Decreased medial entorhinal cortical thickness in olanzapine exposed female rats is not ameliorated by exercise.

Aerobic exercise has been associated with hippocampal plasticity, both in healthy adults and in psychosis patients, but its impact on cortical regions remains unclear. The entorhinal cortex serves as a critical gateway for the hippocampus, and recent studies suggest that this region may also be impacted following an exercise regime. In order to investigate the effects of antipsychotic medications and exercise on the entorhinal cortex, female rats were chronically administered either olanzapine or vehicle and were either sedentary or had access to a running wheel for 9 weeks. Olanzapine-treated rats had decreased medial entorhinal cortical thickness compared to vehicle-treated rats. A statistically significant interaction was observed for layer II of the entorhinal cortex, with exercising rats having significantly greater thickness compared to sedentary rats in the vehicle group, but not the olanzapine group. Greater total entorhinal and lateral entorhinal cortical thickness was associated with greater average activity. In exercising rats, decreasing glucose intolerance was associated with larger total entorhinal and layer II cortical thickness. Lower fasting insulin levels were associated with greater total entorhinal, lateral entorhinal, and layer II cortical thickness. The relationship between increased activity and greater entorhinal cortical thickness was mediated by reduced fasting insulin, indicating that regulation of metabolic risk factors may contribute to impact of aerobic exercise on the entorhinal cortex. Aerobic exercise may be helpful in counteracting metabolic side effects of antipsychotic medications and managing these side effects may be key to promoting entorhinal cortical plasticity in patients treated with second-generation antipsychotic drugs.

Hippocampal volume and vasculature before and after exercise in treatment-resistant schizophrenia.

BACKGROUND: Schizophrenia is associated with poor cognitive function and elevated cardiometabolic disease risk. These health concerns may exacerbate neurocognitive dysfunction associated with hippocampal abnormalities, particularly hippocampal volume reductions. Regular exercise is thought to improve symptom severity, reduce depression, and improve cognition in schizophrenia, and may trigger exercise-mediated hippocampal growth. The potential for the benefits of exercise for treatment-resistant schizophrenia patients has not been clearly assessed. This study aims to assess the effect of exercise on hippocampal plasticity and clinical outcomes in chronic schizophrenia. METHODS: Seventeen DSM-IV criteria schizophrenia or schizoaffective disorder patients completed a customized moderate intensity 12-week aerobic or weight-bearing exercise program. Adherence rates were 83% ±â€¯9.4%) with 70% of participants completing the entire exercise program. Concomitant neuroimaging, clinical and cognitive assessments were obtained at baseline and 12-weeks. RESULTS: At follow-up, symptom severity scores (t(16) = -16.8, p. ≤ 0.0001) and social functioning (t(16) = 4.4, p. = 0.0004) improved. A trend for improved depression scores (t(16) = -2.0, p. = 0.06) with no change in anxiety, or extrapyramidal symptoms were seen. Hippocampal volume increased (t(16) = -2.54, p. = 0.02), specifically in the left CA-1 field (F(16) = -2.33, p. = 0.03). Hippocampal vascular volume was unchanged. Change in hippocampal volume and vascular volume was not significantly correlated with change in symptom severity or affect scores. CONCLUSIONS: Adjunct exercise may accelerate symptom improvement in treatment-resistant psychosis patients. While the underlying mechanism remains unclear, these results indicate that chronic schizophrenia patients experience hippocampal plasticity in response to exercise. STUDY REGISTRATION: Clinical Trials.govNCT01392885.

Diagnosis and body mass index effects on hippocampal volumes and neurochemistry in bipolar disorder.

We previously reported that higher body mass index (BMI) was associated with greater hippocampal glutamate+glutamine in people with bipolar disorder (BD), but not in non-BD healthy comparator subjects (HSs). In the current report, we extend these findings by examining the impact of BD diagnosis and BMI on hippocampal volumes and the concentrations of several additional neurochemicals in 57 early-stage BD patients and 31 HSs. Using 3-T magnetic resonance imaging and magnetic resonance spectroscopy, we measured bilateral hippocampal volumes and the hippocampal concentrations of four neurochemicals relevant to BD: N-acetylaspartate+N-acteylaspartylglutamate (tNAA), creatine+phosphocreatine (Cre), myoinositol (Ins) and glycerophosphocholine+phosphatidylcholine (Cho). We used multivariate factorial analysis of covariance to investigate the impact of diagnosis (patient vs HS) and BMI category (normal weight vs overweight/obese) on these variables. We found a main effect of diagnosis on hippocampal volumes, with patients having smaller hippocampi than HSs. There was no association between BMI and hippocampal volumes. We found diagnosis and BMI effects on hippocampal neurochemistry, with patients having lower Cre, Ins and Cho, and overweight/obese subjects having higher levels of these chemicals. In patient-only models that controlled for clinical and treatment variables, we detected an additional association between higher BMI and lower tNAA that was absent in HSs. To our knowledge, this was the first study to investigate the relative contributions of BD diagnosis and BMI to hippocampal volumes, and only the second to investigate their contributions to hippocampal chemistry. It provides further evidence that diagnosis and elevated BMI both impact limbic brain areas relevant to BD.

Cortical morphology and early adverse birth events in men with first-episode psychosis.

BACKGROUND: Reduced cortical gray-matter volume is commonly observed in patients with psychosis. Cortical volume is a composite measure that includes surface area, thickness and gyrification. These three indices show distinct maturational patterns and may be differentially affected by early adverse events. The study goal was to determine the impact of two distinct obstetrical complications (OCs) on cortical morphology. METHOD: A detailed birth history and MRI scans were obtained for 36 patients with first-episode psychosis and 16 healthy volunteers. RESULTS: Perinatal hypoxia and slow fetal growth were associated with cortical volume (Cohen's d = 0.76 and d = 0.89, respectively) in patients. However, the pattern of associations differed across the three components of cortical volume. Both hypoxia and fetal growth were associated with cortical surface area (d = 0.88 and d = 0.72, respectively), neither of these two OCs was related to cortical thickness, and hypoxia but not fetal growth was associated with gyrification (d = 0.85). No significant associations were found within the control sample. CONCLUSIONS: Cortical dysmorphology was associated with OCs. The use of a global measure of cortical morphology or a global measure of OCs obscured important relationships between these measures. Gyrification is complete before 2 years and its strong relationship with hypoxia suggests an early disruption to brain development. Cortical thickness matures later and, consistent with previous research, we found no association between thickness and OCs. Finally, cortical surface area is largely complete by puberty and the present results suggest that events during childhood do not fully compensate for the effects of early disruptive events.

White matter tract abnormalities in first-episode psychosis.

Fibers connecting fronto-temporal and fronto-medial structures that pass through the anterior limb of the internal capsule (ALIC) subserve executive and psychomotor functioning. Both of these functions are adversely affected in schizophrenia, and may be abnormal at illness onset. In a study of first-episode psychosis, we used diffusion tensor imaging (DTI) and cognitive testing to examine ALIC integrity. Fourteen early psychosis patients and 29 healthy volunteers were included. Symptoms were assessed with the Positive and Negative Syndromes Scale (PANSS). All structural and diffusion scans were acquired on a GE Signa 1.5T scanner. A T1-weighted 3D FSPGR Inversion Recovery imaging series was acquired for manual seeding in structural space. Diffusion tensor imaging (DTI) was performed, and all DTI images were co-registered to structural space. Seeds were manually drawn bilaterally on the coronal plane at a specified location. Diffusion images were post-processed for subsequent Tract-based Spatial Statistics (TBSS) analysis. First-episode psychosis patients had significantly smaller fronto-medial and fronto-temporal AIC tract volumes compared to healthy volunteers on the left and the right (p-values<0.04). No differences in mean fractional anisotropy (FA) were seen within either left or right tracts (p-values>0.05), nor did TBSS reveal any other differences in FA values between groups in other regions. Relationships between tract volumes and symptom severity were not observed in this study.

Anterior internal capsule volumes increase in patients with schizophrenia switched from typical antipsychotics to olanzapine.

Abnormalities in connectivity are thought to contribute to the symptoms of schizophrenia. Accumulating evidence suggests that antipsychotic medication affects both subcortical and cortical grey and white matter volumes. The goal of this study was to investigate the effects of antipsychotic medication on two white matter tracts: a subcortical-cortical tract, the anterior and posterior limbs of the internal capsule; and a cortical-cortical tract, the corpus callosum. Magnetic resonance imaging was conducted on 10 chronic schizophrenia patients treated with typical antipsychotics and 20 healthy controls at baseline. Patients were switched to olanzapine and both groups were rescanned after 1 year. At baseline, the volume of the anterior limb of the internal capsule was 24% smaller in typical-treated patients than controls (p = 0.009). Patients treated with greater amounts of chlorpromazine-equivalent daily dosage had smaller anterior internal capsule volumes at baseline (r = -0.65, p = 0.04). At follow-up, after being switched to olanzapine, there were no significant differences between patients and controls. Patients with schizophrenia had a significant 25% increase in anterior internal capsule volume from baseline to follow-up compared with controls (p = 0.04). These effects were most prominent in the anterior limb of the internal capsule, which consists of fronto-thalamic pathways, and were not statistically significant in the posterior limb of the internal capsule or corpus callosum. Olanzapine may be effective in normalizing fronto-thalamic structural connectivity in schizophrenia.

Localization of the subthalamic nucleus: optimization with susceptibility-weighted phase MR imaging.

BACKGROUND AND PURPOSE: On clinical MR images, the subthalamic nuclei (STN) are poorly delineated from adjacent structures, impeding safe direct targeting for placement of electrodes in the treatment of Parkinson disease. Susceptibility-weighted MR phase imaging offers improved contrast and spatial resolution at reduced imaging times relative to clinically used T2-weighted spin-echo imaging for STN visualization. Our purpose was to assess STN visibility by using phase imaging, comparing phase and magnitude images obtained concurrently by using susceptibility-weighted imaging (SWI). The goal was to identify an efficient scanning protocol for high-quality phase images of STN. MATERIALS AND METHODS: Seventy-eight SWI scans were acquired at 3T by using different TEs and acceleration factors. STN visibility and delimitation from adjacent structures were scored from 0 (not interpretable) to 5 (excellent). Regression analyses assessed the relationship of STN visibility to scanning parameters RESULTS: STN were identified at all studied TEs on phase images. Visibility and delimitation of STN were consistently superior on phase images compared with magnitude images. Good visualization (score of >or=4) of STN on phase imaging occurred at a mean TE of 20.0 ms and a sensitivity encoding (SENSE) of 1.40. Scores of STN visualization on phase images were dependent on SENSE (P < .002) and TE (P < .031). Good delimitation of the STN on phase imaging occurred at a mean TE of 21.6 ms and a SENSE of 1.36. CONCLUSIONS: Visualization and delimitation of STN was superior on phase images and was achieved at 3T in <2.5 minutes. A TE of 20 ms and an acceleration factor of

Reduced anterior internal capsule and thalamic volumes in first-episode psychosis.

BACKGROUND: The thalamus is the gateway for sensory and motor information en route to the cortex. Information is processed via thalamocortical and corticothalamic pathways coursing through the internal capsules. In this study, we investigated the relationship between the anterior limb of the internal capsule, posterior limb of the internal capsule, and thalamus in first-episode psychosis (FEP). METHODS: Twenty-nine FEP subjects (26 DSM-IV schizophrenia, 2 schizoaffective disorder, 1 psychosis not otherwise specified) and 22 healthy volunteers participated in this study. Anterior limb of the internal capsule (AIC), posterior limb of the internal capsule (PIC), and the thalamus volumes were manually determined from MRI scans. RESULTS: FEP subjects had reduced AIC volumes (F(1,45)=6.18, p=0.017) and thalamic volumes (F(1,45)=8.00, p=0.007) compared to healthy volunteers. PIC volumes did not differ. Significant correlations between AIC volumes and thalamic volumes were observed in subjects with FEP, but not in healthy volunteers. Negative relationships between thalamic volumes and symptom severity were also observed. CONCLUSIONS: The AIC and thalamic volumes were reduced in subjects with FEP compared to healthy volunteers. Abnormalities in thalamocortical and orticothalamic pathways may contribute to functional disruption of neural circuits in psychosis.

Abnormalities of myelination in schizophrenia detected in vivo with MRI, and post-mortem with analysis of oligodendrocyte proteins.

Schizophrenia unfolds during the late period of brain maturation, while myelination is still continuing. In the present study, we used MRI and T2 relaxation analysis to measure the myelin water fraction in schizophrenia. In schizophrenia (n=30) compared with healthy subjects (n=27), overall white matter showed 12% lower myelin water fraction (P=0.031), with the most prominent effects on the left genu of the corpus callosum (36% lower, P=0.002). The left anterior genu was affected in both first-episode (P=0.035) and chronic patients (P=0.011). In healthy subjects, myelin water fraction in total white matter and in frontal white matter increased with age, and with years of education, indicating ongoing maturation. In patients with schizophrenia, neither relation was statistically significant. Post-mortem studies of anterior frontal cortex demonstrated less immunoreactivity of two oligodendrocyte-associated proteins in schizophrenia (2',3'-cyclic nucleotide 3'-phosphodiesterase by 33%, P=0.05; myelin-associated glycoprotein by 27%, P=0.14). Impaired myelination in schizophrenia could contribute to abnormalities of neural connectivity and persistent functional impairment in the illness.

Clinical validation of new pacing-sensing configurations for atrial automatic capture verification in pacemakers.

INTRODUCTION: This study evaluated an atrial automatic capture verification scheme based on atrial evoked response (AER). Atrial pacing was between Atip and Can (Atip-Can) using different coupling capacitances (CCs). Independent pairs of sensing electrodes between Aring and Vtip (Aring-Vtip) or between Aring and a separate indifferent electrode (Aring-Indiff) were used to reduce pacing-induced afterpotentials. METHODS AND RESULTS: A custom-made external pacing system was used to perform automatic step-up and step-down pacing (0.1 to 7.1 V at 0.5 msec, step size of 0.1 V) using different CCs (2 or 15 microF). Intracardiac signals from Aring-Indiff and Aring-Vtip were independently recorded and analyzed both in real time and off-line to detect AER. Every paced beat also was visually inspected and compared with surface ECG to verify the captures. With the intracardiac signals properly filtered, AER detection was based on the signal within a window of 12 to 65 msec after the stimulus. Data from 27 patients (4 chronic and 23 acute implantations; age 65.6+/-13.9 years) were analyzed. Bipolar atrial lead measurements using a standard pacing system analyzer were as follows (mean +/- SD): impedance 695+/-227 ohms, P wave amplitude 4.2+/-2.3 mV, slew rate 1.1+/-0.9 V/sec, and pacing threshold at 0.5 msec 1.0+/-0.5 V. The results with CC = 2 microF showed that of 9,500 atrial paced beats, correct capture verification rates were 99.8% (Aring-Indiff) and 99.4% (Aring-Vtip). Similar results were achieved with CC = 15 microF (99.7% and 99.5%, respectively). CONCLUSION: AER can be reliably detected using independent pacing (Atip-Can) and sensing (Aring-Vtip or Aring-Indiff) electrodes. Therefore, atrial automatic capture verification by AER detection is feasible.

An MRI study of basal ganglia volumes in first-episode schizophrenia patients treated with risperidone.

OBJECTIVE: The basal ganglia may contribute to extrapyramidal movement disorders, affective disturbances, and cognitive deficits in schizophrenia. Basal ganglia volumes are putatively affected by antipsychotic medications. The purpose of this study was to determine the long-term effects of risperidone treatment in a cohort of first-episode patients with schizophrenia. METHOD: The subjects were 30 patients with first-episode schizophrenia, 12 patients chronically treated with typical antipsychotics, and 23 healthy comparison subjects. They were scanned by magnetic resonance imaging at baseline. The first-episode patients received 1 year of continuous risperidone treatment, after which they and the comparison subjects were rescanned. Caudate, putamen, and globus pallidus volumes were determined from coronal images. RESULTS: The baseline caudate, putamen, and globus pallidus volumes were significantly larger in the chronically treated patients than in the untreated first-episode subjects and comparison subjects. These volumes did not differ between the first-episode patients and healthy comparison subjects. Basal ganglia volumes were unchanged after 1 year of exposure to risperidone in the first-episode subjects. Extrapyramidal movement disorders were present in the majority of chronically treated patients and more than one-third of the never-medicated first-episode patients at baseline. CONCLUSIONS: This group of first-episode patients did not exhibit abnormalities of basal ganglia volumes, nor were basal ganglia volumes affected by exposure to risperidone. Movement disorders were observed in both first-episode and chronically treated patients, suggesting effects of both illness and medications.

Hemodynamic sensors.

Present adaptive-rate pacemakers use a range of sensors for implementation in open-loop and closed-loop control systems. Hemodynamic sensors that detect the mechanical action of the heart and blood flow offer additional features to implement physiologic rate adaption in rate-controlling systems and rate-limiting systems. Examples of 2 such sensors are presented.

Efficacy of preoxygenation with tidal volume breathing. Comparison of breathing systems.

BACKGROUND: Preoxygenation before tracheal intubation is intended to increase oxygen reserves and delay the onset of hypoxemia during apnea. Various systems are used for preoxygenation. Designed specifically for preoxygenation, the NasOral system uses a small nasal mask for inspiration and a mouthpiece for exhalation. One-way valves in the nasal mask and the mouthpiece ensure unidirectional flow. This investigation compares the efficacy of preoxygenation using the standard circle system with the NasOral system and five different resuscitation bags. METHODS: Twenty consenting, healthy volunteers were studied in the supine position for 5-min periods of tidal volume breathing using the circle absorber system, the NasOral system, and five resuscitation bags in a randomized order. Data were collected during room air breathing and at 30-s intervals during 5 min of oxygen administration. Inspired oxygen, end-tidal oxygen, and end-tidal nitrogen were measured by mass spectrometry. RESULTS: At 2. 5 min of oxygenation, end-tidal oxygen plateaued at 88.1 +/- 4.8 and 89.3 +/- 6.4% (mean +/- SD) for the circle absorber and NasOral systems, respectively. This was associated with inverse decreases in end-tidal nitrogen. At no time did these end-tidal oxygen or nitrogen values differ from each other. Three of the resuscitation bags (one disk type and two duck-bill type with one-way exhalation valves) delivered inspired oxygen more than 90%, and the end-tidal oxygen plateaued between 77 and 89% at 2 min of tidal volume breathing. The other two resuscitation bags (both duck-bill bags without exhalation valves) delivered inspired oxygen less than 40%, and the end-tidal oxygen values ranged between 21.8 +/- 5.0 and 31.9 +/- 8.7%. CONCLUSIONS: The circle absorber and NasOral systems were equally effective in achieving maximal preoxygenation during tidal volume breathing. Resuscitation bags differed markedly in effectiveness during preoxygenation; those with duck-bill valves without one-way exhalation valves were the least effective. Thus, the use of these bags should be avoided for preoxygenation.

Detection of atrial arrhythmia for cardiac rhythm management by implantable devices.

Implantable atrial defibrillators (IAD) should provide pacing therapy whenever appropriate (ie, typical atrial flutter) to minimize shock-related patient discomfort. Additionally, IADs should provide diagnostics regarding atrial arrhythmia type and frequency of occurrence to enable improved physician management of atrial arrhythmia. To achieve this, IADs should accurately classify atrial arrhythmia such as atrial fibrillation (AF) and atrial flutter (AFL) This article evaluates the performance of an algorithm, atrial rhythm classification (ARC), designed to classify AF and AFL. The ARC algorithm uses maximum rate, standard deviation, and range of the 12 most recent atrial cycle lengths to plot a point in a three-dimensional space. A decision boundary divides the space into 2 regions--faster/unstable atrial cycle lengths (AF) or slower/stable cycle lengths (AFL). Classifications are made on a sliding window of 12 consecutive cycles until the end of the episode is reached. In this way, continuous episode feedback is provided that can be used to help guide device therapy, measure arrhythmia type and frequency of occurrence. Bipolar (1-cm) electrogram episodes of AF (n = 16) and AFL (n = 7) were acquired from 20 patients and retrospectively analyzed using the ARC algorithm. The sensitivity and specificity in this study was 0.993 and 0.982, respectively. The ARC algorithm would have appropriately guided atrial therapy and minimized discomfort associated with defibrillation shocks in this small patient data set warranting further studies. The ARC algorithm may also be beneficial as a diagnostic tool to assist physician management of atrial arrhythmia.

A preview of implantable cardioverter defibrillator systems in the next millennium: an integrative cardiac rhythm management approach.

The implantable cardioverter defibrillator (ICD), a primary therapeutic option for preventing sudden cardiac death, has rapidly evolved since being introduced clinically in 1980. Technologic advances in several key areas have enabled ICDs to provide more sophisticated rhythm management. Recent emphasis has been placed on dual-chamber ICDs possessing adaptive-rate pacing capabilities. Adoption of dual-chamber ICD systems has been rapid. The capabilities of future ICD systems will be governed by an integrative strategy that brings together sets of features specifically targeted at multifaceted rhythm disorders. The addition of atrial therapy will require more sophisticated rhythm discrimination algorithms. ICD technology will improve on several fronts including leads, integrated circuits, batteries, and capacitors. Additionally, state-of-the-art pacemaker technology will continue to be incorporated into ICDs. As these new ICD systems become increasingly sophisticated from an engineering viewpoint, tremendous emphasis will be placed on decreasing the complexity of programming, device interrogation, and patient monitoring during routine patient follow-up. Vast improvements in ICD programming systems may ultimately permit the 1-minute follow-up.

Future of bradyarrhythmia therapy systems: automaticity.

Since the first fixed-rate ventricular pacemaker was introduced in the late 1950s, pacing systems have evolved rapidly. Current developments focus on making devices more sophisticated and less complex--a challenging combination. Automaticity features such as beat-by-beat capture verification, sensitivity threshold adaptation, and algorithms to govern dynamically the maximum sensor rate have either recently been introduced or are likely to be introduced in the near future. Technologic advances are likely to allow meaningful improvements in current drain, battery performance, memory capacity, signal processing, telemetry, and programmer interface. Bradyarrhythmia therapy devices of the future promise to go beyond the pacemaker. Ultimately, pacing systems will become part of integrated cardiac rhythm management systems.

A new defibrillator discrimination algorithm utilizing electrogram morphology analysis.

Inappropriate therapies delivered by implantable cardioverter defibrillators (ICDs) for supraventricular arrhythmias remain a common problem, particularly in the event of rapidly conducted atrial fibrillation or marked sinus tachycardia. The ability to differentiate between ventricular tachycardia and supraventricular arrhythmias is the major goal of discrimination algorithms. Therefore, we developed a new algorithm, SimDis, utilizing morphological features of the shocking electrograms. This algorithm was developed from electrogram data obtained from 36 patients undergoing ICD implantation. An independent test set was evaluated in 25 patients. Recordings were made in sinus rhythm, sinus tachycardia, and following the induction of ventricular tachycardia and atrial fibrillation. The arrhythmia complex is defined as wide if the duration is at least 30% greater than the template in sinus rhythm. For narrow complexes, four maximum and minimum values were measured to form a 4-element feature vector, which was compared with a representative feature vector during normal sinus rhythm. For each rhythm, any wide complex was classified as ventricular tachycardia. For narrow complexes, the second step of the algorithm compared the electrogram with the template, computing similarity and dissimilarity values. These values were then mapped to determine if they fell within a previously established discrimination boundary. On the independent test set, the SimDis algorithm correctly classified 100% of ventricular tachycardias (27/27), 98% of sinus tachycardias (54/55), and 100% of episodes of atrial fibrillation (37/37). We conclude that the SimDis algorithm yields high sensitivity (100%) and specificity (99%) for arrhythmia discrimination, using the computational capabilities of an ICD system.

Improved internal defibrillation success with shocks timed to the morphology electrogram.

BACKGROUND: A previous retrospective study by our group suggested that shocks timed to the upslope of the shocking lead electrogram improved defibrillation efficacy. The goal of this study was to prospectively determine whether defibrillation threshold could be reduced by use of an algorithm that timed shocks to the upslope of coarse ventricular fibrillation (test treatment) compared with shocks delivered asynchronously after 10 seconds of fibrillation (control treatment). METHODS AND RESULTS: Ten pigs were instrumented with a 3-lead system for internal defibrillation. Initial estimates of the energy required to achieve defibrillation E50 for both treatments were made by an up/down method. Subsequently, additional shocks at V50+/-10% and V50-20% were given for each treatment to obtain data points at higher and lower intensities. Probability-of-success curves were estimated for both treatments by the best-fit method. Energies required were significantly lower for the timed shocks than for the asynchronous shocks (P<0.00 1). E80 was reduced 15.5%, from 27.1+/-2.5 to 22.9+/-1.8 J (P<0.002). The width of the probability-of-success curve (E80-E20) for the test treatment was also significantly narrower than that for the control treatment (7.1+/-0.9 versus 10.8+/-1.7, P<0.01). Normalized curve width (E80-E20)/E50 was decreased from 51+/-5% of E50 for control shocks to 37+/-4% of E50 for synchronous shocks (P<0.02). CONCLUSIONS: In this model, defibrillation threshold is lower and more deterministic when shocks are timed to the upslope of the shocking lead electrogram. If a similar reduction is observed in humans, shock timing may lower defibrillation threshold and simplify programming of shock intensity.

Shock timing lowers transvenous defibrillation energy requirement.

Previous studies suggested that time periods exist during ventricular fibrillation when defibrillation shocks are more effective. However, there is no agreement on the amount of energy that can be saved or whether an implantable defibrillator can time shocks to these time periods. We conducted a study having two parts to investigate if there was any advantage to synchronizing internal defibrillation shocks to morphological patterns in ventricular fibrillation (VF). VF electrograms were recorded from the same three-electrode lead system used for internal defibrillation. In Part 1, we found no difference in the probability of successful defibrillation between shocks that were delivered into coarse and fine VF (48% vs 46%). However, shocks that were delivered to the upslope of coarse VF electrograms were more efficacious than those to the downslope of the waveform (67% vs 39%, P < .001). In the second study, we developed a real time computer system to prospectively deliver shocks on the upslope feature we identified in the first study. We found that the energy requirements at E50 and E80 were significantly lower for shocks delivered on the upslope of coarse VF than those delivered randomly at the end of 10 sec. We estimated a probability of success (POS) defibrillation curve using a maximum likelihood method for the timed and random shocks. The POS curve width was significantly narrower for shocks that were delivered to the upslope feature than the control treatment (7.1 +/- 0.9 vs. 10.8 +/- 1.7 J, P < 0.01). If these findings extend to clinical defibrillation, they may allow programming of internal defibrillators at lower energies. This could reduce potential postshock cardiac dysfunction, allow production of smaller devices, and improve battery life.

Effect of shock timing on defibrillation success.

The goal of this study was to determine whether delivering transvenous defibrillation shocks, coordinated with the up/down-slope VF waveform patterns in the shocking lead, would improve the probability of successful defibrillation. Anesthetized swine (32-38 kg, n = 8) were implanted with an RV-->SVC + SQArray transvenous system to measure VF waveform patterns and to deliver shocks. The shocks were generated by a Cardiac Pacemakers Inc. biphasic waveform generator. Energy required for 50% success probability (E50) was determined using the multishock up-down protocol. VF was repeatedly induced and defibrillation shocks at E50 were given after 10 seconds. The defibrillation outcome, delivered energy (Ed), peak voltage (V), peak current (I), system impedance (Z) and VF waveform pattern at the time of shock were recorded and measured. Out of a total of 685 shocks, 324 (47%) succeeded and 361 (53%) failed. The Ed, V, I, and Z were similar for the two defibrillation outcome groups (success or failure). VF patterns were classified as high or low amplitude at the time of the shock based on the peak-to-peak amplitude of signals recorded between the shocking electrodes. Shocks that coincided with high amplitude VF patterns were further divided into shocks that occurred on the up-slope or on the down-slope. The probability of success when the E50 shocks were coincident with high or low amplitude fibrillation did not differ significantly (Student's t-test: 46% vs 48%. P = NS). However, during high amplitude fibrillation, shocks delivered on the up-slope were significantly more successful than those delivered on the down-slope (Chi-square: 67% vs 39%; P < 0.001). These results suggest that delivering defibrillation shocks during the up-slope of the high amplitude signal in the shocking lead may improve the probability of successful defibrillation of ICDs.