Valproate use associated with frontal and cerebellar gray matter volume reductions: A voxel‐based morphometry study

Shin, Ji Hye; Song, Min Ji; Kim, Ji Hyun

doi:10.1111/epi.17825

Cited by 3 publications

(1 citation statement)

References 18 publications

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“…Part of the difficulty in the mechanistic understanding of VPA-associated autism arises from the population-based nature of the association studies, thus capturing a cohort of patients with autism arising from in utero exposure to VPA has been difficult. Towards an understanding of the network effects of VPA exposure, the impact of VPA use on brain volume was evaluated based on exposure to the drug ( 136 ). In this study, VPA was found to be associated with diminished gray matter in the cerebellum, frontal cortex, and hippocampus, which correlates to the cerebro-cerebellar network connectivity that has previously been discussed and with areas of increased AMPA receptor expression ( Figure 1 ).…”

Section: Autism Associated With Prenatal Anti-seizure Medication Expo...mentioning

confidence: 99%

Understanding the role of AMPA receptors in autism: insights from circuit and synapse dysfunction

Jimenez-Gomez,

Nguyen,

Gill

2024

Front. Psychiatry

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Autism spectrum disorders represent a diverse etiological spectrum that converge on a syndrome characterized by discrepant deficits in developmental domains often highlighted by concerns in socialization, sensory integration, and autonomic functioning. Importantly, the incidence and prevalence of autism spectrum disorders have seen sharp increases since the syndrome was first described in the 1940s. The wide etiological spectrum and rising number of individuals being diagnosed with the condition lend urgency to capturing a more nuanced understanding of the pathogenic mechanisms underlying the autism spectrum disorders. The current review seeks to understand how the disruption of AMPA receptor (AMPAr)-mediated neurotransmission in the cerebro-cerebellar circuit, particularly in genetic autism related to SHANK3 or SYNGAP1 protein dysfunction function and autism associated with in utero exposure to the anti-seizure medications valproic acid and topiramate, may contribute to the disease presentation. Initially, a discussion contextualizing AMPAr signaling in the cerebro-cerebellar circuitry and microstructural circuit considerations is offered. Subsequently, a detailed review of the literature implicating mutations or deletions of SHANK3 and SYNGAP1 in disrupted AMPAr signaling reveals how bidirectional pathogenic modulation of this key circuit may contribute to autism. Finally, how pharmacological exposure may interact with this pathway, via increased risk of autism diagnosis with valproic acid and topiramate exposure and potential treatment of autism using AMPAr modulator perampanel, is discussed. Through the lens of the review, we will offer speculation on how neuromodulation may be used as a rational adjunct to therapy. Together, the present review seeks to synthesize the disparate considerations of circuit understanding, genetic etiology, and pharmacological modulation to understand the mechanistic interaction of this important and complex disorder.

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Section: Autism Associated With Prenatal Anti-seizure Medication Expo...mentioning

confidence: 99%

Understanding the role of AMPA receptors in autism: insights from circuit and synapse dysfunction

Jimenez-Gomez,

Nguyen,

Gill

2024

Front. Psychiatry

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Sodium Valproate Modulates Cortical Morphology in Juvenile Myoclonic Epilepsy

Pimentel,

Kuchukhidze,

Xiao

et al. 2024

Preprint

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Importance: Idiopathic generalized epilepsy syndromes in are associated with cortical thinning of the premotor areas. Whether this represents an underlying disease signature, a consequence of seizure activity or is related to anti-seizure medication is unknown. Objective: To investigate valproate-related effects on cortical morphology in people with juvenile myoclonic epilepsy (JME), one of the most common IGE syndromes. Design: Retrospective neuroimaging case-control study. Setting: Recruitment took place in epilepsy clinics in two European epilepsy referral centers. Participants: We matched individuals with JME on valproate (n=36) to a group of healthy controls (n=36), as well as individuals with JME not on valproate (n=36) and a group of people with temporal lobe epilepsy (n=19) on valproate using propensity scores for age, sex, occurrence of bilateral tonic-clonic seizures and drug refractoriness. Main outcomes and Measures: All participants underwent structural T1-weighted brain imaging and MRI-derived vertex-wise measurements of cortical thickness were calculated. Results were reported in effect-sizes using cohen's d. Results: Compared to healthy controls, individuals with JME on valproate demonstrated cortical thinning bilaterally in the precentral gyri (left: d = -1.0, p <.001; right: d = -1.0, p <.001). This effect was localized to the left precentral gyrus when comparing JME on VPA with individuals with JME not on valproate (d = -0.89; p <.01) or with individuals with temporal lobe epilepsy on valproate (d = - 0.18, p <.001). No significant differences in cortical thickness were detected between individuals with JME not on valproate and healthy controls. Cortical thinning in precentral gyrus, postcentral gyrus and superior frontal was more marked with increasing valproate dose (left: t = -6,65, p <.0001; right: t = -5,20, p <.0001). Conclusions and Relevance: In this cross-sectional study of 91 patients with epilepsy, valproate treatment was associated with JME-specific and dose-dependent cortical thinning of the precentral gyri. Our findings suggest a valproate-induced reorganization of disease-specific areas in JME that may not only help explain the high efficacy of this medication in IGEs but also potentially account for previously described changes of cortical thickness in this disease group.

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Sodium valproate is associated with cortical thinning of disease-specific areas in juvenile myoclonic epilepsy

Crespo Pimentel,

Kuchukhidze,

Xiao

et al. 2024

J Neurol Neurosurg Psychiatry

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BackgroundJuvenile myoclonic epilepsy (JME) is associated with cortical thinning of the motor areas. The relative contribution of antiseizure medication to cortical thickness is unknown. We aimed to investigate how valproate influences the cortical morphology of JME.MethodsIn this cross-sectional study, individuals with JME with and without valproate, with temporal lobe epilepsy (TLE) with valproate and controls were selected through propensity score matching. Participants underwent T1-weighted brain imaging and vertex-wise calculation of cortical thickness.ResultsWe matched 36 individuals with JME on valproate with 36 individuals with JME without valproate, 36 controls and 19 individuals with TLE on valproate. JME on valproate showed thinning of the precentral gyri (left and right, p<0.001) compared with controls and thinning of the left precentral gyrus when compared with JME not on valproate (p<0.01) or to TLE on valproate (p<0.001). Valproate dose correlated negatively with the thickness of the precentral gyri, postcentral gyri and superior frontal gyrus in JME (left and right p<0.0001), but not in TLE.ConclusionsValproate was associated with JME-specific and dose-dependent thinning of the cortical motor regions. This suggests that valproate is a key modulator of cortical morphology in JME, an effect that may underlie its high efficacy in this syndrome.

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Valproate use associated with frontal and cerebellar gray matter volume reductions: A voxel‐based morphometry study

Cited by 3 publications

References 18 publications

Understanding the role of AMPA receptors in autism: insights from circuit and synapse dysfunction

Understanding the role of AMPA receptors in autism: insights from circuit and synapse dysfunction

Sodium Valproate Modulates Cortical Morphology in Juvenile Myoclonic Epilepsy

Sodium valproate is associated with cortical thinning of disease-specific areas in juvenile myoclonic epilepsy

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