Applications of teleneuropsychology to the screening and monitoring of epilepsy.

Epilepsy is an inherently dynamic disease and neuropsychology plays a key role in the formulation, monitoring and management of the condition. Teleneuropsychology provides an opportunity for neuropsychology to increase its accessibility, reach and efficiency, using focussed assessments to target epilepsy relevant domains at critical timepoints in the disease trajectory. Neuropsychologists working with epilepsy have, however, been comparatively slow to adopt telehealth methods. Here we review recent developments in teleneuropsychology, with particular reference to applications and considerations in Late Onset Epilepsy. Three different approaches to remote assessment of cognition are discussed: unsupervised, computer-administered assessments; telephone-based assessments; and videoconference-based assessments. Uptake of unsupervised, computer-administered (browser or app-based) assessments has been strongest in aging research, where there is now evidence of feasibility, reliability, and validity, especially for measures of speed and working memory. Telephone-based assessments are well established in older aged cohorts and have recently been applied in epilepsy. Such assessments are widely accessible from a technology perspective, though reliance on a purely oral medium limits cognitive domain coverage. Videoconference based assessments have partially addressed this limitation, though continue to rely largely upon finding ways to administer legacy materials via the medium rather than intrinsically exploiting the technology. We argue that the future of neuropsychology requires development of integrated videoconference-based, computer-assisted cognitive testing, combining the benefits of computerised assessments with the advantages of human led assessments. Such an approach will be applicable across neuropsychological conditions, from childhood through to older adults.

Work productivity, quality of life, and care needs: An unfolding epilepsy burden revealed in the Australian Epilepsy Project pilot study.

OBJECTIVE: Epilepsy is a common and serious neurological disorder. This cross-sectional analysis addresses the burden of epilepsy at different stages of the disease. METHODS: This pilot study is embedded within the Australian Epilepsy Project (AEP), aiming to provide epilepsy support through a national network of dedicated sites. For this analysis, adults aged 18-65 years with first unprovoked seizure (FUS), newly diagnosed epilepsy (NDE), or drug-resistant epilepsy (DRE) were recruited between February-August 2022. Baseline clinicodemographic data were collected from the participants who completed questionnaires to assess their quality of life (QOLIE-31, EQ-5D-5L), work productivity (Work Productivity and Activity Impairment [WPAI]), and care needs. Univariate analysis and multivariate regression was performed. RESULTS: 172 participants formed the study cohort (median age 34, interquartile range [IQR]: 26-45), comprising FUS (n = 44), NDE (n = 53), and DRE (n = 75). Mean QOLIE-31 score was 56 (standard deviation [SD] ± 18) and median EQ-5D-5L score was 0.77 (IQR: 0.56-0.92). QOLIE-31 but not EQ-5D-5L scores were significantly lower in the DRE group compared to FUS and NDE groups (p < 0.001). Overall, 64.5% of participants participated in paid work, with fewer DRE (52.0%) compared with FUS (76.7%) and NDE (72.5%) (p < 0.001). Compared to those not in paid employment, those in paid employment had significantly higher quality of life scores (p < 0.001). Almost 5.8% of participants required formal care (median 20 h/week, IQR: 12-55) and 17.7% required informal care (median 16 h/week, IQR: 7-101). SIGNIFICANCE: Epilepsy is associated with a large burden in terms of quality of life, productivity and care needs. PLAIN LANGUAGE SUMMARY: This is a pilot study from the Australian Epilepsy Project (AEP). It reports health economic data for adults of working age who live with epilepsy. It found that people with focal drug-resistant epilepsy had lower quality of life scores and were less likely to participate in paid employment compared to people with new diagnosis epilepsy. This study provides important local data regarding the burden of epilepsy and will help researchers in the future to measure the impact of the AEP on important personal and societal health economic outcomes.

Cognitive and psychological dysfunction is present after a first seizure, prior to epilepsy diagnosis and treatment at a First Seizure Clinic.

OBJECTIVE: Neuropsychological comorbidities found in chronic epilepsy have also been reported earlier in the disease course. However, recurrent seizures, antiseizure medication (ASM), and adjustment to a chronic diagnosis remain potential confounds of this literature. It thus remains unclear whether these comorbidities are primary or secondary attributes of epilepsy. To capture individuals as close to disease onset as possible, we studied the cognitive and psychological functioning in adults after their first seizure, yet prior to epilepsy diagnosis and treatment. METHODS: Using a telehealth-based prospective design, we screened cognition, mood, and anxiety symptoms in adult patients referred to a First Seizure Clinic (FSC), who were over 18 years, English-speaking and not taking ASM. We screened cognition via telephone, and psychological symptoms via online questionnaires, all prior to the patients' diagnostic evaluation. Data were collected on 32 individuals subsequently diagnosed with epilepsy at the FSC, and 30 healthy controls from the community, who were matched to the epilepsy group for age, gender, and education. RESULTS: A multivariate analysis of variance revealed that the groups differed significantly on combined cognitive measures with a large effect size (F[1,56] = 5.75, p < 0.001, η2 = 0.45). Post-hoc analyses showed that performances on measures of verbal memory, working memory, and executive functions were significantly worse for the newly diagnosed epilepsy group than controls. The epilepsy group also exhibited higher rates of clinically significant depressive and anxiety symptoms. SIGNIFICANCE: Cognitive and psychological dysfunction is prevalent in people with epilepsy as early as the first seizure event, before the influence of diagnosis, ASM and recurrent seizures. Their neuropsychological profile parallels that seen in chronic epilepsy, showing that this dysfunction is already present at the very onset of the disease. The current study demonstrates the viability of telehealth neuropsychological screening for all new epilepsy cases. PLAIN LANGUAGE STATEMENT: The results of this study show, using telephone-based cognitive assessment and online questionnaires, that people with newly diagnosed epilepsy can experience problems with their thinking and memory skills, and low mood and anxiety, as early as after their first seizure. These issues are apparent at the very beginning of the disease, before an epilepsy diagnosis is made and before antiseizure medication is commenced, which suggests that they are due to the underlying brain disturbance, rather than the secondary effects of seizures, treatment, or lifestyle changes. Telehealth-screening of thinking skills and mental health for all new epilepsy cases is recommended to promote early management of such problems.

Phase II randomised placebo-controlled trial of sodium selenate as a disease-modifying treatment in chronic drug-resistant temporal lobe epilepsy: the SeLECT study protocol.

INTRODUCTION: Epilepsy is one of the most common neurological conditions worldwide. Despite many antiseizure medications (ASMs) being available, up to one-third of patients do not achieve seizure control. Preclinical studies have shown treatment with sodium selenate to have a disease-modifying effect in a rat model of chronic temporal lobe epilepsy (TLE). AIM: This randomised placebo-controlled trial aims to evaluate the antiseizure and disease-modifying effects of sodium selenate in people with drug-resistant TLE. METHODS: This will be a randomised placebo-controlled trial of sodium selenate. One hundred and twenty-four adults with drug-resistant TLE and ≥4 countable seizures/month will be recruited. Outcomes of interest will be measured at baseline, week 26 and week 52 and include an 8-week seizure diary, 24-hour electroencephalogram and cognitive, neuropsychiatric and quality of life measures. Participants will then be randomised to receive a sustained release formulation of sodium selenate (initially 10 mg three times a day, increasing to 15 mg three times a day at week 4 if tolerated) or a matching placebo for 26 weeks. OUTCOMES: The primary outcome will be a consumer codesigned epilepsy-Desirability of Outcome Rank (DOOR), combining change in seizure frequency, adverse events, quality of life and ASM burden measures into a single outcome measure, compared between treatment arms over the whole 52-week period. Secondary outcomes will compare baseline measures to week 26 (antiseizure) and week 52 (disease modification). Exploratory measures will include biomarkers of treatment response. ETHICS AND DISSEMINATION: The study has been approved by the lead site, Alfred Hospital Ethics Committee (594/20). Each participant will provide written informed consent prior to any trial procedures. The results of the study will be presented at national and international conferences, published in peer-reviewed journals and disseminated through consumer organisations. CONCLUSION: This study will be the first disease-modification randomised controlled trial in patients with drug-resistant TLE. TRIAL REGISTRATION NUMBER: ANZCTR; ACTRN12623000446662.

Aberrant neural network activation during reliving of autobiographical memories in adolescent depression.

BACKGROUND: Adolescents with depression exhibit negative biases in autobiographical memory with detrimental consequences for their self-concept and well-being. Investigating how adolescents relive positive autobiographical memories and activate the underlying neural networks could reveal mechanisms that drive such biases. This study investigated neural networks when reliving positive and neutral memories, and how neural activity is modulated by valence and vividness in adolescents with and without depression. METHODS: Adolescents (N = 69; n = 17 with depression) retrieved positive and neutral autobiographical memories. On a separate day, they relived these memories during fMRI scanning, and reported on pleasantness and vividness after reliving each memory. We used a multivariate, data-driven approach - event-related independent component analysis (eICA) - to characterize neural networks supporting autobiographical recollection. RESULTS: Adolescents with depression reported their positive memories as significantly less pleasant compared to healthy controls, while subjective vividness was unaffected. Using eICA, we identified a broad autobiographical memory network, and subnetworks related to reliving positive vs neutral memories. These subnetworks comprised a 'self-referential processing network' including medial prefrontal cortex, posterior cingulate cortex/precuneus, and temporoparietal junction, anti-correlating with parts of the central executive network and salience network. Adolescents with depression exhibited aberrant activation in this self-referential network, but only when reliving relatively 'low' pleasant memories. CONCLUSIONS: Our findings provide first insights into how the quality of reliving autobiographical memories in adolescents with depression may relate to aberrant self-referential neural network activation, and underscore the potential of targeting memory reliving in therapeutic interventions to foster self-esteem and diminish depressive symptoms.

The Spatial Learning Task of Lhermitte and Signoret (1972): Normative Data in Adults Aged 18-45.

Objective: The Spatial Learning Task of Lhermitte and Signoret is an object-location arbitrary associative learning task. The task was originally developed to evaluate adults with severe amnesia. It is currently used in populations where the memory system either is not yet fully developed or where it has been compromised (e.g. epilepsy, traumatic brain injury, electroconvulsive therapy, cerebrovascular disease and dementia). Normative data have been published for paediatric cohorts and for older adults, however no data exist for the intervening adult years. Method: Here, we address this gap, collecting normative data from 101 adults aged 18-45. Results: Our data indicate that performance on the Spatial Learning Task is not influenced by age, gender, level of education or overall IQ. Less than 10% of the variance in learning scores is associated with variability in verbal memory. Ninety percent of participants achieved perfect scores on two successive trials (T2Cr) within five or fewer trials on the Spatial Learning Task. A T2Cr score of 6 is suggestive of impairment and a T2Cr score of 7 or more is statistically abnormal. Conclusion: These data expand the clinical utility of the Spatial Learning Task in the adult population. Future work should examine performance in lower IQ cohorts, including intellectual disability, and explore sensitivity to disease factors such as laterality of mesial temporal lobe damage.

Compromised future thinking: another cognitive cost of temporal lobe epilepsy.

The ability to mentally travel forward through time allows humans to envisage a diverse array of possible events taking place in the future, helping us to choose which pathway to take in life. In epilepsy, we assume that patients use this cognitive ability when deciding between various treatment options, but this assumption has not been robustly tested. The temporal lobes are key contributors to this 'future thinking' and its building blocks include cognitive functions commonly impaired in temporal lobe epilepsy such as memory and language, giving rise to a hypothesis that 'future thinking' is impaired in this patient cohort. Participants were 68 adults: 37 with neurosurgically-naïve, unilateral temporal lobe epilepsy (51% right lateralized) and 31 healthy controls of similar age, sex and intellectual ability to the participants with epilepsy. Future thinking was measured using an imagined experiences task validated in other neurological populations. Tools well-established in temporal lobe epilepsy were used to measure potential cognitive correlates of future thinking. Analysis of variance revealed significantly impoverished future thinking in both left and right temporal lobe epilepsy relative to controls (P = 0.001, η p 2=0.206), with no difference between temporal lobe epilepsy groups (P > 0.05). Future thinking deficits in left temporal lobe epilepsy were paralleled by deficits in scene construction, whereas impoverished future thinking in right temporal lobe epilepsy occurred in the setting of intact scene construction. Deficits in future thinking were associated with reductions in lexical access and episodic autobiographic memory in both epilepsy groups. In sum, future thinking is compromised in both left and right temporal lobe epilepsy. The deficit in left temporal lobe epilepsy is largely explainable by dysfunction in verbal cognitive processes including scene construction. While the basis of the deficits observed with right temporal foci shares features with that of left temporal lobe epilepsy, their intact scene construction raises questions about the role of the left and right temporal lobes in future thinking and scene construction and the relationship between these two constructs, including whether right temporal lobe might play a specific role in future thinking in terms of creative processing. Clinicians should take impaired future thinking into account when counselling temporal lobe epilepsy patients about various treatment options, as they may struggle to vividly imagine what different outcomes might mean for their future selves.

Teleneuropsychology in the time of COVID-19: The experience of The Australian Epilepsy Project.

PURPOSE: Traditional neuropsychological testing carries elevated COVID-19 risk for both examinee and examiner. Here we describe how the pilot study of the Australian Epilepsy Project (AEP) has transitioned to tele-neuropsychology (teleNP), enabling continued safe operations during the pandemic. METHODS: The AEP includes adults (age 18-60) with a first unprovoked seizure, new diagnosis of epilepsy or drug resistant focal epilepsy. Shortly after launching the study, COVID-related restrictions necessitated adaptation to teleNP, including delivery of verbal tasks via videoconference; visual stimulus delivery via document camera; use of web-hosted, computerised assessment; substitution of oral versions for written tests; online delivery of questionnaires; and discontinuation of telehealth incompatible tasks. RESULTS: To date, we have completed 24 teleNP assessments: 18 remotely (participant in own home) and six on-site (participant using equipment at research facility). Five face-to-face assessments were conducted prior to the transition to teleNP. Eight of 408 tests administered via teleNP (1.9 %) have been invalidated, for a variety of reasons (technical, procedural, environmental). Data confirm typical patterns of epilepsy-related deficits (p < .05) affecting processing speed, executive function, language and memory. Questionnaire responses indicate elevated rates of patients at high risk of mood (34 %) and anxiety disorder (38 %). CONCLUSION: Research teleNP assessments reveal a typical pattern of impairments in epilepsy. A range of issues must be considered when introducing teleNP, such as technical and administrative set up, test selection and delivery, and cohort suitability. TeleNP enables large-scale neuropsychological research during periods of social distancing (and beyond), and offers an opportunity to expand the reach and breadth of neuropsychological services.

Integrity of Multiple Memory Systems in Individuals With Untreated Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is associated with working- and autobiographical-memory impairments, and high rates of mood disorder. This study aimed to examine (i) behavioral responses and (ii) neural activation patterns elicited by autobiographical and working memory tasks in moderate-severe untreated OSA patients and healthy controls, and (iii) whether variability in autobiographical and working memory activation are associated with task performance, OSA severity and psychological symptomatology (depression, anxiety). In order to control for the potential confounding effect of elevated rates of clinical depression in OSA, we excluded individuals with a current psychiatric condition. Seventeen untreated OSA participants and 16 healthy controls were comparable with regards to both activation and behavioral performance. OSA was associated with worse subclinical mood symptoms and poorer personal semantic memory. Higher levels of nocturnal hypoxia were associated with increased activation in the occipital cortex and right cerebellum during the working memory task in OSA participants, however, no significant relationships between activation and task performance or depressive/anxiety symptomatology were observed. The neurocognitive substrates supporting autobiographical recall of recent events and working memory in younger, recently diagnosed individuals with OSA appear to be indistinguishable from healthy age-matched individuals. These findings point to the importance of early diagnosis and treatment of OSA in order to preserve cognitive function.

Clinical benefit of presurgical EEG-fMRI in difficult-to-localize focal epilepsy: A single-institution retrospective review.

OBJECTIVE: The aim of this report is to present our clinical experience of electroencephalography-functional magnetic resonance imaging (EEG-fMRI) in localizing the epileptogenic focus, and to evaluate the clinical impact and challenges associated with the use of EEG-fMRI in pharmacoresistant focal epilepsy. METHODS: We identified EEG-fMRI studies (n = 118) in people with focal epilepsy performed at our center from 2003 to 2018. Participants were referred from our Comprehensive Epilepsy Program in an exploratory research effort to address often difficult clinical questions, due to complex and difficult-to-localize epilepsy. We assessed the success of each study, the clinical utility of the result, and when surgery was performed, the postoperative outcome. RESULTS: Overall, 50% of EEG-fMRI studies were successful, meaning that data were of good quality and interictal epileptiform discharges were recorded. With an altered recruitment strategy since 2012 with increased inclusion of patients who were inpatients for video-EEG monitoring, we found that this patients in this selected group were more likely to have epileptic discharges detected during EEG-fMRI (96% of inpatients vs 29% of outpatients, P<.0001). To date, 48% (57 of 118) of patients have undergone epilepsy surgery. In 10 cases (17% of the 59 successful studies) the EEG-fMRI result had a "critical impact" on the surgical decision. These patients were difficult to localize because of subtle abnormalities, apparently normal MRI, or extensive structural abnormalities. All 10 had a good seizure outcome at 1 year after surgery (mean follow-up 6.5 years). SIGNIFICANCE: EEG-fMRI results can assist identification of the epileptogenic focus in otherwise difficult-to-localize cases of pharmacoresistant focal epilepsy. Surgery determined largely by localization from the EEG-fMRI result can lead to good seizure outcomes. A limitation of this study is its retrospective design with nonconsecutive recruitment. Prospective clinical trials with well-defined inclusion criteria are needed to determine the overall benefit of EEG-fMRI for preoperative localization and postoperative outcome in focal epilepsy.

Looking beyond lesions for causes of neuropsychological impairment in epilepsy.

OBJECTIVE: Patients with temporal lobe epilepsy (TLE) are similar in their epileptology regardless of whether they have a lesion evident on MRI; this study aims to prospectively clarify whether they are also similar in their neuropsychological profiles. METHODS: Participants comprised 152 adults: 79 patients with TLE and 73 healthy controls. Patients and controls did not differ in age, sex, or education (p > 0.05). Sixty-two percent of patients had an MRI-resolvable lesion (39% with presumed hippocampal sclerosis [HS-TLE], 61% with a lesion other than HS [MRI-positive TLE]); the remaining 38% of patients were lesion-negative. Psychometric measures well established in epilepsy were used. RESULTS: Relative to controls, all 3 patient subgroups showed significantly impaired autobiographical, verbal, and visual memory (p < 0.05-0.001) and significantly more depression and anxiety (p < 0.05-0.01). Yet, contrary to expectations, the 3 TLE subgroups did not differ in their severity of memory or mood impairment (p > 0.05). Lower Full-Scale IQ predicted memory impairments across all TLE subtypes, with early age at seizure onset a predictor unique to MRI-negative TLE. CONCLUSIONS: MRI-negative TLE is associated with memory and mood dysfunction equivalent to that seen in patients with hippocampal sclerosis and other MRI-resolvable pathologies. As such, neuropsychological impairments in TLE are not contingent on a macroscopic lesion and might be an intrinsic property of the underlying network disease.

Cognitive impairment in epilepsy: the role of reduced network flexibility.

Objective: The dominant model of cognitive impairment in focal epilepsy has emphasised structural bases for cognitive deficits. Current theories of cognition in the healthy brain emphasise the importance of the reweighting of brain network interactions in support of task performance. Here, we explore the hypothesis that cognitive deficits in epilepsy arise through abnormalities of dynamic functional network interactions. Method: We studied 19 healthy controls and 37 temporal lobe epilepsy (TLE) patients, using a behavioural measure of verbal fluency (the Controlled Oral Word Association Test) and an fMRI verbal fluency paradigm (Orthographic Lexical Retrieval). Results: Behaviourally, verbal fluency was significantly impaired in TLE. Psychophysiological interaction analyses of the fMRI data, which capture state-dependent changes in network connectivity, revealed reduced task-dependent modulations of connectivity from left superior medial frontal cortex to left middle frontal gyrus in TLE patients. Individual differences in verbal fluency among TLE cases was correlated with task-dependent changes in connectivity from left posterior cingulate to left superior medial frontal cortex, and from left superior medial frontal cortex to a range of right predominant brain areas. Interpretation: These data reveal that the typical pattern of task-driven shifts in network connectivity is not observed in TLE. Our observations go beyond simple structure-function associations and suggest that failure of network flexibility can be an important contributor to cognitive impairment in epilepsy.

Identification of a Neurocognitive Mechanism Underpinning Awareness of Chronic Tinnitus.

Tinnitus (ringing in the ears) is a common auditory sensation that can become a chronic debilitating health condition with pervasive effects on health and wellbeing, substantive economic burden, and no known cure. Here we investigate if impaired functioning of the cognitive control network that directs attentional focus is a mechanism erroneously maintaining the tinnitus sensation. Fifteen people with chronic tinnitus and 15 healthy controls matched for age and gender from the community performed a cognitively demanding task known to activate the cognitive control network in this functional magnetic resonance imaging study. We identify attenuated activation of a core node of the cognitive control network (the right middle frontal gyrus), and altered baseline connectivity between this node and nodes of the salience and autobiographical memory networks. Our findings indicate that in addition to auditory dysfunction, altered interactions between non-auditory neurocognitive networks maintain chronic tinnitus awareness, revealing new avenues for the identification of effective treatments.

Current Concepts of Memory Disorder in Epilepsy: Edging Towards a Network Account.

PURPOSE OF REVIEW: A paradigm shift in contemporary epileptology has been the reframing of both epilepsy and its comorbid memory disorders as the product of diseased brain networks. The current review discusses some of the clinical and theoretical implications that stem from this shift. RECENT FINDINGS: Some implications of a network conceptualisation of epilepsy include a need for more widespread cognitive phenotyping in epilepsy; recognition that memory disorders in epilepsy can be multi-determined, including by non-structural factors; deeper consideration given to the neurodevelopmental context in which memory problems emerge; the utility of new methods to characterise memory impairments in epilepsy; and a call for greater recognition of the close interrelationships between memory comorbidities and psychiatric symptoms in epilepsy. Memory disorder significantly worsens the quality of life of people with epilepsy, underscoring the importance to patient wellbeing of giving due consideration to the up-to-date neuropsychological practises outlined in this review.

The spatiotemporal substrates of autobiographical recollection: Using event-related ICA to study cognitive networks in action.

Higher cognitive functions depend upon dynamically unfolding brain network interactions. Autobiographical recollection - the autonoetic re-experiencing of context rich, emotionally laden, personally experienced episodes - is an excellent example of such a process. Autobiographical recollection unfolds over time, with different cognitive processes engaged at different times throughout. In this paper we apply a recently developed analysis technique - event related independent components analysis (eICA) - to study the spatiotemporal dynamics of neural activity supporting autobiographical recollection. Participants completed an in-scanner autobiographical recollection paradigm in which the recalled episodes varied in chronological age and emotional content. By combining eICA with these cognitive manipulations we show that the brain-wide response to autobiographical recollection comprises brain networks with (i) different sensitivities to psychological aspects of the to-be-recollected material and (ii) distinct temporal profiles of activity during recollection. We identified networks with transient activations (in language and cognitive control related regions) and deactivations (in auditory and sensorimotor regions) to each autobiographical probe question, as well as networks with responses that are sustained over the course of the recollection period. These latter networks together overlapped spatially with the broader default mode network (DMN), indicating subspecialisation within the DMN. The vividness of participants' recollection was associated with the magnitude of activation in left dorsolateral prefrontal cortex and deactivation in visual association cortices. We interpret our results in the context of current theories of the spatial and temporal organisation of the human autobiographical memory system. Our findings demonstrate the utility of eICA as a tool for studying higher cognitive functions. The application of eICA to high spatial and temporal resolution datasets identifies in a single experimental protocol spatially specific networks that are recruited during cognitive activity, as well as the temporal order of activation of these networks.

The diminishing dominance of the dominant hemisphere: Language fMRI in focal epilepsy.

"Which is the dominant hemisphere?" is a question that arises frequently in patients considered for neurosurgery. The concept of the dominant hemisphere implies uniformity of language lateralisation throughout the brain. It is increasingly recognised that this is not the case in the healthy control brain, and it is especially not so in neurological diseases such as epilepsy. In the present work we adapt our published objective lateralisation method (based on the construction of laterality curves) for use with sub-lobar cortical, subcortical and cerebellar regions of interest (ROIs). We apply this method to investigate regional lateralisation of language activation in 12 healthy controls and 18 focal epilepsy patients, using three different block design language fMRI paradigms, each tapping different aspects of language processing. We compared lateralisation within each ROI across tasks, and investigated how the quantity of data collected affected the ability to robustly estimate laterality across ROIs. In controls, lateralisation was stronger, and the variance across individuals smaller, in cortical ROIs, particularly in the Inferior Frontal (Broca) region. Lateralisation within temporal ROIs was dependent on the nature of the language task employed. One of the healthy controls was left lateralised anteriorly and right lateralised posteriorly. Consistent with previous work, departures from normality occurred in ~ 15-50% of focal epilepsy patients across the different ROIs, with atypicality most common in the Lateral Temporal (Wernicke) region. Across tasks and ROIs the absolute magnitude of the laterality estimate increased and its across participant variance decreased as more cycles of task and rest were included, stabilising at ~ 4 cycles (~ 4 min of data collection). Our data highlight the importance of considering language as a complex task where lateralisation varies at the subhemispheric scale. This is especially important for presurgical planning for focal resections where the concept of 'hemispheric dominance' may be misleading. This is a precision medicine approach that enables objective evaluation of language dominance within specific brain regions and can reveal surprising and unexpected anomalies that may be clinically important for individual cases.

MRI-negative temporal lobe epilepsy: A network disorder of neocortical connectivity.

OBJECTIVE: To define the functional network changes that characterize MRI-negative temporal lobe epilepsy (TLE) and TLE with hippocampal sclerosis (HS-TLE). METHODS: We studied 36 patients with medically refractory unilateral TLE, having either a normal clinical MRI (n = 18) or unilateral hippocampal sclerosis (n = 18). Patients were compared to healthy controls of equivalent age and sex (n = 27). Functional connectivity in 10 minutes of task-free functional MRI was assessed using a voxel-resolution graph theoretic analysis, using the metrics of degree, clustering coefficient, eigenvector, and betweenness centrality. Significant clusters were further explored with a seed-based analysis. RESULTS: MRI-negative TLE showed decreased connectivity at the ipsilateral superior and middle temporal gyri compared to controls (decreased eigenvector centrality). No functional abnormality was detected within mesial temporal structures. In contrast, HS-TLE showed increased connectivity within the affected hippocampus and anterior thalamus (increased clustering coefficient) and decreased connectivity of the ventromesial prefrontal cortex (decreased betweenness centrality). Using the detected clusters as seed regions revealed decreased connectivity from the sclerotic hippocampus to both the contralateral temporal lobe and regions of the default mode network. CONCLUSION: MRI-negative TLE is associated with impaired interictal connectivity of the temporal neocortex, lateralized to the epileptic side. HS-TLE shows a different pattern, with functional segregation of the sclerotic hippocampus and impairment of its long-range connectivity. This suggests that MRI-negative TLE is not merely a subtle version of hippocampal sclerosis, but is rather a separate condition that involves distinct brain networks.

Resting state functional connectivity changes induced by prior brain state are not network specific.

Resting state functional connectivity (rFC) is used to identify functionally related brain areas without requiring subjects to perform specific tasks. Previous work suggests that prior brain state, as determined by the activity engaged in immediately prior to collection of resting state data, can influence the networks recovered by rFC analyses. We determined the prevalence and network specificity of rFC changes induced by manipulations of prior state (including an unstructured (unconstrained) state, and language and motor tasks). Three blocks of rest data (one after each of the specified prior states) were acquired on each of 25 subjects. We hypothesised that prior state induced changes in rFC would be greatest within the networks most actively recruited by that prior state. Changes in rFC were greatest following the motor task and, contrary to our hypothesis, were not network specific. This was demonstrated by comparing (1) the timecourses within a set of ROIs selected on the basis of task-related de/activation, and (2) seed-based whole brain voxel-wise connectivity maps, seeded from local maxima in the task-related de/activation maps. Changes in connectivity strength tended to manifest as increases in rFC relative to that in the unstructured rest state, with change maps resembling partially complete maps of the primary sensory cortices and the cognitive control network. The majority of rFC changes occurred in areas moderately (but not weakly) connected to the seeds. Constrained prior states were associated with lower across-participant variance in rFC. This systematic investigation of the effect of prior brain state on rFC indicates that the rFC changes induced by prior brain state occur both in brain networks related to that brain activity and in networks nominally unrelated to that brain activity.

Reading difficulty is associated with failure to lateralize temporooccipital function.

OBJECTIVE: Studies of focal epilepsy have revealed abnormalities of language organization; however, little attention has been paid to disorders of reading in this group. We hypothesized that language functional magnetic resonance imaging (fMRI) would reveal differences in language organization between focal epilepsy patients with and without reading difficulties. METHODS: We conducted language fMRI studies of 10 focal epilepsy patients with reading difficulties, 34 focal epilepsy patients without reading difficulties, and 42 healthy controls. RESULTS: We defined regions of interests on the basis of activation patterns on an orthographic lexical retrieval task. Comparison of activations within these ROIs on a second Noun-Verb task revealed epilepsy-related effects (relative to healthy controls: reduced activation in left inferior frontal cortex), as well as greater activation in the right temporooccipital cortex specific to the reading difficulty group. SIGNIFICANCE: These findings identify a focal epilepsy effect in the left frontal region (present in patients with and without reading difficulties), and a functional abnormality specific to the reading difficulty group localized to right temporooccipital cortex-a region implicated in lexicosemantic processing. Our observations suggest a failure of left hemisphere specialization among focal epilepsy patients with reading difficulties.

Texture-dependent motion signals in primate middle temporal area.

Neurons in the middle temporal (MT) area of primate cortex provide an important stage in the analysis of visual motion. For simple stimuli such as bars and plaids some neurons in area MT--pattern cells--seem to signal motion independent of contour orientation, but many neurons--component cells--do not. Why area MT supports both types of receptive field is unclear. To address this we made extracellular recordings from single units in area MT of anaesthetised marmoset monkeys and examined responses to two-dimensional images with a large range of orientations and spatial frequencies. Component and pattern cell response remained distinct during presentation of these complex spatial textures. Direction tuning curves were sharpest in component cells when a texture contained a narrow range of orientations, but were similar across all neurons for textures containing all orientations. Response magnitude of pattern cells, but not component cells, increased with the spatial bandwidth of the texture. In addition, response variability in all neurons was reduced when the stimulus was rich in spatial texture. Fisher information analysis showed that component cells provide more informative responses than pattern cells when a texture contains a narrow range of orientations, but pattern cells had more informative responses for broadband textures. Component cells and pattern cells may therefore coexist because they provide complementary and parallel motion signals.