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Physiological consequences of abnormal connectivity in a developmental epilepsy - PubMed

Physiological consequences of abnormal connectivity in a developmental epilepsy

Mouhsin M Shafi et al. Ann Neurol. 2015 Mar.

Abstract

Objective: Many forms of epilepsy are associated with aberrant neuronal connections, but the relationship between such pathological connectivity and the underlying physiological predisposition to seizures is unclear. We sought to characterize the cortical excitability profile of a developmental form of epilepsy known to have structural and functional connectivity abnormalities.

Methods: We employed transcranial magnetic stimulation (TMS) with simultaneous electroencephalographic (EEG) recording in 8 patients with epilepsy from periventricular nodular heterotopia and matched healthy controls. We used connectivity imaging findings to guide TMS targeting and compared the evoked responses to single-pulse stimulation from different cortical regions.

Results: Heterotopia patients with active epilepsy demonstrated a relatively augmented late cortical response that was greater than that of matched controls. This abnormality was specific to cortical regions with connectivity to subcortical heterotopic gray matter. Topographic mapping of the late response differences showed distributed cortical networks that were not limited to the stimulation site, and source analysis in 1 subject revealed that the generator of abnormal TMS-evoked activity overlapped with the spike and seizure onset zone.

Interpretation: Our findings indicate that patients with epilepsy from gray matter heterotopia have altered cortical physiology consistent with hyperexcitability, and that this abnormality is specifically linked to the presence of aberrant connectivity. These results support the idea that TMS-EEG could be a useful biomarker in epilepsy in gray matter heterotopia, expand our understanding of circuit mechanisms of epileptogenesis, and have potential implications for therapeutic neuromodulation in similar epileptic conditions associated with deep lesions.

© 2015 American Neurological Association.

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Figures

Figure 1
Figure 1. Anatomy and functional connectivity in patients with PNH

T1-weighted MR brain images show unilateral posterior gray matter heterotopia along the wall of the lateral ventricle in one patient, subject 3 in Table 1 (sagittal image in A), and diffuse bilateral periventricular heterotopic nodules in another patient, subject 7 (axial image in B), as indicated by red arrows. BOLD images acquired in these patients reveal discrete regions of cerebral cortex that demonstrate aberrant functional connectivity with the heterotopic gray matter during the task-free resting state (green areas show significant functional activation in C and D); these regions were then chosen as cortical targets for TMS in our experimental design.

Figure 2
Figure 2. Connectivity-derived targets for cortical stimulation in patients with PNH

Cortical regions that demonstrate significant resting-state functional connectivity to periventricular gray matter nodules in eight patients with heterotopia, labeled according to subject number as listed in Table 1 and shown on surface brain MR renderings, were identified. Connected targets (red) for neuronavigation-guided TMS were then placed within these regions in each case. Non-connected cortical targets (blue), in regions without such connectivity, were also identified within the same hemisphere for each subject. Each control subject had neuronavigation-guided TMS of the same targets as his or her matched heterotopia subject.

Figure 3
Figure 3. Augmented late TMS-evoked cortical responses in patients with PNH and active epilepsy

A. The TMS-evoked response produced by stimulation of the connected target site in subject 2. Note the relatively large evoked potential at 289 ms as compared to earlier potentials. B. The GMFP between 100 and 700 ms after stimulation of the connected target in a PNH patient, subject 2 (solid black line), and his matched control (dashed red line). The pink region corresponds to the first time period (100 – 225 ms after the pulse), the blue to the second (225- 400 ms), and the yellow to the third (400 – 700 ms). C. The TMS-evoked response produced by stimulation of the same site (as in Panel A) in the matched control for subject 2. Note that the potential at 167 ms is substantially larger than later potentials. D. The ratio of the normalized AUC-GMFP after stimulation of the connected target for each of the 5 PNH subjects with active epilepsy to the equivalent measure in their matched healthy controls, during the 225-400 ms and 400-700 ms time periods. A ratio greater than 1 indicates an augmented late cortical response in the epilepsy patient (E) as compared to the healthy control (HC). E. The mean GMFP over time, across subjects, evoked by stimulation of the connected target site for the 5 PNH subjects with active epilepsy (thick black line) and their matched controls (thick dashed red line). The gray and red bands indicate +/− standard error of the mean. F. The normalized AUC-GMFP averaged across all PNH subjects with active epilepsy and their matched healthy controls during the same two time periods as in Panel D. Asterisks indicate significant differences (Bonferroni corrected p < 0.05). Note that the raw evoked potentials in A and C are not plotted on a uniform scale.

Figure 4
Figure 4. Persistent TMS-evoked activity in a patient with PNH and active epilepsy, but with a normal interictal EEG

A. The TMS-evoked response produced by stimulation of the connected target site in subject 1. B. The TMS-evoked response produced by stimulation of the same site in the matched healthy control subject. The later peaks (>225 ms) in the PNH subject are of the same size as or larger than earlier peaks, whereas the later peaks are smaller than the earlier peaks in the matched healthy control subject. Notably, subject 1 had entirely normal interictal findings on prolonged continuous EEG monitoring. Note that the evoked potentials are not plotted on a uniform scale.

Figure 5
Figure 5. Augmented late TMS-evoked cortical responses specific to stimulation of cortical regions with aberrant functional connectivity

A. The mean GMFP over time, across all PNH subjects, evoked by stimulation of the connected target site (thick black line) and the non-connected target site (thick blue line). The gray and blue bands indicate +/− standard error of the mean. B. The ratio of the normalized AUC-GMFP after stimulation of the connected target to the equivalent measure after stimulation of the non-connected target in each of the PNH subjects, during the 225-400 ms and 400-700 ms time periods. A ratio greater than 1 indicates an augmented late cortical response after stimulation of the connected target (CT) as compared to the non-connected target (NCT). C. The mean GMFP over time, across all healthy control subjects, evoked by stimulation of the connected target site (thick dashed red line) and the non-connected target site (thick dashed purple line). The red and purple bands indicate +/− standard error of the mean. D. The normalized AUC-GMFP averaged across all connected and non-connected targets in the PNH subjects for the same two time periods as in Panel B. Asterisks indicate significant differences (Bonferroni corrected p < 0.05).

Figure 6
Figure 6. Topography of differences in TMS-evoked activity between patients with PNH and active epilepsy and matched healthy controls

The plots show the differences between PNH patients with active epilepsy (subjects 1 through 5) and their matched healthy controls in the log-transformed normalized RMSV at each electrode evoked by stimulation of the connected target. Warm colors indicate regions where the evoked activity was greater in the patient; cool colors indicate that the evoked activity was greater in the control. Asterisks indicate the site of stimulation (the connected target site). The left side of each image represents the left side of the brain.

Figure 7
Figure 7. Source analysis results of TMS-evoked activity, interictal epileptiform activity, and ictal onset activity

In subject 2, the only PNH patient in this study with an identifiable epileptogenic zone on scalp EEG, electrical source imaging was performed on the two late TMS-EEG peaks seen after stimulation of the connected target (A,B), two prominent interictal epileptiform discharges seen on conventional scalp EEG recording (C,E), and the ictal onsets of the two recorded seizures available on scalp EEG (D,F). Warm colors represent positive maxima, while cool colors represent negative maxima. In all instances, results converge on an area of the right frontal lobe that was not the site of stimulation, but overlapped with a cortical region that demonstrated functional connectivity to an underlying heterotopic nodule.

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