Examining lactate in severe TBI using proton magnetic resonance

Brain Injury, August 2007; 21(9): 981–991

CASE STUDY

Examining lactate in severe TBI using proton magnetic

resonance spectroscopy

F. G. HILLARY1,2, W. C. LIU3, H. M. GENOVA4,5, A. H. MANIKER3, K. KEPLER3,B. D. GREENWALD3, B. M. CORTESE2, A. HOMNICK3, & J. DELUCA3,4

1Psychology Department, Pennsylvania State University, University Park, PA, USA, 2Hershey Medical Center,

Hershey, PA, USA, 3University of Medicine and Dentistry at New Jersey, New Jersey Medical School, Newark, NJ,

USA, 4Kessler Medical Rehabilitation Research and Education Corporation, West Orange, NJ, USA, and5The Integrative Neuroscience Program Graduate School of Biomedical Sciences, Newark, NJ, USA

(Received 11 January 2007; revised 8 March 2007; accepted 23 March 2007)

AbstractPrimary objective: Clinical management of acute traumatic brain injury (TBI) has emphasized identification of secondarymechanisms of pathophysiology. An important objective in this study is to use proton magnetic resonance spectroscopy(pMRS) to examine early metabolic disturbance due to TBI.Research design: The current design is a case study with repeated measures.Method and procedure: Proton magnetic resonance imaging was used to examine neurometabolism in this case of very severebrain trauma at 9 and 23 days post-injury. MRI was performed on a clinical 1.5 Tesla scanner.Main outcomes and results: These data also reveal that pMRS methods can detect lactate elevations in an adult survivingsevere head trauma and are sensitive to changes in basic neurometabolism during the first month of recovery.Conclusions: The current case study demonstrates the sensitivity of pMRS in detecting metabolic alterations during the acuterecovery period. The case study reveals that lactate elevations may be apparent for weeks after severe neurotrauma. Furtherwork in this area should endeavour to determine the ideal time periods for pMRS examination in severe TBI as well as theideal locations of data acquisition (e.g. adjacent or distal to lesion sites).

Keywords: TBI, MRI, MRS, Coma, brain injury, lactate

Background

Traumatic brain injury (TBI) has been defined as aninjury to the brain resulting from an externalmechanical force, which may lead to significantimpairment in the individual’s physical, cognitiveand psychosocial functioning [1]. The chiefclinical feature characterizing severe TBI is aperiod of altered consciousness, lasting from severalhours to even days or weeks in the most severe cases.Acute recovery from moderate and severe TBItypically includes progression from diminishedresponsiveness, to periods of agitation and

restlessness, to post-traumatic amnesia and, finally,re-orientation [2–4].

The early recovery course following TBI dependslargely upon the location of brain insult, the injuryseverity and mechanism of pathophysiology [5].There is an extensive literature examining thesecondary physiological effects that exacerbate andextend the effects of neurotrauma [6–9] and onecommon form of secondary injury is cerebraloedema. Simply defined, brain oedema followingtrauma is due to an increase in water volume whichin turn increases tissue volume [10] and examiners

Correspondence: Frank G. Hillary, PhD, Assisant Professor, Psychology Department, Pennsylvania State University, 223 Moore Building, University Park,PA 16802, USA. E-mail: [email protected]

ISSN 0269–9052 print/ISSN 1362–301X online � 2007 Informa UK Ltd.DOI: 10.1080/02699050701426964

of brain trauma have been aware of the influences ofvasogenic, cytotoxic and osmotic sources for brainoedema for over 4 decades [11, 12]. Cytotoxicoedema has been attributed to hyperglycolysis orthe interstitial accumulation of glutamate andwidespread neural excitation during a period ofmetabolic crisis [13, 14]. Stimulation of glutamatereceptors also results in an influx of water bindingions into the cell, resulting in cellular oedema (NAþ,Hþ, Ca2þ, Cl�) [15, 16]. In experimental TBI,elevations in glucose metabolism have been shown tooccur within minutes of the injury [17] and earlyelevations in glutamate have been shown to lastfor 7–9 days following TBI [18]. It is important tonote that these periods of energy crisis and anaerobiccellular respiration result in elevations in lactate,a marker for ischemia. The examination of Lactateand its role in secondary injury in ischemic processeshas received considerable attention over the pasttwo decades [19–22] and is a central feature in thiscase study.

Attempts to examine the basic brain changesassociated with coma emergence have been hinderedby several factors including medical instability inpatients with TBI and methodological limitationsusing invasive neurosurgical procedures such asmicrodialysis [23]. Clinical challenges remainin prognostication and acute treatment planningfollowing severe neurotrauma and informationregarding local neurometabolism cannot be reliablyobtained via peripheral measurements (e.g. blood,serum). Continued work is required thatintegrates information about the neural environmentwith clinical/behavioural indicators of recovery.Procedures, such as pMRS, afford such an oppor-tunity to examine, non-invasively, the neurometa-bolic abnormalities associated with oedema andassociated ischemia in severe neurotrauma.

Proton magnetic resonance spectroscopy (pMRS)

Proton magnetic resonance spectroscopy (pMRS) isbased on the same basic physical principlesemployed in conventional MR sequences; however,the signal is not derived simply from water or lipidas in conventional MR imaging. Signals arising inpMRS are produced by hydrogen nuclei in largermacromolecules creating distinct local magneticenvironments. Because of this, pMRS provides anon-invasive method for in vivo measurementof specific neurometabolites following severe TBI.Moreover, pMRS affords the opportunity to exam-ine neurometabolic status locally, thus allowingfor comparisons between distinct sites within thebrain (e.g. areas proximal and distal to lesions).

pMRS has received considerable recent attentionin the study of TBI for both humans and animals

and much of this work has documented changesin N-acetylaspartate (NAA) and Choline (Cho)concentrations. In humans, pMRS has been usedto document white matter degradation of the corpuscallosum [24] and widely applied in chronic TBIexamining the relationships between NAA and Chovalues and injury severity [25] and cognitiveperformance measured at 1 and 6 monthsfollowing the injury [26–28]. Separately, glutamateand Cho elevations, specifically, have been linkedto patient outcome 6–12 months post-injury [29].This work has established that metabolites suchas NAA and Cho remain abnormal when measuredmonths after the injury and are importantindicators of injury severity and predictive of patientoutcome.

This literature has established the utility inusing pMRS methods to characterize chronicTBI; however, few investigations have usedlongitudinal methods to examine the evolution ofneurometabolism over time. Two studies examiningmoderate and severe TBI have compared pMRSdata collected within the first few days after injury tomeasurements taken months later [30, 31] andCondon et al. [32] presented a case of moderatehead injury where lactate was elevated only within afocal area of contusion at 8 hours and 6 days post-injury. These important efforts further validate theuse pMRS methods in acute neurotrauma and offerinsight into the early metabolic processes during acritical period of recovery where energy crisis islikely. Of interest, lactate elevations have beeninconsistently observed using pMRS methods inadults, with many examiners failing to detect lactateelevations [25, 31, 33–35] and others noting Lacelevations in isolated cases [31, 32]. Moreover,Condon et al. [32] are the only examiners inTBI that have used serial, acute pMRS measure-ments and no study to date has used pMRS todocument lactate elevations after the first weekof injury.

Employing serial acute pMRS acquisition offersthe opportunity to study important early indicatorsof secondary injury and recovery in TBI. Thecurrent case study uses serial pMRS measurementsto document neurometabolic disruption followingsevere TBI during the first month of recovery. Thereare three aims in presenting this case study: (1) toshow that serial examination of pMRS is sensitive todocumenting changes in baseline neurometabolismduring acute recovery from severe TBI, (2) todemonstrate that elevations in lactate may persistfor weeks in the case of very severe TBI and (3) todemonstrate that even in very severe TBI, lactate isonly inconsistently observable and dependent uponthe location that tissue is sampled.

982 F. G. Hillary et al.

Methodology

Participants

The study participant, VH, was a 43 year old AfricanAmerican male admitted to a Level I Trauma Centrein the northeastern US after being found uncon-scious in a dwelling. He had been assaulted with ablunt instrument, sustaining what appeared to berepeated blows to the right anterior and posteriorportions of the skull. His admission GCS scorewas initially a 6T, but this score varied over thecourse of the first 3 weeks in the hospital (see Table Ifor injury severity and descriptive clinical informa-tion). In order to make inferences about baselinemetabolic functioning, the results from this partici-pant were compared to the averaged findings in twohealthy adults of comparable age. The two healthyparticipants were solicited from within the localcommunity through newspaper advertisementand by public postings of flyers (e.g. in localsupermarkets, hospitals).

Procedure

The overall aim of this case study was to usepMRS, a non-invasive neuroimaging technique, tocharacterize the evolution of neurometabolismduring recovery from severe TBI. To do so, thefollowing procedure was used: (1) family interviewto determine if the patient was a potential candidatefor the study and, with IRB approved consent,review of medical records, (2) two pMRS scans,the first during week 1 of recovery and the secondat week 3 and (3) neuropsychological assessmentat 6 months post-injury.

A total of four contacts were required for studycompletion. Once the patient was medically stable,an initial interview was conducted with the patient’swife. The aims and scope of this investigation were

broached with the patient’s wife to determineinterest and if the patient was appropriate for thestudy. The exclusionary criteria were carefullyaddressed with her in order to guarantee that sheunderstood that participation in the study wasvoluntary and independent from the treatmentreceived at the hospital. Upon entry into the study,the patient’s wife was required to sign anIRB-approved consent form. With informedconsent, medical records were reviewed to documentclinical information regarding the nature andmagnitude of the brain injury. At 9 days post-injury,the first pMRS scanning was performed and at23 days post-injury, the second pMRS scan wasperformed. Finally, at 6 months post-injury,outpatient follow-up and cognitive assessment wasconducted. It was the intention to conduct pMRSscanning at the 6-month pMRS follow-up interval,but the subject had undergone placement of aprogrammable shunt to monitor CSF levels,between the time of the second scan and the6-month follow-up, precluding MRI scanning.

Neuroimaging procedures

All MRI data acquisition was carried out on a 1.5GE MR whole body scanner used for clinical andresearch purposes. A highly reproducible acquisitionprotocol was followed consistent with Brooks et al.[36] to ensure accurate localization of pMRS voxelsbetween subjects and across examinations. Thisapproach has been validated in additional studies[37] and employed for the study of TBI over time[34]. All MRI data acquisition was carried out on a1.5 GE MRI Signa scanner (General ElectricMedical System, Milwaukee, WI) using availableproduct software. Imaging sequences includedT1-weighted sagittal and coronal localizers(TE¼16 ms, TR¼500 ms, 256�128 matrix,

Table I. Variables describing clinical progression of VH.

Days post-injury GCS ICP CRS score Rancho Clinical notes

2 6 20–30 * * Localize to pain, pupil non-reactive,Flexor> extensor

3 * 18–25 * *4 * 16–32 * * Decerebrate posturing6 4–6T * * * Extensor posturing7 4–5 12–30 * *8 4 18–27 * *

*9 4 18–25 * * Decerebrate posturing10 4 <20 * *12 * * 4 II

*24 * * 8 * Not following commands26 * * 6 II–III Not following commands34 * * 10.5 II–III Not following commands

CRS¼Coma Recovery Scale, Rancho¼Rancho Los Amigos Level of Cognitive Functioning Scale,ICP¼ intracranial pressure in mmHg, GCS¼Glasgow Coma Scale.*Dates of MRI Scanning (day 9 and day 23).

Examining lactate in severe TBI 983

5 mm thick slices with a 2.5 mm gap), a T1-weightedvolume axial series (MPRage, TE¼ 6.9 ms,TR¼ 17.7 ms, flip angle¼25�, 256�192 matrix,1.5 mm contiguous slices) and a conventional T1FLAIR (TE, echo time¼ 140, TR, repetitiontime¼ 10 000/140, TI, time of inversion¼ 2200,FOV¼ 20 cm, 5 mm/skip 0) composed of 24 slicesproviding whole brain coverage. For each scan, theAC-PC was aligned with the 11th axial slice.

For single-voxel spectroscopic acquisition, aSTEAM pulse sequence, including both water-suppressed (metabolite) and water-unsuppressedacquisitions, were employed to sample a voxel of2�2�2 cm (TE¼ 30 ms, TR¼ 2000 ms, 128averages) within three brain locations: thalamusgray matter, midline occipital gray matter and frontalgray. For multiple voxel data acquisition, theidentical 1.5 T GE MRI machine was used. APRESS pulse sequence was used to sample a voxelof 1� 1� 1 mm (TE¼144, TR¼ 1500, FOV¼ 24,NEX¼ 8). Multi-voxel data were collected in frontalgray and white matter. Figure 1 illustrates the sitesfor single voxel locations in midline occipital frontalwhite matter and thalamus as well as the multi-voxeldata in frontal areas for the current case study.

To maximize reproducibility, data was acquiredobliquely by aligning the slices for T1 acquisitionwith the anterior commissure and posteriorcommissure (AC-PC). At the time of the first scan,an image documenting the x and y coordinates inthe z-plane was created and maintained in theDepartment of Radiology on the University PACSsystem for use at the time of follow-up scanning.

This procedure provided a conservative estimatefor voxel placement at the time of subsequentscanning and maximized the reproducibility ofthe results.

Imaging data reconstruction

MR images corresponding to pMRS voxels weremasked by voxel coordinates and segmented usingsemi-automated histogram analysis to obtain frac-tions of gray matter, white matter and cerebrospinalfluid (CSF). Fractional tissue percentage (% gray/white) were used as a covariate in all analysescomparing metabolite concentrations. Single voxelspectroscopic data were analysed using LCModel[38] and quantification code written at theUniversity of Washington kindly provided byDr Seth Friedman. Briefly, for metabolite quantifi-cation, water unsuppressed and metabolite spectrawere fit using LCModel [38] in an unsupervisedbatch run. For the single voxel data analysis,LCModel is advantageous because it utilizesa library of available chemistry in the protonspectrum for spectral fitting. This approach,combined with the marked benefits of high-field onspectral resolution, allowed optimal measurementof the major metabolic peaks (Cho, Cre, NAA, Lac).

Multiple voxel data were analysed separately usingSAGE software. The data were reconstructed andanalysed on a voxelwise basis with specific attentiongiven to metabolites in the chemical shift rangebetween 1.0–3.7 (NAA appearing between2.01–2.14, Cre appearing between 3.08–3.15 and

Figure 1. Example of data acquisition sites for subject VH at time 1 (day 9). Single voxel data were acquired in midline occipital, frontalwhite matter, thalamus and multi-voxel data were acquired in frontal white and gray matter.


Cho appearing between 2.26–3.35). Raw multi-voxel data were reconstructed using SAGE softwarethe peaks for water, NAA, Cre and Cho were fittedusing Marquardt fitting algorithm determiningthe amplitude, frequency, width and area of therelevant spectra. Spectral width was used to aidin determining adequate baseline to spectral differ-entiation and any spectra with a width of greaterthan 10 were excluded.

Clinical course and study results

Clinical progression

As noted, the patient’s medical records indicatedthat at the time of the injury VH was found‘groaning’ and not following commands. Hisresponse to painful stimuli varied over the course ofthe first 2–3 days, but between days 4–10 he showedprimarily decerebrate posturing. Unspecified seizureactivity was noted on the day of the injury andthe patient was febrile over the course of thefollowing several days. Initial CT results revealedright hemisphere intraparenchymal haemorrhage,temporal and parietal haematomas, leftsubarachnoid haemorrhage, sphenoid, mastoid andbasilar skull fractures. An emergent craniotomy wasperformed and evacuation of a left hemispheresubdural haematoma. Table I summarizes clinicalprogression of VH during the first month of recovery.

Neuropsychological functioning at 6 months

Table II summarizes results of the neuropsychologi-cal assessment. The assessment measures completedby VH focused on areas commonly reported to bedeficient in individuals with TBI: speeded informa-tion processing, attention and episodic memory[39, 40]. He was administered the Digit Spansub-test of the Wechsler Adult IntelligenceScale–Third Edition, a measure of simple attentionand working memory, the Information sub-test fromthe WAIS-III, a measure of general knowledge,Trails A and B which are tests of speededvisual processing, sequencing and mental flexibility,the Rey Complex Figure, a measure of visuo-construction and visual memory, the HopkinsVerbal Learning Test (HVLT) a list learning task,Matrix Reasoning from the WAIS-III, a test ofproblem-solving and mental flexibility, and the WideRange Achievement Test–Third Edition (WRAT-3)reading sub-test, a test of word recognition.The patient had significant residual motor impair-ment and consequently he was unable to completetasks requiring motor responses, including speededwritten tasks. For most tasks completed, the patientperformed in the impaired range with relative

weaknesses in the area of cognitive flexibility, newlearning and visuospatial construction. He showedpreserved cognitive skills in the areas ofsimple attention and working memory, which wasunexpected given the severity of this injury.

pMRS findings

Consistent with prior work examining chronic TBI,VH showed relative differences in basic neurometa-bolic functioning compared to healthy adults(see Table III). Example spectra for a HC subjectare illustrated in Figure 2. Specifically, in all areasexamined (midline occipital, frontal white matterand thalamus), VH showed diminished NAA andelevated Cho. As noted in Table III, in the case ofVH the data were occasionally unreliable and werenot interpreted when the percentage standarddeviation (% SD) for any neurometabolic valuewas greater than 20. Potential reasons for thesesources of error are subject movement and local fieldinhomogeneity attributable to haemorrhage andthese are discussed in greater detail below. In themulti-voxel data, comparison of individual voxelsacross time points and averaging results across voxelsrevealed consistent increases in NAA and decreasesin Cho from time 1 to time 2 (see Figure 5).

An important finding illustrated in the currentcase study is the significant elevation in lactate atboth time points of data acquisition. The elevationsin lactate observable at 9 days post-injury were veryhigh and these elevations remain apparent at 23 dayspost-injury (see Figures 3 and 4). The latest of thesefindings occurred over 1 week after there were any

Table II. Neuropsychological testing results at 6 monthspost-injury.

Test Raw score Performance range

Digit SpanForward 9 Average rangeBackward 7 Average rangeTotal 16 Average range

Information 15 Borderline range

Trails A 200’’ <1st PercentileTrails B D/C at 144’’ <1st Percentile

Rey complex figureCopy 10 Severely impairedImmediate 8 Severely impairedDelay 7 Severely impaired

HVLTTrial 1 4 Impaired rangeTrial 2 6 Impaired rangeTrial 3 8 Impaired rangeTotal 18 Impaired rangeRecognition 12/12 Average range

Matrix reasoning 3 Severely impaired

WRAT–Reading sub-test 43 Low average range


clinical indicators of elevated ICP. While spectralanalysis did not allow for direct quantification of thelipid/lactate peak, its absolute concentrations inthe healthy brain typically make it undetectable

in the spectra. Consistent with work examininglactate elevations in children, lactate was treated hereas a dichotomous variable and is either ‘present’ or‘absent’ [41] and, in the current case study,

Figure 2. Example of LC Model data sheet and healthy adult data taken from frontal gray matter. The highest peak (after suppression ofthe water signal) is NAA, the second and third highest are creatine and choline, respectively. Notice that at 1.33 ppm (lactate) there is nodiscernable signal from baseline.

Table III. Neurometabolic functioning in healthy control subjects (HC) and TBI case, VH (for scans 1 and 2) for single voxel data. Valueswith an ‘*’ were considered unreliable and not included in overall average.

Choline (% SD) NAA (% SD)

HC 1 Midline occipital 0.748 (11) 6.545 (13)Thalamus 1.169 (10) 7.243 (7)Frontal gray 1.273 (9) 6.479 (7)Frontal corpus callosum 1.44 (10) 6.698 (10)

1.1575 6.74125HC 2 Midline occipital 1.356 (10) 4.81 (11)

Thalamus 1.284 (10) 6.988 (15)Frontal gray 0.837 (14) 7.676 (7)Frontal corpus callosum 1.625 (6) 6.319 (6)

0.9365 5.245TBI Midline occipital 0.996 (12) 2.72 (16)Scan 1 Thalamus 0.894 (9) 2.12 (24)

Frontal corpus callosum 0.343* (24) 0* (999)0.94 2.42

Scan 2 Midline occipital 0.275* (47) 3.845 (16)Thalamus 1.244 (8) 5.70 (8)Frontal corpus callosum 1.448 (10) 2.152* (24)

1.34 4.77


elevations at 1.33 ppm at both time points in thesingle voxel date were unequivocal. Multi-voxel datadetermined to be reliable for both scans arepresented in Figure 5; consistent change in therelationship between NAA and Cho is evidentbetween the first scan (day 9) and the second scan(day 23). Note, however, that the multi-voxel datadid not reveal elevations in lactate.

Discussion

The current case study reveals, through the useof pMRS methods, changes in neurometabolism

during acute recovery from severe TBI. Lactate,specifically, was observed in conjunction withelevated ICP and, importantly, remained apparentat over 3 weeks post-injury. The authors are unawareof any other adult case showing a similar metabolicprofile while surviving the injury. The currentpatient demonstrated preserved simple attentionand working memory, was communicative and wasindependent for some activities of daily living(see follow-up data in Table II). This case studyprovides three important findings regarding neuro-metabolism following severe brain trauma: (1) serialexamination of pMRS is sensitive to neurometabolic

Figure 3. Raw data illustrating significant elevation in lactate/lipid peaks at days 9 and 23. Lactate is a doublet appearing at 1.33 ppm andthese chemical shift data illustrate that lactate is significantly elevated, with an absolute concentration comparable to that of NAA at day 9and, although integration of the curve at day 23 was not possible, it remains elevated.

Figure 4. Comparison of structural and pMRS data at 9 and 23 days post-injury (NAA is N-acetylaspartate, Cho is choline and lactate isLac). At day 9, haemorrhage and oedema result in complete effacement of right lateral ventricle and at day 23, much of the oedema andventricular shift has resolved.


dysregulation in acute TBI, (2) elevations in lactatemay persist for weeks in the case of very severe TBIand (3) elevations in lactate may be isolated to areasof lesion, even in very severe TBI.

Acute serial pMRS

This case study demonstrates that serial pMRS scansacquired during early recovery from TBI aresensitive to changes in neurometabolites such asNAA, Cho and lactate. Much of the work to date hasused pMRS to examine neurometabolic functioningat a single time point following TBI and, while thiscross-sectional work has proven valuable, futurework should focus on longitudinal within-subjectdesigns that monitor changes in the neural environ-ment over the recovery period. The few studies to

date using repeated measures have typically acquireddata during the acute or sub-acute period and thenseveral months later. The current data confirm thatpMRS is sensitive to neurometabolic changes inacute TBI when both time points for data acquisitionoccur during the first month of injury and priorto any significant behavioural improvement(i.e. both scans occurred prior to coma emergence).

Elevations in lactate over time

While the role of lactate elevations in severe TBIremains unclear, in this case study lactate appears tobe (at least initially) linked to increased intracranialpressure, subsequent anaerobic respiration andpotential ischemia. These data re-confirm thatpMRS can detect lactate in areas of haemorrhage

Figure 5. The average NAA and Cho values for multi-voxel data within pre-frontal gray and white matter at 9 and 23 days post-injury.


in adults and is sensitive to changes in lactateconcentration over time. The current data alsoreveal that adults exhibiting elevations in ICP andprobable ischemia can continue to show increasedlactate for weeks and potentially even after ICP hasreturned to baseline. In this case study, the firstpMRS data were acquired over 1 week post-injuryand remarkably, even at this time, lactate elevationsremained comparable to that of NAA.

The relationship between lactate and secondaryinjury in severe TBI remains unclear. As a secondaryeffect of elevated ICP and associated ischemia,lactate has been associated with more severe injuriesand predictive of poor outcomes [16, 41, 42].Elevations in lactate, however, have been thoughtto be only non-specific indicators of pathology andhave not been directly linked to ischemic cell death[42]. Moreover, the thresholds for determiningischemic cell death have yet to be firmly established[43]. Separately, other investigators have morerecently posited that that excessive lactate mayactually serve as ‘fuel’ facilitating metabolic pro-cesses later during recovery [22]. Thus, the roleof lactate in recovery from TBI remains equivocaland, even in the current case, lactate remainedmoderately elevated long after intracranial pressurehad subsided, when it was unlikely to be directlyattributable to ischemia.

pMRS methods and observing lactate

In regards to detecting lactate elevations, the currentcase study demonstrates that voxel placementrelative to areas of brain injury is critical fordetection of abnormal neurometabolism. Figures 3and 4 illustrate elevations in lactate in a voxel oftissue in midline occipital lobe that is consistentof significant oedema/haemorrhage. However,multivoxel data collected in frontal areas typicallydid not sample from contused or haemorrhagictissue and failed to reveal lactate elevations. Thesesame areas, however, did demonstrate NAA andCho derangements that improved from day 9 today 23 (again, see Figure 5). Taken together, thesedata indicate that lactate elevations may be detect-able when sampling directly from areas of lesion and,unlike NAA or Cho, which may be reflective of thegeneral neural environment, lactate elevations maybe isolated to local areas of significant metaboliccrisis. These data are consistent with prior investiga-tions of severe trauma using pMRS that havefailed to consistently show elevations in lactateacross subjects and commonly revealed lactateelevations to be isolated to areas of contusion [29].

There is one final methodological concern for thecurrent data and, in one regard, for measuringlactate more generally. As noted, several voxels

yielded unreliable data and there are two potentialreasons for this. First, while head movement duringdata acquisition was not a problem in a majority ofthe data, for a few data sets, the spectra were clearlyinfluenced by movement, making them unreliable,and they were therefore discarded based upon SD %determined a priori. A second, and potentiallygreater, problem for this type of analysis, in general,has to do with the influence of haemorrhage on theMRI signal locally. Sites of haemorrhage can causelocal field inhomogeneities and, in the current case,this may have been an additional source of signaldisruption in the current study. Future work shouldexamine MR manipulations (e.g. chemical shiftimaging, shimming, longer acquisition times) todetermine the ideal methods for acquiring validpMRS data in areas of acute haemorrhage/contusion.

Conclusion

In sum, in the current study, serial pMRS dataacquisition was used to examine acute changes inneurometabolism in a case of very severe neuro-trauma. The data show that pMRS is sensitive toearly metabolic abnormalities and can be used todocument important changes in NAA, Cho andlactate that may precede any clinical/behaviouralimprovement. Ultimately, to maximize its clinicalutility, the application of pMRS to TBI requiresrefinement by delineating the ideal timing for dataacquisition, the combination of neurometabolitesmost predictive of outcome and the most informativesites for pMRS data acquisition (e.g. distal/adjacentto lesion site).

Acknowledgement

This work was supported by NIH grant1R03HD042085.

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Examining lactate in severe TBI using proton magnetic resonance