Neural correlates of working memory in Temporal Lobe Epilepsy--an fMRI study.

It has traditionally been held that the hippocampus is not part of the neural substrate of working memory (WM), and that WM is preserved in Temporal Lobe Epilepsy (TLE). Recent imaging and neuropsychological data suggest this view may need revision. The aim of this study was to investigate the neural correlates of WM in TLE using functional MRI (fMRI). We used a visuo-spatial 'n-back' paradigm to compare WM network activity in 38 unilateral hippocampal sclerosis (HS) patients (19 left) and 15 healthy controls. WM performance was impaired in both left and right HS groups compared to controls. The TLE groups showed reduced right superior parietal lobe activity during single- and multiple-item WM. No significant hippocampal activation was found during the active task in any group, but the hippocampi progressively deactivated as the task demand increased. This effect was bilateral for controls, whereas the TLE patients showed progressive unilateral deactivation only contralateral to the side of the hippocampal sclerosis and seizure focus. Progressive deactivation of the posterior medial temporal lobe was associated with better performance in all groups. Our results suggest that WM is impaired in unilateral HS and the underlying neural correlates of WM are disrupted. Our findings suggest that hippocampal activity is progressively suppressed as the WM load increases, with maintenance of good performance. Implications for understanding the role of the hippocampus in WM are discussed

Hippocampal sclerosis affects fMR-adaptation of lyrics and melodies in songs

Songs constitute a natural combination of lyrics and melodies, but it is unclear whether and how these two song components are integrated during the emergence of a memory trace. Network theories of memory suggest a prominent role of the hippocampus, together with unimodal sensory areas, in the build-up of conjunctive representations. The present study tested the modulatory influence of the hippocampus on neural adaptation to songs in lateral temporal areas. Patients with unilateral hippocampal sclerosis and healthy matched controls were presented with blocks of short songs in which lyrics and/or melodies were varied or repeated in a crossed factorial design. Neural adaptation effects were taken as correlates of incidental emergent memory traces. We hypothesized that hippocampal lesions, particularly in the left hemisphere, would weaken adaptation effects, especially the integration of lyrics and melodies. Results revealed that lateral temporal lobe regions showed weaker adaptation to repeated lyrics as well as a reduced interaction of the adaptation effects for lyrics and melodies in patients with left hippocampal sclerosis. This suggests a deficient build-up of a sensory memory trace for lyrics and a reduced integration of lyrics with melodies, compared to healthy controls. Patients with right hippocampal sclerosis showed a similar profile of results although the effects did not reach significance in this population. We highlight the finding that the integrated representation of lyrics and melodies typically shown in healthy participants is likely tied to the integrity of the left medial temporal lobe. This novel finding provides the first neuroimaging evidence for the role of the hippocampus during repetitive exposure to lyrics and melodies and their integration into a song

Temporal Lobe Epilepsy Alters Auditory-motor Integration For Voice Control

Temporal lobe epilepsy (TLE) is the most common drug-refractory focal epilepsy in adults. Previous research has shown that patients with TLE exhibit decreased performance in listening to speech sounds and deficits in the cortical processing of auditory information. Whether TLE compromises auditory-motor integration for voice control, however, remains largely unknown. To address this question, event-related potentials (ERPs) and vocal responses to vocal pitch errors (1/2 or 2 semitones upward) heard in auditory feedback were compared across 28 patients with TLE and 28 healthy controls. Patients with TLE produced significantly larger vocal responses but smaller P2 responses than healthy controls. Moreover, patients with TLE exhibited a positive correlation between vocal response magnitude and baseline voice variability and a negative correlation between P2 amplitude and disease duration. Graphical network analyses revealed a disrupted neuronal network for patients with TLE with a significant increase of clustering coefficients and path lengths as compared to healthy controls. These findings provide strong evidence that TLE is associated with an atypical integration of the auditory and motor systems for vocal pitch regulation, and that the functional networks that support the auditory-motor processing of pitch feedback errors differ between patients with TLE and healthy controls

Structural correlates of impaired working memory in hippocampal sclerosis

PURPOSE: Temporal lobe epilepsy (TLE) has been considered to impair long-term memory, whilst not affecting working memory, but recent evidence suggests that working memory is compromised. Functional MRI (fMRI) studies demonstrate that working memory involves a bilateral frontoparietal network the activation of which is disrupted in hippocampal sclerosis (HS). A specific role of the hippocampus to deactivate during working memory has been proposed with this mechanism faulty in patients with HS. Structural correlates of disrupted working memory in HS have not been explored. METHODS: We studied 54 individuals with medically refractory TLE and unilateral HS (29 left) and 28 healthy controls. Subjects underwent 3T structural MRI, a visuospatial n-back fMRI paradigm and diffusion tensor imaging (DTI). Working memory capacity assessed by three span tasks (digit span backwards, gesture span, motor sequences) was combined with performance in the visuospatial paradigm to give a global working memory measure. Gray and white matter changes were investigated using voxel-based morphometry and voxel-based analysis of DTI, respectively. KEY FINDINGS: Individuals with left or right HS performed less well than healthy controls on all measures of working memory. fMRI demonstrated a bilateral frontoparietal network during the working memory task with reduced activation of the right parietal lobe in both patient groups. In left HS, gray matter loss was seen in the ipsilateral hippocampus and parietal lobe, with maintenance of the gray matter volume of the contralateral parietal lobe associated with better performance. White matter integrity within the frontoparietal network, in particular the superior longitudinal fasciculus and cingulum, and the contralateral temporal lobe, was associated with working memory performance. In right HS, gray matter loss was also seen in the ipsilateral hippocampus and parietal lobe. Working memory performance correlated with the gray matter volume of both frontal lobes and white matter integrity within the frontoparietal network and contralateral temporal lobe. SIGNIFICANCE: Our data provide further evidence that working memory is disrupted in HS and impaired integrity of both gray and white matter is seen in functionally relevant areas. We suggest this forms the structural basis of the impairment of working memory, indicating widespread and functionally significant structural changes in patients with apparently isolated HS

Improving language mapping in clinical fMRI through assessment of grammar.

IntroductionBrain surgery in the language dominant hemisphere remains challenging due to unintended post-surgical language deficits, despite using pre-surgical functional magnetic resonance (fMRI) and intraoperative cortical stimulation. Moreover, patients are often recommended not to undergo surgery if the accompanying risk to language appears to be too high. While standard fMRI language mapping protocols may have relatively good predictive value at the group level, they remain sub-optimal on an individual level. The standard tests used typically assess lexico-semantic aspects of language, and they do not accurately reflect the complexity of language either in comprehension or production at the sentence level. Among patients who had left hemisphere language dominance we assessed which tests are best at activating language areas in the brain.MethodWe compared grammar tests (items testing word order in actives and passives, wh-subject and object questions, relativized subject and object clauses and past tense marking) with standard tests (object naming, auditory and visual responsive naming), using pre-operative fMRI. Twenty-five surgical candidates (13 females) participated in this study. Sixteen patients presented with a brain tumor, and nine with epilepsy. All participants underwent two pre-operative fMRI protocols: one including CYCLE-N grammar tests (items testing word order in actives and passives, wh-subject and object questions, relativized subject and object clauses and past tense marking); and a second one with standard fMRI tests (object naming, auditory and visual responsive naming). fMRI activations during performance in both protocols were compared at the group level, as well as in individual candidates.ResultsThe grammar tests generated more volume of activation in the left hemisphere (left/right angular gyrus, right anterior/posterior superior temporal gyrus) and identified additional language regions not shown by the standard tests (e.g., left anterior/posterior supramarginal gyrus). The standard tests produced more activation in left BA 47. Ten participants had more robust activations in the left hemisphere in the grammar tests and two in the standard tests. The grammar tests also elicited substantial activations in the right hemisphere and thus turned out to be superior at identifying both right and left hemisphere contribution to language processing.ConclusionThe grammar tests may be an important addition to the standard pre-operative fMRI testing

Disorganization of language and working memory systems in frontal versus temporal lobe epilepsy

Cognitive impairment is a common comorbidity of epilepsy, and adversely impacts people with both frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE). While its neural substrates have been extensively investigated in TLE, functional imaging studies in FLE are scarce. In this study, we profiled the neural processes underlying cognitive impairment in FLE, and directly compared FLE and TLE to establish commonalities and differences. We investigated 172 adult participants (56 with FLE, 64 with TLE, and 52 controls) using neuropsychological tests and four functional MRI tasks probing expressive language (verbal fluency, verb generation) and working memory (verbal and visuo-spatial). Patient groups were comparable in disease duration and anti-seizure medication load. We devise a multiscale approach to map brain activation and deactivation during cognition, and track reorganization in FLE and TLE. Voxel-based analyses were complemented with profiling of task effects across established motifs of functional brain organization: (i) canonical resting-state functional systems, and (ii) the principal functional connectivity gradient, which encodes a continuous transition of regional connectivity profiles, anchoring lower-level sensory and transmodal brain areas at the opposite ends of a spectrum. We show that cognitive impairment in FLE is associated with reduced activation across attentional and executive systems, and reduced deactivation of the default mode system, indicative of a large-scale disorganization of task-related recruitment. The imaging signatures of dysfunction in FLE were broadly similar to those in TLE, but some patterns were syndrome-specific: altered default-mode deactivation was more prominent in FLE, while impaired recruitment of posterior language areas during a task with semantic demands was more marked in TLE. Functional abnormalities in FLE and TLE appeared overall modulated by disease load. On balance, our study elucidates neural processes underlying language and working memory impairment in FLE, identifies shared and syndrome-specific alterations in the two most common focal epilepsies, and sheds light on system behavior that may be amenable to future remediation strategies

Causal hierarchy within the thalamo-cortical network in spike and wave discharges

Background: Generalised spike wave (GSW) discharges are the electroencephalographic (EEG) hallmark of absence seizures, clinically characterised by a transitory interruption of ongoing activities and impaired consciousness, occurring during states of reduced awareness. Several theories have been proposed to explain the pathophysiology of GSW discharges and the role of thalamus and cortex as generators. In this work we extend the existing theories by hypothesizing a role for the precuneus, a brain region neglected in previous works on GSW generation but already known to be linked to consciousness and awareness. We analysed fMRI data using dynamic causal modelling (DCM) to investigate the effective connectivity between precuneus, thalamus and prefrontal cortex in patients with GSW discharges. Methodology and Principal Findings: We analysed fMRI data from seven patients affected by Idiopathic Generalized Epilepsy (IGE) with frequent GSW discharges and significant GSW-correlated haemodynamic signal changes in the thalamus, the prefrontal cortex and the precuneus. Using DCM we assessed their effective connectivity, i.e. which region drives another region. Three dynamic causal models were constructed: GSW was modelled as autonomous input to the thalamus (model A), ventromedial prefrontal cortex (model B), and precuneus (model C). Bayesian model comparison revealed Model C (GSW as autonomous input to precuneus), to be the best in 5 patients while model A prevailed in two cases. At the group level model C dominated and at the population-level the p value of model C was ∼1. Conclusion: Our results provide strong evidence that activity in the precuneus gates GSW discharges in the thalamo-(fronto) cortical network. This study is the first demonstration of a causal link between haemodynamic changes in the precuneus - an index of awareness - and the occurrence of pathological discharges in epilepsy. © 2009 Vaudano et al

Network perspectives on epilepsy using EEG/MEG source connectivity

The evolution of EEG/MEG source connectivity is both, a promising, and controversial advance in the characterization of epileptic brain activity. In this narrative review we elucidate the potential of this technology to provide an intuitive view of the epileptic network at its origin, the different brain regions involved in the epilepsy, without the limitation of electrodes at the scalp level. Several studies have confirmed the added value of using source connectivity to localize the seizure onset zone and irritative zone or to quantify the propagation of epileptic activity over time. It has been shown in pilot studies that source connectivity has the potential to obtain prognostic correlates, to assist in the diagnosis of the epilepsy type even in the absence of visually noticeable epileptic activity in the EEG/MEG, and to predict treatment outcome. Nevertheless, prospective validation studies in large and heterogeneous patient cohorts are still lacking and are needed to bring these techniques into clinical use. Moreover, the methodological approach is challenging, with several poorly examined parameters that most likely impact the resulting network patterns. These fundamental challenges affect all potential applications of EEG/MEG source connectivity analysis, be it in a resting, spiking, or ictal state, and also its application to cognitive activation of the eloquent area in presurgical evaluation. However, such method can allow unique insights into physiological and pathological brain functions and have great potential in (clinical) neuroscience