Physiological responses and perceived comfort to high-flow nasal cannula therapy in awake adults: effects of flow magnitude and temperature.

Clinical use of heated, high-flow nasal cannula (HFNC) for noninvasive respiratory support is increasing and may have a therapeutic role in stabilizing the upper airway in obstructive sleep apnea (OSA). However, physiological mechanisms by which HFNC therapy may improve upper airway function and effects of different temperature modes are unclear. Accordingly, this study aimed to determine effects of incremental flows and temperature modes (heated and nonheated) of HFNC on upper airway muscle activity (genioglossus), pharyngeal airway pressure, breathing parameters, and perceived comfort. Six participants (2 females, aged 35 ± 14 yr) were studied during wakefulness in the supine position and received HFNC at variable flows (0-60 L/min) during heated (37°C) and nonheated (21°C) modes. Breathing parameters via calibrated Respitrace inductance bands (chest and abdomen), upper airway pressures via airway transducers, and genioglossus muscle activity via intramuscular bipolar fine wire electrodes were measured. Comfort levels during HFNC were quantified using a visual analog scale. Increasing HFNC flows did not increase genioglossus muscle activation despite increased negative epiglottic pressure swings (P = 0.009). HFNC provided ∼7 cmH2O positive airway pressure at 60 L/min in nonheated and heated modes. In addition, increasing the magnitude of HFNC flow reduced breathing frequency (P = 0.045), increased expiratory time (P = 0.040), increased peak inspiratory flow (P = 0.002), and increased discomfort (P = 0.004). Greater discomfort occurred at higher flows in the nonheated versus the heated mode (P = 0.034). These findings provide novel insight into key physiological changes that occur with HFNC for respiratory support and indicate that the primary mechanism for improved upper airway stability is positive airway pressure, not increased pharyngeal muscle activity.NEW & NOTEWORTHY This study evaluated upper airway muscle function, breathing, and comfort across different HFNC flows and temperatures. There were no increases in genioglossus muscle activity at higher flows despite greater negative epiglottic pressure swings. Increasing negative pressure swings was associated with increasing discomfort in the nonheated mode. HFNC was associated with ∼7 cmH2O increase in positive airway pressure, which may be the primary mechanism for upper airway stability with HFNC rather than increases in pharyngeal muscle activity.

Nocturnal swallowing augments arousal intensity and arousal tachycardia.

Cortical arousal from sleep is associated with autonomic activation and acute increases in heart rate. Arousals vary considerably in their frequency, intensity/duration, and physiological effects. Sleep and arousability impact health acutely (daytime cognitive function) and long-term (cardiovascular outcomes). Yet factors that modify the arousal intensity and autonomic activity remain enigmatic. In this study of healthy human adults, we examined whether reflex airway defense mechanisms, specifically swallowing or glottic adduction, influenced cardiac autonomic activity and cortical arousal from sleep. We found, in all subjects, that swallows trigger rapid, robust, and patterned tachycardia conserved across wake, sleep, and arousal states. Tachycardia onset was temporally matched to glottic adduction-the first phase of swallow motor program. Multiple swallows increase the magnitude of tachycardia via temporal summation, and blood pressure increases as a function of the degree of tachycardia. During sleep, swallows were overwhelmingly associated with arousal. Critically, swallows were causally linked to the intense, prolonged cortical arousals and marked tachycardia. Arousal duration and tachycardia increased in parallel as a function of swallow incidence. Our findings suggest that cortical feedback and tachycardia are integrated responses of the swallow motor program. Our work highlights the functional influence of episodic, involuntary airway defense reflexes on sleep and vigilance and cardiovascular function in healthy individuals.

Differential activation of the human costal and crural diaphragm during voluntary and involuntary breaths.

The diaphragm is the primary muscle that generates the negative intrathoracic pressure to drive inspiratory airflow. The diaphragm consists of two parts, the costal and crural portions, with different roles during inspiration in animals, particularly when the stimulus to breathe is increased. In this study, the neural drive to the costal and crural portions of the diaphragm was assessed in nine healthy participants [8 male, aged 32 ± 13 yr (mean ± SD)]. Inspiratory electromyographic activity (EMG) was recorded from the costal diaphragm by using an intramuscular electrode and from the crural diaphragm with a multipair gastroesophageal catheter. Participants performed voluntary augmented breaths at 120%, 140%, and 160% of their tidal volume and also underwent progressive hypercapnia to induce involuntary breathing. Irrespective of the task, the increase in crural activity (normalized to quiet breathing) was only ~60% of the increase in costal activity (slope: 0.56 ± 0.30, P < 0.001). The onset and peak timing of EMG activity was similar for the costal and crural diaphragm during quiet breathing. Thus, when stimulated by either a voluntary or involuntary drive to breathe above tidal volume, the neural drive to the diaphragm was greater to the costal than to the crural portion.NEW & NOTEWORTHY Simultaneous electromyographic recordings from the human costal and crural diaphragm during voluntary augmented breathing and involuntary rebreathing show that the increase in inspiratory crural diaphragm activity was ~60% of the increase in costal diaphragm activity. However costal to crural diaphragm activation did not differ between the two tasks. The dissociation in the amplitude of activation of the costal and crural diaphragm becomes apparent only as the drive to breathe increases above tidal breathing.

The occupied electronic structure of ultrathin boron doped diamond.

Using angle-resolved photoelectron spectroscopy, we compare the electronic band structure of an ultrathin (1.8 nm) δ-layer of boron-doped diamond with a bulk-like boron doped diamond film (3 µm). Surprisingly, the measurements indicate that except for a small change in the effective mass, there is no significant difference between the electronic structure of these samples, irrespective of their physical dimensionality, except for a small modification of the effective mass. While this suggests that, at the current time, it is not possible to fabricate boron-doped diamond structures with quantum properties, it also means that nanoscale boron doped diamond structures can be fabricated which retain the classical electronic properties of bulk-doped diamond, without a need to consider the influence of quantum confinement.

Discharge properties of human diaphragm motor units with ageing.

KEY POINTS: Ageing is associated with changes in the respiratory system including in the lungs, rib cage and muscles. Neural drive to the diaphragm, the principal inspiratory muscle, has been reported to increase during quiet breathing with ageing. We demonstrated that low-threshold motor units of the human diaphragm recruited during quiet breathing have similar discharge frequencies across age groups and shorter discharge times in older age. With ageing, motor unit action potential area increased. We propose that there are minimal functionally significant changes in the discharge properties of diaphragm motor units with ageing despite remodelling of the motor unit in the periphery. ABSTRACT: There are changes in the skeletal, pulmonary and respiratory neuromuscular systems with healthy ageing. During eupnoea, one study has shown relatively higher crural diaphragm electromyographic activity (EMG) in healthy older adults (>51 years) than in younger adults, but these measures may be affected by the normalisation process used. A more direct method to assess neural drive involves the measurement of discharge properties of motor units. Here, to assess age-related changes in neural drive to the diaphragm during eupnoea, EMG was recorded from the costal diaphragm using a monopolar needle electrode in participants from three age groups (n ≥ 7 each): older (65-80 years); middle-aged (43-55 years) and young (23-26 years). In each group, 154, 174 and 110 single motor units were discriminated, respectively. A mixed-effects linear model showed no significant differences between age groups for onset (group mean range 9.5-10.2 Hz), peak (14.1-15.0 Hz) or offset (7.8-8.5 Hz) discharge frequencies during eupnoea. The motor unit recruitment was delayed in the older group (by ∼15% of inspiratory time; p = 0.02 cf. middle-aged group) and had an earlier offset time (by ∼15% of inspiratory time; p = 0.04 cf. young group). However, the onset of multiunit activity was similar across groups, consistent with no global increase in neural drive to the diaphragm with ageing. The area of diaphragm motor unit potentials was ∼40% larger in the middle-aged and older groups (P < 0.02), which indicates axonal sprouting and re-innervation of muscle fibres associated with ageing, even in middle-aged participants.

Abdominal Functional Electrical Stimulation to Augment Respiratory Function in Spinal Cord Injury.

Background: Functional electrical stimulation (FES) is the application of electrical pulses to a nerve to achieve a functional muscle contraction. Surface electrical stimulation of the nerves that innervate the abdominal muscles, termed abdominal FES, can cause the abdominal muscles to contract, even when paralysed after spinal cord injury. As the abdominal muscles are the major expiratory muscles, and commonly partially or completely paralysed in tetraplegia, abdominal FES offers a promising method of improving respiratory function for this patient group. Objective: The aim of the article is to provide readers with a better understanding of how abdominal FES can be used to improve the health of the spinal cord-injured population. Methods: A narrative review of the abdominal FES literature was performed. Results: Abdominal FES can achieve an immediate effective cough in patients with tetraplegia, while the repeated application over 6 weeks of abdominal FES can improve unassisted respiratory function. Ventilator duration and tracheostomy cannulation time can also be reduced with repeated abdominal FES. Conclusion: Abdominal FES is a noninvasive method to achieve functional improvements in cough and respiratory function in acute and chronically injured people with tetraplegia. Potential practical outcomes of this include reduced ventilation duration, assisted tracheostomy decannulation, and a reduction in respiratory complications. All of these outcomes can contribute to reduced morbidity and mortality, improved quality of life, and significant potential cost savings for local health care providers.

Antibody Repertoire Development in Swine.

We describe the domestication of the species, explore its value to agriculture and bioscience, and compare its immunoglobulin (Ig) genes to those of other vertebrates. For encyclopedic information, we cite earlier reviews and chapters. We provide current gene maps for the heavy and light chain loci and describe their polygeny and polymorphy. B-cell and antibody repertoire development is a major focus, and we present findings that challenge several mouse-centric paradigms. We focus special attention on the role of ileal Peyer's patches, the largest secondary lymphoid tissues in newborn piglets and a feature of all artiodactyls. We believe swine fetal development and early class switch evolved to provide natural secretory IgA antibodies able to prevent translocation of bacteria from the gut while the bacterial PAMPs drive development of adaptive immunity. We discuss the value of using the isolator piglet model to address these issues.

Single-crystal diamond refractive lens for focusing X-rays in two dimensions. Erratum.

A correction is made to a citation in the article by Antipov et al. (2016) [J. Synchrotron Rad. 23, 163-168].

Single-crystal diamond refractive lens for focusing X-rays in two dimensions.

The fabrication and performance evaluation of single-crystal diamond refractive X-ray lenses of which the surfaces are paraboloids of revolution for focusing X-rays in two dimensions simultaneously are reported. The lenses were manufactured using a femtosecond laser micromachining process and tested using X-ray synchrotron radiation. Such lenses were stacked together to form a standard compound refractive lens (CRL). Owing to the superior physical properties of the material, diamond CRLs could become indispensable wavefront-preserving primary focusing optics for X-ray free-electron lasers and the next-generation synchrotron storage rings. They can be used for highly efficient refocusing of the extremely bright X-ray sources for secondary optical schemes with limited aperture such as nanofocusing Fresnel zone plates and multilayer Laue lenses.

Respiratory muscle training may improve respiratory function and obstructive sleep apnoea in people with cervical spinal cord injury.

STUDY DESIGN: This is a double-blind crossover case study series. OBJECTIVES: The objective of this study was to assess the feasibility of respiratory muscle training (RMT) as an effective intervention to improve lung function and obstructive sleep apnoea (OSA) in cervical spinal cord injury (SCI) patients. SETTING: This study was conducted in Australia. METHODS: Three adults (C5-6, AIS A-C) participated in this study. They trained with an RMT device (active or sham) for 4 weeks followed by 2 weeks of rest, and then trained with the alternate device for 4 weeks. RMT occurred twice daily, 5 days a week, and it consisted of three sets of 12 inspirations and three sets of 12 expirations. Training intensity commenced at 30% maximal inspiratory pressure (MIP) and 30% maximal expiratory pressure (MEP), which was increased every second day by 10%. Spirometry, MIP, MEP, polysomnography and Epworth Sleepiness Scale (ESS) were measured before and after every 4 weeks of training. RESULTS: After active RMT, vital capacity and inspiratory capacity improved from baseline in all participants (by 44%, 60% and 18% and by 18%, 46% and 5%, respectively); MIP improved by 40 and 17% from baseline in two subjects; and MEP improved in all participants. Two participants had OSA, and after active training their obstructive apnoea-hypopnoea index improved from 30 to 21events per hour and from 72 to 18 events per hour, and ESS marginally improved. Sham RMT resulted in minimal changes in all measures. CONCLUSION: RMT is feasible and likely effective to increase respiratory muscle strength, to improve lung function, and to reduce the severity of OSA and sleepiness in people with cervical SCI. A randomised controlled trial is planned to validate these findings and to examine respiratory-related morbidity and quality of life.

Porcine reproductive and respiratory syndrome (PRRS): an immune dysregulatory pandemic.

Porcine reproductive and respiratory disease syndrome (PRRS) is a viral pandemic that especially affects neonates within the "critical window" of immunological development. PRRS was recognized in 1987 and within a few years became pandemic causing an estimated yearly $600,000 economic loss in the USA with comparative losses in most other countries. The causative agent is a single-stranded, positive-sense enveloped arterivirus (PRRSV) that infects macrophages and plasmacytoid dendritic cells. Despite the discovery of PRRSV in 1991 and the publication of >2,000 articles, the control of PRRS is problematic. Despite the large volume of literature on this disease, the cellular and molecular mechanisms describing how PRRSV dysregulates the host immune system are poorly understood. We know that PRRSV suppresses innate immunity and causes abnormal B cell proliferation and repertoire development, often lymphopenia and thymic atrophy. The PRRSV genome is highly diverse, rapidly evolving but amenable to the generation of many mutants and chimeric viruses for experimental studies. PRRSV only replicates in swine which adds to the experimental difficulty since no inbred well-defined animal models are available. In this article, we summarize current knowledge and apply it toward developing a series of provocative and testable hypotheses to explain how PRRSV immunomodulates the porcine immune system with the goal of adding new perspectives on this disease.

Antibody repertoire development in fetal and neonatal piglets. XIV. Highly restricted IGKV gene usage parallels the pattern seen with IGLV and IGHV.

Kappa transcripts from fetal piglets were compared to the recently reported kappa genome. Although five IGKV gene families are present in the genome, only IGKV1 and IGKV2 family genes are transcribed; the latter comprises >95% of the repertoire, in which two genes account for ~80%. We provisionally identified a new sequence allele of IGKV2-10 and two new IGKV genes that were not present in the genome of a single Duroc sow. One of these (IGKV2-1) accounted for 39% of the total pre-immune repertoire. The discovery of new IGKV genes and alleles in only 90 transcripts from mixed breeds, suggests considerable polymorphism and polygeny in the kappa locus of swine. Similar to lambda rearrangements, CDR3 length and diversity is restricted. The somatic mutation frequency is low and accumulates in especially CDR1. This transcriptional analysis of the pre-immune kappa repertoire completes a comparative study of all three Ig loci which has allowed the potential and actual combinatorial repertoire to be determined. Calculations show that combinatorial diversity in all three loci contribute comparatively little to the swine pre-immune antibody repertoire. Compared to humans that can potentially generate a million binding site variants, only 16-48 variant comprise 70% of the swine repertoire and 224 account for 95-100%. The frequency of somatic mutation does not differ among rearrangements from all three loci and the CDR3 diversity index shows that swine overwhelmingly generate their pre-immune repertoire by junctional diversity in heavy chain rearrangements.

Resolution of an immunodiagnostic dilemma: heavy chain chimeric antibodies for species in which plasmocytomas are unknown.

The immunoglobulin (Ig) genes of many vertebrates have been characterized but IgG subclasses, IgD and IgE proteins are only available for three species in which plasmacytomas occur. This creates a major problem in the production and specificity verification of diagnostic anti-Ig reagents for the vast majority of mammals. We describe a novel solution using the swine system with its eleven different variants of IgG. It involves the in vitro synthesis of chimeric porcine-camelid heavy chain antibodies (HCAbs) that do not require light chains and therefore only a single transfection vector. The expressed chimeric HCAbs are comprised of the camelid VHH domain encoding specificity for lysozyme and the hinge, CH2 and CH3 domains of the various porcine IgGs. These HCAb retain their antigenic integrity and their ability to recognize lysozyme. The engineered specificity assures that these HCAb can be immobilized in native configuration when used for testing the specificity of anti-swine IgG antibodies. Comparative data to illustrate the importance of this point are provided. These are now available for use in hybridoma selection and as reference standards for evaluating the specificity of currently available anti-swine IgG antibodies.

Cathodoluminescence of natural, plastically deformed pink diamonds.

The 49 type I natural pink diamonds examined exhibit color restricted to lamellae or bands oriented along {111} that are created by plastic deformation. Pink diamonds fall into two groups: (1) diamonds from Argyle in Australia and Santa Elena in Venezuela are heavily strained throughout and exhibit pink bands alternating with colorless areas, and (2) diamonds from other localities have strain localized near the discrete pink lamellae. Growth zones are highlighted by a blue cathodoluminescence (CL) and crosscut by the pink lamellae that emit yellowish-green CL that originates from the H3 center. This center probably forms by the recombination of nitrogen-related centers (A-aggregates) and vacancies mobilized by natural annealing in the Earth's mantle. Twinning is the most likely mechanism through which plastic deformation is accommodated for the two groups of diamonds. The plastic deformation creates new centers visible through spectroscopic methods, including the one responsible for the pink color, which remains unidentified. The differences in the plastic deformation features, and resulting CL properties, for the two groups might correlate to the particular geologic conditions under which the diamonds formed; those from Argyle and Santa Elena are deposits located within Proterozoic cratons, whereas most diamonds originate from Archean cratons.

Antibody repertoire development in fetal and neonatal piglets. XXIII: fetal piglets infected with a vaccine strain of PRRS Virus display the same immune dysregulation seen in isolator piglets.

The Ig levels and antibody repertoire diversification in fetal piglets infected with an attenuated Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) were measured. Serum Ig levels were greatly elevated in PRRSV-infected fetuses; IgG was elevated >50-fold, IgM>5-15-fold and IgA>2-fold compared to control fetuses. Their IgM to IgG to IgA profile was the same as that in isolator piglets infected for the same period with wild-type PRRSV. Fetal animals showed less repertoire diversification than even isolator piglets that were maintained germfree (GF) while the repertoire diversification index (RDI) for PRRSV-infected isolator piglets was 10-fold higher and comparable to littermates infected with swine influenza (S-FLU). However, when expressed as the RDI:Ig ratio, infected fetuses appeared 10-fold less capable of repertoire diversification than uninfected littermates and GF isolator piglets. Compared to S-FLU isolator piglets that resolve the infection, the RDI:Ig of PRRSV-infected isolator piglets was 100-fold lower. Overall, infection of fetuses with an attenuated virus shows the same immune dysregulation seen postnatally in wild type infected isolator piglets, indicating that: (a) attenuation did not alter the ability of the virus to cause dysregulation and (b) the isolator infectious model reflects the fetal disease.

Linkage haplotype for allotypic variants of porcine IgA and IgG subclass genes.

Six putative subclasses of expressed porcine IgG have been described from gene sequences and allotypic variants for five of these have been proposed. We tested this hypothesis by studying the transcription of these 11 variants in outbred hemizygous farm pigs. Since Cγ subclass genes are closely linked, they are most likely inherited as a haplotype. Since hemizygous pigs can only express genes encoded on one chromosome, identifying the expressed genes can indicate which allelic variants are linked as well as testing whether the putative alleles are indeed alleles or separate subclass genes. The procedure for producing B cell knockout pigs has recently been described; our study examines transcripts from the hemizygous parents and offspring generated by this technology. More than 570 Cγ gene clones from hemizygous animals were identified according to subclass and allotype by a combination of clone hybridization and sequencing. IgG3 accounted for 80% in newborn animals but <5% in adults. IgG1 accounted for ~50% of all clones recovered from adults and IgG4 was the least frequently recovered (4%). Results indicate that IgG1(b), IgG2(a), IgG3, IgG4(a), IgG5(a), and IgG6(a) are linked and also linked to IgA(a). This comprises a haplotype for domesticated swine. For simplicity, we propose that the current nomenclature for the allotypes of IgG1 be reversed so that all genes in the Cγ(a)-Cα(a) haplotype are designated "a".

Leukogram abnormalities in gnotobiotic pigs infected with porcine circovirus type 2.

Porcine circovirus type 2 (PCV2) is a single-stranded circular DNA virus that is the causative agent of porcine circovirus associated disease (PCVAD), a disease complex affecting swine around the world. Although this virus is believed to negatively affect the host's immune system, the mechanism by which PCV2 induces disease is not completely understood. This report describes a series of PCV2 experiments using the gnotobiotic pig model in which a relationship was demonstrated between abnormal leukograms and development of clinical disease in PCV2-infected pigs. When compared to control pigs the leukogram was characterized by a decrease in lymphocytes within 14 days post inoculation (dpi) followed by an increase in neutrophils 7-14 days later. No significant changes in the circulating monocyte, basophil, and eosinophil cell populations were detected. The combination of an absolute neutrophilia and lymphopenia produced a neutrophil/lymphocyte ratio that was predictive of clinical disease and was inversely correlated with the presence of neutralizing antibodies. Based on previous reports, the lymphopenia may be attributed to a direct cytolytic effect of the virus and could negatively affect the pig's immune response. The role of the neutrophilia in the pathogenesis of PCVAD in gnotobiotic pigs is unknown.

Note: Laser ablation technique for electrically contacting a buried implant layer in single crystal diamond.

The creation of thin, buried, and electrically conducting layers within an otherwise insulating diamond by annealed ion implantation damage is well known. Establishing facile electrical contact to the shallow buried layer has been an unmet challenge. We demonstrate a new method, based on laser micro-machining (laser ablation), to make reliable electrical contact to a buried implant layer in diamond. Comparison is made to focused ion beam milling.

Movement of the human upper airway during inspiration with and without inspiratory resistive loading.

The electromyographic (EMG) activity of human upper airway muscles, particularly the genioglossus, has been widely measured, but the relationship between EMG activity and physical movement of the airway muscles remains unclear. We aimed to measure the motion of the soft tissues surrounding the airway during normal and loaded inspiration on the basis of the hypothesis that this motion would be affected by the addition of resistance to breathing during inspiration. Tagged MR imaging of seven healthy subjects was performed in a 3-T scanner. Tagged 8.6-mm-spaced grids were used, and complementary spatial modulation of magnetization images were acquired beginning ∼200 ms before inspiratory airflow. Deformation of tag line intersections was measured. The genioglossus moved anteriorly during normal and loaded inspiration, with less movement during loaded inspiration. The motion of tissues at the anterior border of the upper airway was nonuniform, with larger motions inferiorly. At the level of the soft palate, the lateral dimension of the airway decreased significantly during loaded inspiration (-0.15 ± 0.09 and -0.48 ± 0.09 mm during unloaded and loaded inspiration, respectively, P < 0.05). When resistance to inspiratory flow was added, genioglossus motion and lateral dimensions of the airway at the level of the soft palate decreased. Our results suggest that genioglossus motion begins early to dilate the airway prior to airflow and that inspiratory loading reduces the anterior motion of the genioglossus and increases the collapse of the lateral airway walls at the level of the soft palate.

Voluntary and involuntary ventilation do not alter the human inspiratory muscle loading reflex.

The reflex mechanism of the short-latency inhibitory reflex to transient loading of human inspiratory muscles is unresolved. Muscle afferents mediate this reflex, but they may act via pontomedullary inspiratory centers, other bulbar networks, or spinal circuits. We hypothesized that altered chemical drive to breathe would alter the initial inhibitory reflex if the neural pathways involve inspiratory medullary centers. Inspiration was transiently loaded in 11 subjects during spontaneous hypercapnic hyperpnea and matched voluntary hyperventilation. Electromyographic activity was recorded bilaterally from scalene muscles with surface electrodes. The latencies of the initial inhibitory response (IR) onset (32 +/- 0.7 and 38 +/- 1 ms for spontaneous and voluntary conditions respectively, P < 0.001) and subsequent excitatory response (ER) onset (80 +/- 2.9 and 78 +/- 2.6 ms, respectively, P = 0.46) and the normalized sizes of IR (65 +/- 2 and 67 +/- 3%, respectively, P = 0.50) and ER (51 +/- 8 and 69 +/- 6%, respectively, P = 0.005) were measured. Mean end-tidal Pco(2) was 43 +/- 1.5 Torr with dead space ventilation and was 14 +/- 0.6 Torr with matched voluntary hyperventilation (P < 0.001). A mean minute volume >30 liters was achieved in both conditions. The absence of significant difference in the size of the IR suggested that the IR reflex arc does not transit the brain stem inspiratory centers and that the reflex may be integrated at a spinal level. In voluntary hyperventilation, an initial excitation occurred more frequently and, consequently, the IR onset latency was significantly longer. The size of the later ER was also greater during voluntary hyperventilation, which is consistent with it being mediated via longer, presumably cortical, pathways, which are influenced by voluntary drive.