Brain Communications最新文献

{"title":"Chronic inflammation with microglia senescence at basal forebrain: impact on cholinergic deficit in Alzheimer’s brain hemodynamics","authors":"Dong Liu, Shih-Chang Hsueh, D. Tweedie, Nate Price, Elliot Glotfelty, D. Lecca, Richard Telljohann, Rafael deCabo, Barry J. Hoffer, Nigel H. Greig","doi":"10.1093/braincomms/fcae204","DOIUrl":"https://doi.org/10.1093/braincomms/fcae204","url":null,"abstract":"\u0000 Cholinergic innervation in brain is involved in modulating neurovascular function including cerebral blood flow hemodynamics in response to neuronal activity. Cholinergic deficit is associated with pathophysiology in Alzheimer’s disease, albeit the etiology remains to clarify. In current study, neocortex cerebral blood flow response to acetylcholine was evaluated by Laser-Doppler Flowmetry in 3xTgAD Alzheimer’s disease model) and wild type mice of two age groups. The peak of cerebral blood flow to acetylcholine (i.v.) from baseline levels (% ΔrCBF) were higher in young 3xTgAD vs. in wild type mice (48.35; CI:27.03-69.67 vs. 22.70; CI:15.5-29.91, p < 0.05); this was reversed in old 3xTgAD mice (21.44; CI:2.52-40.35 vs. 23.25; CI:23.25-39). Choline acetyltransferase protein was reduced in neocortex, while cerebrovascular reactivity to acetylcholine was preserved in young 3xTgAD mice. This suggests of endogenous acetylcholine deficit and possible cholinergic denervation from selected cholinergic nuclei within basal forebrain. The early deposition of tauopathy moieties (mutant hTau and pTau181) and its coincidence in cholinergic cell clusters, were observed occasionally at basal forebrain of 3xTgAD mice including substantia innominate, nucleus Basalis of Meynert and nucleus of horizontal limb diagonal band of Broca. A prominent feature was microglia interacting tauopathy and demonstrated a variety of morphology changes particularly when located in proximity to tauopathy. The microglia ramified phenotype was reduced as evaluated by the ramification index and Fractal analysis. Increased microglia senescence, identified as SASP (senescence-associated secretory phenotype), was colocalization with p16Ink4ɑ, a marker of irreversible cell cycle arrest in old 3xTgAD vs. wild type mice (p = 0.001). The p16Ink4ɑ was also observed in neuronal cells bearing tauopathy within basal forebrain of 3xTgAD mice. TNF-ɑ, the pro-inflammatory cytokine elevated persistently in microglia (Peason’s correlation coefficient = 0.62), and the loss of cholinergic cells in vulnerable basal forebrain environment was indicated by image analysis in 3xTgAD mice, which linked to the cholinergic deficits in neocortex rCBF hemodynamics. Our study revealed the early change of CBF hemodynamics to acetylcholine in 3xTgAD model. As a major effector of brain innate immune activation, microglia SASP with age related disease progression is indicative of immune cell senescence, which contributes to chronic inflammation and cholinergic deficits at basal forebrain. Targeting neuroinflammation and senescence may mitigate cholinergic pathophysiology in Alzheimer’s disease.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"120 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141351940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SuperAging functional connectomics from resting-state functional MRI","authors":"Bram Ryder Diamond, Jaiashre Sridhar, Jessica Maier, Adam Martersteck, Emily J Rogalski","doi":"10.1093/braincomms/fcae205","DOIUrl":"https://doi.org/10.1093/braincomms/fcae205","url":null,"abstract":"\u0000 Understanding the relationship between functional connectivity (FC) of higher-order neurocognitive networks and age-related cognitive decline is a complex and evolving field of research. Decreases in FC have been associated with cognitive decline in persons with Alzheimer’s disease and related dementias (ADRD). However, the contributions of FC have been less straightforward in typical cognitive aging. Some investigations suggest relatively robust FC within neurocognitive networks differentiates unusually successful cognitive aging from average aging, while others do not. Methodologic limitations in data processing and varying definitions of “successful aging” may have contributed to the inconsistent results to date. The current study seeks to address previous limitations by optimized MRI methods to examine FC in the well-established SuperAging phenotype, defined by age and cognitive performance as individuals 80 and older with episodic memory performance equal to or better than 50-to-60-year-olds. Within- and between-network FC of large-scale neurocognitive networks were compared between 24 SuperAgers and 16 cognitively average older-aged control (OACs) with stable cognitive profiles using resting state functional MRI (rs-fMRI) from a single visit. Group classification was determined based on measures of episodic memory, executive functioning, verbal fluency, and picture naming. Inclusion criteria required stable cognitive status across two visits. First, we investigated the FC within and between seven resting state networks from a common atlas parcellation. A separate index of network segregation was also compared between groups. Second, we investigated the FC between six subcomponents of the default mode network (DMN), the neurocognitive network commonly associated with memory performance and disrupted in persons with ADRD. For each analysis, FCs were compared across groups using two-sample independent t-tests and corrected for multiple comparisons. There were no significant between-group differences in demographic characteristics including age, sex, and education. At the group-level, within-network FC, between-network FC, and segregation measurements of seven large-scale networks, including subcomponents of the DMN, were not a primary differentiator between cognitively average aging and SuperAging phenotypes. Thus, FC within or between large-scale networks does not appear to be a primary driver of the exceptional memory performance observed in SuperAgers. These results have relevance for differentiating the role of FC changes associated with cognitive aging from those associated with ADRD.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"36 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141360174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Downregulation of the silent potassium channel Kv8.1 increases motor neuron vulnerability in amyotrophic lateral sclerosis","authors":"Xuan Huang, Seungkyu Lee, Kuchuan Chen, R. Kawaguchi, Ole Wiskow, Sulagna Ghosh, Devlin Frost, Laura Perrault, Roshan Pandey, Joseph R. Klim, Bruno Boivin, Crystal Hermawan, K. Livak, Daniel H. Geschwind, Brian J. Wainger, Kevin Eggan, Bruce P Bean, Clifford J. Woolf","doi":"10.1093/braincomms/fcae202","DOIUrl":"https://doi.org/10.1093/braincomms/fcae202","url":null,"abstract":"\u0000 While voltage-gated potassium channels have critical roles in controlling neuronal excitability they also have non-ion conducting functions. Kv8.1, encoded by the KCNV1 gene, is a “silent” ion channel subunit whose biological role is complex since Kv8.1 subunits do not form functional homotetramers but assemble with Kv2 to modify its ion channel properties. We profiled changes in ion channel expression in Amyotrophic lateral sclerosis patient-derived motor neurons carrying a SOD1(A4V) mutation to identify what drives their hyperexcitability. A major change identified was a substantial reduction of KCNV1/Kv8.1 expression, which was also observed in patient-derived neurons with C9orf72 expansion. We then studied the effect of reducing KCNV1/Kv8.1 expression in healthy motor neurons and found it did not change neuronal firing but increased vulnerability to cell death. A transcriptomic analysis revealed dysregulated metabolism and lipid/protein transport pathways in KCNV1/Kv8.1 deficient motor neurons. The increased neuronal vulnerability produced by the loss of KCNV1/Kv8.1 was rescued by knocking down Kv2.2, suggesting a potential Kv2.2-dependent downstream mechanism in cell death. Our study reveals, therefore, unsuspected, and distinct roles of Kv8.1 and Kv2.2 in Amyotrophic lateral sclerosis related neurodegeneration.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"42 25","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141358757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroanatomy of cerebellar mutism syndrome: the role of lesion location","authors":"Jax Skye, J. Bruss, S. Toescu, Kristian Aquilina, A. Grafft, Gino Bardi Lola, Aaron D Boes","doi":"10.1093/braincomms/fcae197","DOIUrl":"https://doi.org/10.1093/braincomms/fcae197","url":null,"abstract":"\u0000 Approximately 25% of pediatric patients who undergo cerebellar tumor resection develop cerebellar mutism syndrome. Our group recently showed that damage to the cerebellar deep nuclei and superior cerebellar peduncles, which we refer to as the cerebellar outflow pathway, is associated with an increased risk of cerebellar mutism syndrome. Here, we tested whether these findings replicate in an independent cohort. We evaluated the relationship between lesion location and the development of cerebellar mutism syndrome in an observational study of 56 pediatric patients ranging from five months to 14 years of age who underwent cerebellar tumor resection. We hypothesized that individuals who developed cerebellar mutism syndrome after surgery, relative to those who did not, would have lesions that preferentially intersect with: 1) the cerebellar outflow pathway and 2) a previously generated ‘lesion-symptom map’ of cerebellar mutism syndrome. Analyses were conducted in accordance with pre-registered hypotheses and analytic methods (https://osf.io/r8yjv/). We found supporting evidence for both hypotheses. Compared to patients who did not develop cerebellar mutism syndrome, patients with cerebellar mutism syndrome (n=10) had lesions with greater overlap with the cerebellar outflow pathway (Cohen’s d=.73, p=.05), and the cerebellar mutism syndrome lesion-symptom map (Cohen’s d=1.1, p=.004). These results strengthen the association of lesion location with the risk of developing cerebellar mutism syndrome and demonstrate generalizability across cohorts. These findings may help to inform the optimal surgical approach to pediatric cerebellar tumors.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"40 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141381830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of evening smartphone use on sleep and declarative memory consolidation in male adolescents and young adults","authors":"C. Höhn, Michael A. Hahn, Georg Gruber, Belinda Pletzer, Christian Cajochen, K. Hoedlmoser","doi":"10.1093/braincomms/fcae173","DOIUrl":"https://doi.org/10.1093/braincomms/fcae173","url":null,"abstract":"\u0000 Exposure to short-wavelength light before bedtime is known to disrupt nocturnal melatonin secretion and can impair subsequent sleep. However, while it has been demonstrated that older adults are less affected by short-wavelength light, there is limited research exploring differences between adolescents and young adults. Furthermore, it remains unclear whether the effects of evening short-wavelength light on sleep architecture extend to sleep-related processes, such as declarative memory consolidation. Here, we recorded polysomnography from 33 male adolescents (15.42 ± 0.97 years) and 35 male young adults (21.51 ± 2.06 years) in a within-subjects design during three different nights to investigate the impact of reading for 90min either on a smartphone with or without a blue-light filter or from a printed book. We measured subjective sleepiness, melatonin secretion, sleep physiology, and sleep-dependent memory consolidation. While subjective sleepiness remained unaffected, we observed a significant melatonin-attenuation effect in both age groups immediately after reading on the smartphone without a blue-light filter. Interestingly, adolescents fully recovered from the melatonin attenuation in the following 50min before bedtime, whereas adults still, at bedtime, exhibited significantly reduced melatonin levels. Sleep-dependent memory consolidation and the coupling between sleep spindles and slow oscillations were not affected by short-wavelength light in both age groups. Nevertheless, adults showed a reduction in N3 sleep during the first night-quarter. In summary, avoiding smartphone use in the last hour before bedtime is advisable for adolescents and young adults to prevent sleep disturbances. Our research empirically supports general sleep hygiene advice and can inform future recommendations regarding the use of smartphones and other screen-based devices before bedtime.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140962892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain structure and connectivity mediate the association of lifestyle and cognition: the Maastricht study","authors":"N. R. DeJong, J. Jansen, M. P. J. van Boxtel, M. T. Schram, C. Stehouwer, M. V. van Greevenbroek, C. V. D. van der Kallen, A. Koster, S. Eussen, B. D. de Galan, W. Backes, S. Koehler","doi":"10.1093/braincomms/fcae171","DOIUrl":"https://doi.org/10.1093/braincomms/fcae171","url":null,"abstract":"\u0000 Life-course exposure to risk and protective factors impacts brain macro- and micro-structure, which in turn affects cognition. The concept of Brain Age Gap (BAG) assesses brain health by comparing an individual’s neuroimaging-based predicted age with their calendar age. Higher BAG implies accelerated brain aging and is expected to be associated with worse cognition. In this study, we comprehensively modelled mutual associations between brain-health and lifestyle factors, brain age, and cognition in a large, middle-aged population. For this study, cognitive test scores, lifestyle, and 3T MRI data for n=4881 participants (mean age (±SD) = 59.2 (±8.6), 50.1% male) were available from The Maastricht Study, a population-based cohort study with extensive phenotyping. Whole brain volumes (grey matter (GM), cerebrospinal fluid (CSF), white matter hyperintensity (WMH)), cerebral microbleeds (CMB), and structural white matter connectivity were calculated. Lifestyle factors were combined into an adapted LIfestyle for BRAin health (LIBRA) weighted sum score, with higher score indicating greater dementia risk. Cognition was calculated by averaging z-scores across three cognitive domains (memory, information processing speed, executive function and attention). BAG was calculated by comparing calendar age to predictions from a neuroimaging-based multivariable regression model. Paths between LIBRA tertiles, BAG and cognitive function were tested using linear regression and structural equation modelling, adjusting for sociodemographic and clinical confounders. Results show that CSF, GM, WMH and CMB best predicted BAG (R2 = 0.455, RMSE = 6.44). In regression analysis, higher LIBRA scores (greater dementia risk) were associated with higher BAG (standardized regression coefficient ß = 0.126, p < 0.001) and worse cognition (ß = -0.046, p = 0.013), while higher BAG was associated with worse cognition (ß=-0.163, p<0.001). In mediation analysis, 24.7% of the total difference in cognition between the highest and lowest LIBRA tertile was mediated by BAG (ßindirect = -0.049, p < 0.001; ßtotal = -0.198, p < 0.001), and an additional 3.8% was mediated via connectivity (ßindirect = -0.006, p < 0.001; ßtotal = -0.150, p < 0.001). Findings suggest that associations between health- and lifestyle-based risk/protective factors (LIBRA) and cognition can be partially explained by structural brain health markers (BAG) and white matter connectivity markers. Lifestyle interventions targeted at high-risk individuals in mid to late life may be effective in promoting and preserving cognitive function in the general public.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"16 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140968872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization in the rat of the individual tendency to rely on alcohol to cope with distress and the ensuing vulnerability to drink compulsively","authors":"Lucia Marti-Prats, D. Belin","doi":"10.1093/braincomms/fcae169","DOIUrl":"https://doi.org/10.1093/braincomms/fcae169","url":null,"abstract":"\u0000 Only some vulnerable individuals who recreationally drink alcohol eventually develop the compulsive drinking pattern that characterizes alcohol use disorder. A new frontier in biomedical research lies in understanding the neurobehavioral mechanisms of this individual vulnerability, a necessary step towards developing novel effective therapeutic strategies. Translational research has been hindered by the lack of valid, reliable and robust approaches that enable the study of the influence of the reliance on alcohol to cope with stress or self-medicate negative emotional states on the subsequent transition to alcohol use disorder.\u0000 We have therefore developed a behavioral task in the rat that enables the investigation of the neural and cellular basis of the exacerbation of the vulnerability to develop compulsive alcohol drinking by the use of alcohol to develop an adjunctive, anxiolytic, polydipsic drinking behavior in a schedule-induced polydipsia procedure. Hence, in our task, alcohol is introduced in the schedule-induced polydipsia context after several weeks of training with water so that rats are exposed to alcohol for the first time in a distressing context and learn to drink alcohol as a coping strategy. Capitalizing on this protocol, we have consistently been able to identify a subpopulation of rats that were unable to learn to cope with negative states by drinking water and relied on alcohol to do so. This maladaptive reliance on alcohol-drinking to cope with distress has been shown to be associated with an exacerbation of the subsequent transition to compulsive drinking. Furthermore, these vulnerable rats reached blood alcohol levels comparable to that of intoxication in humans, thereby developing two key features of alcohol use disorder, namely excessive alcohol intake and compulsive drinking. Altogether, this behavioral task provides a novel and unique tool for the investigation of the neurobehavioral mechanisms underlying the exacerbation of the individual vulnerability to developing compulsive alcohol drinking by the use of alcohol as a strategy to cope with distress, and for the evaluation of the efficacy of potential therapeutic strategies in a personalized medicine approach. This procedure, which focuses on an understudied but key factor of the development of alcohol use disorder, may become widely used as it benefits the fields of alcohol, emotion regulation and stress, the interest in which has substantially increased since the evidence of a profound exacerbation of alcohol use and alcohol-related negative consequences by the distress and social isolation engendered by the various measures implemented worldwide in response to the COVID-19 pandemic.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"27 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140979715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to: ‘Acute flaccid myelitis in low to middle income countries: diagnosis and surveillance’","authors":"Sam Olum, Charlotte Scolding, V. Omona, Kansiime Jackson, Neil Scolding","doi":"10.1093/braincomms/fcae168","DOIUrl":"https://doi.org/10.1093/braincomms/fcae168","url":null,"abstract":"","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":" 37","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140992784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A pathway linking pulse pressure to dementia in adults with Down syndrome","authors":"Batool Rizvi, Patrick J Lao, M. Sathishkumar, Lisa Taylor, Nazek Queder, L. McMillan, Natalie C. Edwards, D. Keator, E. Doran, C. Hom, Dana Nguyen, H. D. Rosas, F. Lai, N. Schupf, Jose Gutierrez, W. Silverman, Ira T. Lott, M. Mapstone, D. M. Wilcock, Elizabeth Head, M. Yassa, Adam M. Brickman","doi":"10.1093/braincomms/fcae157","DOIUrl":"https://doi.org/10.1093/braincomms/fcae157","url":null,"abstract":"Abstract Adults with Down syndrome are less likely to have hypertension than neurotypical adults. However, whether blood pressure measures are associated with brain health and clinical outcomes in this population has not been studied in detail. Here, we assessed whether pulse pressure is associated with markers of cerebrovascular disease and is linked to a diagnosis of dementia in adults with Down syndrome via structural imaging markers of cerebrovascular disease and atrophy. The study included participants with Down syndrome from the Alzheimer’s Disease - Down Syndrome study (n = 195, age = 50.6 ± 7.2 years, 44% women, 18% diagnosed with dementia). Higher pulse pressure was associated with greater global, parietal and occipital white matter hyperintensity volume but not with enlarged perivascular spaces, microbleeds or infarcts. Using a structural equation model, we found that pulse pressure was associated with greater white matter hyperintensity volume, which in turn was related to increased neurodegeneration, and subsequent dementia diagnosis. Pulse pressure is an important determinant of brain health and clinical outcomes in individuals with Down syndrome despite the low likelihood of frank hypertension.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":" 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140995132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting thalamocortical circuits for closed-loop stimulation in Lennox–Gastaut syndrome","authors":"Aaron E L Warren, Christopher R Butson, Matthew P Hook, L. Dalic, John S Archer, Emma Macdonald-Laurs, Frederic L. W. V. J. Schaper, Lauren Hart, Hargunbir Singh, Lise Johnson, Katie L Bullinger, Robert E. Gross, Martha J. Morrell, John D Rolston","doi":"10.1093/braincomms/fcae161","DOIUrl":"https://doi.org/10.1093/braincomms/fcae161","url":null,"abstract":"Abstract This paper outlines the therapeutic rationale and neurosurgical targeting technique for bilateral, closed-loop, thalamocortical stimulation in Lennox–Gastaut syndrome, a severe form of childhood-onset epilepsy. Thalamic stimulation can be an effective treatment for Lennox–Gastaut syndrome, but complete seizure control is rarely achieved. Outcomes may be improved by stimulating areas beyond the thalamus, including cortex, but the optimal targets are unknown. We aimed to identify a cortical target by synthesizing prior neuroimaging studies, and to use this knowledge to advance a dual thalamic (centromedian) and cortical (frontal) approach for closed-loop stimulation. Multi-modal brain network maps from three group-level studies of Lennox–Gastaut syndrome were averaged to define the area of peak overlap: simultaneous EEG-functional MRI of generalized paroxysmal fast activity, [18F]fluorodeoxyglucose PET of cortical hypometabolism and diffusion MRI structural connectivity associated with clinical efficacy in a previous trial of thalamic deep brain stimulation. The resulting ‘hotspot’ was used as a seed in a normative functional MRI connectivity analysis to identify connected networks. Intracranial electrophysiology was reviewed in the first two trial patients undergoing bilateral implantations guided by this hotspot. Simultaneous recordings from cortex and thalamus were analysed for presence and synchrony of epileptiform activity. The peak overlap was in bilateral premotor cortex/caudal middle frontal gyrus. Functional connectivity of this hotspot revealed a distributed network of frontoparietal cortex resembling the diffuse abnormalities seen on EEG-functional MRI and PET. Intracranial electrophysiology showed characteristic epileptiform activity of Lennox–Gastaut syndrome in both the cortical hotspot and thalamus; most detected events occurred first in the cortex before appearing in the thalamus. Premotor frontal cortex shows peak involvement in Lennox–Gastaut syndrome and functional connectivity of this region resembles the wider epileptic brain network. Thus, it may be an optimal target for a range of neuromodulation therapies, including thalamocortical stimulation and emerging non-invasive treatments like focused ultrasound or transcranial magnetic stimulation. Compared to thalamus-only approaches, the addition of this cortical target may allow more rapid detections of seizures, more diverse stimulation paradigms and broader modulation of the epileptic network. A prospective, multi-centre trial of closed-loop thalamocortical stimulation for Lennox–Gastaut syndrome is currently underway.","PeriodicalId":504765,"journal":{"name":"Brain Communications","volume":"59 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141003391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}