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Original Investigation |

An Imbalance Between Excitatory and Inhibitory Neurotransmitters in Amyotrophic Lateral Sclerosis Revealed by Use of 3-T Proton Magnetic Resonance Spectroscopy FREE

Bradley R. Foerster, MD1,4,5; Martin G. Pomper, MD, PhD5; Brian C. Callaghan, MD, MS2; Myria Petrou, MA, MBChB, MS1,5; Richard A. E. Edden, PhD5,6; Mona A. Mohamed, MD, PhD, MPH5,6; Robert C. Welsh, PhD1,3; Ruth C. Carlos, MD, MS1; Peter B. Barker, DPhil5,6; Eva L. Feldman, MD, PhD2
[+] Author Affiliations
1Department of Radiology, University of Michigan, Ann Arbor
2Department of Neurology, University of Michigan, Ann Arbor
3Department of Psychiatry, University of Michigan, Ann Arbor
4Department of Veterans Affairs Ann Arbor Healthcare System, Michigan
5Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland
6F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland
JAMA Neurol. 2013;70(8):1009-1016. doi:10.1001/jamaneurol.2013.234.
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Published online

Importance  A lack of neuroinhibitory function may result in unopposed excitotoxic neuronal damage in amyotrophic lateral sclerosis (ALS).

Objective  To determine whether there are reductions in γ-aminobutyric acid (GABA) levels and elevations in glutamate-glutamine (Glx) levels in selected brain regions of patients with ALS by use of proton magnetic resonance spectroscopy.

Design  Case-control study using short echo time and GABA-edited proton magnetic resonance spectroscopy at 3 T with regions of interest in the left motor cortex, left subcortical white matter, and pons; data analyzed using logistic regression, t tests, and Pearson correlations; and post hoc analyses performed to investigate differences between riluzole-naive and riluzole-treated patients with ALS.

Setting  Tertiary referral center.

Participants  Twenty-nine patients with ALS and 30 age- and sex-matched healthy controls.

Exposure  Fifteen patients were taking 50 mg of riluzole twice a day as part of their routine clinical care for ALS.

Main Outcomes and Measures  Levels of GABA, Glx, choline (a marker of cell membrane turnover), creatine (a marker of energy metabolism), myo-inositol (a marker of glial cells), and N-acetylaspartate (a marker of neuronal integrity).

Results  Patients with ALS had significantly lower levels of GABA in the motor cortex than did healthy controls (P < .01). Patients with ALS also had significantly lower levels of N-acetylaspartate in the motor cortex (P < .01), subcortical white matter (P < .05), and pons (P < .01) and higher levels of myo-inositol in the motor cortex (P < .001) and subcortical white matter (P < .01) than did healthy controls. Riluzole-naive patients with ALS had higher levels of Glx than did riluzole-treated patients with ALS (P < .05 for pons and motor cortex) and healthy controls (P < .05 for pons and motor cortex). Riluzole-naive patients with ALS had higher levels of creatine in the motor cortex (P < .001 for both comparisons) and subcortical white matter (P ≤ .05 for both comparisons) than did riluzole-treated patients with ALS and healthy controls. Riluzole-naive patients with ALS had higher levels of N-acetylaspartate in the motor cortex than did riluzole-treated patients with ALS (P < .01).

Conclusions and Relevance  There are reduced levels of GABA in the motor cortex of patients with ALS. There are elevated levels of Glx in riluzole-naive patients with ALS compared with riluzole-treated patients with ALS and healthy controls. These results point to an imbalance between excitatory and inhibitory neurotransmitters as being important in the pathogenesis of ALS and an antiglutamatergic basis for the effects of riluzole, although additional research efforts are needed.

Figures in this Article

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative motor neuron disease involving the motor cortex, corticospinal tract, brainstem, and spinal anterior horn neurons.1 The disease is uniformly fatal, although the clinical presentation and course are heterogeneous, with median survival times between 2 and 4 years.2 Patients present most commonly with combined upper motor neuron (UMN) and lower motor neuron (LMN) features, although, earlier in the disease course, only UMN or LMN signs may be present. Although electromyography confirms LMN signs in ALS, UMN signs are solely assessed on clinical grounds that can delay diagnosis. This is due in part to the fact that UMN signs in ALS can be masked by LMN weakness and secondary hyporeflexia rather than hyperreflexia.3 Riluzole, the only medication for ALS approved by the US Food and Drug Administration, has limited efficacy, extending average life expectancy by only 3 to 6 months.4,5 Riluzole is postulated to modulate excitatory neurotransmission, although the exact in vivo pharmacologic actions are not well understood.6

To further the understanding of the disease process and perhaps to diagnose the disease at an earlier stage, advanced magnetic resonance imaging techniques have been applied to the study of ALS. Proton magnetic resonance spectroscopy (1H-MRS) is one such imaging technique that has been used in a number of studies to investigate ALS.7 The techniques of 1H-MRS require the placement of a voxel or region of interest to specify a volume of brain tissue in which to measure brain metabolites. Conventional in vivo 1H-MRS at 3 T can quantify various brain metabolites, including N-acetylaspartate (NAA; a marker of neuronal integrity), choline (Cho; a marker of cell membrane turnover), creatine (Cr; a marker of energy metabolism), myo-inositol (mI; a marker of glial cells), and glutamate-glutamine (Glx).8 γ-Aminobutyric acid (GABA), the major inhibitory neurotransmitter, is difficult to quantify using conventional 1H-MRS but can be measured using spectral-editing techniques.9,10 There is increasing evidence that reduced inhibitory function may play an important role in the pathogenesis of ALS.11 Given our limited prior knowledge of in vivo GABA changes in ALS, direct interrogation of GABA may lead to a new understanding of this complex disease and may provide opportunities for the development of new disease-modifying treatments.

The most common finding reported in 1H-MRS studies of ALS is reduced NAA in the motor cortex, which is generally interpreted as neuronal loss.12 Although riluzole is thought to modulate excitatory neurotransmission, only 2 published 1H-MRS studies13,14 have explored the effect of riluzole on brain metabolites and measured only Cho, Cr, and NAA. We recently published the first 1H-MRS study15 reporting a decrease in GABA motor cortex levels in a small ALS cohort (n = 10), which suggested reductions in inhibitory neurotransmission. However, our prior study15 did not consider the excitatory contribution of Glx. The aim of the present study was to study both inhibitory neurotransmission, as measured by GABA, and excitatory neurotransmission, as measured by Glx. Our hypothesis is that there is an imbalance between excitatory and inhibitory neurotransmitters in ALS. The GABA and Glx levels were measured in the left motor cortex and left subcortical white matter, and Glx levels were measured in the pons as well. A secondary aim was to determine differences between brain metabolite profiles of riluzole-treated vs riluzole treatment-naive patients with ALS.

Twenty-nine patients with ALS were recruited from our institution’s ALS clinic. Thirty age- and sex-matched healthy controls were also recruited. The patients with ALS met the El Escorial Criteria for probable (n = 15), probable laboratory-supported (n = 10), or definite (n = 4) ALS.16 Participants were excluded if they had a history of central nervous system infection, head injury, or cerebrovascular disease; were active substance abusers; or had a contraindication for magnetic resonance imaging. All participants were right-handed. Our institutional review board approved all study protocols, and informed consent was obtained from all participants. The UMN scores were graded by combining the Ashworth Spasticity Scale (range, 0-8)17 with the presence of pathological reflexes (range, 0-24)18,19 and a scale for measuring the pseudobulbar affect (range, 0-1),20 with a total scale ranging from 0 to 33 (a higher score reflecting higher disease burden). Participant characteristics are presented in Table 1.

Table Graphic Jump LocationTable 1.  Participant Characteristics
Proton Magnetic Resonance Spectroscopy

Nineteen participants (10 patients with ALS and 9 healthy controls) were imaged on a Philips Achieva 3T system using an 8-channel receive head coil; the GABA results from this cohort have been previously published.15 In addition, 40 participants (19 patients with ALS and 21 healthy controls) were imaged on a Philips Ingenia 3T system using a 15-channel receive head coil. T1-weighted 3-dimensional magnetization-prepared rapid acquisition gradient echo images were used to place 3.0 × 3.0 × 2.0-cm voxels in the left motor cortex and left subcortical white matter located caudally to the motor cortex for single-voxel point-resolved spectroscopy (PRESS) and Mescher-Garwood PRESS (MEGA-PRESS) data acquisitions.9 A 1.4 × 1.4 × 1.8-cm voxel was placed centrally in the pons for PRESS data acquisition (Figure 1).

Place holder to copy figure label and caption
Figure 1.
Voxel Placement and Mescher-Garwood Point-Resolved Spectroscopy (MEGA-PRESS) Spectrum

The box in each T1-weighted image shows the single-voxel placement centered on the pons in the sagittal (A) and axial projections (B), on the left motor cortex in the sagittal (C) and axial projections (D), and on the left subcortical white matter located caudal to the motor cortex in the sagittal (E) and axial projections (F). A representative proton magnetic resonance spectroscopy spectrum was obtained from the pons using the conventional PRESS technique (G). A representative proton magnetic resonance spectroscopy spectrum was obtained from the left motor cortex using the MEGA-PRESS editing technique (H). The combined measure of glutamine and glutamate (Glx) is resolved at 3.8 ppm, and γ-aminobutyric acid (GABA) is resolved at 3.0 ppm with an inverted N-acetylaspartate (NAA) peak at 2.0 ppm. Cho indicates choline; Cr, creatine; mI, myo-inositol.

Graphic Jump Location
Conventional PRESS Data Acquisition

The PRESS spectra (with a repetition time [TR] of 2000 milliseconds and an echo time [TE] of 35 milliseconds) were acquired using VAPOR (variable power and optimized relaxation delays) water suppression: 32 averages were performed for the motor cortex and subcortical white matter voxels, and 96 averages were performed for the pons voxels. Conventional PRESS data were analyzed using LCModel version 6.1-4A.21 Metabolite concentrations from LCModel were only used for statistical analysis if the Cramér-Rao lower bounds were less than 20% for the motor cortex and subcortical white matter voxels and less than 25% for the pons voxel. Cerebral spinal fluid correction was performed for each voxel using magnetization-prepared rapid acquisition gradient echo images and Statistical Parametric Mapping version 5 (Wellcome Trust Centre for Neuroimaging).

MEGA-PRESS Data Acquisition

The MEGA-PRESS experiment for editing GABA was performed with the following parameters: TE = 68 milliseconds (TE1 = 15 milliseconds and TE2 = 53 milliseconds); TR = 1.8 seconds; 256 averages; and frequency-selective editing pulses (14 milliseconds) applied at 1.9 ppm (on) and 7.46 ppm (off). Slice-selective refocusing was performed using amplitude-modulated pulse “GTST1203” (length, 7 milliseconds; bandwidth, 1.2 kHz); MEGA-PRESS was analyzed using in-house postprocessing software in Matlab 2012a (Mathworks) with Gaussian curve fitting to the GABA and inverted NAA peaks. The GABA levels were expressed relative to the NAA signal in the edited spectra.22 The GABA:NAA ratio was then multiplied by the NAA concentration determined from LCModel analysis of a short-TE PRESS spectrum of the same voxel to provide an estimate of GABA concentration. Note that the metabolite concentration is in international units (IU) because various factors are not corrected, including editing efficiency and relaxation times.

Statistical Analyses

Logistic regression analyses were performed between disease status and individual metabolites using scanner type (Achieva or Ingenia) as a covariate to determine if there were significant differences between the Philips Achieva 3T and Ingenia 3T systems. Two-tailed independent-sample t tests were performed to determine differences in brain metabolites between patients with ALS and healthy controls. Pearson correlations were performed for associations between brain metabolites and clinical status (using UMN scores, disease duration, the revised ALS Functional Rating Scale [ALSFRS-R], and the rate of disease progression [defined as (48 − ALSFRS-R score at evaluation)/disease duration from symptom onset to evaluation]). A subset analysis was also performed to compare riluzole-treated vs riluzole-naive patients with ALS. We also compared riluzole-naive patients with ALS vs healthy controls. Stata version 11 (StataCorp) was used for statistical analysis. The significance threshold was set a priori at P = .05.

For the conventional PRESS spectra, 2 patients with ALS had an inadequate signal to noise ratio from the pons voxels and were excluded, and the pons Glx value from 1 patient with ALS was excluded owing to a high Cramér-Rao bound. For the MEGA-PRESS spectra, the GABA spectra in the motor cortex of 2 patients with ALS and 1 healthy control and in the subcortical white matter of 1 patient with ALS had an inadequate signal to noise ratio. Four of the patients with ALS were unable to complete the entire imaging protocol and did not undergo 1H-MRS of the subcortical white matter. The logistic regression analysis showed no significant effects of scanner type (z > 0.05) for all of the metabolites, which indicates that the data from the cohorts scanned on the different machines are comparable.

MEGA-PRESS Results

As shown in Figure 2, patients with ALS demonstrated significantly lower levels of GABA in the motor cortex than did healthy controls (P = .002). There were no significant differences in GABA levels in the left subcortical white matter between patients with ALS and healthy controls (P = .30). There was a significant correlation between GABA level in the motor cortex and disease duration (r = −0.39; P = .05). The patients with ALS who had the 5 lowest GABA levels had a disease duration (33 months) that was almost double that of the patients with ALS who had the 5 highest GABA levels (18 months), although the ALSFRS-R and UMN scores were close (ie, the ALSFRS-R score was 5 points lower, and the UMN score was 2 points higher, for the lowest GABA levels).

Place holder to copy figure label and caption
Figure 2.
Decreased γ-Aminobutyric Acid (GABA) Levels in the Motor Cortex of Patients With Amyotrophic Lateral Sclerosis (ALS)

The diamonds represent GABA levels in the left motor cortex (A) and subcortical white matter located caudal to the motor cortex (B) for individual healthy controls (open diamonds) and patients with ALS (filled diamonds). The horizontal bars indicate the mean. Patients with ALS have reduced levels of GABA in the left motor cortex compared with healthy controls. There is no difference in GABA levels in the left subcortical white matter between patients with ALS and healthy controls.

Graphic Jump Location
Conventional PRESS Results

Results are summarized in Table 2. The levels of NAA in the motor cortex (P = .008), subcortical white matter (P = .02), and pons (P = .003) were significantly lower in patients with ALS than in healthy controls. The levels of mI in the motor cortex (P < .001) and subcortical white matter (P = .002) were significantly higher in patients with ALS than in healthy controls. There were significant correlations between NAA level in the motor cortex and ALSFRS-R score (r = 0.39; P < .05), between mI level in the subcortical white matter and disease duration (r = 0.43; P < .05), and between Glx level in the pons and UMN score (r = −0.63; P < .001). There was a significant correlation between NAA and GABA levels (r = 0.57; P = .002). There were no significant correlations between GABA and Glx levels within the same voxel location or between voxel locations.

Table Graphic Jump LocationTable 2.  Conventional Point-Resolved Spectroscopy Results
Riluzole Treatment Subanalyses

Subgroup characteristics are presented in Table 3. As seen in Figure 3, there were significantly higher levels of Cr, Glx, and NAA in the motor cortex of riluzole-naive patients with ALS compared with the riluzole-treated patients with ALS. There were also significantly higher levels of Glx in the pons (P = .01) and higher levels of Cr in the subcortical white matter (P = .05) of the riluzole-naive patients with ALS compared with the riluzole-treated patients with ALS. There were no significant differences in the levels of GABA or other metabolites between the 2 subgroups. The levels of Glx in the motor cortex (P = .03) and the pons (P = .04) were significantly higher for riluzole-naive patients with ALS (mean [SD] levels of 6.49 [1.52] IU and 8.28 [2.53] IU, respectively) than for healthy controls (mean [SD] levels of 5.62 [1.00] IU and 6.83 [1.77] IU, respectively). The levels of Cr in the motor cortex (P < .001) and the subcortical white matter (P = .03) were significantly higher for riluzole-naive patients with ALS (mean [SD] levels of 5.46 [0.58] IU and 4.47 [0.30] IU, respectively) than for healthy controls (mean [SD] levels of 4.93 [0.33] IU and 4.21 [0.35] IU, respectively).

Table Graphic Jump LocationTable 3.  Riluzole Subgroup Characteristics
Place holder to copy figure label and caption
Figure 3.
Metabolite Levels in the Left Motor Cortex for Riluzole-Naive Patients With Amyotrophic Lateral Sclerosis (ALS) and Riluzole-Treated Patients With ALS

The diamonds represent the respective brain metabolites of creatine (Cr [A]), glutamate and glutamine (Glx [B]), and N-acetylaspartate (NAA [C]). Riluzole-naive patients with ALS have elevated levels of Cr, Glx, and NAA in the left motor cortex compared with riluzole-treated patients with ALS.

Graphic Jump Location

Our study demonstrates reductions of GABA levels in the motor cortex of patients with ALS compared with healthy controls. In addition, it was found that Glx levels were elevated in riluzole-naive patients with ALS compared with riluzole-treated patients with ALS and healthy controls. The inclusion of an additional 19 patients with ALS augments the significance of our prior study15 that found lower levels of GABA in the motor cortex of 10 patients with ALS. To our knowledge, this is the first report of in vivo measurements of both GABA and Glx in patients with ALS, thereby investigating both the GABAergic (inhibitory) and the glutamatergic (excitatory) neurotransmitter systems in the same patients.

The cause of ALS remains elusive, although excitotoxic neuronal injury is thought to play an important role, which is primarily mediated through glutamate toxicity.2,23 There is increasing evidence that an “interneuronopathy” may be a central player in the pathophysiology of ALS.24 Interneuronopathy is the hypothesis that inhibitory or GABAergic dysfunction results in relatively unopposed excitotoxic neuronal damage. Neuroimaging, animal, histochemical, genetic, and clinical studies support the role of an interneuronopathy in ALS.11 An ALS functional magnetic resonance imaging study25 demonstrated increased functional connectivity in ALS, suggesting a loss of inhibitory neuronal tone. An animal model of ALS demonstrated that cortical excitability is explained by reduced GABAergic inhibition.26 In addition, human histochemical and positron emission tomography studies have implicated GABA receptor alterations in the motor cortex of patients with ALS.27,28

A significant barrier to further supporting the interneuronal hypothesis has been the challenge of directly measuring in vivo GABA concentrations. γ-Aminobutyric acid has chemical shift overlap with other brain metabolites such as Cr, Glx, and NAA, which are present in brain tissue at higher concentrations than GABA.29 The 1H-MRS editing techniques allow for improved differentiation of metabolites and quantification of GABA by editing out the overlapping Cr peak at 3.0 ppm.10 The current result of decreased levels of GABA in the motor cortex provides further in vivo evidence of reduced inhibitory function in the pathophysiology of ALS and suggests the possibility of the development of new ALS disease-modifying treatments aimed at increasing inhibitory neuronal tone.

Higher levels of Glx were also found in the motor cortex and pons of riluzole-naive patients compared with riluzole-treated patients and healthy controls. Glutamate and glutamine are difficult to resolve independently at field strengths of 3 T or lower, and are usually reported as a combined measure (ie, Glx); however, in a normal brain, glutamate is the larger contributor to this peak by about a 4:1 ratio.30 Owing to concerns of a potential relationship between NAA and Glx, we confirmed that there was not a significant correlation between the NAA levels and the Glx levels for the overall group or the treatment subgroups. Riluzole is thought to act on both the glutamatergic and GABAergic systems.31,32 Riluzole has been shown to decrease glutamatergic neurotransmission by acting as an antagonist of presynaptic N-methyl-d-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors, as well as by increasing glutamate transporter uptake.3335 Riluzole has been shown to increase GABA levels in cell cultures, although the levels required for GABA modulation are thought to be higher than those required for glutamatergic inhibition, which may explain the lack of effect of riluzole on the GABA levels seen in the present study.36,37 Reduced motor cortex excitability has been demonstrated after riluzole administration in healthy subjects, as well as partial normalization of increased cortical excitability in patients with ALS, which is thought to be mediated through glutamatergic rather than GABAergic interactions.38,39

A moderate negative correlation between GABA levels and disease duration was found. The patients with ALS who had the lowest GABA levels had longer disease durations than did the patients with ALS who had the highest GABA levels. It may be that patients with ALS who have a more rapid course have a reflexive increase in inhibitory tone relative to those with a more prolonged disease course. There may be a release of GABA from rapidly denervated interneurons resulting in higher relative levels in patients with ALS who had a short disease duration. Interestingly, both Filippini et al40 and Iwata et al41 found in their cross-sectional studies that fractional anisotropy, a measurement of white matter integrity, was paradoxically higher in patients with ALS who had the longest disease duration. Fractional anisotropy is a different advanced neuroimaging metric, but, taken together, these findings suggest that long-term survivors have different pathophysiologic processes. Although there was no significant direct correlation between GABA and Glx levels, it is possible that there may be a relative GABA threshold for each respective patient, allowing for the excitotoxic effects of glutamate rather than a linear relationship between GABA and glutamate. It is interesting to note that there was a significant correlation between NAA and GABA levels, which suggests an association between neuronal integrity and neuronal inhibitory tone. A longitudinal imaging trial is required to address these issues.

The riluzole-treated patients with ALS had lower levels of Cr than both the riluzole-naive patients with ALS and the healthy controls. It has been proposed that an energy-depleted state may be an inciting factor in ALS31 and that riluzole may reduce neuronal cellular energy demand.42 A potential confounding factor to these findings is that the riluzole-treated patients with ALS had lower levels of NAA than did the riluzole-naive patients with ALS. There was a moderate correlation between NAA and Cr levels in the motor cortex (r = 0.49; P = .01) for the 29 patients with ALS. Two prior studies13,14 have reported a longitudinal increase in the NAA:Cr ratio of patients with ALS after short periods (≤3 weeks) of riluzole treatment; however, these 2 studies13,14 did not report absolute concentrations of the NAA and Cr metabolites, which makes direct comparison difficult. However, overall, these results do suggest the potential of 1H-MRS measurements of GABA and Glx as surrogate markers of disease progression and treatment response, which might be useful in future pharmacological trials.

As in our study, almost all prior 1H-MRS studies have reported decreases in levels of NAA or NAA:CR ratios, particularly in the motor cortex. The finding of elevated mI levels in the motor cortex and subcortical white matter is thought to represent increased numbers of glial cells.8 Although mI has not been investigated to the same extent as NAA, prior studies4345 have reported mI (or mI:Cr ratio) elevations in the motor cortex. Interestingly, only a few studies have measured Glx, with 2 studies reporting elevations in Glx as reported by increased Glx:Cr ratios in the medulla in the study by Pioro et al46 and increased Glx:Cr ratios in the motor cortex in the study by Han and Ma.47 Of the prior studies that measured Glx, it is important to note that riluzole status, which is a potential mediating factor (as the present study would indicate), was either not mentioned43,4648 or unclear.44

As reported before, the limitations of 1H-MRS (including the MEGA-PRESS technique) include its inability to differentiate between the intracellular and extracellular contribution of the metabolites, its potential macromolecular component contributions, and the relatively large voxel sizes required. Our study includes the GABA data of 10 patients with ALS and 9 healthy controls from previously published results. We did not perform a statistical correction for multiple comparisons, which can result in type I errors. As such, subsequent studies are needed to confirm our findings. We were not able to implement the MEGA-PRESS sequence to measure GABA levels in the pons given the relatively small volume. The riluzole-treated group of patients with ALS had, on average, a lower ALSFRS-R score than did the riluzole-naive group of patients with ALS, indicating greater disability, although the UMN disease burden was not significantly different between these 2 groups. Direct causality between riluzole treatment and effect on brain metabolites cannot be established given the cross-sectional nature of our study. A longitudinal imaging trial enrolling patients at initial diagnosis would be required to better establish the response of brain metabolites to treatment, as well as to probe ALS central nervous system changes, including the direct relationship between GABA and Glx over time.

In conclusion, reductions in GABA levels in the motor cortex of patients with ALS were observed, as well as elevations of Glx in riluzole-naive patients with ALS compared with riluzole-treated patients with ALS and healthy controls. The results support the hypothesis that an imbalance between excitatory and inhibitory neurotransmitters is an important factor in the pathogenesis of ALS, as well as the antiglutamatergic basis for the effects of riluzole. These findings also support the potential of 1H-MRS to establish Glx and GABA measurements as clinically relevant markers of disease, although additional research efforts are needed to better understand the findings reported herein.

Accepted for Publication: January 25, 2013.

Corresponding Author: Bradley R. Foerster, MD, Department of Radiology, University of Michigan, 1500 E Medical Center Dr, UH B2 A205H, Ann Arbor, MI 48109-5030 (compfun@umich.edu).

Published Online: June 24, 2013. doi:10.1001/jamaneurol.2013.234.

Author Contributions:Study concept and design: Foerster, Pomper, Mohamed, Carlos, Barker, Feldman.

Acquisition of data: Foerster, Callaghan, Petrou.

Analysis and interpretation of data: Foerster, Pomper, Edden, Mohamed, Welsh, Carlos, Feldman.

Drafting of the manuscript: Foerster.

Critical revision of the manuscript for important intellectual content: Pomper, Callaghan, Petrou, Edden, Mohamed, Welsh, Carlos, Barker, Feldman.

Statistical analysis: Foerster.

Obtained funding: Foerster, Mohamed, Feldman.

Administrative, technical, and material support: Edden, Mohamed, Welsh.

Study supervision: Foerster, Pomper, Feldman.

Conflict of Interest Disclosure: Dr Carlos has served as a consultant for Philips Healthcare.

Funding/Support: This study funded by the A. Alfred Taubman Medical Research Institute.

Additional Contributions: We thank Andrea Smith, MS, for her assistance in the coordination of the study.

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Bohannon  RW, Smith  MB.  Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys Ther. 1987;67(2):206-207.
PubMed
Turner  MR, Cagnin  A, Turkheimer  FE,  et al.  Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis. 2004;15(3):601-609.
PubMed   |  Link to Article
Ellis  CM, Simmons  A, Jones  DK,  et al.  Diffusion tensor MRI assesses corticospinal tract damage in ALS. Neurology. 1999;53(5):1051-1058.
PubMed   |  Link to Article
Smith  RA, Berg  JE, Pope  LE, Thisted  RA.  Measuring pseudobulbar affect in ALS. Amyotroph Lateral Scler Other Motor Neuron Disord2004;5(suppl 1):99-102.
PubMed   |  Link to Article
Provencher  SW.  Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med. 1993;30(6):672-679.
PubMed   |  Link to Article
Stagg  CJ, Best  JG, Stephenson  MC,  et al.  Polarity-sensitive modulation of cortical neurotransmitters by transcranial stimulation. J Neurosci. 2009;29(16):5202-5206.
PubMed   |  Link to Article
Rothstein  JD.  Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann Neurol. 2009;65(suppl 1):S3-S9.
PubMed   |  Link to Article
Kiernan  MC, Petri  S.  Hyperexcitability and amyotrophic lateral sclerosis. Neurology. 2012;78(20):1544-1545.
PubMed   |  Link to Article
Douaud  G, Filippini  N, Knight  S, Talbot  K, Turner  MR.  Integration of structural and functional magnetic resonance imaging in amyotrophic lateral sclerosis. Brain. 2011;134(pt 12):3470-3479.
PubMed   |  Link to Article
Nieto-Gonzalez  JL, Moser  J, Lauritzen  M, Schmitt-John  T, Jensen  K.  Reduced GABAergic inhibition explains cortical hyperexcitability in the wobbler mouse model of ALS. Cereb Cortex. 2011;21(3):625-635.
PubMed   |  Link to Article
Petri  S, Krampfl  K, Hashemi  F,  et al.  Distribution of GABAA receptor mRNA in the motor cortex of ALS patients. J Neuropathol Exp Neurol. 2003;62(10):1041-1051.
PubMed
Turner  MR, Osei-Lah  AD, Hammers  A,  et al.  Abnormal cortical excitability in sporadic but not homozygous D90A SOD1 ALS. J Neurol Neurosurg Psychiatry. 2005;76(9):1279-1285.
PubMed   |  Link to Article
Puts  NA, Edden  RA.  In vivo magnetic resonance spectroscopy of GABA: a methodological review. Prog Nucl Magn Reson Spectrosc. 2012;60:29-41.
PubMed   |  Link to Article
Tkác  I, Oz  G, Adriany  G, Uğurbil  K, Gruetter  R.  In vivo 1H NMR spectroscopy of the human brain at high magnetic fields: metabolite quantification at 4T vs. 7T. Magn Reson Med. 2009;62(4):868-879.
PubMed   |  Link to Article
Cheah  BC, Vucic  S, Krishnan  AV, Kiernan  MC.  Riluzole, neuroprotection and amyotrophic lateral sclerosis. Curr Med Chem. 2010;17(18):1942-1959.
PubMed   |  Link to Article
Cifra  A, Mazzone  GL, Nistri  A.  Riluzole: what it does to spinal and brainstem neurons and how it does it. Neuroscientist. 2013;19(2):137-144.
PubMed   |  Link to Article
Lamanauskas  N, Nistri  A.  Riluzole blocks persistent Na+ and Ca2+ currents and modulates release of glutamate via presynaptic NMDA receptors on neonatal rat hypoglossal motoneurons in vitro. Eur J Neurosci. 2008;27(10):2501-2514.
PubMed   |  Link to Article
Albo  F, Pieri  M, Zona  C.  Modulation of AMPA receptors in spinal motor neurons by the neuroprotective agent riluzole. J Neurosci Res. 2004;78(2):200-207.
PubMed   |  Link to Article
Fumagalli  E, Funicello  M, Rauen  T, Gobbi  M, Mennini  T.  Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1. Eur J Pharmacol. 2008;578(2-3):171-176.
PubMed   |  Link to Article
He  Y, Benz  A, Fu  T,  et al.  Neuroprotective agent riluzole potentiates postsynaptic GABA(A) receptor function. Neuropharmacology. 2002;42(2):199-209.
PubMed   |  Link to Article
Mantz  J, Laudenbach  V, Lecharny  JB, Henzel  D, Desmonts  JM.  Riluzole, a novel antiglutamate, blocks GABA uptake by striatal synaptosomes. Eur J Pharmacol. 1994;257(1-2):R7-R8.
PubMed   |  Link to Article
Stefan  K, Kunesch  E, Benecke  R, Classen  J.  Effects of riluzole on cortical excitability in patients with amyotrophic lateral sclerosis. Ann Neurol. 2001;49(4):536-539.
PubMed   |  Link to Article
Schwenkreis  P, Liepert  J, Witscher  K,  et al.  Riluzole suppresses motor cortex facilitation in correlation to its plasma level: a study using transcranial magnetic stimulation. Exp Brain Res. 2000;135(3):293-299.
PubMed   |  Link to Article
Filippini  N, Douaud  G, Mackay  CE, Knight  S, Talbot  K, Turner  MR.  Corpus callosum involvement is a consistent feature of amyotrophic lateral sclerosis. Neurology. 2010;75(18):1645-1652.
PubMed   |  Link to Article
Iwata  NK, Kwan  JY, Danielian  LE,  et al.  White matter alterations differ in primary lateral sclerosis and amyotrophic lateral sclerosis. Brain. 2011;134(pt 9):2642-2655.
PubMed   |  Link to Article
Storch  A, Burkhardt  K, Ludolph  AC, Schwarz  J.  Protective effects of riluzole on dopamine neurons: involvement of oxidative stress and cellular energy metabolism. J Neurochem. 2000;75(6):2259-2269.
PubMed   |  Link to Article
Block  W, Karitzky  J, Träber  F,  et al.  Proton magnetic resonance spectroscopy of the primary motor cortex in patients with motor neuron disease: subgroup analysis and follow-up measurements. Arch Neurol. 1998;55(7):931-936.
PubMed   |  Link to Article
Bowen  BC, Pattany  PM, Bradley  WG,  et al.  MR imaging and localized proton spectroscopy of the precentral gyrus in amyotrophic lateral sclerosis. AJNR Am J Neuroradiol. 2000;21(4):647-658.
PubMed
Kalra  S, Hanstock  CC, Martin  WR, Allen  PS, Johnston  WS.  Detection of cerebral degeneration in amyotrophic lateral sclerosis using high-field magnetic resonance spectroscopy. Arch Neurol. 2006;63(8):1144-1148.
PubMed   |  Link to Article
Pioro  EP, Majors  AW, Mitsumoto  H, Nelson  DR, Ng  TC.  1H-MRS evidence of neurodegeneration and excess glutamate + glutamine in ALS medulla. Neurology. 1999;53(1):71-79.
PubMed   |  Link to Article
Han  J, Ma  L.  Study of the features of proton MR spectroscopy ((1)H-MRS) on amyotrophic lateral sclerosis. J Magn Reson Imaging. 2010;31(2):305-308.
PubMed   |  Link to Article
Bradley  WG, Bowen  BC, Pattany  PM, Rotta  F.  1H-magnetic resonance spectroscopy in amyotrophic lateral sclerosis. J Neurol Sci. 1999;169(1-2):84-86.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Voxel Placement and Mescher-Garwood Point-Resolved Spectroscopy (MEGA-PRESS) Spectrum

The box in each T1-weighted image shows the single-voxel placement centered on the pons in the sagittal (A) and axial projections (B), on the left motor cortex in the sagittal (C) and axial projections (D), and on the left subcortical white matter located caudal to the motor cortex in the sagittal (E) and axial projections (F). A representative proton magnetic resonance spectroscopy spectrum was obtained from the pons using the conventional PRESS technique (G). A representative proton magnetic resonance spectroscopy spectrum was obtained from the left motor cortex using the MEGA-PRESS editing technique (H). The combined measure of glutamine and glutamate (Glx) is resolved at 3.8 ppm, and γ-aminobutyric acid (GABA) is resolved at 3.0 ppm with an inverted N-acetylaspartate (NAA) peak at 2.0 ppm. Cho indicates choline; Cr, creatine; mI, myo-inositol.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Decreased γ-Aminobutyric Acid (GABA) Levels in the Motor Cortex of Patients With Amyotrophic Lateral Sclerosis (ALS)

The diamonds represent GABA levels in the left motor cortex (A) and subcortical white matter located caudal to the motor cortex (B) for individual healthy controls (open diamonds) and patients with ALS (filled diamonds). The horizontal bars indicate the mean. Patients with ALS have reduced levels of GABA in the left motor cortex compared with healthy controls. There is no difference in GABA levels in the left subcortical white matter between patients with ALS and healthy controls.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Metabolite Levels in the Left Motor Cortex for Riluzole-Naive Patients With Amyotrophic Lateral Sclerosis (ALS) and Riluzole-Treated Patients With ALS

The diamonds represent the respective brain metabolites of creatine (Cr [A]), glutamate and glutamine (Glx [B]), and N-acetylaspartate (NAA [C]). Riluzole-naive patients with ALS have elevated levels of Cr, Glx, and NAA in the left motor cortex compared with riluzole-treated patients with ALS.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Participant Characteristics
Table Graphic Jump LocationTable 2.  Conventional Point-Resolved Spectroscopy Results
Table Graphic Jump LocationTable 3.  Riluzole Subgroup Characteristics

References

Turner  MR, Kiernan  MC, Leigh  PN, Talbot  K.  Biomarkers in amyotrophic lateral sclerosis. Lancet Neurol. 2009;8(1):94-109.
PubMed   |  Link to Article
Kiernan  MC, Vucic  S, Cheah  BC,  et al.  Amyotrophic lateral sclerosis. Lancet. 2011;377(9769):942-955.
PubMed   |  Link to Article
Swash  M.  Why are upper motor neuron signs difficult to elicit in amyotrophic lateral sclerosis? J Neurol Neurosurg Psychiatry. 2012;83(6):659-662.
PubMed   |  Link to Article
Miller  RG, Mitchell  JD, Lyon  M, Moore  DH.  Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2007;(1):CD001447.
PubMed
Lacomblez  L, Bensimon  G, Leigh  PN, Guillet  P, Meininger  V; Amyotrophic Lateral Sclerosis/Riluzole Study Group II.  Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet. 1996;347(9013):1425-1431.
PubMed
Doble  A.  The pharmacology and mechanism of action of riluzole. Neurology. 1996;47(6)(suppl 4):S233-S241.
PubMed   |  Link to Article
Turner  MR, Modo  M.  Advances in the application of MRI to amyotrophic lateral sclerosis. Expert Opin Med Diagn. 2010;4(6):483-496.
PubMed   |  Link to Article
Gujar  SK, Maheshwari  S, Björkman-Burtscher  I, Sundgren  PC.  Magnetic resonance spectroscopy. J Neuroophthalmol. 2005;25(3):217-226.
PubMed   |  Link to Article
Mescher  M, Merkle  H, Kirsch  J, Garwood  M, Gruetter  R.  Simultaneous in vivo spectral editing and water suppression. NMR Biomed. 1998;11(6):266-272.
PubMed   |  Link to Article
Edden  RA, Barker  PB.  Spatial effects in the detection of gamma-aminobutyric acid: improved sensitivity at high fields using inner volume saturation. Magn Reson Med. 2007;58(6):1276-1282.
PubMed   |  Link to Article
Turner  MR, Kiernan  MC.  Does interneuronal dysfunction contribute to neurodegeneration in amyotrophic lateral sclerosis? Amyotroph Lateral Scler. 2012;13(3):245-250.
PubMed   |  Link to Article
Agosta  F, Chiò  A, Cosottini  M,  et al.  The present and the future of neuroimaging in amyotrophic lateral sclerosis. AJNR Am J Neuroradiol. 2010;31(10):1769-1777.
PubMed   |  Link to Article
Kalra  S, Cashman  NR, Genge  A, Arnold  DL.  Recovery of N-acetylaspartate in corticomotor neurons of patients with ALS after riluzole therapy. Neuroreport. 1998;9(8):1757-1761.
PubMed   |  Link to Article
Kalra  S, Tai  P, Genge  A, Arnold  DL.  Rapid improvement in cortical neuronal integrity in amyotrophic lateral sclerosis detected by proton magnetic resonance spectroscopic imaging. J Neurol. 2006;253(8):1060-1063.
PubMed   |  Link to Article
Foerster  BR, Callaghan  BC, Petrou  M, Edden  RA, Chenevert  TL, Feldman  EL.  Decreased motor cortex γ-aminobutyric acid in amyotrophic lateral sclerosis. Neurology. 2012;78(20):1596-1600.
PubMed   |  Link to Article
Brooks  BR, Miller  RG, Swash  M, Munsat  TL; World Federation of Neurology Research Group on Motor Neuron Diseases.  El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;1(5):293-299.
PubMed   |  Link to Article
Bohannon  RW, Smith  MB.  Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys Ther. 1987;67(2):206-207.
PubMed
Turner  MR, Cagnin  A, Turkheimer  FE,  et al.  Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis. 2004;15(3):601-609.
PubMed   |  Link to Article
Ellis  CM, Simmons  A, Jones  DK,  et al.  Diffusion tensor MRI assesses corticospinal tract damage in ALS. Neurology. 1999;53(5):1051-1058.
PubMed   |  Link to Article
Smith  RA, Berg  JE, Pope  LE, Thisted  RA.  Measuring pseudobulbar affect in ALS. Amyotroph Lateral Scler Other Motor Neuron Disord2004;5(suppl 1):99-102.
PubMed   |  Link to Article
Provencher  SW.  Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med. 1993;30(6):672-679.
PubMed   |  Link to Article
Stagg  CJ, Best  JG, Stephenson  MC,  et al.  Polarity-sensitive modulation of cortical neurotransmitters by transcranial stimulation. J Neurosci. 2009;29(16):5202-5206.
PubMed   |  Link to Article
Rothstein  JD.  Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann Neurol. 2009;65(suppl 1):S3-S9.
PubMed   |  Link to Article
Kiernan  MC, Petri  S.  Hyperexcitability and amyotrophic lateral sclerosis. Neurology. 2012;78(20):1544-1545.
PubMed   |  Link to Article
Douaud  G, Filippini  N, Knight  S, Talbot  K, Turner  MR.  Integration of structural and functional magnetic resonance imaging in amyotrophic lateral sclerosis. Brain. 2011;134(pt 12):3470-3479.
PubMed   |  Link to Article
Nieto-Gonzalez  JL, Moser  J, Lauritzen  M, Schmitt-John  T, Jensen  K.  Reduced GABAergic inhibition explains cortical hyperexcitability in the wobbler mouse model of ALS. Cereb Cortex. 2011;21(3):625-635.
PubMed   |  Link to Article
Petri  S, Krampfl  K, Hashemi  F,  et al.  Distribution of GABAA receptor mRNA in the motor cortex of ALS patients. J Neuropathol Exp Neurol. 2003;62(10):1041-1051.
PubMed
Turner  MR, Osei-Lah  AD, Hammers  A,  et al.  Abnormal cortical excitability in sporadic but not homozygous D90A SOD1 ALS. J Neurol Neurosurg Psychiatry. 2005;76(9):1279-1285.
PubMed   |  Link to Article
Puts  NA, Edden  RA.  In vivo magnetic resonance spectroscopy of GABA: a methodological review. Prog Nucl Magn Reson Spectrosc. 2012;60:29-41.
PubMed   |  Link to Article
Tkác  I, Oz  G, Adriany  G, Uğurbil  K, Gruetter  R.  In vivo 1H NMR spectroscopy of the human brain at high magnetic fields: metabolite quantification at 4T vs. 7T. Magn Reson Med. 2009;62(4):868-879.
PubMed   |  Link to Article
Cheah  BC, Vucic  S, Krishnan  AV, Kiernan  MC.  Riluzole, neuroprotection and amyotrophic lateral sclerosis. Curr Med Chem. 2010;17(18):1942-1959.
PubMed   |  Link to Article
Cifra  A, Mazzone  GL, Nistri  A.  Riluzole: what it does to spinal and brainstem neurons and how it does it. Neuroscientist. 2013;19(2):137-144.
PubMed   |  Link to Article
Lamanauskas  N, Nistri  A.  Riluzole blocks persistent Na+ and Ca2+ currents and modulates release of glutamate via presynaptic NMDA receptors on neonatal rat hypoglossal motoneurons in vitro. Eur J Neurosci. 2008;27(10):2501-2514.
PubMed   |  Link to Article
Albo  F, Pieri  M, Zona  C.  Modulation of AMPA receptors in spinal motor neurons by the neuroprotective agent riluzole. J Neurosci Res. 2004;78(2):200-207.
PubMed   |  Link to Article
Fumagalli  E, Funicello  M, Rauen  T, Gobbi  M, Mennini  T.  Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1. Eur J Pharmacol. 2008;578(2-3):171-176.
PubMed   |  Link to Article
He  Y, Benz  A, Fu  T,  et al.  Neuroprotective agent riluzole potentiates postsynaptic GABA(A) receptor function. Neuropharmacology. 2002;42(2):199-209.
PubMed   |  Link to Article
Mantz  J, Laudenbach  V, Lecharny  JB, Henzel  D, Desmonts  JM.  Riluzole, a novel antiglutamate, blocks GABA uptake by striatal synaptosomes. Eur J Pharmacol. 1994;257(1-2):R7-R8.
PubMed   |  Link to Article
Stefan  K, Kunesch  E, Benecke  R, Classen  J.  Effects of riluzole on cortical excitability in patients with amyotrophic lateral sclerosis. Ann Neurol. 2001;49(4):536-539.
PubMed   |  Link to Article
Schwenkreis  P, Liepert  J, Witscher  K,  et al.  Riluzole suppresses motor cortex facilitation in correlation to its plasma level: a study using transcranial magnetic stimulation. Exp Brain Res. 2000;135(3):293-299.
PubMed   |  Link to Article
Filippini  N, Douaud  G, Mackay  CE, Knight  S, Talbot  K, Turner  MR.  Corpus callosum involvement is a consistent feature of amyotrophic lateral sclerosis. Neurology. 2010;75(18):1645-1652.
PubMed   |  Link to Article
Iwata  NK, Kwan  JY, Danielian  LE,  et al.  White matter alterations differ in primary lateral sclerosis and amyotrophic lateral sclerosis. Brain. 2011;134(pt 9):2642-2655.
PubMed   |  Link to Article
Storch  A, Burkhardt  K, Ludolph  AC, Schwarz  J.  Protective effects of riluzole on dopamine neurons: involvement of oxidative stress and cellular energy metabolism. J Neurochem. 2000;75(6):2259-2269.
PubMed   |  Link to Article
Block  W, Karitzky  J, Träber  F,  et al.  Proton magnetic resonance spectroscopy of the primary motor cortex in patients with motor neuron disease: subgroup analysis and follow-up measurements. Arch Neurol. 1998;55(7):931-936.
PubMed   |  Link to Article
Bowen  BC, Pattany  PM, Bradley  WG,  et al.  MR imaging and localized proton spectroscopy of the precentral gyrus in amyotrophic lateral sclerosis. AJNR Am J Neuroradiol. 2000;21(4):647-658.
PubMed
Kalra  S, Hanstock  CC, Martin  WR, Allen  PS, Johnston  WS.  Detection of cerebral degeneration in amyotrophic lateral sclerosis using high-field magnetic resonance spectroscopy. Arch Neurol. 2006;63(8):1144-1148.
PubMed   |  Link to Article
Pioro  EP, Majors  AW, Mitsumoto  H, Nelson  DR, Ng  TC.  1H-MRS evidence of neurodegeneration and excess glutamate + glutamine in ALS medulla. Neurology. 1999;53(1):71-79.
PubMed   |  Link to Article
Han  J, Ma  L.  Study of the features of proton MR spectroscopy ((1)H-MRS) on amyotrophic lateral sclerosis. J Magn Reson Imaging. 2010;31(2):305-308.
PubMed   |  Link to Article
Bradley  WG, Bowen  BC, Pattany  PM, Rotta  F.  1H-magnetic resonance spectroscopy in amyotrophic lateral sclerosis. J Neurol Sci. 1999;169(1-2):84-86.
PubMed   |  Link to Article

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