Poster No:
135
Submission Type:
Abstract Submission
Authors:
Sicong Tu1, Colin Mahoney1, William Huynh1, Matthew Kiernan1
Institutions:
1The University of Sydney, Sydney, New South Wales
First Author:
Sicong Tu
The University of Sydney
Sydney, New South Wales
Co-Author(s):
Introduction:
Hyperexcitability of the motor cortices is a disease phenomena present in the early stage of the rare neurodegenerative disorder Amyotrophic Lateral Sclerosis (ALS)[Vucic et al., 2006]. Clinically, this is measured using threshold-tracking transcranial magnetic stimulation (TT-TMS) whereby changes in mean short interval cortical inhibition (SICI; 1-7ms) has been shown to be a robust indicator of hyperexcitability in ALS patients[1]. This change is believed to reflect an underlying imbalance in excitatory/inhibitory inter-neuronal circuits. To date the majority of TMS and MRS research in ALS have been performed independently[Cheong et al., 2017; Menon et al., 2020]. The current study aimed to: (i) characterise the relationship between cortical excitability and localised metabolite abnormalities, (ii) examine the longitudinal profile of cortical motor metabolite concentration in ALS patients relative to clinical progression.
Methods:
32 non-familial ALS patients and 17 age-education matched healthy controls were prospectively recruited and assessed at the Brain and Mind Centre, The University of Sydney. All participants received an MRI scan (3T GE MR750; 32-channel head coil) and single-voxel 1H-MRS (PRESS; TE/TR=35/2000ms; 20mm3) was sequentially acquired from the hand region of the left and right motor cortices. 1H-MRS metabolites of interest were quantified in LC Model for relative concentration of N-acetyaspartate (NAA) as a surrogate marker of neuronal integrity, and glutamate (Glx) a primary excitatory neurotransmitter. All patients underwent specialised TT-TMS and stratified as having a 'normal' or 'hyper' excitable motor cortex based on mean change in SICI (≤5.5%). Additionally, severity of functional motor impairment was assessed in all patients according to the revised ALS functional rating scale (ALSFRS-R). A subset of patients (n=10) underwent a 6-month follow-up MRI scan.
Results:
As a whole, ALS patients demonstrated a consistent reduction in NAA/Cr in the left (p=0.02) and right (p=0.01) hand region, without evidence of significant hemispheric imbalance, relative to controls. Patients classified as having a hyperexcitable motor cortex, demonstrated significantly higher levels of Glx/Cr across both hemispheres (p values < 0.05), relative to patients with a normal SICI. While NAA/Cr was significantly reduced in ALS patients with a normal SICI relative to healthy controls (p<0.05), Glx/Cr concentration was similar to control participants. Additionally, a notable dissociation was observed in longitudinal cortical motor metabolite concentrations, whereby ALS patients with a normal SICI demonstrated the greatest change in glutamate concentration (~10%). In contrast longitudinal glutamate concentration remained relatively stable in ALS patients with an abnormal SICI (~3%). Clinical correlations indicated a significant association between cortical motor metabolite concentrations and increasing disease duration (p<0.01), but not with functional severity of motor impairments.
Conclusions:
Evolving cortical motor dysfunction in ALS is reflected by progressive metabolite changes in NAA as well as glutamate. Notably, cortical motor metabolite abnormalities appears tied to the presence of neurophysiological dysfunction as measured by threshold tracking TMS. These findings provide further multi-modal support of an imbalance in excitatory/inhibitory inter-neuronal circuits as a prominent mechanism of disease in early ALS. MR spectroscopy may serve as a useful biomarker of upper motor neuron dysfunction, which remains difficult to objectively assess through routine clinical examination.
Brain Stimulation:
Non-invasive Magnetic/TMS 2
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Keywords:
Degenerative Disease
Magnetic Resonance Spectroscopy (MRS)
Motor
Transcranial Magnetic Stimulation (TMS)
Other - motor neuron disease
1|2Indicates the priority used for review
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Please indicate below if your study was a "resting state" or "task-activation” study.
Other
Healthy subjects only or patients (note that patient studies may also involve healthy subjects):
Patients
Was this research conducted in the United States?
No
Were any human subjects research approved by the relevant Institutional Review Board or ethics panel?
NOTE: Any human subjects studies without IRB approval will be automatically rejected.
Yes
Were any animal research approved by the relevant IACUC or other animal research panel?
NOTE: Any animal studies without IACUC approval will be automatically rejected.
Not applicable
Please indicate which methods were used in your research:
Structural MRI
TMS
Other, Please specify
-
MRS
For human MRI, what field strength scanner do you use?
3.0T
Which processing packages did you use for your study?
Free Surfer
Other, Please list
-
LC Model
Provide references using APA citation style.
Cheong I, Marjanska M, Deelchand DK, Eberly LE, Walk D, Oz G. (2017). Ultra-High Field Proton MR Spectroscopy in Early-Stage Amyotrophic Lateral Sclerosis. Neurochemical Research, 42(6),1833-1844.
Menon P, Higashihara M, van den Bos M, Geevasinga N, Kiernan MC, Vucic S. (2020). Cortical hyperexcitability evolves with disease progression in ALS. Annals of Clinical and Translational Neurology, 7(5), 733-741.
Vucic S, Howells J, Trevillion L, Kiernan MC. (2006). Assessment of cortical excitability using threshold tracking techniques. Muscle Nerve, 33(4), 477-86.
No