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Neuronal nitric oxide synthase gene transfer promotes cardiac vagal gain of function.
Nitric oxide (NO) generated from neuronal nitric oxide synthase (NOS-1) in intrinsic cardiac ganglia has been implicated in parasympathetic-induced bradycardia. We provide direct evidence that NOS-1 acts in a site-specific manner to promote cardiac vagal neurotransmission and bradycardia. NOS-1 gene transfer to the guinea pig right atrium increased protein expression and NOS-1 immunolocalization in cholinergic ganglia. It also increased the release of acetylcholine and enhanced the heart rate (HR) response to vagal nerve stimulation (VNS) in vitro and in vivo. NOS inhibition normalized the HR response to VNS in the NOS-1-treated group compared with the control groups (enhanced green fluorescent protein and sham) in vitro. In contrast, an acetylcholine analogue reduced HR to the same extent in all groups before and during NOS inhibition. These results demonstrate that NOS-1-derived NO acts presynaptically to facilitate vagally induced bradycardia and that upregulation of NOS-1 via gene transfer may provide a novel method for increasing cardiac vagal function.
Imaging electrocardiographic dispersion of depolarization and repolarization during ischemia: simultaneous body surface and epicardial mapping.
BACKGROUND: Myocardial ischemia creates abnormal electrophysiological substrates that result in life-threatening ventricular arrhythmias. Identifying patients at risk of such abnormalities by use of body surface electrical measures is controversial. We investigated the sensitivity of torso measures, recorded simultaneously with epicardial electrograms, to changes in dispersion of depolarization and repolarization during localized ventricular ischemia. METHODS AND RESULTS: Ventricular epicardial electrograms were recorded from 5 anesthetized pigs with a 127-electrode sock. A controllable suture snare was used to ligate the left anterior descending coronary artery (LAD). The chest was reclosed, and a vest with 256 ECG electrodes was fitted to the torso. Simultaneous arrays of epicardial electrograms and torso ECGs were recorded during LAD occlusion and reperfusion. Activation-recovery intervals (ARIs), QTu and RTu dispersion (where u indicates upstroke), and QRST integrals were calculated, and these data were fitted to anatomically customized computational models of the swine ventricular epicardium and torso. LAD occlusion caused the epicardial ARI dispersion to steadily increase, whereas the location of shortest ARI shifted from the posterobasal ventricular tissue (control) to the anteroapical myocardium, distal to the suture snare. These changes were associated with a steady increase in the torso RTu dispersion as the shortest RTu interval moved from the right shoulder (control) to the sternum. QTu and RTu dispersion determined from the 12-lead ECG did not consistently reflect the myocardial changes. CONCLUSIONS: Although changes in myocardial repolarization dispersion resulting from localized ischemia are not reliably reflected in temporal indices derived from the 12-lead ECG, they can be readily identified with high-resolution torso ECG mapping.
Disruption of inhibitory G-proteins mediates a reduction in atrial beta-adrenergic signaling by enhancing eNOS expression.
OBJECTIVE: Cardiac parasympathetic nerve activity is reduced in most cardiovascular disease states, and this may contribute to enhanced cardiac sympathetic responsiveness. Disruption of inhibitory G-proteins (Gi) ablates the cholinergic pathway and increases cardiac endothelial nitric oxide (NO) synthase (eNOS) expression, suggesting that NO may offset the impaired attenuation of beta-adrenergic regulation of supraventricular excitability. To test this, we investigated the role of endogenous NO production on beta-adrenergic regulation of rate (HR), contraction (CR) and calcium (Ca2+) handling in atria following blockade of Gi-coupled muscarinic receptors. METHODS: Mice were administered pertussis toxin (PTx, n=105) or saline (C, n=100) intraperitoneally. After 3 days, we measured CR, HR, and NOS protein levels in isolated atria. Intracellular calcium (Ca2+) transients and Ca2+ current density (I(Ca)) were also measured in atrial myocytes. RESULTS: PTx treatment increased atrial myocyte eNOS protein levels compared to C (P<0.05). This did not affect basal atrial function but was associated with a significant reduction in the CR and HR response to isoprenaline (ISO) compared with C. NOS inhibition normalized responses in PTx atria with respect to responses in C atria (P<0.05), which were unaffected. Furthermore, PTx did not affect ISO-stimulated HR and CR in eNOS gene knockout mice (n=40). In agreement with these findings, the ISO-mediated increase in Ca2+ transient was suppressed in PTx-treated myocytes (P<0.05), whereas I(Ca) did not differ between groups. CONCLUSION: eNOS-derived NO inhibits beta-adrenergic responses following disruption of Gi signaling. This suggests that increased eNOS expression may be a compensatory mechanism which reduces beta-adrenergic regulation of heart rate when cardiac parasympathetic control is impaired.
Impaired regulation of neuronal nitric oxide synthase and heart rate during exercise in mice lacking one nNOS allele.
We tested the hypothesis that a single allele deletion of neuronal nitric oxide synthase (nNOS) would impair the neural control of heart rate following physical training, and that this phenotype could be restored following targeted gene transfer of nNOS. Voluntary wheel-running (+EX) in heterozygous nNOS knockout mice (nNOS(+/-), +EX; n= 52; peak performance 9.1 +/- 1.8 km day(-1)) was undertaken and compared to wild-type mice (n= 38; 9.5 +/- 0.8 km day(-1)). In anaesthetized wild-type mice, exercise increased phenylephrine-induced bradycardia by 67% (measured as heart rate change, in beats per minute, divided by the change in arterial blood pressure, in mmHg) or pulse interval response to phenylephrine by 52% (measured as interbeat interval change, in milliseconds, divided by the change in blood pressure). Heart rate changes or interbeat interval changes in response to right vagal nerve stimulation were also enhanced by exercise in wild-type atria (P < 0.05), whereas both in vivo and in vitro responses to exercise were absent in nNOS(+/-) mice. nNOS inhibition attenuated heart rate responses to vagal nerve stimulation in all atria (P < 0.05) and normalized the responses in wild-type, +EX with respect to wild-type with no exercise (-EX) atria. Atrial nNOS mRNA and protein were increased in wild-type, +EX compared to wild-type, -EX (P < 0.05), although exercise failed to have any effect in nNOS(+/-) atria. In vivo nNOS gene transfer using adenoviruses targeted to atrial ganglia enhanced choline acetyltransferase-nNOS co-localization (P < 0.05) and increased phenylephrine-induced bradycardia in vivo and heart rate responses to vagal nerve stimulation in vitro compared to gene transfer of enhanced green fluorescent protein (eGFP, P < 0.01). This difference was abolished by nNOS inhibition (P < 0.05). In conclusion, genomic regulation of NO bioavailability from nNOS in cardiac autonomic ganglia in response to training is dependent on both alleles of the gene. Although basal expression of nNOS is normal, polymorphisms of nNOS may interfere with neural regulation of heart rate following training. Targeted gene transfer of nNOS can restore this impairment.
Enhanced neuronal nitric oxide synthase expression is central to cardiac vagal phenotype in exercise-trained mice.
We investigated whether enhanced cardiac vagal responsiveness elicited by exercise training is dependent on neuronal nitric oxide synthase (NOS-1), since the NO-cGMP pathway facilitates acetylcholine release. Isolated atria with intact right vagal innervation were taken from male mice (18-22 weeks old) after a period of 10 weeks voluntary wheel-running (+EX, n = 27; peaked 9.8 +/- 0.6 km day(-1) at 5 weeks), and from mice housed in cages without wheels (-EX, n = 27). Immunostaining of whole atria for NOS-1 identified intrinsic neurones, all of which co-localized with choline acetyltransferase-positive ganglia. Western blot analysis confirmed that NOS-1 protein level was significantly greater in +EX compared to -EX atria (P < 0.05, unpaired t test). Basal heart rates (HR) were slower in +EX than in -EX atria (322 +/- 6 versus 360 +/- 7 beats min(-1); P < 0.05, unpaired t test) However, in +EX atria, HR responses to vagal stimulation (VNS, 3 and 5 Hz) were significantly enhanced compared to -EX atria (3 Hz, +EX: -76 +/- 8 beats min(-1) versus -EX: -62 +/- 7 beats min(-1); 5 Hz, +EX: -106 +/- 4 beats min(-1) versus -EX: -93 +/- 3 beats min(-1); P < 0.01, unpaired t test). Inhibition of NOS-1 with vinyl-L-N-5-(1-imino-3-butenyl)-L-ornithine (L-VNIO, 100 microM) or soluble guanylyl cyclase with 1H-[1, 2, 4]oxadiazolo[4, 3-a]quinoxalin-1-one (ODQ, 10 microM) abolished the difference in HR responses to VNS between +EX and -EX atria, and effects of L-VNIO were reversed by excess L-arginine (1 mM; P < 0.01, ANOVA). There were no differences between the HR responses to the bath-applied acetylcholine analogue carbamylcholine chloride in +EX and -EX atria (IC(50) concentrations were 5.9 +/- 0.4 microM (-EX) and 5.7 +/- 0.4 microM (+EX)), suggesting that the changes in vagal responsiveness resulted from presynaptic facilitation of neurotransmission. In conclusion, NOS-1 appears to be a key protein in generating the cardiac vagal gain of function elicited by exercise training.
The cardiac sympathetic co-transmitter neuropeptide Y is pro-arrhythmic following ST-elevation myocardial infarction despite beta-blockade.
AIMS: ST-elevation myocardial infarction is associated with high levels of cardiac sympathetic drive and release of the co-transmitter neuropeptide Y (NPY). We hypothesized that despite beta-blockade, NPY promotes arrhythmogenesis via ventricular myocyte receptors. METHODS AND RESULTS: In 78 patients treated with primary percutaneous coronary intervention, sustained ventricular tachycardia (VT) or fibrillation (VF) occurred in 6 (7.7%) within 48 h. These patients had significantly (P
Nitric oxide modulates cardiomyocyte pH control through a biphasic effect on sodium/hydrogen exchanger-1.
AIMS: When activated, Na+/H+ exchanger-1 (NHE1) produces some of the largest ionic fluxes in the heart. NHE1-dependent H+ extrusion and Na+ entry strongly modulate cardiac physiology through the direct effects of pH on proteins and by influencing intracellular Ca2+ handling. To attain an appropriate level of activation, cardiac NHE1 must respond to myocyte-derived cues. Among physiologically important cues is nitric oxide (NO), which regulates a myriad of cardiac functions, but its actions on NHE1 are unclear. METHODS AND RESULTS: NHE1 activity was measured using pH-sensitive cSNARF1 fluorescence after acid-loading adult ventricular myocytes by an ammonium prepulse solution manoeuvre. NO signalling was manipulated by knockout of its major constitutive synthase nNOS, adenoviral nNOS gene delivery, nNOS inhibition, and application of NO-donors. NHE1 flux was found to be activated by low [NO], but inhibited at high [NO]. These responses involved cGMP-dependent signalling, rather than S-nitros(yl)ation. Stronger cGMP signals, that can inhibit phosphodiesterase enzymes, allowed [cAMP] to rise, as demonstrated by a FRET-based sensor. Inferring from the actions of membrane-permeant analogues, cGMP was determined to activate NHE1, whereas cAMP was inhibitory, which explains the biphasic regulation by NO. Activation of NHE1-dependent Na+ influx by low [NO] also increased the frequency of spontaneous Ca2+ waves, whereas high [NO] suppressed these aberrant forms of Ca2+ signalling. CONCLUSIONS: Physiological levels of NO stimulation increase NHE1 activity, which boosts pH control during acid-disturbances and results in Na+-driven cellular Ca2+ loading. These responses are positively inotropic but also increase the likelihood of aberrant Ca2+ signals, and hence arrhythmia. Stronger NO signals inhibit NHE1, leading to a reversal of the aforementioned effects, ostensibly as a potential cardioprotective intervention to curtail NHE1 overdrive.
Mammalian γ2 AMPK regulates intrinsic heart rate.
AMPK is a conserved serine/threonine kinase whose activity maintains cellular energy homeostasis. Eukaryotic AMPK exists as αβγ complexes, whose regulatory γ subunit confers energy sensor function by binding adenine nucleotides. Humans bearing activating mutations in the γ2 subunit exhibit a phenotype including unexplained slowing of heart rate (bradycardia). Here, we show that γ2 AMPK activation downregulates fundamental sinoatrial cell pacemaker mechanisms to lower heart rate, including sarcolemmal hyperpolarization-activated current (I f) and ryanodine receptor-derived diastolic local subsarcolemmal Ca2+ release. In contrast, loss of γ2 AMPK induces a reciprocal phenotype of increased heart rate, and prevents the adaptive intrinsic bradycardia of endurance training. Our results reveal that in mammals, for which heart rate is a key determinant of cardiac energy demand, AMPK functions in an organ-specific manner to maintain cardiac energy homeostasis and determines cardiac physiological adaptation to exercise by modulating intrinsic sinoatrial cell behavior.
Controlling the lungs via the brain: a novel neurosurgical method to improve lung function in humans.
Deep brain stimulation (DBS) of subcortical brain areas such as the periaqueductal grey and subthalamic nucleus has been shown to alter cardiovascular autonomic performance. The supramedullary circuitry controlling respiratory airways is not well defined and has not been tested in humans. To use direct electric stimulation via DBS macroelectrodes to test whether airway resistance could be manipulated by these areas in awake humans. Thirty-seven patients with in-dwelling deep brain electrodes for movement disorders or chronic pain underwent spirometry according to the European Respiratory Society guidelines. Testing was performed randomly 3 times on stimulation and 3 times off stimulation; patients were blinded to the test. Thoracic diameter changes were measured by a circumferential pressure-sensitive thoracic band. Ten periaqueductal grey and 10 subthalamic nucleus patients were tested. To control for confounding pain and movement disorder relief, the sensory thalamus in 7 patients and globus pallidus interna in 10 patients, respectively, were also tested. Peak expiratory flow rate (PEFR) increased significantly with periaqueductal grey and subthalamic nucleus stimulation by up to 14% (P = .02 and .005, respectively, paired-samples Student t tests). Stimulation of control nuclei produced no significant PEFR change. Similarly, changes in thoracic diameter reflecting skeletal activity rather than airway caliber did not correlate with the improvement in PEFR. Forced expiratory volume in 1 second was unchanged by stimulation. DBS can improve PEFR in chronic pain and movement disorder patients. This finding provides insights into the neural modulation of respiratory performance and may explain some of the subjective benefits of DBS.
Phosphodiesterase 2A as a therapeutic target to restore cardiac neurotransmission during sympathetic hyperactivity.
Elevated levels of brain natriuretic peptide (BNP) are regarded as an early compensatory response to cardiac myocyte hypertrophy, although exogenously administered BNP shows poor clinical efficacy in heart failure and hypertension. We tested whether phosphodiesterase 2A (PDE2A), which regulates the action of BNP-activated cyclic guanosine monophosphate (cGMP), was directly involved in modulating Ca2+ handling from stellate ganglia (SG) neurons and cardiac norepinephrine (NE) release in rats and humans with an enhanced sympathetic phenotype. SG were also isolated from patients with sympathetic hyperactivity and healthy donor patients. PDE2A activity of the SG was greater in both spontaneously hypertensive rats (SHRs) and patients compared with their respective controls, whereas PDE2A mRNA was only high in SHR SG. BNP significantly reduced the magnitude of the calcium transients and ICaN in normal Wistar Kyoto (WKY) SG neurons, but not in the SHRs. cGMP levels stimulated by BNP were also attenuated in SHR SG neurons. Overexpression of PDE2A in WKY neurons recapitulated the calcium phenotype seen in SHR neurons. Functionally, BNP significantly reduced [3H]-NE release in the WKY rats, but not in the SHRs. Blockade of overexpressed PDE2A with Bay 60-7550 or overexpression of catalytically inactive PDE2A reestablished the modulatory action of BNP in SHR SG neurons. This suggests that PDE2A may be a key target in modulating the action of BNP to reduce sympathetic hyperactivity.
RNA Sequencing Reveals Novel Transcripts from Sympathetic Stellate Ganglia During Cardiac Sympathetic Hyperactivity.
Cardiovascular disease is the most prevalent age-related illness worldwide, causing approximately 15 million deaths every year. Hypertension is central in determining cardiovascular risk and is a strong predictive indicator of morbidity and mortality; however, there remains an unmet clinical need for disease-modifying and prophylactic interventions. Enhanced sympathetic activity is a well-established contributor to the pathophysiology of hypertension, however the cellular and molecular changes that increase sympathetic neurotransmission are not known. The aim of this study was to identify key changes in the transcriptome in normotensive and spontaneously hypertensive rats. We validated 15 of our top-scoring genes using qRT-PCR, and network and enrichment analyses suggest that glutamatergic signalling plays a key role in modulating Ca2+ balance within these ganglia. Additionally, phosphodiesterase activity was found to be altered in stellates obtained from the hypertensive rat, suggesting that impaired cyclic nucleotide signalling may contribute to disturbed Ca2+ homeostasis and sympathetic hyperactivity in hypertension. We have also confirmed the presence of these transcripts in human donor stellate samples, suggesting that key genes coupled to neurotransmission are conserved. The data described here may provide novel targets for future interventions aimed at treating sympathetic hyperactivity associated with cardiovascular disease and other dysautonomias.
The cardiac sympathetic co-transmitter galanin reduces acetylcholine release and vagal bradycardia: Implications for neural control of cardiac excitability
The autonomic phenotype of congestive cardiac failure is characterised by high sympathetic drive and impaired vagal tone, which are independent predictors of mortality. We hypothesize that impaired bradycardia to peripheral vagal stimulation following high-level sympathetic drive is due to sympatho-vagal crosstalk by the adrenergic co-transmitters galanin and neuropeptide-Y (NPY). Moreover we hypothesize that galanin acts similarly to NPY by reducing vagal acetylcholine release via a receptor mediated, protein kinase-dependent pathway. Prolonged right stellate ganglion stimulation (10Hz, 2min, in the presence of 10μM metoprolol) in an isolated guinea pig atrial preparation with dual autonomic innervation leads to a significant (p<0.05) reduction in the magnitude of vagal bradycardia (5Hz) maintained over the subsequent 20min (n=6). Immunohistochemistry demonstrated the presence of galanin in a small number of tyrosine hydroxylase positive neurons from freshly dissected stellate ganglion tissue sections. Following 3days of tissue culture however, most stellate neurons expressed galanin. Stellate stimulation caused the release of low levels of galanin and significantly higher levels of NPY into the surrounding perfusate (n=6, using ELISA). The reduction in vagal bradycardia post sympathetic stimulation was partially reversed by the galanin receptor antagonist M40 after 10min (1μM, n=5), and completely reversed with the NPY Y 2 receptor antagonist BIIE 0246 at all time points (1μM, n=6). Exogenous galanin (n=6, 50-500nM) also reduced the heart rate response to vagal stimulation but had no effect on the response to carbamylcholine that produced similar degrees of bradycardia (n=6). Galanin (500nM) also significantly attenuated the release of 3H-acetylcholine from isolated atria during field stimulation (5Hz, n=5). The effect of galanin on vagal bradycardia could be abolished by the galanin receptor antagonist M40 (n=5). Importantly the GalR 1 receptor was immunofluorescently co-localised with choline acetyl-transferase containing neurons at the sinoatrial node. The protein kinase C inhibitor calphostin (100nM, n=6) abolished the effect of galanin on vagal bradycardia whilst the protein kinase A inhibitor H89 (500nM, n=6) had no effect. These results demonstrate that prolonged sympathetic activation releases the slowly diffusing adrenergic co-transmitter galanin in addition to NPY, and that this contributes to the attenuation in vagal bradycardia via a reduction in acetylcholine release. This effect is mediated by GalR 1 receptors on vagal neurons coupled to protein kinase C dependent signalling pathways. The role of galanin may become more important following an acute injury response where galanin expression is increased. © 2011 Elsevier Ltd.
Pravastatin normalises peripheral cardiac sympathetic hyperactivity in the spontaneously hypertensive rat
Hypertension is associated with heightened cardiac sympathetic drive whilst statins reduce angiotensin II (ATII) signalling, superoxide anion production and increase nitric oxide bioavailability, events that can potentially reduce peripheral cardiac sympathetic neurotransmission. We therefore investigated whether pravastatin alters peripheral cardiac sympathetic control in the spontaneously hypertensive rat (SHR). SHRs (16-18weeks) had significantly (p<0.05) enhanced atrial 3H-norepinephrine (3H-NE) release to field stimulation compared to normotensive WKYs. 2-week pravastatin supplementation significantly reduced 3H-NE release to levels observed in the WKY. In-vivo, pravastatin lowered resting heart rate (HR) in the SHR despite not affecting arterial blood pressure or serum cholesterol. In SHR atria/right stellate ganglion preparations, the HR response to stellate stimulation (1, 3, and 5Hz) was also significantly reduced by pravastatin whilst the HR response to exogenous NE (0.025-5μmol) remained similar. The nitric oxide synthase (NOS) inhibitor l-NAME (1mmol/l) increased 3H-NE release by similar amounts in atria from supplemented and non-supplemented SHRs, whilst Western blotting showed no difference in protein levels of nNOS, eNOS, guanylyl cyclase, or the NADPH oxidase subunits Gp91 and P40phox. Pravastatin significantly reduced cardiac ATII levels and angiotensin converting enzyme 1 and 2 expressions whilst protein levels of the ATII receptor (ATR1) remained unchanged in the SHR. Immunohistochemistry co-localised ATR1 with tyrosine hydroxylase positive neurons in the stellate ganglion. The ATR1 antagonist Losartan (5μmol) equalised release of 3H-NE to comparable levels in supplemented and non-supplemented SHRs. These results suggest 2-week pravastatin treatment reduces cardiac ATII, and prevents its facilitatory effect on NE release thus normalising cardiac sympathetic hyper-responsiveness in SHRs. © 2010 Elsevier Ltd.
Nitric oxide-cGMP pathway facilitates acetylcholine release and bradycardia during vagal nerve stimulation in the guinea-pig in vitro.
1. We tested the hypothesis that nitric oxide (NO) augments vagal neurotransmission and bradycardia via phosphorylation of presynaptic calcium channels to increase vesicular release of acetylcholine. 2. The effects of enzyme inhibitors and calcium channel blockers on the actions of the NO donor sodium nitroprusside (SNP) were evaluated in isolated guinea-pig atrial-right vagal nerve preparations. 3. SNP (10 microM) augmented the heart rate response to vagal nerve stimulation but not to the acetylcholine analogue carbamylcholine (100 nM). SNP also increased the release of [3H]acetylcholine in response to field stimulation. No effect of SNP was observed on either the release of [3H] acetylcholine or the HR response to vagal nerve stimulation in the presence of the guanylyl cyclase inhibitor 1H-(1,2,4)-oxadiazolo-(4,3-a)-quinoxalin-1-one (ODQ, 10 microM). 4. The phosphodiesterase 3 (PDE 3) inhibitor milrinone (1 microM) increased the release of [3H] acetylcholine and the vagal bradycardia and prevented any further increase by SNP. SNP was still able to augment the vagal bradycardia in the presence of the protein kinase G inhibitor KT5823 (1 microM) but not after protein kinase A (PKA) inhibition with H-89 (0.5 microM) or KT5720 (1 microM) had reduced the HR response to vagal nerve stimulation. Neither milrinone nor H-89 changed the HR response to carbamylcholine. 5. SNP had no effect on the magnitude of the vagal bradycardia after inhibition of N-type calcium channels with omega-conotoxin GVIA (100 nM). 6. These results suggests that NO acts presynaptically to facilitate vagal neurotransmission via a cGMP-PDE 3-dependent pathway leading to an increase in cAMP-PKA-dependent phosphorylation of presynaptic N-type calcium channels. This pathway may augment the HR response to vagal nerve stimulation by increasing presynaptic calcium influx and vesicular release of acetylcholine.
Deep brain stimulation can regulate arterial blood pressure in awake humans.
The periaqueductal grey matter is known to play a role in cardiovascular control in animals. Cardiovascular responses to electrical stimulation of the periventricular/periaqueductal grey matter were measured in 15 awake human study participants following implantation of deep brain stimulating electrodes for treatment of chronic pain. We found that stimulation of the ventral periventricular/periaqueductal grey matter caused a mean reduction in systolic blood pressure of 14.2+/-3.6 mmHg in seven patients and stimulation of the dorsal periventricular/periaqueductal grey matter caused a mean increase of 16.7+/-5.9 mmHg in six patients. A comparison between ventral and dorsal electrodes demonstrated significant differences (P<0.05). These changes were accompanied by analogous changes in diastolic blood pressure, pulse pressure, maximum dP/dt but not in the time interval between each R wave on the electrocardiogram.
Depiction of the neuroscientific principles of human motion 2 millennia ago by Lucretius.
Titus Lucretius Carus was an ancient Roman philosopher of the Epicurean school whose epic poem On the Nature of Things described numerous aspects of the natural world. In fact, much contemporary scientific understanding is consistent with or inspired by his work. Among Lucretius's contributions to neurology were his descriptions of epileptic seizures, sleep, and his theory of vision. This report identifies how Lucretius's description of human motion recognized the fundamental principles understood by contemporary neurologists and neuroscientists, namely the importance of the mind and intelligence in determining whether to move, in the initiation of motion and its effect on the rest of the body; the importance of mental imagery and perception of the motor task's nature and workload in addition to the necessary systemic changes occurring in parallel with the muscle activity. Lucretius was the first commentator to introduce into Epicurean poetry the concept of such a mechanism consisting of a logical order of processes which are still consistent with modern concepts.