Hippocampal-orbitofrontal connectivity in human: An electrical stimulation study

Clinical Neurophysiology 116 (2005) 1779–1784 www.elsevier.com/locate/clinph

Hippocampal-orbitofrontal connectivity in human: An electrical stimulation study H. Catenoixa,d, M. Magninb,d, M. Gue´notc,d, J. Isnarda,d, F. Mauguie`rea,d, P. Ryvlina,d,* a

Department of Functional Neurology and Epileptology, Neurological Hospital, Lyon, France b INSERM, EMI 342, Neurological Hospital, Lyon, France c Department of Functional Neurosurgery, Neurological Hospital, Lyon, France d Federative Institute of Neuroscience, INSERM IFR 19, Lyon, France Accepted 25 March 2005

Abstract Objective: The identification of the pathways involved in seizure propagation remains poorly understood in humans. For instance, the respective role of the orbitofrontal cortex (OFC) and of the commissural pathways in the interhemispheric propagation of mesial temporal lobe seizures (mTLS) is a matter of debate. In order to address this issue, we have directly tested the functional connectivity between the hippocampus and the OFC in 3 epileptic patients undergoing an intra-cranial stereotactic EEG investigation. Methods: Bipolar electrical stimulations, consisting of two series of 25 pulses of 1 ms duration, 0.2 Hz frequency, and 3 mA intensity, were delivered in the hippocampus. Evoked potentials (EPs) were analysed for each series, separately. Grand average of reproducible EPs was then used to calculate latency of the first peak of each individual potential. Results: Hippocampal stimulations evoked reproducible responses in the OFC in all 3 patients, with a mean latency of the first peak of 222 ms (range: 185–258 ms). Conclusions: Our data confirm a functionnal connectivity between the hippocampus and the OFC in human. Significance: This connectivity supports the potential role of the OFC in the propagation of mTLS. q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Epilepsy; hippocampus; Orbito-frontal cortex; Intra-cranial electrical stimulation; Connectivity

1. Introduction The identification of the pathways involved in seizure propagation is an important clinical issue, which remains poorly understood in humans. Regarding the inter-hemispheric propagation of mesial temporal lobe seizures (mTLS), Gloor et al. (1993) suggested that the latter could be mediated by the dorsal hippocampal commissure. However, this issue remains controversial. In fact, electrical stimulations coupled with evoked potentials (EPs) of human mesiotemporal structures failed to elicit contralateral * Corresponding author. Address: Hoˆpital Neurologique, 59 Bd Pinel, Lyon 69003, France. Tel.: C33 4 72 35 79 02; fax: C33 4 72 35 73 97. E-mail address: [email protected] (P. Ryvlin).

homotopic responses in several studies (Buser et al., 1968; Wilson et al., 1990). Furthermore, the low coherence measured between seizure activity in ipsilateral and contralateral hippocampi suggests a minor role of the hippocampal commissure in the inter-hemispheric propagation of mTLS (Bertashius, 1991; Lieb et al., 1987a,b; Wilson and Engel, 1993). Alternatively, this propagation could follow a frontal pathway. Indeed, some authors have suggested the role of the orbitofrontal cortex (OFC) in the interhemispheric propagation of mTLS (Lieb et al., 1991; Wilson and Engel, 1993) and shown that electrical stimulations of the OFC were effective in evoking contralateral homotopic responses (Wilson and Engel, 1993). However, no study has yet described the responses recorded in the OFC following

1388-2457/$30.00 q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2005.03.016

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electrical stimulation of temporomesial structures in humans. To investigate the functional anatomical connectivity between these two regions, we performed electrical stimulations of the hippocampus in 3 patients who underwent an intra-cranial EEG investigation (SEEG), and search for EPs within the OFC.

2. Methods and material 2.1. Patients The 3 patients (A, B and C) included in this study were a man and two women aged 46, 32 and 15 years with an onset of epilepsy of 16, 12 and 5 years, respectively. In two patients

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O3– O4 Ref – O4 O4– O5 Ref – O5 O5– O6 Ref – O6 O6– O7 Ref – O7 O7– O8 Ref – O8 O8– O9 Ref – O9 O9– O10 Ref – O1O O10– O11 Ref – O11 O11– O12 Ref – O12

100 µV 250 ms

Fig. 1. Evoked potentials recorded in OFC following ipsilateral hippocampal stimulations in patient A. Top, localization of electrode contacts used in the hippocampus (left) and ipsilateral OFC (right) on stereotactic coronal MRI sections. Antero-posterior (AP) levels are referred to the posterior commissure. L and R, left and right hemispheres; scale, 10 mm. Bottom, averaged evoked OFC potentials in referential (left) and bipolar (right) montages following ipsilateral hippocampal stimulations. The averages of the two series of stimulations are superimposed showing the reproducibility of the responses. Positive polarity is upward. Latency of the first peak was measured on bipolar montage (arrow).

H. Catenoix et al. / Clinical Neurophysiology 116 (2005) 1779–1784

(B and C), MRI was unremarkable, including normal hippocampal volume, while patient A demonstrated lateral temporal post-traumatic atrophy. In two patients (A and B) whose electro-clinical data suggested the possibility of an epileptogenic zone involving the temporal lobe as well as territories outside the usual boundaries of an anterior temporal lobectomy (Ryvlin, 2003), SEEG was carried out in order to precisely assess the extent of the ictal onset zone. In a third patient (C), whose seizures suggested a frontal ictal onset, SEEG was performed with the hope to delineate an epileptogenic zone which could be surgically resected. All patients gave their informed consent to this study. 2.2. Stereotactic implantation of depth electrodes The brain regions to be explored were determined for each patient, based on individual presurgical data. The pertinent targets were then identified on the 3D-MRI and adapted to

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the vascular constraints evidenced by co-registered digitized angiography. Electrodes were implanted perpendicular to the midline vertical plane with the patient’s head fixed in the Talairach stereotactic frame. The electrodes had a diameter of 0.8 mm and 5–15 recording contacts, 2 mm long, separated by 1.5 mm. Ten electrodes were implanted in patient A, 13 in patient B and 10 in patients C. In all 3 patients, one electrode was placed in the OFC and another directed at the anterior (patients A and C; Figs. 1 and 3) or posterior (patient B; Fig. 2) part of the hippocampus ipsilateral to the suspected epileptogenic zone. In patient B, another electrode targeted the contralateral hippocampus. The exact position of each electrode was verified by fusing the post-implantation frontal radiography with the corresponding frontal MRI section. Finally, we resliced 1 mm thick coronal MRI sections using MRIcro software (Rorden and Brett, 2000), and reported the stereotactic coordinates of the electrodes contacts on these sections.

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Fig. 2. Patient B. Top, localization of electrode contacts used in hippocampus (left) and ipsilateral OFC (right) on stereotactic coronal MRI sections. Anteroposterior (AP) levels are referred to the posterior commissure. L and R, left and right hemispheres; scale, 10 mm. Bottom, averaged evoked OFC potentials in referential (left) and bipolar (right) montages following ipsilateral hippocampal stimulations. The averages of the two series of stimulations are superimposed showing the reproducibility of the responses. Positive polarity is upward. Latency of the first peak was measured on bipolar montage (arrow).

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Fig. 3. Patient C. Top, localization of electrode contacts used in the hippocampus (left) and ipsilateral OFC (right) on stereotactic coronal MRI sections. Antero-posterior (AP) levels are referred to the posterior commissure. L and R, left and right hemispheres; scale, 10 mm. Bottom, averaged evoked OFC potentials in referential (left) and bipolar (right) montages following ipsilateral hippocampal stimulations. The averages of the two series of stimulations are superimposed showing the reproducibility of the responses. Positive polarity is upward. Latency of the first peak was measured on bipolar montage (arrow).

2.3. Stimulation paradigm Intra-cerebral electrical stimulations were performed as part of the usual clinical assessement of hippocampal epileptogenicity using low frequency stimulation (%1 Hz) (Munari et al., 1993). These stimulations were produced by a current-regulated neurostimulator designed for a safe diagnostic stimulation of the human brain (Babb et al., 1980). Square pulses of current were applied between two adjacent contacts localized in the hippocampus (bipolar stimulation). The stimulation parameters were choosen to avoid tissue damage (Gordon et al., 1990). They consisted of two series of 25 pulses of 1 ms duration, 0.2 Hz

frequency and 3 mA intensity. Three to four pairs of adjacent hippocampal contacts were stimulated per patient. 2.4. Data collection and analysis Data were recorded using a band pass filter of 0.53–250 Hz, and a sampling rate of 512 Hz. They were analysed in bipolar montage from adjacent contacts. For a given OFC electrodes, 5–11 pairs of contacts localized in the OFC ipsilateral to the hippocampal stimulation could be recorded. We also searched contralateral hippocampal response in patient B, where both the right and left hippocampus were investigated with depth electrodes.

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EPs were averaged from the 25 stimuli of each series separately, and considered significant when reproducible on the two consecutive series, with an amplitude at least twice that of the background level. The latency of the first peak of each potential was measured on the grand average (see Figs. 1–3). This measurement was repeated for each of 3–4 stimulated hippocampal contacts, resulting in a mean latencyGSD in every individual patient.

3. Results Patients clinical data are summarized in the Table 1. SEEG investigations demonstrated that the epileptogenic zone included the right hippocampal formation in patient A, the left hippocampal formation and ipsilateral OFC in patient B, and none of these regions in patient C, where seizure onset was localized in the right dorsolateral frontal cortex. 3.1. Characteristics of EPs recorded in the OFC ipsilateral to the hippocampal stimulation In two patients (A and C), EPs were consistently recorded following all hippocampal stimulations, whereas in the third patient (patient B), the presence of EPs depended on the hippocampal contacts that were stimulated. When present, the EPs recorded in the ipsilateral OFC were always reproducible on the two consecutive series of 25 pulses, and consisted in polyphasic oscillations of varying complexity and duration (Figs. 1–3). However, the mean individual latency of the first peak was reproducible, 258G55 ms in patient A, 185G3 ms in patient B and 222G13 ms in patient C. Responses of shorter latency could be observed in referential montage, but were not considered significant on bipolar montage. 3.2. Contralateral EPs following hippocampal stimulation In patient B, who benefited from a bilateral hippocampal implantation, no response was recorded in contralateral homotopic hippocampus following hippocampal stimulation.

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4. Discussion Hippocampal stimulation was effective in producing reproducible EPs in the ipsilateral OFC, with a mean latency of 222 ms, a finding not previously reported in humans. Conversley, no contralateral hippocampal homotopic EP was recorded in the single patient where this was evaluated, confirming results from previous studies (Buser et al., 1968; Wilson et al., 1990). Because of the spatial sampling limitations of SEEG, the lack of contralateral hippocampal response does not exclude commissural propagation in unexplored hippocampal sub-regions. However, this consistent finding across series suggests a minor role of the commissural pathways in interhemispheric spread of mTLS in humans (Bertashius, 1991; Lieb et al., 1987a,b; Wilson and Engel, 1993), in contrast to non-primate animals (Andersen, 1959). Several brain regions have been suggested as possible pathways for the contralateral spread of mTLS, including the lateral temporal cortex, the mesial frontal region, the cingulate gyrus or the thalamus (Bertashius, 1991; Bossi et al., 1984; Lieb et al., 1991; Wilson and Engel, 1993). In particular, Lieb et al. (1991) have shown that the ipsilateral OFC was frequently and rapidly involved in the propagation of seizures initiated in the mesial temporal lobe and speculate that it might play a role in the interhemispheric propagation of mTLS. Similary, Adam et al. (1994) reported a multidirectional propagation of temporal lobe seizures, most frequently to the frontal lobes. Our study, displaying the presence of reproducible EPs in the OFC following hippocampal stimulation, supports a functional connectivity between these two regions in humans and the potential role of the orbital frontal pathway in interhemispheric propagation of temporomesial discharges. This connectivity is further supported by neuroanatomical studies in monkey demonstrating that the OFC, particulary its medial sector, was connected monosynaptically with the ipsilateral hippocampus (Cavada et al., 2000; Morecraft et al., 1992). The long latency of the main response observed in our patients (222 ms on average) rather suggests a polysynaptic projection of the hippocampus to the OFC. However, very early responses within

Table 1 Patients characteristics Age

Gender

Age at onset of epilepsy

MRI findings

Ictal semiology

Number of electrodes

Seizure onset zone

46

M

16

Facial grimacing, chewing, left wiping automatism

10 (10R)

R. mesial and lateral temporal

32

F

12

R. lateral temporal atrophy Normal

13 (11L, 2R)

L. mesial temporal and orbito-frontal

15

F

5

Cycling movements, right head and eye version, chewing, loss of awareness, right clonic movements Cry, fear, abdominal pain, hypermotor activity

10 (10R)

R. middle and posterior portions of the 1st and 2nd frontal gyrus

F, female; M, male; R, right; L, left.

Normal

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the 10 first ms could not be specifically evaluated, due to the presence of a stimulation induced artefact. In addition, lowamplitude potentials of uncertain significance were observed in some of our patient, in particular when using referential montage. Such potentials might also prove significant on bipolar montage provided a higher number of stimuli. Regarding our longer latency potentials, the amygdala nucleus might represent a possible relay between the hippocampus and the OFC, since it is strongly connected with both structures (Buser and Bancaud, 1983; Porrino et al., 1981; Rutecki et al., 1989; Wilson et al., 1990). Accordingly we recorded shorter latency EPs (25–40 ms) in the amygdala of one of our patient (A) who also benefited from an amygdala implantation, following ipsilateral hippocampal stimulation, as previously reported by others (Wilson et al., 1990). The OFC EPs recorded in our patients varied in terms of morphology and amplitude. One explanation for this finding is the variable location of hippocampal stimulations and OFC recordings. The different epileptogenic zones delineated in our 3 patients might also account for their variable EPs. Indeed, the stimulated hippocampus was found to be epileptogenic in patients A and B, but not in patient C, whereas the recorded OFC structures were part of the ictal onset zone in patient B only. In patient C, in whom neither the hippocampus nor the OFC were primarily involved in the epileptic discharges, EPs appear of more complex and of higher amplitude than in the two other patients. This issue should be addressed in a larger population. Finally, our results show that the coupling of intra-cerebral low-frequency stimulation and EPs recordings is an effective method to study cortico-cortical connectivity. Though one can hardly extrapolate physiological conclusions from data obtained in patients with epilepsy, such data remain relevant to the issue of epileptic discharges propagation. In conclusion, our results confirm a functional connectivity between the hippocampus and the OFC in patients with epilepsy, and support the potential role of the OFC in the controlateral propagation of mTLS.

References Adam C, Saint-Hilaire JM, Richer F. Temporal and spatial characteristics of intracerebral seizure propagation: predictive value in surgery for temporal lobe epilepsy. Epilepsia 1994;35(5):1065–72. Andersen P. Interhippocampal impulses I Origine, course and distribution in cat, rabbit and rat. Acta Physiol Scand 1959;47:63–90.

Babb TL, Mariani E, Seidner KA, Mutafyan G, Halgren E, Wilson CL, Crandall Ph. A circuit for safe diagnostic electrical stimulation of human brain. Neurol Res 1980;2:181–97. Bertashius K. Propagation of human complex-partial seizures: a correlation analysis. Electroencephalogr Clin Neurophysiol 1991;78:333–40. Bossi L, Munari C, Stoffels C, Bonis A, Bacia T, Talairach J, Bancaud J. Somatomotor manifestations in temporal lobe seizures. Epilepsia 1984; 25(1):70–6. Buser P, Bancaud J. Unilateral connections between amygdala and hippocampus in man A study of epileptic patients with depth electrodes. Electroencephalogr Clin Neurophysiol 1983;55:1–12. Buser P, Bancaud J, Talairach J, Szikla G. Interconnexions amygdalohippocampiques chez l’homme Etude physiologique au cours d’explorations ste´re´otaxiques. Rev Neurol 1968;119(3):283–8. Cavada C, Company T, Tejedor J, Cruz-Rizzolo RJ, Reinoso-Suarez F. The anatomical connections of the macaque monkey orbitofrontal cortex— A review. Cereb Cortex 2000;10(3):220–42. Gloor P, Salanova V, Olivier A, Quesney L. The human dorsal hippocampal commissure An anatomical identifiable and functional pathway. Brain 1993;116:1249–73. Gordon B, Lesser R, Rance N, Hart J, Webber R, Umatsu S, Fisher R. Parameters for direct cortical electric stimulation in the human: histopathologic confirmation. Electroencephalogr Clin Neurophysiol 1990;75:375–7. Lieb J, Babb T, Engel J, Darcey T. Propagation patwhays of interhemispheric seizure discharges compared in human and animal hippocampal epilepsy. In: Engel J et al, editor. Fundamental mechanism of human brain function. New York: Raven Press;, 1987a. p. 165–70. Lieb J, Hoque K, Skomer C, Song X. Inter-hemispheric propagation of human mesial temporal lobe seizures: a coherence/phase analysis. Electroencephalogr Clin Neurophysiol 1987b;67:101–19. Lieb J, Dasheiff R, Engel J. Role of the frontal lobe in the propagation of mesial temporal lobe seizures. Epilepsia 1991;32(6):822–37. Morecraft R, Geula C, Mesulam M. Cytoarchitecture and neural afferents of orbitofrontal cortex in the brain of the monkey. J Comp Neuro 1992; 323:341–58. Munari C, Kahane P, Tassi L, Francione S, Hoffmann D, Lo Russo G, Benabid AL. Intracerebral low frequency electrical stimulation: a new tool for the definition of the epileptogenic area? Acta Neurochir 1993; 58:181–5. Porrino LJ, Crane AM, Goldman-Rakik PS. Direct and indirect patwhays from the amygdala to the frontal lobe in rhesus monkeys. J Comp Neurol 1981;198(1):121–36. Rorden C, Brett M. Stereotaxic display of brain lesions. Behav Neurol 2000;12:191–200. Rutecki P, Grossman R, Armstrong D, Irish-Loewen S. Electrophysiological connections between the hippocampus and entorhinal cortex in patients with complex partial seizures. J Neurosurg 1989;70:667–75. Ryvlin P. Beyond pharmacotherapy: surgical management. Epilepsia 2003; 44:23–8. Wilson C, Engel J. Electrical stimulation of the human epileptic limbic cortex. In: Devinsky O, Beric A, Dogali M, editors. Electrical and magnetic stimulation of the brain and spinal cord, Vol. 8. New-York: Raven press; 1993. p. 103–13. Wilson C, Isokawa M, Babb T, Crandall P. Functionnal connections in the human temporal lobe I. Analysis of limbic system pathways using neuronal responses evoked by electrical stimulation. Exp Brain Res 1990;279–92.