I n 1628, William Harvey hinted at a link between the brain and the heart when he wrote, "For every affection of the mind that is attended with either pain or pleasure, hope or fear, is the cause of an agitation whose influence extends to the heart."1 For the past half century, numerous anatomic and physiological studies of cardiac autonomic nervous system (ANS) 2-6 have investigated this link and found it to be very complex. Autonomic activation alters not only heart rate, conduction, and hemodynamics, but also cellular and subcellular properties of individual myocytes. The characterization of extrinsic cardiac ANS and intrinsic cardiac ANS ranges from the recognition of anatomic relationships at the gross level to discovery of chemoreceptors, mechanoreceptors, and intracardiac ganglia lining specific regions along the cardiac chambers and great vessels. Moreover, studies beginning >80 years ago [7][8][9] have demonstrated the critical role of cardiac ANS in cardiac arrhythmogenesis. This topic has garnered much recent interest because of mounting evidence showing that neural modulation either by ablation or stimulation can effectively control a wide spectrum of cardiac arrhythmias. [10][11][12][13] In this review, we will briefly discuss the anatomic aspects of cardiac ANS, focusing on how autonomic activities influence cardiac electrophysiology. We will also discuss specific autonomic triggers of various cardiac arrhythmias, including atrial fibrillation (AF), ventricular arrhythmias, and inherited arrhythmia syndromes. Lastly, we will discuss the latest avenues of research and clinical trials regarding the application of neural modulation in the treatment of specific cardiac arrhythmias.

Prospective studies of infants at risk for autism spectrum disorder have provided important clues about the early behavioural symptoms of autism spectrum disorder. Diagnosis of autism spectrum disorder, however, is not currently made until at least 18 months of age. There is substantially less research on potential brain-based differences in the period between 6 and 12 months of age. Our objective in the current study was to use magnetic resonance imaging to identify any consistently observable brain anomalies in 6-9 month old infants who would later develop autism spectrum disorder. We conducted a prospective infant sibling study with longitudinal magnetic resonance imaging scans at three time points (6-9, 12-15, and 18-24 months of age), in conjunction with intensive behavioural assessments. Fifty-five infants (33 'high-risk' infants having an older sibling with autism spectrum disorder and 22 'low-risk' infants having no relatives with autism spectrum disorder) were imaged at 6-9 months; 43 of these (27 high-risk and 16 low-risk) were imaged at 12-15 months; and 42 (26 high-risk and 16 low-risk) were imaged again at 18-24 months. Infants were classified as meeting criteria for autism spectrum disorder, other developmental delays, or typical development at 24 months or later (mean age at outcome: 32.5 months). Compared with the other two groups, infants who developed autism spectrum disorder (n = 10) had significantly greater extra-axial fluid at 6-9 months, which persisted and remained elevated at 12-15 and 18-24 months. Extra-axial fluid is characterized by excessive cerebrospinal fluid in the subarachnoid space, particularly over the frontal lobes. The amount of extra-axial fluid detected as early as 6 months was predictive of more severe autism spectrum disorder symptoms at the time of outcome. Infants who developed autism spectrum disorder also had significantly larger total cerebral volumes at both 12-15 and 18-24 months of age. This is the first magnetic resonance imaging study to prospectively evaluate brain growth trajectories from infancy in children who develop autism spectrum disorder. The presence of excessive extra-axial fluid detected as early as 6 months and the lack of resolution by 24 months is a hitherto unreported brain anomaly in infants who later develop autism spectrum disorder. This is also the first magnetic resonance imaging evidence of brain enlargement in autism before age 2. These findings raise the potential for the use of structural magnetic resonance imaging to aid in the early detection of children at risk for autism spectrum disorder or other neurodevelopmental disorders.

Rationale Fibrillation-defibrillation episodes in failing ventricles may be followed by action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (SVF). Objective We hypothesized that activation of apamin-sensitive small-conductance Ca2+-activated K+ (SK) channels are responsible for the postshock APD shortening in failing ventricles. Methods and Results A rabbit model of tachycardia-induced heart failure was used. Simultaneous optical mapping of intracellular Ca2+ and membrane potential (Vm) was performed in failing and non-failing ventricles. Three failing ventricles developed SVF (SVF group), 9 did not (no-SVF group). None of the 10 non-failing ventricles developed SVF. Increased pacing rate and duration augmented the magnitude of APD shortening. Apamin (1 μmol/L) eliminated recurrent SVF, increased postshock APD80 in SVF group from 126±5 ms to 153±4 ms (p<0.05), in no-SVF group from147±2 ms to 162±3 ms (p<0.05) but did not change of APD80 in non-failing group. Whole cell patch-clamp studies at 36°C showed that the apamin-sensitive K+ current (IKAS) density was significantly larger in the failing than in the normal ventricular epicardial myocytes, and epicardial IKAS density is significantly higher than midmyocardial and endocardial myocytes. Steady-state Ca2+ response of IKAS was leftward-shifted in the failing cells compared with the normal control cells, indicating increased Ca2+ sensitivity of IKAS in failing ventricles. The Kd was 232 ± 5 nM for failing myocytes and 553 ± 78 nM for normal myocytes (p = 0.002). Conclusions Heart failure heterogeneously increases the sensitivity of IKAS to intracellular Ca2+, leading to upregulation of IKAS, postshock APD shortening and recurrent SVF.

Background Little is known about the relationship between intrinsic cardiac nerve activity (ICNA) and spontaneous arrhythmias in ambulatory animals. Methods and Results We implanted radiotransmitters to record extrinsic cardiac nerve activity (ECNA, including stellate ganglion nerve activity, SGNA; vagal nerve activity, VNA) and ICNA (including superior left ganglionated plexi nerve activity, SLGPNA; ligament of Marshall nerve activity, LOMNA) in 6 ambulatory dogs. Intermittent rapid left atrial pacing was performed to induce paroxysmal atrial fibrillation (PAF) or atrial tachycardia (PAT). The vast majority (94%) of LOMNA were preceded or co-activated with ECNA (SGNA or VNA), whereas 6% of episodes were activated alone without concomitant SGNA or VNA. PAF and PAT were invariably (100%) preceded (<5 s) by ICNA. Most of PAT events (89%) were preceded by ICNA and sympathovagal co-activation, whereas 11% were preceded by ICNA and SGNA-only activation. Most of PAF events were preceded only by ICNA (72%); the remaining 28% by ECNA and ICNA together. Complex fractionated atrial electrograms (CFAEs) were observed during ICNA discharges that preceded the onset of PAT and PAF. Immunostaining confirmed the presence of both adrenergic and cholinergic nerve at ICNA sites. Conclusions There is a significant temporal relationship between ECNA and ICNA. However, ICNA can also activate alone. All PAT and PAF episodes were invariably preceded by ICNA. These findings suggest that ICNA (either alone or in collaboration with ECNA) is an invariable trigger of paroxysmal atrial tachyarrhythmias. ICNA might contaminate local atrial electrograms, resulting in CFAE-like activity.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social deficits and repetitive behaviors that typically emerge by 24 months of age. To develop effective early interventions that can potentially ameliorate the defining deficits of ASD and improve long-term outcomes, early detection is essential. Using prospective neuroimaging of 59 6-month-old infants with a high familial risk for ASD, we show that functional connectivity magnetic resonance imaging correctly identified which individual children would receive a research clinical best-estimate diagnosis of ASD at 24 months of age. Functional brain connections were defined in 6-month-old infants that correlated with 24-month scores on measures of social behavior, language, motor development, and repetitive behavior, which are all features common to the diagnosis of ASD. A fully cross-validated machine learning algorithm applied at age 6 months had a positive predictive value of 100% [95% confidence interval (CI), 62.9 to 100], correctly predicting 9 of 11 infants who received a diagnosis of ASD at 24 months (sensitivity, 81.8%; 95% CI, 47.8 to 96.8). All 48 6-month-old infants who were not diagnosed with ASD were correctly classified [specificity, 100% (95% CI, 90.8 to 100); negative predictive value, 96.0% (95% CI, 85.1 to 99.3)]. These findings have clinical implications for early risk assessment and the feasibility of developing early preventative interventions for ASD.

Background We hypothesize that left sided low-level vagus nerve stimulation (LL-VNS) can suppress sympathetic outflow and reduce atrial tachyarrhythmias in ambulatory dogs. Methods and Results We implanted in 12 dogs a neurostimulator to stimulate left cervical vagus nerve and a radiotransmitter for continuous recording of left stellate ganglion nerve activities (SGNA), vagal nerve activities (VNA) and electrocardiograms. Group 1 dogs (N=6) underwent 1 week continuous LL-VNS. Group 2 dogs (N=6) underwent intermittent rapid atrial pacing followed by active or sham LL-VNS on alternate weeks. Integrated SGNA was significantly reduced during LL-VNS (7.8 mV-s; 95% confidence interval [CI] 6.94 to 8.66] vs. 9.4 mV-s [CI, 8.5 to 10.3] at baseline, P=0.033) in Group 1.The reduction was most apparent at 8 AM, along with a significantly reduced heart rate (P=0.008). LL-VNS did not change VNA. The density of tyrosine hydroxylase-positive nerves in the left stellate ganglion one week after cessation of LL-VNS were 99684 µm2/mm2 (CI, 28850 to 170517) in LL-VNS dogs and 186561 µm2/ mm2 (CI, 154956 to 218166; P=0.008) in normal dogs. In Group 2, the frequencies of paroxysmal atrial fibrillation and tachycardia during active LL-VNS were 1.4/day (CI, 0.5/day to 5.1/day) and 8.0/day (CI, 5.3/day to 12.0/day), respectively, significantly lower than during sham stimulation (9.2/day [CI, 5.3/day to 13.1/day], P=0.001 and 22.0/day [CI, 19.1/day to 25.5/day], P<0.001, respectively). Conclusions LL-VNS suppresses SGNA and reduces the incidences of paroxysmal atrial tachyarrhythmias in ambulatory dogs. Significant neural remodeling of the left stellate ganglion is evident one week after cessation of chronic LL-VNS.

Background We previously reported that infants who developed ASD had increased CSF in the subarachnoid space (i.e., extra-axial CSF) from 6–24 months of age (1). We attempt to confirm and extend this finding in a larger, independent sample. Methods A longitudinal MRI study of infants at-risk for ASD was carried out on 343 infants, who underwent neuroimaging at 6, 12, and 24 months; 221 were high-risk for ASD because of an older sibling with ASD; 122 were low-risk with no family history of ASD. Forty-seven infants were diagnosed with ASD at 24 months and were compared with 174 high-risk and 122 low-risk infants without ASD. Results Infants who developed ASD had significantly greater extra-axial CSF volume at 6 months compared to both comparison groups without ASD (18% greater than high-risk infants without ASD; Cohen’s d=0.54). Extra-axial CSF volume remained elevated through 24 months (d=0.46). Infants with more severe autism symptoms had an even greater volume of extra-axial CSF from 6–24 months (24% greater at 6 months, d=0.70; 15% greater at 24 months, d=0.70). Extra-axial CSF volume at 6 months predicted which high-risk infants would be diagnosed with ASD at 24 months with an overall accuracy of 69% and corresponding 66% sensitivity and 68% specificity, which was fully cross-validated in a separate sample. Conclusions This study confirms and extends previous findings that increased extra-axial CSF is detectable at 6 months in high-risk infants who develop ASD. Future studies will address whether this anomaly is a contributing factor to the etiology of ASD or an early risk marker for ASD.

BackgroundMagnetic resonance imaging (MRI) has been widely used in studies evaluating the neuropathology of autism spectrum disorder (ASD). Studies are often limited, however, to higher functioning individuals with ASD. MRI studies of individuals with ASD and comorbid intellectual disability (ID) are lacking, due in part to the challenges of acquiring images without the use of sedation.MethodsUtilizing principles of applied behavior analysis (ABA), we developed a protocol for acquiring structural MRI scans in school-aged children with ASD and intellectual impairment. Board certified behavior analysts worked closely with each child and their parent(s), utilizing behavior change techniques such as pairing, shaping, desensitization, and positive reinforcement, through a series of mock scanner visits to prepare the child for the MRI scan. An objective, quantitative assessment of motion artifact in T1- and diffusion-weighted scans was implemented to ensure that high-quality images were acquired.ResultsThe sample consisted of 17 children with ASD who are participants in the UC Davis Autism Phenome Project, a longitudinal MRI study aimed at evaluating brain developmental trajectories from early to middle childhood. At the time of their initial scan (2–3.5 years), all 17 children had a diagnosis of ASD and development quotient (DQ) <70. At the time of the current scan (9–13 years), 13 participants continued to have IQs in the range of ID (mean IQ = 54.1, sd = 12.1), and four participants had IQs in the normal range (mean = 102.2, sd = 7.5). The success rate in acquiring T1-weighted images that met quality assurance for acceptable motion artifact was 100 %. The success rate for acquiring high-quality diffusion-weighted images was 94 %.ConclusionsBy using principles of ABA in a research MRI setting, it is feasible to acquire high-quality images in school-aged children with ASD and intellectual impairment without the use of sedation. This is especially critical to ensure that ongoing longitudinal studies of brain development can extend from infancy and early childhood into middle childhood in children with ASD at all levels of functioning, including those with comorbid ID.Electronic supplementary materialThe online version of this article (doi:10.1186/s11689-016-9154-9) contains supplementary material, which is available to authorized users.