Summary: In the article titled, “Abnormal Cortex Plasticity in Juvenile Myoclonic Epilepsy”, the authors investigate the role of defective motor plasticity in the pathogenesis of Juvenile Myoclonic Epilepsy (Strigaro et al.). Prior to this study, JME was linked to motor cortex hyper-excitability and to the abnormal function of thalamic networks. This study, identifies a new mechanism that can cause JME, a common form of generalized epilepsy seen in children. The motor cortex plasticity was studied using an interesting technique called the Paired Associated Stimulation (PAS). The details of this technique are discussed in the methodology section. The role of cortical plasticity in epilepsy has been shown in animal models. It needs to be established in clinical cases. The current study investigates the role of cortical plasticity in human patients.
Background: Transcranial magnetic stimulation is a non-invasive, non-expensive and efficient technique to measure cortical excitability. TMS technique was combined with (PAS) Paired Associated Stimulation. In this, there is a pairing of an electrical stimulation of the median nerve, followed by lateral transcranial magnetic stimulation over the contralateral motor cortex. This technique produces cortical excitability. By altering the pulse and interval between the PAS and TMS, it is possible to enhance or suppress the cortical excitability. A PAS interval of 25 msec has an enhancing effect on cortical excitability. The aim of this study was to test the outcome of PAS 25 in patients with JME (Juvenile myoclonic epilepsy) and in healthy control. If this study is successful in establishing the link between the cortical excitability and JME, the cortical excitability will become an additional biomarker to diagnose and study the progress of the disease. Though the pathology of JME is largely unknown, the scientist has previously observed a change in cortical and subcortical architecture. (Wong)
Transcranial Magnetic Stimulation, is used as a diagnostic and study tool in a number of neurological and psychiatric diseases (Theodore). It is used in epilepsy patients to study cortical excitability and also the effect of anti-epileptic drugs on cortical excitability. The researchers also suggest that in the future, this technique could be developed into a treatment modality for epilepsy. TMS measures motor threshold. This is the minimum threshold of stimuli required to evoke a response in the target muscle. The parameter that is measured is the motor evoked potential (MEP) amplitude. From TMS studies that were conducted by different researchers, it was understood that cortical excitability increases in generalized epilepsy syndrome (Reutens et al.).
Methodology and Result: The study is approved by the ethical committee and consent were obtained from all participants. Thirteen JME patients (with a mean age of 32.8 years) and 13 healthy individuals (with a mean age of 27.9 years) participated in the study. The patients are described below. Eight patients were photosensitive and all the patients were symptom free at the time of the study. All subjects who participated in the study reported of not taking any neuroactive drug (including alcohol or caffeine), 72 hrs. prior to the experiment. All the participants were right handed. The details of TMS, EMG recording and PAS protocol are provided. Patients were on standard epileptic treatment. Motor Evoked Potential (MEP) was recorded from the Abductor Pollicis Brevis muscle. Resting Motor Threshold (RMT) and MEP size were measured. Statistical test, ANOVA was used for the analysis. The main factors in the analysis were the different time period (T10, T15, T30) at which the readings were recorded. The two groups in the analysis are: patients and control. Paired t-test was also used to compare the mean of the values, between groups.
There was no significant difference in RMT and baseline MEP amplitude between the patient and control groups. However, following PAS25 and TMS, the MEP size increased significantly in the control group at T10, T15 and T30, when compared to the patient group. The MEP difference in patients and control are presented in a bar diagram and is easy to follow. The MEP values following, PAS25 stimulation was higher than the baseline value in both groups. The mean ± SE of all data are shown in this study.
My opinion on the study and discussion: After I read the result, I was not able to understand the novelty of the work, except that the scientist has used PAS. I found it difficult to associate the results with the aim of the study. Though the researchers have suggested the novelty of cortical hyperactivity in JME, I have come across papers where cortical hyperactivity has been already reported in generalized epilepsy. The baseline stimulation MEP value, in both control and patients were same. When compared to the other epilepsy patients, in JME, patients did not have a high MEP (i.e. the expected marker of cortical hyper excitability). According to the researchers, PAS is expected to alter synaptic plasticity in the motor cortex, by increasing the efficacy of synaptic transmission of neurons. I could not still understand the role of synaptic plasticity in this disease. If synaptic plasticity was the most important aim of the study, the researchers could have explained it well and its role in JME. The most consistent finding in the study was the inhibition of short interval cortical inhibition seen in patients with JME. The patients had abnormal motor cortex excitability. On PAS 25 stimulation, patients demonstrated a disrupted motor cortex excitability. The authors of the paper suggest that an abnormal form of plasticity is responsible for this type of motor cortex excitability. The abnormal plasticity could cause an imbalance in the excitatory and inhibitory circuit, that underlies the pathophysiology of diseases like JME. Though, the initial hypothesis was that JME patients has altered cortical excitability, the PAS & TMS studies show increase in excitability in the healthy population, when compared to the control. There was no significant increase or decrease in the MES value of patients. Additional experiments may be essential to prove the role of plasticity in this process. Though the authors suggest that a drug that reduces plasticity could be effective in treating the diseases; the initial hypothesis is not on plasticity and it would be too premature to make any kind of statement about plasticity, based on the present results. Motor cortex is an element of fronto-thalamic network.
I find it difficult to agree with their research question and the methodology used to prove it. The discussion section does not emphasize the importance of the insight that can be drawn from the result. Instead, the discussion was largely based on the work of another scientist in the field. The significance of this study and its contribution to existing knowledge is not well understood. I am not convinced about the involvement of cortical excitability in this study.
JME has a distinct pathology from other generalized form of epilepsy. Unlike in other diseases, in this particular disease, the frontal regions of the brain play a dominant role in pathogens. Its clinical manifestation is also distinct from another form of seizures. It is difficult to diagnose this disease through neuroimaging as it is almost normal. Electroencephalographic (EEG) abnormalities are used for clinical diagnosis. (Carroll, Cavazos and Talavera)
It would be suitable, if the authors have explained the perspective of their findings in treating or diagnosing JME. The conclusion presented in this study was as follows: “the present data provides evidence for defective LTP like plasticity in a cohort of patients with JME, which may be primarily involved in the pathogenesis of myoclonus in this frequent form of epilepsy” (Strigaro et al.). This conclusion of the paper is highly arbitrary and I don’t agree that the data supports this.
Work cited
Carroll, Elizabeth, Jose Cavazos, and Francisco Talavera. "Juvenile Myoclonic Epilepsy Workup: Approach Considerations, Electroencephalography, Magnetic Resonance Imaging". Emedicine.medscape.com. N.P., 2016. Web. 31 Mar. 2016.
Reutens, David C. et al. "Magnetic Stimulation of the Brain In Generalized Epilepsy: Reversal Of Cortical Hyper-excitability By Anticonvulsants". Annals of Neurology 34.3 (1993): 351-355. Web.
Strigaro, Gionata et al. "Abnormal Motor Cortex Plasticity in Juvenile Myoclonic Epilepsy". Seizure 30 (2015): 101-105. Web. 31 Mar. 2016.
Theodore, William H. "Transcranial Magnetic Stimulation in Epilepsy". Epilepsy Currents 3.6 (2003): 191-197. Web. 31 Mar. 2016.
Wong, Michael. "Juvenile Myoclonic Epilepsy: Is It an Idiopathic Epilepsy Caused by A Malformation Of Cortical Development?". Epilepsy Currents 10.3 (2010): 69-71. Web. 30 Mar. 2016.
