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Anatomical regions with significant gray matter atrophy in benign adult familial myoclonic epilepsy. A significance threshold with voxel-wise P\u200A<\u200A.001 in conjunction with cluster-wise P\u200A<\u200A.05 to correct for multiple comparisons based on Gaussian random field theory and a cluster size \u2265 50 voxels were used.
Source publication
Benign adult familial myoclonic epilepsy (BAFME) is a non-progressive monogenic epilepsy syndrome. So far, the structural and functional brain reorganizations in BAFME remain uncharacterized. This study aims to investigate gray matter atrophy and related functional connectivity alterations in patients with BAFME using magnetic resonance imaging (MR...
Citations
... The asymmetric structural pattern is consistent with previous research (including asymmetric cortical metabolic, functional, and structural alterations). 6,10,12,19,44 However, because of the relatively small sample sizes and low statistical power, the results did not provide sufficient evidence to suggest cerebral morphological changes in patients with BAFME1. This is consistent with previous pathology findings showing limited involvement of the sensorimotor cortex, 3 which further supported that cortical hyperactivity might result from the failure of cerebello-cortical control. ...
Objective
Cortical tremor/myoclonus is the hallmark feature of benign adult familial myoclonic epilepsy (BAFME), the mechanism of which remains elusive. A hypothesis is that a defective control in the preexisting cerebellar‐motor loop drives cortical tremor. Meanwhile, the basal ganglia system might also participate in BAFME. This study aimed to discover the structural basis of cortical tremor/myoclonus in BAFME.
Methods
Nineteen patients with BAFME type 1 (BAFME1) and 30 matched healthy controls underwent T1‐weighted and diffusion tensor imaging scans. FreeSurfer and spatially unbiased infratentorial template (SUIT) toolboxes were utilized to assess the motor cortex and the cerebellum. Probabilistic tractography was generated for two fibers to test the hypothesis: the dentato‐thalamo‐(M1) (primary motor cortex) and globus pallidus internus (GPi)‐thalamic projections. Average fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) of each tract were extracted.
Results
Cerebellar atrophy and dentate nucleus alteration were observed in the patients. In addition, patients with BAFME1 exhibited reduced AD and FA in the left and right dentato‐thalamo‐M1 nondecussating fibers, respectively false discovery rate (FDR) correction q < .05. Cerebellar projections showed negative correlations with somatosensory‐evoked potential P25‐N33 amplitude and were independent of disease duration and medication. BAFME1 patients also had increased FA and decreased MD in the left GPi‐thalamic projection. Higher FA and lower RD in the right GPi‐thalamic projection were also observed (FDR q < .05).
Significance
The present findings support the hypothesis that the cerebello‐thalamo‐M1 loop might be the structural basis of cortical tremor in BAFME1. The basal ganglia system also participates in BAFME1 and probably serves a regulatory role.
... Cognitive impairment is frequent in FCMTE families (Guerrini et al., 2001;Suppa et al., 2009;Sharma et al., 2014;Zeng et al., 2015). While ataxia is not classic in FCMTE, other cerebellar signs (gait instability, downbeat nystagmus, dysarthria) do feature (van Rootselaar et al., 2005;Magnin et al., 2009;Sharma et al., 2014;Gao et al., 2016). ...
Cortical tremor is a fine rhythmic oscillation involving distal upper limbs, linked to increased sensorimotor cortex excitability, as seen in cortical myoclonus. Cortical tremor is the hallmark feature of autosomal dominant familial cortical myoclonic tremor and epilepsy (FCMTE), a syndrome not yet officially recognized and characterized by clinical and genetic heterogeneity. Non-coding repeat expansions in different genes have been recently recognized to play an essential role in its pathogenesis. Cortical tremor is considered a rhythmic variant of cortical myoclonus and is part of the 'spectrum of cortical myoclonus', i.e. a wide range of clinical motor phenomena, from reflex myoclonus to myoclonic epilepsy, caused by abnormal sensorimotor cortical discharges. The aim of this update is to provide a detailed analysis of the mechanisms defining cortical tremor, as seen in FCMTE. After reviewing the clinical and genetic features of FCMTE, we discuss the possible mechanisms generating the distinct elements of the cortical myoclonus spectrum, and how cortical tremor fits into it. We propose that the spectrum is due to the evolution from a spatially limited focus of excitability to recruitment of more complex mechanisms capable of sustaining repetitive activity, overcoming inhibitory mechanisms that restrict excitatory bursts, and engaging wide areas of cortex. Finally, we provide evidence for a possible common denominator of the elements of the spectrum, i.e. the cerebellum, and discuss its role in FCMTE, according to recent genetic findings.
... A functional MRI/voxel-based morphometry (VBM) study indicated gray matter loss in cortical and subcortical structures with connectivity alterations. 70 In a resting state fMRI study, compared to ET and healthy controls, the right fusiform gyrus and the posterior cingulate cortex showed decreased amplitude of low-frequency fluctuation (ALFF), and the frontal lobe showed increased ALFF that correlated with disease duration. 55 In two FCMTE patients with gait difficulties but no benefit from L-dopa in one, MRI showed frontal atrophy and single positron emission computed tomography (SPECT) showed dopamine depletion. ...
... 52 Supratentorial gray matter loss outside the motor circuit might be secondary. 70 Also, cerebellar atrophy and ataxia have frequently been noted in patients with epilepsy. 87 Repetitive TMS over the cerebellar cortex was able to reduce seizure frequency in drug-resistant epilepsy. ...
... For instance, both the imaging and the pathology findings involving cerebellar changes have largely been confined to a South African patient (linkage exclusion 2p, 8q), a Dutch pedigree (FCMTE3), and Chinese patients (linkage exclusion 2p, 8q) making the generalizability of the findings problematic. 10,39,51-53, 65,70 Several mutations (ACMSD, ADRA2B, UBR5, PLA2G6) have been proposed but pathogenicity has still to be proven. [46][47][48]59 Conclusion FCMTE, also known under different names and acronyms, is a clinical entity not (yet) listed by the ILAE. ...
Background
Autosomal dominant familial cortical myoclonic tremor and epilepsy (FCMTE) is characterized by distal tremulous myoclonus, generalized seizures, and signs of cortical reflex myoclonus. FCMTE has been described in over 100 pedigrees worldwide, under several different names and acronyms. Pathological changes have been located in the cerebellum. This systematic review discusses the clinical spectrum, treatment, pathophysiology, and genetic findings.
Methods
We carried out a PubMed search, using a combination of the following search terms: cortical tremor, myoclonus, epilepsy, benign course, adult onset, familial, and autosomal dominant; this resulted in a total of 77 studies (761 patients; 126 pedigrees) fulfilling the inclusion and exclusion criteria.
Results
Phenotypic differences across pedigrees exist, possibly related to underlying genetic differences. A “benign” phenotype has been described in several Japanese families and pedigrees linked to 8q (FCMTE1). French patients (5p linkage; FCMTE3) exhibit more severe progression, and in Japanese/Chinese pedigrees (with unknown linkage) anticipation has been suggested. Preferred treatment is with valproate (mind teratogenicity), levetiracetam, and/or clonazepam. Several genes have been identified, which differ in potential pathogenicity.
Discussion
Based on the core features (above), the syndrome can be considered a distinct clinical entity. Clinical features may also include proximal myoclonus and mild progression with aging. Valproate or levetiracetam, with or without clonazepam, reduces symptoms. FCMTE is a heterogeneous disorder, and likely to include a variety of different conditions with mutations of different genes. Distinct phenotypic traits might reflect different genetic mutations. Genes involved in Purkinje cell outgrowth or those encoding for ion channels or neurotransmitters seem good candidate genes.
... A functional MRI/voxel-based morphometry (VBM) study indicated gray matter loss in cortical and subcortical structures with connectivity alterations. 70 In a resting state fMRI study, compared to ET and healthy controls, the right fusiform gyrus and the posterior cingulate cortex showed decreased amplitude of low-frequency fluctuation (ALFF), and the frontal lobe showed increased ALFF that correlated with disease duration. 55 In two FCMTE patients with gait difficulties but no benefit from L-dopa in one, MRI showed frontal atrophy and single positron emission computed tomography (SPECT) showed dopamine depletion. ...
... 52 Supratentorial gray matter loss outside the motor circuit might be secondary. 70 Also, cerebellar atrophy and ataxia have frequently been noted in patients with epilepsy. 87 Repetitive TMS over the cerebellar cortex was able to reduce seizure frequency in drug-resistant epilepsy. ...
... For instance, both the imaging and the pathology findings involving cerebellar changes have largely been confined to a South African patient (linkage exclusion 2p, 8q), a Dutch pedigree (FCMTE3), and Chinese patients (linkage exclusion 2p, 8q) making the generalizability of the findings problematic. 10,39,51-53, 65,70 Several mutations (ACMSD, ADRA2B, UBR5, PLA2G6) have been proposed but pathogenicity has still to be proven. [46][47][48]59 Conclusion FCMTE, also known under different names and acronyms, is a clinical entity not (yet) listed by the ILAE. ...
... In our previous study, we demonstrated gray matter loss and related functional connectivity (FC) changes in BAFME. 14 Therefore, we hypothesized that brain network abnormalities may exist in patients with BAFME, especially abnormal FC between the cerebellum and cerebrum. ...
Objective:
The pathogenesis of benign adult familial myoclonic epilepsy (BAFME) remains unknown, although cerebellar pathologic changes and brain hyperexcitability have been reported. We used resting-state functional magnetic resonance imaging (fMRI) to examine the functional connectivity between the cerebellum and cerebrum in a Chinese family with BAFME for the first time.
Methods:
Eleven adults with BAFME and 15 matched healthy controls underwent resting-state blood oxygen level-dependent (BOLD) fMRI scanning. The cerebellar seeds, including the bilateral crus I, lobule VIII, lobule VIIb, and lobule IV&V, were defined a priori. Next, regional time courses were obtained for each individual by averaging the BOLD time series over all voxels in each seed region. Then, seed-based functional connectivity z-maps were produced by computing Pearson's correlation coefficients (converted to z-scores by Fisher transformation) between each seed signal and the time series from all other voxels within the entire brain. Finally, a second-level random-effect two-sample t-test was performed on the individual z-maps in a voxel-wise manner.
Results:
Reduced functional connectivity of the right cerebellar crus I with the left middle frontal gyrus and right cerebellar lobule IX was observed in the default network of BAFME. Enhanced functional connectivity of the left cerebellar lobule VIII with the bilateral middle temporal gyri, right putamen, and left cerebellar crus I was found in the dorsal attention network of BAFME. Enhanced functional connectivity between the left cerebellar lobule VIIb and right frontal pole was found in the control network of BAFME.
Significance:
Altered cerebellar-cerebral functional connectivity may contribute to the understanding of the nosogenesis of BAFME and explain the cognitive dysfunction in this Chinese family with BAFME.
Familial adult myoclonus epilepsy (FAME) is characterized by cortical myoclonus and often epileptic seizures, but the pathophysiology of this condition remains uncertain. Here, we review the neuroimaging and neuropathological findings in FAME. Imaging findings, including functional magnetic resonance imaging, are in line with a cortical origin of involuntary tremulous movements (cortical myoclonic tremor) and indicate a complex pattern of cerebellar functional connectivity. Scarce neuropathological reports, mainly from a single family, provide evidence of morphological changes in the Purkinje cells. Cerebellar changes seem to be part of the syndrome, in at least some FAME pedigrees. Cortical hyperexcitability in FAME, resulting in the cardinal clinical symptoms, might be the result of decreased cortical inhibition via the cerebellothalamocortical loop. The pathological findings might share some similarities with other pentanucleotide repeat disorders. The relation with genetic findings in FAME needs to be elucidated.
Development and maintenance of chronic pain is associated with structural and functional brain reorganization. However, few studies have explored the impact of drug treatments on such changes. The extent to which long-term analgesia is related to brain adaptations and its effects on the reversibility of brain reorganization remain unclear. In a randomized placebo-controlled clinical trial, we contrasted pain relief (3-month treatment period), and anatomical (gray matter density [GMD], assessed by voxel-based morphometry) and functional connectivity (resting state fMRI nodal degree count [DC]) adaptations, in 39 knee osteoarthritis (OA) patients (22 females), randomized to duloxetine (DLX, 60 mg once daily) or placebo. Pain relief was equivalent between treatment types. However, distinct circuitry (GMD and DC) could explain pain relief in each group: up to 85% of variance for placebo analgesia and 49% of variance for DLX analgesia. No behavioral measures (collected at entry into the study) could independently explain observed analgesia. Identified circuitry were outside of nociceptive circuitry and minimally overlapped with OA-abnormal or placebo response predictive brain regions. Mediation analysis revealed that changes in GMD and DC can influence each other across remote brain regions to explain observed analgesia. Therefore, we can conclude that distinct brain mechanisms underlie DLX and placebo analgesia in OA. The results demonstrate that even in the absence of differences in subjective pain relief, pharmacological treatments can be differentiated from placebo based on objective brain biomarkers. This is a crucial step to untangling mechanisms and advancing personalized therapy approaches for chronic pain.
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