Abnormal sensorimotor cortex and thalamo-cortical networks in familial adult myoclonic epilepsy type 2: pathophysiology and diagnostic implications

Abstract

Familial Adult Myoclonic Epilepsy type 2 is a hereditary condition characterized by cortical tremor, myoclonus, and epilepsy. It belongs to the spectrum of cortical myoclonus and the sensorimotor cortex hyperexcitability represents an important pathogenic mechanism underlying this condition. Besides pericentral cortical structures, the impairment of subcortical networks seems also to play a pathogenetic role, mainly via the thalamo-cortical pathway. However, the mechanisms underlying cortical-subcortical circuits dysfunction, as well as their impact on clinical manifestations, are still unknown. Therefore, the main aims of our study were to systematically study with an extensive electrophysiological battery the cortical sensorimotor as well as thalamo-cortical networks in genetically confirmed Familial Adult Myoclonic Epilepsy patients and to establish reliable neurophysiological biomarkers for the diagnosis. In 26 Familial Myoclonic Epilepsy subjects, harbouring the intronic ATTTC repeat expansion in the StAR-related lipid transfer domain-containing 7 gene, 17 Juvenile Myoclonic Epilepsy patients and 22 healthy controls, we evaluated the facilitatory and inhibitory circuits within the primary motor cortex using single and paired-pulse transcranial magnetic stimulation paradigms. We also probed the excitability of the somatosensory as well as the thalamo-somatosensory cortex connection by using ad hoc somatosensory evoked potential protocols. The sensitivity and specificity of transcranial magnetic stimulation and somatosensory evoked potential metrics were derived from receiver operating curve analysis. Familial Adult Myoclonic Epilepsy patients displayed increased facilitation and decreased inhibition within the sensorimotor cortex compared with Juvenile Myoclonic Epilepsy patients (all p< 0.05) and healthy controls (all p< 0.05). Somatosensory evoked potential protocols also displayed a significant reduction of early high-frequency oscillations and less inhibition at paired-pulse protocol, suggesting a concomitant failure of thalamo-somatosensory cortex circuits. Disease onset and duration, and myoclonus severity did not correlate either with sensorimotor hyperexcitability or thalamo-cortical measures (all p> 0.05). Patients with a longer disease duration had a more severe myoclonus (r= 0.467, p= 0.02) associated with a lower frequency (r= -0.607, p= 0.001) and higher power of tremor (r= 0.479, p= 0.02). Finally, Familial Adult Myoclonic Epilepsy was reliably diagnosed using transcranial magnetic stimulation, demonstrating its superiority as a diagnostic factor compared to somatosensory evoked potential measures. In conclusion, sensorimotor cortical and thalamo-cortical circuits are involved in the pathophysiology of Familial Adult Myoclonic Epilepsy even if these alterations are not associated with clinical severity. Transcranial magnetic stimulation-based measurements display an overall higher accuracy than somatosensory evoked potential parameters to reliably distinguish Familial Adult Myoclonic Epilepsy from Juvenile Myoclonic Epilepsy and healthy controls.

Relationship between high-frequency activity in the cortical sensory and the motor hand areas, and their myelin content

“…The results of this study also have important implications for the clinical neurophysiological assessment of cortical dysfunction. For instance, abnormally enlarged high-frequency somatosensory oscillations were shown in patients with movement disorders, such as Parkinson disease and myoclonus epilepsy [79,80], and slowing of high-frequency bursts was observed in myoclonus epilepsy [79] and multiple sclerosis [81], the latter being also affected by the reduction of cortical myelin content [82,83].…”

Effect of whole-hand water flow stimulation on the neural balance between excitation and inhibition in the primary somatosensory cortex

“…The sensorimotor cortex hyperexcitability represents an important pathogenic mechanism underlying several neurological diseases such as familial adult myoclonic epilepsy type 2 (FAME2) ( Dubbioso et al, 2022 ), ALS ( Ranieri et al, 2020 ), dystonia ( Erro et al, 2018 ), fibromyalgia ( Lim et al, 2015 ), and schizophrenia ( Daskalakis et al, 2020 ). These diseases are typically caused by the abnormal neural balance between excitation and inhibition.…”

“…Second, we measured only SEP and PPI to evaluate S1 excitability. To clarify the change in neural balance between excitation and inhibition in the S1 in greater detail, it would be preferable to investigate other biomarkers of inhibitory function such as early and late components of SEP high-frequency oscillation (e- and l-HFO) ( Erro et al, 2018 ; Dubbioso et al, 2022 ; Tomasevic et al, 2022 ), which reflect the activity of thalamocortical fibers directed to areas 3b and 1 within S1 and intracortical inhibition in S1, putatively a result of local GABAergic interneurons. Third, the effects of the present interventions on several somatosensory functions remain unclear.…”

Relationship between high-frequency activity in the cortical sensory and the motor hand areas, and their myelin content

“…The results of this study also have important implications for the clinical neurophysiological assessment of cortical dysfunction. For instance, abnormally enlarged high-frequency somatosensory oscillations were shown in patients with movement disorders, such as Parkinson disease and myoclonus epilepsy [77,78], and slowing of high-frequency bursts was observed in myoclonus epilepsy [77] and multiple sclerosis [79], the latter being also affected by the reduction of cortical myelin content [80,81].…”