The role of BDNF in mediating the prophylactic effects of (R,S)-ketamine on fear generalization and extinction.

Fear generalization is a conserved survival mechanism that can become maladaptive in the face of traumatic situations, a feature central to certain anxiety disorders including posttraumatic stress disorder (PTSD). However, the neural circuitry and molecular mechanisms underlying fear generalization remain unclear. Recent studies have shown that prophylactic treatment with (R,S)-ketamine confers protective effects in stress-induced depressive behaviors and enhances contextual fear discrimination, but the extent to which these effects extend to fear generalization after auditory fear conditioning remains unclear. Here, we build on this work by using a behavioral model of fear generalization in mice involving foot shocks with differential intensity levels during auditory fear conditioning. We find that prophylactic (R,S)-ketamine treatment exerts protective effects that results in enhanced fear discrimination in wild type mice. As the growth factor, brain-derived neurotrophic factor (BDNF), has been shown to mediate the rapid antidepressant actions of (R,S)-ketamine, we used a loss-of-function BDNF mouse line (BDNF Val66Met) to determine whether BDNF is involved in (R,S)-ketamine's prophylactic effects on fear generalization. We found that BDNF Val66Met mice were resistant to the protective effects of prophylactic (R,S)-ketamine administration on fear generalization and extinction. We then used fiber photometry to parse out underlying neural activity and found that in the ventral hippocampus there were significant fear generalization-dependent patterns of activity for wild type and BDNF Val66Met mice that were altered by prophylactic (R,S)-ketamine treatment. Overall, these findings indicate a role for the ventral hippocampus and BDNF signaling in modulating the mitigating effects of prophylactic (R,S)-ketamine treatment on generalized fear.

Endocannabinoid Signaling Collapse Mediates Stress-Induced Amygdalo-Cortical Strengthening.

Functional coupling between the amygdala and the dorsomedial prefrontal cortex (dmPFC) has been implicated in the generation of negative affective states; however, the mechanisms by which stress increases amygdala-dmPFC synaptic strength and generates anxiety-like behaviors are not well understood. Here, we show that the mouse basolateral amygdala (BLA)-prelimbic prefrontal cortex (plPFC) circuit is engaged by stress and activation of this pathway in anxiogenic. Furthermore, we demonstrate that acute stress exposure leads to a lasting increase in synaptic strength within a reciprocal BLA-plPFC-BLA subcircuit. Importantly, we identify 2-arachidonoylglycerol (2-AG)-mediated endocannabinoid signaling as a key mechanism limiting glutamate release at BLA-plPFC synapses and the functional collapse of multimodal 2-AG signaling as a molecular mechanism leading to persistent circuit-specific synaptic strengthening and anxiety-like behaviors after stress exposure. These data suggest that circuit-specific impairment in 2-AG signaling could facilitate functional coupling between the BLA and plPFC and the translation of environmental stress to affective pathology.

Safety and compatibility of smart device heart rhythm monitoring in patients with cardiovascular implantable electronic devices.

INTRODUCTION: Emerging medical technology has allowed for monitoring of heart rhythm abnormalities using smartphone compatible devices. The safety and utility of such devices have not been established in patients with cardiac implantable electronic devices (CIEDs). We sought to assess the safety and compatibility of the Food and Drug Administration-approved AliveCor Kardia device in patients with CIEDs. METHODS AND RESULTS: We prospectively recruited patients with CIED for a Kardia recording during their routine device interrogation. A recording was obtained in paced and nonpaced states. Adverse clinical events were noted at the time of recording. Electrograms (EGMs) from the cardiac device were obtained at the time of recording to assess for any electromagnetic interference (EMI) introduced by Kardia. Recordings were analyzed for quality and given a score of 3 (interpretable rhythm, no noise), 2 (interpretable rhythm, significant noise) or 1 (uninterpretable). A total of 251 patients were recruited (59% with a pacemaker and 41% with ICD). There were no adverse clinical events noted at the time of recording and no changes to CIED settings. Review of all EGMs revealed no EMI introduced by Kardia. Recordings were correctly interpreted in 90% of paced recordings (183 had a score of 3, 43 of 2, and 25 of 1) and 94.7% of nonpaced recordings (147 of 3, 15 of 2, and 9 of 1). CONCLUSION: The AliveCor Kardia device has an excellent safety profile when used in conjunction with most CIEDs. The quality of recordings was preserved in this population. The device, therefore, can be considered for heart rhythm monitoring in patients with CIEDs.

Real-world experience with leadless cardiac pacing.

BACKGROUND: Leadless cardiac pacing (LCP) has emerged as a new modality for permanent pacing. We sought to describe comparative outcomes between LCP and transvenous pacemakers. METHODS: Patients receiving LCP (Micra [Medtronic, Minneapolis, MN, USA] and Nanostim [St. Jude Medical/Abbott Laboratories, Chicago, IL, USA]) between 2014 and 2017 at the Mayo Clinic Heart Rhythm Enterprise practice (Rochester, MN, USA; Jacksonville, FL, USA; and Scottsdale, AZ, USA) were identified. We identified 1:1 age- and sex-matched controls receiving single-chamber transvenous ventricular pacemakers (TVP). Statistical analyses were performed with JMP 13.0.0 (SAS, Institute Cary, NC, USA). RESULTS: Ninety patients underwent LCP implantation (73 Micra and 17 Nanostim) with a median follow-up duration of 62 (interquartile range 28-169) days. Both groups had 100% successful device implant rates. There were no differences in procedure-related major (0% vs 1%) or minor complications (8% vs 3%) in the LCP versus TVP groups (P > 0.05). Excluding Nanostim patients, there was a lower rate of device-related revision or extraction in the Micra versus TVP groups (0% vs 5%, P = 0.028). Device endocarditis was more common in the TVP group (0% vs 3%, P = 0.04). Estimated longevity was greater for the LCP group (median 12.0 vs 10.0 years, P < 0.0001). An increase in severity of tricuspid valve regurgitation (TR) by ≥2 grades occurred in none of the LCP patients, and in 19% of the TVP patients (P = 0.017). CONCLUSION: There are no significant differences in procedural complications among patients receiving LCP versus TVP. The Micra group had lower rates of device-related revision/extraction compared to the TVP group. Patients with leadless pacemaker were less likely to develop endocarditis or worsening TR.

Sex Differences in the Rat Hippocampal Opioid System After Oxycodone Conditioned Place Preference.

Although opioid addiction has risen dramatically, the role of gender in addiction has been difficult to elucidate. We previously found sex-dependent differences in the hippocampal opioid system of Sprague-Dawley rats that may promote associative learning relevant to drug abuse. The present studies show that although female and male rats acquired conditioned place preference (CPP) to the mu-opioid receptor (MOR) agonist oxycodone (3 mg/kg, I.P.), hippocampal opioid circuits were differentially altered. In CA3, Leu-Enkephalin-containing mossy fibers had elevated levels in oxycodone CPP (Oxy) males comparable to those in females and sprouted in Oxy-females, suggesting different mechanisms for enhancing opioid sensitivity. Electron microscopy revealed that in Oxy-males delta opioid receptors (DORs) redistributed to mossy fiber-CA3 synapses in a manner resembling females that we previously showed is important for opioid-mediated long-term potentiation. Moreover, in Oxy-females DORs redistributed to CA3 pyramidal cell spines, suggesting the potential for enhanced plasticity processes. In Saline-injected (Sal) females, dentate hilar parvalbumin-containing basket interneuron dendrites had fewer MORs, however plasmalemmal and total MORs increased in Oxy-females. In dentate hilar GABAergic dendrites that contain neuropeptide Y, Sal-females compared to Sal-males had higher plasmalemmal DORs, and near-plasmalemmal DORs increased in Oxy-females. This redistribution of MORs and DORs within hilar interneurons in Oxy-females would potentially enhance disinhibition of granule cells via two different circuits. Together, these results indicate that oxycodone CPP induces sex-dependent redistributions of opioid receptors in hippocampal circuits in a manner facilitating opioid-associative learning processes and may help explain the increased susceptibility of females to opioid addiction acquisition and relapse.

Oversensing of transthoracic excitation stimuli in contemporary pacemakers.

BACKGROUND: Transthoracic impedance measurements (TIM) is primarily used for minute ventilation rate adaptive sensors in pacemakers. With elevated impedance, the TIM electrical signal itself is oversensed, causing device malfunction. OBJECTIVE: We report an increased incidence of TIM oversensing. METHOD: Retrospective chart review. We review existing records of 18 patients who have demonstrated device malfunction with TIM oversensing. RESULTS: We have found a 1.8% incidence of TIM-related oversensing in our patient population of 959 patients with contemporary Boston Scientific (Marlborough, MA, USA) pacemakers and cardiac resynchronization therapy pacemakers. One patient experienced a syncopal episode. CONCLUSION: Oversensing with pacing inhibition is apparent with the potential of adverse effects to patients.

Predictors of intraoperative electrosurgery-induced implantable cardioverter defibrillator (ICD) detection.

BACKGROUND: In the USA, the number of people needing implantable cardioverter defibrillators (ICDs) has grown dramatically. Many ICD recipients will need to undergo a surgical procedure at some point following ICD implantation. Most surgeries involve the use of electrocautery. Currently, the effects of electrocautery-induced electromagnetic interference (EI-EMI) on ICDs are poorly understood. The aim of this study was to study EI-EMI using prospectively collected clinical data. METHODS: We analyzed prospectively collected ICD data from patients undergoing a surgical procedure at Mayo Clinic between 2011 and 2012. Information on clinical, device history, device interrogation pre- and post-surgery, and surgical information were collected for all patients. ICDs were programmed with detections on and therapies off. The patients were then categorized into two groups: those with EI-EMI inappropriate arrhythmia detection and those without detection. The stored electrograms were reviewed. Clinical and device parameters were analyzed to identify predictors of EI-EMI. RESULTS: Of 103 patients studied, bipolar cautery did not induce EI-EMI (0/11 cases), whereas monopolar cautery resulted in noise detection in 11/92 procedures. Among 11 inappropriate episodes of detection, 10 had surgery at chest, neck, and upper extremity sites with cautery current across the ICD lead tip; 1 had abdominal surgery; and none had back or low extremity surgery. On average, the near-field electrogram amplitude values were greater than the far-field amplitude values. CONCLUSIONS: EI-EMI does not occur when bipolar cautery or monopolar cautery is used below the hips with the dispersive ground pad applied to the lower extremities. In contrast to external EMI, EI-EMI may be larger on near-field than far-field electrograms.