Muscular blood flow responses as an early predictor of the severity of diabetic neuropathy at a later stage in streptozotocin-induced type I diabetic rats: a diffuse correlation spectroscopy study

We propose a novel application of diffuse correlation spectroscopy to evaluate microvascular malfunctions of muscle tissue affected by hyperglycemia and determine their correlation with the severity of diabetic neuropathy at a later stage. Microvascular responses of the thigh muscle and the mechanical pain threshold of the hind paw of streptozotocin-induced type I diabetic rats were continuously monitored once per week for 70 days. Significantly decreased baseline blood flow and reactive hyperemia responses were observed as early as 1 week after hyperglycemia induction. The reactive hyperemia response at 2 weeks of hyperglycemia was highly correlated with the mechanical pain threshold at 8 weeks, at which time a decreased pain threshold was statistically confirmed in hyperglycemic rats relative to controls. © 2018 Optical Society of America.1

Gait-combined closed-loop brain stimulation can improve walking dynamics in Parkinsonian gait disturbances: a randomised-control trial

日本発、歩行リハビリテーションの未来への一歩 パーキンソン病に新たな光明. 京都大学プレスリリース. 2023-06-23.[Objective] Gait disturbance lowers activities of daily living in patients with Parkinson’s disease (PD) and related disorders. However, the effectiveness of pharmacological, surgical and rehabilitative treatments is limited. We recently developed a novel neuromodulation approach using gait-combined closed-loop transcranial electrical stimulation (tES) for healthy volunteers and patients who are post-stroke, and achieved significant entrainment of gait rhythm and an increase in gait speed. Here, we tested the efficacy of this intervention in patients with Parkinsonian gait disturbances. [Methods] Twenty-three patients were randomly assigned to a real intervention group using gait-combined closed-loop oscillatory tES over the cerebellum at the frequency of individualised comfortable gait rhythm, and to a sham control group. [Results] Ten intervention sessions were completed for all patients and showed that the gait speed (F(1, 21)=13.0, p=0.002) and stride length (F(1, 21)=8.9, p=0.007) were significantly increased after tES, but not after sham stimulation. Moreover, gait symmetry measured by swing phase time (F(1, 21)=11.9, p=0.002) and subjective feelings about freezing (F(1, 21)=14.9, p=0.001) were significantly improved during gait. [Conclusions] These findings showed that gait-combined closed-loop tES over the cerebellum improved Parkinsonian gait disturbances, possibly through the modulation of brain networks generating gait rhythms. This new non-pharmacological and non-invasive intervention could be a breakthrough in restoring gait function in patients with PD and related disorders

Case report: A novel approach of closed-loop brain stimulation combined with robot gait training in post-stroke gait disturbance

Most post-stroke patients have long-lasting gait disturbances that reduce their daily activities. They often show impaired hip and knee joint flexion and ankle dorsiflexion of the lower limbs during the swing phase of gait, which is controlled by the corticospinal tract from the primary motor cortex (M1). Recently, we reported that gait-synchronized closed-loop brain stimulation targeting swing phase-related activity in the affected M1 can improve gait function in post-stroke patients. Subsequently, a gait-training robot (Orthobot®) was developed that could assist lower-limb joint movements during the swing phase of gait. Therefore, we investigated whether gait-synchronized closed-loop brain stimulation combined with robot-assisted training targeting the swing phase could enhance the recovery of post-stroke gait disturbance. A 57-year-old female patient with chronic post-stroke hemiparesis underwent closed-loop brain stimulation combined with robot-assisted training for 10 min 2 years after left pons infarction. For closed-loop brain stimulation, we used transcranial oscillatory electrical current stimulation over the lesioned M1 foot area with 1.5 mA of DC offset and 0–3 mA of sine-wave formed currents triggered by the paretic heel contact to set the maximum current just before the swing phase (intervention A; two times repeated, A1 and A2). According to the N-of-1 study design, we also performed sham stimulation (intervention B) and control stimulation not targeting the swing phase (intervention C) combined with robot-assisted training in the order of A1-B-A2-C interventions. As a result, we found larger improvements in gait speed, the Timed Up and Go test result, and muscle strength after the A1 and A2 interventions than after the B and C interventions. After confirming the short-term effects, we performed an additional long-term intervention twice a week for 5 weeks, for a total of 10 sessions. Gait parameters also largely improved after long-term intervention. Gait-synchronized closed-loop brain stimulation combined with robot-assisted training targeting the swing phase of gait may promote the recovery of gait function in post-stroke patients. Further studies with a larger number of patients are necessary

Differential Modulation of GABAA Receptors Underlies Postsynaptic Depolarization- and Purinoceptor-Mediated Enhancement of Cerebellar Inhibitory Transmission: A Non-Stationary Fluctuation Analysis Study.

Cerebellar GABAergic inhibitory transmission between interneurons and Purkinje cells (PCs) undergoes a long-lasting enhancement following different stimulations, such as brief depolarization or activation of purinergic receptors of postsynaptic PCs. The underlying mechanisms, however, are not completely understood. Using a peak-scaled non-stationary fluctuation analysis, we therefore aimed at characterizing changes in the electrophysiological properties of GABAA receptors in PCs of rat cerebellar cortex during depolarization-induced "rebound potentiation (RP)" and purinoceptor-mediated long-term potentiation (PM-LTP), because both RP and PM-LTP likely depend on postsynaptic mechanisms. Stimulation-evoked inhibitory postsynaptic currents (eIPSCs) were recorded from PCs in neonatal rat cerebellar slices. Our analysis showed that postsynaptic membrane depolarization induced RP of eIPSCs in association with significant increase in the number of synaptic GABAA receptors without changing the channel conductance. By contrast, bath application of ATP induced PM-LTP of eIPSCs with a significant increase of the channel conductance of GABAA receptors without affecting the receptor number. Pretreatment with protein kinase A (PKA) inhibitors, H-89 and cAMPS-Rp, completely abolished the PM-LTP. The CaMKII inhibitor KN-62 reported to abolish RP did not alter PM-LTP. These results suggest that the signaling mechanism underlying PM-LTP could involve ATP-induced phosphorylation of synaptic GABAA receptors, thereby resulting in upregulation of the channel conductance by stimulating adenylyl cyclase-PKA signaling cascade, possibly via activation of P2Y11 purinoceptor. Thus, our findings reveal that postsynaptic GABAA receptors at the interneuron-PC inhibitory synapses are under the control of two distinct forms of long-term potentiation linked with different second messenger cascades

Chewing Prevents Stress-Induced Hippocampal LTD Formation and Anxiety-Related Behaviors: A Possible Role of the Dopaminergic System

The present study examined the effects of chewing on stress-induced long-term depression (LTD) and anxiogenic behavior. Experiments were performed in adult male rats under three conditions: restraint stress condition, voluntary chewing condition during stress, and control condition without any treatments except handling. Chewing ameliorated LTD development in the hippocampal CA1 region. It also counteracted the stress-suppressed number of entries to the center region of the open field when they were tested immediately, 30 min, or 60 min after restraint. At the latter two poststress time periods, chewing during restraint significantly increased the number of times of open arm entries in the elevated plus maze, when compared with those without chewing. The in vivo microdialysis further revealed that extracellular dopamine concentration in the ventral hippocampus, which is involved in anxiety-related behavior, was significantly greater in chewing rats than in those without chewing from 30 to 105 min after stress exposure. Development of LTD and anxiolytic effects ameliorated by chewing were counteracted by administering the D1 dopamine receptor antagonist SCH23390, which suggested that chewing may activate the dopaminergic system in the ventral hippocampus to suppress stress-induced anxiogenic behavior

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Rebound potentiation (RP) and purinoceptor-mediated long-term potentiation (PM-LTP) of eIPSCs at basket cell-PC synapses.

<p>(A) Time course changes of eIPSC amplitude in the course of RP (n = 8, left panel) and PM-LTP (n = 6, right panel). RP was induced by depolarization pulses given to individual PCs at the time point indicated by an arrow. PM-LTP was induced by bath-application of 100 μM ATP during the period of 5 min indicated by a horizontal bar. (B) Mean amplitude of eIPSCs during the period of 10 to 15 min after induction of RP or PM-LTP. Asterisk indicates a statistically significant difference compared to mean amplitude of eIPSCs before induction of RP or PM-LTP (p<0.01).</p