Advances in imaging explosive blast mild traumatic brain injury.

In the past, direct physical evidence of mild traumatic brain injury (mTBI) from explosive blast has been difficult to obtain through conventional imaging modalities such as T1- and T2-weighted magnetic resonance imaging (MRI) and computed tomography (CT). Here, we review current progress in detecting evidence of brain injury from explosive blast using advanced imaging, including diffusion tensor imaging (DTI), functional MRI (fMRI), and the metabolic imaging methods such as positron emission tomography (PET) and magnetic resonance spectroscopic imaging (MRSI), where each targets different aspects of the pathology involved in mTBI. DTI provides a highly sensitive measure to detect primary changes in the microstructure of white matter tracts. fMRI enables the measurement of changes in brain activity in response to different stimuli or tasks. Remarkably, all three of these paradigms have found significant success in conventional mTBI where conventional clinical imaging frequently fails to provide definitive differences. Additionally, although used less frequently for conventional mTBI, PET has the potential to characterize a variety of neurotransmitter systems using target agents and will undoubtedly play a larger role, once the basic mechanisms of injury are better understood and techniques to identify the injury are more common. Finally, our MRSI imaging studies, although acquired at much lower spatial resolution, have demonstrated selectivity to different metabolic and physiologic processes, uncovering some of the most profound differences on an individual by individual basis, suggesting the potential for utility in the management of individual patients.

Selective homonuclear polarization transfer for spectroscopic imaging of GABA at 7T.

We develop and implement a selective homonuclear polarization transfer method for the detection of 3.0 ppm C-4 GABA resonance by spectroscopic imaging in the human brain at 7T. This single shot method is demonstrated with simulations and phantoms, which achieves comparable efficiency of detection to that of J-difference editing. The macromolecule resonance that commonly co-edits with GABA is suppressed at 7T through use of a narrow band preacquisition suppression pulse. This technique is implemented in humans with an eight channel transceiver array and high degree B(0) shimming to measure supplementary motor area and thalamic GABA in controls (n = 8) and epilepsy patients (n = 8 total). We find that the GABA/N-acetyl aspartate ratio in the thalamus of control volunteers, well controlled and poorly controlled epilepsy patients are 0.053 ± 0.012 (n = 8), 0.090 ± 0.012 (n = 2), and 0.038 ± 0.009 (n = 6), respectively.

Metabolic networks in epilepsy by MR spectroscopic imaging.

OBJECTIVE: The concept of an epileptic network has long been suggested from both animal and human studies of epilepsy. Based on the common observation that the MR spectroscopic imaging measure of NAA/Cr is sensitive to neuronal function and injury, we use this parameter to assess for the presence of a metabolic network in mesial temporal lobe epilepsy (MTLE) patients. MATERIALS AND METHODS: A multivariate factor analysis is performed with controls and MTLE patients, using NAA/Cr measures from 12 loci: the bilateral hippocampi, thalami, basal ganglia, and insula. The factor analysis determines which and to what extent these loci are metabolically covarying. RESULTS: We extract two independent factors that explain the data's variability in control and MTLE patients. In controls, these factors characterize a 'thalamic' and 'dominant subcortical' function. The MTLE patients also exhibit a 'thalamic' factor, in addition to a second factor involving the ipsilateral insula and bilateral basal ganglia. CONCLUSIONS: These data suggest that MTLE patients demonstrate a metabolic network that involves the thalami, also seen in controls. The MTLE patients also display a second set of metabolically covarying regions that may be a manifestation of the epileptic network that characterizes limbic seizure propagation.

J-refocused coherence transfer spectroscopic imaging at 7 T in human brain.

Short echo spectroscopy is commonly used to minimize signal modulation due to J-evolution of the cerebral amino acids. However, short echo acquisitions suffer from high sensitivity to macromolecules which make accurate baseline determination difficult. In this report, we describe implementation at 7 T of a double echo J-refocused coherence transfer sequence at echo time (TE) of 34 msec to minimize J-modulation of amino acids while also decreasing interfering macromolecule signals. Simulation of the pulse sequence at 7 T shows excellent resolution of glutamate, glutamine, and N-acetyl aspartate. B(1) sufficiency at 7 T for the double echo acquisition is achieved using a transceiver array with radiofrequency (RF) shimming. Using an alternate RF distribution to minimize receiver phase cancellation in the transceiver, accurate phase determination for the coherence transfer is achieved with rapid single scan calibration. This method is demonstrated in spectroscopic imaging mode with n = 5 healthy volunteers resulting in metabolite values consistent with literature and in a patient with epilepsy.

Hippocampal correlates of pain in healthy elderly adults: a pilot study.

BACKGROUND: Few neuroimaging investigations of pain in elderly adults have focused on the hippocampus, a brain structure involved in nociceptive processing that is also subject to involution associated with dementing disorders. The goal of this pilot study was to examine MRI- and magnetic resonance spectroscopy (MRS)-derived hippocampal correlates of pain in older adults. METHODS: A subset of 20 nondemented older adults was drawn from the Einstein Aging Study, a community-based sample from the Bronx, NY. Pain was measured on 3 time scales: 1) acute pain right now (pain severity); 2) pain over the past 4 weeks (Short Form-36 Bodily Pain); 3) chronic pain over the past 3 months (Total Pain Index). Hippocampal data included volume data normalized to midsagittal area and N-acetylaspartate to creatine ratios (NAA/Cr). RESULTS: Smaller hippocampal volume was associated with higher ratings on the Short Form-36 Bodily Pain (r(s) = 0.52, p = 0.02) and a nonsignificant trend was noted for higher ratings of acute pain severity (r(s) = -0.44, p = 0.06). Lower levels of hippocampal NAA/Cr were associated with higher acute pain severity (r(s) = -0.45, p = 0.05). Individuals with chronic pain had a nonsignificant trend for smaller hippocampal volumes (t = 2.00, p = 0.06) and lower levels of hippocampal NAA/Cr (t = 1.71, p = 0.10). CONCLUSIONS: Older adults who report more severe acute or chronic pain have smaller hippocampal volumes and lower levels of hippocampal N-acetylaspartate/creatine, a marker of neuronal integrity. Future studies should consider the role of the hippocampus and other brain structures in the development and experience of pain in healthy elderly and individuals with Alzheimer disease.

Intracranial EEG power and metabolism in human epilepsy.

EEG power and high frequency activity in the seizure onset zone has been increasingly considered for its relationship with seizures in animal and human studies of epilepsy. We examine the relationship between quantitative EEG measures and metabolic imaging in epilepsy patients undergoing intracranial EEG (icEEG) analysis for seizure localization. Patients with mesial temporal lobe epilepsy (MTLE) and neocortical epilepsy (NE) were studied. Metabolic imaging was performed with MR spectroscopic imaging using N-acetyl aspartate (NAA) and creatine (Cr). All data were acquired from the mesial temporal lobe such that a direct comparison of the same anatomical regions between the two groups could be performed. While no difference was seen in the total power recorded from the mesial temporal lobe, the MTLE group had significantly greater power in the high frequency bands. There was a significant positive exponential relationship between total icEEG power with NAA/Cr in MTLE, R=+0.84 and p<0.001, which was not seen in NE. There was also a significant negative relationship between fractional gamma power with NAA/Cr in MTLE, R=-0.66 and p<0.02, also not seen in NE. These data argue that within the seizure onset zone, the tight correlation between total power and NAA/Cr suggests that total electrical output is powered by available mitochondrial function. These data are also consistent with the hypothesis that high frequency activity is an abnormal manifestation of tissue injury.

Short echo spectroscopic imaging of the human brain at 7T using transceiver arrays.

Recent advances in magnet technology have enabled the construction of ultrahigh-field magnets (7T and higher) that can accommodate the human head and body. Despite the intrinsic advantages of performing spectroscopic imaging at 7T, increased signal-to-noise ratio (SNR), and spectral resolution, few studies have been reported to date. This limitation is largely due to increased power deposition and B(1) inhomogeneity. To overcome these limitations, we used an 8-channel transceiver array with a short TE (15 ms) spectroscopic imaging sequence. Utilizing phase and amplitude mapping and optimization schemes, the 8-element transceiver array provided both improved efficiency (17% less power for equivalent peak B(1)) and homogeneity (SD(B(1)) = +/-10% versus +/-22%) in comparison to a transverse electromagnetic (TEM) volume coil. To minimize the echo time to measure J-modulating compounds such as glutamate, we developed a short TE sequence utilizing a single-slice selective excitation pulse followed by a broadband semiselective refocusing pulse. Extracerebral lipid resonances were suppressed with an inversion recovery pulse and delay. The short TE sequence enabled visualization of a variety of resonances, including glutamate, in both a control subject and a patient with a Grade II oligodendroglioma.

Hippocampal extracellular GABA correlates with metabolism in human epilepsy.

As the major inhibitory neurotransmitter in human brain, GABA is an important modulator of hyperexcitability in epilepsy patients. Given the high energetic cost of neurotransmission and synaptic activity, GABA concentrations may be hypothesized to correlate with metabolic function. We studied human epilepsy patients undergoing intracranial EEG monitoring for seizure localization to examine microdialysis measures of extracellular GABA (ecGABA), pre-operative MR spectroscopic measures of neuronal mitochondrial function (NAA/Cr), and wherever possible, neuropathology and hippocampal volumetry. Two groups undergoing intracranial monitoring for seizure localization were studied: surgically treated hippocampal epilepsy (MTLE) and neocortical (non-hippocampal seizure onset) epilepsy. All data are hippocampal and thus these groups allow comparisons between the epileptogenic and non-epileptogenic regions. ecGABA was measured using in vivo microdialysis performed during intracranial monitoring. Pre-operative in vivo MR spectroscopic imaging was performed to measure the ratio of N-acetyl aspartate (NAA) to creatine. Standard methods for neuropathology and hippocampal volumetry were used. In the neocortical group, increased ecGABA correlated with greater NAA/Cr (R = +0.70, p < 0.015, n = 12) while in the MTLE group, increased ecGABA linked with decreased NAA/Cr (R = -0.94, p < 0.001, n = 8). In MTLE, ecGABA (increased) and NAA/Cr (decreased) correlated with increased glial cell numbers (R = +0.71, p < 0.01, n = 12, R = -0.76 p < 0.03 respectively). No relationship was seen between ecGABA and hippocampal volumes in either group. In epilepsy, ecGABA increases occur across a range of metabolic function. Outside the seizure focus, ecGABA and NAA/Cr increase together; in contrast, within the seizure focus, ecGABA increases with declining mitochondrial function.

Hippocampal neurochemistry, neuromorphometry, and verbal memory in nondemented older adults.

BACKGROUND: Characterization of the behavioral correlates of neuromorphometry and neurochemistry in older adults has important implications for an improved understanding of the aging process. The objective of this study was to test the hypothesis that a measure of hippocampal neuronal metabolism was associated with verbal memory in nondemented older adults after controlling for hippocampal volume. METHODS: 4-T MRI, proton magnetic resonance spectroscopy ((1)H MRS), and neuropsychological assessment were conducted in 48 older adults (23 women; mean age 81 years). Average hippocampal N-acetyl aspartate/creatine ratios (NAA/Cr) and hippocampal volumes were obtained. Neuropsychological evaluation included tests of verbal memory (Buschke and Grober Free and Cued Selective Reminding Test-Immediate Recall [FCSRT-IR], Wechsler Memory Scale-Revised Logical Memory subtest) and attention and executive function (Trail Making Test Parts A and B). RESULTS: Linear regression analysis indicated that after adjusting for age, hippocampal NAA/Cr was a significant predictor of FCSRT-IR performance (beta = 0.38, p = 0.01, R (2) = 0.21). Hippocampal volume was also a significant predictor of FCSRT-IR performance after adjusting for age and midsagittal area (beta = 0.47, p = 0.01, R (2) = 0.24). In a combined model, hippocampal NAA/Cr (beta = 0.33, p = 0.03) and volume (beta = 0.35, p = 0.03) were independent predictors of FCSRT-IR performance, accounting for 30% of the variance in memory. CONCLUSIONS: These findings indicate that nondemented older adults with smaller hippocampal volumes and lower levels of hippocampal N-acetyl aspartate/creatine ratio metabolites perform more poorly on a test of verbal memory. The integrity of both the structure and metabolism of the hippocampus may underlie verbal memory function in nondemented elderly.

Levetiracetam has no acute effects on brain gamma-aminobutyric acid levels.

OBJECTIVE: The mechanism of action of levetiracetam (LEV), an antiepileptic drug, is related to a novel binding site, SV2, but LEV acts on GABA-A receptors. The objective of the study described here was to determine if LEV modulates brain GABA in vivo. METHODS: Concentrations of cerebral GABA and serum LEV were obtained in seven healthy individuals using 1H magnetic resonance spectroscopy at baseline and 3 and 6 hours following oral administration of 1 g of LEV. RESULTS: Brain cerebral GABA acutely concentrations did not change from baseline. CONCLUSION: The results indicate that LEV does not increase human cerebral GABA concentrations acutely in healthy individuals.

A subcortical network of dysfunction in TLE measured by magnetic resonance spectroscopy.

OBJECTIVE: The goal of this work was to evaluate the relationship between neuronal injury/loss in the hippocampus, thalamus, and putamen in temporal lobe epilepsy (TLE) patients using (1)H magnetic resonance spectroscopic imaging. METHODS: (1)H spectroscopic images from the hippocampus and thalamus of controls and patients with TLE were acquired at 4 T. The spectroscopic imaging data were reconstructed using an automated voxel-shifting method based on anatomic landmarks providing four, six, and three loci for the hippocampus, thalamus, and putamen, respectively. For correlation analysis, the hippocampal and striatal loci were averaged to provide single estimates of the entire structure, whereas the thalamus was divided into two regions, an anterior and posterior measure, using the average of three loci each. RESULTS: The ratio of N-acetyl aspartate to creatine (NAA/Cr), a measure of neuronal injury/loss, was significantly reduced in both the ipsilateral and contralateral hippocampi and thalami. NAA/Cr in the ipsilateral hippocampus was significantly correlated with the ipsilateral and contralateral anterior and posterior thalami, putamen, and contralateral hippocampus. In control subjects, the hippocampi were only correlated with each other. CONCLUSIONS: The data demonstrate that there is significant neuronal injury/loss in both the ipsilateral and contralateral thalami in temporal lobe epilepsy patients, with greater impairment in the anterior portions of the ipsilateral thalamus. The degree of injury/loss in the ipsilateral and contralateral thalamus and putamen is directly correlated with that of the ipsilateral hippocampus. This is consistent with the hypothesis that the impairment and damage associated with recurrent seizures as measured by N-acetyl aspartate originating in the hippocampus results in injury and impairment in other subcortical structures.

Spectroscopic imaging of the pilocarpine model of human epilepsy suggests that early NAA reduction predicts epilepsy.

Reduced hippocampal N-acetyl aspartate (NAA) is commonly observed in patients with advanced, chronic temporal lobe epilepsy (TLE). It is unclear, however, whether an NAA deficit is also present during the clinically quiescent latent period that characterizes early TLE. This question has important implications for the use of MR spectroscopic imaging (MRSI) in the early identification of patients at risk for TLE. To determine whether NAA is diminished during the latent period, we obtained high-resolution (1)H spectroscopic imaging during the latent period of the rat pilocarpine model of human TLE. We used actively detuneable surface reception and volume transmission coils to enhance sensitivity and a semiautomated voxel shifting method to accurately position voxels within the hippocampi. During the latent period, 2 and 7 d following pilocarpine treatment, hippocampal NAA was significantly reduced by 27.5 +/- 6.9% (P < 0.001) and 17.3 +/- 6.9% (P < 0.001) at 2 and 7 d, respectively. Quantitative estimates of neuronal loss at 7 d (2.3 +/- 7.7% reduction; P = 0.58, not significant) demonstrate that the NAA deficit is not due to neuron loss and therefore likely represents metabolic impairment of hippocampal neurons during the latent phase. Therefore, spectroscopic imaging provides an early marker for metabolic dysfunction in this model of TLE.

4 T Actively detuneable double-tuned 1H/31P head volume coil and four-channel 31P phased array for human brain spectroscopy.

Typically 31P in vivo magnetic resonance spectroscopic studies are limited by SNR considerations. Although phased arrays can improve the SNR; to date 31P phased arrays for high-field systems have not been combined with 31P volume transmit coils. Additionally, to provide anatomical reference for the 31P studies, without removal of the coil or patient from the magnet, double-tuning (31P/1H) of the volume coil is required. In this work we describe a series of methods for active detuning and decoupling enabling use of phased arrays with double-tuned volume coils. To demonstrate these principles we have built and characterized an actively detuneable 31P/1H TEM volume transmit/four-channel 31P phased array for 4 T magnetic resonance spectroscopic imaging (MRSI) of the human brain. The coil can be used either in volume-transmit/array-receive mode or in TEM transmit/receive mode with the array detuned. Threefold SNR improvement was obtained at the periphery of the brain using the phased array as compared to the volume coil.

Regional energetic dysfunction in hippocampal epilepsy.

OBJECTIVES: There is increasing evidence for a dysfunctional metabolic network in human mesial temporal lobe epilepsy (MTLE). To further describe this, we evaluated the bioenergetic status in unilateral MTLE inter-regionally and in relation to neuropathology. MATERIALS AND METHODS: We used whole brain high field (4 T) 31P MR spectroscopic imaging to determine in vivo PCr and ATP, studying n=22 patients (all candidates for hippocampal resection) and n=14 control volunteers. The degree of bioenergetic impairment was assessed by calculating the ratio of PCr to ATP. RESULTS: Compared to controls, patients demonstrated significant decreases in PCr/ATP from the ipsilateral amygdala and pes (0.84 +/- 0.14, 0.87 +/- 0.10, respectively, patients vs 0.97 +/- 0.15, 0.98 +/- 0.16, controls). In patients, the ipsilateral thalamic energetics positively correlated with contralateral hippocampal energetics. In addition, the ipsilateral thalamic and striatal energetics negatively correlated with hippocampal total glial counts. CONCLUSIONS: These data are consistent with a view that in MTLE, the bilateral hippocampi, ipsilateral thalamus and striatum are linked in their energetic depression, possibly reflecting the propagation of seizures throughout the brain.

Metabolic differences between multiple sclerosis subtypes measured by quantitative MR spectroscopy.

We used quantitative magnetic resonance (MR) spectroscopic imaging with T1-based image segmentation to evaluate the subtypes of multiple sclerosis (MS) (eight patients each group of relapsing-remitting [RR], secondary progressive [SP] and primary progressive [PP]). There was no significant difference in age between the PP group with the RP, SP or control group. We found that the metabolite ratio of choline/NA from the periventricular white matter region was not significantly different between the RR and SP groups. Using an ANOVA, the ratios of periventricular choline/NA or creatine/NA of these combined groups were significantly higher than the PP and control groups. Quantification of these data suggest that the major cause of the elevation of these parameters is due to an increase in choline and creatine in the RR group while NA is decreased in the SP group. Thus, early PP disease appears to be relatively intact with respect to neuronal loss.

Modulation of cerebral GABA by topiramate, lamotrigine, and gabapentin in healthy adults.

BACKGROUND: Anticonvulsant drugs have multiple mechanisms of action. Recent in vivo MRS studies suggest that cerebral gamma-aminobutyric acid (GABA) increases occur with the administration of certain anticonvulsants in humans. OBJECTIVE: To investigate the effect of topiramate, gabapentin, and lamotrigine on cerebral GABA concentrations in healthy volunteers and correlate the GABA concentrations with serum drug levels. METHODS: Seventeen healthy adults were randomly assigned to receive topiramate, gabapentin, and lamotrigine and underwent GABA measurements using a 4.1-T magnet from a 13.5-mL volume over the occipital region. GABA concentrations and serum levels were measured at 3 and 6 hours following administration of an acute single dose of one of the drugs. Thereafter, drugs were titrated over 4 weeks to target doses, with GABA measurements performed at 2 and 4 weeks. RESULTS: Cerebral GABA concentrations rose 70% in the acute phase compared with baseline for topiramate. GABA rose 48% at 6 hours with gabapentin but not with lamotrigine. With long-term dosing and once target doses were achieved at 4 weeks, significant elevations in GABA were observed compared with baseline for all three drugs (topiramate 46%, gabapentin 25%, lamotrigine 25%). CONCLUSION: This study demonstrates that single doses of topiramate and gabapentin increase cerebral GABA concentrations acutely (hours) in healthy individuals, but all drugs at clinically utilized doses increase cerebral GABA at 4 weeks. These results suggest that the mechanisms of action of anticonvulsant drugs are more complex and are likely to be multiple in nature.

Measurement of beta-hydroxybutyrate in acute hyperketonemia in human brain.

We report the measurement of D-beta-hydroxybutyrate (BHB) in the brains of six normal adult subjects during acute infusions of BHB. We used high field in vivo (1)H magnetic resonance (MR) spectroscopy in the occipital lobe in conjunction with an acute infusion protocol to elevate plasma BHB levels from overnight fasted levels (0.20 +/- 0.10 mM) to a steady state value of 2.12 +/- 0.30 mM. At this level of hyperketonemia, we determined a tissue BHB level of 0.24 +/- 0.04 mM. No increases in brain lactate levels were seen in these data. The concentrations of BHB and lactate were both considerably lower in comparison with previous data acquired in fasted adult subjects. This suggests that up-regulation of the monocarboxylic acid transporter occurs with fasting.

Differentiation of glucose transport in human brain gray and white matter.

Localized 1H nuclear magnetic resonance spectroscopy has been applied to determine human brain gray matter and white matter glucose transport kinetics by measuring the steady-state glucose concentration under normoglycemia and two levels of hyperglycemia. Nuclear magnetic resonance spectroscopic measurements were simultaneously performed on three 12-mL volumes, containing predominantly gray or white matter. The exact volume compositions were determined from quantitative T1 relaxation magnetic resonance images. The absolute brain glucose concentration as a function of the plasma glucose level was fitted with two kinetic transport models, based on standard (irreversible) or reversible Michaelis-Menten kinetics. The steady-state brain glucose levels were similar for cerebral gray and white matter, although the white matter levels were consistently 15% to 20% higher. The ratio of the maximum glucose transport rate, V(max), to the cerebral metabolic utilization rate of glucose, CMR(Glc), was 3.2 +/- 0.10 and 3.9 +/- 0.15 for gray matter and white matter using the standard transport model and 1.8 +/- 0.10 and 2.2 +/- 0.12 for gray matter and white matter using the reversible transport model. The Michaelis-Menten constant K(m) was 6.2 +/- 0.85 and 7.3 +/- 1.1 mmol/L for gray matter and white matter in the standard model and 1.1 +/- 0.66 and 1.7 +/- 0.88 mmol/L in the reversible model. Taking into account the threefold lower rate of CMR(Glc) in white matter, this finding suggests that blood--brain barrier glucose transport activity is lower by a similar amount in white matter. The regulation of glucose transport activity at the blood--brain barrier may be an important mechanism for maintaining glucose homeostasis throughout the cerebral cortex.

Alkaline pH changes in the cerebellum of asymptomatic HIV-infected individuals.

Human immunodeficiency virus (HIV) infection of the brain causes a complex cascade of cellular events involving several different cell types that eventually leads to neuronal cell death and the manifestation of the AIDS-associated dementia complex (ADC). Upon autopsy HIV-infected individuals show lesions within subcortical regions of the brain, including the cerebellum. Previously we have demonstrated, in primary and cell culture models of rat and human astrocytes, a change in intracellular pH (pH(i)) due to increased Na(+)/H(+) exchange following exposure to inactivated virus or gp120, the major HIV envelope glycoprotein. To further investigate whether any such in vivo pH(i) changes occur in human brains subsequent to HIV infection, we measured the pH(i) of the cerebellum in eight HIV-positive individuals and nine healthy volunteers using (31)P magnetic resonance spectroscopy imaging (MRSI) at high field strength (4.1 T). The results showed a significant difference between the age-adjusted mean pH(i) in the cerebellum in control group and patient groups (7.11 +/- 0.03 vs 7.16 +/- 0.04), and further HIV-infected individuals displayed a significant increase in the number of cerebellar volume elements that were alkaline. We hypothesize that this propensity towards alterations in cerebellar pH(i) may portend later neurological involvement resulting from HIV infection.