Voluntary Motor Command Release Coincides with Restricted Sensorimotor Beta Rhythm Phases.

Sensory perception and memory are enhanced during restricted phases of ongoing brain rhythms, but whether voluntary movement is constrained by brain rhythm phase is not known. Voluntary movement requires motor commands to be released from motor cortex (M1) and transmitted to spinal motoneurons and effector muscles. Here, we tested the hypothesis that motor commands are preferentially released from M1 during circumscribed phases of ongoing sensorimotor rhythms. Healthy humans of both sexes performed a self-paced finger movement task during electroencephalography (EEG) and electromyography (EMG) recordings. We first estimated the time of motor command release preceding each finger movement by subtracting individually measured corticomuscular transmission latencies from EMG-determined movement onset times. Then, we determined the phase of ipsilateral and contralateral sensorimotor mu (8-12 Hz) and beta (13-35 Hz) rhythms during release of each motor command. We report that motor commands were most often released between 120 and 140° along the contralateral beta cycle but were released uniformly along the contralateral mu cycle. Motor commands were also released uniformly along ipsilateral mu and beta cycles. Results demonstrate that motor command release coincides with restricted phases of the contralateral sensorimotor beta rhythm, suggesting that sensorimotor beta rhythm phase may sculpt the timing of voluntary human movement.SIGNIFICANCE STATEMENT Perceptual and cognitive function is optimal during specific brain rhythm phases. Although brain rhythm phase influences motor cortical neuronal activity and communication between the motor cortex and spinal cord, its role in voluntary movement is poorly understood. Here, we show that the motor commands needed to produce voluntary movements are preferentially released from the motor cortex during contralateral sensorimotor beta rhythm phases. Our findings are consistent with the notion that sensorimotor rhythm phase influences the timing of voluntary human movement.

Phase-dependent offline enhancement of human motor memory.

BACKGROUND: Skill learning engages offline activity in the primary motor cortex (M1). Sensorimotor cortical activity oscillates between excitatory trough and inhibitory peak phases of the mu (8-12 Hz) rhythm. We recently showed that these mu phases influence the magnitude and direction of neuroplasticity induction within M1. However, the contribution of M1 activity during mu peak and trough phases to human skill learning has not been investigated. OBJECTIVE: To evaluate the effects of phase-dependent TMS during mu peak and trough phases on offline learning of a newly-acquired motor skill. METHODS: On Day 1, three groups of healthy adults practiced an explicit motor sequence learning task with their non-dominant left hand. After practice, phase-dependent TMS was applied to the right M1 during either mu peak or mu trough phases. The third group received sham TMS during random mu phases. On Day 2, all subjects were re-tested on the same task to evaluate offline learning. RESULTS: Subjects who received phase-dependent TMS during mu trough phases showed increased offline skill learning compared to those who received phase-dependent TMS during mu peak phases or sham TMS during random mu phases. Additionally, phase-dependent TMS during mu trough phases elicited stronger whole-brain broadband oscillatory power responses than phase-dependent TMS during mu peak phases. CONCLUSIONS: We conclude that sensorimotor mu trough phases reflect brief windows of opportunity during which TMS can strengthen newly-acquired skill memories.

Reactive Gliosis Contributes to Nrf2-Dependent Neuroprotection by Pretreatment with Dimethyl Fumarate or Korean Red Ginseng Against Hypoxic-Ischemia: Focus on Hippocampal Injury.

Recently, dimethyl fumarate (DMF) and Korean red ginseng (ginseng), based on their purported antioxidative and anti-inflammatory properties, have exhibited protective potential in various neurological conditions. Their effects on cerebral ischemia and underlying mechanisms remain inconclusive; however, increasing evidence indicates the involvement of the transcriptional factor Nrf2. This study evaluated the preventive effects of DMF and ginseng on hippocampal neuronal damage following hypoxia-ischemia (HI) and assessed the contributions of reactive gliosis and the Nrf2 pathway. Adult wild type (WT) and Nrf2-/- mice were pretreated with DMF or ginseng for 7 days prior to HI. At 24 h after HI, DMF or ginseng significantly reduced infarct volume (52.5 ± 12.3% and 47.8 ± 10.7%), brain edema (61.5 ± 17.4% and 39.3 ± 12.8%), and hippocampal CA1 neuronal degeneration, and induced expressions of Nrf2 target proteins in WT, but not Nrf2-/-, mice. Such hippocampal neuroprotective benefits were also observed at 6 h and 7 days after HI. The dynamic attenuation of reactive gliosis in microglia and astrocytes correlated well with this sustained neuroprotection in an Nrf2-dependent manner. In both early and late stages of HI, astrocytic dysfunctions in extracellular glutamate clearance and water transport, as indicated by glutamine synthetase and aquaporin 4, were also attenuated after HI in WT, but not Nrf2-/-, mice treated with DMF or ginseng. Together, DMF and ginseng confer robust and prolonged Nrf2-dependent neuroprotection against ischemic hippocampal damage. The salutary Nrf2-dependent attenuation of reactive gliosis may contribute to this neuroprotection, offering new insight into the cellular basis of an Nrf2-targeting strategy for stroke prevention or treatment.

Nrf2 Plays an Essential Role in Long-Term Brain Damage and Neuroprotection of Korean Red Ginseng in a Permanent Cerebral Ischemia Model.

Cerebral ischemia is a devastating disease with a high incidence of death and disability; however, effective therapeutics remain limited. The transcriptional factor Nrf2 has been shown to play a pivotal role in the endogenous defense against brain oxidative stress and inflammation, and therefore represents a promising target for stroke intervention. However, the long-term effects of Nrf2 and the standardized Korean red ginseng (ginseng), a potent Nrf2 natural inducer, on permanent cerebral ischemic damage have not yet been reported. Wildtype (WT) and Nrf2-/- adult mice were pretreated with either vehicle or ginseng, and were subjected to permanent distal middle cerebral artery occlusion (pdMCAO). The infarct volume, the reactive astrocytes and microglia, and the water regulatory protein aquaporin 4 (AQP4) were examined at 28 days after stroke. When compared with the WT matched controls, the Nrf2 disruption significantly enlarged the infarct volume (40.4 ± 10.1%) and exacerbated the progression of reactive gliosis and AQP4 protein levels after pdMCAO. In contrast, ginseng significantly reduced the infarct volume and attenuated the reactive gliosis and AQP4 in the ischemic WT mice (47.3 ± 6.9%), but not in the Nrf2-/- mice (25.5 ± 5.6%). In conclusion, Nrf2 plays an important role in the long-term recovery of permanent cerebral ischemic damage and the neuroprotection of ginseng.

Pretreatment with Korean red ginseng or dimethyl fumarate attenuates reactive gliosis and confers sustained neuroprotection against cerebral hypoxic-ischemic damage by an Nrf2-dependent mechanism.

The transcriptional factor Nrf2, a master regulator of oxidative stress and inflammation that are tightly linked to the development and progression of cerebral ischemia pathology, plays a vital role in inducing the endogenous neuroprotective process. Here, hypoxic-ischemia (HI) was performed in adult Nrf2 knockout and wildtype mice that were orally pretreated either with standardized Korean red ginseng extract (Ginseng) or dimethyl fumarate (DMF), two candidate Nrf2 inducers, to determine whether the putative protection was through an Nrf2-dependent mechanism involving the attenuation of reactive gliosis. Results show that Nrf2 target cytoprotective genes were distinctly elevated following HI. Pretreatment with Ginseng or DMF elicited robust neuroprotection against the deterioration of acute cerebral ischemia damage in an Nrf2-dependent manner as revealed by the reductions of neurological deficits score, infarct volume and brain edema, as well as enhanced expression levels of Nrf2 target antioxidant proteins and anti-inflammation mediators. In both ischemic striatum and cortex, the dynamic pattern of attenuated reactive gliosis in astrocytes and microglia, including affected astrocytic dysfunction in glutamate metabolism and water homeostasis, correlated well with the Nrf2-dependent neuroprotection by Ginseng or DMF. Furthermore, such neuroprotective benefits extended to the late phase of ischemic brain damage after HI, as evidenced by improvements in neurobehavioral outcomes, infarct volume and brain edema. Overall, pretreatment with Ginseng or DMF identically attenuates reactive gliosis and confers long-lasting neuroprotective efficacy against ischemic brain damage through an Nrf2-dependent mechanism. This study also provides new insight into the profitable contribution of reactive gliosis in the Nrf2-dependent neuroprotection in acute brain injury.

Korean Red Ginseng Pretreatment Protects Against Long-Term Sensorimotor Deficits After Ischemic Stroke Likely Through Nrf2.

Endogenous neuroprotective mechanisms by which the brain protects itself against noxious stimuli and recovers from ischemic damage are key targets of stroke research, ultimately facilitating functional recovery. Transcriptional factor Nrf2, enriched in astrocytes, is a master regulator of endogenous defense systems against oxidative stress and inflammation. Korean Red Ginseng (Ginseng), one most widely used herbal medicine, has exhibited promising potentials in neuroprotection. Our study aimed to determine whether the standardized Ginseng extract pretreatment could attenuate acute sensorimotor deficits and improve long-term functional recovery after ischemic stroke though Nrf2 pathway and whether reactive astrogliosis is associated with such effect. Adult Nrf2-/- and matched wildtype control (WT) mice were pretreated with Ginseng orally for 7 days prior to permanent distal middle cerebral artery occlusion (pdMCAO). Using an optimized method that can accurately assess either severe or mild pdMCAO-induced sensorimotor deficits, neurobehavioral tests were performed over 28 days. The progression of lesion volume and the evolution of astrocytic and microglial activation were determined in the acute stage of ischemic stroke after pdMCAO (0-3 days). Nrf2-downstream target antioxidant genes expression levels was assessed by Western blot. We found that Ginseng pretreatment ameliorated acute sensorimotor deficits and promoted long-term functional recovery, prevented the acute enlargement of lesion volume (36.37 ± 7.45% on day 3), attenuated reactive astroglial progression but not microglia activation, and enhanced the induction of Nrf2-downstream target proteins after ischemic insult in WT mice, an effect which was lost in Nrf2 knockouts. The spatiotemporal pattern of reactive astrogliosis evaluation correlated well with acute ischemic damage progression in an Nrf2-dependent fashion during the acute phase of ischemia. In contrast, Nrf2 deficiency mice exhibited exacerbated ischemic condition compared to WT controls. Together, Ginseng pretreatment protects against acute sensorimotor deficits and promotes its long-term recovery after pdMCAO, at least partly, through Nrf2 activation, highlighting the potential efficacy of oral consumption of Ginseng for stroke preventative intervention in patients who are at great risk of recurrent stroke or transient ischemic attack. The attenuated reactive astrogliosis contributes to the Nrf2 pathway related neuroprotection against acute ischemic outcome and substantially long-term sensorimotor deficits in the context of ischemic stroke under pdMCAO.