Current Literature In Clinical Science
Connecting the Dots? Linking Anatomy, Connectivity, and Physiology in Epilepsy
Physiological Consequences of Abnormal Connectivity in a Developmental Epilepsy. Shafi MM, Marin Vernet, Klooster D, Chu CJ, Boric K, Barnard ME, Romatoski K, Westover MB, Christodoulou JA, Gabrieli JDE, Whitfield-Gabrieli S, Pascual-Leone A, Chang BS. Ann Neurol 2015;77(3):487–503.
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.
Commentary Although epilepsy has been recognized for thousands of years, there are still large gaps in our understanding of the pathophysiology of how seizures start and stop. The concept of epilepsy as a network disease and the importance of connections between brain regions in seizures has been the dominant theory in the 21st century. Intracranial EEG, PET, and SPECT data were initially utilized to describe three networks important in human epilepsy: the medial temporal-limbic network, the medial occipital-lateral temporal network, and the superior parietal-medial frontal network (1). The combination of imaging advances in structural MRI, fMRI, and MEG along with improved methods for analyzing connectivity mathematically have allowed for less-invasive exploration of networks within the human brain in both physiologic and pathologic states. These advances have facilitated advances in the field of connectomics, which in turn holds promise for building on our understanding of epilepsy and seizures (2).
Epilepsy Currents, Vol. 16, No. 1 (January/February) 2016 pp. 14–15 © American Epilepsy Society
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The authors of this study have chosen to explore connectivity and cortical hyperexcitability in patients with periventricular nodular heterotopia (PNH). Seizures arising in young adulthood, normal intelligence, and reading dysfluency are the typical clinical characteristics of patients with PNH (3). Ictal onsets, detected with intracranial EEG, have been demonstrated in both the heterotopia as well as in the overlying cortex and the hippocampus (4, 5). In an earlier study from the same research group, structural connectivity using diffusion tensor tractography and functional connectivity using blood oxygen level–dependent (BOLD) fMRI were assessed in 11 patients (6). In all but one patient, at least one of the manually identified heterotopic regions was connected by a tract to overlying cortex (69% of the 45 identified heterotopias were structurally connected to overlying cortex). Less frequent connections to ipsilateral cortex and homologous and nonhomologous contralateral cortex as well as subcortical structures and other heterotopias were also noted. Functional connectivity to discrete regions of overlying cortex, assessed by resting-state correlations between the heterotopia and other voxels, was seen for all patients and in 96% of the heterotopias that were identified. Functional correlations were also seen for other ipsilateral and contralateral brain regions. In addition, the authors noted that a quantification of the degree of correlation
Connecting the Dots?
(the high peak correlation coefficient) correlated with a longer duration of epilepsy. These data support the hypothesis that the structural and functional connections identified here may play a role in epileptogenesis. Utilizing eight subjects from that group of patients with PNH, the authors performed a separate study to explore the role of these regions of PNH in a reading task using fMRI (7). Across 7 primary task contrast conditions, 6 (75%) subjects showed BOLD activation in at least 1 region of periventricular gray-matter region; for all 42 instances assessed, 14 (33%) elicited activation of periventricular gray matter; and in all instances, this was associated with co-activation of discrete regions of cortex. Resting-state connectivity to these regions of task-induced BOLD activations was seen for 79% of subjects. These data provide further support for the integration of these heterotopic gray-matter regions into functional networks. In the present study, the authors aim to demonstrate, by using single-pulse transcranial magnetic stimulation (TMS) in eight subjects, that the connectivity to these subcortical heterotopias is associated with hyperexcitability. The authors delivered stimulation to a cortical target site that was connected (based upon BOLD signal analysis) to a region of PNH as well as to a region in the same hemisphere that lacked this functional connectivity to the PNH. These stimulations were also compared with responses in age-, sex-, and handednessmatched controls. Evidence for increased late responses (based upon the group mean field potential, which is the method of quantifying the brain response to TMS) following TMS was seen in cortical regions with functional connectivity to the PNH. These findings support the hypothesis that connectivity between cortex and subcortical heterotopias can lead to alterations in physiology; these alterations provide a plausible model for epileptogenesis in patients with PNH. Although PNHs represent a minority of cases with treatment-resistant epilepsy, this population provided a unique opportunity to correlate structural abnormalities on MRI with connectivity for both resting-state and task-based
fMRI responses and then assess the physiologic responses to TMS in aberrantly connected cortex (i.e., cortex connected to heterotopias). As the ability to assess structural and functional connections in the human brain increases through both diffusion tensor imaging and fMRI, linking these findings to physiology and pathophysiology becomes an important next step. The multimodal approach utilized here provides an enticing look at a potential way to identify abnormal connections that may generate seizures. Whether these methods will allow us to connect the dots between anatomy, connectivity, and physiology in other lesional and nonlesional forms of epilepsy remains to be seen. by Chad Carlson, MD References 1. Spencer SS. Neural networks in human epilepsy: Evidence of and implications for treatment. Epilepsia 2002;43:219–227. 2. Richardson MP. Large scale brain models of epilepsy: Dynamics meets connectomics. J Neurol, Neurosurg, Psych 2012;83:1238–1248. 3. Battaglia G, Chiapparini L, Franceschetti S, Freri E, Tassi L, Bassanini S, Villani F, Spreafico R, D’Incerti L, Granata T. Periventricular nodular heterotopia: Classification, epileptic history, and genesis of epileptic discharges. Epilepsia 2006;47:86–97. 4. Kothare SV, VanLandingham K, Armon C, Luther JS, Friedman A, Radtke RA. Seizure onset from periventricular nodular heterotopias: Depth-electrode study. Neurology 1998;51:1723–1727. 5. Tassi L, Colombo N, Cossu M, Mai R, Francione S, Lo Russo G, Galli C, Bramerio M, Battaglia G, Garbelli R, Meroni A, Spreafico R. Electroclinical, MRI and neuropathological study of 10 patients with nodular heterotopia, with surgical outcomes. Brain 2005;128(pt 2):321–337. 6. Christodoulou JA, Walker LM, Del Tufo SN, Katzir T, Gabrieli JD, Whitfield-Gabrieli S, Chang BS. Abnormal structural and functional brain connectivity in gray matter heterotopia. Epilepsia 2012;53:1024–1032. 7. Christodoulou JA, Barnard ME, Del Tufo SN, Katzir T, Whitfield-Gabrieli S, Gabrieli JD, Chang BS. Integration of gray matter nodules into functional cortical circuits in periventricular heterotopia. Epilepsy Behav 2013;29:400–406.
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Connecting the Dots? Linking Anatomy, Connectivity, and Physiology in Epilepsy
Physiological Consequences of Abnormal Connectivity in a Developmental Epilepsy. Shafi MM, Marin Vernet, Klooster D, Chu CJ, Boric K, Barnard ME, Romatoski K, Westover MB, Christodoulou JA, Gabrieli JDE, Whitfield-Gabrieli S, Pascual-Leone A, Chang BS. Ann Neurol 2015;77(3):487–503.
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.
Commentary Although epilepsy has been recognized for thousands of years, there are still large gaps in our understanding of the pathophysiology of how seizures start and stop. The concept of epilepsy as a network disease and the importance of connections between brain regions in seizures has been the dominant theory in the 21st century. Intracranial EEG, PET, and SPECT data were initially utilized to describe three networks important in human epilepsy: the medial temporal-limbic network, the medial occipital-lateral temporal network, and the superior parietal-medial frontal network (1). The combination of imaging advances in structural MRI, fMRI, and MEG along with improved methods for analyzing connectivity mathematically have allowed for less-invasive exploration of networks within the human brain in both physiologic and pathologic states. These advances have facilitated advances in the field of connectomics, which in turn holds promise for building on our understanding of epilepsy and seizures (2).
Epilepsy Currents, Vol. 16, No. 1 (January/February) 2016 pp. 14–15 © American Epilepsy Society
14
The authors of this study have chosen to explore connectivity and cortical hyperexcitability in patients with periventricular nodular heterotopia (PNH). Seizures arising in young adulthood, normal intelligence, and reading dysfluency are the typical clinical characteristics of patients with PNH (3). Ictal onsets, detected with intracranial EEG, have been demonstrated in both the heterotopia as well as in the overlying cortex and the hippocampus (4, 5). In an earlier study from the same research group, structural connectivity using diffusion tensor tractography and functional connectivity using blood oxygen level–dependent (BOLD) fMRI were assessed in 11 patients (6). In all but one patient, at least one of the manually identified heterotopic regions was connected by a tract to overlying cortex (69% of the 45 identified heterotopias were structurally connected to overlying cortex). Less frequent connections to ipsilateral cortex and homologous and nonhomologous contralateral cortex as well as subcortical structures and other heterotopias were also noted. Functional connectivity to discrete regions of overlying cortex, assessed by resting-state correlations between the heterotopia and other voxels, was seen for all patients and in 96% of the heterotopias that were identified. Functional correlations were also seen for other ipsilateral and contralateral brain regions. In addition, the authors noted that a quantification of the degree of correlation
Connecting the Dots?
(the high peak correlation coefficient) correlated with a longer duration of epilepsy. These data support the hypothesis that the structural and functional connections identified here may play a role in epileptogenesis. Utilizing eight subjects from that group of patients with PNH, the authors performed a separate study to explore the role of these regions of PNH in a reading task using fMRI (7). Across 7 primary task contrast conditions, 6 (75%) subjects showed BOLD activation in at least 1 region of periventricular gray-matter region; for all 42 instances assessed, 14 (33%) elicited activation of periventricular gray matter; and in all instances, this was associated with co-activation of discrete regions of cortex. Resting-state connectivity to these regions of task-induced BOLD activations was seen for 79% of subjects. These data provide further support for the integration of these heterotopic gray-matter regions into functional networks. In the present study, the authors aim to demonstrate, by using single-pulse transcranial magnetic stimulation (TMS) in eight subjects, that the connectivity to these subcortical heterotopias is associated with hyperexcitability. The authors delivered stimulation to a cortical target site that was connected (based upon BOLD signal analysis) to a region of PNH as well as to a region in the same hemisphere that lacked this functional connectivity to the PNH. These stimulations were also compared with responses in age-, sex-, and handednessmatched controls. Evidence for increased late responses (based upon the group mean field potential, which is the method of quantifying the brain response to TMS) following TMS was seen in cortical regions with functional connectivity to the PNH. These findings support the hypothesis that connectivity between cortex and subcortical heterotopias can lead to alterations in physiology; these alterations provide a plausible model for epileptogenesis in patients with PNH. Although PNHs represent a minority of cases with treatment-resistant epilepsy, this population provided a unique opportunity to correlate structural abnormalities on MRI with connectivity for both resting-state and task-based
fMRI responses and then assess the physiologic responses to TMS in aberrantly connected cortex (i.e., cortex connected to heterotopias). As the ability to assess structural and functional connections in the human brain increases through both diffusion tensor imaging and fMRI, linking these findings to physiology and pathophysiology becomes an important next step. The multimodal approach utilized here provides an enticing look at a potential way to identify abnormal connections that may generate seizures. Whether these methods will allow us to connect the dots between anatomy, connectivity, and physiology in other lesional and nonlesional forms of epilepsy remains to be seen. by Chad Carlson, MD References 1. Spencer SS. Neural networks in human epilepsy: Evidence of and implications for treatment. Epilepsia 2002;43:219–227. 2. Richardson MP. Large scale brain models of epilepsy: Dynamics meets connectomics. J Neurol, Neurosurg, Psych 2012;83:1238–1248. 3. Battaglia G, Chiapparini L, Franceschetti S, Freri E, Tassi L, Bassanini S, Villani F, Spreafico R, D’Incerti L, Granata T. Periventricular nodular heterotopia: Classification, epileptic history, and genesis of epileptic discharges. Epilepsia 2006;47:86–97. 4. Kothare SV, VanLandingham K, Armon C, Luther JS, Friedman A, Radtke RA. Seizure onset from periventricular nodular heterotopias: Depth-electrode study. Neurology 1998;51:1723–1727. 5. Tassi L, Colombo N, Cossu M, Mai R, Francione S, Lo Russo G, Galli C, Bramerio M, Battaglia G, Garbelli R, Meroni A, Spreafico R. Electroclinical, MRI and neuropathological study of 10 patients with nodular heterotopia, with surgical outcomes. Brain 2005;128(pt 2):321–337. 6. Christodoulou JA, Walker LM, Del Tufo SN, Katzir T, Gabrieli JD, Whitfield-Gabrieli S, Chang BS. Abnormal structural and functional brain connectivity in gray matter heterotopia. Epilepsia 2012;53:1024–1032. 7. Christodoulou JA, Barnard ME, Del Tufo SN, Katzir T, Whitfield-Gabrieli S, Gabrieli JD, Chang BS. Integration of gray matter nodules into functional cortical circuits in periventricular heterotopia. Epilepsy Behav 2013;29:400–406.
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