Lovastatin Modulates Cortical Excitability, E/I Balance, and Antioxidant Markers in Drug-Resistant Epilepsy: A Proof-of-Concept Study

Lovastatin Modulates Cortical Excitability, E/I Balance, and Antioxidant Markers in Drug-Resistant Epilepsy: A Proof-of-Concept Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Lovastatin Modulates Cortical Excitability, E/I Balance, and Antioxidant Markers in Drug-Resistant Epilepsy: A Proof-of-Concept Study Sulaiman Abuhaiba, Catarina Duarte, Francisco Sales, Miguel Castelo-Branco This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8180994/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 16 You are reading this latest preprint version Abstract Background Drug-resistant epilepsy (DRE) is a major clinical challenge, with neuroinflammation and excitatory/inhibitory (E/I) imbalance implicated in its pathophysiology. This proof-of-concept case series aimed to investigate the neurochemical and neurophysiological effects of a short course of lovastatin in individuals with DRE. Methods Five participants with drug-resistant temporal lobe epilepsy completed a double-blind, placebo-controlled, crossover protocol involving oral administration of lovastatin (60 mg/day) and placebo for three consecutive days. Post-intervention assessments included: 1) magnetic resonance spectroscopy (MRS) in the visual cortex to quantify GABA+, Glutamate (Glx), and Glutathione (GSH); 2) resting-state EEG to measure the frequency of interictal epileptiform discharges (IEDs); and 3) event-related potentials (ERPs) during a facial recognition task. Results Compared to placebo, lovastatin administration was associated with a significant reduction in the GABA+/Glx ratio (p = 0.041) and IED frequency (p = 0.04), alongside a significant increase in GSH concentration (p = 0.039). Lovastatin also modulated visual processing ERPs, significantly delaying the P100 latency (p = 0.04) and reducing the absolute N110 peak amplitude (p = 0.04). Conclusion This study demonstrates that a short course of lovastatin can modulate key in-vivo biomarkers of E/I balance, redox state, and cortical excitability in patients with DRE. These preliminary findings provide a mechanistic rationale for further, larger studies to explore the potential of statins as a novel strategy for modifying pathological brain activity. GABA Glutamate Lovastatin Glutathione Occipital Cortex Excitotoxicity Figures Figure 1 1 Introduction Epilepsy is a common neurologic disorder that is characterized by recurrent seizures and is diagnosed in about 1% of the general population with one third of patients having poor control despite the availability of novel and wide range of antiepileptic drugs (AED) (Sasa, 2006 ; Canevini et al., 2010 ). Of those with drug resistant epilepsy, inflammatory processes appear to play an important role as increasing evidence has emerged pointing towards the possible involvement of astrocytes, other immune cells, and blood-brain-barrier breakdown in epileptogenesis (Friedman and Dingledine, 2011 ). Additionally, several animal models of epilepsy have strong evidence for neuroinflammation (Turrin and Rivest, 2004 ; Gorter et al., 2006 ; Dedeurwaerdere et al., 2012 ). There is evidence that statins may modulate excitation-inhibition (E/I) balance (Dionísio et al., 2022) which is very relevant in epilepsy, as suggested by our recent tDCS study showing beneficial modulation in this condition (Abuhaiba et al., 2022 ). Epilepsy has long been seen as a disorder of hypersynchronization/desynchronization with GABAergic inhibition as the main driver for abnormal synchronization and the generation of pathologic high frequency oscillations, especially temporal lobe onset epilepsy (Tamás et al., 2000 ; Klausberger and Somogyi, 2008 ). This makes such a cohort optimal for the study of lovastatin effects on excitation-inhibition. Atorvastatin has a neuroprotective effect by reducing excitotoxicity by inhibiting NMDA glutamate receptor activity in rodents with KA-induced absence seizures (Moezi et al., 2012 ; Shafaroodi et al., 2012 ). Simvastatin reduced the number of seizures in animal models of KA-induced epilepsy (Ramirez et al., 2011 ; Xie et al., 2011a ), and was abolished the risk of status epilepticus in such animals (Sun et al., 2012 ). Lovastatin has been found to have a similar anti-epileptic profile to atorvastatin by modulating NMDA glutamate receptors, mitigate the impact of excitotoxicity and to have an inhibitory cortical effect ((Serbanescu et al., 2004 ; Üzüm et al., 2010a ; Funck et al., 2011a ; Osterweil et al., 2013 ). Lovastatin appears to be an effective antiepileptic in fragile X syndrome (Osterweil et al., 2013 ) and is known to improve cognitive function in neurofibromatosis type 1 due to the inhibitory cortical effect (Mainberger et al., 2013 ; Bernardino et al., 2022 ). There is a current emphasis on the role of anti-inflammatories as adjuvant treatments for epilepsy (Dedeurwaerdere et al., 2012 ; D’Ambrosio et al., 2013 ; Vezzani et al., 2013a ). Statins, which are commonly prescribed in today’s medical practice for cerebrovascular and cardiovascular conditions are also known to have inherit anti-inflammatory effects (Weber et al., 2006 ; Clarke et al., 2008 ) and protective blood-brain-barrier effects. (Pannu et al., 2007 ). It has long been known that statins interact with other antiepileptic drugs as they are potent P450 enzyme inducers, but more recent studies suggested that they may have actual antiepileptic effects per se. Modulation of E/I by statins may also influence neurophysiological oscillatory processes related to cognition such as face recognition. Mooney faces, which are abstract two-tone stimuli that challenge holistic perceptual processing consisting of degraded pictures of human faces, are good inducers of physiologic oscillations, which are shaped by cortical inhibitory circuits, and the GABAergic system (Castelhano et al., 2009 , 2013 , 2018 ). Accordingly, studying neurophysiological signatures such as event related potential evoked by this visual task may also provide clues into the effects of statins with cortical inhibition and visual information processing. While the epileptogenic zone in temporal lobe epilepsy (TLE) represents the core site of seizure generation, metabolic measurements on the visual cortex provides a potential window into the long-range network-level pathophysiology of the disorder. TLE is increasingly understood not as a focal disease but as a network disorder, where epileptic activity propagates from the temporal lobe to anatomically and functionally connected regions, including the occipital lobe (Spencer, 2002 ; Bernhardt et al., 2013 ). This propagation can induce downstream metabolic and structural alterations even in regions that are not the primary seizure focus. Measuring brain metabolites with Magnetic Resonance Spectroscopy (MRS) in the visual cortex can, therefore, reveal the extent of this network-level disruption. For instance, alterations in N-acetylaspartate (NAA), a marker of neuronal viability, or in the balance of excitatory (Glutamate) and inhibitory (GABA) neurotransmitters in the occipital lobe can reflect the chronic impact of seizures on brain regions distant from the epileptogenic zone (Mueller et al., 2014 ). Furthermore, from a methodological standpoint, acquiring high-quality MRS data from the occipital lobe is often more feasible than from the mesial temporal regions (Jansen et al., 2006 ; Wellard et al., 2005 ). The main aim of this study is to investigate the effects of lovastatin on brain metabolites, visual processing of faces which is known to be dependent on cortical GABAergic networks, and to link that with the effect of lovastatin on the frequency of interictal discharges in a cohort of patients with drug resistant epilepsy. Our hypothesis is that lovastatin has the potential to modulate cortical excitotoxicity and neuroinflammation in patients with drug resistant epilepsy and such effects can be directly (via MRS) or indirectly (by electrophysiology) assessed by studing the facial recognition circuit in the visual cortex. 2 Experimental Procedures 2.1 Participants This study was conducted as a prospective, exploratory case series to investigate the effects of lovastatin on cerebral biomarkers of neuroinflammation and excitatory/inhibitory (E/I) balance. We recruited five participants who presented with a stable, chronic neurological condition characterized by cortical hyperexcitability—namely, drug-resistant focal temporal lobe epilepsy. This cohort was selected to serve as a human model for investigating the modulation of E/I dynamics in a hyperexcitable state. Participants were recruited from the epilepsy monitoring unit at the Centro Hospitalar e Universitário de Coimbra. The inclusion criteria were designed to select for a homogeneous group with clear evidence of cortical hyperexcitability, including a high frequency of interictal discharges noted during previous clinical evaluations. To ensure a stable baseline for measuring the effects of the intervention, participants were required to be over 18 years old, not seizure-free in the last three months, and to agree to no changes in their antiepileptic medication regimen for the duration of the study. For logistical reasons related to the intensive visit schedule, recruitment was limited to the Coimbra district. Exclusion criteria included any history of cardiovascular or cerebrovascular disease, dyslipidemia, previous use of or adverse reaction to statins, and contraindications for magnetic resonance imaging (MRI) such as implanted electronic devices or metallic hardware in the head. Participants with a vagal nerve stimulation device or other comorbid neurological conditions were also excluded. Women who were pregnant or lactating were not eligible for participation. Intervention and Assessment Protocol The study followed a within-subject, repeated-measure protocol to assess the impact of a short course of lovastatin. Although the study is presented as a case series, a double-blind, placebo-controlled crossover procedure was utilized to minimize expectation bias. Participants attended three visits at the Institute of Nuclear Sciences Applied to Health (ICNAS), University of Coimbra. Visit 1 (Baseline) : The study protocol was explained to the participants, and written informed consent was obtained. Following this, they were given the first batch of pills (either lovastatin or placebo) and instructed to take three pills daily at bedtime for three consecutive days. Visit 2 (Assessment 1) : On the morning of the fourth day, participants returned to ICNAS for the first assessment battery, which included resting-state electroencephalography (EEG), task-based EEG during a visual face-recognition task, and magnetic resonance spectroscopy (MRS). At the end of this visit, they were given the second batch of pills and instructed to wait for notification before starting them. Washout and Crossover : A four-week washout period was instituted, calculated from the first day of the initial intervention. Following a follow-up call two weeks into this period to monitor for any adverse effects, participants were contacted at the end of the four weeks and instructed to begin the second 3-day course of pills. Visit 3 (Assessment 2) : On the fourth day after starting the second batch of pills, participants underwent the identical assessment battery (EEG, task-EEG, and MRS) for a second time. Ethics Declarations : All procedures conformed to the principles of the Declaration of Helsinki. The study protocol was reviewed and approved by the Faculty of Medicine of the University of Coimbra Research Ethics Committee and the Clinical Academic Center (references: CE010/17 and CHUC 024 − 18). The study was registered as a clinical trial (ClinicalTrials.gov ID: trial registration number NCT06789497). All individuals provided written informed consent before their inclusion in the study. 2.2 Physiologic Challenge Intervention Each participant underwent two treatment conditions: lovastatin (60 mg/day) and placebo, administered in a randomized crossover design. Participants took the assigned treatment for three consecutive days, followed by EEG, ERP, and MRS assessments. A washout period of four weeks separated the two conditions. 2.3 Outcome Measures 2.3.1 Resting Electroencephalography and IED (interictal epileptiform discharges) Counting Participants were instructed to relax for 20 minutes during this EEG acquisition. This EEG trace was used to count the number of IEDs. Resting state EEG was performed in the second and third visits to ICNAS before doing EEG with visual task and MRS. EEG was recorded using a 64 electrodes cap (QuickCap, NeuroScan, USA) with electrodes placed according to the extended 10/20 system. Electrodes impedances were kept below 5 KΩ and the signal was amplified and recorded at a sampling rate of 1000 Hz using a SynAmps2/RT amplifier (NeuroScan, USA). A low-pass filter at 200 Hz was applied. The signal was recorded using Scan 4 (NeuroScan, USA), with the acquisition reference electrode placed at a half distance between CZ and FCZ. Counting of the IEDs was performed with Curry 7 (Compumedics, Charlotte, NC, USA). The EEG signal was down sampled to 400 Hz and band filtered between 1 and 30 Hz. Two electrodes in average montage with the highest amplitude of the spike-slow-wave complex were selected and template matching was performed at a sensitivity level of 75% for objective automated identification of the spikes. The selected spikes were reviewed by an expert epileptologist. The average number of automated counted spikes was recorded for each participant. The same steps were done for the counting of spikes in the other resting EEG that was performed in the third visit. 2.3.2 Visual Task and Event Related Potential Analysis Participants were presented with two categories of Mooney pictures: Mooney faces and scrambled non-face stimuli. Each participant was instructed to report if a face was present (response button 1, right hand), or not (response button 2, left hand) after the stimulus onset. The stimuli were presented using Matlab. The stimulus duration was 250 ms, inter-stimulus-interval varied randomly between 1900 and 2150 ms, and each experiment consisted of two runs containing 80 stimuli per run (40 of each category). EEG data were acquired using a 64 electrodes cap (QuickCap, NeuroScan, USA) with electrodes placed according to the extended 10/20 system at a sampling rate of 2 kHz. No filters were applied during the recording and data were analyzed offline. An average of the ERP in electrodes PO8 and PO4 was calculated and P1 amplitude, and latency, N1 amplitude, and latency, difference in peak amplitude between P1 and N1, and the latency of N1 relative to P1 were extracted. These parameters were compared post-placebo versus post-lovastatin. Data analysis was performed with Brainstorm, which is documented and freely available for download under the GNU general public license. The EEG signal was down sampled to 400 Hz and band filtered between 1 and 100 Hz. The dataset was cleaned using an automated rejection threshold-based tool, with a threshold of 120 uV for all electrodes. The recordings were re-referenced to the average of all remaining channels. 2.3.3 MRS Acquisitions and Analysis Patients underwent structural and spectroscopy imaging using a Siemens 3T Scanner (Siemens Magnetom 3 T Tim Trio, Erlangen, Germany). T1-weighted structural images of the brain were obtained with an MPRAGE sequence with a 1 mm 3 isotropic voxel, repetition time 2.53 s, echo time 3.42 ms, inversion time 1,000 ms, flip angle 7 o , field of view 256 x 256 mm 2 , 256 x 256 matrix, 176 slices, and GeneRalized Autocalibrating Partial Parallel Acquisition (GRAPPA) acceleration factor of 2. The anatomical images were analyzed for any structural abnormalities. One MRS voxel was position medially in the occipital cortex, as shown in Fig. 1 and it had a volume of 27 cm 3 . We employed the Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES) method (Chan et al., 2016 ) to measure concentrations of GABA, Glx, and glutathione. Structural images were reviewed for abnormalities and bright object detection. HERMES data were processed using Gannet software (Edden et al., 2014 ), yielding signals for GABA, Glx, glutathione, and creatine from the edited spectra. Metabolite peaks were modeled using a simple Gaussian fit, while the creatine signal was fitted to a double Lorentzian model. The results were expressed as metabolite/Cr levels, with normalization to creatine used to minimize intersubject variability due to differing signal-to-noise ratios and CSF fractions in the voxel (Bogner et al., 2010 ). Given the known contamination of GABA signals by other macromolecules (Aufhaus et al., 2013 ), we will refer to it as GABA + going forward. Spectra were only considered valid if the model fit error was below 10%, and any spectra with higher errors were treated as missing data. 2.4 Statistical Analysis Statistical analyses were performed with IBM SPSS Statistics version 27 software. Nonparametric tests for related samples (Wilcoxon) and correlation (spearman’s rho) were used. Our statistical significance threshold was set at a p < 0.05. 3 Results 3.1 Impact of Lovastatin on Occipital Neurotransmitters and Glutathione The administration of lovastatin resulted in significant changes to the neurochemical profile of the occipital cortex in our cohort. As detailed in Table 1 , these changes point to a modulation of both the excitation-inhibition (E/I) balance and markers of the cellular redox state. Specifically, the concentration of the primary inhibitory neurotransmitter, GABA, showed a statistically significant decrease from a mean of 0.087 ± 0.010 after placebo to 0.075 ± 0.012 after lovastatin (p = 0.035). While the concentration of Glutamate also decreased from 0.091 ± 0.010 to 0.081 ± 0.008, this change did not reach statistical significance (p = 0.123). Furthermore, we observed a marked and statistically significant increase in the concentration of Glutathione, a key antioxidant, which rose from 0.040 ± 0.014 in the placebo condition to 0.063 ± 0.014 after the lovastatin intervention (p = 0.039). Reflecting the shifts in inhibitory and excitatory neurotransmitters, the overall I-E ratio (GABA/Glx) was significantly reduced from 1.479 ± 0.416 to 0.937 ± 0.140 (p = 0.041). 3.2 Effect of Lovastatin on the Frequency of Epileptic Discharges The intervention with lovastatin was associated with a statistically significant reduction in the rate of interictal epileptiform discharges (IEDs) recorded during resting-state EEG. The mean frequency of IEDs decreased from 11.4 ± 2.94 events per minute following the placebo condition to 8.87 ± 1.53 events per minute following lovastatin administration (p = 0.04). For this analysis, the quantification of IEDs included the counting of spike-slow-wave complexes. Despite this clear effect on electrographic activity, a subsequent correlational analysis did not reveal a significant relationship between the reduction in IED frequency and the changes observed in the occipital brain metabolites measured by MRS. 3.3 Lovastatin's Influence on Facial Processing ERPs The administration of lovastatin modulated several key components of the event-related potential (ERP) elicited during the facial processing task. The specific effects on the amplitude and latency of these components are summarized in Table 2. While no significant change was observed in the early P1 peak amplitude (p = 0.89), the latency of the subsequent P100 component was significantly delayed following the lovastatin intervention, increasing from a mean of 113 ± 10 ms to 128 ± 4ms (p = 0.04). The amplitude of the N110 peak was also significantly altered, becoming less negative (− 2.6 ± 1.08) compared to the placebo condition (− 5.03 ± 2.14), which indicates a reduction in the component's absolute magnitude (p = 0.04). Furthermore, the latency between the P100 and N170 peaks was significantly shorter after lovastatin, decreasing from 0.059 ± 0.012 s to 0.049 ± 0.008 s (p = 0.04). A trend towards a reduction in the peak-to-peak amplitude difference between the P100 and N170 components was also noted, although it did not reach statistical significance (p = 0.06). Finally, a correlational analysis was conducted to investigate potential relationships between these electrophysiological changes and other measured variables. We found no significant correlation between the changes in any of the ERP parameters and the changes observed in brain metabolites via MRS. Additionally, no correlation was found between the ERP changes and the frequency of interictal epileptiform discharges. 4 Discussion This exploratory case series provides a novel, multimodal window into the central nervous system effects of a short course of lovastatin in individuals with drug-resistant epilepsy. To our knowledge, this is the first study to simultaneously investigate lovastatin's impact on brain metabolites, the cellular redox state, and cortical inhibition-based visual processing using a recently developed MRS sequence (HERMES). The principal findings of this proof-of-concept study are that a three-day course of lovastatin was associated with: 1) a significant reduction in occipital GABA concentration and the GABA/Glx ratio; 2) a significant increase in occipital Glutathione concentration; 3) a significant reduction in the frequency of interictal epileptiform discharges (IEDs); and 4) significant modulations of event-related potentials (ERPs) during a face processing task. 4.1 Interpretation of Metabolic Changes in the Occipital Cortex A key finding was the reduction in the GABA/Glx ratio, a putative marker of the local excitatory/inhibitory (E/I) balance. This was driven by a significant decrease in GABA and a concurrent, though not statistically significant, trend towards reduced Glutamate. The observation that lovastatin influences the balance of these neurotransmitters is consistent with preclinical literature suggesting statins possess broad neuroprotective properties (Fracassi et al., 2019 ). The reduction in GABA is particularly noteworthy. While a decrease in the primary inhibitory neurotransmitter might intuitively seem pro-convulsant, the role of GABA in chronic epilepsy is complex. A compelling body of evidence suggests that in the context of the chronically epileptic brain, particularly in temporal lobe epilepsy, GABAergic transmission can become paradoxically excitatory and contribute to network hyperexcitability and neurotoxicity (Remy and Beck, 2006 ; Cepeda et al., 2020 ). While this phenomenon is most clearly established at the primary epileptogenic focus, the widespread network effects of chronic epilepsy could plausibly lead to similar dysregulation in connected cortical regions. From this perspective, the lovastatin-induced decrease in GABA observed in our cohort could be interpreted not as a loss of inhibition, but as a reduction in aberrant, potentially excitotoxic, signaling. However, this interpretation remains speculative without direct measurements from the epileptogenic zone itself. This study also revealed a significant increase in occipital Glutathione. As a primary endogenous antioxidant, the elevation of Glutathione suggests a potential impact on the cellular redox state and may reflect a reduction in oxidative stress. This aligns with preclinical studies demonstrating the anti-inflammatory and antioxidant properties of statins (Afshordel et al., 2015 ; Pihl-Jensen et al., 2015 ). Given that neuroinflammation and oxidative stress are thought to play a pivotal role in the pathophysiology of drug-resistant epilepsy (Vezzani et al., 2013b ), this finding provides a potential mechanistic pathway for lovastatin's action. 4.2 Modulation of Cortical Excitability and Electrophysiology We observed a significant reduction in the frequency of IEDs following lovastatin administration. It is crucial to interpret this finding with caution. While IEDs are a hallmark of epilepsy, their frequency does not directly correlate with clinical seizure frequency, and they should be viewed as a biomarker of cortical hyperexcitability rather than a direct surrogate for seizure activity. Indeed, the relationship between IEDs and ictogenesis is complex, with some evidence suggesting that certain interictal patterns may even have a seizure-constraining role (Avoli et al., 2006 ). Therefore, we do not claim that lovastatin has a definitive antiepileptic effect based on this single measure. Rather, we present this as preliminary evidence that lovastatin can modulate a key electrophysiological marker of cortical irritability in this patient population. The ERP results provide a functional correlate to the observed metabolic changes. The significantly delayed P100 latency after lovastatin is noteworthy, as previous research has linked longer P1 latencies to reduced GABAergic neurotransmission in the visual cortex (Yoon et al., 2010 ), a finding consistent with our MRS results. Furthermore, the significant reduction in the absolute amplitude of the N110 component and the shortened latency between the P100 and N170 peaks suggest that lovastatin altered the dynamics of visual network engagement during face processing. These findings support the hypothesis that lovastatin can influence the function of cortical circuits involved in sensory processing. 4.3 Long range changes in the Occipital Lobe A critical aspect of our design was the focus on the occipital cortex rather than the temporal lobe, the presumed epileptogenic zone in this cohort. This choice was based on three distinct lines of reasoning. First, TLE is increasingly recognized as a network disorder in which pathological activity propagates and induces functional and structural changes in remote, yet highly connected, brain regions such as the visual cortex (Spencer, 2002 ). Investigating these extra-focal regions is crucial for understanding the widespread impact of the disease. Second, from a methodological standpoint, the anatomy of the occipital cortex allows for more reliable placement of an MRS voxel, yielding a higher-quality sample of pure grey matter with fewer artifacts compared to the anatomically complex and heterogeneous mesial temporal lobe (Jansen et al., 2006 ). Finally, subtle deficits in visual processing have been reported in TLE, providing a functional rationale for assessing the physiological status of this brain region (Noble et al., 2023 ). 4.4 Limitations and Future Directions This study has several important limitations inherent to its exploratory, case-series design. The most significant is the small sample size, which precludes generalization of the findings. This work should be considered a hypothesis-generating, physiological proof-of-concept study. While our within-subject design provides a robust internal control for each participant, future studies must include larger cohorts and a healthy control group to confirm these preliminary findings. Furthermore, the short three-day treatment regimen can only inform on the acute physiological response to lovastatin and does not provide insight into long-term efficacy, safety, or potential for sustained clinical effects. The rationale for this duration was to establish acute target engagement without confounding from long-term metabolic adaptation. Future research should explore longer treatment periods to assess the durability of these effects and their correlation with clinical outcomes, such as seizure frequency. Lastly, we did not perform a detailed analysis of potential interactions between lovastatin and the participants' diverse anti-seizure medications via the cytochrome P450 system; this represents an important variable that should be systematically controlled for in subsequent, larger trials (Gouveia et al., 2014 ). Conclusion In conclusion, this case series provides preliminary evidence that a short course of lovastatin can modulate key neurochemical and electrophysiological markers in the brains of patients with drug-resistant epilepsy. Specifically, lovastatin was associated with a lower GABA/Glx ratio, higher Glutathione levels, and a reduced frequency of IEDs in the occipital cortex. These inherent biological effects suggest that lovastatin influences both the E/I balance and the cellular redox state. While it is premature to suggest a clinical antiepileptic role, these findings provide a compelling rationale for further, more definitive studies to investigate the therapeutic potential of statins as a novel adjunctive strategy for modifying brain excitability in epilepsy. Declarations Ethics Declarations: All procedures conformed to the principles of the Declaration of Helsinki. The study protocol was reviewed and approved by the Faculty of Medicine of the University of Coimbra Research Ethics Committee and the Clinical Academic Center (references: CE010/17 and CHUC 024-18). The study was registered as a clinical trial (ClinicalTrials.gov ID: trial registration number NCT06789497 Registration 17.01.2025). All individuals provided written informed consent before their inclusion in the study. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Author Contribution SA conceptualized, collected data, analyzed, and helped in writing this manuscript. CD helped in recruiting participants and data collection. FS helped in selecting and recruiting participants. MCB conceptualized, supervised, and helped in analyzing and writing the manuscript. Data Availability The datasets [GENERATED/ANALYZED] for this study can be requested by emailing the corresponding author. References Abuhaiba SI, Duarte IC, Castelhano J, Dionísio A, Sales F, Edden R, Castelo-Branco M. (2022) The impact of cathodal tDCS on the GABAergic system in the epileptogenic zone: A multimodal imaging study. Front Neurol 13 Available at: https://pubmed.ncbi.nlm.nih.gov/35989912/ [Accessed September 28, 2024]. Afshordel S, Kern B, Clasohm J, König H, Priester M, Weissenberger J, Kögel D, Eckert GP. (2015) Lovastatin and perillyl alcohol inhibit glioma cell invasion, migration, and proliferation–impact of Ras-/Rho-prenylation. Pharmacol Res 91:69–77 Available at: https://pubmed.ncbi.nlm.nih.gov/25497898/ [Accessed September 11, 2023]. Aufhaus E, Weber-Fahr W, Sack M, Tunc-Skarka N, Oberthuer G, Hoerst M, Meyer-Lindenberg A, Boettcher U, Ende G. (2013) Absence of changes in GABA concentrations with age and gender in the human anterior cingulate cortex: A MEGA-PRESS study with symmetric editing pulse frequencies for macromolecule suppression. Magn Reson Med 69:317–320 Available at: http://doi.wiley.com/10.1002/mrm.24257 [Accessed July 17, 2020]. Avoli M, D'Antuono M, Louvel J, Köhling R, Biagini G, Pumain R. Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system in vitro. Prog Neurobiol. 2006;78(3–5):202–19. Bernardino I, Dionísio A, Castelo-Branco M. (2022) Cortical inhibition in neurofibromatosis type 1 is modulated by lovastatin, as demonstrated by a randomized, triple-blind, placebo-controlled clinical trial. Scientific Reports 2022 12:1 12:1–10 Available at: https://www.nature.com/articles/s41598-022-17873-x [Accessed March 4, 2024]. Bernhardt BC, Bernasconi N, Bernasconi A. The multifaceted role of the human hippocampus in temporal lobe epilepsy. Nat Reviews Neurol. 2013;9(8):423–34. Wellard JW, Briellmann RS, Jackson GD. Methodological considerations for proton MR spectroscopy of the hippocampus. J Magn Reson Imaging. 2005;22(5):696–701. Bogner W, Gruber S, Doelken M, Stadlbauer A, Ganslandt O, Boettcher U, Trattnig S, Doerfler A, Stefan H, Hammen T. In vivo quantification of intracerebral GABA by single-voxel (1)H-MRS-How reproducible are the results? Eur J Radiol. 2010;73:526–31. Bösel J, Gandor F, Harms C, Synowitz M, Harms U, Djoufack PC, Megow D, Dirnagl U, Hörtnagl H, Fink KB, Endres M. (2005) Neuroprotective effects of atorvastatin against glutamate-induced excitotoxicity in primary cortical neurones. J Neurochem 92:1386–1398 Available at: https://pubmed.ncbi.nlm.nih.gov/15748157/ [Accessed September 11, 2023]. Canevini MP et al. (2010) Relationship between adverse effects of antiepileptic drugs, number of coprescribed drugs, and drug load in a large cohort of consecutive patients with drug-refractory epilepsy. Epilepsia 51:797–804 Available at: https://pubmed.ncbi.nlm.nih.gov/20545754/ [Accessed September 11, 2023]. Castelhano J, Rebola J, Leitão B, Rodriguez E, Castelo-Branco M. (2013) To Perceive or Not Perceive: The Role of Gamma-band Activity in Signaling Object Percepts. PLoS One 8 Available at: /pmc/articles/PMC3681966/?report = abstract [Accessed November 10, 2020]. Castelhano J, Rebola J, Rodriguez E, Castelo-Branco M. Neural synchronization in the gamma frequency range is tightly associated with detection of ambiguous face stimuli. NeuroImage. 2009;47:S155. Castelhano J, Tavares P, Mouga S, Oliveira G, Castelo-Branco M. Stimulus dependent neural oscillatory patterns show reliable statistical identification of autism spectrum disorder in a face perceptual decision task. Clin Neurophysiol. 2018;129:981–9. Cepeda C, Levinson S, Nariai H, Yazon VW, Tran C, Barry J, Oikonomou KD, Vinters HV, Fallah A, Mathern GW, Wu JY. Pathological high frequency oscillations associate with increased GABA synaptic activity in pediatric epilepsy surgery patients. Neurobiol Dis. 2020;134:104618. Chan KL, Puts NAJ, Schär M, Barker PB, Edden RAE. (2016) HERMES: Hadamard encoding and reconstruction of MEGA-edited spectroscopy. Magn Reson Med 76:11–19 Available at: http://doi.wiley.com/10.1002/mrm.26233 [Accessed October 24, 2020]. Clarke RM, Lyons A, O’Connell F, Deighan BF, Barry CE, Anyakoha NG, Nicolaou A, Lynch MA. (2008) A pivotal role for interleukin-4 in atorvastatin-associated neuroprotection in rat brain. J Biol Chem 283:1808–1817 Available at: https://pubmed.ncbi.nlm.nih.gov/17981803/ [Accessed September 11, 2023]. D’Ambrosio R, Eastman CL, Fattore C, Perucca E. (2013) Novel frontiers in epilepsy treatments: preventing epileptogenesis by targeting inflammation. Expert Rev Neurother 13:615–625 Available at: https://pubmed.ncbi.nlm.nih.gov/23738999/ [Accessed September 11, 2023]. Dedeurwaerdere S, Friedman A, Fabene PF, Mazarati A, Murashima YL, Vezzani A, Baram TZ. (2012) Finding a better drug for epilepsy: Antiinflammatory targets. Epilepsia 53:1113–1118 Available at: https://onlinelibrary.wiley.com/doi/full/ 10.1111/j.1528-1167.2012.03520.x [Accessed September 11, 2023]. Edden RAE, Puts NAJ, Harris AD, Barker PB, Evans CJ. (2014) Gannet: A batch-processing tool for the quantitative analysis of gamma-aminobutyric acid–edited MR spectroscopy spectra. J Magn Reson Imaging 40:1445–1452 Available at: https://pubmed.ncbi.nlm.nih.gov/25548816/ [Accessed March 4, 2024]. Fracassi A, Marangoni M, Rosso P, Pallottini V, Fioramonti M, Siteni S, Segatto M. (2019) Statins and the Brain: More than Lipid Lowering Agents? Curr Neuropharmacol 17:59 Available at: /pmc/articles/PMC6341496/ [Accessed September 11, 2023]. Friedman A, Dingledine R. (2011) Molecular cascades that mediate the influence of inflammation on epilepsy. Epilepsia 52:33–39 Available at: https://onlinelibrary.wiley.com/doi/full/ 10.1111/j.1528-1167.2011.03034.x [Accessed September 11, 2023]. Funck VR, De Oliveira CV, Pereira LM, Rambo LM, Ribeiro LR, Royes LFF, Ferreira J, Guerra GP, Furian AF, Oliveira MS, Mallmann CA, De Mello CF, Oliveira MS. (2011a) Differential effects of atorvastatin treatment and withdrawal on pentylenetetrazol-induced seizures. Epilepsia 52:2094–2104 Available at: https://pubmed.ncbi.nlm.nih.gov/21906051/ [Accessed September 11, 2023]. Funck VR, De Oliveira CV, Pereira LM, Rambo LM, Ribeiro LR, Royes LFF, Ferreira J, Guerra GP, Furian AF, Oliveira MS, Mallmann CA, De Mello CF, Oliveira MS. (2011b) Differential effects of atorvastatin treatment and withdrawal on pentylenetetrazol-induced seizures. Epilepsia 52:2094–2104 Available at: https://pubmed.ncbi.nlm.nih.gov/21906051/ [Accessed September 11, 2023]. Gorter JA, Van Vliet EA, Aronica E, Breit T, Rauwerda H, Lopes Da Silva FH, Wadman WJ. (2006) Potential New Antiepileptogenic Targets Indicated by Microarray Analysis in a Rat Model for Temporal Lobe Epilepsy. Journal of Neuroscience 26:11083–11110 Available at: https://www.jneurosci.org/content/26/43/11083 [Accessed September 11, 2023]. Gouveia TL, Nejm MB, Naffah-Mazacoratti MDG, Cavalheiro EA, Scorza FA. Statins and epilepsy: new findings to be explored. Expert Opin Ther Pat. 2014;24(7):743–55. Homayoun H, Moghaddam B. (2007) NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 27:11496–11500 Available at: https://pubmed.ncbi.nlm.nih.gov/17959792/ [Accessed September 11, 2023. Jansen JFA, Backes WH, Nicolay K, Kooi ME. 1H MR spectroscopy of the brain: absolute quantification of metabolites. Radiology. 2006;240(2):318–32. Jansen JF, Backes WH, Nicolay K, Kooi ME. 1H MR spectroscopy of the brain: absolute quantification of metabolites. Radiology. 2006;240(2):318–32. Klausberger T, Somogyi P. (2008) Neuronal Diversity and Temporal Dynamics: The Unity of Hippocampal Circuit Operations. Science (1979) 321:53–57 Available at: http://www.ncbi.nlm.nih.gov/pubmed/18599766 [Accessed April 15, 2020]. Lee JK, Won JS, Singh AK, Singh I. (2008) Statin inhibits kainic acid-induced seizure and associated inflammation and hippocampal cell death. Neurosci Lett 440:260–264 Available at: https://pubmed.ncbi.nlm.nih.gov/18583044/ [Accessed September 11, 2023]. Levy LM, Degnan AJ. (2013) GABA-based evaluation of neurologic conditions: MR spectroscopy. AJNR Am J Neuroradiol 34:259–265 Available at: http://www.ncbi.nlm.nih.gov/pubmed/22268095 [Accessed May 14, 2020]. Mainberger F, Jung NH, Zenker M, Wahlländer U, Freudenberg L, Langer S, Berweck S, Winkler T, Straube A, Heinen F, Granström S, Mautner V-F, Lidzba K, Mall V. (2013) Lovastatin improves impaired synaptic plasticity and phasic alertness in patients with neurofibromatosis type 1. BMC Neurol 13:131 Available at: http://www.ncbi.nlm.nih.gov/pubmed/24088225 [Accessed August 30, 2016]. Moezi L, Shafaroodi H, Hassanipour M, Fakhrzad A, Hassanpour S, Dehpour AR. (2012) Chronic administration of atorvastatin induced anti-convulsant effects in mice: the role of nitric oxide. Epilepsy Behav 23:399–404 Available at: https://pubmed.ncbi.nlm.nih.gov/22405864/ [Accessed September 11, 2023]. Mueller SG, Laxer KD, Scanlon C, Garcia P, Paul B, Weiner MW. Different patterns of regional GABA and glutamate deficits in generalized and partial epilepsy. Epilepsia. 2014;55(6):851–9. Nejm MB, Gouveia TL, da Graça Naffah-Mazacoratti M, Scorza CA, Cavalheiro EA, Scorza FA. (2013) Lovastatin and sudden unexpected death in epilepsy: a matter for debate. Epilepsy Behav 28:10–11 Available at: http://www.ncbi.nlm.nih.gov/pubmed/23648273 [Accessed August 30, 2016]. Noble K, O'Keeffe F, Mills T, Tsereteli D, O'Brien A, O'Sullivan M, Doherty CP. Functional vision in temporal lobe epilepsy: A study of contrast sensitivity, visual fields, and quality of life. Epilepsia Open. 2023;8(3):963–71. Osterweil EK, Chuang SC, Chubykin AA, Sidorov M, Bianchi R, Wong RKS, Bear MF. (2013) Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile X syndrome. Neuron 77:243–250 Available at: https://pubmed.ncbi.nlm.nih.gov/23352161/ [Accessed September 11, 2023]. Pannu R, Christie DK, Barbosa E, Singh I, Singh AK. (2007) Post-trauma Lipitor treatment prevents endothelial dysfunction, facilitates neuroprotection, and promotes locomotor recovery following spinal cord injury. J Neurochem 101:182–200 Available at: https://onlinelibrary.wiley.com/doi/full/ 10.1111/j.1471-4159.2006.04354.x [Accessed September 11, 2023]. Picton TW. (Terence W) (n.d.) Human auditory evoked potentials.:634 Available at: https://books.google.com/books/about/Human_Auditory_Evoked_Potentials.html?id=-N22CwAAQBAJ [Accessed September 11, 2023]. Piermartiri TCB, Figueiredo CP, Rial D, Duarte FS, Bezerra SC, Mancini G, de Bem AF, Prediger RDS, Tasca CI. (2010) Atorvastatin prevents hippocampal cell death, neuroinflammation and oxidative stress following amyloid-β(1–40) administration in mice: evidence for dissociation between cognitive deficits and neuronal damage. Exp Neurol 226:274–284 Available at: https://pubmed.ncbi.nlm.nih.gov/20816828/ [Accessed September 11, 2023]. Pihl-Jensen G, Tsakiri A, Frederiksen JL. (2015) Statin treatment in multiple sclerosis: a systematic review and meta-analysis. CNS Drugs 29:277–291 Available at: https://pubmed.ncbi.nlm.nih.gov/25795002/ [Accessed September 11, 2023]. Ramirez C, Tercero I, Pineda A, Burgos JS. (2011) Simvastatin is the statin that most efficiently protects against kainate-induced excitotoxicity and memory impairment. J Alzheimers Dis 24:161–174 Available at: https://pubmed.ncbi.nlm.nih.gov/21224519/ [Accessed September 11, 2023]. Ravizza T, Rizzi M, Perego C, Richichi C, Velískǒvá J, Moshé SL, De Simoni MG, Vezzani A. (2005) Inflammatory response and glia activation in developing rat hippocampus after status epilepticus. Epilepsia 46 Suppl 5:113–117 Available at: https://pubmed.ncbi.nlm.nih.gov/15987264/ [Accessed September 11, 2023]. Remy S, Beck H. (2006) Molecular and cellular mechanisms of pharmacoresistance in epilepsy. Brain 129:18–35 Available at: http://academic.oup.com/brain/article/129/1/18/311849/Molecular-and-cellular-mechanisms-of [Accessed May 14, 2020]. Sasa M. (2006) A new frontier in epilepsy: novel antiepileptogenic drugs. J Pharmacol Sci 100:487–494 Available at: https://pubmed.ncbi.nlm.nih.gov/16799261/ [Accessed September 11, 2023]. Serbanescu I, Ryan MA, Shukla R, Cortez MA, Snead OC, Cunnane SC. (2004) Lovastatin exacerbates atypical absence seizures with only minimal effects on brain sterols. J Lipid Res 45:2038–2043 Available at: https://pubmed.ncbi.nlm.nih.gov/15314096/ [Accessed September 11, 2023]. Shafaroodi H, Moezi L, Fakhrzad A, Hassanipour M, Rezayat M, Dehpour AR. (2012) The involvement of nitric oxide in the anti-seizure effect of acute atorvastatin treatment in mice. Neurol Res 34:847–853 Available at: https://pubmed.ncbi.nlm.nih.gov/22909758/ [Accessed September 11, 2023]. Sierra-Marcos A, Alvarez V, Faouzi M, Burnand B, Rossetti AO. (2015) Statins are associated with decreased mortality risk after status epilepticus. Eur J Neurol 22:402–405 Available at: http://www.ncbi.nlm.nih.gov/pubmed/24684345 [Accessed August 30, 2016]. Spencer SS. Neural networks in human epilepsy: evidence of and implications for treatment. Epilepsia. 2002;43(3):219–27. Sousa D, Ferreira A, Rodrigues D, Pereira HC, Amaral J, Crisostomo J, Simoes M, Ribeiro M, Teixeira M, Castelo-Branco M. (2023) A neurophysiological signature of dynamic emotion recognition associated with social communication skills and cortical gamma-aminobutyric acid levels in children. Front Neurosci 17 Available at: https://pubmed.ncbi.nlm.nih.gov/38164245/ [Accessed September 28, 2024]. Spencer SS. Neural networks in human epilepsy: evidence of and implications for treatment. Epilepsia. 2002;43(3):219–27. Sun J, Xie C, Liu W, Lu D, Qiao W, Huang Q, Huo Z, Shen H, Lin Z. (2012) The effects of simvastatin on hippocampal caspase-3 and Bcl-2 expression following kainate-induced seizures in rats. Int J Mol Med 30:739–746 Available at: https://pubmed.ncbi.nlm.nih.gov/22842798/ [Accessed September 11, 2023]. Taki MM, Harada M, Mori K, Kubo H, Nose A, Matsuda T, Nishitani H. (2009) High gamma-aminobutyric acid level in cortical tubers in epileptic infants with tuberous sclerosis complex measured with the MEGA-editing J-difference method and a three-Tesla clinical MRI Instrument. Neuroimage 47:1207–1214 Available at: https://pubmed.ncbi.nlm.nih.gov/19481612/ [Accessed October 24, 2020]. Tamás G, Buhl EH, Lörincz A, Somogyi P. (2000) Proximally targeted GABAergic synapses and gap junctions synchronize cortical interneurons. Nat Neurosci 3:366–371 Available at: https://pubmed.ncbi.nlm.nih.gov/10725926/[Accessed October 24, 2020]. Turrin NP, Rivest S. (2004) Innate immune reaction in response to seizures: Implications for the neuropathology associated with epilepsy. Neurobiol Dis 16:321–334 Available at: https://pubmed.ncbi.nlm.nih.gov/15193289/ [Accessed September 11, 2023]. Üzüm G, Akgün-Dar K, Aksu U. (2010a) The effects of atorvastatin on memory deficit and seizure susceptibility in pentylentetrazole-kindled rats. Epilepsy Behav 19:284–289 Available at: https://pubmed.ncbi.nlm.nih.gov/20888302/ [Accessed September 11, 2023]. Üzüm G, Akgün-Dar K, Aksu U. (2010b) The effects of atorvastatin on memory deficit and seizure susceptibility in pentylentetrazole-kindled rats. Epilepsy Behav 19:284–289 Available at: https://pubmed.ncbi.nlm.nih.gov/20888302/ [Accessed September 11, 2023]. Vezzani A, Aronica E, Mazarati A, Pittman QJ. (2013a) Epilepsy and brain inflammation. Exp Neurol 244:11–21 Available at: https://pubmed.ncbi.nlm.nih.gov/21985866/ [Accessed September 11, 2023]. Vezzani A, Aronica E, Mazarati A, Pittman QJ. (2013b) Epilepsy and brain inflammation. Exp Neurol 244:11–21 Available at: https://pubmed.ncbi.nlm.nih.gov/21985866/ [Accessed September 11, 2023]. Weber MS, Youssef S, Dunn SE, Prod’homme T, Neuhaus O, Stuve O, Greenwood J, Steinman L, Zamvil SS. Statins in the treatment of central nervous system autoimmune disease. J Neuroimmunol. 2006;178:140–8. Xie C, Sun J, Qiao W, Lu D, Wei L, Na M, Song Y, Hou X, Lin Z. (2011a) Administration of Simvastatin after Kainic Acid-Induced Status Epilepticus Restrains Chronic Temporal Lobe Epilepsy. PLoS One 6:e24966 Available at: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024966 [Accessed September 11, 2023]. Xie C, Sun J, Qiao W, Lu D, Wei L, Na M, Song Y, Hou X, Lin Z. (2011b) Administration of Simvastatin after Kainic Acid-Induced Status Epilepticus Restrains Chronic Temporal Lobe Epilepsy. PLoS One 6:e24966 Available at: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024966 [Accessed September 11, 2023]. Yoon JH, Maddock RJ, Rokem A, Silver MA, Minzenberg MJ, Ragland JD, Carter CS. (2010) GABA concentration is reduced in visual cortex in schizophrenia and correlates with orientation-specific surround suppression. J Neurosci 30:3777–3781 Available at: https://pubmed.ncbi.nlm.nih.gov/20220012/ [Accessed September 11, 2023]. Tables Table 1 Title: Lovastatin effect on brain metabolites. Concentration after Placebo Concentration after Lovastatin p-value GABA 0.087 + 0.010 0.075 + 0.012 0.035 Glutamate 0.091 + 0.010 0.081 + 0.008 0.123 Glutathione 0.040 + 0.014 0.063 + 0.014 0.039 I-E Ratio (GABA/Glx) 1.479 + 0.416 0.937 + 0.140 0.041 Table 1: Legend: It appears that GABA, Glx, and GABA/Glx ratio were all decreased after our participants took lovastatin. Glutathione, on the other hand, was increased. This reached statistical significance for all parameters except glutamate. These values are corrected for Cr. Table 2 title: Lovastatin effect on the event related potential (ERP) of facial recognition. Mean after placebo Mean after lovastatin p-value P1 Peak Amplitude 5.45 + 3.16 4.75 + 2.92 0.89 P100 Latency 0.113 + 0.010 0.128 + 0.004 0.04 N110 Peak Amplitude - 5.03 + 2.14 - 2.6 + 1.08 0.04 N1 Latency 0.172 + 0.004 0.176 + 0.008 0.14 P100 to N170 Difference in Peak Amplitude 10.48 + 4.52 7.37 + 3.62 0.06 P100 to N170 Latency 0.059 + 0.012 0.049 + 0.008 0.04 Table 2: Effects of lovastatin on P100, N170, and P100 to N170 parameters from the ERP of facial recognition. Measurement unit: mV Additional Declarations No competing interests reported. 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1","display":"","copyAsset":false,"role":"figure","size":324326,"visible":true,"origin":"","legend":"\u003cp\u003eA to C show the placement of the occipital MRS voxel in coronal, sagittal and axial planes. D. shows the extracted spectra of GABA/Glx and of GSH from one of our participants. As depicted, there is a good fit between the model and the measured data.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8180994/v1/ba8f948e431f1f6c753a0b5c.png"},{"id":98783614,"identity":"a33de201-e88f-4a3f-a0e0-c2c6fdc86646","added_by":"auto","created_at":"2025-12-22 12:42:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1045730,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8180994/v1/a76747ac-1616-463a-a1de-d8aacdeb2ad9.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eLovastatin Modulates Cortical Excitability, E/I Balance, and Antioxidant Markers in Drug-Resistant Epilepsy: A Proof-of-Concept Study\u003c/p\u003e","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eEpilepsy is a common neurologic disorder that is characterized by recurrent seizures and is diagnosed in about 1% of the general population with one third of patients having poor control despite the availability of novel and wide range of antiepileptic drugs (AED) (Sasa, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Canevini et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). Of those with drug resistant epilepsy, inflammatory processes appear to play an important role as increasing evidence has emerged pointing towards the possible involvement of astrocytes, other immune cells, and blood-brain-barrier breakdown in epileptogenesis (Friedman and Dingledine, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). Additionally, several animal models of epilepsy have strong evidence for neuroinflammation (Turrin and Rivest, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Gorter et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Dedeurwaerdere et al., \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2012\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThere is evidence that statins may modulate excitation-inhibition (E/I) balance (Dion\u0026iacute;sio et al., 2022) which is very relevant in epilepsy, as suggested by our recent tDCS study showing beneficial modulation in this condition (Abuhaiba et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Epilepsy has long been seen as a disorder of hypersynchronization/desynchronization with GABAergic inhibition as the main driver for abnormal synchronization and the generation of pathologic high frequency oscillations, especially temporal lobe onset epilepsy (Tam\u0026aacute;s et al., \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e2000\u003c/span\u003e; Klausberger and Somogyi, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). This makes such a cohort optimal for the study of lovastatin effects on excitation-inhibition.\u003c/p\u003e \u003cp\u003eAtorvastatin has a neuroprotective effect by reducing excitotoxicity by inhibiting NMDA glutamate receptor activity in rodents with KA-induced absence seizures (Moezi et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Shafaroodi et al., \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). Simvastatin reduced the number of seizures in animal models of KA-induced epilepsy (Ramirez et al., \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Xie et al., \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2011a\u003c/span\u003e), and was abolished the risk of status epilepticus in such animals (Sun et al., \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). Lovastatin has been found to have a similar anti-epileptic profile to atorvastatin by modulating NMDA glutamate receptors, mitigate the impact of excitotoxicity and to have an inhibitory cortical effect ((Serbanescu et al., \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; \u0026Uuml;z\u0026uuml;m et al., \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2010a\u003c/span\u003e; Funck et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2011a\u003c/span\u003e; Osterweil et al., \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). Lovastatin appears to be an effective antiepileptic in fragile X syndrome (Osterweil et al., \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2013\u003c/span\u003e) and is known to improve cognitive function in neurofibromatosis type 1 due to the inhibitory cortical effect (Mainberger et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Bernardino et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThere is a current emphasis on the role of anti-inflammatories as adjuvant treatments for epilepsy (Dedeurwaerdere et al., \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; D\u0026rsquo;Ambrosio et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Vezzani et al., \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e2013a\u003c/span\u003e). Statins, which are commonly prescribed in today\u0026rsquo;s medical practice for cerebrovascular and cardiovascular conditions are also known to have inherit anti-inflammatory effects (Weber et al., \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Clarke et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2008\u003c/span\u003e) and protective blood-brain-barrier effects. (Pannu et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2007\u003c/span\u003e). It has long been known that statins interact with other antiepileptic drugs as they are potent P450 enzyme inducers, but more recent studies suggested that they may have actual antiepileptic effects per se.\u003c/p\u003e \u003cp\u003eModulation of E/I by statins may also influence neurophysiological oscillatory processes related to cognition such as face recognition. Mooney faces, which are abstract two-tone stimuli that challenge holistic perceptual processing consisting of degraded pictures of human faces, are good inducers of physiologic oscillations, which are shaped by cortical inhibitory circuits, and the GABAergic system (Castelhano et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2009\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2013\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Accordingly, studying neurophysiological signatures such as event related potential evoked by this visual task may also provide clues into the effects of statins with cortical inhibition and visual information processing.\u003c/p\u003e \u003cp\u003eWhile the epileptogenic zone in temporal lobe epilepsy (TLE) represents the core site of seizure generation, metabolic measurements on the visual cortex provides a potential window into the long-range network-level pathophysiology of the disorder. TLE is increasingly understood not as a focal disease but as a network disorder, where epileptic activity propagates from the temporal lobe to anatomically and functionally connected regions, including the occipital lobe (Spencer, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2002\u003c/span\u003e; Bernhardt et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). This propagation can induce downstream metabolic and structural alterations even in regions that are not the primary seizure focus. Measuring brain metabolites with Magnetic Resonance Spectroscopy (MRS) in the visual cortex can, therefore, reveal the extent of this network-level disruption. For instance, alterations in N-acetylaspartate (NAA), a marker of neuronal viability, or in the balance of excitatory (Glutamate) and inhibitory (GABA) neurotransmitters in the occipital lobe can reflect the chronic impact of seizures on brain regions distant from the epileptogenic zone (Mueller et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). Furthermore, from a methodological standpoint, acquiring high-quality MRS data from the occipital lobe is often more feasible than from the mesial temporal regions (Jansen et al., \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Wellard et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2005\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe main aim of this study is to investigate the effects of lovastatin on brain metabolites, visual processing of faces which is known to be dependent on cortical GABAergic networks, and to link that with the effect of lovastatin on the frequency of interictal discharges in a cohort of patients with drug resistant epilepsy. Our hypothesis is that lovastatin has the potential to modulate cortical excitotoxicity and neuroinflammation in patients with drug resistant epilepsy and such effects can be directly (via MRS) or indirectly (by electrophysiology) assessed by studing the facial recognition circuit in the visual cortex.\u003c/p\u003e "},{"header":"2 Experimental Procedures","content":"\u003cp\u003e2.1 Participants\u003c/p\u003e\n\u003cp\u003eThis study was conducted as a prospective, exploratory case series to investigate the effects of lovastatin on cerebral biomarkers of neuroinflammation and excitatory/inhibitory (E/I) balance. We recruited five participants who presented with a stable, chronic neurological condition characterized by cortical hyperexcitability\u0026mdash;namely, drug-resistant focal temporal lobe epilepsy. This cohort was selected to serve as a human model for investigating the modulation of E/I dynamics in a hyperexcitable state.\u003c/p\u003e\n\u003cp\u003eParticipants were recruited from the epilepsy monitoring unit at the Centro Hospitalar e Universit\u0026aacute;rio de Coimbra. The inclusion criteria were designed to select for a homogeneous group with clear evidence of cortical hyperexcitability, including a high frequency of interictal discharges noted during previous clinical evaluations. To ensure a stable baseline for measuring the effects of the intervention, participants were required to be over 18 years old, not seizure-free in the last three months, and to agree to no changes in their antiepileptic medication regimen for the duration of the study. For logistical reasons related to the intensive visit schedule, recruitment was limited to the Coimbra district.\u003c/p\u003e\n\u003cp\u003eExclusion criteria included any history of cardiovascular or cerebrovascular disease, dyslipidemia, previous use of or adverse reaction to statins, and contraindications for magnetic resonance imaging (MRI) such as implanted electronic devices or metallic hardware in the head. Participants with a vagal nerve stimulation device or other comorbid neurological conditions were also excluded. Women who were pregnant or lactating were not eligible for participation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention and Assessment Protocol\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study followed a within-subject, repeated-measure protocol to assess the impact of a short course of lovastatin. Although the study is presented as a case series, a double-blind, placebo-controlled crossover procedure was utilized to minimize expectation bias. Participants attended three visits at the Institute of Nuclear Sciences Applied to Health (ICNAS), University of Coimbra.\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eVisit 1 (Baseline)\u003c/strong\u003e: The study protocol was explained to the participants, and written informed consent was obtained. Following this, they were given the first batch of pills (either lovastatin or placebo) and instructed to take three pills daily at bedtime for three consecutive days.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eVisit 2 (Assessment 1)\u003c/strong\u003e: On the morning of the fourth day, participants returned to ICNAS for the first assessment battery, which included resting-state electroencephalography (EEG), task-based EEG during a visual face-recognition task, and magnetic resonance spectroscopy (MRS). At the end of this visit, they were given the second batch of pills and instructed to wait for notification before starting them.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eWashout and Crossover\u003c/strong\u003e: A four-week washout period was instituted, calculated from the first day of the initial intervention. Following a follow-up call two weeks into this period to monitor for any adverse effects, participants were contacted at the end of the four weeks and instructed to begin the second 3-day course of pills.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eVisit 3 (Assessment 2)\u003c/strong\u003e: On the fourth day after starting the second batch of pills, participants underwent the identical assessment battery (EEG, task-EEG, and MRS) for a second time.\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Declarations\u003c/strong\u003e: All procedures conformed to the principles of the Declaration of Helsinki. The study protocol was reviewed and approved by the Faculty of Medicine of the University of Coimbra Research Ethics Committee and the Clinical Academic Center (references: CE010/17 and CHUC 024\u0026thinsp;\u0026minus;\u0026thinsp;18). The study was registered as a clinical trial (ClinicalTrials.gov ID: trial registration number NCT06789497). All individuals provided written informed consent before their inclusion in the study.\u003c/p\u003e\n\u003cp\u003e2.2 Physiologic Challenge Intervention\u003c/p\u003e\n\u003cp\u003eEach participant underwent two treatment conditions: lovastatin (60 mg/day) and placebo, administered in a randomized crossover design. Participants took the assigned treatment for three consecutive days, followed by EEG, ERP, and MRS assessments. A washout period of four weeks separated the two conditions.\u003c/p\u003e\n\u003cp\u003e2.3 Outcome Measures\u003c/p\u003e\n\u003cdiv id=\"Sec3\" class=\"Section3\"\u003e\n \u003cdiv class=\"Heading\"\u003e2.3.1 Resting Electroencephalography and IED (interictal epileptiform discharges) Counting\u003c/div\u003e\n \u003cp\u003eParticipants were instructed to relax for 20 minutes during this EEG acquisition. This EEG trace was used to count the number of IEDs. Resting state EEG was performed in the second and third visits to ICNAS before doing EEG with visual task and MRS.\u003c/p\u003e\n \u003cp\u003eEEG was recorded using a 64 electrodes cap (QuickCap, NeuroScan, USA) with electrodes placed according to the extended 10/20 system. Electrodes impedances were kept below 5 KΩ and the signal was amplified and recorded at a sampling rate of 1000 Hz using a SynAmps2/RT amplifier (NeuroScan, USA). A low-pass filter at 200 Hz was applied. The signal was recorded using Scan 4 (NeuroScan, USA), with the acquisition reference electrode placed at a half distance between CZ and FCZ.\u003c/p\u003e\n \u003cp\u003eCounting of the IEDs was performed with Curry 7 (Compumedics, Charlotte, NC, USA). The EEG signal was down sampled to 400 Hz and band filtered between 1 and 30 Hz. Two electrodes in average montage with the highest amplitude of the spike-slow-wave complex were selected and template matching was performed at a sensitivity level of 75% for objective automated identification of the spikes. The selected spikes were reviewed by an expert epileptologist. The average number of automated counted spikes was recorded for each participant. The same steps were done for the counting of spikes in the other resting EEG that was performed in the third visit.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section3\"\u003e\n \u003cdiv class=\"Heading\"\u003e2.3.2 Visual Task and Event Related Potential Analysis\u003c/div\u003e\n \u003cp\u003eParticipants were presented with two categories of Mooney pictures: Mooney faces and scrambled non-face stimuli. Each participant was instructed to report if a face was present (response button 1, right hand), or not (response button 2, left hand) after the stimulus onset. The stimuli were presented using Matlab. The stimulus duration was 250 ms, inter-stimulus-interval varied randomly between 1900 and 2150 ms, and each experiment consisted of two runs containing 80 stimuli per run (40 of each category). EEG data were acquired using a 64 electrodes cap (QuickCap, NeuroScan, USA) with electrodes placed according to the extended 10/20 system at a sampling rate of 2 kHz. No filters were applied during the recording and data were analyzed offline.\u003c/p\u003e\n \u003cp\u003eAn average of the ERP in electrodes PO8 and PO4 was calculated and P1 amplitude, and latency, N1 amplitude, and latency, difference in peak amplitude between P1 and N1, and the latency of N1 relative to P1 were extracted. These parameters were compared post-placebo versus post-lovastatin.\u003c/p\u003e\n \u003cp\u003eData analysis was performed with Brainstorm, which is documented and freely available for download under the GNU general public license. The EEG signal was down sampled to 400 Hz and band filtered between 1 and 100 Hz. The dataset was cleaned using an automated rejection threshold-based tool, with a threshold of 120 uV for all electrodes. The recordings were re-referenced to the average of all remaining channels.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section3\"\u003e\n \u003cdiv class=\"Heading\"\u003e2.3.3 MRS Acquisitions and Analysis\u003c/div\u003e\n \u003cp\u003ePatients underwent structural and spectroscopy imaging using a Siemens 3T Scanner (Siemens Magnetom 3 T Tim Trio, Erlangen, Germany). T1-weighted structural images of the brain were obtained with an MPRAGE sequence with a 1 mm\u003csup\u003e3\u003c/sup\u003e isotropic voxel, repetition time 2.53 s, echo time 3.42 ms, inversion time 1,000 ms, flip angle 7\u003csup\u003eo\u003c/sup\u003e, field of view 256 x 256 mm\u003csup\u003e2\u003c/sup\u003e, 256 x 256 matrix, 176 slices, and GeneRalized Autocalibrating Partial Parallel Acquisition (GRAPPA) acceleration factor of 2. The anatomical images were analyzed for any structural abnormalities.\u003c/p\u003e\n \u003cp\u003eOne MRS voxel was position medially in the occipital cortex, as shown in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and it had a volume of 27 cm\u003csup\u003e3\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eWe employed the Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES) method (Chan et al., \u003cspan class=\"CitationRef\"\u003e2016\u003c/span\u003e) to measure concentrations of GABA, Glx, and glutathione. Structural images were reviewed for abnormalities and bright object detection. HERMES data were processed using Gannet software (Edden et al., \u003cspan class=\"CitationRef\"\u003e2014\u003c/span\u003e), yielding signals for GABA, Glx, glutathione, and creatine from the edited spectra. Metabolite peaks were modeled using a simple Gaussian fit, while the creatine signal was fitted to a double Lorentzian model. The results were expressed as metabolite/Cr levels, with normalization to creatine used to minimize intersubject variability due to differing signal-to-noise ratios and CSF fractions in the voxel (Bogner et al., \u003cspan class=\"CitationRef\"\u003e2010\u003c/span\u003e). Given the known contamination of GABA signals by other macromolecules (Aufhaus et al., \u003cspan class=\"CitationRef\"\u003e2013\u003c/span\u003e), we will refer to it as GABA\u0026thinsp;+\u0026thinsp;going forward. Spectra were only considered valid if the model fit error was below 10%, and any spectra with higher errors were treated as missing data.\u003c/p\u003e\n \u003cp\u003e2.4 Statistical Analysis\u003c/p\u003e\n \u003cp\u003eStatistical analyses were performed with IBM SPSS Statistics version 27 software. Nonparametric tests for related samples (Wilcoxon) and correlation (spearman\u0026rsquo;s rho) were used. Our statistical significance threshold was set at a p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"3 Results","content":"\u003cp\u003e3.1 Impact of Lovastatin on Occipital Neurotransmitters and Glutathione\u003c/p\u003e\n\u003cp\u003eThe administration of lovastatin resulted in significant changes to the neurochemical profile of the occipital cortex in our cohort. As detailed in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, these changes point to a modulation of both the excitation-inhibition (E/I) balance and markers of the cellular redox state.\u003c/p\u003e\n\u003cp\u003eSpecifically, the concentration of the primary inhibitory neurotransmitter, GABA, showed a statistically significant decrease from a mean of 0.087\u0026thinsp;\u0026plusmn;\u0026thinsp;0.010 after placebo to 0.075\u0026thinsp;\u0026plusmn;\u0026thinsp;0.012 after lovastatin (p\u0026thinsp;=\u0026thinsp;0.035). While the concentration of Glutamate also decreased from 0.091\u0026thinsp;\u0026plusmn;\u0026thinsp;0.010 to 0.081\u0026thinsp;\u0026plusmn;\u0026thinsp;0.008, this change did not reach statistical significance (p\u0026thinsp;=\u0026thinsp;0.123).\u003c/p\u003e\n\u003cp\u003eFurthermore, we observed a marked and statistically significant increase in the concentration of Glutathione, a key antioxidant, which rose from 0.040\u0026thinsp;\u0026plusmn;\u0026thinsp;0.014 in the placebo condition to 0.063\u0026thinsp;\u0026plusmn;\u0026thinsp;0.014 after the lovastatin intervention (p\u0026thinsp;=\u0026thinsp;0.039). Reflecting the shifts in inhibitory and excitatory neurotransmitters, the overall I-E ratio (GABA/Glx) was significantly reduced from 1.479\u0026thinsp;\u0026plusmn;\u0026thinsp;0.416 to 0.937\u0026thinsp;\u0026plusmn;\u0026thinsp;0.140 (p\u0026thinsp;=\u0026thinsp;0.041).\u003c/p\u003e\n\u003cp\u003e3.2 Effect of Lovastatin on the Frequency of Epileptic Discharges\u003c/p\u003e\n\u003cp\u003eThe intervention with lovastatin was associated with a statistically significant reduction in the rate of interictal epileptiform discharges (IEDs) recorded during resting-state EEG. The mean frequency of IEDs decreased from 11.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.94 events per minute following the placebo condition to 8.87\u0026thinsp;\u0026plusmn;\u0026thinsp;1.53 events per minute following lovastatin administration (p\u0026thinsp;=\u0026thinsp;0.04). For this analysis, the quantification of IEDs included the counting of spike-slow-wave complexes.\u003c/p\u003e\n\u003cp\u003eDespite this clear effect on electrographic activity, a subsequent correlational analysis did not reveal a significant relationship between the reduction in IED frequency and the changes observed in the occipital brain metabolites measured by MRS.\u003c/p\u003e\n\u003cp\u003e3.3 Lovastatin\u0026apos;s Influence on Facial Processing ERPs\u003c/p\u003e\n\u003cp\u003eThe administration of lovastatin modulated several key components of the event-related potential (ERP) elicited during the facial processing task. The specific effects on the amplitude and latency of these components are summarized in Table\u0026nbsp;2.\u003c/p\u003e\n\u003cp\u003eWhile no significant change was observed in the early P1 peak amplitude (p\u0026thinsp;=\u0026thinsp;0.89), the latency of the subsequent P100 component was significantly delayed following the lovastatin intervention, increasing from a mean of 113\u0026thinsp;\u0026plusmn;\u0026thinsp;10 ms to 128\u0026thinsp;\u0026plusmn;\u0026thinsp;4ms (p\u0026thinsp;=\u0026thinsp;0.04). The amplitude of the N110 peak was also significantly altered, becoming less negative (\u0026minus;\u0026thinsp;2.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.08) compared to the placebo condition (\u0026minus;\u0026thinsp;5.03\u0026thinsp;\u0026plusmn;\u0026thinsp;2.14), which indicates a reduction in the component\u0026apos;s absolute magnitude (p\u0026thinsp;=\u0026thinsp;0.04). Furthermore, the latency between the P100 and N170 peaks was significantly shorter after lovastatin, decreasing from 0.059\u0026thinsp;\u0026plusmn;\u0026thinsp;0.012 s to 0.049\u0026thinsp;\u0026plusmn;\u0026thinsp;0.008 s (p\u0026thinsp;=\u0026thinsp;0.04). A trend towards a reduction in the peak-to-peak amplitude difference between the P100 and N170 components was also noted, although it did not reach statistical significance (p\u0026thinsp;=\u0026thinsp;0.06).\u003c/p\u003e\n\u003cp\u003eFinally, a correlational analysis was conducted to investigate potential relationships between these electrophysiological changes and other measured variables. We found no significant correlation between the changes in any of the ERP parameters and the changes observed in brain metabolites via MRS. Additionally, no correlation was found between the ERP changes and the frequency of interictal epileptiform discharges.\u003c/p\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eThis exploratory case series provides a novel, multimodal window into the central nervous system effects of a short course of lovastatin in individuals with drug-resistant epilepsy. To our knowledge, this is the first study to simultaneously investigate lovastatin's impact on brain metabolites, the cellular redox state, and cortical inhibition-based visual processing using a recently developed MRS sequence (HERMES). The principal findings of this proof-of-concept study are that a three-day course of lovastatin was associated with: 1) a significant reduction in occipital GABA concentration and the GABA/Glx ratio; 2) a significant increase in occipital Glutathione concentration; 3) a significant reduction in the frequency of interictal epileptiform discharges (IEDs); and 4) significant modulations of event-related potentials (ERPs) during a face processing task.\u003c/p\u003e \u003cp\u003e4.1 Interpretation of Metabolic Changes in the Occipital Cortex\u003c/p\u003e \u003cp\u003eA key finding was the reduction in the GABA/Glx ratio, a putative marker of the local excitatory/inhibitory (E/I) balance. This was driven by a significant decrease in GABA and a concurrent, though not statistically significant, trend towards reduced Glutamate. The observation that lovastatin influences the balance of these neurotransmitters is consistent with preclinical literature suggesting statins possess broad neuroprotective properties (Fracassi et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2019\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe reduction in GABA is particularly noteworthy. While a decrease in the primary inhibitory neurotransmitter might intuitively seem pro-convulsant, the role of GABA in chronic epilepsy is complex. A compelling body of evidence suggests that in the context of the chronically epileptic brain, particularly in temporal lobe epilepsy, GABAergic transmission can become paradoxically excitatory and contribute to network hyperexcitability and neurotoxicity (Remy and Beck, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Cepeda et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). While this phenomenon is most clearly established at the primary epileptogenic focus, the widespread network effects of chronic epilepsy could plausibly lead to similar dysregulation in connected cortical regions. From this perspective, the lovastatin-induced decrease in GABA observed in our cohort could be interpreted not as a loss of inhibition, but as a reduction in aberrant, potentially excitotoxic, signaling. However, this interpretation remains speculative without direct measurements from the epileptogenic zone itself.\u003c/p\u003e \u003cp\u003eThis study also revealed a significant increase in occipital Glutathione. As a primary endogenous antioxidant, the elevation of Glutathione suggests a potential impact on the cellular redox state and may reflect a reduction in oxidative stress. This aligns with preclinical studies demonstrating the anti-inflammatory and antioxidant properties of statins (Afshordel et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Pihl-Jensen et al., \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). Given that neuroinflammation and oxidative stress are thought to play a pivotal role in the pathophysiology of drug-resistant epilepsy (Vezzani et al., \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e2013b\u003c/span\u003e), this finding provides a potential mechanistic pathway for lovastatin's action.\u003c/p\u003e \u003cp\u003e4.2 Modulation of Cortical Excitability and Electrophysiology\u003c/p\u003e \u003cp\u003eWe observed a significant reduction in the frequency of IEDs following lovastatin administration. It is crucial to interpret this finding with caution. While IEDs are a hallmark of epilepsy, their frequency does not directly correlate with clinical seizure frequency, and they should be viewed as a biomarker of cortical hyperexcitability rather than a direct surrogate for seizure activity. Indeed, the relationship between IEDs and ictogenesis is complex, with some evidence suggesting that certain interictal patterns may even have a seizure-constraining role (Avoli et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). Therefore, we do not claim that lovastatin has a definitive antiepileptic effect based on this single measure. Rather, we present this as preliminary evidence that lovastatin can modulate a key electrophysiological marker of cortical irritability in this patient population.\u003c/p\u003e \u003cp\u003eThe ERP results provide a functional correlate to the observed metabolic changes. The significantly delayed P100 latency after lovastatin is noteworthy, as previous research has linked longer P1 latencies to reduced GABAergic neurotransmission in the visual cortex (Yoon et al., \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e2010\u003c/span\u003e), a finding consistent with our MRS results. Furthermore, the significant reduction in the absolute amplitude of the N110 component and the shortened latency between the P100 and N170 peaks suggest that lovastatin altered the dynamics of visual network engagement during face processing. These findings support the hypothesis that lovastatin can influence the function of cortical circuits involved in sensory processing.\u003c/p\u003e \u003cp\u003e4.3 Long range changes in the Occipital Lobe\u003c/p\u003e \u003cp\u003eA critical aspect of our design was the focus on the occipital cortex rather than the temporal lobe, the presumed epileptogenic zone in this cohort. This choice was based on three distinct lines of reasoning. First, TLE is increasingly recognized as a network disorder in which pathological activity propagates and induces functional and structural changes in remote, yet highly connected, brain regions such as the visual cortex (Spencer, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2002\u003c/span\u003e). Investigating these extra-focal regions is crucial for understanding the widespread impact of the disease. Second, from a methodological standpoint, the anatomy of the occipital cortex allows for more reliable placement of an MRS voxel, yielding a higher-quality sample of pure grey matter with fewer artifacts compared to the anatomically complex and heterogeneous mesial temporal lobe (Jansen et al., \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). Finally, subtle deficits in visual processing have been reported in TLE, providing a functional rationale for assessing the physiological status of this brain region (Noble et al., \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e4.4 Limitations and Future Directions\u003c/p\u003e \u003cp\u003eThis study has several important limitations inherent to its exploratory, case-series design. The most significant is the small sample size, which precludes generalization of the findings. This work should be considered a hypothesis-generating, physiological proof-of-concept study. While our within-subject design provides a robust internal control for each participant, future studies must include larger cohorts and a healthy control group to confirm these preliminary findings.\u003c/p\u003e \u003cp\u003eFurthermore, the short three-day treatment regimen can only inform on the acute physiological response to lovastatin and does not provide insight into long-term efficacy, safety, or potential for sustained clinical effects. The rationale for this duration was to establish acute target engagement without confounding from long-term metabolic adaptation. Future research should explore longer treatment periods to assess the durability of these effects and their correlation with clinical outcomes, such as seizure frequency. Lastly, we did not perform a detailed analysis of potential interactions between lovastatin and the participants' diverse anti-seizure medications via the cytochrome P450 system; this represents an important variable that should be systematically controlled for in subsequent, larger trials (Gouveia et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2014\u003c/span\u003e).\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, this case series provides preliminary evidence that a short course of lovastatin can modulate key neurochemical and electrophysiological markers in the brains of patients with drug-resistant epilepsy. Specifically, lovastatin was associated with a lower GABA/Glx ratio, higher Glutathione levels, and a reduced frequency of IEDs in the occipital cortex. These inherent biological effects suggest that lovastatin influences both the E/I balance and the cellular redox state. While it is premature to suggest a clinical antiepileptic role, these findings provide a compelling rationale for further, more definitive studies to investigate the therapeutic potential of statins as a novel adjunctive strategy for modifying brain excitability in epilepsy.\u003c/p\u003e "},{"header":"Declarations","content":"\u003ch2\u003eEthics Declarations: \u003c/h2\u003e\n\u003cp\u003eAll procedures conformed to the principles of the Declaration of Helsinki. The study protocol was reviewed and approved by the Faculty of Medicine of the University of Coimbra Research Ethics Committee and the Clinical Academic Center (references: CE010/17 and CHUC 024-18). The study was registered as a clinical trial (ClinicalTrials.gov ID: trial registration number NCT06789497 Registration 17.01.2025). All individuals provided written informed consent before their inclusion in the study.\u003c/p\u003e\n\u003ch2\u003eConflict of Interest\u003c/h2\u003e \u003cp\u003e \u003cem\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest\u003c/em\u003e.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eSA conceptualized, collected data, analyzed, and helped in writing this manuscript. CD helped in recruiting participants and data collection. FS helped in selecting and recruiting participants. MCB conceptualized, supervised, and helped in analyzing and writing the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets [GENERATED/ANALYZED] for this study can be requested by emailing the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAbuhaiba SI, Duarte IC, Castelhano J, Dion\u0026iacute;sio A, Sales F, Edden R, Castelo-Branco M. (2022) The impact of cathodal tDCS on the GABAergic system in the epileptogenic zone: A multimodal imaging study. Front Neurol 13 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/35989912/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/35989912/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 28, 2024].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAfshordel S, Kern B, Clasohm J, K\u0026ouml;nig H, Priester M, Weissenberger J, K\u0026ouml;gel D, Eckert GP. (2015) Lovastatin and perillyl alcohol inhibit glioma cell invasion, migration, and proliferation\u0026ndash;impact of Ras-/Rho-prenylation. Pharmacol Res 91:69\u0026ndash;77 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/25497898/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/25497898/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAufhaus E, Weber-Fahr W, Sack M, Tunc-Skarka N, Oberthuer G, Hoerst M, Meyer-Lindenberg A, Boettcher U, Ende G. (2013) Absence of changes in GABA concentrations with age and gender in the human anterior cingulate cortex: A MEGA-PRESS study with symmetric editing pulse frequencies for macromolecule suppression. Magn Reson Med 69:317\u0026ndash;320 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://doi.wiley.com/10.1002/mrm.24257\u003c/span\u003e\u003cspan address=\"http://doi.wiley.com/10.1002/mrm.24257\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed July 17, 2020].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAvoli M, D'Antuono M, Louvel J, K\u0026ouml;hling R, Biagini G, Pumain R. Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system in vitro. Prog Neurobiol. 2006;78(3\u0026ndash;5):202\u0026ndash;19.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBernardino I, Dion\u0026iacute;sio A, Castelo-Branco M. (2022) Cortical inhibition in neurofibromatosis type 1 is modulated by lovastatin, as demonstrated by a randomized, triple-blind, placebo-controlled clinical trial. Scientific Reports 2022 12:1 12:1\u0026ndash;10 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.nature.com/articles/s41598-022-17873-x\u003c/span\u003e\u003cspan address=\"https://www.nature.com/articles/s41598-022-17873-x\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed March 4, 2024].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBernhardt BC, Bernasconi N, Bernasconi A. The multifaceted role of the human hippocampus in temporal lobe epilepsy. Nat Reviews Neurol. 2013;9(8):423\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWellard JW, Briellmann RS, Jackson GD. Methodological considerations for proton MR spectroscopy of the hippocampus. J Magn Reson Imaging. 2005;22(5):696\u0026ndash;701.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBogner W, Gruber S, Doelken M, Stadlbauer A, Ganslandt O, Boettcher U, Trattnig S, Doerfler A, Stefan H, Hammen T. In vivo quantification of intracerebral GABA by single-voxel (1)H-MRS-How reproducible are the results? Eur J Radiol. 2010;73:526\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eB\u0026ouml;sel J, Gandor F, Harms C, Synowitz M, Harms U, Djoufack PC, Megow D, Dirnagl U, H\u0026ouml;rtnagl H, Fink KB, Endres M. (2005) Neuroprotective effects of atorvastatin against glutamate-induced excitotoxicity in primary cortical neurones. J Neurochem 92:1386\u0026ndash;1398 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/15748157/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/15748157/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCanevini MP et al. (2010) Relationship between adverse effects of antiepileptic drugs, number of coprescribed drugs, and drug load in a large cohort of consecutive patients with drug-refractory epilepsy. Epilepsia 51:797\u0026ndash;804 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/20545754/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/20545754/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCastelhano J, Rebola J, Leit\u0026atilde;o B, Rodriguez E, Castelo-Branco M. (2013) To Perceive or Not Perceive: The Role of Gamma-band Activity in Signaling Object Percepts. PLoS One 8 Available at: /pmc/articles/PMC3681966/?report\u0026thinsp;=\u0026thinsp;abstract [Accessed November 10, 2020].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCastelhano J, Rebola J, Rodriguez E, Castelo-Branco M. Neural synchronization in the gamma frequency range is tightly associated with detection of ambiguous face stimuli. NeuroImage. 2009;47:S155.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCastelhano J, Tavares P, Mouga S, Oliveira G, Castelo-Branco M. Stimulus dependent neural oscillatory patterns show reliable statistical identification of autism spectrum disorder in a face perceptual decision task. Clin Neurophysiol. 2018;129:981\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCepeda C, Levinson S, Nariai H, Yazon VW, Tran C, Barry J, Oikonomou KD, Vinters HV, Fallah A, Mathern GW, Wu JY. Pathological high frequency oscillations associate with increased GABA synaptic activity in pediatric epilepsy surgery patients. Neurobiol Dis. 2020;134:104618.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChan KL, Puts NAJ, Sch\u0026auml;r M, Barker PB, Edden RAE. (2016) HERMES: Hadamard encoding and reconstruction of MEGA-edited spectroscopy. Magn Reson Med 76:11\u0026ndash;19 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://doi.wiley.com/10.1002/mrm.26233\u003c/span\u003e\u003cspan address=\"http://doi.wiley.com/10.1002/mrm.26233\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed October 24, 2020].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClarke RM, Lyons A, O\u0026rsquo;Connell F, Deighan BF, Barry CE, Anyakoha NG, Nicolaou A, Lynch MA. (2008) A pivotal role for interleukin-4 in atorvastatin-associated neuroprotection in rat brain. J Biol Chem 283:1808\u0026ndash;1817 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/17981803/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/17981803/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eD\u0026rsquo;Ambrosio R, Eastman CL, Fattore C, Perucca E. (2013) Novel frontiers in epilepsy treatments: preventing epileptogenesis by targeting inflammation. Expert Rev Neurother 13:615\u0026ndash;625 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/23738999/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/23738999/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDedeurwaerdere S, Friedman A, Fabene PF, Mazarati A, Murashima YL, Vezzani A, Baram TZ. (2012) Finding a better drug for epilepsy: Antiinflammatory targets. Epilepsia 53:1113\u0026ndash;1118 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://onlinelibrary.wiley.com/doi/full/\u003c/span\u003e\u003cspan address=\"https://onlinelibrary.wiley.com/doi/full/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1528-1167.2012.03520.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1528-1167.2012.03520.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEdden RAE, Puts NAJ, Harris AD, Barker PB, Evans CJ. (2014) Gannet: A batch-processing tool for the quantitative analysis of gamma-aminobutyric acid\u0026ndash;edited MR spectroscopy spectra. J Magn Reson Imaging 40:1445\u0026ndash;1452 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/25548816/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/25548816/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed March 4, 2024].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFracassi A, Marangoni M, Rosso P, Pallottini V, Fioramonti M, Siteni S, Segatto M. (2019) Statins and the Brain: More than Lipid Lowering Agents? Curr Neuropharmacol 17:59 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e/pmc/articles/PMC6341496/\u003c/span\u003e\u003cspan address=\"http:///pmc/articles/PMC6341496/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFriedman A, Dingledine R. (2011) Molecular cascades that mediate the influence of inflammation on epilepsy. Epilepsia 52:33\u0026ndash;39 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://onlinelibrary.wiley.com/doi/full/\u003c/span\u003e\u003cspan address=\"https://onlinelibrary.wiley.com/doi/full/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1528-1167.2011.03034.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1528-1167.2011.03034.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFunck VR, De Oliveira CV, Pereira LM, Rambo LM, Ribeiro LR, Royes LFF, Ferreira J, Guerra GP, Furian AF, Oliveira MS, Mallmann CA, De Mello CF, Oliveira MS. (2011a) Differential effects of atorvastatin treatment and withdrawal on pentylenetetrazol-induced seizures. Epilepsia 52:2094\u0026ndash;2104 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/21906051/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/21906051/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFunck VR, De Oliveira CV, Pereira LM, Rambo LM, Ribeiro LR, Royes LFF, Ferreira J, Guerra GP, Furian AF, Oliveira MS, Mallmann CA, De Mello CF, Oliveira MS. (2011b) Differential effects of atorvastatin treatment and withdrawal on pentylenetetrazol-induced seizures. Epilepsia 52:2094\u0026ndash;2104 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/21906051/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/21906051/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGorter JA, Van Vliet EA, Aronica E, Breit T, Rauwerda H, Lopes Da Silva FH, Wadman WJ. (2006) Potential New Antiepileptogenic Targets Indicated by Microarray Analysis in a Rat Model for Temporal Lobe Epilepsy. Journal of Neuroscience 26:11083\u0026ndash;11110 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.jneurosci.org/content/26/43/11083\u003c/span\u003e\u003cspan address=\"https://www.jneurosci.org/content/26/43/11083\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGouveia TL, Nejm MB, Naffah-Mazacoratti MDG, Cavalheiro EA, Scorza FA. Statins and epilepsy: new findings to be explored. Expert Opin Ther Pat. 2014;24(7):743\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHomayoun H, Moghaddam B. (2007) NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 27:11496\u0026ndash;11500 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/17959792/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/17959792/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJansen JFA, Backes WH, Nicolay K, Kooi ME. 1H MR spectroscopy of the brain: absolute quantification of metabolites. Radiology. 2006;240(2):318\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJansen JF, Backes WH, Nicolay K, Kooi ME. 1H MR spectroscopy of the brain: absolute quantification of metabolites. Radiology. 2006;240(2):318\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKlausberger T, Somogyi P. (2008) Neuronal Diversity and Temporal Dynamics: The Unity of Hippocampal Circuit Operations. Science (1979) 321:53\u0026ndash;57 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ncbi.nlm.nih.gov/pubmed/18599766\u003c/span\u003e\u003cspan address=\"http://www.ncbi.nlm.nih.gov/pubmed/18599766\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed April 15, 2020].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee JK, Won JS, Singh AK, Singh I. (2008) Statin inhibits kainic acid-induced seizure and associated inflammation and hippocampal cell death. Neurosci Lett 440:260\u0026ndash;264 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/18583044/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/18583044/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLevy LM, Degnan AJ. (2013) GABA-based evaluation of neurologic conditions: MR spectroscopy. AJNR Am J Neuroradiol 34:259\u0026ndash;265 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ncbi.nlm.nih.gov/pubmed/22268095\u003c/span\u003e\u003cspan address=\"http://www.ncbi.nlm.nih.gov/pubmed/22268095\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed May 14, 2020].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMainberger F, Jung NH, Zenker M, Wahll\u0026auml;nder U, Freudenberg L, Langer S, Berweck S, Winkler T, Straube A, Heinen F, Granstr\u0026ouml;m S, Mautner V-F, Lidzba K, Mall V. (2013) Lovastatin improves impaired synaptic plasticity and phasic alertness in patients with neurofibromatosis type 1. BMC Neurol 13:131 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ncbi.nlm.nih.gov/pubmed/24088225\u003c/span\u003e\u003cspan address=\"http://www.ncbi.nlm.nih.gov/pubmed/24088225\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed August 30, 2016].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoezi L, Shafaroodi H, Hassanipour M, Fakhrzad A, Hassanpour S, Dehpour AR. (2012) Chronic administration of atorvastatin induced anti-convulsant effects in mice: the role of nitric oxide. Epilepsy Behav 23:399\u0026ndash;404 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/22405864/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/22405864/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMueller SG, Laxer KD, Scanlon C, Garcia P, Paul B, Weiner MW. Different patterns of regional GABA and glutamate deficits in generalized and partial epilepsy. Epilepsia. 2014;55(6):851\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNejm MB, Gouveia TL, da Gra\u0026ccedil;a Naffah-Mazacoratti M, Scorza CA, Cavalheiro EA, Scorza FA. (2013) Lovastatin and sudden unexpected death in epilepsy: a matter for debate. Epilepsy Behav 28:10\u0026ndash;11 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ncbi.nlm.nih.gov/pubmed/23648273\u003c/span\u003e\u003cspan address=\"http://www.ncbi.nlm.nih.gov/pubmed/23648273\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed August 30, 2016].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNoble K, O'Keeffe F, Mills T, Tsereteli D, O'Brien A, O'Sullivan M, Doherty CP. Functional vision in temporal lobe epilepsy: A study of contrast sensitivity, visual fields, and quality of life. Epilepsia Open. 2023;8(3):963\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOsterweil EK, Chuang SC, Chubykin AA, Sidorov M, Bianchi R, Wong RKS, Bear MF. (2013) Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile X syndrome. Neuron 77:243\u0026ndash;250 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/23352161/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/23352161/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePannu R, Christie DK, Barbosa E, Singh I, Singh AK. (2007) Post-trauma Lipitor treatment prevents endothelial dysfunction, facilitates neuroprotection, and promotes locomotor recovery following spinal cord injury. J Neurochem 101:182\u0026ndash;200 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://onlinelibrary.wiley.com/doi/full/\u003c/span\u003e\u003cspan address=\"https://onlinelibrary.wiley.com/doi/full/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1471-4159.2006.04354.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1471-4159.2006.04354.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePicton TW. (Terence W) (n.d.) Human auditory evoked potentials.:634 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://books.google.com/books/about/Human_Auditory_Evoked_Potentials.html?id=-N22CwAAQBAJ\u003c/span\u003e\u003cspan address=\"https://books.google.com/books/about/Human_Auditory_Evoked_Potentials.html?id=-N22CwAAQBAJ\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePiermartiri TCB, Figueiredo CP, Rial D, Duarte FS, Bezerra SC, Mancini G, de Bem AF, Prediger RDS, Tasca CI. (2010) Atorvastatin prevents hippocampal cell death, neuroinflammation and oxidative stress following amyloid-β(1\u0026ndash;40) administration in mice: evidence for dissociation between cognitive deficits and neuronal damage. Exp Neurol 226:274\u0026ndash;284 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/20816828/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/20816828/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePihl-Jensen G, Tsakiri A, Frederiksen JL. (2015) Statin treatment in multiple sclerosis: a systematic review and meta-analysis. CNS Drugs 29:277\u0026ndash;291 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/25795002/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/25795002/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRamirez C, Tercero I, Pineda A, Burgos JS. (2011) Simvastatin is the statin that most efficiently protects against kainate-induced excitotoxicity and memory impairment. J Alzheimers Dis 24:161\u0026ndash;174 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/21224519/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/21224519/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRavizza T, Rizzi M, Perego C, Richichi C, Vel\u0026iacute;skǒv\u0026aacute; J, Mosh\u0026eacute; SL, De Simoni MG, Vezzani A. (2005) Inflammatory response and glia activation in developing rat hippocampus after status epilepticus. Epilepsia 46 Suppl 5:113\u0026ndash;117 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/15987264/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/15987264/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRemy S, Beck H. (2006) Molecular and cellular mechanisms of pharmacoresistance in epilepsy. Brain 129:18\u0026ndash;35 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://academic.oup.com/brain/article/129/1/18/311849/Molecular-and-cellular-mechanisms-of\u003c/span\u003e\u003cspan address=\"http://academic.oup.com/brain/article/129/1/18/311849/Molecular-and-cellular-mechanisms-of\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed May 14, 2020].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSasa M. (2006) A new frontier in epilepsy: novel antiepileptogenic drugs. J Pharmacol Sci 100:487\u0026ndash;494 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/16799261/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/16799261/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSerbanescu I, Ryan MA, Shukla R, Cortez MA, Snead OC, Cunnane SC. (2004) Lovastatin exacerbates atypical absence seizures with only minimal effects on brain sterols. J Lipid Res 45:2038\u0026ndash;2043 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/15314096/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/15314096/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShafaroodi H, Moezi L, Fakhrzad A, Hassanipour M, Rezayat M, Dehpour AR. (2012) The involvement of nitric oxide in the anti-seizure effect of acute atorvastatin treatment in mice. Neurol Res 34:847\u0026ndash;853 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/22909758/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/22909758/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSierra-Marcos A, Alvarez V, Faouzi M, Burnand B, Rossetti AO. (2015) Statins are associated with decreased mortality risk after status epilepticus. Eur J Neurol 22:402\u0026ndash;405 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ncbi.nlm.nih.gov/pubmed/24684345\u003c/span\u003e\u003cspan address=\"http://www.ncbi.nlm.nih.gov/pubmed/24684345\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed August 30, 2016].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpencer SS. Neural networks in human epilepsy: evidence of and implications for treatment. Epilepsia. 2002;43(3):219\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSousa D, Ferreira A, Rodrigues D, Pereira HC, Amaral J, Crisostomo J, Simoes M, Ribeiro M, Teixeira M, Castelo-Branco M. (2023) A neurophysiological signature of dynamic emotion recognition associated with social communication skills and cortical gamma-aminobutyric acid levels in children. Front Neurosci 17 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/38164245/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/38164245/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 28, 2024].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpencer SS. Neural networks in human epilepsy: evidence of and implications for treatment. Epilepsia. 2002;43(3):219\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun J, Xie C, Liu W, Lu D, Qiao W, Huang Q, Huo Z, Shen H, Lin Z. (2012) The effects of simvastatin on hippocampal caspase-3 and Bcl-2 expression following kainate-induced seizures in rats. Int J Mol Med 30:739\u0026ndash;746 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/22842798/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/22842798/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTaki MM, Harada M, Mori K, Kubo H, Nose A, Matsuda T, Nishitani H. (2009) High gamma-aminobutyric acid level in cortical tubers in epileptic infants with tuberous sclerosis complex measured with the MEGA-editing J-difference method and a three-Tesla clinical MRI Instrument. Neuroimage 47:1207\u0026ndash;1214 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/19481612/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/19481612/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed October 24, 2020].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTam\u0026aacute;s G, Buhl EH, L\u0026ouml;rincz A, Somogyi P. (2000) Proximally targeted GABAergic synapses and gap junctions synchronize cortical interneurons. Nat Neurosci 3:366\u0026ndash;371 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/10725926/[Accessed\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/10725926/[Accessed\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e October 24, 2020].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTurrin NP, Rivest S. (2004) Innate immune reaction in response to seizures: Implications for the neuropathology associated with epilepsy. Neurobiol Dis 16:321\u0026ndash;334 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/15193289/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/15193289/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e\u0026Uuml;z\u0026uuml;m G, Akg\u0026uuml;n-Dar K, Aksu U. (2010a) The effects of atorvastatin on memory deficit and seizure susceptibility in pentylentetrazole-kindled rats. Epilepsy Behav 19:284\u0026ndash;289 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/20888302/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/20888302/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e\u0026Uuml;z\u0026uuml;m G, Akg\u0026uuml;n-Dar K, Aksu U. (2010b) The effects of atorvastatin on memory deficit and seizure susceptibility in pentylentetrazole-kindled rats. Epilepsy Behav 19:284\u0026ndash;289 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/20888302/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/20888302/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVezzani A, Aronica E, Mazarati A, Pittman QJ. (2013a) Epilepsy and brain inflammation. Exp Neurol 244:11\u0026ndash;21 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/21985866/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/21985866/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVezzani A, Aronica E, Mazarati A, Pittman QJ. (2013b) Epilepsy and brain inflammation. Exp Neurol 244:11\u0026ndash;21 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/21985866/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/21985866/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeber MS, Youssef S, Dunn SE, Prod\u0026rsquo;homme T, Neuhaus O, Stuve O, Greenwood J, Steinman L, Zamvil SS. Statins in the treatment of central nervous system autoimmune disease. J Neuroimmunol. 2006;178:140\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXie C, Sun J, Qiao W, Lu D, Wei L, Na M, Song Y, Hou X, Lin Z. (2011a) Administration of Simvastatin after Kainic Acid-Induced Status Epilepticus Restrains Chronic Temporal Lobe Epilepsy. PLoS One 6:e24966 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024966\u003c/span\u003e\u003cspan address=\"https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024966\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXie C, Sun J, Qiao W, Lu D, Wei L, Na M, Song Y, Hou X, Lin Z. (2011b) Administration of Simvastatin after Kainic Acid-Induced Status Epilepticus Restrains Chronic Temporal Lobe Epilepsy. PLoS One 6:e24966 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024966\u003c/span\u003e\u003cspan address=\"https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024966\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoon JH, Maddock RJ, Rokem A, Silver MA, Minzenberg MJ, Ragland JD, Carter CS. (2010) GABA concentration is reduced in visual cortex in schizophrenia and correlates with orientation-specific surround suppression. J Neurosci 30:3777\u0026ndash;3781 Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://pubmed.ncbi.nlm.nih.gov/20220012/\u003c/span\u003e\u003cspan address=\"https://pubmed.ncbi.nlm.nih.gov/20220012/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Accessed September 11, 2023].\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 Title: Lovastatin effect on brain metabolites.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" style=\"margin-left: calc(0%); width: 100%;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eConcentration after Placebo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eConcentration after Lovastatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eGABA\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.087 \u003cu\u003e+\u003c/u\u003e 0.010\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.075 \u003cu\u003e+\u003c/u\u003e 0.012\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.035\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eGlutamate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.091 \u003cu\u003e+\u003c/u\u003e 0.010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.081 \u003cu\u003e+\u003c/u\u003e 0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.123\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eGlutathione\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.040 \u003cu\u003e+\u003c/u\u003e 0.014\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.063 \u003cu\u003e+\u003c/u\u003e 0.014\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.039\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eI-E Ratio (GABA/Glx)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e1.479 \u003cu\u003e+\u003c/u\u003e 0.416\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.937 \u003cu\u003e+\u003c/u\u003e 0.140\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.041\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 1: Legend: It appears that GABA, Glx, and GABA/Glx ratio were all decreased after our participants took lovastatin. Glutathione, on the other hand, was increased. This reached statistical significance for all parameters except glutamate. These values are corrected for Cr.\u003c/p\u003e\n\u003cp\u003eTable 2 title: Lovastatin effect on the event related potential (ERP) of facial recognition.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eMean after placebo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eMean after lovastatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eP1 Peak Amplitude\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e5.45 \u003cu\u003e+\u003c/u\u003e 3.16\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e4.75 \u003cu\u003e+\u003c/u\u003e 2.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.89\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP100 Latency\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.113 \u0026nbsp;\u003cu\u003e+\u003c/u\u003e 0.010\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.128 \u003cu\u003e+\u003c/u\u003e 0.004\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.04\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eN110 Peak Amplitude\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e- 5.03 \u003cu\u003e+\u003c/u\u003e 2.14\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e- 2.6 \u003cu\u003e+\u003c/u\u003e 1.08\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.04\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eN1 Latency\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.172 \u003cu\u003e+\u003c/u\u003e 0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.176 \u003cu\u003e+\u003c/u\u003e 0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP100 to N170 Difference in Peak Amplitude\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e10.48 \u003cu\u003e+\u003c/u\u003e 4.52\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e7.37 \u003cu\u003e+\u003c/u\u003e 3.62\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.06\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP100 to N170 Latency\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.059 \u003cu\u003e+\u003c/u\u003e 0.012\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.049 \u003cu\u003e+\u003c/u\u003e 0.008\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.04\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 2: Effects of lovastatin on P100, N170, and P100 to N170 parameters from the ERP of facial recognition. Measurement unit: mV\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pharmacological-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prep","sideBox":"Learn more about [Pharmacological Reports](https://link.springer.com/journal/43440)","snPcode":"43440","submissionUrl":"https://submission.springernature.com/new-submission/43440/3","title":"Pharmacological Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"GABA, Glutamate, Lovastatin, Glutathione, Occipital Cortex, Excitotoxicity","lastPublishedDoi":"10.21203/rs.3.rs-8180994/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8180994/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eDrug-resistant epilepsy (DRE) is a major clinical challenge, with neuroinflammation and excitatory/inhibitory (E/I) imbalance implicated in its pathophysiology. This proof-of-concept case series aimed to investigate the neurochemical and neurophysiological effects of a short course of lovastatin in individuals with DRE.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eFive participants with drug-resistant temporal lobe epilepsy completed a double-blind, placebo-controlled, crossover protocol involving oral administration of lovastatin (60 mg/day) and placebo for three consecutive days. Post-intervention assessments included: 1) magnetic resonance spectroscopy (MRS) in the visual cortex to quantify GABA+, Glutamate (Glx), and Glutathione (GSH); 2) resting-state EEG to measure the frequency of interictal epileptiform discharges (IEDs); and 3) event-related potentials (ERPs) during a facial recognition task.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eCompared to placebo, lovastatin administration was associated with a significant reduction in the GABA+/Glx ratio (p\u0026thinsp;=\u0026thinsp;0.041) and IED frequency (p\u0026thinsp;=\u0026thinsp;0.04), alongside a significant increase in GSH concentration (p\u0026thinsp;=\u0026thinsp;0.039). Lovastatin also modulated visual processing ERPs, significantly delaying the P100 latency (p\u0026thinsp;=\u0026thinsp;0.04) and reducing the absolute N110 peak amplitude (p\u0026thinsp;=\u0026thinsp;0.04).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis study demonstrates that a short course of lovastatin can modulate key in-vivo biomarkers of E/I balance, redox state, and cortical excitability in patients with DRE. These preliminary findings provide a mechanistic rationale for further, larger studies to explore the potential of statins as a novel strategy for modifying pathological brain activity.\u003c/p\u003e","manuscriptTitle":"Lovastatin Modulates Cortical Excitability, E/I Balance, and Antioxidant Markers in Drug-Resistant Epilepsy: A Proof-of-Concept Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-22 08:52:12","doi":"10.21203/rs.3.rs-8180994/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-22T10:59:04+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-14T09:53:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"157321358355073921329159303571901442282","date":"2026-04-04T15:07:59+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-04T10:53:42+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-03T13:12:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"93319943048623194340464608880568592797","date":"2026-03-30T08:24:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"145638632288138973805475808025952809178","date":"2026-03-29T08:35:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"235371831691312934638245641930994690271","date":"2026-03-29T07:33:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"215335898681725444607533973177711198350","date":"2026-03-27T11:48:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"17229287211769380471140005392459689359","date":"2026-03-27T07:55:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"6200448478726637935011309857122877718","date":"2026-03-27T07:50:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"269045636321458400508132201789213334075","date":"2026-01-29T11:50:13+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-12T00:53:23+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-27T11:31:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-26T05:03:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pharmacological Reports","date":"2025-11-22T14:12:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pharmacological-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prep","sideBox":"Learn more about [Pharmacological Reports](https://link.springer.com/journal/43440)","snPcode":"43440","submissionUrl":"https://submission.springernature.com/new-submission/43440/3","title":"Pharmacological Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"dad37f99-88df-4496-a920-169eeb66879f","owner":[],"postedDate":"December 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-13T10:27:04+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-22 08:52:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8180994","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8180994","identity":"rs-8180994","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}