Somatosensory & Motor Research

ISSN: 0899-0220 (Print) 1369-1651 (Online) Journal homepage: http://www.tandfonline.com/loi/ismr20

Detecting neuronal dysfunction of hand motor

cortex in ALS: A MRSI study

Yuzhou Wang, Xiaodi Li, Wenming Chen, Zhanhang Wang, Yan Xu, Jingpan
Luo, Hanbo Lin & Guijun Sun

To cite this article: Yuzhou Wang, Xiaodi Li, Wenming Chen, Zhanhang Wang, Yan Xu,
Jingpan Luo, Hanbo Lin & Guijun Sun (2017) Detecting neuronal dysfunction of hand
motor cortex in ALS: A MRSI study, Somatosensory & Motor Research, 34:1, 15-20, DOI:
10.1080/08990220.2016.1275544

To link to this article: http://dx.doi.org/10.1080/08990220.2016.1275544

2017 The Author(s). Published by Informa

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SOMATOSENSORY & MOTOR RESEARCH, 2017
VOL. 34, NO. 1, 1520
http://dx.doi.org/10.1080/08990220.2016.1275544

ORIGINAL ARTICLE

Detecting neuronal dysfunction of hand motor cortex in ALS: A MRSI study

Yuzhou Wanga, Xiaodi Lia, Wenming Chena, Zhanhang Wanga, Yan Xua, Jingpan Luoa, Hanbo Linb and
Guijun Sunb
a
Department of Neurology, Guangdong 999 Brain Hospital, Guangzhou, China; bDepartment of Neuroradiology, Guangdong 999 Brain
Hospital, Guangzhou, China

ABSTRACT ARTICLE HISTORY

Background: Although hand motor cortex (HMC) has been constantly used for identification of pri- Received 8 August 2016
mary motor cortex in magnetic resonance spectroscopy (MRS) studies of amyotrophic lateral sclerosis Revised 17 November 2016
(ALS), neurochemical profiles of HMC have never been assessed independently. As HMC has a constant Accepted 7 December 2016
location and the clinicanatomic correlation between hand motor function and HMC has been estab-
KEYWORDS
lished, we hypothesize that HMC may serve as a promising region of interest in diagnosing ALS. Amyotrophic lateral
Patients and methods: Fourteen ALS patients and 14 age- and gender-matched healthy controls (HC) sclerosis; hand motor
were recruited in this study. An optimized magnetic resonance spectroscopic imaging (MRSI) method cortex; magnetic resonance
was developed and for each subject bilateral HMC areas were scanned separately (two-dimensional spectroscopic imaging
multi-voxel MRSI, voxel size 0.56 cm3). N-acetyl aspartate (NAA)creatine (Cr) ratio was measured from
HMC and the adjacent postcentral gyrus.
Results: Compared with HC, NAA/Cr ratios from HMC and the postcentral gyrus were significantly
reduced in ALS. However, in each group the difference of NAA/Cr ratios between HMC and the post-
central gyrus was not significant. Limb predominance of HMC was not found in either ALS or HC. In
ALS, there was a significant difference in NAA/Cr ratio between the most affected HMC and the less
affected HMC. A positive relationship between NAA/Cr ratio of HMC and the severity of hand strength
(assessed by finger tapping speed) was demonstrated.
Conclusion: Neuronal dysfunction of HMC can differentiate ALS patients from HC when represented as
reduced NAA/Cr ratio. Postcentral gyrus could not serve as normal internal reference tissue in diagnos-
ing ALS. Asymmetrical NAA/Cr ratios from bilateral HMC may serve as a promising diagnostic bio-
marker of ALS at the individual level.

Introduction the feasibility of using HMC as a ROI for ALS, we performed a

Amyotrophic lateral sclerosis (ALS) is a heterogeneous neuro-
degenerative disease affecting both upper and lower motor
neurons. Proton magnetic resonance spectroscopy (MRS)
studies have consistently shown evidence of neuronal dys-
function in the primary motor cortex (PMC) of ALS (Filippi
et al. 2010). However, no consensus has been reached on the
standard protocols for performing MRS scans in ALS.
Specifically, the location and volume of the region of interest
(ROI) varies from study to study, making it difficult to recon-
cile results from different groups. Besides, the relationship
between neuroimaging findings and clinical measures is also
inconsistent (Foerster et al. 2013). Hand motor cortex (HMC),
a landmark for PMC (Yousry et al. 1997), has been constantly
used for identification of PMC in these studies. However,
neurochemical profiles of HMC have never been assessed
independently. As the location of HMC is constant and easy
to identify, and the clinicanatomic correlation between
hand motor function and HMC has been established (Back
and Mrowka 2001; Hall and Flint 2008), we propose that
HMC may serve as a promising ROI for ALS detection. To test
magnetic resonance spectroscopic imaging (MRSI) study in a
group of ALS patients and healthy controls. A localized MRSI
protocol was developed to detect neuronal dysfunction in
the HMC area. The nearest postcentral gyrus was also
included in the ROI as potential internal reference tissue. The
correlation between clinical severity and the N-acetyl asparta-
tecreatine (NAA/Cr) ratio of HMC was also tested.
Methods
Subjects
Fourteen patients (8 male, 6 female) diagnosed of definite or
probable sporadic ALS according to the revised El Escorial cri-
teria (Brooks et al. 2000) were enrolled over a 1-year period.
Their score on the revised ALS functional rating scale
(ALSFRS-R) (Cedarbaum et al. 1999) was recorded. ALSFRS-R
progression rate per month was calculated as follows: (48

ALSFRS-R score)/time from symptom onset. As an indication
of the severity of hand motor function impairment, finger

CONTACT Yuzhou Wang wangyuzhou2013@gmail.com Department of Neurology, Guangdong 999 Brain Hospital, 578 Shatai Road, 510510 Guangzhou,
China
2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any
way.
16 Y. WANG ET AL.

Figure 1. Illustrations of two different magnetic resonance spectroscopy imaging (MRSI) methods and their resulting spectra. (A, F) Coronal view of calibration scan
in a routine MRSI method (upper row) and the localized MRSI method (lower row). (B, G) Positioning of the region of interest and the position of the target voxel.
(C, F) N-acetyl aspartate (NAA) concentration map automatically generated by the Functool software. Voxels from the blue area (Shown as gray area in the Print ver-
sion) have higher NAA concentration. Note that the target voxel is fully included in the blue area (Shown as gray area in the Print version) by the localized MRSI
method (F). (D, I) Signal-to-noise ratio (SNR) distribution map automatically generated by the Functool software. Voxels from the red area (Shown as dark area in
the Print version) have better SNR. Target voxel is not included in the red area (Shown as dark area in the Print version) by the routine MRSI method (D). (E, J)
Spectra of the same target voxel from two MRSI methods. The resulting SNR is 1.42 and the NAA concentration is 129 528 arbitrary MR units with routine MRSI
method (E), while the SNR is elevated to 2.04 and NAA concentration is elevated to 172 872 arbitrary MR units with the localized MRSI method (J).

tapping speed was measured for three 15-s epochs and aver-
aged for each hand. In this study, the contralateral hemi-
sphere of the initially involved upper limb was defined as the
most affected hemisphere. Fourteen age- and gender-
matched healthy adults (7 male, 7 female) were recruited as
normal controls. Neither patients nor controls had a history
of cerebrovascular disease, intracranial pathology, or any
other neurological diseases. No patients had received riluzole
treatment prior to the study. Patients with respiratory insuffi-
ciency were also excluded because they could not tolerate
the long acquisition time of magnetic resonance (MR) scans.
All subjects were right handed. The study was approved by
the institutional ethics committee. All subjects or their next
of kin provided written informed consent prior to MRSI
examination.
Image acquisition
MRSI studies were conducted on a 3 T MR system (Signa
HDxt; General Electric, Waukesha, Wiscosin, USA) using a
standard 8-channel head coil. Following a sagittal T1-
weighted localizer imaging series, an axial T2-weighted axial
MRSI localizer imaging series (TR/TE 4480/120 ms, slice
thickness 2 mm, gap 0 mm, total 4045 slices) was
acquired to cover the whole supratentorial brain. The center
of the ASSET Calibration sequence was located in the uni-
lateral central sulcus, just between the HMC and the postcen-
tral gyrus. Single slice two-dimensional MRSI was acquired
using a PROBE-SI sequence (TR 1000 ms, TE 144 ms,
NEX 1, 10 mm section thickness) with automated shim and
water suppression. Each ROI encompassed unilateral HMC
and postcentral gyrus, including a total of 46 voxels. Six
outer volume saturation slabs were placed outside the ROI to
suppress lipid signals from the scalp. Acquisition time was
approximately 6 min for each scan. The resulting nominal
MRSI voxel size was 0.75 cm 0.75 cm 1.0 cm 0.56 cm3.
Off-line spectral post-processing was carried out using semi-
automated software (Functool, Version 9.4.05; GE Medical
Systems, Waukesha, Wiscosin, USA). MRSI results were
reviewed by two neuroradiologists who were blind to the
diagnosis. Compared with routine MRSI protocols, this local-
ized MRSI method resulted in a better spectrum with higher
signal-to-noise ratio (SNR) (Figure 1). A detailed illustration of
this method is shown in Figure 2.
Statistics
The ShapiroWilk test was used to assess the normality of
data. For comparison of demographic and clinical data
between two groups, independent samples t-test or
MannWhitney U-test was used as appropriate. For compari-
son of the group level difference in NAA/Cr ratios between
ALS and HC, and between HMC and postcentral gyrus, data
from the left and right hemispheres was pooled together
and two independent samples t-tests were used. Intra-group
comparison of NAA/Cr ratio was carried out using paired
t-test. Correlations with clinical measures lacking lateral bias
(age, disease duration, ALSFRS-R, and disease rate) were
tested with mean NAA/Cr ratio or NAA/Cr ratios from the
most affected hemispheres. Unilateral tapping speeds were
tested for associations with contralateral NAA/Cr ratios.
Results
Demographic and clinical features of the subjects
Mean age of patients and healthy controls (HC) were 54 8
(range 4269) years and 54 9 (range 3966) years,
 SOMATOSENSORY & MOTOR RESEARCH 17

Figure 2. Illustration of the optimized magnetic resonance spectroscopy imaging (MRSI) protocol and resulting spectrum from right hand motor cortex and post-
central gyrus of a normal subject. (A) Saggital view of axial T2-weighted localizer imaging series. (B) Axial T2-weighted image. Black cross indicates the center of
the ASSET Calibration sequence. (C) Coronal view of the calibration sequence. (D) Right hand motor cortex and corresponding postcentral gyrus are included in the
region of interest. Four outer volume saturation slabs are shown. (EH) Representative spectrum from right hand motor cortex (E, F) and postcentral gyrus (G, H) of
a normal subject.

Table 1. Demographic and clinical data from healthy controls and patients with amyotrophic lateral sclerosis (ALS).
ALS patients Healthy controls p
Age (years) 54 8 (4269) 54 9 (3966) 0.932
Women 6/14 7/14 0.458
Upper limb/Lower limb/Bulbar onset 9/2/3
Disease duration (months) 23 11 (842)
ALSFRS-R 36 5 (2744)
Disease progression rate (units/months) 0.66 0.45 (0.251.6)
Pyramidal signs of upper limbs (number/total) 6/14
Neurogenic damage of hand small muscles on EMG 10/14
Finger tapping speed (taps/s; R/L) 3.2 1.5/3.4 1.5 6.3 0.4/6.5 0.5 <0.001/<0.001

respectively (p 0.932). In ALS patients, the mean disease
duration was 23 11 months (range 842 months) and the
mean ALSFRS-R score was 36 5 (range 2744). Among them
9 patients were upper limb onset, 2 patients were lower limb
onset, and the remaining 3 patients were bulbar onset.
Pyramidal signs of upper limbs were observed in only 6
patients while in 10 patients hand small muscles demon-
strated neurogenic damage on electromyography (EMG). The
disease progression rate was 0.64 0.45 (range 0.251.6).
Finger tapping speed was significantly lower in ALS patients
(p < 0.001) (Table 1).
MRSI results
A total of 56 scans were performed for all subjects. In all
cases spectra with good quality were obtained. The full width
at half maximum ranged from 5 to 7 Hz, with a mean of
6.0 0.2 Hz in patients and 6.0 0.4 Hz in HC (p > 0.05), indi-
cating that the spectra had good quality and results from
both groups were comparable. Representative spectra from
the HMC and postcentral gyrus of HC are shown in Figure 2.
When we compared the mean NAA/Cr ratios of ALS patients
with HC, we observed a reduction of 22.4% in the HMC
(p < 0.001) and a reduction of 17.0% (p < 0.001) in the post-
central gyrus. In the ALS group and HC group no difference
was revealed between HMC and postcentral gyrus in pooled
NAA/Cr ratios (p 0.500 and 0.870, respectively). No statis-
tical significance was detected between bilateral HMC
(p 0.422) or bilateral postcentral gyrus (p 0.635) in NAA/Cr
ratio of HC. In the NAA/Cr ratio of ALS patients there is no
significant difference between bilateral HMC (p 0.666) or
between bilateral postcentral gyrus (p 0.577) either.
However, the difference between the most affected HMC and
less affected HMC was found to be significant (p < 0.001)
(Table 2). In a total of 14 patients, 12 had a lower value of
the NAA/Cr ratio in the most affected HMC (sensitivity of
85.7%) (Figure 3).
Correlation analysis
When all hemispheres of patients were combined, a moder-
ate but statistically significant correlation, as determined with
Pearson correlation analysis, was found between NAA/Cr
ratios of HMC and the finger tapping speed (r 0.585,
p 0.001). Neither mean NAA/Cr ratio of bilateral HMC nor
NAA/Cr ratio from the most affected HMC correlates with the
18 Y. WANG ET AL.

Table 2. Inter-group and inter-group comparisons of N-acetyl aspartatecreatine ratios between different groups, different hemispheres, and different regions of
interest.
Groups and hemisphere
ALS patients Healthy controls
Region of interest Left Right Bilateral Most affected Less affected Left Right Bilateral
Hand motor cortex 1.56 0.46a 1.49 0.37a,b 1.52 0.41a 1.30 0.27 1.75 0.41c 1.99 0.25 1.94 0.32b 1.96 0.28
Postcentral gyrus 1.62 0.27a 1.56 0.20a,b 1.62 0.29a 1.67 0.28 1.57 0.31d 1.93 0.21 1.97 0.23b 1.95 0.21
pe 0.648 0.609 0.500 0.002 0.380 0.534 0.752 0.870
a
Compared with NAA/Cr ratios from healthy controls, p < 0.05.
b
Compared with NAA/Cr ratios from left hemisphere, p > 0.05.
c
Compared with NAA/Cr ratios from most affected hemisphere, p < 0.05.
d
Compared with NAA/Cr ratios from most affected hemisphere, p > 0.05.
e
Comparison between hand motor cortex and postcentral gyrus.

Figure 3. Magnetic resonance spectroscopy imaging (MRSI) spectrum from a patient presented with predominantly left upper limb weakness. A 35-year-old man
developed progressive weakness of the left arm for 10 months. Neurological examinations revealed profound weakness and atrophy in the left arm, mild weakness
with spasticity in the right arm and the tongue, and increased tendon reflexes with abnormal plantar extensor responses in bilateral lower limbs.
Electrophysiological examinations demonstrated widespread denervation and reinnervation consistent with a clinical diagnosis of definite amyotrophic lateral scler-
osis (ALS). MRSI scan revealed an N-acetyl aspartatecreatine (NAA/Cr) ratio of 2.36 (region of interest 5, upper row) in the left hand motor cortex (the less affected
hemisphere) and an NAA/Cr ratio of 1.23 (region of interest 3, lower row) in the right side (the most affected hemisphere), which was in accordance with clinical
findings.

ALSFRS-R score (p 0.583 and 0.213, respectively). They also
have no correlation with the progression rate of ALSFRS-R
score (p 0.852 and 0.205, respectively). However, NAA/Cr
ratio from the most affected HMC was found to correlate
with disease duration (r 0.561, p 0.037).
Discussion
ALS is a rare disease with a median incidence rate of 1.9 per
100 000 person-years (Chio et al. 2013). Evidence of upper
motor neuron involvement is crucial for the diagnosis of ALS.
In this study we confirmed previous findings that a
decreased NAA/Cr ratio was found in both precentral and
postcentral gyrus (Pioro et al. 1994; Sanjay et al. 2003), which
was in accordance with the pathology of ALS (Martin and
Swash 1995). The difference between the most affected
hemisphere and the less affected hemisphere of HMC was
also significant (p < 0.001) and the unilateral NAA/Cr ratio of
HMC correlated well with hand tapping speed in ALS
patients, allowing us to further differentiate ALS patients
from HC.
Currently it is difficult to confirm or exclude the diagnosis
of ALS at the individual level. Technically there are at least
three strategies to overcome this problem. The first one is
the most commonly used strategy, which is to compare the
neurochemical profiles of the patient with that from normal
control subjects. If the reduced NAA/Cr ratio of the patient is
found to be below the lower limit of HC (e.g., below 2 stand-
ard deviations from the average level if the NAA/Cr ratio of
PMC has a normal distribution in the healthy population),
then the diagnosis of ALS will be established. However, sensi-
tivity and specificity of this strategy for ALS diagnosis is rela-
tively limited (sensitivity: 5070%; specificity: 4090%) (Turner
and Modo 2010). Reduction of the NAA/Cr ratio was only
mild to moderate (Foerster et al. 2013) and there was consid-
erable overlap in metabolite ratios of PMC between ALS
patients and normal controls (Ellis et al. 1998; Kalra et al.
2006b). Such overlapping is probably a combined result of
the physical feature of cerebral cortex and limitation of MRS
scanning. While a typical ROI in single-voxel spectroscopy
(SVS) studies has a size of 8 cm3 (2 cm  2 cm  2 cm), the
undulating and folded appearance of cerebral cortex causes
difficulty in defining the pathological area accurately. The
focality of motor neuron degeneration further complicates
the picture (Ravits and La Spada 2009). Therefore, it is inevit-
able to have signal contamination from surrounding areas
including the unaffected region of PMC, adjacent normal par-
enchyma, and even cerebral spinal fluid. As a result, neuro-
chemical differences between patients and controls might be
underestimated. Because larger ROI gives rise to a better
spectrum, reducing the volume of ROI at the expense of SNR
ratio will not improve detection sensitivity. Therefore, the
inherent deficit of SVS limits its clinical application in this dis-
ease. These issues have been addressed by Mitsumoto et al.
(2007). However, they still failed to find improved perform-
ance in MSRI study even with increased spatial resolution
and reduced motor cortex voxel tissue heterogeneity
(Mitsumoto et al. 2007). It appears that spectrum quality and
SOMATOSENSORY & MOTOR RESEARCH 19
reproducibility may degrade when voxels are located away
from the magnet isocenter or near the tissuebone interface.
Positioning of voxel becomes even more critical when the
motor cortex is sampled, which may have contributed to
relatively lower reproducibility of NAA measurement in this
region (Suhy et al. 2002). Previously we found that the voxels
localized in the central part of the ROI have higher SNR ratios
and better spectral quality (see illustrations in Figure 1).
Based on these findings, we developed a localized MRSI
method to scan the bilateral HMC area separately. Therefore,
in this study we used HMC as a ROI and its neurochemical
change as biomarker for ALS detection. As far as we know,
no similar study design has been reported.
The second strategy is to compare the neurochemical pro-
files from HMC with that from an internal reference tissue of
the brain, such as, the postcentral gyrus or premotor cortex.
However, in previous studies widespread degeneration of the
brain was reported (Turner and Modo 2010), and it is not
known if the postcentral gyrus could serve as an internal ref-
erence tissue to facilitate the interpretation of the spectrum
obtained from PMC. In this study the difference of the NAA/
Cr ratio between precentral and postcentral gyrus was not
significant either in patients or in HC, making the postcentral
gyrus not suitable to serve as a normal internal reference tis-
sue for clinical diagnosis of ALS.
The third strategy is to compare the neurochemical pro-
files from the most affected hemisphere of the patient with
that from the less affected hemisphere. Asymmetrical symp-
toms (Ravits et al. 2007) and brain pathology (Mochizuki
et al. 1995) are established features of early stage ALS. When
asymmetrical metabolic ratios of motor cortex correlate with
laterality of clinical symptoms (Pohl et al. 2001), the diagnosis
of ALS may be more certain. However, asymmetrical neuroi-
maging findings from ALS should be interpreted with precise
knowledge of limb predominance in the human brain
(Turner et al. 2011). Previously, Nagae-Poetscher et al. (2004)
did not find asymmetric metabolite concentrations or ratios
in the sensorimotor region of normal adults. Devine et al.
(2015) used a voxel-based morphometry method to explore
gray matter asymmetry in ALS and HC. They found leftward
predominance in the normal population while in the ALS
patients, limb predominance was absent and interpreted as
pathological change. It seems that limb dominance is not
only a significant factor underlying the onset and progression
of ALS (Devine et al. 2014), but also an important confound-
ing factor when interpreting asymmetrical MRSI findings
from ALS. In this study we tested the limb predominance
effect in a group of healthy adults and we only found a mar-
ginal difference (p 0.422) between bilateral HMC, which
contradicts a previous study (Devine et al. 2015). In a total of
14 patients, 12 had a lower value of the NAA/Cr ratio in the
most affected HMC, with a sensitivity of 85.7%. It should be
stressed these data are preliminary. It is important to define
a cut-off value for the asymmetry of the metabolic ratios
before this tool can be suggested for clinical routine. In the
future, defining the upper limit for physiological difference
between bilateral HMC will be a critical step.
Previous studies have shown a moderate correlation
between NAA concentration (and its ratios) in the motor
20 Y. WANG ET AL.
cortex and clinical severity (Kalra et al. 2006a), extent of
upper motor neuron signs (Wang et al. 2006), and maximum
finger tapping rate (Rooney et al. 1998). Although a close
clinicanatomic correlation between hand motor function
and HMC has been established, we didnt find a strong rela-
tionship between the hand tapping speed and NAA/Cr ratios
of the HMC. This may partly be due to the heterogeneity of
the patient group and the limited patient number of the
study. We suggest that in future studies other clinical meas-
ures like grip strength or Medical Research Council scale
should be included and their relationships with neurochem-
ical profiles of HMC should also be tested.
Conclusion
Neuronal dysfunction of HMC detected by this optimized
MRSI method can differentiate ALS patients from HC when
represented as reduced NAA/Cr ratio. In the future longitu-
dinal studies with a larger sample size are needed to confirm
these findings and to establish the importance of HMC in
MRSI study of ALS.
Disclosure statement
The authors report no conflicts of interest. The authors declare that the
work described was original research that has not been published previ-
ously, and not under consideration for publication elsewhere, in whole
or in part. All the authors listed have approved the paper. The authors
declare that they have no financial or personal relationships with other
people or organizations that can inappropriately influence their work.
There is no professional or other personal interest of any nature or kind
in any product, service, and/or company that could be construed as
influencing the position presented in this paper.
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