Defective interhemispheric inhibition in drug-treated focal epilepsies
Introduction
Epilepsy is a common neurological disorder characterized by an enduring predisposition to generate epileptic seizures [1]. Its pathophysiology is complex and largely related to hyperexcitable neural networks resulting from the imbalance between excitatory and inhibitory circuits [2]. The classical dichotomy in focal (FE) and generalized epilepsy (GE) reflects the origin of the epileptic discharge, whether it arises in a lateralized network or it rapidly involves bilateral structures.
Abnormalities in both excitatory and inhibitory neural circuits not only affect the seizure focus, but may also involve distant areas such as the primary motor cortex (M1) [3], [4], [5]. White-matter bundles connecting distant cortical areas are the likely anatomical substrate of seizure propagation [6]. Of these, the corpus callosum represents the largest commissure connecting the two hemispheres [7]. Its major role in seizure propagation is suggested by the efficacy of the palliative corpus callosotomy procedure in severe drug-resistant epilepsies [8]. Previous neuroimaging and anatomical studies have explored the role of corpus callosum in interhemispheric propagation [9], [10]. However, its physiological role in FE and GE is still a matter of debate [6], [11]. Changes in cortical excitability in the hemisphere ipsilateral and contralateral to the seizure focus (i.e. “focal” and “non-focal” hemisphere respectively) may well be a background factor for the propagation of the epileptic discharge, and may distinguish FE from GE [12]. A second factor may be an exaggerated interhemispheric transmission/defective inhibition through the corpus callosum. Interhemispheric inhibition (IHI) by means of paired pulse transcranial magnetic stimulation (TMS) was first described by Ferbert et al. [13]. This paradigm employs a standard single TMS stimulus over the hand area of M1 that evokes a test motor evoked potential (MEP) in a muscle of interest. This stimulus can be preceded at different intervals by a conditioning stimulus (CS) over the hand area of the opposite hemisphere [14]. The CS changes the amplitude of the test MEP at critical intervals with an “inter-hemispheric” inhibition with a latency of 6–50 ms [13], [15], [16], [17]. IHI is mediated by transcallosal fibers since the effects were absent in patients with no corpus callosum [18]. This method was subsequently validated by several studies in the normal subject [17], [19], [20] and patients with different neurological abnormalities [11], [21], [22], [23], [24], including one describing the changes between the M1s following the removal of the epileptic focus in FE [11].
The present study was designed to examine the excitability of bilateral M1-to-M1 interhemispheric connections in patients with FE and genetic GE (GGE) compared to healthy subjects (HS). In principle, we hypothesized that IHI would be defective in FE patients, particularly that the “focal” hemisphere would respond excessively to inputs from the “non-focal hemisphere”.
Section snippets
Materials and methods
All neurophysiologic studies took place between 2:00 and 6.30 p.m. in a quiet room, at a standard temperature of 22 °C.
Results
Table 2 shows the demographic features, baseline physiological measures and p values. Briefly, all the participants were in their adulthood and the groups were similar for age and sex with no statistical differences (p > 0.05). Patients with GGE and FE showed a significantly higher baseline rMT compared to controls, for both the left (F (2,47) = 4.707, p = 0.014) and the right hemisphere (F (2,47) = 4.701, p = 0.014). When considering interhemispheric differences, significantly higher rMT in
Discussion
To our knowledge, this is the first TMS study evaluating IHI in patients with drug-treated focal and generalized epilepsy. We found that patients with FE had a bilateral defective IHI at short and long ISIs (i.e. 10 and 50 ms), whilst IHI in patients with GGE was similar to healthy individuals. We selected these two intervals (i.e. 10 and 50 ms) from a wide range of ISIs (6–50 ms) [13], [15] because they showed the maximum inhibitory effects in previous studies [29]. IHI is deficient in
Conclusions
A disrupted transcallosal inhibition between the focal and the non-focal hemisphere, as studied by TMS, may contribute to the pathogenesis of FEs. Particularly, this may represent one key factor for the contralateral spread of the epileptic discharge and seizure generalization.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest
None of the authors has any conflict of interest to disclose.
Acknowledgements
None.
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