Neurofilament-light in former athletes: a potential biomarker of neurodegeneration and progression.

BACKGROUND/OBJECTIVE: This study aimed to evaluate serum neurofilament light chain (NF-L) levels in former professional contact sports athletes with multiple concussions (ExPro) as a potential biomarker of neurodegeneration and predictor of white-matter (WM) abnormality progression. METHODS: Concentrations of NF-L in the serum of fifty-two cognitively normal ExPro and twenty-one healthy controls (HC) with no history of concussions were measured using single molecule array (Simoa) technology. Both groups underwent neuroimaging at the time of serum collection. Eighteen of the participants in the ExPro underwent follow-up imaging after 2 years. RESULTS: Levels of serum NF-L were not significantly different between the ExPro and HC. However, in the ExPro group, NF-L levels were positively correlated with the mean diffusivity (MD) of corpus callosum (CC) and fornix, and total ventricular volume. Moreover, NF-L levels in the ExPro group at the first visit were positively correlated with the amount of increase in CC MD at the 2-year follow-up. CONCLUSIONS: NF-L levels reflect neuronal changes in the ExPro group and predict the extent of decrease in white matter integrity over time. Serum NF-L might be a biomarker of neurodegeneration and WM abnormality progression in ExPro.

Measures of entropy and complexity in altered states of consciousness.

Quantification of complexity in neurophysiological signals has been studied using different methods, especially those from information or dynamical system theory. These studies have revealed a dependence on different states of consciousness, and in particular that wakefulness is characterized by a greater complexity of brain signals, perhaps due to the necessity for the brain to handle varied sensorimotor information. Thus, these frameworks are very useful in attempts to quantify cognitive states. We set out to analyze different types of signals obtained from scalp electroencephalography (EEG), intracranial EEG and magnetoencephalography recording in subjects during different states of consciousness: resting wakefulness, different sleep stages and epileptic seizures. The signals were analyzed using a statistical (permutation entropy) and a deterministic (permutation Lempel-Ziv complexity) analytical method. The results are presented in complexity versus entropy graphs, showing that the values of entropy and complexity of the signals tend to be greatest when the subjects are in fully alert states, falling in states with loss of awareness or consciousness. These findings were robust for all three types of recordings. We propose that the investigation of the structure of cognition using the frameworks of complexity will reveal mechanistic aspects of brain dynamics associated not only with altered states of consciousness but also with normal and pathological conditions.

Comparison between Bilistick System and transcutaneous bilirubin in assessing total bilirubin serum concentration in jaundiced newborns.

OBJECTIVE: To compare the performance and accuracy of the JM-103 transcutaneous bilirubinometer and Bilistick System in measuring total serum bilirubin for the early identification of neonatal hyperbilirubinemia. STUDY DESIGN: The study was performed on 126 consecutive term and near-term (⩾36 weeks' gestational age) jaundiced newborns in Cairo University Children Hospital NICU, Egypt. Total serum bilirubin was assayed concurrently by the clinical laboratory and Bilistick System and estimated using the JM-103 transcutaneous bilirubin instrument. Bland-Altman analysis was used to evaluate the agreement between determinations. RESULT: The limits of agreement of the Bilistick System (-5.8 to 3.3 mg dl-1) and JM-103 system (-5.4 to 6.0 mg dl-1) versus the clinical laboratory results were similar. CONCLUSION: The Bilistick System is an accurate alternative to transcutaneous (TcB) determination for early diagnosis and proper management of the neonatal jaundice.

Consciousness as a global property of brain dynamic activity.

We seek general principles of the structure of the cellular collective activity associated with conscious awareness. Can we obtain evidence for features of the optimal brain organization that allows for adequate processing of stimuli and that may guide the emergence of cognition and consciousness? Analyzing brain recordings in conscious and unconscious states, we followed initially the classic approach in physics when it comes to understanding collective behaviours of systems composed of a myriad of units: the assessment of the number of possible configurations (microstates) that the system can adopt, for which we use a global entropic measure associated with the number of connected brain regions. Having found maximal entropy in conscious states, we then inspected the microscopic nature of the configurations of connections using an adequate complexity measure and found higher complexity in states characterized not only by conscious awareness but also by subconscious cognitive processing, such as sleep stages. Our observations indicate that conscious awareness is associated with maximal global (macroscopic) entropy and with the short time scale (microscopic) complexity of the configurations of connected brain networks in pathological unconscious states (seizures and coma), but the microscopic view captures the high complexity in physiological unconscious states (sleep) where there is information processing. As such, our results support the global nature of conscious awareness, as advocated by several theories of cognition. We thus hope that our studies represent preliminary steps to reveal aspects of the structure of cognition that leads to conscious awareness.

Statistical mechanics of consciousness: Maximization of information content of network is associated with conscious awareness.

It is said that complexity lies between order and disorder. In the case of brain activity and physiology in general, complexity issues are being considered with increased emphasis. We sought to identify features of brain organization that are optimal for sensory processing, and that may guide the emergence of cognition and consciousness, by analyzing neurophysiological recordings in conscious and unconscious states. We find a surprisingly simple result: Normal wakeful states are characterized by the greatest number of possible configurations of interactions between brain networks, representing highest entropy values. Therefore, the information content is larger in the network associated to conscious states, suggesting that consciousness could be the result of an optimization of information processing. These findings help to guide in a more formal sense inquiry into how consciousness arises from the organization of matter.

A decision-making tool for exchange transfusions in infants with severe hyperbilirubinemia in resource-limited settings.

Late presentation and ineffective phototherapy account for excessive rates of avoidable exchange transfusions (ETs) in many low- and middle-income countries. Several system-based constraints sometimes limit the ability to provide timely ETs for all infants at risk of kernicterus, thus necessitating a treatment triage to optimize available resources. This article proposes a practical priority-setting model for term and near-term infants requiring ET after the first 48 h of life. The proposed model combines plasma/serum bilirubin estimation, clinical signs of acute bilirubin encephalopathy and neurotoxicity risk factors for predicting the risk of kernicterus based on available evidence in the literature.

Frontotemporal correlates of impulsivity and machine learning in retired professional athletes with a history of multiple concussions.

The frontotemporal cortical network is associated with behaviours such as impulsivity and aggression. The health of the uncinate fasciculus (UF) that connects the orbitofrontal cortex (OFC) with the anterior temporal lobe (ATL) may be a crucial determinant of behavioural regulation. Behavioural changes can emerge after repeated concussion and thus we used MRI to examine the UF and connected gray matter as it relates to impulsivity and aggression in retired professional football players who had sustained multiple concussions. Behaviourally, athletes had faster reaction times and an increased error rate on a go/no-go task, and increased aggression and mania compared to controls. MRI revealed that the athletes had (1) cortical thinning of the ATL, (2) negative correlations of OFC thickness with aggression and task errors, indicative of impulsivity, (3) negative correlations of UF axial diffusivity with error rates and aggression, and (4) elevated resting-state functional connectivity between the ATL and OFC. Using machine learning, we found that UF diffusion imaging differentiates athletes from healthy controls with significant classifiers based on UF mean and radial diffusivity showing 79-84 % sensitivity and specificity, and 0.8 areas under the ROC curves. The spatial pattern of classifier weights revealed hot spots at the orbitofrontal and temporal ends of the UF. These data implicate the UF system in the pathological outcomes of repeated concussion as they relate to impulsive behaviour. Furthermore, a support vector machine has potential utility in the general assessment and diagnosis of brain abnormalities following concussion.

Bilistick: a low-cost point-of-care system to measure total plasma bilirubin.

BACKGROUND: Severe neonatal hyperbilirubinemia, with consequent encephalopathy, remains a common cause of morbidity and death in many regions of the world. Poor access to clinical laboratory resources and screening programs to measure plasma bilirubin levels is a major contributor to delayed treatment in developing countries, and the cost of existing point-of-care screening instruments precludes their dissemination. OBJECTIVES: We are evaluating the accuracy of a low-cost, minimally invasive point-of-care system (Bilistick) requiring a 25-µl blood sample that could be used in low-resource environments to evaluate patients with neonatal jaundice. METHODS: We compared plasma bilirubin levels in divided blood samples by clinical laboratories and by Bilistick at two medical centers serving term and near-term newborns from ethnically different populations. RESULTS: 118 neonates with bilirubin levels ranging from 24.8 to 501.0 µmol/l were analyzed. The mean bilirubin concentration (±SD) was 215.6 ± 85.5 µmol/l for Bilistick and 226.1 ± 86.4 µmol/l by laboratory determination. Pearson's correlation coefficient between all paired results was 0.961, and the Bland-Altman analysis showed a mean difference of 10.3 µmol/l with a 95% interval of agreement of -38.0 to 58.7 µmol/l. CONCLUSION: Bilistick is a minimally invasive method for measuring total bilirubin concentration over a wide range of values and should provide an affordable and accurate system for pre-discharge and follow-up screening of jaundiced infants, particularly in low-resource environments.

The contribution of 18F-FDG PET in preoperative epilepsy surgery evaluation for patients with temporal lobe epilepsy A meta-analysis.

OBJECTIVE: To assess the predictive diagnostic added value of positron emission tomography (PET) in preoperative epilepsy surgery evaluation for patients with temporal lobe epilepsy (TLE). METHODS: A meta-analysis of publications from 1992 to 2006 was performed. Forty-six studies were identified that met inclusion criteria presenting detailed diagnostic test results and a classified postoperative outcome. Studies exclusively reporting on patients with brain tumors or on children were excluded. RESULTS: The analyses were complicated by significant differences in study design and often by lack of precise patient data. Ipsilateral PET hypometabolism showed a predictive value of 86% for good outcome. The predictive value was 80% in patients with normal MRI and 72% in patients with non-localized ictal scalp EEG. In a selected population of 153 TLE patients with a follow-up of >12 months PET correlated well with other non-invasive diagnostic tests, but none of the odds ratios of any test combination was significant. CONCLUSION: Our data confirm that ipsilateral PET hypometabolism may be an indicator for good postoperative outcome in presurgical evaluation of drug-resistant TLE, although the actual diagnostic added value remained questionable and unclear. PET does not appear to add value in patients localized by ictal scalp EEG and MRI. Prospective studies limited to non-localized ictal scalp EEG or MRI-negative patients are required for validation.

Complex phase synchronization in epileptic seizures: evidence for a devil's staircase.

We describe multifrequency phase synchronization in epileptic seizures. Using magnetoencephalographic recordings from three patients suffering generalized seizures, the evidence is presented that, in addition to the commonly studied 1:1 frequency locking, there exists complex multifrequency coordination that, in some cases, follows a classical "devil's staircase." Within the limitations of observing this phenomenon in a clinical experimental setting, these observations reveal that in pathological brain activity, complex frequency locking can be found similar to that identified in certain pathological cardiac re-entrant arrhythmias. This may suggest the existence of similar re-entrant mechanisms active in cerebral neocortex during epileptic seizures.

Movement disorders in patients taking anticonvulsants.

BACKGROUND: A wide variety of movement disorders may occur as a consequence of the administration of antiepileptic drugs (AEDs). Although it has been suggested that the risk of parkinsonism is 10-fold higher in those taking valproate as compared with other AEDs, there have been no large, systematic trials assessing this. AIM: To establish more precisely the prevalence of and risk factors for developing parkinsonism associated with valproate use,and to assess the occurrence of movement disorders with the newer AEDs. METHODS: Patients with epilepsy were recruited from the Toronto Western Hospital Epilepsy Clinic (University of Toronto, Toronto, Ontario, Canada). Each patient was examined by a movement disorder specialist who was blinded to the treatment status of the patient. RESULTS: 201 patients were included. Postural tremor was the most common movement disorder (45%), followed by parkinsonism (4.5%). The odds of having parkinsonism were 5 times higher with valproate than with other AEDs. No single factor predicted the presence of parkinsonism; however, many (5/9) of the patients concurrently used other drugs or had comorbidities that could have caused or exacerbated parkinsonism. None of the newer AEDs were clearly associated with the presence of movement disorders; however, the numbers were too small to make a formal analysis. CONCLUSION: Although the risk of parkinsonism with valproate is higher than with other AEDs, it is lower than originally reported. The cases available were not enough to accurately comment on the prevalence of movement disorders with the newer AEDs.

The role of 1H magnetic resonance spectroscopy in pre-operative evaluation for epilepsy surgery. A meta-analysis.

PURPOSE: We aimed to assess the additional pre-operative value of (1)H MRS in identifying the epileptogenic zone (EZ) for epilepsy surgery by performing a meta-analysis considering publications from 1992 to 2003. METHODS: From an extensive computer and hand search 22 studies were included. For inclusion, studies had to report post-operative outcome and detailed diagnostic test results for each individual patient. Studies exclusively reporting on patients with brain tumors or on children were excluded. RESULTS: Great heterogeneity among studies regarding methodological and technical aspects and concerning evaluation and interpretation of data was observed. Only patients with intractable temporal lobe epilepsy were presented. Sixty-four percent of all patients and 72% of patients with good outcome had an ipsilateral MRS abnormality concordant with the EZ. The positive predictive value of all patients with ipsilateral MRS abnormality for good outcome was 82%. An odds ratio weighted by inverse variance showed a 4.891 better chance of seizure free outcome [CI=1.965-12.172; Q=2.748; d.f.=5; critical chi2-value=11.07] in patients with an ipsilateral MRS abnormality when compared to patients with bilateral MRS abnormalities. Data for MRI-negative patients were conflicting. One study stressed a role for MRS in patients with bilateral hippocampal atrophy at MRI. CONCLUSIONS: MRS still remains a research tool with clinical potential. Our findings indicate the connection of ipsilateral MRS abnormality to good outcome. The ability for prediction of post-operative outcome may depend on the assessed population. Prospective studies limited to non-localized ictal scalp EEG or MRI-negative patients are required for validation of these data.

Bidirectional multisite seizure propagation in the intact isolated hippocampus: the multifocality of the seizure "focus".

Localizing the seizure focus is difficult and frequently, multiple sites are found. This reflects our poor understanding of the fundamental mechanisms of seizure generation and propagation. We used multisite electrophysiological recordings in two seizure models and voltage-sensitive dye imaging, to spatiotemporally characterize the initiation and propagation of seizures in an intact epileptogenic brain region, the isolated hippocampus. In low-magnesium perfusate, seizures always originated in the temporal region, and propagated along the septotemporal axis to the septal region. After the seizure spread across the hippocampus, the bursts within a seizure became bidirectional, with different propagation patterns at different frequencies. When the intact hippocampus was separated along the septotemporal axis, independent bidirectional activity was observed in the two halves, and region-specific cuts to the tissue reveal that the CA3 region is critical for seizure generation and propagation. In a second seizure model, using focal tetanic stimulation of the septal and temporal CA3 region, seizures always originated at the stimulated site with bidirectionality later developing at different frequencies, as noted in the low magnesium model, behavior compatible with coupled neuronal network oscillators. These data provide novel insights into the dynamic multifocality of seizure onset and propagation, revealing that the current concept of a single seizure "focus" is complex.

Long-term follow-up of patients with thalamic deep brain stimulation for epilepsy.

The authors describe long-term follow-up (mean, 5 years) in patients with anterior (AN) (n = 6) or centromedian (n = 2) thalamic deep brain stimulation (DBS) for epilepsy. Five patients (all AN) had > or = 50% seizure reduction, although benefit was delayed in two until years 5 to 6, after changes in antiepileptic drugs. DBS electrode implantation in AN patients was followed by seizure reduction 1 to 3 months before active stimulation, raising the possibility of a beneficial microthalamotomy effect.

Changes in motor cortex excitability with stimulation of anterior thalamus in epilepsy.

BACKGROUND: Deep brain stimulation (DBS) is an effective treatment for movement disorders and pain. Recently, bilateral DBS of the anterior nucleus of thalamus (AN) was performed for the treatment of intractable epilepsy. This surgery reduced seizure frequency in an initial group of patients. However, its physiologic effects on the cortex and mechanisms of action remain poorly understood. Different classes of antiepileptic drugs (AEDs) have distinct effects on the excitatory and inhibitory circuits in the motor cortex, which can be studied noninvasively by transcranial magnetic stimulation (TMS). OBJECTIVE: To examine the effects of bilateral AN DBS on motor cortex excitability in epilepsy and compare these to the known effects of AEDs. METHODS: Cortical excitability was assessed in five medicated epilepsy patients with bilateral stimulators implanted in the anterior thalamus and nine healthy controls. Single and paired TMS were used to examine cortical inhibitory and facilitatory circuits. Electromyography was recorded from the dominant hand, and TMS was applied over the contralateral motor cortex. Patients were studied during DBS turned off (OFF condition), DBS with cycling stimulation mode (1 minute on, 5 minutes off; CYCLE), and DBS with continuous stimulation (CONTINUOUS) in random order on 3 consecutive days. RESULTS: Motor thresholds were increased in the patients regardless of DBS condition. Active short-interval intracortical inhibition (SICI) was significantly reduced in the OFF and CYCLE conditions but returned toward normal levels in the CONTINUOUS condition. Rest SICI, long interval intracortical inhibition, and silent period duration were unchanged. CONCLUSIONS: Increased short-interval intracortical inhibition with continuous deep brain stimulation (DBS) suggests that thalamic DBS might drive cortical inhibitory circuits, similar to antiepileptic drugs that enhance gamma-aminobutyric acid inhibition.

H2(15)O or 13NH3 PET and electromagnetic tomography (LORETA) during partial status epilepticus.

The authors evaluated the feasibility and source localization utility of H2(15)O or 13NH3 PET and low-resolution electromagnetic tomography (LORETA) in three patients with partial status epilepticus (SE). Results were correlated with findings from intraoperative electrocorticographic recordings and surgical outcomes. PET studies of cerebral blood flow and noninvasive source modeling with LORETA using statistical nonparametric mapping provided useful information for localizing the ictal activity in patients with partial SE.

Estimation of coupling between oscillators from short time series via phase dynamics modeling: limitations and application to EEG data.

We demonstrate in numerical experiments that estimators of strength and directionality of coupling between oscillators based on modeling of their phase dynamics [D. A. Smirnov and B. P. Bezruchko, Phys. Rev. E 68, 046209 (2003)] are widely applicable. Namely, although the expressions for the estimators and their confidence bands are derived for linear uncoupled oscillators under the influence of independent sources of Gaussian white noise, they turn out to allow reliable characterization of coupling from relatively short time series for different properties of noise, significant phase nonlinearity of the oscillators, and nonvanishing coupling between them. We apply the estimators to analyze a two-channel human intracranial epileptic electroencephalogram (EEG) recording with the purpose of epileptic focus localization.

EEG nonstationarity during intracranially recorded seizures: statistical and dynamical analysis.

OBJECTIVE: The investigation of nonstationarity in complex, multivariable signals, such as electroencephalographic (EEG) recordings, requires the application of different and novel approaches to analysis. In this study, we have divided the EEG recordings during epileptic seizures into sequential stages using spectral and statistical analysis, and have as well reconstructed discrete-time models (maps) that reflect dynamical (deterministic) properties of the EEG voltage time series. METHODS: Intracranial human EEG recordings with epileptic seizures from three different subjects with medically intractable temporal lobe epilepsy were studied. The methods of statistical (power spectra, wavelet spectra, and one-dimensional probability distribution functions) and dynamical (comparison of dynamical models) nonstationarity analysis were applied. RESULTS: Dynamical nonstationarity analysis revealed more detailed inner structure within the seizures than the statistical analysis. Three or four stages with different dynamics are typically present within seizures. The difference between interictal activity and seizure events was also more evident through dynamical analysis. CONCLUSIONS: Nonstationarity analysis can reveal temporal structure within an epileptic seizure, which could further understanding of how seizures evolve. The method could also be used for identification of seizure onset. SIGNIFICANCE: Our approach reveals new information about the temporal structure of seizures, which is inaccessible using conventional methods.