White Matter Abnormalities in Post-traumatic Stress Disorder Following a Specific Traumatic Event

Studies of posttraumatic stress disorder (PTSD) are complicated by wide variability in the intensity and duration of prior stressors in patient participants, secondary effects of chronic psychiatric illness, and a variable history of treatment with psychiatric medications. In magnetic resonance imaging (MRI) studies, patient samples have often been small, and they were not often compared to similarly stressed patients without PTSD in order to control for general stress effects. Findings from these studies have been inconsistent. The present study investigated whole-brain microstructural alterations of white matter in a large drug-naive population who survived a specific, severe traumatic event (a major 8.0-magnitude earthquake). Using diffusion tensor imaging (DTI), we explored group differences between 88 PTSD patients and 91 matched traumatized non-PTSD controls in fractional anisotropy (FA), as well as its component elements axial diffusivity (AD) and radial diffusivity (RD), and examined these findings in relation to findings from deterministic DTI tractography. Relations between white matter alterations and psychiatric symptom severity were examined. PTSD patients, relative to similarly stressed controls, showed an FA increase as well as AD and RD changes in the white matter beneath left dorsolateral prefrontal cortex and forceps major. The observation of increased FA in the PTSD group suggests that the pathophysiology of PTSD after a specific acute traumatic event is distinct from what has been reported in patients with several years duration of illness. Alterations in dorsolateral prefrontal cortex may be an important aspect of illness pathophysiology, possibly via the region's established role in fear extinction circuitry. Use-dependent myelination or other secondary compensatory changes in response to heightened demands for threat appraisal and emotion regulation may be involved

Verbal fluency functional magnetic resonance imaging detects anti-seizure effects and affective side effects of perampanel in people with focal epilepsy

Perampanel, a noncompetitive antagonist of the postsynaptic a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor, is effective for controlling focal to bilateral tonic-clonic seizures but is also known to increase feelings of anger. Using statistical parametric mapping-derived measures of activation and task-modulated functional connectivity (psychophysiologic interaction), we investigated 14 people with focal epilepsy who had verbal fluency functional magnetic resonance imaging (fMRI) twice, before and after the add-on treatment of perampanel. For comparison, we included 28 people with epilepsy, propensity-matched for clinical characteristics, who had two scans but no change in anti-seizure medication (ASM) regimen in-between. After commencing perampanel, individuals had higher task-related activations in left orbitofrontal cortex (OFC), fewer task-related activations in the subcortical regions including the left thalamus and left caudate, and lower task-related thalamocaudate and caudate-subtantial nigra connectivity. Decreased task-related connectivity is observed between the left OFC and precuneus and left medial frontal lobe. Our results highlight the brain regions associated with the beneficiary therapeutic effects on focal to bilateral tonic-clonic seizures (thalamus and caudate) but also the undesired affective side effects of perampanel with increased anger and aggression (OFC)

Cognitive phenotype of juvenile absence epilepsy: An investigation of patients and unaffected siblings

Objective: The cognitive profile of juvenile absence epilepsy (JAE) remains largely uncharacterized. This study aimed to: (1) elucidate the neuropsychological profile of JAE; (2) identify familial cognitive traits by investigating unaffected JAE siblings; (3) establish the clinical meaningfulness of JAE-associated cognitive traits; (4) determine whether cognitive traits across the idiopathic generalized epilepsy (IGE) spectrum are shared or syndrome-specific, by comparing JAE to juvenile myoclonic epilepsy (JME); and (5) identify relationships between cognitive abilities and clinical characteristics. Methods: We investigated 123 participants—23 patients with JAE, 16 unaffected siblings of JAE patients, 45 healthy controls, and 39 patients with JME—who underwent a comprehensive neuropsychological test battery including measures within four cognitive domains: attention/psychomotor speed, language, memory, and executive function. We correlated clinical measures with cognitive performance data to decode effects of age at onset and duration of epilepsy. Results: Cognitive performance in individuals with JAE was reduced compared to controls across attention/psychomotor speed, language, and executive function domains; those with ongoing seizures additionally showed lower memory scores. Patients with JAE and their unaffected siblings had similar language impairment compared to controls. Individuals with JME had worse response inhibition than those with JAE. Across all patients, those with older age at onset had better attention/psychomotor speed performance. Significance: JAE is associated with wide-ranging cognitive difficulties that encompass domains reliant on frontal lobe processing, including language, attention, and executive function. JAE siblings share impairment with patients on linguistic measures, indicative of a familial trait. Executive function subdomains may be differentially affected across the IGE spectrum. Cognitive abilities are detrimentally modulated by an early age at seizure onset

The Impact of Temporal Lobe Epilepsy Surgery on Picture Naming and its Relationship to Network Metric Change

Background: Anterior temporal lobe resection (ATLR) is a successful treatment for medically-refractory temporal lobe epilepsy (TLE). In the language-dominant hemisphere, 30%- 50% of individuals experience a naming decline which can impact upon daily life. Measures of structural networks are associated with language performance pre-operatively. It is unclear if analysis of network measures may predict post-operative decline. Methods: White matter fibre tractography was performed on preoperative diffusion MRI of 44 left lateralised and left resection individuals with TLE to reconstruct the preoperative structural network. Resection masks, drawn on co-registered pre- and post-operative T1-weighted MRI scans, were used as exclusion regions on pre-operative tractography to estimate the post-operative network. Changes in graph theory metrics, cortical strength, betweenness centrality, and clustering coefficient were generated by comparing the estimated pre- and post-operative networks. These were thresholded based on the presence of the connection in each patient, ranging from 75% to 100% in steps of 5%. The average graph theory metric across thresholds was taken. We incorporated leave-one-out cross-validation with smoothly clipped absolute deviation (SCAD) least absolute shrinkage and selection operator (LASSO) feature selection and a support vector classifier to assess graph theory metrics on picture naming decline. Picture naming was assessed via the Graded Naming Test preoperatively and at 3 and 12 months post-operatively and the outcome was classified using the reliable change index (RCI) to identify clinically significant decline. The best feature combination and model was selected using the area under the curve (AUC). The sensitivity, specificity and F1-score were also reported. Permutation testing was performed to assess the machine learning model and selected regions difference significance. Results: A combination of clinical and graph theory metrics were able to classify outcome of picture naming at 3 months with an AUC of 0.84. At 12 months, change in strength to cortical regions was best able to correctly classify outcome with an AUC of 0.86. Longitudinal analysis revealed that betweenness centrality was the best metric to identify patients who declined at 3 months, who will then continue to experience decline from 3-12 months. Both models were significantly higher AUC values than a random classifier. Conclusion: Our results suggest that inferred changes of network integrity were able to correctly classify picture naming decline after ATLR. These measures may be used to prospectively to identify patients who are at risk of picture naming decline after surgery and could potentially be utilised to assist tailoring the resection in order to prevent this decline

Effect of Anti-seizure Medications on Functional Anatomy of Language: A Perspective From Language Functional Magnetic Resonance Imaging

BACKGROUND 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. METHODS 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; n = 119, 56 females) or severe (topiramate, zonisamide) side-effects; n = 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 (n = 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. RESULTS In people taking "moderate" ASMs (n = 119), we observed higher verbal-fluency related to left inferior frontal gyrus and right inferior parietal fMRI activations than in people taking "severe" ASMs (n = 119). Irrespective of the specific ASM, people on monotherapy (n = 60), showed greater frontal activations than people taking two (n = 60), or three ASMs (n = 60). People on two ASMs showed less default mode (precuneus) deactivation than those on monotherapy. In people treated with "moderate" ASMs (n = 180), increased drug load correlated with reduced activation of language-related regions and the right piriform cortex. CONCLUSION 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

Effect of Anti-seizure Medications on Functional Anatomy of Language: A Perspective From Language Functional Magnetic Resonance Imaging

Background: 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. Methods: 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; n = 119, 56 females) or severe (topiramate, zonisamide) side-effects; n = 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 (n = 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. Results: In people taking "moderate" ASMs (n = 119), we observed higher verbal-fluency related to left inferior frontal gyrus and right inferior parietal fMRI activations than in people taking "severe" ASMs (n = 119). Irrespective of the specific ASM, people on monotherapy (n = 60), showed greater frontal activations than people taking two (n = 60), or three ASMs (n = 60). People on two ASMs showed less default mode (precuneus) deactivation than those on monotherapy. In people treated with "moderate" ASMs (n = 180), increased drug load correlated with reduced activation of language-related regions and the right piriform cortex. Conclusion: 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

Identification of different MRI atrophy progression trajectories in epilepsy by subtype and stage inference

Artificial intelligence (AI)-based tools are widely employed, but their use for diagnosis and prognosis of neurological disorders is still evolving. Here we analyse a cross-sectional multicentre structural MRI dataset of 696 people with epilepsy and 118 control subjects. We use an innovative machine-learning algorithm, Subtype and Stage Inference, to develop a novel data-driven disease taxonomy, whereby epilepsy subtypes correspond to distinct patterns of spatiotemporal progression of brain atrophy.In a discovery cohort of 814 individuals, we identify two subtypes common to focal and idiopathic generalized epilepsies, characterized by progression of grey matter atrophy driven by the cortex or the basal ganglia. A third subtype, only detected in focal epilepsies, was characterized by hippocampal atrophy. We corroborate external validity via an independent cohort of 254 people and confirm that the basal ganglia subtype is associated with the most severe epilepsy.Our findings suggest fundamental processes underlying the progression of epilepsy-related brain atrophy. We deliver a novel MRI- and AI-guided epilepsy taxonomy, which could be used for individualized prognostics and targeted therapeutics

Thalamostriatal disconnection underpins long-term seizure freedom in frontal lobe epilepsy surgery

Around 50% of patients undergoing frontal lobe surgery for focal drug-resistant epilepsy become seizure free post-operatively; however, only about 30% of patients remain seizure free in the long-term. Early seizure recurrence is likely to be caused by partial resection of the epileptogenic lesion, whilst delayed seizure recurrence can occur even if the epileptogenic lesion has been completely excised. This suggests a coexistent epileptogenic network facilitating ictogenesis in close or distant dormant epileptic foci. As thalamic and striatal dysregulation can support epileptogenesis and disconnection of cortico-thalamostriatal pathways through hemispherotomy or neuromodulation can improve seizure outcome regardless of focality, we hypothesize that projections from the striatum and the thalamus to the cortex may contribute to this common epileptogenic network. To this end, we retrospectively reviewed a series of 47 consecutive individuals who underwent surgery for drug-resistant frontal lobe epilepsy. We performed voxel-based and tractography disconnectome analyses to investigate shared patterns of disconnection associated with long-term seizure freedom. Seizure freedom after 3 and 5 years was independently associated with disconnection of the anterior thalamic radiation and anterior cortico-striatal projections. This was also confirmed in a subgroup of 29 patients with complete resections, suggesting these pathways may play a critical role in supporting the development of novel epileptic networks. Our study indicates that network dysfunction in frontal lobe epilepsy may extend beyond the resection and putative epileptogenic zone. This may be critical in the pathogenesis of delayed seizure recurrence as thalamic and striatal networks may promote epileptogenesis and disconnection may underpin long-term seizure freedom

The Impact of Temporal Lobe Epilepsy Surgery on Picture Naming and its Relationship to Network Metric Change

BackgroundAnterior temporal lobe resection (ATLR) is a successful treatment for medically-refractory temporal lobe epilepsy (TLE). In the language-dominant hemisphere, 30%- 50% of individuals experience a naming decline which can impact upon daily life. Measures of structural networks are associated with language performance pre-operatively. It is unclear if analysis of network measures may predict post-operative decline.MethodsWhite matter fibre tractography was performed on preoperative diffusion MRI of 44 left lateralised and left resection individuals with TLE to reconstruct the preoperative structural network. Resection masks, drawn on co-registered pre- and post-operative T1-weighted MRI scans, were used as exclusion regions on pre-operative tractography to estimate the post-operative network. Changes in graph theory metrics, cortical strength, betweenness centrality, and clustering coefficient were generated by comparing the estimated pre- and post-operative networks. These were thresholded based on the presence of the connection in each patient, ranging from 75% to 100% in steps of 5%. The average graph theory metric across thresholds was taken.We incorporated leave-one-out cross-validation with smoothly clipped absolute deviation (SCAD) least absolute shrinkage and selection operator (LASSO) feature selection and a support vector classifier to assess graph theory metrics on picture naming decline. Picture naming was assessed via the Graded Naming Test preoperatively and at 3 and 12 months post-operatively and the outcome was classified using the reliable change index (RCI) to identify clinically significant decline. The best feature combination and model was selected using the area under the curve (AUC). The sensitivity, specificity and F1-score were also reported. Permutation testing was performed to assess the machine learning model and selected regions difference significance.ResultsA combination of clinical and graph theory metrics were able to classify outcome of picture naming at 3 months with an AUC of 0.84. At 12 months, change in strength to cortical regions was best able to correctly classify outcome with an AUC of 0.86. Longitudinal analysis revealed that betweenness centrality was the best metric to identify patients who declined at 3 months, who will then continue to experience decline from 3-12 months. Both models were significantly higher AUC values than a random classifier.ConclusionOur results suggest that inferred changes of network integrity were able to correctly classify picture naming decline after ATLR. These measures may be used to prospectively to identify patients who are at risk of picture naming decline after surgery and could potentially be utilised to assist tailoring the resection in order to prevent this decline