Objective: Determine if GABA and glutamate levels within sensorimotor network nodes correlate with symptom severity in cervical dystonia (CD) and are altered by botulinum neurotoxin (BoNT) therapy.

Background: CD is an adult-onset focal dystonia characterized by excessive involuntary muscle contractions of the neck. BoNT can lessen muscle spasms and reduce pain and disability in CD. Evidence from pathophysiological studies support that an excitatory-inhibitory imbalance underlies motor symptoms in dystonia.2-4 However whether changes in excitatory and inhibitory neurotransmitters within key nodes of the sensorimotor network correlates with CD symptom severity is not known.

Method: Magnetic resonance spectroscopy (MRS) using PRESS and MEGA-PRESS pulse sequences was used to estimate levels of GABA and glutamate/glutamine [Glx] in the sensorimotor cortex (SMC), basal ganglia (BG) and cerebellum (CBL). 8-9MRS scans were acquired: 1) 0-2 weeks before BoNT injections (“OFF”), and 2) 4-6 weeks after BoNT treatment (“ON”). CD severity was assessed at OFF and ON using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS-2) and neck scores of the Burke-Fahn-Marsden (BFM) and Global Dystonia Rating Scales (GDRS). Data analysis was performed using t-tests and Pearson’s coefficients. Significance is set at p<0.05.

Results: Twelve CD patients (59±11.5 yrs; 10F) have been enrolled. Modest improvement in symptom severity at ON was noted by TWSTRS-2-total (p<0.06), but not by BFM (p<0.14) or GDRS (p<0.17). No significant group level difference in GABA or Glx was seen between OFF and ON for any voxel. However, at OFF BG GABA levels correlated with TWSTRS-2-severity (r=0.6; p<0.05) and TWSTRS-2-total (r=0.65 p<0.03). At ON, BG GABA correlated with TWSTRS-2-severity (r=0.58 p<0.06), BFM (r=0.64 p<0.04), and GDRS (r=0.74 p=0.009). Percent change in BG GABA between OFF and ON correlated with percent improvement in BFM (r=-0.61 p<0.05). Additionally, SMC Glx correlated with BFM at ON (r=0.70 p=0.01). No correlations between CBL GABA or Glx and symptoms were found at OFF or ON.

Conclusion: E-I balance within key sensorimotor network nodes was not modified by BoNT therapy at the group level, however GABA levels in the BG correlated with motor severity and changes in their levels after BoNT correlated with changes in a symptom rating scale score. These findings suggest BG GABA could serve as a marker for motor severity in CD.

References: 1.Jankovic, J., Tsui, J. & Brin, M. F. Treatment of cervical dystonia with Botox (onabotulinumtoxinA): Development, insights, and impact. Medicine (Baltimore) 102, e32403 (2023).
2. Hallett, M. Neurophysiology of dystonia: The role of inhibition. Neurobiol Dis 42, 177–184 (2011).
3.Groth, C. L. et al. Cervical Dystonia Is Associated With Aberrant Inhibitory Signaling Within the Thalamus. Front Neurol 11, 575879 (2020).
4.Impaired brain GABA in focal dystonia – Levy – 2002 – Annals of Neurology – Wiley Online Library. https://onlinelibrary.wiley.com/doi/10.1002/ana.10073.
5. Hok, P. et al. Botulinum toxin injection changes resting state cerebellar connectivity in cervical dystonia. Sci Rep 11, 8322 (2021).
6.Brodoehl, S. et al. Cause or effect: Altered brain and network activity in cervical dystonia is partially normalized by botulinum toxin treatment. Neuroimage Clin 22, 101792 (2019).
7.Nevrlý, M. et al. Changes in sensorimotor network activation after botulinum toxin type A injections in patients with cervical dystonia: a functional MRI study. Exp Brain Res 236, 2627–2637 (2018).
8.Baeshen, A. et al. Test-Retest Reliability of the Brain Metabolites GABA and Glx With JPRESS, PRESS, and MEGA-PRESS MRS Sequences in vivo at 3T. J Magn Reson Imaging 51, 1181–1191 (2020).
9. Prisciandaro, J. J., Mikkelsen, M., Saleh, M. G. & Edden, R. A. E. An evaluation of the reproducibility of 1H-MRS GABA and GSH levels acquired in healthy volunteers with J-difference editing sequences at varying echo times. Magn Reson Imaging 65, 109–113 (2020).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gaba-in-the-basal-ganglia-tracks-motor-severity-and-response-to-bont-treatment-in-cervical-dystonia/