Focal to bilateral tonic-clonic seizures are associated with lower quality of life, higher risk of seizure-related injuries, increased chance of sudden unexpected death, and unfavourable treatment ...outcomes. Achieving greater understanding of their underlying circuitry offers better opportunity to control these seizures. Towards this goal, we provide a network science perspective of the interactive pathways among basal ganglia, thalamus and cortex, to explore the imprinting of secondary seizure generalization on the mesoscale brain network in temporal lobe epilepsy. Specifically, we parameterized the functional organization of both the thalamocortical network and the basal ganglia-thalamus network with resting state functional MRI in three groups of patients with different focal to bilateral tonic-clonic seizure histories. Using the participation coefficient to describe the pattern of thalamocortical connections among different cortical networks, we showed that, compared to patients with no previous history, those with positive histories of focal to bilateral tonic-clonic seizures, including both remote (none for >1 year) and current (within the past year) histories, presented more uniform distribution patterns of thalamocortical connections in the ipsilateral medial-dorsal thalamic nuclei. As a sign of greater thalamus-mediated cortico-cortical communication, this result comports with greater susceptibility to secondary seizure generalization from the epileptogenic temporal lobe to broader brain networks in these patients. Using interregional integration to characterize the functional interaction between basal ganglia and thalamus, we demonstrated that patients with current history presented increased interaction between putamen and globus pallidus internus, and decreased interaction between the latter and the thalamus, compared to the other two patient groups. Importantly, through a series of 'disconnection' simulations, we showed that these changes in interactive profiles of the basal ganglia-thalamus network in the current history group mainly depended upon the direct but not the indirect basal ganglia pathway. It is intuitively plausible that such disruption in the striatum-modulated tonic inhibition of the thalamus from the globus pallidus internus could lead to an under-suppressed thalamus, which in turn may account for their greater vulnerability to secondary seizure generalization. Collectively, these findings suggest that the broken balance between basal ganglia inhibition and thalamus synchronization can inform the presence and effective control of focal to bilateral tonic-clonic seizures. The mechanistic underpinnings we uncover may shed light on the development of new treatment strategies for patients with temporal lobe epilepsy.
Summary Epileptic seizures are generally unpredictable and arise spontaneously. Patients often report non-specific triggers such as stress or sleep deprivation, but only rarely do seizures occur as a ...reflex event, in which they are objectively and consistently modulated, precipitated, or inhibited by external sensory stimuli or specific cognitive processes. The seizures triggered by such stimuli and processes in susceptible individuals can have different latencies. Once seizure-suppressing mechanisms fail and a critical mass (the so-called tipping point) of cortical activation is reached, reflex seizures stereotypically manifest with common motor features independent of the physiological network involved. The complexity of stimuli increases from simple sensory to complex cognitive-emotional with increasing age of onset. The topography of physiological networks involved follows the posterior-to-anterior trajectory of brain development, reflecting age-related changes in brain excitability. Reflex seizures and traits probably represent the extremes of a continuum, and understanding of their underlying mechanisms might help to elucidate the transition of normal physiological function to paroxysmal epileptic activity.
Recent work has demonstrated that the relationship between structural and functional connectivity varies regionally across the human brain, with reduced coupling emerging along the ...sensory-association cortical hierarchy. The biological underpinnings driving this expression, however, remain largely unknown. Here, we postulate that intracortical myelination and excitation-inhibition (EI) balance mediate the heterogeneous expression of structure-function coupling (SFC) and its temporal variance across the cortical hierarchy. We employ atlas- and voxel-based connectivity approaches to analyze neuroimaging data acquired from two groups of healthy participants. Our findings are consistent across six complementary processing pipelines: 1) SFC and its temporal variance respectively decrease and increase across the unimodal-transmodal and granular-agranular gradients; 2) increased myelination and lower EI-ratio are associated with more rigid SFC and restricted moment-to-moment SFC fluctuations; 3) a gradual shift from EI-ratio to myelination as the principal predictor of SFC occurs when traversing from granular to agranular cortical regions. Collectively, our work delivers a framework to conceptualize structure-function relationships in the human brain, paving the way for an improved understanding of how demyelination and/or EI-imbalances induce reorganization in brain disorders.
Genetic generalized epilepsies (GGE), previously called idiopathic generalized epilepsies, constitute about 20% of all epilepsies, and include childhood absence epilepsy, juvenile absence epilepsy, ...juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone (CAE, JAE, JME, and GGE-GTCS, respectively). GGE are characterized by high heritability, likely underlain by polygenetic mechanisms, which may relate to atypical neurodevelopmental trajectories. Age of onset ranges from pre-school years, for CAE, to early adulthood for GGE-GTCS. Traditionally, GGE have been considered benign, a belief contrary to evidence from neuropsychology studies conducted over the last two decades. In JME, deficits in executive and social functioning are common findings and relate to impaired frontal lobe function. Studies using neuropsychological measures and cognitive imaging paradigms provide evidence for hyperconnectivity between prefrontal and motor cortices, aberrant fronto-thalamo-cortical connectivity, and reduced fronto-cortical and subcortical gray matter volumes, which are associated with altered cognitive performance. Recent research has also identified associations between abnormal hippocampal morphometry and fronto-temporal activation during episodic memory. Longitudinal studies on individuals with newly diagnosed JME have observed cortical dysmaturation, which is paralleled by delayed cognitive development compared to the patients' peers. Comorbidities and cognitive deficits observed in other GGE subtypes, such as visuo-spatial and language deficits in both CAE and JAE, have also been correlated with atypical neurodevelopment. Although it remains unclear whether cognitive impairment profiles differ amongst GGE subtypes, effects may become more pronounced with disease duration, particularly in absence epilepsies. Finally, there is substantial evidence that patients with JME and their unaffected siblings share patterns of cognitive deficits, which is indicative of an underlying genetic etiology (endophenotype), independent of seizures and anti-epileptic medication.
Objective
To investigate alterations of language networks and their relation to impaired naming performance in temporal lobe epilepsy (TLE) using functional MRI.
Methods
Seventy-two adult TLE ...patients (41 left) and 36 controls were studied with overt auditory and picture naming fMRI tasks to assess temporal lobe language areas, and a covert verbal fluency task to probe frontal lobe language regions. Correlation of fMRI activation with clinical naming scores, and alteration of language network patterns in relation to epilepsy duration, age at onset and seizure frequency, were investigated with whole-brain multiple regression analyses.
Results
Auditory and picture naming fMRI activated the left posterior temporal lobe, and stronger activation correlated with better clinical naming scores. Verbal fluency MRI mainly activated frontal lobe regions. In left and right TLE, a later age of epilepsy onset related to stronger temporal lobe activations, while earlier age of onset was associated with impaired deactivation of extratemporal regions. In left TLE patients, longer disease duration and higher seizure frequency were associated with reduced deactivation. Frontal lobe language networks were unaffected by disease characteristics.
Conclusions
While frontal lobe language regions appear spared, temporal lobe language areas are susceptible to dysfunction and reorganisation, particularly in left TLE. Early onset and long duration of epilepsy, and high seizure frequency, were associated with compromised activation and deactivation patterns of task-associated regions, which might account for impaired naming performance in individuals with TLE.
Approximately one third of patients with epilepsy are refractory to medical treatment. Adverse effects associated with Anti-Epileptic Drugs (AEDs) are considered to affect quality of life often more ...than seizures themselves. Neuroimaging techniques, particularly Magnetic Resonance Imaging (MRI), have proven instrumental in clinical decision making in relation to epilepsy surgery, but may also provide further insights into the mechanisms underlying treatment response and side effects associated with AEDs.
We searched PubMed and Scopus databases for original articles and reviews published in the last two decades, which addressed the effects of AEDs on structural MRI, functional MRI and Magnetic Resonance Spectroscopy (MRS) measures.
The majority of investigations implemented task-based fMRI, and probed the influence of widely used anti-epileptic drugs on tasks assessing language, executive functions and emotion recognition. Collectively, MRI allows detecting reproducible AED-related effects on regions and networks relevant to disease pathomechanisms, thus elucidating the anatomo-functional substrates of cognitive side effects. MRS analyses shed light on the molecular correlates of AED action, and may provide indicators of treatment response.
MRI techniques have considerably improved our understanding of the effects of AEDs at a regional and network level, and provide biomarkers with potential to improve routine clinical decision making in epilepsy.
Longitudinal EEG recorded by implanted devices is critical for understanding and managing epilepsy. Recent research reports patient-specific, multi-day cycles in device-detected epileptiform events ...that coincide with increased likelihood of clinical seizures. Understanding these cycles could elucidate mechanisms generating seizures and advance drug and neurostimulation therapies.
We hypothesize that seizure-correlated cycles are present in background neural activity, independent of interictal epileptiform spikes, and that neurostimulation may temporarily interrupt these cycles.
We analyzed regularly-recorded seizure-free data epochs from 20 patients implanted with a responsive neurostimulation (RNS) device for at least 1.5 years, to explore the relationship between cycles in device-detected interictal epileptiform activity (dIEA), clinician-validated interictal spikes, background EEG features, and neurostimulation.
Background EEG features tracked the cycle phase of dIEA in all patients (AUC: 0.63 0.56–0.67) with a greater effect size compared to clinically annotated spike rate alone (AUC: 0.55 0.53–0.61, p < 0.01). After accounting for circadian variation and spike rate, we observed significant population trends in elevated theta and beta band power and theta and alpha connectivity features at the cycle peaks (sign test, p < 0.05). In the period directly after stimulation we observe a decreased association between cycle phase and EEG features compared to background recordings (AUC: 0.58 0.55–0.64).
Our findings suggest that seizure-correlated dIEA cycles are not solely due to epileptiform discharges but are associated with background measures of brain state; and that neurostimulation may temporarily interrupt these cycles. These results may help elucidate mechanisms underlying seizure generation, provide new biomarkers for seizure risk, and facilitate monitoring, treating, and managing epilepsy with implantable devices.
•Background EEG features track multidien cycles in RNS dIEA.•dIEA linked EEG features are patient-specific and may differ with cortical structure.•Responsive neurostimulation suppresses EEG-dIEA coupling.
•First principal subcortical gradient follows lower to higher computational hierarchy.•Patients with temporal lobe epilepsy (TLE) have an expanded first principal gradient.•The ipsilateral ...hippocampus drives expanded principal gradient in right vs. left TLE.
Functional gradients have been used to study differences in connectivity between healthy and diseased brain states, however this work has largely focused on the cortex. Because the subcortex plays a key role in seizure initiation in temporal lobe epilepsy (TLE), subcortical functional-connectivity gradients may help further elucidate differences between healthy brains and TLE, as well as differences between left (L)-TLE and right (R)-TLE.
In this work, we calculated subcortical functional-connectivity gradients (SFGs) from resting-state functional MRI (rs-fMRI) by measuring the similarity in connectivity profiles of subcortical voxels to cortical gray matter voxels. We performed this analysis in 24 R-TLE patients and 31 L-TLE patients (who were otherwise matched for age, gender, disease specific characteristics, and other clinical variables), and 16 controls. To measure differences in SFGs between L-TLE and R-TLE, we quantified deviations in the average functional gradient distributions, as well as their variance, across subcortical structures.
We found an expansion, measured by increased variance, in the principal SFG of TLE relative to controls. When comparing the gradient across subcortical structures between L-TLE and R-TLE, we found that abnormalities in the ipsilateral hippocampal gradient distributions were significantly different between L-TLE and R-TLE.
Our results suggest that expansion of the SFG is characteristic of TLE. Subcortical functional gradient differences exist between left and right TLE and are driven by connectivity changes in the hippocampus ipsilateral to the seizure onset zone.
In epilepsy, cognitive difficulties are common, partly a consequence of anti-seizure medications (ASM), and cognitive side-effects are often considered to be more disabling than seizures and ...significantly affect quality of life. Functional MRI during verbal fluency tasks demonstrated impaired frontal activation patterns and failed default mode network deactivation in people taking ASM with unfavourable cognitive profiles. The cognitive effect of ASMs given at different dosages in monotherapy, or in different combinations, remains to be determined.
Here, we compared the effects of different drug loads on verbal fluency functional MRI (fMRI) in people (i) taking dual therapy of ASMs either considered to be associated with moderate (levetiracetam, lamotrigine, lacosamide, carbamazepine/oxcarbazepine, eslicarbazepine, valproic acid;
= 119, 56 females) or severe (topiramate, zonisamide) side-effects;
= 119, 56 females), (ii) taking moderate ASMs in either mono-, dual- or triple-therapy (60 subjects in each group), or (iii) taking different dosages of ASMs with moderate side-effect profiles (
= 180). "Drug load" was defined as a composite value of numbers and dosages of medications, normalised to account for the highest and lowest dose of each specific prescribed medication.
In people taking "moderate" ASMs (
= 119), we observed higher verbal-fluency related to left inferior frontal gyrus and right inferior parietal fMRI activations than in people taking "severe" ASMs (
= 119). Irrespective of the specific ASM, people on monotherapy (
= 60), showed greater frontal activations than people taking two (
= 60), or three ASMs (
= 60). People on two ASMs showed less default mode (precuneus) deactivation than those on monotherapy. In people treated with "moderate" ASMs (
= 180), increased drug load correlated with reduced activation of language-related regions and the right piriform cortex.
Our study delineates the effects of polytherapy and high doses of ASMs when given in monotherapy on the functional anatomy of language. Irrespective of the cognitive profile of individual ASMs, each additional ASM results in additional alterations of cognitive activation patterns. Selection of ASMs with moderate cognitive side effects, and low doses of ASMs when given in polytherapy, could reduce the cognitive effect.
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