Radiographic evaluation of patellofemoral alignment in kinematically aligned total knee arthroplasty: A comparative study with mechanically aligned total knee arthroplasty.

BACKGROUND: Kinematically aligned total knee arthroplasty (KA-TKA), in which femoral component is placed 3-5° of internal rotation relative to mechanically aligned (MA)-TKA, may have a potential risk of patellofemoral malalignment. This study aimed to assess patellofemoral alignment and compare the data between KA-TKA and MA-TKA, and the relationship with patellofemoral radiographic parameters and patient reported outcomes. METHODS: Among patients who underwent TKA in 2015 and 2016 in our institute, 28 KA-TKAs with a metal-backed patellar component were retrospectively assessed for patellofemoral alignment, and 28 MA-TKAs with a metal-backed patellar component served as controls. A year postoperatively, patellar tilt and shift at 30°, 60°, and 90° knee flexion were measured on Merchant views and compared between the two TKAs. Implant positioning in each patient was assessed based on preoperative CT images and correlations of femoral component positioning with patellar tilt/shift were assessed. RESULTS: Patellar shift at 30° flexion was significantly greater in KA-TKA than in MA-TKA (p = 0.04), whereas patellar tilt angle was comparable between the two TKAs. No statistical correlation was evident between femoral component positioning and patellar shift/tilt, regardless of knee flexion angle in the two TKAs. Knee Society Score 2011 at 1 year follow-up was comparable in all subcategories between the two TKAs. CONCLUSION: Radiographic analysis of KA-TKA revealed lateral shift of the patella at 30° knee flexion at 1 year postoperatively, however patients with patellar shift were asymptomatic. Further long-term observation is required to examine the impact of KA-TKA on the patellofemoral complication.

Topical application of L-carnosine to skeletal muscle excites the sympathetic nerve innervating the contralateral skeletal muscle in rats.

We previously obtained evidence suggesting that physical exercise increases the release of L-carnosine (CAR) from muscles and that CAR affects autonomic neurotransmission and physiological phenomena in rats. It has also been reported that exercise elicits an increase in activity of the sympathetic nerve innervating the skeletal muscle. Therefore, in this study, we investigated the effect of CAR application, onto the surface of the right femoral muscle, on activity of the sympathetic nerve innervating the left femoral muscle, in urethane-anesthetized rats. Topical application of 10 pg (44.2 fmol) of CAR increased either skeletal muscle sympathetic nerve activity (skeletal muscle-SNA) or skeletal muscle blood flow (skeletal muscle-BF) of the contralateral skeletal muscle. Furthermore, thioperamide, a histamine H3-antagonist, inhibited the increase in skeletal muscle-SNA, and butoxamine, a ß2-antagonist, abolished the increase in skeletal muscle-BF caused by topical application of CAR. The present results suggest that CAR released from muscles during physical exercise might affect skeletal muscle-SNA and skeletal muscle-BF on the opposite side of the body via a CAR evoked effect in muscles.

Kinematically aligned total knee arthroplasty reduces knee adduction moment more than mechanically aligned total knee arthroplasty.

PURPOSE: Knee adduction moment (KAM) has been recognized as a good clinical surrogate for medial tibiofemoral joint loading and is associated with implant durability after total knee arthroplasty (TKA). This study aimed to examine the effects of joint line obliquity in kinematically aligned TKA (KA-TKA) on KAM during gait. METHODS: The study enrolled 21 knees from 18 patients who underwent cylindrical axis reference KA-TKA and a matched group of 21 knees from 18 patients who underwent mechanically aligned (MA)-TKA as controls. Gait analyses were performed the day before TKA and at an overall mean of 2.6 years postoperatively. First peak KAM and variables associated with frontal knee kinetics were determined and compared between groups. RESULTS: In KA-TKA, the proximal tibia was resected with 3.4° ± 1.5° of varus in relation to the mechanical axis, and the final femorotibial shaft axis was 176.7° ± 3.8° with KA-TKA and 174.4° ± 3.0° with MA-TKA. KAM was significantly smaller with KA-TKA than with MA-TKA (p < 0.032). Regarding variables affecting KAM, significant differences were evident between the two TKAs for knee adduction angle (p = 0.0021), lever arm (p = 0.028), and Δlever arm (p = 0.0001). CONCLUSIONS: In KA-TKA, joint line obliquity reduced peak KAM during gait, despite slight varus limb alignment, and this reduced KAM in KA-TKA can tolerate constitutional varus alignment. In clinical settings, KA-TKA thus represents a promising technical option for patients with large coronal bowing of the shaft carrying a risk of increased KAM after TKA. LEVEL OF EVIDENCE: III.

Odors generated from the Maillard reaction affect autonomic nervous activity and decrease blood pressure through the olfactory system.

BACKGROUND: Systolic blood pressure (SBP) of rats decreases significantly following exposure to the odor generated from the Maillard reaction of protein digests with xylose. This study identified active odorants that affect blood pressure and demonstrated the mechanism of action. RESULTS: Among the four potent odorants that contribute most to the odor of the Maillard reaction sample, 2,5-dimethyl-4-hydroxy-3(2H)-furanone (DMHF) and 5-methyl-2-pyrazinemethanol (MPM) decreased SBP significantly. The earliest decrease in blood pressure was observed 5 min after exposure to DMHF. Application of zinc sulfate to the nasal cavity eliminated the effect. Furthermore, gastric vagal (parasympathetic) nerve activity was elevated and renal sympathetic nerve activity was lowered after exposure to DMHF. CONCLUSION: It is indicated that DMHF affects blood pressure through the olfactory system, and the mechanism for the effect of DMHF on blood pressure involves the autonomic nervous system. © 2017 Society of Chemical Industry.

Comparison between cylindrical axis-reference and articular surface-reference femoral bone cut for total knee arthroplasty.

PURPOSE: Reproducing a functional flexion-extension axis (FEA) of the femur is key to achieving successful collateral ligament balance and joint line in total knee arthroplasty (TKA). This study compared the feasibility of cylindrical axis (CA)-reference bone cut and articular surface-reference bone cuts in reproducing the FEA for Japanese osteoarthritis patients. METHODS: The study enrolled 122 knees from 86 patients who underwent primary TKA due to grade III or IV osteoarthritis. Data from pre-operative CT were reconstructed into three-dimensional (3D) models using 3D-planning software. Cylindrical radii of the condyles were measured, and femoral bone cut angles relative to anatomical landmarks were determined in the coronal and axial reference planes based on CA-reference and articular surface-reference methods. RESULTS: Mean cylindrical radii for medial and lateral femoral condyles were 17.4 ± 1.6 and 17.3 ± 1.4 mm, respectively. Of the 122 knees, 46 exhibited >1 mm of difference between condyles. Fifty-three and 22 knees exhibited >2° of angular difference between CA-reference and articular surface-reference bone cuts in the coronal and axial planes. Mean angle of the CA and surgical epicondylar axis in 3D space was 4.6 ± 2.1°. As practical parameters for TKA, the angle between CA and IM rod was significantly larger than that between the distal articular surface line and IM rod in the coronal plane (p < 0.0001), indicating that CA-reference involves a smaller valgus bone cut of the distal femur than articular surface reference. CONCLUSIONS: CA-reference bone cut of the femur is preferable to articular surface-reference bone cut for reproducing FEA in Japanese OA patients, in whom more than one-third of knees exhibited asymmetry of radii between medial and lateral condyles. In clinical practice, the CA-reference bone cut represents a good technical option for kinematically aligned TKA in the Japanese population.

Mechanically aligned total knee arthroplasty carries a risk of bony gap changes and flexion-extension axis displacement.

PURPOSE: The flexion-extension axis (FEA) of the femur is substantially changed after mechanically aligned total knee arthroplasty (TKA) due to a discrepancy in bone cut thickness between the posterior and distal femoral regions. This study assessed the bony gap changes and FEA displacement caused by this problem in osteoarthritis patients. METHODS: The study enrolled 60 knees from 60 patients for whom primary TKA was planned due to medial knee osteoarthritis. All patients underwent computed tomography, and 3-dimensional (3D) bone models were reconstructed on 3D-planning software. Bone cuts of the distal femur and proximal tibia were simulated to be perpendicular to each mechanical axis. Bony gap change was computed as the difference in bone cut thickness between medial and lateral compartments. Each femoral condyle was assessed for potential FEA displacement, as the difference in bone cut thickness between posterior and distal femoral regions. RESULTS: The mean magnitude of bony gap discrepancy necessary for mediolateral balancing was 1.6 ± 3.3 mm (range -7 to 8.2 mm) at 0° extension and -0.2 ± 2.6 mm (range -6.4 to 4.3 mm) at 90° flexion. At least 2 mm of bony gap discrepancy at 0° extension and 90° flexion was found in 40 patients (67%) and 26 patients (43%), respectively. In terms of femoral bone cut, posterior bone cut thickness was significantly larger than distal bone cut thickness in the medial compartment (p < 0.001). Bony gap discrepancy between distal and posterior regions of the femoral condyle was ≥2 mm in 28 patients (47%). CONCLUSIONS: This study focused on two flaws of mechanically aligned TKA in OA patients. Substantial numbers of patients inevitably required >2 mm of medial collateral ligament release at 0° extension and showed a bone cut discrepancy between distal and posterior regions, carrying a risk of FEA displacement and subsequent unnatural knee motions during knee extension and flexion. Level of evidence IV.

Effects of femoral bone tunnel characteristics on graft-bending angle in double-bundle anterior cruciate ligament reconstruction: a comparison of the outside-in and transportal techniques.

PURPOSE: Bone tunnel creation techniques influence the 3-dimensional (3D) position of bone tunnels and graft-bending angle in anterior cruciate ligament (ACL) reconstruction. This study assessed graft-bending angle and 3D characteristics of femoral bone tunnels and compared them between outside-in (OI) and transportal (TP) techniques. METHODS: Participants comprised 64 patients who underwent anatomic double-bundle ACL reconstruction, allocated to OI and TP groups (n = 32 each). The graft orientation plane exhibiting the largest graft-bending angle at the femoral tunnel aperture with the knee in extension was reconstructed from CT data using 3D imaging software. In this plane, graft-bending angle was compared between the OI and TP techniques. RESULTS: Although positionings of the intra-articular apertures of the femoral and tibial bone tunnels were similar, several spatial parameters of bone tunnels differed between techniques. Graft-bending angles of both anteromedial and posterolateral bundles were significantly more acute with the OI technique than with the TP technique. On coronal-plane CT, angle of the bone tunnel axis relative to the distal condylar axis correlated negatively with graft-bending angle, while in the axial plane, angle of the bone tunnel axis relative to the posterior condylar axis correlated positively with graft-bending angle. Lysholm score, pivot shift test, and anteroposterior laxity at >2.5-year follow-up demonstrated no significant differences between techniques. DISCUSSION: Different bone tunnel directions in OI and TP techniques substantially affected graft-bending angle , despite similar positionings of the intra-articular apertures. Graft-bending angle with the OI technique was acute, but risk of posterior blowout of the lateral femoral condyle was decreased. Surgeons should create the femoral tunnel while considering an obtuse graft-bending angle without increasing the risk of posterior blowout. LEVEL OF EVIDENCE: III.

Effects of Reduction Osteotomy on Gap Balancing During Total Knee Arthroplasty for Severe Varus Deformity.

This study aimed to assess the effects of down-sizing and lateralizing of the tibial component (reduction osteotomy) on gap balancing in TKA, and the clinical feasibility of an uncemented modular trabecular metal tibial tray in this technique. Reduction osteotomy was performed for 39 knees of 36 patients with knee OA with a mean tibiofemoral angle of 21° varus. In 20 knees, appropriate gap balance was achieved by release of the deep medial collateral ligament alone. Flexion gap imbalance could be reduced by approximately 1.7° and 2.8° for 4-mm osteotomy and 8-mm osteotomy, respectively. Within the first postoperative year, clinically-stable tibial component subsidence was observed in 9 knees, but it was not progressive, and the clinical results were excellent at a mean follow-up of 3.3 years.

Role of L-carnosine in the control of blood glucose, blood pressure, thermogenesis, and lipolysis by autonomic nerves in rats: involvement of the circadian clock and histamine.

L-carnosine (ß-alanyl-L-histidine; CAR) is synthesized in mammalian skeletal muscle. Although the physiological roles of CAR have not yet been clarified, there is evidence that the release of CAR from skeletal muscle during physical exercise affects autonomic neurotransmission and physiological functions. In particular, CAR affects the activity of sympathetic and parasympathetic nerves innervating the adrenal glands, liver, kidney, pancreas, stomach, and white and brown adipose tissues, thereby causing changes in blood pressure, blood glucose, appetite, lipolysis, and thermogenesis. CAR-mediated changes in neurotransmission and physiological functions were eliminated by histamine H1 or H3 receptor antagonists (diphenhydramine or thioperamide) and bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN), a master circadian clock. Moreover, a carnosine-degrading enzyme (carnosinase 2) was shown to be localized to histamine neurons in the hypothalamic tuberomammillary nucleus (TMN). Thus, CAR released from skeletal muscle during exercise may be transported into TMN-histamine neurons and hydrolyzed. The resulting L-histidine may subsequently be converted into histamine, which could be responsible for the effects of CAR on neurotransmission and physiological function. Thus, CAR appears to influence hypoglycemic, hypotensive, and lipolytic activity through regulation of autonomic nerves and with the involvement of the SCN and histamine. These findings are reviewed and discussed in the context of other recent reports, including those on carnosine synthetases, carnosinases, and carnosine transport.

CKIepsilon/delta-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock.

A striking feature of the circadian clock is its flexible yet robust response to various environmental conditions. To analyze the biochemical processes underlying this flexible-yet-robust characteristic, we examined the effects of 1,260 pharmacologically active compounds in mouse and human clock cell lines. Compounds that markedly (>10 s.d.) lengthened the period in both cell lines, also lengthened it in central clock tissues and peripheral clock cells. Most compounds inhibited casein kinase Iepsilon (CKIepsilon) or CKIdelta phosphorylation of the PER2 protein. Manipulation of CKIepsilon/delta-dependent phosphorylation by these compounds lengthened the period of the mammalian clock from circadian (24 h) to circabidian (48 h), revealing its high sensitivity to chemical perturbation. The degradation rate of PER2, which is regulated by CKIepsilon/delta-dependent phosphorylation, was temperature-insensitive in living clock cells, yet sensitive to chemical perturbations. This temperature-insensitivity was preserved in the CKIepsilon/delta-dependent phosphorylation of a synthetic peptide in vitro. Thus, CKIepsilon/delta-dependent phosphorylation is likely a temperature-insensitive period-determining process in the mammalian circadian clock.

Skin application of urea-containing cream affected cutaneous arterial sympathetic nerve activity, blood flow, and water evaporation.

BACKGROUND/PURPOSE: We observed that olfactory stimulation with scent of grapefruit oil elevated the activities of sympathetic nerves, and increased the plasma glycerol concentration and blood pressure. In contrast, olfactory stimulation with scent of lavender oil had opposite effects in rats. These suggest that changes in autonomic activities cause physiological functions via histaminergic H1 and H3 receptor. Moreover, it has been reported that somatic sensory stimulation affected autonomic neurotransmission. To examine effects of skin application of urea-containing cream on cutaneous arterial sympathetic nerve activity (CASNA), blood flow, and transepidermal water loss (TEWL). METHOD: The activity of CASNA was determined by electrophysiological method, and cutaneous blood flow was determined using laser flowmeter in urethane-anesthetized rats, TEWL was measured using VapoMeter in the back skin of HWY hairless rats. RESULTS: CASNA was markedly and significantly inhibited by skin application of 10% urea-containing cream, whereas cutaneous blood flow was significantly elevated via histaminergic H3-receptor. In conscious hairless rats, TEWL was significantly decreased 24 h after application of 10% urea-containing cream to the back skin. CONCLUSION: These findings suggest that skin application of 10% urea-containing cream increases the cutaneous blood flow and water retaining ability, and that histaminergic H3-receptors may mediate these effects.

Effect of anserine ingestion on hyperglycemia and the autonomic nerves in rats and humans.

Anserine and L-carnosine are similar dipeptides synthesized by muscles of vertebrates. The functional role of anserine is unknown, although previous studies showed hypoglycemic effects of carnosine through autonomic nerves. Thus, we evaluated the effects of anserine on blood glucose levels and the neural activities. Intraperitoneal administration of specific doses of anserine to hyperglycemic rats reduced hyperglycemia and plasma glucagon concentrations, whereas thioperamide eliminated the effects of anserine. Intraduodenal injection of 0.1 mg anserine to anesthetized rats after laparotomy suppressed sympathetic nerve activity and enhanced activity of the vagal gastric efferent. In addition, oral administration of anserine reduced blood glucose levels during oral glucose tolerance testing in humans. These results suggest the possibility that anserine might be a control factor for the blood glucose, and that histaminergic nerves may be involved in the hypoglycemic effects of anserine.

Effect of anserine ingestion on the hyperglycemia and autonomic nerves in rats and humans.

Anserine and L-carnosine are similar dipeptides synthesized by muscles of vertebrates. The functional role of anserine is unknown, although previous studies showed hypoglycemic effects of carnosine through autonomic nerves. Thus, we evaluated the effects of anserine on blood glucose levels and neural activities. Intraperitoneal administration of specific doses of anserine to hyperglycemic rats reduced hyperglycemia and plasma glucagon concentrations, whereas thioperamide eliminated the effects of anserine. Intraduodenal injection of 0.1 mg anserine to anesthetized rats after laparotomy suppressed sympathetic nerve activity and enhanced activity of the vagal gastric efferent. In addition, oral administration of anserine reduced blood glucose levels during oral glucose tolerance testing in humans. These results suggest the possibility that anserine might be a control factor for blood glucose, and that histaminergic nerves may be involved in the hypoglycemic effects of anserine.

Effects of ethyl hexanoate on activities of sympathetic nerves innervating the brown and white adipose tissues, body temperature, and plasma fatty acids.

The autonomic nervous system (ANS) is implicated in maintaining homeostasis of the internal environment in mammals. Therefore, changes occurring in the ANS can cause alterations of physiological phenomena. Ethyl hexanoate (EH) is known as the aroma component of apples. To study the action of ethyl hexanoate on physiological phenomena, we examined the effect of an intragastric (IG) injection of 1 mL/kg body weight of 0.1 ppm EH solution on sympathetic nerve activity innervating the brown adipose tissue (BAT) and white adipose tissue (WAT) in anesthetized rats. Consequently, IG administration of EH increased activity of the sympathetic nerves innervating both the BAT and WAT. In addition, the effects of the IG injection on body temperature above the interscapular BAT and plasma free fatty acid (FFA) concentration were also examined in conscious rats. In this attempt IG injection of EH elevated both the body temperature and plasma FFA levels. Furthermore, subdiaphragmatic vagotomy eliminated the effects of EH on sympathetic nerves innervating BAT and WAT. These findings suggest that EH causes excitations of sympathetic nerves innervating BAT and WAT, and enhances thermogenesis and lipolysis via the afferent vagus nerve. Thus, these present findings also suggest the possibility that EH might have anti-obesity effects.

Lipocalin-type prostaglandin D synthase regulates light-induced phase advance of the central circadian rhythm in mice.

We previously showed that mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP) exhibit attenuated light-induced phase shift. To explore the underlying mechanisms, we performed gene expression analysis of laser capture microdissected suprachiasmatic nuclei (SCNs) and found that lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is involved in the impaired response to light stimulation in the late subjective night in PACAP-deficient mice. L-PGDS-deficient mice also showed impaired light-induced phase advance, but normal phase delay and nonvisual light responses. Then, we examined the receptors involved in the response and observed that mice deficient for type 2 PGD2 receptor DP2/CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells) show impaired light-induced phase advance. Concordant results were observed using the selective DP2/CRTH2 antagonist CAY10471. These results indicate that L-PGDS is involved in a mechanism of light-induced phase advance via DP2/CRTH2 signaling.

Depression-like behavior in the forced swimming test in PACAP-deficient mice: amelioration by the atypical antipsychotic risperidone.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with pleiotropic functions. We report here that PACAP-deficient (PACAP-/-) mice showed increased immobility in a forced swimming test, which was reduced by the antidepressant desipramine, to a similar extent as in wild-type mice. The atypical antipsychotic risperidone and the selective serotonin (5-HT)(2) antagonist ritanserin normalized the depression-like behavior in PACAP-/- mice. The 5-HT(2) agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine-induced 5-HT syndrome was exaggerated in PACAP-/- mice, which suggests a 5-HT(2)-receptor-dependent mechanism in the depression-like behavior. The circadian rhythm of plasma corticosterone and body core temperature was significantly flattened in the mutants. mRNA expression of glucocorticoid receptor was reduced in the mutant hippocampus. The present results suggest that alterations in PACAP signaling might contribute to the pathogenesis of certain depressive conditions amenable to atypical antipsychotic drugs.

Possible role of the histaminergic system in autonomic and cardiovascular responses to neuropeptide Y.

Previous studies have demonstrated that neuropeptide Y (NPY) affects blood pressure (BP) in anesthetized rats. Here, we examined the effects of the third cerebral ventricular (3CV) injection of various doses of NPY on renal sympathetic nerve activity (RSNA) and BP in anesthetized rats. 3CV injection of NPY suppressed RSNA and BP in a dose-dependent manner. Moreover, suppressing effects of NPY on RSNA and BP were eliminated by lateral cerebral ventricular (LCV) preinjection of thioperamide, an antagonist of histaminergic H3-receptor, not diphenhydramine, an antagonist of histaminergic H1-receptor. In addition, 3CV injection of NPY accelerated gastric vagal nerve activity (GVNA) and inhibited brown adipose tissue sympathetic nerve activity (BAT-SNA) of anesthetized rats, and lowered brown adipose tissue temperature (BAT-T) of conscious rats. Thus, these evidences suggest that central NPY affects autonomic nerves containing RSNA, GVNA or BAT-SNA, and BP by mediating central histaminergic H3-receptors.

Autonomic and cardiovascular effects of central neuromedin U in rats.

Previous studies have demonstrated that neuromedin U (NMU) affects cardiovascular functions such as blood pressure (BP) or heart rate (HR) in rats. Here, we examined the effects of the lateral cerebral ventricular (ICV) injection of various doses of NMU on renal sympathetic nerve activity (RSNA) and BP in urethane-anesthetized rats. ICV injection of NMU elevated RSNA, BP and HR in a dose-dependent manner. Moreover, neither ICV pretreatment of thioperamide, an antagonist of histaminergic H3-receptor, or of diphenhydramine, an antagonist of histaminergic H1-receptor, abolished increasing effects of NMU on RSNA, BP and HR In addition, ICV injection of NMU suppressed gastric vagal nerve activity (GVNA) and activated brown adipose tissue sympathetic nerve activity (BAT-SNA) of anesthetized rats, and elevated brown adipose tissue temperature (BAT-T) of conscious rats. Thus, these evidence suggest that NMU affects neural activities of autonomic nerves containing RSNA, GVNA or BAT-SNA, and BP by mediating central mechanism.

Effects of flavangenol on autonomic nerve activities and dietary body weight gain in rats.

In a previous report, evidence was presented that flavangenol supplementation has an anti-ischemic effects in rats. In the study presented here, we examined the autonomic effects of intraduodenal (ID) injection of flavangenol in urethane-anesthetized rats and found that it increased sympathetic nerve activity innervating brown adipose tissue (BAT-SNA) in a dose-dependent manner, while it suppressed gastric vagal nerve activity (GVNA). In addition, intra-oral (IO) injection of flavangenol elevated brown adipose tissue temperature (BAT-T). Furthermore, flavangenol drinking for 15 d reduced body weight gain in rats fed a high-fat diet. These results thus suggest that flavangenol supplementation exerts its reducing action on body weight through changes in autonomic neurotransmission.

Effect of auditory stimulation on parasympathetic nerve activity in urethane-anesthetized rats.

Previously, it has been demonstrated that auditory stimulation with music (Traeumerei [TM] by Schumann) decreased renal sympathetic nerve activity (RSNA) and blood pressure (BP) with a central mechanism, while it is unknown whether TM affects parasympathetic nerve activity. Here, the effects of auditory stimulation with TM on gastric vagal nerve activity (GVNA) in urethane-anesthetized rats were investigated. Auditory stimulation with TM, but not with white noise (WN) caused a significant elevation of GVNA. In addition, exposure to TM increased the number of c-Fos-immunoreactive cells in the auditory cortex (AuC). These findings suggest that exposure to music can increase GVNA through the auditory pathway.