain swelling after TBI. In this study the authors used magnetic resonance (MR) imaging techniques to identify the type of edema that occurs in patients with TBI.


Diffusion-weighted MR imaging was used to evaluate the apparent diffusion coefficient (ADC) in 44 patients with TBI (Glasgow Coma Scale Score < 8) and in eight healthy volunteers. Higher ADC values have been associated with vasogenic edema, and lower ADC values with a predominantly cellular form of edema. Regional measurements of ADC in patients with focal and diffuse injury were computed. The water content of brain tissue was also assessed in absolute terms by using MR imaging to measure the percentage of water per gram of tissue. Cerebral blood flow (CBF) was measured using stable Xe–computerized tomography (CT) studies to rule out ischemia as a cause of cellular edema.

The mean ADC value in the healthy volunteers was 0.82 ± 0.05 × 10−3 mm2/second. The ADC values in the patients with diffuse brain injury without swelling were close to the mean for the healthy volunteers. In contrast, the patients with brain swelling had increased brain water content and low ADC values (mean 0.74 ± 0.05 × 10−3 mm2/second). The ADC values correlated with CT classifications. In all patients with low ADC values, the CBF values were outside the range for ischemia.


The brain swelling observed in patients with TBI appears to be predominantly cellular, as signaled by low ADC values in brain tissue with high levels of water content.

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Stefano Signoretti, Anthony Marmarou, Gunes A. Aygok, Panos P. Fatouros, Gina Portella and Ross M. Bullock


The goal of this study was to demonstrate the posttraumatic neurochemical damage in normal-appearing brain and to assess mitochondrial dysfunction by measuring N-acetylaspartate (NAA) levels in patients with severe head injuries, using proton (H) magnetic resonance (MR) spectroscopy.


Semiquantitative analysis of NAA relative to creatine-containing compounds (Cr) and choline (Cho) was carried out from proton spectra obtained by means of chemical shift (CS) imaging and single-voxel (SV) methods in 25 patients with severe traumatic brain injuries (TBIs) (Glasgow Coma Scale scores ≤ 8) using a 1.5-tesla MR unit. Proton MR spectroscopy was also performed in 5 healthy volunteers (controls).


The SV studies in patients with diffuse TBI showed partial reduction of NAA/Cho and NAA/Cr ratios within the first 10 days after injury (means ± standard deviations 1.59 ± 0.46 and 1.44 ± 0.21, respectively, in the patients compared with 2.08 ± 0.26 and 2.04 ± 0.31, respectively, in the controls; nonsignificant difference). The ratios gradually declined in all patients as time from injury increased (mean minimum values NAA/Cho 1.05 ± 0.44 and NAA/Cr 1.05 ± 0.30, p < 0.03 and p < 0.02, respectively). This reduction was greater in patients with less favorable outcomes. In patients with focal injuries, the periphery of the lesions revealed identical trends of NAA/Cho and NAA/Cr decrease. These reductions correlated with outcome at 6 months (p < 0.01). Assessment with multivoxel methods (CS imaging) demonstrated that, in diffuse injury, NAA levels declined uniformly throughout the brain. At 40 days postinjury, initially low NAA/Cho levels had recovered to near baseline in patients who had good outcomes, whereas no recovery was evident in patients with poor outcomes (p < 0.01).


Using 1H-MR spectroscopy, it is possible to detect the posttraumatic neurochemical damage of the injured brain when conventional neuroimaging techniques reveal no abnormality. Reduction of NAA levels is a dynamic process, evolving over time, decreasing and remaining low throughout the involved tissue in patients with poor outcomes. Recovery of NAA levels in patients with favorable outcomes suggests marginal mitochondrial impairment and possible resynthesis from vital neurons.

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Anthony Marmarou, Panos P. Fatouros, Pal Barzó, Gennarina Portella, Masaaki Yoshihara, Osamu Tsuji, Takuji Yamamoto, Fred Laine, Stefano Signoretti, John D. Ward, M. Ross Bullock and Harold F. Young

Object. The pathogenesis of traumatic brain swelling remains unclear. The generally held view is that brain swelling is caused primarily by vascular engorgement and that edema plays a relatively minor role in the swelling process. The goal of this study was to examine the roles of cerebral blood volume (CBV) and edema in traumatic brain swelling.

Methods. Both brain-tissue water and CBV were measured in 76 head-injured patients, and the relative contribution of edema and blood to total brain swelling was determined. Comparable measures of brain-tissue water were obtained in 30 healthy volunteers and CBV in seven volunteers. Brain edema was measured using magnetic resonance imaging, implementing a new technique for accurate measurement of total tissue water. Measurements of CBV in a subgroup of 31 head-injured patients were based on consecutive measures of cerebral blood flow (CBF) obtained using stable xenon and calculation of mean transit time by dynamic computerized tomography scanning after a rapid bolus injection of iodinated contrast material. The mean (± standard deviation) percentage of swelling due to water was 9.37 ± 8.7%, whereas that due to blood was −0.8 ± 1.32%.

Conclusions. The results of this study showed that brain edema is the major fluid component contributing to traumatic brain swelling. Moreover, CBV is reduced in proportion to CBF reduction following severe brain injury.