RESUMEN
It has been demonstrated that intrinsic auricular muscles zone stimulation (IAMZS) can improve the motor symptoms of Parkinson's disease (PD) patients who are examined with the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores. In the present pilot study, using motion capture technology, we aimed to investigate the efficacy of IAMZS compared to medication alone or in combination with medication. Ten PD patients (mean age: 54.8 ± 10.1 years) were enrolled. Each participant participated in three different sessions: sole medication, sole stimulation-20 min of IAMZS, and combined IAMZS (20 min) and medication. Each session was performed on different days but at the same time to be aligned with patients' drug intake. Motion capture recording sessions took place at baseline, 20, 40, and 60 min. Statistical analysis was conducted using one-way repeated measures ANOVA. Bonferroni correction was implemented for pairwise comparisons. The sole medication was ineffective to improve gait-related parameters of stride length, stride velocity, stance, swing, and turning speed. In the sole-stimulation group, pace-related gait parameters were significantly increased at 20 and 40 min. These improvements were observed in stride length at 20 (p = 0.0498) and 40 (p = 0.03) min, and also in the normalized stride velocity at 40 min (p-value = 0.02). Stride velocity also tended to be significant at 20 min (p = 0.06) in the sole-stimulation group. Combined IAMZS and medication demonstrated significant improvements in all the time segments for pace-related gait parameters [stride length: 20 min (p = 0.04), 40 min (p = 0.01), and 60 min (p < 0.01); stride velocity: 20 min (p < 0.01), 40 min (p = 0.01), and 60 min (p < 0.01)]. These findings demonstrated the fast action of the IAMZS on PD motor symptoms. Moreover, following the termination of IAMZS, a prolonged improvement in symptoms was observed at 40 min. The combined use of IAMZS with medication showed the most profound improvements. The IAMZS may be particularly useful during medication off periods and may also postpone the long-term side effects of high-dose levodopa. A large scale multicentric trial is required to validate the results obtained from this pilot study. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03907007.
RESUMEN
OBJECTIVE: Glycogen in astrocyte processes contributes to maintenance of low extracellular glutamate and K+ concentrations around excitatory synapses. Sleep deprivation (SD), a common migraine trigger, induces transcriptional changes in astrocytes, reducing glycogen breakdown. We hypothesize that when glycogen utilization cannot match synaptic energy demand, extracellular K+ can rise to levels that activate neuronal pannexin-1 channels and downstream inflammatory pathway, which might be one of the mechanisms initiating migraine headaches. METHODS: We suppressed glycogen breakdown by inhibiting glycogen phosphorylation with 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) and by SD. RESULTS: DAB caused neuronal pannexin-1 large pore opening and activation of the downstream inflammatory pathway as shown by procaspase-1 cleavage and HMGB1 release from neurons. Six-hour SD induced pannexin-1 mRNA. DAB and SD also lowered the cortical spreading depression (CSD) induction threshold, which was reversed by glucose or lactate supplement, suggesting that glycogen-derived energy substrates are needed to prevent CSD generation. Supporting this, knocking down the neuronal lactate transporter MCT2 with an antisense oligonucleotide or inhibiting glucose transport from vessels to astrocytes with intracerebroventricularly delivered phloretin reduced the CSD threshold. In vivo recordings with a K+ -sensitive/selective fluoroprobe, Asante Potassium Green-4, revealed that DAB treatment or SD caused a significant rise in extracellular K+ during whisker stimulation, illustrating the critical role of glycogen in extracellular K+ clearance. INTERPRETATION: Synaptic metabolic stress caused by insufficient glycogen-derived energy substrate supply can activate neuronal pannexin-1 channels as well as lower the CSD threshold. Therefore, conditions that limit energy supply to synapses (eg, SD) may predispose to migraine attacks, as suggested by genetic studies associating glucose or lactate transporter deficiency with migraine. Ann Neurol 2018;83:61-73.