- Email: [email protected]
Probing circuit of Papez with stimulation of anterior nucleus of the thalamus and hippocampal evoked potentials
Epilepsy Research 159 (2020) 106248
Contents lists available at ScienceDirect
Epilepsy Research journal homepage: www.elsevier.com/locate/epilepsyres
Probing circuit of Papez with stimulation of anterior nucleus of the thalamus and hippocampal evoked potentials
T
Yu-Chi Wanga,b, Vaclav Kremena,e,h, Benjamin H. Brinkmanna,e, Erik H. Middlebrooksc,d, Brian N. Lundstroma,e, Sanjeet S. Grewald, Hari Guragaina,e, Min-Hsien Wug, Jamie J. Van Gompelf, Bryan T. Klassena,e, Matt Steada,e,*, Gregory A. Worrella,e,* a
Mayo Systems Electrophysiology Laboratory, Mayo Clinic, Rochester, Minnesota, USA Department of Neurosurgery, Chang Gung Memorial Hospital in Linkou, PhD. Program of Biomedical Engineering, Chang Gung University, Taiwan c Department of Radiology, Mayo Clinic, Jacksonville, Florida, USA d Department of Neurosurgery, Mayo Clinic, Jacksonville, Florida, USA e Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA f Department of Neurosurgery, Mayo Clinic, Rochester, Minnesota, USA g Graduate Institute of Biomedical Engineering, Chang Gung University, Taiwan h Czech Institute of Informatics, Robotics, and Cybernetics, Czech Technical University in Prague, Prague, Czech Republic b
A R T I C LE I N FO
A B S T R A C T
Keywords: Epilepsy Deep brain stimulation Anterior nucleus of thalamus Evoked potentials Mesial temporal sclerosis
Purpose: Despite documented clinical effectiveness, deep brain stimulation (DBS) therapy for drug-resistant epilepsy rarely yields long-term seizure free outcomes. Methods: This pilot study in five patients investigated circuit of Papez evoked potentials (EPs) using hippocampal sensing during anterior nucleus of the thalamus (ANT) electrical stimulation. We hypothesize that hippocampal EP is a potential biomarker that could be useful for ANT electrode targeting and improving seizure reduction. We obtained bilateral circuit of Papez EPs in five patients with bilateral temporal lobe epilepsy (TLE). The circuit of Papez EPs were measured and assessed by signal amplitude. Volumetric analysis of relevant mesial temporal structures and ANT stimulation analysis was performed on immediate post-implantation images. Results: The patient with the most favorable seizure outcome, which meant long-term seizure reduction greater than 50 % compared to baseline, had strong bilateral EPs and normal hippocampal structure. Conversely, those without clinical benefit with ANT DBS had absent or weak bilateral EPs as well as MRI findings consistent with mesial temporal sclerosis (MTS). Conclusion: The data support the hypothesis that hippocampal EPs with ANT stimulation may be used to as a surrogate marker to probe circuit of Papez and predict ANT DBS efficacy.
1. Introduction When resective surgery for drug-resistant epilepsy is contraindicated or ineffective, ANT DBS has emerged as an important treatment option.(Li and Cook, 2018) Previous experimental studies showing by electrophysiology have provided support that ANT DBS in animal models of TLE reduces hippocampal excitability and causes anticonvulsant effect.(Gibson et al., 2016; Hunter and Jasper, 1949; Mirski et al., 1997) Circuit of Papez is one of the most well-studied networks for seizure generation and propagation in TLE.(Oikawa et al., 2001) Multiple points for electrical stimulation along this pathway—including the hippocampi and ANT—have demonstrated effective modulation of seizure propagation and decreased the ⁎
frequency of refractory seizures.(Bondallaz et al., 2013; Fisher et al., 2010; van Rijckevorsel et al., 2005) In this study, we investigated hippocampal EPs resulting from ANT DBS in five patients with bilateral medial TLE. We utilized an investigational device for sensing and stimulation (PC + S, Medtronic Inc.) using bilateral ANT and hippocampal electrodes. We hypothesize that hippocampal EP is a biomarker indicating intact Papez circuitry, and perhaps response would correlate with improved seizure outcomes.
Corresponding authors at: Department of Neurology, Mayo Systems Electrophysiology Laboratory, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA. E-mail addresses: [email protected] (M. Stead), [email protected] (G.A. Worrell).
https://doi.org/10.1016/j.eplepsyres.2019.106248 Received 18 October 2019; Received in revised form 21 November 2019; Accepted 28 November 2019 Available online 29 November 2019 0920-1211/ © 2019 Published by Elsevier B.V.
Epilepsy Research 159 (2020) 106248
Y.-C. Wang, et al.
Table 1 Patients Demographics and Clinical Summary. Patient
Age at Surgery (Years)
Gender
Seizure Duration (Years)
Focal Seizure Type
Mesial Temporal Structure Zop (p value) Hippocampus
Amygdala Left: 1.15 (.126) Right: 1.37 (.087) Left: 1.55 (.062) Right: 1.23 (.110) Left: 1.18 (.121) *Right: 2.32 (.010) Left: 1.35 (.089) *Right: 1.95 (.026) Left: -1.51 (0.066) Right: 0.57 (0.284)
1
25
Male
10
With and without impaired awareness
Left: 0.3 (.382) Right: 0.0 (.499)
2
32
Female
30
With impaired awareness
*Left: -1.75 (.040) Right: -1.32 (.094)
3
33
Female
21
Without impaired awareness
*Left: -3.33 (< .0001) Right: -0.74 (.229)
4
39
Male
30
With impaired awareness
Left: -0.02 (.492) Right: -0.02 (.494)
5
32
Female
8
With impaired awareness
*Left: -3.57 (< .0001) *Right: -2.81 (.003)
Follow Up (Months)
Long-term Response to DBS#
52
No
52
Yes
41
No
42
No
35
No
DBS, Deep brain stimulation. Zop, Effect size for discrepancy between patient’s observed and normative volume. # Seizure reduction > 50% preoperative baseline frequency. *p < 0.05.
2. Materials and methods
atrophy. Volumes of bilateral hippocampi and amygdala were calculated using an automated atlas-based segmentation algorithm (Free Surfer 6.0). A volumetric comparison between measured volumes with volumes obtained from a cohort of age- and gender-matched healthy individual (Potvin et al., 2016) in the hippocampus and amygdala was performed.
2.1. Patient selection The study was carried out under a Food and Drug Administration Investigational Device Exemption (FDA IDE #G130166; ClinicalTrials.gov NCT02235792) and approved by the Mayo Clinic Institutional Review Board. Patients were prospectively recruited after multidisciplinary epilepsy surgery evaluation and conference presentation. The inclusion criteria were drug-resistant epilepsy (defined as refractory to trials of at least two appropriately chosen anti-seizure medications), not suitable candidates for surgical resection, and bilateral medial TLE. All patients consented to the DBS protocol using bilateral ANT and bilateral medial temporal lobe electrodes and the Medtronic Activa PC + S investigational device(Stanslaski et al., 2012) for treatment of epilepsy.
2.4. Evoked potentials (EPs) and stimulation program Hippocampal EPs were evaluated during continuous stimulation of ANT using 2 Hz stimulation frequency, amplitude 4 V, pulse width 90 μs, and 30 s duration. Hippocampal sensing (sampling rate 422 or 800 Hz) used the most distal to most proximal electrode contacts. In total 60 trials of EPs were averaged and classified with amplitude as absent (EP < 10 μV), weak (10 μV < EP < 20 μV), or strong (EP > 20 μV). All patients initially received ANT stimulation, while adjuvant hippocampal stimulation (AHS) was later trialed in patients without significant reduction in seizures. Chronic continuous 2 Hz ANT stimulation was initially used for all patients and parameters were adjusted in order to achieve better seizure control as necessary. Patients could be transitioned to the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTE) trial protocol (5 V, 90 μs pulses, 145 Hz with 1 min on and 5 min off) (Fisher et al., 2010) if clinically there was no improvement. Patients with ≥50% seizure reduction compared to baseline were considered responders to DBS treatment.
2.2. Surgical approach and implantation The details of our implantation have been previously described.(Van Gompel et al., 2015; Wang et al., 2019) In brief, stereotactic magnetic resonance images (MRI) were performed after Leksell (Elekta) frame fixation. Medtronic 3389 electrodes were then implanted in the ANT, which was targeted indirectly. Medtronic 3391 electrodes were implanted into the hippocampus through a direct targeting method. After confirmation of the electrode location with intraoperative post-placement computed tomography (CT), the leads were connected to extensions and tunneled to a multifunctional stimulator and recording pulse generator unit battery in the standard infraclavicular pocket.
3. Results Two male and three female adult patients were implanted with ANT and hippocampal leads, bilaterally, connected to the PC + S device. The patients’ clinical summary is shown in Table 1. All patients had seizure reduction after DBS compared to their preoperative baseline. Patient 2 had the most favorable outcome after DBS and was defined as a responder. The remaining four patients failed to have a ≥50% seizure reduction long-term (> 1 year) and were classified as non-responders.
2.3. Analysis of image and volume of tissue activated (VTA) The details of our targeting analysis and VTA have been previously described.(Middlebrooks et al., 2018; Wang et al., 2019) Briefly, the postoperative CT and pre-operative MRI were co-registered. Comparison of contact position relative to the ANT was performed, and VTA was generated with each patient’s recorded DBS stimulator settings. The VTA intersection with ANT was counted as ANT stimulation volume. The evidence for mesial temporal sclerosis (MTS) was characterized by increased FLAIR signal intensity and significant hippocampal
3.1. Image analysis and ANT stimulation volume Patients 3 and 5 had MRI evidence for bilateral MTS. Relative zscores for each subject’s observed versus normative volumes are shown in Table 1. 2
Epilepsy Research 159 (2020) 106248
Y.-C. Wang, et al.
hippocampus, as a mechanism of action of ANT DBS in the treatment of epilepsy.(Middlebrooks et al., 2018) Analysis of VTA indicated that all 5 patients had ANT stimulated, whereas possibly due to small sample size, the EP was not statistically correlated to ANT stimulation volume. Impairment of the circuit of Papez, either structural or functional, may not allow generation of evoked hippocampal potentials, which we suspect is the reason for unilateral weak EP of patient 4. Clear unilateral ANT electrode contact and larger right side stimulation volume in patients 1 and 3 may have contributed to different EP results. In patient 1, the strong EPs were detected in the ipsilateral hippocampus on the side with the ANT contact, while the contralateral side showed no EPs. In patient 3, no EPs were detected on either side of the sclerotic hippocampus, despite the right side definitely stimulated ANT. Lastly, no EPs were found in either hippocampus of patient 5 who had evidence for bilateral MTS and smaller ANT stimulation volumes. Based on these findings, we hypothesize that whether electrode contacts were clearly within ANT can have influence on EPs, and MTS could explain the complete absence of hippocampal EPs. Due to the severe neuronal reduction that accompanies MTS, the pathway is disrupted and the ability to excite hippocampal neurons may be reduced. Successful production of EPs requires that the neuronal network in the circuit of Papez be adequately functional to achieve a satisfactory response to stimulation. Notably, the net accuracy of co-registration of pre-operative MRI and post-implant CT procedure may be influenced by pneumocephalus or other intraoperative changes. The accuracy of DBS targeting ANT could theoretically be improved through a combination of a recently described direct targeting method using a high-resolution Fast Gray Matter Acquisition T1 Recovery (FGATIR) MRI sequence combined with real-time hippocampal EPs sensing intraoperatively.(Grewal et al., 2018) This alternative method of targeting ANT could compensate for inter-individual variations, particularly for patients with long-term epilepsy and potential ANT and hippocampal atrophy.
Fig. 1. Implantation (white, DBS electrode; green, ANT) and VTA (orange) analysis of patient 2. The area of VTA intersection with ANT was counted as ANT stimulation volume. ANT, Anterior nucleus of the thalamus; VTA, volume of tissue activated.
All patients had VTA intersection with ANT. Patients 2 (Fig. 1) and 4, had the greatest overlap of VTA with the ANT bilaterally. Patient 1 and patient 3 had excellent overlap of VTA with ANT on the right side, but less overlap on the left side. In patient 5 VTA overlapped with ANT, but the bilateral average of ANT stimulation volume was the smallest among 5 patients (Fig. 2). 3.2. EP analysis and stimulation programs For patient 2, the hippocampal EP with 2 Hz ANT stimulation was strong bilaterally. Unilateral hippocampal EPs presented in patients 1 (strong) and 4 (weak). For patients 3 and 5 hippocampal EPs were absent bilaterally (Fig. 2). Yet, the ANT stimulation volume did not statistically correlate with EPs (R2 = 0.12; p = 0.32). All patients received multiple program adjustment with or without AHS. However, no specific protocol was identified to correlate with better seizure outcome. 4. Discussion
5. Conclusion
We report here on a small series of 5 patients implanted with bilateral ANT and hippocampal electrodes, connected to a novel bi-directional stimulation and sensing device.(Stanslaski et al., 2012) The results of this pilot study demonstrate the safety and feasibility of ANT DBS combined with hippocampal sensing. The number of patients is small, but interestingly the single patient with strong bilateral circuit of Papez EPs had good seizure control with ANT DBS. This result is consistent with modulation of the limbic network, particularly the
Despite its clinical promise, long-term responsive rates of DBS therapy for epilepsy remain low. In this small pilot study we report evidence of using bilateral ANT and hippocampal electrodes to deliver ANT DBS and record circuit of Papez EPs. Hippocampal EPs were recorded with ANT stimulation in the 3 patients without evidence for MTS. The small number of patients in this cohort dictates that the
Fig. 2. Five patient’s parameters and EP level (left) and signal waveform demonstration (right). Patient with the most favorable treatment response was marked with red. MTS, Mesial temporal sclerosis; ANT, Anterior nucleus of the thalamus; EP, evoked potential. 3
Epilepsy Research 159 (2020) 106248
Y.-C. Wang, et al.
findings be interpreted cautiously, but the correlation of long-term seizure outcomes and strong circuit Papez EPs warrants further investigation, and may be useful to aid electrode targeting and predict individual patient responses to DBS.
Fountain, N., Bazil, C., Goodman, R., McKhann, G., Babu Krishnamurthy, K., Papavassiliou, S., Epstein, C., Pollard, J., Tonder, L., Grebin, J., Coffey, R., Graves, N., Group, S.S., 2010. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 51, 899–908. Gibson, W.S., Ross, E.K., Han, S.R., Van Gompel, J.J., Min, H.K., Lee, K.H., 2016. Anterior thalamic deep brain stimulation: functional activation patterns in a large animal model. Brain Stimul. 9, 770–773. Grewal, S.S., Middlebrooks, E.H., Kaufmann, T.J., Stead, M., Lundstrom, B.N., Worrell, G.A., Lin, C., Baydin, S., Van Gompel, J.J., 2018. Fast gray matter acquisition T1 inversion recovery MRI to delineate the mammillothalamic tract for preoperative direct targeting of the anterior nucleus of the thalamus for deep brain stimulation in epilepsy. Neurosurg. Focus 45, E6. Hunter, J., Jasper, H.H., 1949. Effects of thalamic stimulation in unanaesthetised animals; the arrest reaction and petit mal-like seizures, activation patterns and generalized convulsions. Electroencephalogr. Clin. Neurophysiol. 1, 305–324. Li, M.C.H., Cook, M.J., 2018. Deep brain stimulation for drug-resistant epilepsy. Epilepsia 59, 273–290. Middlebrooks, E.H., Grewal, S.S., Stead, M., Lundstrom, B.N., Worrell, G.A., Van Gompel, J.J., 2018. Differences in functional connectivity profiles as a predictor of response to anterior thalamic nucleus deep brain stimulation for epilepsy: a hypothesis for the mechanism of action and a potential biomarker for outcomes. Neurosurg. Focus 45, E7. Mirski, M.A., Rossell, L.A., Terry, J.B., Fisher, R.S., 1997. Anticonvulsant effect of anterior thalamic high frequency electrical stimulation in the rat. Epilepsy Res. 28, 89–100. Oikawa, H., Sasaki, M., Tamakawa, Y., Kamei, A., 2001. The circuit of Papez in mesial temporal sclerosis: MRI. Neuroradiology 43, 205–210. Potvin, O., Mouiha, A., Dieumegarde, L., Duchesne, S., Disease, Alzheimer’s, Neuroimaging, I., 2016. Normative data for subcortical regional volumes over the lifetime of the adult human brain. Neuroimage 137, 9–20. Stanslaski, S., Afshar, P., Cong, P., Giftakis, J., Stypulkowski, P., Carlson, D., Linde, D., Ullestad, D., Avestruz, A.T., Denison, T., 2012. Design and validation of a fully implantable, chronic, closed-loop neuromodulation device with concurrent sensing and stimulation. IEEE Trans. Neural Syst. Rehabil. Eng. 20, 410–421. Van Gompel, J.J., Klassen, B.T., Worrell, G.A., Lee, K.H., Shin, C., Zhao, C.Z., Brown, D.A., Goerss, S.J., Kall, B.A., Stead, M., 2015. Anterior nuclear deep brain stimulation guided by concordant hippocampal recording. Neurosurg. Focus 38, E9. van Rijckevorsel, K., Abu Serieh, B., de Tourtchaninoff, M., Raftopoulos, C., 2005. Deep EEG recordings of the mammillary body in epilepsy patients. Epilepsia 46, 781–785. Wang, Y.C., Grewal, S.S., Middlebrooks, E.H., Worrell, G.A., Stead, M., Lundstrom, B.N., Britton, J.W., Wu, M.H., Van Gompel, J.J., 2019. Targeting analysis of a novel parietal approach for deep brain stimulation of the anterior nucleus of the thalamus for epilepsy. Epilepsy Res. 153, 1–6.
Disclosure This study was supported by Medtronic and Cadence Neuroscience Inc. Drs. Brinkmann, Stead, Worrell, and Van Gompel have rights to receive future royalties from the licensing of technology related to brain stimulation research developed by Cadence Neuroscience Inc, which is co-owned by Mayo Clinic. The development of Cadence Neuroscience Inc. has been assisted by Drs. Brinkmann, Stead, Worrell, Van Gompel, and Lundstrom. The authors confirm that they have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Acknowledgments The authors thank Karla K. Crockett, and Erin M. Jagodzinski for their support of research coordination and administrative affairs. This research was supported by NIH grants UH2NS095495 and R01NS092882, and institutional resources for research by Czech Technical University in Prague, Czech Republic. References Bondallaz, P., Boex, C., Rossetti, A.O., Foletti, G., Spinelli, L., Vulliemoz, S., Seeck, M., Pollo, C., 2013. Electrode location and clinical outcome in hippocampal electrical stimulation for mesial temporal lobe epilepsy. Seizure 22, 390–395. Fisher, R., Salanova, V., Witt, T., Worth, R., Henry, T., Gross, R., Oommen, K., Osorio, I., Nazzaro, J., Labar, D., Kaplitt, M., Sperling, M., Sandok, E., Neal, J., Handforth, A., Stern, J., DeSalles, A., Chung, S., Shetter, A., Bergen, D., Bakay, R., Henderson, J., French, J., Baltuch, G., Rosenfeld, W., Youkilis, A., Marks, W., Garcia, P., Barbaro, N.,
4
Contents lists available at ScienceDirect
Epilepsy Research journal homepage: www.elsevier.com/locate/epilepsyres
Probing circuit of Papez with stimulation of anterior nucleus of the thalamus and hippocampal evoked potentials
T
Yu-Chi Wanga,b, Vaclav Kremena,e,h, Benjamin H. Brinkmanna,e, Erik H. Middlebrooksc,d, Brian N. Lundstroma,e, Sanjeet S. Grewald, Hari Guragaina,e, Min-Hsien Wug, Jamie J. Van Gompelf, Bryan T. Klassena,e, Matt Steada,e,*, Gregory A. Worrella,e,* a
Mayo Systems Electrophysiology Laboratory, Mayo Clinic, Rochester, Minnesota, USA Department of Neurosurgery, Chang Gung Memorial Hospital in Linkou, PhD. Program of Biomedical Engineering, Chang Gung University, Taiwan c Department of Radiology, Mayo Clinic, Jacksonville, Florida, USA d Department of Neurosurgery, Mayo Clinic, Jacksonville, Florida, USA e Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA f Department of Neurosurgery, Mayo Clinic, Rochester, Minnesota, USA g Graduate Institute of Biomedical Engineering, Chang Gung University, Taiwan h Czech Institute of Informatics, Robotics, and Cybernetics, Czech Technical University in Prague, Prague, Czech Republic b
A R T I C LE I N FO
A B S T R A C T
Keywords: Epilepsy Deep brain stimulation Anterior nucleus of thalamus Evoked potentials Mesial temporal sclerosis
Purpose: Despite documented clinical effectiveness, deep brain stimulation (DBS) therapy for drug-resistant epilepsy rarely yields long-term seizure free outcomes. Methods: This pilot study in five patients investigated circuit of Papez evoked potentials (EPs) using hippocampal sensing during anterior nucleus of the thalamus (ANT) electrical stimulation. We hypothesize that hippocampal EP is a potential biomarker that could be useful for ANT electrode targeting and improving seizure reduction. We obtained bilateral circuit of Papez EPs in five patients with bilateral temporal lobe epilepsy (TLE). The circuit of Papez EPs were measured and assessed by signal amplitude. Volumetric analysis of relevant mesial temporal structures and ANT stimulation analysis was performed on immediate post-implantation images. Results: The patient with the most favorable seizure outcome, which meant long-term seizure reduction greater than 50 % compared to baseline, had strong bilateral EPs and normal hippocampal structure. Conversely, those without clinical benefit with ANT DBS had absent or weak bilateral EPs as well as MRI findings consistent with mesial temporal sclerosis (MTS). Conclusion: The data support the hypothesis that hippocampal EPs with ANT stimulation may be used to as a surrogate marker to probe circuit of Papez and predict ANT DBS efficacy.
1. Introduction When resective surgery for drug-resistant epilepsy is contraindicated or ineffective, ANT DBS has emerged as an important treatment option.(Li and Cook, 2018) Previous experimental studies showing by electrophysiology have provided support that ANT DBS in animal models of TLE reduces hippocampal excitability and causes anticonvulsant effect.(Gibson et al., 2016; Hunter and Jasper, 1949; Mirski et al., 1997) Circuit of Papez is one of the most well-studied networks for seizure generation and propagation in TLE.(Oikawa et al., 2001) Multiple points for electrical stimulation along this pathway—including the hippocampi and ANT—have demonstrated effective modulation of seizure propagation and decreased the ⁎
frequency of refractory seizures.(Bondallaz et al., 2013; Fisher et al., 2010; van Rijckevorsel et al., 2005) In this study, we investigated hippocampal EPs resulting from ANT DBS in five patients with bilateral medial TLE. We utilized an investigational device for sensing and stimulation (PC + S, Medtronic Inc.) using bilateral ANT and hippocampal electrodes. We hypothesize that hippocampal EP is a biomarker indicating intact Papez circuitry, and perhaps response would correlate with improved seizure outcomes.
Corresponding authors at: Department of Neurology, Mayo Systems Electrophysiology Laboratory, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA. E-mail addresses: [email protected] (M. Stead), [email protected] (G.A. Worrell).
https://doi.org/10.1016/j.eplepsyres.2019.106248 Received 18 October 2019; Received in revised form 21 November 2019; Accepted 28 November 2019 Available online 29 November 2019 0920-1211/ © 2019 Published by Elsevier B.V.
Epilepsy Research 159 (2020) 106248
Y.-C. Wang, et al.
Table 1 Patients Demographics and Clinical Summary. Patient
Age at Surgery (Years)
Gender
Seizure Duration (Years)
Focal Seizure Type
Mesial Temporal Structure Zop (p value) Hippocampus
Amygdala Left: 1.15 (.126) Right: 1.37 (.087) Left: 1.55 (.062) Right: 1.23 (.110) Left: 1.18 (.121) *Right: 2.32 (.010) Left: 1.35 (.089) *Right: 1.95 (.026) Left: -1.51 (0.066) Right: 0.57 (0.284)
1
25
Male
10
With and without impaired awareness
Left: 0.3 (.382) Right: 0.0 (.499)
2
32
Female
30
With impaired awareness
*Left: -1.75 (.040) Right: -1.32 (.094)
3
33
Female
21
Without impaired awareness
*Left: -3.33 (< .0001) Right: -0.74 (.229)
4
39
Male
30
With impaired awareness
Left: -0.02 (.492) Right: -0.02 (.494)
5
32
Female
8
With impaired awareness
*Left: -3.57 (< .0001) *Right: -2.81 (.003)
Follow Up (Months)
Long-term Response to DBS#
52
No
52
Yes
41
No
42
No
35
No
DBS, Deep brain stimulation. Zop, Effect size for discrepancy between patient’s observed and normative volume. # Seizure reduction > 50% preoperative baseline frequency. *p < 0.05.
2. Materials and methods
atrophy. Volumes of bilateral hippocampi and amygdala were calculated using an automated atlas-based segmentation algorithm (Free Surfer 6.0). A volumetric comparison between measured volumes with volumes obtained from a cohort of age- and gender-matched healthy individual (Potvin et al., 2016) in the hippocampus and amygdala was performed.
2.1. Patient selection The study was carried out under a Food and Drug Administration Investigational Device Exemption (FDA IDE #G130166; ClinicalTrials.gov NCT02235792) and approved by the Mayo Clinic Institutional Review Board. Patients were prospectively recruited after multidisciplinary epilepsy surgery evaluation and conference presentation. The inclusion criteria were drug-resistant epilepsy (defined as refractory to trials of at least two appropriately chosen anti-seizure medications), not suitable candidates for surgical resection, and bilateral medial TLE. All patients consented to the DBS protocol using bilateral ANT and bilateral medial temporal lobe electrodes and the Medtronic Activa PC + S investigational device(Stanslaski et al., 2012) for treatment of epilepsy.
2.4. Evoked potentials (EPs) and stimulation program Hippocampal EPs were evaluated during continuous stimulation of ANT using 2 Hz stimulation frequency, amplitude 4 V, pulse width 90 μs, and 30 s duration. Hippocampal sensing (sampling rate 422 or 800 Hz) used the most distal to most proximal electrode contacts. In total 60 trials of EPs were averaged and classified with amplitude as absent (EP < 10 μV), weak (10 μV < EP < 20 μV), or strong (EP > 20 μV). All patients initially received ANT stimulation, while adjuvant hippocampal stimulation (AHS) was later trialed in patients without significant reduction in seizures. Chronic continuous 2 Hz ANT stimulation was initially used for all patients and parameters were adjusted in order to achieve better seizure control as necessary. Patients could be transitioned to the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTE) trial protocol (5 V, 90 μs pulses, 145 Hz with 1 min on and 5 min off) (Fisher et al., 2010) if clinically there was no improvement. Patients with ≥50% seizure reduction compared to baseline were considered responders to DBS treatment.
2.2. Surgical approach and implantation The details of our implantation have been previously described.(Van Gompel et al., 2015; Wang et al., 2019) In brief, stereotactic magnetic resonance images (MRI) were performed after Leksell (Elekta) frame fixation. Medtronic 3389 electrodes were then implanted in the ANT, which was targeted indirectly. Medtronic 3391 electrodes were implanted into the hippocampus through a direct targeting method. After confirmation of the electrode location with intraoperative post-placement computed tomography (CT), the leads were connected to extensions and tunneled to a multifunctional stimulator and recording pulse generator unit battery in the standard infraclavicular pocket.
3. Results Two male and three female adult patients were implanted with ANT and hippocampal leads, bilaterally, connected to the PC + S device. The patients’ clinical summary is shown in Table 1. All patients had seizure reduction after DBS compared to their preoperative baseline. Patient 2 had the most favorable outcome after DBS and was defined as a responder. The remaining four patients failed to have a ≥50% seizure reduction long-term (> 1 year) and were classified as non-responders.
2.3. Analysis of image and volume of tissue activated (VTA) The details of our targeting analysis and VTA have been previously described.(Middlebrooks et al., 2018; Wang et al., 2019) Briefly, the postoperative CT and pre-operative MRI were co-registered. Comparison of contact position relative to the ANT was performed, and VTA was generated with each patient’s recorded DBS stimulator settings. The VTA intersection with ANT was counted as ANT stimulation volume. The evidence for mesial temporal sclerosis (MTS) was characterized by increased FLAIR signal intensity and significant hippocampal
3.1. Image analysis and ANT stimulation volume Patients 3 and 5 had MRI evidence for bilateral MTS. Relative zscores for each subject’s observed versus normative volumes are shown in Table 1. 2
Epilepsy Research 159 (2020) 106248
Y.-C. Wang, et al.
hippocampus, as a mechanism of action of ANT DBS in the treatment of epilepsy.(Middlebrooks et al., 2018) Analysis of VTA indicated that all 5 patients had ANT stimulated, whereas possibly due to small sample size, the EP was not statistically correlated to ANT stimulation volume. Impairment of the circuit of Papez, either structural or functional, may not allow generation of evoked hippocampal potentials, which we suspect is the reason for unilateral weak EP of patient 4. Clear unilateral ANT electrode contact and larger right side stimulation volume in patients 1 and 3 may have contributed to different EP results. In patient 1, the strong EPs were detected in the ipsilateral hippocampus on the side with the ANT contact, while the contralateral side showed no EPs. In patient 3, no EPs were detected on either side of the sclerotic hippocampus, despite the right side definitely stimulated ANT. Lastly, no EPs were found in either hippocampus of patient 5 who had evidence for bilateral MTS and smaller ANT stimulation volumes. Based on these findings, we hypothesize that whether electrode contacts were clearly within ANT can have influence on EPs, and MTS could explain the complete absence of hippocampal EPs. Due to the severe neuronal reduction that accompanies MTS, the pathway is disrupted and the ability to excite hippocampal neurons may be reduced. Successful production of EPs requires that the neuronal network in the circuit of Papez be adequately functional to achieve a satisfactory response to stimulation. Notably, the net accuracy of co-registration of pre-operative MRI and post-implant CT procedure may be influenced by pneumocephalus or other intraoperative changes. The accuracy of DBS targeting ANT could theoretically be improved through a combination of a recently described direct targeting method using a high-resolution Fast Gray Matter Acquisition T1 Recovery (FGATIR) MRI sequence combined with real-time hippocampal EPs sensing intraoperatively.(Grewal et al., 2018) This alternative method of targeting ANT could compensate for inter-individual variations, particularly for patients with long-term epilepsy and potential ANT and hippocampal atrophy.
Fig. 1. Implantation (white, DBS electrode; green, ANT) and VTA (orange) analysis of patient 2. The area of VTA intersection with ANT was counted as ANT stimulation volume. ANT, Anterior nucleus of the thalamus; VTA, volume of tissue activated.
All patients had VTA intersection with ANT. Patients 2 (Fig. 1) and 4, had the greatest overlap of VTA with the ANT bilaterally. Patient 1 and patient 3 had excellent overlap of VTA with ANT on the right side, but less overlap on the left side. In patient 5 VTA overlapped with ANT, but the bilateral average of ANT stimulation volume was the smallest among 5 patients (Fig. 2). 3.2. EP analysis and stimulation programs For patient 2, the hippocampal EP with 2 Hz ANT stimulation was strong bilaterally. Unilateral hippocampal EPs presented in patients 1 (strong) and 4 (weak). For patients 3 and 5 hippocampal EPs were absent bilaterally (Fig. 2). Yet, the ANT stimulation volume did not statistically correlate with EPs (R2 = 0.12; p = 0.32). All patients received multiple program adjustment with or without AHS. However, no specific protocol was identified to correlate with better seizure outcome. 4. Discussion
5. Conclusion
We report here on a small series of 5 patients implanted with bilateral ANT and hippocampal electrodes, connected to a novel bi-directional stimulation and sensing device.(Stanslaski et al., 2012) The results of this pilot study demonstrate the safety and feasibility of ANT DBS combined with hippocampal sensing. The number of patients is small, but interestingly the single patient with strong bilateral circuit of Papez EPs had good seizure control with ANT DBS. This result is consistent with modulation of the limbic network, particularly the
Despite its clinical promise, long-term responsive rates of DBS therapy for epilepsy remain low. In this small pilot study we report evidence of using bilateral ANT and hippocampal electrodes to deliver ANT DBS and record circuit of Papez EPs. Hippocampal EPs were recorded with ANT stimulation in the 3 patients without evidence for MTS. The small number of patients in this cohort dictates that the
Fig. 2. Five patient’s parameters and EP level (left) and signal waveform demonstration (right). Patient with the most favorable treatment response was marked with red. MTS, Mesial temporal sclerosis; ANT, Anterior nucleus of the thalamus; EP, evoked potential. 3
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findings be interpreted cautiously, but the correlation of long-term seizure outcomes and strong circuit Papez EPs warrants further investigation, and may be useful to aid electrode targeting and predict individual patient responses to DBS.
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Disclosure This study was supported by Medtronic and Cadence Neuroscience Inc. Drs. Brinkmann, Stead, Worrell, and Van Gompel have rights to receive future royalties from the licensing of technology related to brain stimulation research developed by Cadence Neuroscience Inc, which is co-owned by Mayo Clinic. The development of Cadence Neuroscience Inc. has been assisted by Drs. Brinkmann, Stead, Worrell, Van Gompel, and Lundstrom. The authors confirm that they have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Acknowledgments The authors thank Karla K. Crockett, and Erin M. Jagodzinski for their support of research coordination and administrative affairs. This research was supported by NIH grants UH2NS095495 and R01NS092882, and institutional resources for research by Czech Technical University in Prague, Czech Republic. References Bondallaz, P., Boex, C., Rossetti, A.O., Foletti, G., Spinelli, L., Vulliemoz, S., Seeck, M., Pollo, C., 2013. Electrode location and clinical outcome in hippocampal electrical stimulation for mesial temporal lobe epilepsy. Seizure 22, 390–395. Fisher, R., Salanova, V., Witt, T., Worth, R., Henry, T., Gross, R., Oommen, K., Osorio, I., Nazzaro, J., Labar, D., Kaplitt, M., Sperling, M., Sandok, E., Neal, J., Handforth, A., Stern, J., DeSalles, A., Chung, S., Shetter, A., Bergen, D., Bakay, R., Henderson, J., French, J., Baltuch, G., Rosenfeld, W., Youkilis, A., Marks, W., Garcia, P., Barbaro, N.,
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