Rt:hahil itaci_ja Utnil-. VII. 11111/ . --1 (2(HJ8J 
-- IS THE MOTOR CORTEX 
HYPEREXCITABLE IN MOTOR 
NEURON DISEASE - A STUDY USING 
PHARMACOLOGICAL fMRI 
S. Azam
1
. B. Koritnik
3
, M. Mehta
2
, S. C. R. Williams
2
, P. N. Leigh
1 
1 
MRC Centre for Neurodegeneration Research and
2 
Centre far Neuroimaging Sciences, King's College London, Institute of Psychiatry, London, UK
3 
Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, Ljubljana, Slovenia 
BACKGROUND 
In motor neuron disease (MNO) functional studies have 
shown altered intracortical inhibition and excitation. 
Excess glutamate induced corticomotor excitability has 
been proposed as a possible mechanism for this imbal­
ance. More recent anatomical studies showing a globa! 
loss of GABAergic interneurones and an altcration in the 
GABAA receptor mRNA expression pattern in pyramidal 
cells have highlighted that GABAergic mediated inhibition 
may also play an important role in the pathophysiology 
of MNO. Midazolam (MZ). a selective GABAA agonist 
allows us to probe the functional status of post-synaptic 
GABAA receptors, allowing us to investigate the role of 
Lhe GABAergic system in MNO. Increased motor effort 
in MNO patients, and subsequent cortical reorganisa­
tion as an adaptive phenomenon where greater effort is 
exerted in carrying out a motor task may explain some of 
the altered cortical activation. Therefore in this study we 
have examined the effects of MZ on motor task activation. 
controlling for effort. 
METHODS 
Using functional imaging (fMRJ) we studied 12 patients 
with MNO as defined by the EI-Escorial Criteria of defi­
nite, probable or possible MNO and two control groups: 12 
healthy volunteers (HV), and 12 patients with multifocal 
motor neuropathy (MMN) matched for weakness with the 
MNO group. A visually paced motor task was performed, 
requiring responses of 5%, 10%, 20% and 30% of maxi­
mum grip strength thereby controlling for efforl. Subjects 
were scanned while they received an intravenous challenge 
of normal saline and on a separate vi sit an infusion of MZ. 
lmage pre-processing and s1a1is1ical analysis were carried 
oul using SPM5. Regions of interest (ROJ) were defined 
to extracl representative dara for the contralateral motor 
lil 
cortex, ipsilateral cerebellum and bilatcral subcortical 
areas. 
RESULTS 
BOLO signal changes in cortical and subcortical motor 
networks during motor task under control conditions were 
comparable between ali groups. In contrast 10 previous 
studies, we did not see a greater increase in BOLO signal 
in the cortex of MNO patients compared to HV. Following 
MZ, direct group comparisons revealed a decreased BOLO 
response in the contaralateral motor cortex (sensorimotor, 
premotor and supplementary motor areas) in HV, bul not 
MNO or MMN. In contrast, after MZ, the BOLO response 
was increased in the pulamen of ali groups. 
CONCLUSION 
The use of a graded motor task matchcd to individual maxi­
mum grip slrengths may be a more precise way of providing 
comparable dala on cortical activation between groups in 
whom motor effort can play an imponanl role in observed 
results. Suppression of BOLO signal in the motor cortex of 
HV is likely to be a direct result of post-synaptic GABAA 
receptor mediated inhibition or due to an indirect reduction 
of glutamatergic outpul from the motor cortex. The increase 
in BOLO signal in the subcortical areas following MZ in 
ali three groups may reflecl a compensatory response from 
parallel motor loops when the task is made more "difficult". 
The lack of conical BOLO signal suppression following 
MZ in the MNO group and in Lhe MMN group who have 
imponantly been matched for weakness, may reflecl further 
compensatory changes due 10 increased motor effort. In the 
MNO group this means tirni during a motor task GABAA 
receptor mediatcd effects seen are likely 10 be a compensa­
tory rcsponse to effort.