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Coronal and axial proton magnetic resonance spectroscopic images show placement of the volume of interest in the left midtemporal region (A) and the left basal ganglia region (B).

Coronal and axial proton magnetic resonance spectroscopic images show placement of the volume of interest in the left midtemporal region (A) and the left basal ganglia region (B).

Table 1. 
Clinical, Demographic, and Spectroscopic Characteristics of the Patients With Traumatic Brain Injury (TBI)
Clinical, Demographic, and Spectroscopic Characteristics of the Patients With Traumatic Brain Injury (TBI)
Table 2. 
Neurochemical and Neuropsychological Comparison Between Patients With Traumatic Brain Injury (TBI) and Healthy Control Subjects*
Neurochemical and Neuropsychological Comparison Between Patients With Traumatic Brain Injury (TBI) and Healthy Control Subjects*
Table 3. 
Correlational Analysis Between Neurochemical and Neuropsychological Data in Patients With Traumatic Brain Injury*
Correlational Analysis Between Neurochemical and Neuropsychological Data in Patients With Traumatic Brain Injury*
1.
Luyten  PRDen Hollander  JA Observation of metabolites in the human brain by MRS spectroscopy. Radiology.1986;161:795-798.
PubMed
2.
Brooks  WMFriedman  SDGasparovic  C Magnetic resonance spectroscopy in traumatic brain injury. J Head Trauma Rehabil.2001;16:149-164.
PubMed
3.
Friedman  SDBrooks  WMJung  REHart  BLYeo  RA Proton MR spectroscopic findings correspond to neuropsychological function in traumatic brain injury. AJNR Am J Neuroradiol.1998;19:1879-1885.
PubMed
4.
Friedman  SDBrooks  WMJung  RE  et al Quantitative proton MRS predicts outcome after traumatic brain injury. Neurology.1999;52:1384-1391.
PubMed
5.
Garnett  MRBlamire  AMRajagopalan  BStyles  PCadoux-Hudson  TA Evidence for cellular damage in normal-appearing white matter correlates with injury severity in patients following traumatic brain injury: a magnetic resonance spectroscopy study. Brain.2000;123:1403-1409.
PubMed
6.
Garnett  MRBlamire  AMCorkill  RGCadoux-Hudson  TARajagopalan  BStyles  P Early proton magnetic resonance spectroscopy in normal-appearing brain correlates with outcome in patients following traumatic brain injury. Brain.2000;123:2046-2054.
PubMed
7.
Ricci  RBarbarella  GMusi  PBoldrini  PTrevisan  CBasaglia  N Localised proton MR specctroscopy of brain metabolism changes in vegetative patients. Neuroradiology.1997;39:313-319.
PubMed
8.
Sinson  GBagley  LJCecil  KM  et al Magnetization transfer imaging and proton MR spectroscopy in the evaluation of axonal injury: correlation with clinical outcome after traumatic brain injury. AJNR Am J Neuroradiol.2001;22:143-151.
PubMed
9.
Brooks  WMStidley  CAPetropoulos  H  et al Metabolic and cognitive response to human traumatic brain injury: a quantitative proton magnetic resonance study. J Neurotrauma.2000;17:629-640.
PubMed
10.
Cecil  KMHills  ECSandel  ME  et al Proton magnetic resonance spectroscopy for detection of axonal injury in the splenium of the corpus callosum of brain-injured patients. J Neurosurg.1998;88:795-801.
PubMed
11.
Katoh  HSima  KNawashiro  HWada  KChigasaki  H The effect of MK-801 on extracellular neuroactive amino acids in hippocampus after closed head injury followed by hypoxia in rats. Brain Res.1997;758:153-162.
PubMed
12.
Nakano  KKayahara  TTsutsumi  TUshiro  H Neural circuits and functional organization of the striatum. J Neurol.2000;247(suppl 5):V1-V15.
PubMed
13.
Calabresi  PPisani  AMercuri  NBBernardi  G On the mechanisms underlying hypoxia-induced membrane depolarization in striatal neurons. Brain.1995;118:1027-1038.
PubMed
Original Contribution
April 2004

Neuropsychological Correlates of Basal Ganglia and Medial Temporal Lobe NAA/Cho Reductions in Traumatic Brain Injury

Author Affiliations

From the Department of Psychiatry and Clinical Psychobiology, University of Barcelona (Mrs Ariza and Drs Junqué and Mataró); Institut d'Investigacions Biomediques August Pi i Sunyer (Dr Junqué), Department of Neurosurgery, Vall d'Hebron University Hospital (Drs Poca and Sahuquillo), and the Department of Radiology, Centre de Diagnòstic per Imatge, Hospital Clinic de Barcelona (Dr Bargalló and Olondo), Barcelona, Spain.

Arch Neurol. 2004;61(4):541-544. doi:10.1001/archneur.61.4.541
Abstract

Background  Proton magnetic resonance spectroscopy can assess neurochemical sequelae in traumatic brain injury. Metabolic abnormalities are present in the acute or subacute period in patients with traumatic brain injury and correlate with outcome on clinical scales.

Objective  To investigate the use of proton magnetic resonance spectroscopy in detecting possible gray subcortical neurochemical impairments and their relationship with neuropsychological performance.

Design  Group comparisons and correlations of brain metabolites with clinical and neuropsychological variables.

Patients and Methods  Metabolite concentrations were acquired from voxels localized to the basal ganglia and medial temporal region in 20 patients with long-term moderate and severe traumatic brain injury and 20 matched control subjects. Both groups underwent neuropsychological assessment.

Results  N-acetylaspartate–choline-containing compounds ratios were decreased in patients in the basal ganglia (t = −3.28, P = .002) and medial temporal region (t = −3.52, P = .001). The basal ganglia ratio correlated to measures of speed, motor scanning, and attention.

Conclusion  Patients with long-term TBI present a regional correlation pattern that may help identify the neurological basis of cognitive sequelae in traumatic brain injury.

Proton magnetic resonance spectroscopy (1H-MRS) can test neurochemical status in patients with traumatic brain injuries (TBIs). The technique allows in vivo detection of neurochemical alterations such component as N-acetylaspartate (NAA), creatinine/phosphocreatinine, and choline-containing compounds (Cho) in selected tissue volumes.1 A decreased concentration of NAA reflects neuronal death, and an increased concentration of Cho is related to inflammation, demyelination, and membrane synthesis or repair. In TBI the main findings are reduced NAA concentrations and increased Cho concentrations.2

Proton magnetic resonance spectroscopy metabolic abnormalities are present in the acute or subacute period in patients with TBI,36 persist after 6 months' evolution3,5 and correlate with outcome on clinical scales.3,58 To our knowledge, only 2 research groups correlated an NAA concentration decrease with neuropsychological deficits.3,4,9

In previous studies MRS voxels were placed in neocortical gray matter3,4,9 or white matter,36,9,10 but none focused on brain structures such as basal ganglia or hippocampus which are sensitive to the hypoxic-ischemic, metabolic, and molecular events in severe head injuries.10,11 The aim of this study was to relate regional neurochemical abnormalities in the basal ganglia and medial temporal lobe to memory and frontal lobe impairment in TBI.

METHOD
PARTICIPANTS

Twenty patients (mean [SD] age, 25.6 [7.15] years; mean [SD] educational status, 11.4 [3.0] years) who had moderate (n = 4) and severe (n = 16) TBI were matched to 20 healthy control subjects according to mean (SD) age (25.4 [7.4] years), sex (16 males), and mean [SD] educational status (12 [3.0] years). Severity was determined using Glasgow Coma Scale (GCS) scores. Patients with moderate TBI had a GCS score between 13 and 8, patients with severe TBI had a GCS score below 8. Patients were recruited from the Neurotraumatology Unit, Vall d'Hebron University Hospital, Barcelona, Spain. Inclusion criteria were a GCS score of 13 or less, an absence of focal lesions in the regions of interest on computed tomography, and a normal educational history. The neuroradiologist (N.B.) evaluated patients' present magnetic resonance imaging (MRI) data. Three patients showed lesions in the prefrontal poles, 4 in the temporal poles, and 1 in both frontal and temporal poles. T2-weighted images showed basal ganglia hyperintensities in 5 patients and hippocampal hyperintensities in 8 patients. Exclusion criteria were abnormal premorbid IQ, aphasia, dysarthria, or motor impairment precluding neuropsychological evaluation. All subjects participated voluntarily; none had a history of TBI or neurological or psychiatric diseases. The local ethical committee approved the study. Signed informed consent was obtained from participants or their parents or guardians. Sample characteristics are listed in Table 1.

1H-MRS STUDY

We used a 1.5-T magnetic resonance scanner (Signa 5.4; General Electric, Milwaukee, Wis) to obtain 2 1H-MRS voxels (2 × 2 × 2 cm3), one in the left basal ganglia and the other in the left midtemporal region from a coronal section (Figure 1). Water-suppressed spectra were acquired using a double-spin, echo point-resolved spectroscopy sequence with a repetition time of 1500 milliseconds and echo times of 114 milliseconds (basal ganglia voxel) and 35 milliseconds (hippocampus voxel). We obtained NAA (at 2.0 ppm) and Cho (at 3.15 ppm) concentration peaks for both locations. Spectra were analyzed using the manufacturer-supplied spectroscopy software package of the MR system.

NEUROPSYCHOLOGICAL ASSESSMENT

The battery neuropsychological tests evaluated frontal and medial temporal lobe functions usually impaired after TBI. To assess memory we used the Rey Auditory Verbal Learning Test, the memory subtests from the Rey Complex Figure 1 Test, and the Warrington Face Recognition Memory Test. Frontal lobe functions were evaluated using the Word Fluency Test (verbal fluency), Continuous Performance Test (attention and information processing speed), Backward Digit Span (working memory), Trail Making Tests (parts A and B) (visual scanning, motor speed, attention, and mental flexibility), Symbol Digit Modalities Test (visual scanning, tracking, and motor speed), and Grooved Pegboard Test (fine motor speed). Global adjustment to activities of daily living and general outcome were assessed using the extended Glasgow Outcome Scale. Neuropsychological tests were administered by a single neuropsychologist (M.A.) blind to clinical and spectroscopic data.

STATISTICAL ANALYSIS

All statistical analyses were done using SPSS version 11.0 for Windows (SPSS Inc, Chicago, Ill). The Kolmogorov-Smirnov test showed that all continuous variables had normal distribution. The t test was, therefore, used for independent samples to compare group means in both neuropsychological and MRS variables. The Pearson product moment correlation test was used to correlate spectroscopic metabolites and neuropsychological tests. Since this was an exploratory study, we did not correct for multiple comparisons, but we applied a 2-tailed level of significance of P<.01.

RESULTS

As expected, NAA/Cho ratios were significantly lower in both regions in patients with TBI than in controls. Patients with TBIs differed significantly from controls in all neuropsychological tests (Table 2).

The NAA/Cho ratio in basal ganglia correlated with measures of fine motor speed and attention: Backward Digit Span (r = 0.63, P = .003), Trail Making Test A (r = 0.58, P = .007) (Table 3). In controls, the relationships between neurochemical levels and neuropsychological performance were not significant. For the whole sample of participants, in the hippocampus we found that the NAA/Cho ratio achieved significant correlations on the Rey Auditory Verbal Learning Test (r = 0.40, P = .009) and on facial memory recognition (the Warrington Face Recognition Memory Test) (r = 0.50, P = .001). In basal ganglia the NAA/Cho ratio correlated with Backward Digit Span (r = 0.64, P = .00) and Trail Making Test A (r = 0.56, P = .00).

We attempted to relate NAA/Cho concentrations to clinical data, in particular to the presence of hypoxia (minimum cerebral perfusion pressure), a minimum brain tissue oxygen concentration (PtiO2), and maximum intracranial pressure. We only found a trend toward correlation between the number of local hypoxic episodes (brain tissue oxygen concentration <15 mm Hg) and the NAA/Cho ratio in the hippocampus (rs = −0.66, P = .02).

COMMENT

Relationships between 1H-MRS measurements of metabolic alteration and neuropsychological impairment have been previously reported.3,4,9 Our results agree with these findings. However, whereas those studies assessed a decrease in the NAA concentration to measure diffuse brain damage, we were looking for focal relationships. As basal ganglia have strong connections with neocortex frontal lobes12 and are involved in cognitive functions, we expected to find a relation between frontal alterations and the decrease in the basal ganglia NAA concentration. Similarly, as the medial temporal regions contain the hippocampus, we expected a relation between a decreased NAA concentration and memory dysfunctions.

Our main finding was the relationship between frontal lobe neuropsychological impairment at 6 months and a decrease in the basal ganglia NAA concentration in patients with TBIs. We found significant correlations between the NAA/Cho ratio with tests that measure frontal lobe functions such as visual scanning, fine motor speed, attention, and working memory. Hippocampal NAA/Cho ratio correlations were less consistent; we only found a tendency for visual recognition.

For the whole sample (patients and controls) we observed significant correlations in both NAA/Cho voxels. The metabolites in the hippocampal region correlated with memory tests and in the basal ganglia region with frontal lobe tests. However, these correlations also reflect the between-group differences in both neuropsychological and spectroscopic findings.

Our voxels focused on gray subcortical structures, but we cannot guarantee that the NAA level decrease was not in fact due to the presence of white matter changes. However, the different correlation patterns observed in the voxels and their relationship with the functional properties of the target structures suggest specificity. So voxel location is a factor in detecting long-term neurological deficits in TBI. We found that decreases in the basal ganglia NAA level reflect neuropsychological sequelae.

Basal ganglia and hippocampus are sensitive to hypoxia and ischemia, and the action of excitotoxins on glutamate receptors influences the development of acute central nervous system injury.11,13 We were unable to relate the NAA level decrease with clinical data reflecting hypoxia or ischemic damage. Further studies with larger samples are needed to investigate these factors. To conclude, our results suggest that abnormal metabolite concentrations in basal ganglia are related to frontal lobe deficits.

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Article Information

Corresponding author: C. Junqué, PhD, Departament de Psiquiatria i Psicobiologia Clínica, Universitat de Barcelona, Institut d'Investigacions Biomediques August Pi i Sunyer, C/Casanova 143, 08036 Barcelona, Spain (e-mail: cjunque@ub.edu).

Accepted for publication October 17, 2003.

Author contributions: Study concept and design (Mrs Ariza and Dr Junqué); acquisition of data (Mrs Ariza and Drs Bargalló and Olondo); analysis and interpretation of data (Mrs Ariza and Drs Junqué, Mataro, Poca, Bargalló, Olondo, and Sahuquillo); drafting of the manuscript (Mrs Ariza and Drs Junqué and Bargalló, ); critical revision of the manuscript for important intellectual content (Drs Mataró, Poca, Bargalló, Olondo, and Sahuquillo); statistical expertise (Mrs Ariza); obtained funding (Drs Junqué, Poca, and Sahuquillo); administrative, technical, and material support (Mrs Ariza and Drs Junqué, Mataró, Bargalló, Olondo, and Sahuquillo); study supervision (Dr Junqué).

This study was supported by the grants PM 98-0192 from Ministerio de Ciencia y Tecnologia, Madrid, Spain, and 2001SGR 00139 from the Generalitat de Catalunya, Catalunya, Spain, and by a research grant from the Ministerio de Ciencia y Tecnologia, Barcelona, Spain (Mrs Ariza).

References
1.
Luyten  PRDen Hollander  JA Observation of metabolites in the human brain by MRS spectroscopy. Radiology.1986;161:795-798.
PubMed
2.
Brooks  WMFriedman  SDGasparovic  C Magnetic resonance spectroscopy in traumatic brain injury. J Head Trauma Rehabil.2001;16:149-164.
PubMed
3.
Friedman  SDBrooks  WMJung  REHart  BLYeo  RA Proton MR spectroscopic findings correspond to neuropsychological function in traumatic brain injury. AJNR Am J Neuroradiol.1998;19:1879-1885.
PubMed
4.
Friedman  SDBrooks  WMJung  RE  et al Quantitative proton MRS predicts outcome after traumatic brain injury. Neurology.1999;52:1384-1391.
PubMed
5.
Garnett  MRBlamire  AMRajagopalan  BStyles  PCadoux-Hudson  TA Evidence for cellular damage in normal-appearing white matter correlates with injury severity in patients following traumatic brain injury: a magnetic resonance spectroscopy study. Brain.2000;123:1403-1409.
PubMed
6.
Garnett  MRBlamire  AMCorkill  RGCadoux-Hudson  TARajagopalan  BStyles  P Early proton magnetic resonance spectroscopy in normal-appearing brain correlates with outcome in patients following traumatic brain injury. Brain.2000;123:2046-2054.
PubMed
7.
Ricci  RBarbarella  GMusi  PBoldrini  PTrevisan  CBasaglia  N Localised proton MR specctroscopy of brain metabolism changes in vegetative patients. Neuroradiology.1997;39:313-319.
PubMed
8.
Sinson  GBagley  LJCecil  KM  et al Magnetization transfer imaging and proton MR spectroscopy in the evaluation of axonal injury: correlation with clinical outcome after traumatic brain injury. AJNR Am J Neuroradiol.2001;22:143-151.
PubMed
9.
Brooks  WMStidley  CAPetropoulos  H  et al Metabolic and cognitive response to human traumatic brain injury: a quantitative proton magnetic resonance study. J Neurotrauma.2000;17:629-640.
PubMed
10.
Cecil  KMHills  ECSandel  ME  et al Proton magnetic resonance spectroscopy for detection of axonal injury in the splenium of the corpus callosum of brain-injured patients. J Neurosurg.1998;88:795-801.
PubMed
11.
Katoh  HSima  KNawashiro  HWada  KChigasaki  H The effect of MK-801 on extracellular neuroactive amino acids in hippocampus after closed head injury followed by hypoxia in rats. Brain Res.1997;758:153-162.
PubMed
12.
Nakano  KKayahara  TTsutsumi  TUshiro  H Neural circuits and functional organization of the striatum. J Neurol.2000;247(suppl 5):V1-V15.
PubMed
13.
Calabresi  PPisani  AMercuri  NBBernardi  G On the mechanisms underlying hypoxia-induced membrane depolarization in striatal neurons. Brain.1995;118:1027-1038.
PubMed
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