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Discussion
Gait and locomotion, turning in bed, arising from a chair, and postural stability all depend on efficient sensorimotor integration (28, 29), which is affected in PD (30–32). The basal ganglia act as an important hub for sensorimotor integration (33, 34) and descending basal ganglia projections to the midbrain have been reported to play an important role in gait and postural control (35, 36). One of the ways in which the basal ganglia are thought to influence sensorimotor integration is by gating or controlling the access of sensory information to motor neurons, via a balance of neurotransmitter activity (30, 37, 38). In PD, the motor systems can become hypo-excitable following an increased inhibition of sensory inputs to the basal ganglia, leading to a diminished motor response to certain sensory stimuli (30). This diminished responsiveness to sensory stimuli is thought to underly the observed difficulties experienced by PD patients in regulating the amplitude of movements in the absence of external visual or auditory cues, when they are dependent on sensory feedback for accurate motor control, (31, 32, 38) and may also contribute to the axial symptoms.
In the present study, the observed link between increased GABA levels in the left basal ganglia in PD patients and the degree of gait disturbance (Figure 2) may be associated with an over-inhibition of the processing of sensory inputs necessary for maintaining posture and initiating locomotion. This observation is consistent with the reported role of GABAergic outputs from the basal ganglia in the control of posture and locomotion (35, 39, 40). However, since locomotion can be initiated by stimulation of the midbrain locomotor region, (36) one would expect corresponding neurotransmitter abnormalities to be observed in the pons, related to problems with gait. In the present study, we were not able to measure GABA in the pons due to the large voxel size required for GABA measurement with MEGA-PRESS, but we did not observe any apparent relationship between the pontine Glx concentrations (from standard PRESS) and problems with gait. However, since the PRESS voxel volume (3.4 mL) is large in comparison to the size of the midbrain locomotor region or the peduculopontine nucleus of the pons, two of the pontine regions implicated in gait control and muscle tone regulation, the lack of an apparent relationship between pontine Glx and posture or gait symptoms may be due to a lack of regional specificity of the pontine MRS measurement. Future studies at higher field strengths (e.g., 7T), where smaller voxel volumes can be used and where GABA can be quantified without the need for spectral editing, may be able to extend the present findings to clarify the link between gait difficulties and pontine neurotransmitter levels.
In the subgroup analysis, the observed link between basal ganglia GABA levels and the gait and axial summary scores seemed to be mostly driven by GABA and symptom changes in the akinetic-rigid subgroup of patients rather than the tremor-dominant patients. Longitudinal studies have shown that the akinetic-rigid subtype of PD presents a risk factor for greater progression of the motor symptoms, including freezing of gait and other axial symptoms. (24, 25, 26) Akinetic-rigid PD patients have also been shown to demonstrate differences in structural and functional connectivity in comparison to tremor-dominant patients, (41, 42, 43) and differences in iron deposition between the subtypes indicates that different pathological mechanisms may underly the observed differences in symptom progression (44). In light of the small group sizes, the subgroup analysis in the present study should be considered exploratory, and we hope these results can be replicated in a larger sample. Given the evidence for differences in brain structure and function as well as symptom progression in different subtypes of PD, it would be interesting to examine differences in the metabolite profile, including neurotransmitter changes, between akinetic-rigid and tremor-dominant PD patients in more detail in a larger cohort.
While basal ganglia GABA levels appeared to be related to gait difficulties, prefrontal Glx levels correlated negatively with difficulties turning in bed (Figure 2), and prefrontal GABA levels correlated negatively with postural stability, in the akinetic-rigid subgroup. The negative correlation between prefrontal Glx and symptom scores would be consistent with previous reports of decreased cortical Glx in PD, (11) under the assumption that patients more severely affected by axial symptoms like turning in bed would have lower prefrontal Glx levels. However, since in the present study no significant differences in prefrontal Glx were observed at the group level, the apparent correlation between frontal Glx and symptom scores seen in the present study cannot be interpreted in the context of abnormal Glx levels in the patient group. The link between prefrontal GABA and posture is also consistent with the putative role of prefrontal and parietal cortical regions in maintaining postural equilibrium, (45) but should also be interpreted with caution in light of the lack of a significant difference in prefrontal GABA between the patient and control groups. It is possible that these associations with individual symptom scores may be affected by outliers, given the small group sizes and the limited distribution of symptoms in some domains. These results should therefore be considered with caution until they can be replicated in a larger sample.
Since the symptom scores were assessed while patients were in the ON medication state, while the MRS was performed just before the next dose was due and thus rather in an OFF state, medication effects could potentially confound the comparison between GABA and Glx levels and the axial symptom scores. While most of the axial symptoms do not typically respond well to levodopa, dopamine replacement therapy has been reported to reduce freezing of gait in patients with PD, (46) and in the present sample the levodopa equivalent dose showed a trend-level association with basal ganglia GABA (p = 0.09, Spearman's rho). The effect of levodopa on freezing of gait may explain why the correlations between basal ganglia GABA levels and the gait and axial symptom summary scores diminished in significance after controlling for the levodopa equivalent dose, particularly in akinetic-rigid patients. In contrast, the association between neurotransmitter levels and other symptom scores such as rising from a chair, turning in bed, posture, and postural stability, seemed relatively independent of levodopa effects, but in addition to levodopa 11 patients were additionally medicated with dopamine agonists. Previous studies in children with attention deficit hyperactivity disorder (ADHD) have reported that treatment with dopamine agonists like methylphenidate can reduce striatal Glx levels (47), although methylphenidate did not appear to influence frontal Glx levels, (47) and another study of medication-naïve and medicated adults with ADHD failed to find differences in Glx related to medication status (48). However, since treatment with dopamine agonists or other medications may introduce additional variability into the Glx and GABA signals measured MRS, it would be instructive to clarify the effects of dopaminergic and other medications on the GABA and Glx levels in a future study, where the cohort of PD patients is sufficiently large to enable separation into subgroups according to medication status.
Conclusion
MRS offers a unique opportunity to study the complex interplay between excitatory and inhibitory neurotransmitter activity both within and outside the motor network. The present pilot study provides evidence of a link between alterations in GABA and glutamate levels and the axial symptoms of Parkinson's disease, lending important insight into the neural origin of these symptoms, and opening up potential avenues for treatment.
Levodopa and magnesium oxide
Attention Non-Tremor Dominant subtype, also called Akinetic-Rigid Parkinson
Ritalin and Parkinson's
Anticholingeric Meds via PD lead to risk of dementia
IPX203 shows sustained safety, efficacy in RISE-PD extension trial
