Dynamic functional connectivity of the EEG in relation to outcome of postanoxic coma.

OBJECTIVE: Early EEG contains reliable information for outcome prediction of comatose patients after cardiac arrest. We introduce dynamic functional connectivity measures and estimate additional predictive values. METHODS: We performed a prospective multicenter cohort study on continuous EEG for outcome prediction of comatose patients after cardiac arrest. We calculated Link Rates (LR) and Link Durations (LD) in the α, δ, and θ band, based on similarity of instantaneous frequencies in five-minute EEG epochs, hourly, during 3 days after cardiac arrest. We studied associations of LR and LD with good (Cerebral Performance Category (CPC) 1-2) or poor outcome (CPC 3-5) with univariate analyses. With random forest classification, we established EEG-based predictive models. We used receiver operating characteristics to estimate additional values of dynamic connectivity measures for outcome prediction. RESULTS: Of 683 patients, 369 (54%) had poor outcome. Patients with poor outcome had significantly lower LR and longer LD, with largest differences 12 h after cardiac arrest (LRθ 1.87 vs. 1.95 Hz and LDα 91 vs. 82 ms). Adding these measures to a model with classical EEG features increased sensitivity for reliable prediction of poor outcome from 34% to 38% at 12 h after cardiac arrest. CONCLUSION: Poor outcome is associated with lower dynamics of connectivity after cardiac arrest. SIGNIFICANCE: Dynamic functional connectivity analysis may improve EEG based outcome prediction.

Normalization of EEG in depression after antidepressant treatment with sertraline? A preliminary report.

BACKGROUND: MDD patients with abnormal EEG patterns seem more likely to be non-responsive to the antidepressants escitalopram and venlafaxine, but not sertraline, than patients without EEG abnormalities. This finding suggests that patients with both MDD and abnormal EEGs may differentially respond to antidepressant treatment. In the current study, we investigated whether depressed patients with an abnormal EEG show a normalization of the EEG related to antidepressant treatment and response and whether such effect is drug specific, and whether having had early life stress (ELS) increases the chance of abnormal activity. METHODS: Baseline and week 8 EEGs and depression symptoms were extracted from a large multicenter study (iSPOT-D, n = 1008) where depressed patients were randomized to escitalopram, sertraline, or venlafaxine-XR treatment. We calculated Odds Ratios of EEG normalization and depression response in patients with an abnormal EEG at baseline, comparing sertraline versus other antidepressants. RESULTS: Fifty seven patients with abnormal EEGs were included. EEGs did not normalize significantly more with sertraline compared to other antidepressants (OR = 1.9, p = .280). However, patients with a normalized EEG taking sertraline were 5.2 times more likely to respond than subjects taking other antidepressants (p = .019). ELS was not significantly related to abnormal activity. LIMITATIONS: Neurophysiological recordings were limited in time (two times 2-minute EEGs) and statistical power (n = 57 abnormal EEGs). CONCLUSIONS: Response rates in patients with normalized EEG taking sertraline were significantly larger than in subjects treated with escitalopram/venlafaxine. This adds to personalized medicine and suggests a possible drug repurposing for sertraline.

Detecting abnormal electroencephalograms using deep convolutional networks.

OBJECTIVES: Electroencephalography (EEG) is a central part of the medical evaluation for patients with neurological disorders. Training an algorithm to label the EEG normal vs abnormal seems challenging, because of EEG heterogeneity and dependence of contextual factors, including age and sleep stage. Our objectives were to validate prior work on an independent data set suggesting that deep learning methods can discriminate between normal vs abnormal EEGs, to understand whether age and sleep stage information can improve discrimination, and to understand what factors lead to errors. METHODS: We train a deep convolutional neural network on a heterogeneous set of 8522 routine EEGs from the Massachusetts General Hospital. We explore several strategies for optimizing model performance, including accounting for age and sleep stage. RESULTS: The area under the receiver operating characteristic curve (AUC) on an independent test set (n = 851) is 0.917 marginally improved by including age (AUC = 0.924), and both age and sleep stages (AUC = 0.925), though not statistically significant. CONCLUSIONS: The model architecture generalizes well to an independent dataset. Adding age and sleep stage to the model does not significantly improve performance. SIGNIFICANCE: Insights learned from misclassified examples, and minimal improvement by adding sleep stage and age suggest fruitful directions for further research.

Detecting interictal discharges in first seizure patients: ambulatory EEG or EEG after sleep deprivation?

PURPOSE: Uncertainty about recurrence after a first unprovoked seizure is a significant psychological burden for patients, and motivates the need for diagnostic tools with high sensitivity and specificity to assess recurrence risk. As the sensitivity of a routine EEG after a first unprovoked seizure is limited, patients often require further diagnostics. Here, we study if ambulatory EEG (aEEG) has similar diagnostic accuracy as sleep deprived EEG (sdEEG). METHODS: In this retrospective cohort, we included patients with an unprovoked first seizure and a normal routine EEG who subsequently underwent an sdEEG or aEEG. All EEGs were reviewed for the presence of interictal epileptiform discharges (IEDs). We calculated specificity and sensitivity of sdEEG and aEEG, using the clinical diagnosis of epilepsy as golden standard. All patients had a follow-up of one year. RESULTS: We included 104 patients. Sensitivities for sdEEG and aEEG were 45% (specificity 91%) and 63% (specificity 95%), respectively. Independent risk factor for recurrent seizure were IEDs on the additional EEG, with a relative risk of 1.5 of having a recurrent seizure within a year. CONCLUSION: Diagnostic accuracies of sdEEG and aEEG are similar and depending on patients' and clinicians' preference both can be considered in patients with a first seizure and a normal routine EEG to determine recurrence risk.

Synaptic damage underlies EEG abnormalities in postanoxic encephalopathy: A computational study.

OBJECTIVE: In postanoxic coma, EEG patterns indicate the severity of encephalopathy and typically evolve in time. We aim to improve the understanding of pathophysiological mechanisms underlying these EEG abnormalities. METHODS: We used a mean field model comprising excitatory and inhibitory neurons, local synaptic connections, and input from thalamic afferents. Anoxic damage is modeled as aggravated short-term synaptic depression, with gradual recovery over many hours. Additionally, excitatory neurotransmission is potentiated, scaling with the severity of anoxic encephalopathy. Simulations were compared with continuous EEG recordings of 155 comatose patients after cardiac arrest. RESULTS: The simulations agree well with six common categories of EEG rhythms in postanoxic encephalopathy, including typical transitions in time. Plausible results were only obtained if excitatory synapses were more severely affected by short-term synaptic depression than inhibitory synapses. CONCLUSIONS: In postanoxic encephalopathy, the evolution of EEG patterns presumably results from gradual improvement of complete synaptic failure, where excitatory synapses are more severely affected than inhibitory synapses. The range of EEG patterns depends on the excitation-inhibition imbalance, probably resulting from long-term potentiation of excitatory neurotransmission. SIGNIFICANCE: Our study is the first to relate microscopic synaptic dynamics in anoxic brain injury to both typical EEG observations and their evolution in time.

EEG in postanoxic coma: Prognostic and diagnostic value.

Evolution of the EEG background pattern is a robust contributor to prediction of poor or good outcome of comatose patients after cardiac arrest. At 24h, persistent isoelectricity, low voltage activity, or burst-suppression with identical bursts predicts a poor outcome without false positives. Rapid recovery toward continuous patterns within 12h is strongly associated with a good neurological outcome. Predictive values are highest in the first 24h, despite the use of mild therapeutic hypothermia and sedative medication. Studies on reactivity or mismatch negativity have not included the EEG background pattern. Therefore, the additional predictive value of reactivity parameters remains unclear. Whether or not treatment of electrographic status epilepticus improves outcome is studied in the randomized multicenter Treatment of Electroencephalographic STatus epilepticus After cardiopulmonary Resuscitation (TELSTAR) trial (NCT02056236).

Continuous EEG Monitoring for Early Detection of Delayed Cerebral Ischemia in Subarachnoid Hemorrhage: A Pilot Study.

INTRODUCTION: Early identification of delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (aSAH) is a major challenge. The aim of this study was to investigate whether quantitative EEG (qEEG) features can detect DCI prior to clinical or radiographic findings. METHODS: A prospective cohort study was performed in aSAH patients in whom continuous EEG (cEEG) was recorded. We studied 12 qEEG features. We compared the time point at which qEEG changed with the time point that clinical deterioration occurred or new ischemia was noted on CT scan. RESULTS: Twenty aSAH patients were included of whom 11 developed DCI. The alpha/delta ratio (ADR) was the most promising feature that showed a significant difference in change over time in the DCI group (median -62% with IQR -87 to -39%) compared to the control group (median +27% with IQR -32 to +104%, p = 0.013). Based on the ROC curve, a threshold was chosen for a combined measure of ADR and alpha variability (AUC: 91.7, 95% CI 74.2-100). The median time that elapsed between change of qEEG and clinical DCI diagnosis was seven hours (IQR -11-25). Delay between qEEG and CT scan changes was 44 h (median, IQR 14-117). CONCLUSION: In this study, ADR and alpha variability could detect DCI development before ischemic changes on CT scan was apparent and before clinical deterioration was noted. Implementation of cEEG in aSAH patients can probably improve early detection of DCI.

Single Pulse Electrical Stimulation to identify epileptogenic cortex: Clinical information obtained from early evoked responses.

OBJECTIVE: Single Pulse Electrical Stimulation (SPES) probes epileptogenic cortex during electrocorticography. Two SPES responses are described: pathological delayed responses (DR, >100 ms) associated with the seizure onset zone (SOZ) and physiological early responses (ER, <100 ms) that map cortical connectivity. We analyzed properties of ERs, including frequencies >80 Hz, in the SOZ and seizure propagation areas. METHODS: We used data from 12 refractory epilepsy patients. SPES consisted of 10 pulses of 1 ms, 4-8 mA and 5s interval on adjacent electrodes pairs. Data were available at 2048 samples/s for six and 512 samples/s (22 bits) for eight patients and analyzed in the time-frequency (TF) and time-domain (TD). RESULTS: Electrodes with ERs were stronger associated with SOZ than non-SOZ electrodes. ERs with frequency content >80 Hz exist and are specific for SOZ channels. ERs evoked by stimulation of seizure onset electrodes were associated with electrodes involved in seizure propagation. CONCLUSION: Analysis of ERs can reveal aspects of pathology, manifested by association with seizure propagation and areas with high ER numbers that coincide with the SOZ. SIGNIFICANCE: Not only DRs, but also ERs could have clinical value for mapping epileptogenic cortex and help to unravel aspects of the epileptic network.

High frequency oscillations in intra-operative electrocorticography before and after epilepsy surgery.

OBJECTIVE: Removal of brain tissue showing high frequency oscillations (HFOs; ripples: 80-250Hz and fast ripples: 250-500Hz) in preresection electrocorticography (preECoG) in epilepsy patients seems a predictor of good surgical outcome. We analyzed occurrence and localization of HFOs in intra-operative preECoG and postresection electrocorticography (postECoG). METHODS: HFOs were automatically detected in one-minute epochs of intra-operative ECoG sampled at 2048Hz of fourteen patients. Ripple, fast ripple, spike, ripples on a spike (RoS) and not on a spike (RnoS) rates were analyzed in pre- and postECoG for resected and nonresected electrodes. RESULTS: Ripple, spike and fast ripple rates decreased after resection. RnoS decreased less than RoS (74% vs. 83%; p=0.01). Most fast ripples in preECoG were located in resected tissue. PostECoG fast ripples occurred in one patient with poor outcome. Patients with good outcome had relatively high postECoG RnoS rates, specifically in the sensorimotor cortex. CONCLUSIONS: Our observations show that fast ripples in intra-operative ECoG, compared to ripples, may be a better biomarker for epileptogenicity. Further studies have to determine the relation between resection of epileptogenic tissue and physiological ripples generated by the sensorimotor cortex. SIGNIFICANCE: Fast ripples in intra-operative ECoG can help identify the epileptogenic zone, while ripples might also be physiological.

Event-related mu-rhythm desynchronization during movement observation is impaired in Parkinson's disease.

OBJECTIVE: Patients with Parkinson's disease often experience difficulties in adapting movements and learning alternative movements to compensate for symptoms. Since observation of movement has been demonstrated to lead to the formation of a lasting specific motor memory that resembled that elicited by physical training we hypothesize that mu-rhythm desynchronization in response to movement observation is impaired in Parkinson's disease. METHOD: In a pilot study with nine patients with Parkinson's disease at a Hoehn and Yahr stage of I or II and eleven age-matched controls, we tested this hypothesis by comparing the event related desynchronization (ERD) patterns from the EEG recorded during the observation of hand action and baseline videos. RESULTS: Healthy subjects showed normal bilateral ERD of the mu-rhythm. In patients with Parkinson's disease this distinct ERD pattern was lacking. CONCLUSION: The results of this study suggest that event-related mu-rhythm desynchronization is impaired in Parkinson's disease, even at early stages of the disease. SIGNIFICANCE: Studying event-related mu-rhythm desynchronization dysfunction in Parkinson's disease patients may enhance our understanding of symptoms as impaired motor learning.

Differential cortical activation during observation and observation-and-imagination.

The activity of the brain during observation or imagination of movements might facilitate the relearning of motor functions after stroke. The present study examines whether there is an additional effect of imagination over observation-only. Eight healthy subjects observed and observed-and-imagined a movement of a hand; 64-channel EEG was used to measure brain activity. The synchronization of the theta (4-8 Hz), alpha (8-13 Hz) and beta (13-25 Hz) frequency bands was calculated and plotted in topoplots. The temporal changes of the sensorimotor area (C3, C4) and the centro-parietal cortex (Pz) were analyzed in the two experimental conditions. During observation-and-imagination, a significant larger desynchronization (p = 0.004) in the sensorimotor area was found compared to observation-only in all electrodes and frequency bands. In addition, temporal differences were found between observation and observation-and-imagination in the alpha frequency bands. During observation-and-imagination, modulations of EEG rhythms were stronger than during observation-only in the theta, alpha and beta frequency bands and during almost the whole activity fragment. These findings suggest an additive effect of imagination to observation in the rehabilitation after stroke.

Suppressors of interictal discharges in idiopathic childhood occipital epilepsy of Gastaut.

Idiopathic childhood occipital epilepsy of Gastaut (ICOE-G) is a rare form of epilepsy, characterized by visual hallucinations, periods of blindness, motor seizures, and migraine-like symptoms. A characteristic EEG feature is fixation-off sensitivity: epileptiform discharges are suppressed by visual input. Here, we present an 11-year-old girl suffering from ICOE-G, who was studied to identify potential additional suppressors of the epileptiform discharges.

Dynamic indices do not predict volume responsiveness in routine clinical practice.

BACKGROUND: Dynamic indices, including pulse pressure, systolic pressure, and stroke volume variation (PPV, SPV, and SVV), are accurate predictors of fluid responsiveness under strict conditions, for example, controlled mechanical ventilation using conventional tidal volumes (TVs) in the absence of cardiac arrhythmias. However, in routine clinical practice, these prerequisites are not always met. We evaluated the effect of regularly used ventilator settings, different calculation methods, and the presence of cardiac arrhythmias on the ability of dynamic indices to predict fluid responsiveness in sedated, mechanically ventilated patients. METHODS: We prospectively evaluated 47 fluid challenges in 29 consecutive cardiac surgery patients. Patients were divided into different groups based on TV. Dynamic indices were calculated in various ways: calculation over 30 s, breath-by-breath (with and without excluding arrhythmias), and with correction for TV. RESULTS: The predictive value was optimal in the group ventilated with TVs >7 ml kg(-1) with correction for TV, calculated breath-by-breath, and with exclusion of arrhythmias [area under the curve (AUC)=0.95, 0.93, and 0.90 for PPV, SPV, and SVV, respectively]. Including patients ventilated with lower TVs decreased the predictive value of all dynamic indices, while calculating dynamic indices over 30 s and not excluding cardiac arrhythmias further reduced the AUC to 0.51, 0.63, and 0.51 for PPV, SPV, and SVV, respectively. CONCLUSIONS: PPV, SPV, and SVV are the only reliable predictors of fluid responsiveness under strict conditions. In routine clinical practice, factors including low TV, cardiac arrhythmias, and the calculation method can substantially reduce their predictive value.

Predicting success of vagus nerve stimulation (VNS) from interictal EEG.

PURPOSE: Vagus nerve stimulation (VNS) has shown to be an effective treatment for drug resistant epilepsy in numerous patients, however, not in all. It is still not possible to predict which patients will profit from VNS. In this pilot study, we explore predictive interictal EEG features for seizure reduction after VNS. METHODS: 19 Patients with medically refractory epilepsy and an implanted VNS system were included. Interictal EEG registrations, recorded before implantation, were retrospectively analysed. A quantative symmetry measure, the pair wise derived brain symmetry index (pdBSI), was tested to predict VNS outcome. Reduction in seizure frequency was used to define the responders. RESULTS: 10 Patients did respond to VNS, of whom 7 patients had a seizure reduction of at least 50% in a follow-up period of 2 years. On average, we find higher pdBSI values for delta, theta, alpha and beta bands for non-responders than for responders. The average pdBSI of the theta and alpha bands could significantly discriminate between responders and non-responders. CONCLUSION: In this study, quantifying EEG symmetry using the pdBSI shows promising results in predicting the reduction of seizure frequency after VNS treatment.

Evaluation of the finger wrinkling test: a pilot study.

PURPOSE: Tilt table testing mainly evaluates the systemic cardiovascular part of the autonomic nervous system, while it is assumed that the finger wrinkling test assesses the peripheral part of the autonomic nervous system. In this study we explored whether the finger wrinkling test could be a useful test for autonomic dysfunction and whether the clinical evaluation of wrinkling can be improved by digital analysis of photographs. METHODS: As much as 20 healthy subjects and 15 patients underwent tilt table testing and finger wrinkling testing. During the finger wrinkling test the right hand was immersed in water at 40 degrees C. The degree of wrinkling was assessed with a 5-point clinical scale at baseline, 5, 15 and 30 min of immersion. Photographs were taken at the same intervals. Several features were evaluated using digital analysis: length and gradient of automatically detected wrinkle and mean, maximum, minimum, variance and derivative of grey value of pixels. RESULTS: Clinical scoring of wrinkling allowed differentiation between healthy subjects and patients with a normal and an abnormal response to tilt table testing. Relevant features obtained with digital analysis were mean grey value and the gradient of automatically detected wrinkle. McNemar's test showed no difference in test results between the tilt table test and the finger wrinkling test with a kappa of 0.68. CONCLUSION: The finger wrinkling test can be used as a screening test before tilt table testing. Visual evaluation of wrinkling is still superior to digital analysis of photographs.

The clinical use of drugs influencing neurotransmitters in the brain to promote motor recovery after stroke; a Cochrane systematic review.

The objective of this review was to compare and to discuss the results of studies that investigated the ability of drugs to improve motor recovery after stroke by influencing dopamine, norepinephrine, or serotonin concentrations in the brain. A systematic literature search up to January 2009 was conducted in MEDLINE, Pubmed, EMBASE and in the database of the Cochrane Stroke Group Trial Register. In addition, the literature reference lists of the relevant publications were checked. The literature search was conducted in order to identify randomized controlled trials focusing on the effects of drugs on motor recovery after stroke. In order to structure the data, motor recovery was sub-divided into motor control and motor function. The methodological quality of the studies was also assessed. Six studies, investigating the effects of 7 different kinds of drugs were included. Methodological scores varied between 10 and 14 (max 19). Motor control was not influenced by any of the drugs. Motor function improved in patients treated with methylphenidate, trazodone, and nortriptyline. Results for fluoxetine and levodopa were contradicting. There is insufficient evidence to conclude that neuromodulating drugs targeting serotonin, norepinephrine, or dopamine influence motor recovery after stroke.

Quetiapine in overdosage: a clinical and pharmacokinetic analysis of 14 cases.

Data on quetiapine overdosage are only sparsely available in the literature. This study provides additional data on the pharmacokinetics and clinical effects of intoxication with this atypical antipsychotic drug. The authors performed a retrospective analysis of all quetiapine intoxications reported to and screened by the toxicological laboratory of the Central Hospital Pharmacy The Hague between January 1999 and December 2003. Cases with known suggested amount of intake and medical outcome were included. From the patient's medical record and from the toxicological laboratory findings, patient demographic characteristics (gender, age), details of quetiapine intoxication (estimated time of ingestion, estimated amount of ingestion, and coingested drugs) and clinical parameters were obtained. Severity of intoxication was graded by the Poisoning Severity Score (PSS). Individual pharmacokinetic parameter values were calculated using a one-compartment open model and a Bayesian fitting procedure. Out of a total of 21 intoxications with quetiapine, 14 fulfilled the inclusion criteria. The ingested dose ranged from 1200 to 18,000 mg. The blood concentration ranged from 1.1 to 8.8 mg/L with a lag time of 1 to 26.2 hours between time of ingestion and blood sampling at the emergency ward. The most frequent findings were somnolence and tachycardia. The PSS was minor in 6 patients (43%), moderate in 5 patients (36%), and severe in 3 patients (21%). Severity of intoxication was not associated with a higher amount of quetiapine intake. The authors found no correlation between the serum concentration of quetiapine and the amount ingested. Elimination t(1/2) was not prolonged. It can be concluded that quetiapine intoxications appear to proceed mildly. Tachycardia and somnolence were the main clinical symptoms in our case series. No fatalities occurred. The severity of clinical symptoms was not associated with either a high serum concentration or the suggested amount ingested of quetiapine.

In vivo analysis of end-plate noise of human extensor digitorum brevis muscle after intramuscularly injected botulinum toxin type A.

To evaluate changes occurring in the neuromuscular junction after injection with botulinum neurotoxin type A (BoTx), three healthy volunteers were injected with 10 U BoTx in the right extensor digitorum brevis muscle. In agreement with previous observations, amplitude of compound muscle action potential (CMAP) decreased to approximately 30% of the initial value at approximately day 8 and slowly returned to baseline values around day 250. Values of the acetylcholine receptor (AChR) open time were determined by spectral analysis of end-plate noise and from single exponential fits to the decay phase of individual miniature end-plate potentials (MEPPs). At baseline, the mean channel open times determined by end-plate noise analysis and the exponential fits were 1.1 +/- 0.2 ms and 1.20 +/- 0.04 ms, respectively. After BoTx injection, initially no end-plate noise could be recorded. From day 9 onwards, however, a gradual recurrence of end-plate noise was observed, with mean channel open times of approximately 2-5 ms, being maximal between days 20 to 140. In addition, the shape of many recorded MEPPs was different from the typical fast rising MEPPs observed at baseline. After day 80, end-plate noise gradually returned to normal and mean channel open times decreased slowly to baseline values. Our findings reflect the changed AChR characteristics of newly formed neuromuscular junctions, which are created after BoTx injection and gradually removed after restoration of the original neuromuscular junctions.