Journal of Neurophysiology

Bingham, Clayton S.; McIntyre, Cameron C.

doi: 10.1152/jn.00004.2022pmid: 35320026

The motor hyperdirect pathway (HDP) is considered a key target in the treatment of Parkinson's disease with subthalamic deep brain stimulation (DBS). This hypothesis is partially derived from the association of HDP activation with evoked potentials (EPs) generated in the motor cortex and subthalamic nucleus (STN) after a DBS pulse. However, the biophysical details of how and when DBS-induced action potentials (APs) in HDP neurons reach their terminations in the cortex or STN remain unclear. Therefore, we used an anatomically detailed representation of the motor HDP, as well as the internal capsule (IC), in a model of human subthalamic DBS to explore AP activation and transmission in the HDP and IC. Our results show that small diameter HDP axons exhibited AP initiation in their subthalamic terminal arbor, which resulted in relatively long transmission latencies to cortex (~3.5-8 ms). Alternatively, large diameter HDP axons were most likely to be directly activated in the capsular region, which resulted in short transmission times to cortex (~1-3 ms). However, those large diameter HDP antidromic APs would be indistinguishable from any other IC axons that were also activated by the stimulus. Conversely, DBS-induced APs in both small and large diameter HDP axons reached their synaptic boutons in the STN with similar timings, but both spanned a wide temporal range. We also found that using anodic or bipolar stimulation helped to bias activation of the HDP over the IC. These computational results provide useful information for linking HDP activation with EP recordings in clinical experiments.

Mavanji, Vijayakumar; Georgopoulos, Apostolos P.; Kotz, Catherine M.

doi: 10.1152/jn.00041.2022pmid: 35353632

The regulation of sleep/wake behavior and energy-homeostasis is maintained in part by the lateral-hypothalamic (LH) neuropeptide orexin-A (OXA, hypocretin). Reduction in OXA-signaling is associated with sleep disorders and obesity, whereas higher OXA-signaling promotes obesity resistance. Similarly, dysregulation of hypothalamic neural-networks is associated with onset of age related obesity and several neurological diseases. Despite the association of obesity and aging, and that adult populations are the target for the majority of pharmaceutical and obesity studies, conventional models for neuronal-networks utilize embryonic neural-cultures rather than adult- neurons. Synchronous activity describes correlated changes in neuronal activity between neurons and is a measure of functional connectivity. Earlier studies show alterations in hypothalamic-synchronicity following behavioral perturbations, in embryonic-neurons obtained from obesity-resistant rats, and following application of OXA onto these cultures. Synchronicity in adult hypothalamic-neurons remain largely undescribed. To address this, we established an adult rat hypothalamic-culture in multi-electrode-array (MEA) dishes, and recorded the field-potentials. Then we studied the effect of OXA on network-synchronization of these cultures. In addition, we studied wake-promoting effects of OXA in vivo when directly injected into the LH. Our results showed that the adult-hypothalamic-cultures are viable for nearly 3 months in vitro, good quality MEA recordings can be obtained from these cultures, and finally, that cultured adult hypothalamus is responsive to OXA. These results support that adult rat hypothalamic-cultures could be used as a model to study the mechanisms underlying obesity. In addition, LH administration of OXA enhanced wakefulness, indicating that OXA enhances wakefulness partly by promoting neural-synchrony in the hypothalamus.

Hagio, Shota; Ishihara, Akihiko; Terada, Masahiro; Tanabe, Hiroko; Kibushi, Benio; Higashibata, Akira; Yamada, Shin; Furukawa, Satoshi; Mukai, Chiaki; Ishioka, Noriaki; Kouzaki, Motoki

doi: 10.1152/jn.00232.2021pmid: 35353615

Movements of the human biological system have adapted to the physical environment under the 1-g gravitational force on Earth. However, the effects of microgravity in space on the underlying functional neuromuscular control behaviors remain poorly understood. Here, we aimed to elucidate the effects of prolonged exposure to a microgravity environment on the functional coordination of multiple muscle activities. The activities of 16 lower limb muscles of 5 astronauts who stayed in space for at least 3 months were recorded while they maintained multidirectional postural control during bipedal standing. The coordinated activation patterns of groups of muscles, i.e., muscle synergies, were estimated from the muscle activation datasets using a factorization algorithm. The experiments were repeated a total of 5 times for each astronaut, once before and 4 times after spaceflight. The compositions of muscle synergies were altered, with a constant number of synergies, after long-term exposure to microgravity, and the extent of the changes was correlated with the severity of the deficits in postural stability. Furthermore, the muscle synergies extracted 3 months after the return were similar in their activation profile but not in their muscle composition compared with those extracted in the preflight condition. These results suggest that the modularity in the neuromuscular system became reorganized to adapt to the microgravity environment and then possibly reoptimized to the new sensorimotor environment after the astronauts were re-exposed to a gravitational force. It is expected that muscle synergies can be used as physiological markers of the status of astronauts with gravity-dependent change.

Ruiz-Martínez, Francisco J.; Morales-Ortiz, Manuel; Gómez, Carlos M.

doi: 10.1152/jn.00313.2021pmid: 35389770

Predictive coding reflects the ability of the human brain to extract environmental patterns in order to reformulate previous expectations. The present report analyzes through the late N1 auditory component and the post imperative negative variation (PINV) the updating of predictions regarding the characteristics of a new trial, depending on the previous trial history, complexity, and type of trial (standard or deviant). Data were obtained from 31 healthy subjects recorded in a previous study, based on two paradigms composed of stimulus sequences of decreasing or increasing frequencies intermingled with the sporadic appearance of unexpected tone endings. Our results showed a higher amplitude for the most complex condition and deviant trials for both the late N1 and the PINV components. Additionally, the N1 and PINV presented a different amplitude response to the standard and deviant trials as a function of previous trial history, suggesting a continuous updating of trial categorization. The results suggest that the late N1 and PINV components are involved in the generation of an internal model about the rules of external auditory stimulation.

Cassar, Isaac R.; Grill, Warren M.

doi: 10.1152/jn.00353.2021pmid: 35389751

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) antidromically activates the motor cortex (M1), and this cortical activation appears to play a role in the treatment of hypokinetic motor behaviors (1, 2). The synchronous antidromic activation takes the form of a short-latency cortical evoked potential (cEP) in electrocorticography (ECoG) recordings of M1. We assessed the utility of the cEP as a biomarker for STN DBS in unilateral 6-hydroxydopamine lesioned female Sprague Dawley rats, with stimulating electrodes implanted in the STN and the ECoG recorded above M1. We quantified the correlations of the cEP magnitude and latency with changes in motor behavior from DBS and compared them to the correlation between motor behaviors and several commonly used spectral-based biomarkers. The cEP features correlated strongly with motor behaviors and were highly consistent across animals, while the spectral biomarkers correlated weakly with motor behaviors and were highly variable across animals. The cEP may thus be a useful biomarker for assessing the therapeutic efficacy of DBS parameters, as its features strongly correlate with motor behavior, it is consistent across time and subjects, it can be recorded under anesthesia, and it is simple to quantify with a large signal-to-noise ratio, enabling rapid, real-time evaluation. Additionally, our work provides further evidence that antidromic cortical activation mediates changes in motor behavior from STN DBS, and that the dependence of DBS efficacy on stimulation frequency may be related to antidromic spike failure.

Ye, Huan; Liu, Zhen-Xu; He, Ya-Jie; Wang, Xin

doi: 10.1152/jn.00332.2021pmid: 35294269

Neuronal persistent activity (PA) is a common phenomenon observed in many types of neurons. PA can be induced in neurons in the mouse auditory nucleus by activating cholinergic receptors with carbachol (CCh), a dual muscarinic and nicotinic receptor agonist. PA is presumed to be associated with learning-related auditory plasticity at the cellular level. However, the mechanism is not clearly understood. Many studies have reported that muscarinic cholinergic receptor agonists inhibit muscarinic-sensitive potassium channels (M channels). Potassium influx through M channels produces potassium currents, called M currents, which play an essential role in regulating neural excitability and synaptic plasticity. Further study is needed to determine whether M currents affect the PA of auditory central neurons and provide additional analysis of the variations in electrophysiological properties. We used in vitro whole-cell patch-clamp recordings in isolated mouse brain slices to investigate the effects of M currents on the PA in pyramidal neurons in layer V of the primary auditory cortex (AI-L5). We found that blocking M currents with XE991 depolarized the AI-L5 pyramidal neurons, which significantly increased the input resistance. The active threshold and threshold intensity were significantly reduced, indicating that the intrinsic excitability was enhanced. Our results also showed that blocking M currents with XE991 switched the neuronal firing patterns in the AI-L5 pyramidal neurons from regular-spiking to intrinsic-bursting. Blocking M currents facilitated PA by increasing the plateau potential and enhancing intrinsic excitability. Our results suggested that blocking M currents might facilitate the PA in AI-L5 pyramidal neurons, which underlies auditory plasticity.

Brunfeldt, Alexander T.; Dromerick, Alexander W.; Bregman, Barbara S.; Lum, Peter S.

doi: 10.1152/jn.00461.2021pmid: 35389759

Bimanual coordination is an essential component of human movement. Cooperative bimanual reaching tasks are widely used to assess the optimal control of goal-directed reaching. However, little is known about the neuromuscular mechanisms governing these tasks. Twelve healthy, right-handed participants performed a bimanual reaching task in a 3-dimensional virtual reality environment. They controlled a shared cursor, located at the midpoint between the hands, and reached to targets located at 80% of full arm extension. Following a baseline of normal reaches, we placed a wrist weight on one arm and measured the change in coordination. Relative contribution (RC) was computed as the displacement of the right hand divided by the sum of displacements of both hands. We used surface electromyography placed over the anterior deltoid and biceps brachii to compute muscle contribution (MC) from root mean squared muscle activity data. We found RC was no different than 50% during baseline, indicating participants reached with equal displacements when no weights were applied. Participants systematically altered limb coordination in response to altered limb dynamics. RC increased by 0.91% and MC decreased by 5.3% relative to baseline when the weight was applied to the left arm; RC decreased by 0.94% and MC increased by 6.3% when the weight was applied to the right arm. Participants adopted an optimal control strategy that attempted to minimize both kinematic and muscular asymmetries between limbs. What emerged was a tradeoff between these two parameters, and we propose this tradeoff as a potential neuromuscular mechanism of cooperative bimanual reaching.

Moreno, F. J.; Caballero, C.; Barbado, D.

doi: 10.1152/jn.00426.2021pmid: 35353616

The complexity of the center of pressure (COP) provides important information regarding the underlying mechanisms of postural control. The relationships between COP complexity and balance performance are not fully established and might depend on the task constraints and the filtering decomposition of the COP signal. This study assessed COP complexity under different task constraints and it was assessed if emergent dynamics of COP fluctuations differ according to fractional components of COP related to peripheral or central adjustments. One hundred and sixty-two participants performed two sitting balance tasks. Accuracy was required by following a target that moved in the mediolateral (ML) or in the anteroposterior (AP) axis. Complexity dynamics of COP were addressed through Detrended Fluctuation Analysis (DFA) in the axis constrained by accuracy requirements and in the one non-constrained. Decomposition of COP components was applied by low-pass, band-pass and high-pass filters. DFA of low-pass and band-pass components of COP in the constrained axis were small-to-moderately related (r = .190 to .237) to balance performance. DFA of the high-pass component of the COP exhibited the opposite relationship (r = -.283 to -.453) in both axes (constrained and non-constrained). This study evidences that COP complexity is linked to better performance. This positive relationship complexity/performance is observed in the low- and mid-frequency components of the COP. These components might be related to central mechanisms of postural control. The lack of relationships between the different frequencies analyzed in the study suggests that they are capturing different components of postural control.

Teku, Faven; Maslovat, Dana; Carlsen, Anthony N.

doi: 10.1152/jn.00476.2021pmid: 35417257

Bimanual actions are typically initiated and executed in a temporally synchronous manner, likely due to planning bilateral commands as a single motor "program." Applying high intensity transcranial magnetic stimulation (TMS) to the motor cortex can result in a contralateral cortical silent period that delays reaction time (RT), if timed to coincide with the final motor output stage. The current study examined the impact of a unilateral TMS silent period on the RT and inter-limb timing of bilateral wrist extension. In addition, because a loud, startling acoustic stimulus (SAS) can result in the involuntary release of pre-programmed actions via increased reticulospinal activation, it was of interest whether startle-induced speeding of response initiation would moderate the impact of the TMS-induced RT delay. Participants performed blocks of unilateral and bilateral wrist extension in response to an acoustic (82dB) go-signal. On selected trials, either TMS was applied to the left motor cortex 70 ms prior to the expected EMG response onset, a SAS (120dB) replaced the go-signal, or both TMS and SAS were delivered. Results showed that TMS led to a significant RT delay in the right limb during both unimanual and bimanual extension but had no impact on the left limb initiation. In addition, the magnitude of the right limb RT delay was smaller when the response was triggered by a SAS. These results imply that preplanned bimanually synchronous movements are susceptible to lateralized dissociation late into the cortical motor output stage and movements triggered by startle involve increased reticulospinal output.

Shang, Jinxing; Wang, Yana; Li, Zhuangzhuang; Jiang, Lijun; Bai, Qingling; Zhang, Xiaoling; Xiao, Guoxin; Zhang, Jinguo

doi: 10.1152/jn.00486.2021pmid: 35417255

Alpha thalassemia/mental retardation syndrome X-linked (ATRX) mutation impairs DNA damage repair in glioblastoma (GBM), making these cells more susceptible to treatment, which may contribute to the survival advantage in GBM patients containing ATRX mutations. To better understand the role of ATRX in GBM, genes correlated with ATRX expression were screened in the Cancer Genome Atlas (702 cases) and Chinese Glioma Genome Atlas (325 cases) databases. Sodium-vitamin C cotransporter 2 (SVCT2) was the most positively correlated gene with ATRX expression. ATRX (about 1.99-fold) and SVCT2 (about 2.25-fold) were upregulated in GBM tissues from 40 patients compared to normal brain tissues from 23 subjects. ShSVCT2 transfection did not alter the in vitro viability of GL261 cells. At the same time, it could inhibit the proliferation of GL261 cells in the orthotopic transplantation model with diminished infiltrating macrophages (CD45highCD11b+), down-regulated chemokine (C-C motif) ligand 2 (Ccl2), Ccl4, C-X-C motif chemokine ligand 1 (Cxcl1), and Cxcl15 expression, and decreased p-IκBα and p-c-Jun expression. Effect of ShSVCT2 transfection could be reversed by overexpression of SVCT2. siRNA interference of ATRX-dependent SVCT2 signal with shSVCT2 could inhibit tumor cell proliferation in Glu261-LuNeo xenograft tumor model with more survival advantage, probably by the inhibited macrophage chemotaxis. These results indicate that ATRX-dependent SVCT2-mediated chemokine-induced macrophage infiltration is regulated by the NF-κB pathway, which could be considered as treatment targets.