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The white matter connectome as an individualized biomarker of language impairment in temporal lobe epilepsy.
ObjectiveThe distributed white matter network underlying language leads to difficulties in extracting clinically meaningful summaries of neural alterations leading to language impairment. Here we determine the predictive ability of the structural connectome (SC), compared with global measures of white matter tract microstructure and clinical data, to discriminate language impaired patients with temporal lobe epilepsy (TLE) from TLE patients without language impairment.MethodsT1- and diffusion-MRI, clinical variables (CVs), and neuropsychological measures of naming and verbal fluency were available for 82 TLE patients. Prediction of language impairment was performed using a robust tree-based classifier (XGBoost) for three models: (1) a CV-model which included demographic and epilepsy-related clinical features, (2) an atlas-based tract-model, including four frontotemporal white matter association tracts implicated in language (i.e., the bilateral arcuate fasciculus, inferior frontal occipital fasciculus, inferior longitudinal fasciculus, and uncinate fasciculus), and (3) a SC-model based on diffusion MRI. For the association tracts, mean fractional anisotropy was calculated as a measure of white matter microstructure for each tract using a diffusion tensor atlas (i.e., AtlasTrack). The SC-model used measurement of cortical-cortical connections arising from a temporal lobe subnetwork derived using probabilistic tractography. Dimensionality reduction of the SC was performed with principal components analysis (PCA). Each model was trained on 49 patients from one epilepsy center and tested on 33 patients from a different center (i.e., an independent dataset). Randomization was performed to test the stability of the results.ResultsThe SC-model yielded a greater area under the curve (AUC; .73) and accuracy (79%) compared to both the tract-model (AUC: .54, p < .001; accuracy: 70%, p < .001) and the CV-model (AUC: .59, p < .001; accuracy: 64%, p < .001). Within the SC-model, lateral temporal connections had the highest importance to model performance, including connections similar to language association tracts such as links between the superior temporal gyrus to pars opercularis. However, in addition to these connections many additional connections that were widely distributed, bilateral and interhemispheric in nature were identified as contributing to SC-model performance.ConclusionThe SC revealed a white matter network contributing to language impairment that was widely distributed, bilateral, and lateral temporal in nature. The distributed network underlying language may be why the SC-model has an advantage in identifying sub-components of the complex fiber networks most relevant for aspects of language performance
Epileptic neuronal networks: methods of identification and clinical relevance
The main objective of this paper is to examine evidence for the concept that epileptic activity should be envisaged in terms of functional connectivity and dynamics of neuronal networks. Basic concepts regarding structure and dynamics of neuronal networks are briefly described. Particular attention is given to approaches that are derived, or related, to the concept of causality, as formulated by Granger. Linear and non-linear methodologies aiming at characterizing the dynamics of neuronal networks applied to EEG/MEG and combined EEG/fMRI signals in epilepsy are critically reviewed. The relevance of functional dynamical analysis of neuronal networks with respect to clinical queries in focal cortical dysplasias, temporal lobe epilepsies, and “generalized” epilepsies is emphasized. In the light of the concepts of epileptic neuronal networks, and recent experimental findings, the dichotomic classification in focal and generalized epilepsy is re-evaluated. It is proposed that so-called “generalized epilepsies,” such as absence seizures, are actually fast spreading epilepsies, the onset of which can be tracked down to particular neuronal networks using appropriate network analysis. Finally new approaches to delineate epileptogenic networks are discussed
Stability and dynamics of a spectral graph model of brain oscillations
AbstractWe explore the stability and dynamic properties of a hierarchical, linearized, and analytic spectral graph model for neural oscillations that integrates the structural wiring of the brain. Previously, we have shown that this model can accurately capture the frequency spectra and the spatial patterns of the alpha and beta frequency bands obtained from magnetoencephalography recordings without regionally varying parameters. Here, we show that this macroscopic model based on long-range excitatory connections exhibits dynamic oscillations with a frequency in the alpha band even without any oscillations implemented at the mesoscopic level. We show that depending on the parameters, the model can exhibit combinations of damped oscillations, limit cycles, or unstable oscillations. We determined bounds on model parameters that ensure stability of the oscillations simulated by the model. Finally, we estimated time-varying model parameters to capture the temporal fluctuations in magnetoencephalography activity. We show that a dynamic spectral graph modeling framework with a parsimonious set of biophysically interpretable model parameters can thereby be employed to capture oscillatory fluctuations observed in electrophysiological data in various brain states and diseases
Interictal Network Dynamics in Paediatric Epilepsy Surgery
Epilepsy is an archetypal brain network disorder. Despite two decades of research
elucidating network mechanisms of disease and correlating these with outcomes, the clinical
management of children with epilepsy does not readily integrate network concepts. For
example, network measures are not used in presurgical evaluation to guide decision making
or surgical management plans.
The aim of this thesis was to investigate novel network frameworks from the perspective of
a clinician, with the explicit aim of finding measures that may be clinically useful and
translatable to directly benefit patient care. We examined networks at three different scales,
namely macro (whole brain diffusion MRI), meso (subnetworks from SEEG recordings) and
micro (single unit networks) scales, consistently finding network abnormalities in children
being evaluated for or undergoing epilepsy surgery. This work also provides a path to clinical
translation, using frameworks such as IDEAL to robustly assess the impact of these new
technologies on management and outcomes.
The thesis sets up a platform from which promising computational technology, that utilises
brain network analyses, can be readily translated to benefit patient care
Influence of deep structures on the EEG and their invasive and non-invasive assessment
Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Fisiología, leída el 22-11-2019El EEG es la prueba diagnóstica de mayor utilidad en el diagnóstico de la epilepsia. Consiste esencialmente en la representación gráfica de los potenciales postsinápticos generados en las neuronas piramidales de la corteza. Los campos eléctricos registrados en la superficie tienen principalmente dos mecanismos de origen: conducción de volumen desde regiones adyacentes y propagación interneuronal sináptica. Las neuronal piramidales se agrupan formando microcircuitos locales siendo estos circuitos los responsables de la generación delos ritmos registrados en el EEG. Uno de los principales retos de la electroencefalografía consiste en descifrar la relación entre la actividad registrada y la actividad subyacente en las redes neuronales. Para encontrar la fuente de dichas actividades, es necesario tener en cuenta complejos mecanismos tanto no lineales como lineales, así como el efecto de la conducción de volumen y la influencia de la morfología y las propiedades eléctricas del cerebro y el cráneo. Además, las regiones cerebrales se encuentran profusamente interconectadas a menudo produciendo una modulación recíproca que añade un mayor grado complejidad...The EEG is the most valuable diagnostic test in epilepsy. In essence, it mainly consists in agraphical representation of the summated postsynaptic potentials generated in the pyramidal neurons from the cortex. The electrical fields can be generated on the scalp by two mechanisms: volume conduction from nearby regions and synaptic inter‐neuronal propagation. Pyramidal cells align conforming local microcircuit configurations which activation lead to the generation of EEG rhythms. One of the main challenges of EEG is to decipher the relation between the recorded EEG activity and the activity in the neuronal networks. To find the source of EEG activity, complex non‐linear and linear mechanisms as well as volume conduction effect and influence of the shape and electrical properties of the brain and skull need to be taken in consideration. In addition, brain regions are profusely interconnected and functionally connected regions often produce mutual modulation that adds additional complexity...Depto. de FisiologíaFac. de MedicinaTRUEunpu
Biochemical investigations into problems relating to epilepsy
Investigations have been carried out in three separate areas
of research related to epilepsy.I. In the first of these investigations an attempt was made to
clarify a possible role of folic acid derivatives in epilepsy.
This investigation took the form of two self- contained studies
involving dogs.A. The first study concerned the effects of anticonvulsant
treatment on
(a) folate activity in cerebrospinal fluid (c.s.f.).
(b) the concentrations of 5- hydroxyindol- 3- ylacetic
acid (5 -HIAA) and hornovanillic acid (HVA) in c.s.f.Routine sampling of ventricular and cisternal c.s.f.
in the dog was achieved by the implantation of permanent
guide tubes to the lateral ventricle and the cisterna magna.
5 -HIAA and HVA in c.s.f. samples were estimated by fluorescence assay techniques. Folate activity in c.s.f. and
plasma samples was estimated microbiologically with a folatedependent strain of 1. casei.In control studies the c.s.f. folate activity was found
to be between 2 and 7 times higher than the plasma folate
activity. A positive correlation was found between c.s.f.
and plasma folate activities. HVA and 5 -HIAA studies confirmed the concentration gradient which exists for these two acids between the lateral ventricular c.s.f. and the
cisternal c.s.f.Selected anticonvulsant drugs (diphenylhydantoin,
7.5 mg/kg; phenobarbitone, 15 mg/kg; sulthiame 15 mg/kg;
carbamazepine 15 mg /kg) were administered daily to the dogs
for a period of five weeks. During this Period no change
was seen in the folate activity of either c.s.f. or plasma.
The anticonvulsants were also without effect on the concentrations of HVA and 5 -HIAA in c.s.f.These findings are discussed in relation to the folate
deficiency states produced in man by chronic anticonvulsant
therapy.B. The second study in the folate investigations was
concerned with the effect of oral folic acid administration
(a) folate activity in plasma, plasma ultrafiltrate
and c.s.f.
(b) the concentrations of HVA and 5 -HIAA in the c.s.f.During the control period of this study no correlation
was found between c.s.f. and plasma folate activity, such as
was found in the first study. Possible reasons to account
for this discrepancy are discussed. Estimation of folate
activity in plasma and plasma ultrafiltrate confirmed that
much of the folate activity in dog plasma is protein- bound.Folic acid (31 mg/kg) was administered daily to dogs
over a 5 -week period. During this treatment period the
mean plasma folate activity was 10 times higher than normal;
plasma ultrafiltrate folate activity was 5 times higher the
normal; but c.s.f. folate activity was unchanged. These
findings were interpreted as evidence for an increased plasma
level of a folate derivative, probably folic acid itself,
which was more strongly bound to protein than normal plasma
folate derivatives, and was unable to enter the c.s.f. In
two experiments in the rabbit no evidence was found for the
active transport of methyl -tetrahydrofolate (normally the
predominant form of folate in the plasma) into the c.s.f.
HVA and 5 -HIAA concentrations in the c.s.f. were unaltered
during the period of folic acid treatment. It was concluded
that oral folic acid administration is unlikely to have any
significant effect on normal cerebral function.The implications of this study are discussed in relation
to
(a) the role of folic acid derivatives in epilepsy
and mental illness.
(b) the mechanisms responsible for the normal distribution of folate activity between c.s.f. and plasma.II. The second investigation concerned the effects of barbiturate
anaesthetics and anticonvulsant drugs on the c.s.f. potassium
fluxes of the conscious dog.A new technique was developed for "open" perfusion of the
cerebroventricular system of the conscious dog. The dog was
perfused from lateral ventricle to cisterna magna with artificial
r c.s.f. containing inulin, and tracer amounts of 42K. K, total
potassium and inulin assays were performed on the inflow and out - flow fluids. From this data it was possible to calculate, for
each sample of outflow fluid collected, values for both the potassium efflux from, and the potassium influx into, the c.s.f.
After a period of between 65 -100 minutes of perfusion a "steady - state" was reached in which the potassium fluxes, as measured by
this technique, were relatively constant. Drugs actions were
studied by administering the drug during the "steady- state" period
and ascertaining the effect upon the "steady- state" potassium
fluxes.It was shown that -
(1) The barbiturate anaesthetics, sodium pentobarbitone and
o sodium thipentone, in doses sufficient to induce light
anaesthesia, may depress both potassium influx into, and
potassium efflux from c.s.f. Both fluxes were affected
equally on any one occasion. Flux alterations of up to
50% were observed.
(2) Diazepam has a consistent depressant effect on the
potassium fluxes of the c.s.f. This effect was less marked,
but more consistently observed, than in the case of the
barbiturate anaesthetics.
- v -
(3) Diphenylhydantoin has no significant effect on potassium
efflux from the c.s.f. but may have a slight depressant
effect on potassium influx into the c.s.f.
(4) Paraldehyde in a dose sufficient to induce light
anaesthesia slightly increases the c.s.f. potassium fluxes.
These results are discussed in relation to
(a) previously published studies on c.s.f. potassium
fluxes in anaesthetised animals
(b) possible mechanisms of action of these drugs.The effects of the barbiturate anaesthetics and diazepam were
interpreted as being secondary to a decrease in potassium exchange
between brain intracellular and entracellular compartments.It was concluded that the anaesthetic or anticonvulsant
action of a drug is not related to the drug's effect on c.s.f.
potassium fluxes.III. The third investigation concerned the development and preliminary application of a method for the analysis of GABA and
associated amino acids in small areas of tissue from the primary
and secondary epileptic foci of rats with a cobalt- induced epileptogenic lesion.The existing specific enzymic methods for GABA analysis were
examined and found to be either too insensitive or too complex to
act as suitable micro- methods. The standard techniques for amino
acid analysis, involving column separation and colorimetric estimation were also considered to be too insensitive.Reaction of the amino group of amino acids with 1- dimethyl- amnonapthalene-5- sulphonyl chloride (dansyl chloride) produces stable,
highly- fluorescent derivatives which can be readily separated by
thin -layer chromatography.A highly sensitive isotope dilution assay, based on the preparation of dansyl derivatives, was evolved for the estimation of
free amino acids in brain tissue.The tissue was homogenised in perchloric acid and known amounts
of ¹⁴C -amino acid standards were added to an aliquot of the perchlorate extract to act as internal standards for recovery of
amino acid through the method. The extract was then taken to pH
9.3 - 9.8 with potassium carbonate solution, precipitating perchlorate as its insoluble potassium salt. An aliquot of the
alkaline extract was dansylated with an equal volume of H³-dansyl
chloride in acetone. After a 30 minute reaction period the
dansylation mixture was taken to dryness and extracted with acetone:
glacial acetic acid solution (3:2). An aliquot of this extract
was applied to a polyamide micro- chromatography plate which was
then developed in two dimensions. Under u.v. light specific
dansyl -amino acid spots were identified by their characteristic
position on the developed plate. These spots were cut from the
plate and counted for ³H and ¹⁴C activity in a liquid scintillation
counter.The total amount of dansyl-amino acid in a spot was calculated
from its ³H activity. Combining this figure with the ¹⁴C activity
of the spot allowed calculation of the specific activity (w.r.t.
¹⁴C) of the dansyl-amino acid in the spot. Comparison of this
specific activity with the specific activity of the ¹⁴C -amino acid
standard which had been added as a recovery standard gave a measure
of the dilution of exogenous radioactive amino acid by endogenous
non-radioactive amino acid. From this dilution factor it was
possible to calculate the concentration of endogenous amino acid
in the original perchlorate extract of brain tissue. Determination of the weight of protein precipitated from the tissue sample
by the perchloric acid extraction allowed calculation of the amino
acid content of tissue in terms of }moles amino acid per 100 mg
protein.The two dimensional chromatography did not achieve a separation
of dansyl glutamine and dansyl -threonine; as a result glutamine
and threonine were estimated as the sum total of their two
concentrations.The method was applied to the estimation of control values
for GABA, glutamate, glutamine/threonine, glycine, aspartate and
hydroxyproline levels in rat cortex. The values obtained for
GABA, glutamate, glutamine /threonine and glycine were highly reproducible and in good agreement with previously published values.
Aspartate was not satisfactorily estimated. Hyroxyproline was
not detected in rat cortex.The dansylation method was applied to the analysis of brain
tissue from three rats with 11 day-old cobalt-induced epileptogenic
lesions in the frontal cortex. There was evidence that GABA and
glutamate levels were lowered, and glutamine/threonine and glycine
levels raised, in the region of the secondary epileptogenic
( "mirror ") focus. This was the site from which epileptiform spike
discharges were most frequent.The significance of these findings have been discussed along
with general comments on the problems of amino acid studies in
brain. It was concluded that disorders in amino acid metabolism
may be involved in epileptic processes
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