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Research Report
Ictal electrographic pattern of focal subcortical seizures induced by sound in rats Lyudmila V. Vinogradovaa,n, Olesya A. Grinenkob a
Institute of Higher Nervous Activity and Neurophysiology Russian Academy of Sciences, Moscow, Russia Burdenko Neurosurgery Institute, Moscow, Russia
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art i cle i nfo
ab st rac t
Article history:
It is now recognized that both generalized and focal seizures may originate in subcortical
Accepted 18 January 2016
structures. The well-known types of focal subcortically-driven seizures are gelastic seizures in patients with the hypothalamic hamartoma and sound-induced seizures in
Keywords:
rodents with audiogenic epilepsy. The seizures are generated by subcortical intrinsically
Epilepsy
epileptogenic focus, the hamartoma in humans and the inferior colliculus (IC) in rodents.
Secondary epileptogenesis
In patients with gelastic epilepsy additional seizure types may develop with time that are
Audiogenic seizure
supposed to result from secondary epileptogenesis and spreading of epileptic discharges to
Kindling
the cortex. Repeated audiogenic seizures can also lead to development of additional
EEG
seizure behavior and secondary epileptic activation of the cortex. This process, named
Hamartoma
audiogenic kindling, may be useful for studying secondary subcortico-cortical epileptogenesis. Using intracollicular and intracortical recordings, we studied an ictal electrographic pattern of focal subcortical seizures induced by repeated sound stimulation in Wistar audiogenic-susceptible rats. The audiogenic seizures, representing brief attacks of paroxysmal unidirectional running, were accompanied by epileptiform abnormalities in the IC, mostly on the side ipsilateral to run direction, and enhanced rhythmic 8–9 Hz activity in the cortex. With repetition of the subcortical seizures and kindling development, a secondary cortical discharge began to follow the IC seizure. The secondary discharge initially involved the cortex homolateral to the side of dominant subcortical epileptiform abnormalities and behaviorally expressed as limbic (partial) clonus. Kindling progression was associated with bilateralization of the secondary cortical discharge, an increase in its amplitude and duration, intensification of associated behavioral seizures (from partial clonus to generalized tonic–clonic convulsions). Thus, ictal recordings during brief audiogenic running seizures showed their focal subcortical origin. Repetition of the subcortical seizures may result in secondary subcortico-cortical epileptogenesis manifested by emergence and progressive intensification of epileptiform discharges in the cortex. & 2016 Published by Elsevier B.V.
n Correspondence to: Institute of Higher Nervous Activity and Neurophysiology Russian Academy of Sciences, 117485 Moscow Butlerova Street 5A. Fax: þ7 499 7430056. E-mail address: [email protected] (L.V. Vinogradova).
http://dx.doi.org/10.1016/j.brainres.2016.01.027 0006-8993/& 2016 Published by Elsevier B.V.
Please cite this article as: Vinogradova, L.V., Grinenko, O.A., Ictal electrographic pattern of focal subcortical seizures induced by sound in rats. Brain Research (2016), http://dx.doi.org/10.1016/j.brainres.2016.01.027
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1.
Introduction
Although human epilepsy is traditionally considered as a result of cortical pathology, it is now recognized that some seizure types may have subcortical origin (Berg et al., 2010), for example, gelastic seizures in patients with hypothalamic hamartoma. These seizures arise directly from the focal subcortical lesion associated with hamartoma (Munari et al., 1995; Kuzniecky et al., 1997) that exhibits intrinsic epileptogenicity (Fenoglio et al., 2007). With time, patients with hypothalamic hamartoma begin to show epileptiform abnormalities in the cortex and additional seizure types, i.e. partial and generalized tonic–clonic seizures (Berkovic et al., 1988). Since the appearance of multiple non-gelastic seizures highly depends on the disease duration, involvement of kindling-like mechanisms and secondary subcortico-cortical epileptogenesis has been suggested to underlie the disease progression (Parvizi et al., 2011). In the course of the hamartoma-related epilepsy, repetitive ictal discharges are supposed to spread from a subcortical lesion to the cerebral cortex, leading to appearance of secondary cortical seizure foci (Kahane et al., 2003; Kerrigan et al., 2005). However, there is no experimental evidence for this hypothesis. The best characterized experimental model for primary subcortical seizures and secondary subcortico-cortical epileptogenesis is audiogenic epilepsy in rodents (Krushinsky et al., 1970; Jobe et al., 1973; Ludvig and Moshe, 1989; Faingold, 2002, 2004; Garcia-Cairasco, 2002; Jobe and Browning, 2006; Vinogradova, 2015). Audiogenic seizures induced by sound in susceptible animals are driven by brainstem networks with a primary focus in the inferior colliculus (IC), the subcortical auditory nucleus showing intrinsic epileptogenicity in rodents with audiogenic epilepsy (Faingold, 2002). Soundinduced seizures may be focal or widely generalized within brainstem networks. Full-blown audiogenic seizures, i.e. running followed by generalized tonic/clonic convulsion, are associated with widespread epileptic activation of the brainstem (Krushinsky et al., 1970; Garcia-Cairasco, 2002; Faingold, 2004; Jobe and Browning, 2006). The initial running component of audiogenic seizures is thought to reflect early focal brainstem excitation (Jobe and Browning, 2006). Rats with high genetic susceptibility to audiogenic seizures (Genetically Epilepsy-prone Rats (GEPRs), Wistar Audiogenic Rats (WARs), KM rats) express explosive running/myoclonic trusts before the onset of severe sound-induced tonic–clonic seizures. In rats with low seizure susceptibility (audiosensitive rats of Wistar and Sprague-Dawley outbred strains) audiogenic seizures usually start with one or two episodes of mild running behavior. Motor asymmetry of the latter running behavior has been described recently Vinogradova and Sharskova, 2012), further supporting the focal nature of the seizure. With repetition of audiogenic seizures, epileptic activity spreads to the forebrain (the amygdala, cortex and hippocampus) and additional forebrain-driven seizure types develop (Marescaux et al., 1987; Naritoku et al., 1992; Simler et al., 1999; Dutra Moraes et al., 2000). During this epileptogenic process, named audiogenic kindling, recurrent subcortical seizures elicit a trans-synaptic and long-lasting increase in excitability of cortico-limbic regions that finally leads to
development of secondary epileptiform discharges in the cortex. Evidence obtained in the kindling model, in which epileptogenesis is determined by expansion of the seizure network from a primary subcortical focus to the cerebral cortex, may be useful for understanding secondary subcortico-cortical epileptogenesis in the human brain. Audiogenic kindling can be produced by repetition of either focal or full-blown generalized seizures. Behavioral and electrographic profiles of the latter kindling paradigm produced by generalized brainstem seizures have been studied previously (Marescaux et al., 1987; Naritoku et al., 1992; Faingold, 2004; Dutra Moraes et al., 2000). Epileptic activation of the cerebral cortex has been reported during the seizures not only in kindled but even in non-kindled animals (Moraes et al., 2005; Carballosa-Gonzales et al., 2013). This suggests co-activation of subcortical and cortical networks during full-blown audiogenic seizures irrespectively of kindling development. Mild paradigm of audiogenic kindling produced by repetition of focal running seizures (in fact the first manifestation of audiogenic seizures) may model epilepsy related with a local subcortical epileptogenic lesion, such as in case of patients with hamartoma. Though a behavioral pattern of the kindling has been characterized previously (Vinogradova, 2008), little is known about electrographic manifestations of the focal audiogenic seizures and secondary kindling-induced epileptogenic changes in the cortex. The present study examined the relationship between the behavioral expression of repeated audiogenic running seizures and ictal electrical activity in the primary subcortical focus (the IC) and in the cerebral cortex secondarily involved in the seizure network. Because a motor asymmetry is a common feature of the audiogenic running seizures in Wistar rats (Vinogradova and Sharskova, 2012), ictal electrographic activity was recorded in both sides of the brain.
2.
Results
In Wistar rats with audiogenic epilepsy, sound stimulation initially evoked only brief running seizures (focal subcortical seizures), i.e., stage-1 seizures according to the scale of Jobe (Jobe et al., 1973). In 6–18 s after the onset of sound stimulation (a latent period of a seizure), rats expressed one or two brief episodes of mild motor behavior (running) without jumps and tonic–clonic convulsions. After interruption of sound stimulation with the seizure onset, self-sustained running behavior continued for 2–11 s. The pattern of the seizure behavior in non-kindled animals varied from a forced unidirectional turning/lateroflexion to rapid locomotion/slow running. In repeated tests the running seizures began to be accompanied by jumping. The sound-induced running had an asymmetric (unidirectional) pattern and its individual directionality was consistent in repeated tests, confirming our previous findings (Vinogradova and Sharskova, 2012). The running seizure was preceded and followed by freezing behavior. The characteristic pattern and latency of repeated running seizures allowed distinguishing the seizure behavior from any non-epileptic locomotion. Electrographic recordings during the initial focal audiogenic seizures in non-kindled rats revealed epileptiform
Please cite this article as: Vinogradova, L.V., Grinenko, O.A., Ictal electrographic pattern of focal subcortical seizures induced by sound in rats. Brain Research (2016), http://dx.doi.org/10.1016/j.brainres.2016.01.027
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Fig. 1 – Ictal electrographic patterns of audiogenic running seizures in non-kindled Wistar rats. Recordings from the right (R) and left (L) parietal cortices (Cx) and inferior colliculi (IC) during sound-induced forced leftward lateroflexion (A and B) and rightward running (C) are presented. B is an expanded fragment marked by rectangle in A. Lines below fragments mark episodes of motor behavior – running seizure (black lines) and non-seizure locomotion (white line in A). Audiogenic seizures are accompanied by rhythmic activity in the cortex and unilateral (A and B) or bilateral asymmetric (C) epileptiform abnormalities in the IC. A lack of movement artifacts during non-seizure locomotion (A) indicates relatively artifact-free EEG recording. Negativity is directed downward. Calibration: 0.2 mV, 5 s (A) or 2 s (B and C).
Fig. 2 – Rhythmic activity in the cortex during sound-induced running seizures. A – typical ictal activity in the parietal cortex of the right (R) and left (L) hemispheres during episode of audiogenic running. Period of running behavior is marked below the recording. Calibration: 0.2 mV, 2 s. B and C – frequency and power of cortical activity in the theta frequency band (4–12 Hz) during the background period (bg), after the onset of sound stimulation (sound stimulation) and during sound-induced motor activity (running seizures in epileptic rats or rapid locomotion in non-epileptic rats). ***po0.001 – significant difference between epileptic (open bars) and non-epileptic (filled bars) rats. Please cite this article as: Vinogradova, L.V., Grinenko, O.A., Ictal electrographic pattern of focal subcortical seizures induced by sound in rats. Brain Research (2016), http://dx.doi.org/10.1016/j.brainres.2016.01.027
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abnormalities in the IC but not in the cortex. Usually mild motor activity during the seizures allowed us to avoid significant movement artifacts in EEG recording. Depth recordings showed the presence of sharp waves, spikes and polispikes in the IC even during the subtle seizure behavior (Fig. 1). The intracollicular epileptiform activity was evident in 23 of 27 artifact-free episodes of mild audiogenic seizures recorded in five rats. The ictal IC discharges had lateralized patterns and were expressed as unilateral (Fig. 1A and B) or bilateral asymmetric (Fig. 1C) activity. The collicular epileptiform activity was predominantly or exclusively recorded on the side ipsilateral to run direction. In the cortex of non-kindled rats, no obvious epileptiform activity was observed during the running seizures. The accentuated oscillations in the theta frequency band were the only and reliable feature of cortical activity during the mild focal audiogenic seizures across rats and in the same animal (Fig. 2A). The period of enhanced rhythmic activity of 8–9 Hz always coincided with sound-induced seizure behavior. ANOVA for repeated measures has shown that both frequency and power of theta cortical oscillations was significantly higher during the ictal behavior as compared to background and sound-induced arousal (po0.001) as well as to rapid locomotion in non-epileptic rats (Fig. 2B and C). In rats that developed audiogenic kindling with repeated running seizures (n¼ 6), epileptiform activity appeared in the cortex, indicating secondary epileptogenic changes in the cortex. Fig. 3 shows a typical example of the first cortical epileptiform discharge recorded after repeated running seizures. The cortical seizure represented a low-frequency (2–4 Hz) selfsustained spike discharge in the hemisphere homolateral to the side of the subcortical seizure. The cortical spiking started with the end of IC-driven seizure (running), continued during the limbic clonus (kindled forebrain-driven seizure behavior) and terminated simultaneously with the end of the clonus. The limbic clonus, that is accepted to model complex partial
Fig. 3 – The first epileptiform discharge recorded in the cortex after the 16th episode of running seizure. The discharge represents unilateral spiking in the right cortex associated with facial clonus (open line) that follows rightward running (filled line below the fragment). Thus sound evokes subsequent activation of the IC (unilateral highamplitude spikes) and cerebral cortex. Abbreviations and calibration are identical to those on Fig. 1.
seizures in patients (Racine, 1972), was initially expressed as eye blinking, facial clonus or unilateral clonic jerking of the pinna contralateral to the cortical discharge. With further sound stimulation and induction of running seizures, the kindled cortical discharge became bilateral and progressively increased in amplitude and duration (Fig. 4A–C). The intensification of the secondary electrographic seizures in the cortex was accompanied by an increasingly severe clonic seizure behavior, evolving in repeated tests from mild limbic (partial) clonus to generalized clonus with rearing and falling (Fig. 4D). The severity of initial running (subcortical) seizure component did not change in repeated tests. At the late kindling stages sound elicited complex two-component seizures consisting of an initial short-lasting (9.270.4 s) subcortical discharge behaviorally manifested as a brief episode of running (Jobe's stage 1 brainstem seizure) and a subsequent prolonged (42.6719.8 s) cortical spike-wave discharge associated with generalized clonic convulsions (Racine's stage 5 limbic seizures).
3.
Discussion
The present study for the first time describes an electrographic pattern of minimal focal subcortical seizures (brief running episodes): their close association with epileptiform abnormalities in the IC and rhythmic activity in the cortex. The epileptogenic zone in audiogenic epilepsy localizes in the IC, the main subcortical area of the auditory system (GarciaCairasco, 2002; Faingold, 2002, 2004). Removal or disconnection of the IC prevents occurrence of audiogenic seizures in susceptible rodents (Browning, 1986), while stimulation of the subcortical nucleus evokes audiogenic seizure-like response in normal rats (Hirsch et al., 1993). The cortex is not involved in the expression of acute audiogenic seizures (Marescaux et al., 1987; Garcia-Cairasco, 2002; Faingold, 2002) and cortical ablation does not influence the incidence and pattern of the seizures (Browning, 1986). Epileptiform activity in the IC during full-blown audiogenic seizures has been reported previously (Ludvig and Moshe, 1989; Dutra Moraes et al., 2000; Moraes et al., 2005). In rodents with high genetic susceptibility to audiogenic seizures (GEPRs, WARs, hamster GASH:Sal), high-amplitude spikes are recorded during the initial running phase of the seizures while electrodecremental and/or spike-wave activity is observed during subsequent tonic and tonic–clonic convulsions (Marescaux et al., 1987; Naritoku et al., 1992; Dutra Moraes et al., 2000; Moraes et al., 2005; Carballosa-Gonzales et al., 2013). In the severe audiogenic seizures, the cortex shows similar electrographic patterns, i.e. spikes during running and electrodecremental pattern during tonic convulsions. The similarity in the electrographic seizure manifestations at the subcortical and cortical levels suggests simultaneous activation of brainstem and cortical substrates during severe generalized audiogenic seizures, including the initial running phase (Dutra Moraes et al., 2000; Moraes et al., 2005). As the current study shows, minimal non-kindled audiogenic seizures (brief running episodes) induced by short sound in Wistar outbred rats are accompanied by epileptiform activation of the IC but not the cortex. Spike activity
Please cite this article as: Vinogradova, L.V., Grinenko, O.A., Ictal electrographic pattern of focal subcortical seizures induced by sound in rats. Brain Research (2016), http://dx.doi.org/10.1016/j.brainres.2016.01.027
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Fig. 4 – Progressive intensification of repeated secondary cortical discharges and associated behavioral seizures during kindling. A – epileptiform discharges recorded in symmetrical sites of the right (upper trace) and left (lower trace) cortex in the same rat after repeated leftward running seizures. The beginning of each trace coincides with the end of a running attack. Negativity is directed downward. Calibration: 0.1 mV, 2 s. B–D – a progressive increase in the mean amplitude (B, po0.05) and duration (C, po0.05) of repeated cortical discharges and in severity of associated limbic seizures (D, po0.0005). D: severity of kindled limbic seizures (circles) was scored according to the 5-point scale of Racine (1972); severity of an initial subcortical (brainstem) component of audiogenic seizures (squares) was scored according to the 9-point scale of Jobe et al. (1973).
recorded in the IC during the mild running seizures is similar to patterns of the IC activity observed during explosive running in rodents with genetic audiogenic epilepsy (Ludvig and Moshe, 1989; Moraes et al., 2005). But the violent running behavior observed in the later rats before tonic–clonic convulsions is accompanied by high-amplitude spikes/polyspikes not only in the IC but in the cortex too (Moraes et al., 2005; Carballosa-Gonzales et al., 2013). The present study in Wistar outbred rats shows a lack of epileptiform activity in the cortex during isolated episodes of running seizures that represents a characteristic feature of primary subcortical seizures. Rhythmic theta activity described in the cortex during the focal audiogenic seizures may result from changes in the activity in the ascending arousal system during soundinduced hyperexcitation of subcortical networks. Theta
oscillations observed in the parietal cortex may reflect activity of hippocampal generators because monopolar EEG recording used in the present study is vulnerable to volume conduction. Remarkably, in patients with the hamartoma of the floor of the fourth ventricle during subcortical seizures the cortex also shows excessive theta activity without epileptic discharges (Pontes-Neto et al., 2006; Delalande et al., 2001). Non-symmetric pattern of the ictal activity of the cortical IC nucleus during audiogenic running seizures described in the present study may indicate lateralized epileptogenicity of subcortical seizure substrates. The ictal electrographic asymmetry of audiogenic running seizures and its relationship with motor asymmetry of the seizures are consistent with the data on unilateral pattern of the IC activation during running seizures induced by direct electrical stimulation of the IC (McCown et al.,
Please cite this article as: Vinogradova, L.V., Grinenko, O.A., Ictal electrographic pattern of focal subcortical seizures induced by sound in rats. Brain Research (2016), http://dx.doi.org/10.1016/j.brainres.2016.01.027
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1991) or by monaural audiogenic priming (Ward, 1971; Ward and Collins, 1971) in Sprague-Dawley and Wistar outbred rats. The finding deserves further investigation. Audiogenic kindling produced by recurrent subcortical seizures leads to secondary epileptic activation of the cerebral cortex (Marescaux et al., 1987; Naritoku et al., 1992; Dutra Moraes et al., 2000). The secondary cortical seizures represent rhythmic spike- or spike-wave discharges starting immediately after the termination of the subcortical IC-driven seizures and accompanied by limbic clonus. Thus, in rats kindled with recurrent running seizures, sound elicits subsequent activation of brainstem and cortical seizure substrates instead of their simultaneous activation observed in rats kindled with repeated full-blown audiogenic seizures (Moraes et al., 2005). During the ictal episodes, a kindled audiogenic running seizure begins as a subcortical event involving the IC and later spreads to the cortex as a running behavior progresses into a limbic clonus. This seizure evolution reflects propagation of seizure discharge from the primary subcortical focus to the cortex. Secondary cortical discharges first appear in the cortex homolateral to the dominant subcortical epileptiform abnormalities. That is primary subcortical seizures and first cortical discharges involve the same hemisphere, suggesting that repetition of focal subcortical seizures may lead to intrahemispheric bottom-up seizure propagation to the cortex. The result reminds clinical evidence obtained in patients with unilateral hamartoma (i.e., lateralized subcortical epileptogenic focus) in which ictal onset of additional seizure types may be asymmetric and lateralized to the side ipsilateral to the hamartoma (Kahane et al., 2003; Troester et al., 2011). The features of focal subcortical seizures induced by sound in animals have many similarities with those of subcortical seizures in patients with hamartoma. Both the IC in rats with audiogenic epilepsy (Faingold, 2002) and the hypothalamic hamartoma in patients (Fenoglio et al., 2007) are intrinsically epileptogenic and could generate brief stereotyped epileptic attacks characterized by paroxysmal running in rats (Garcia-Cairasco, 2002; Faingold, 2002) or laughing in patients (Munari et al., 1995; Kuzniecky et al., 1997). In both animals and humans, only resection of the subcortical focus, but not neocortical ablation, is effective in abolishing the epileptic attacks (Browning, 1986; Delalande et al., 2001; Cascino et al., 1993). Electrical stimulation of the IC or hamartoma elicits seizures similar in their pattern to audiogenic seizures (Hirsch et al., 1993) and hamatromadriven seizures (Kahane et al., 2003) respectively. In patients with the hamartoma of the floor of the fourth ventricle attacks of hemifacial spasms are also supposed to reflect epileptic activation of a subcortical network involving brainstem nuclei (Delalande et al., 2001). Excessive theta activity and no epileptic discharges in the cortex have been described during subcortical seizures in patients with the hamartoma of the floor of the fourth ventricle (Pontes-Neto et al., 2006; Delalande et al., 2001) and hypothalamic hamartoma (Leal et al., 2006). Epilepsy associated with the hypothalamic hamartoma is characterized by progressive evolution. Several years after onset of gelastic seizures patients demonstrate new seizure
types: tonic, complex partial and generalized tonic–clonic (Brandberg et al., 2004; Arzimanoglou et al., 2003). This coincides with progressive EEG epileptiform changes (Arzimanoglou et al., 2003). Partial and generalized seizures can occur separately or with preceding gelastic episodes (Kahane et al., 2003; Arzimanoglou et al., 2003, Berkovic et al., 1988). Berkovic et al. (1988) hypothesized that seizures starting in the intrinsically epileptogenic hamartoma spread by ascending connections to produce cortical ictal discharges. Similar secondary propagation of subcortical seizures to the cerebral cortex with development of cortical ictal discharges and emergence of increasingly complex seizures (running, limbic/partial, generalized tonic–clonic) occurs in audiogenic kindling (Marescaux et al., 1987; Naritoku et al., 1992; Simler et al., 1999; Garcia-Cairasco, 2002; Faingold, 2004; Vinogradova and Sharskova, 2012). That is progressive course of both human gelastic epilepsy and audiogenic kindling is determined by secondary subcortico-cortical epileptogenesis. Despite different neuroanatomical substrates and ictogenic mechanisms of audiogenic and hamartoma-generated seizures, the close similarity in patterns of reflex and spontaneous seizures (Zifkin et al., 2008) allows considering reflex Q5 epilepsy as a valuable tool for studying ictogenesis and epileptogenesis associated with spontaneous seizures. The model of kindling produced by focal reflex subcorticallydriven seizures may be relevant for identification of basic mechanisms of secondary subcortico-cortical epileptogenesis in hamartoma-related epilepsy and searching pharmacological treatments for the medically intractable epileptic syndrome. We believe that audiogenic kindling may be a useful model for studying secondary subcortico-cortical epileptogenesis in patients with symptomatic subcortical epilepsy. This is of interest because clinical data usually do not allow distinguishing between multifocal epilepsies and focal ones with secondary epileptogenesis (Morrell. 1989). Audiogenic kindling, in which primary subcortical epileptogenic zone and secondary cortical foci are clearly separated in time and space, provides unique possibility to study secondary subcortico-cortical epileptogenesis.
4.
Experimental procedures
4.1.
Animals
Adult male Wistar rats (3–5 months, 350–450 g) were used for the experiments. Rats were housed in individual cages under the controlled environmental conditions (a 12-h light-dark cycle, lights on at 7:00 A.M., 20–23 1C) with free access to food and water. The experiments were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and our protocol was approved by the Institutional Animal Care Committee. All efforts were made to minimize animal suffering. Rats susceptible (n ¼20) and unsusceptible (n ¼5) to audiogenic seizures were selected during preliminary screening procedure (three sound stimulations at a week intervals). Wistar rats that reproducibly displayed running seizures in response to three subsequent sound stimulations were
Please cite this article as: Vinogradova, L.V., Grinenko, O.A., Ictal electrographic pattern of focal subcortical seizures induced by sound in rats. Brain Research (2016), http://dx.doi.org/10.1016/j.brainres.2016.01.027
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referred to as susceptible to audiogenic seizures. Rats never showing paroxysmal response to repeated sound stimulation were considered as unsusceptible to audiogenic seizures.
4.4.
7
Data analysis
Data were expressed as mean7SEM. ANOVA for repeated measures was used to evaluate changes in the amplitude and
4.2.
Surgery
duration of electrographic cortical discharges and in severity of seizure behavior in repeated tests as well as to compare
Rats were anesthetized with chloral hydrate (360 mg/kg, i.p.) and treated locally with 2% novocaine. Rats were equipped with both cortical and subcortical electrodes (n¼ 10) or with only cortical electrodes (n ¼10). Depth electrodes, made of vanished nichrome wire (0.5 mm diameter) and insulated except for their cut tips, were implanted bilaterally in the dorsal portion (dorsal cortical nucleus) of the inferior colliculus (stereotaxic coordinates: anteroposterior 9.3–9.5 mm; mediolateral 1–1.5 mm; dorsoventral 3–3.5 mm) (Paxinos and Watson, 1986). Cortical electrodes (stainless steel screws) were placed over the parietal cortex in symmetrical points of the two hemispheres. A stainless-steel screw over the cerebellum was used as a reference electrode. All electrodes were soldered to a pin connector and secured with acrylic cement. The experiment began two weeks after surgery.
4.3.
Experimental design
Audiogenic seizures were induced by standard broad-band sound stimulation (key ringing produced by a purpose-made mechanical vibro-device). Repeated measuring spectral characteristics of the sound with the wide-band spectrum analyzer (Oktava-110A, Digital Instruments, Russia) has shown their high reproducibility (50–60 dB, 13–85 kHz). The sound lasted until the onset of distinct running behavior. If no convulsions occurred, the sound was applied for 60 s. In audiosensitive Wistar rats, the sound stimulation induced minimal seizure response – one or two episodes of running without tonic–clonic convulsions. Each rat was exposed to the sound stimulation once a day at 3– 4-day intervals between repetitions. Twenty five running episodes were induced in each audiosensitive rat. Non-epileptic rats were subjected to 25 sound stimulations. Each animal was individually placed in a shielded chamber (60 50 40 cm3) with a frontal transparent wall and the implanted connector was attached to the recording cable. Swivel system allowed avoiding cable twisting during running behavior. Simultaneous EEG recording and video monitoring (DCR-DVD7E, Sony, Japan; 24 fps) were continuously performed since 1 h before till 1 h after sound stimulation. Synchronous event markers were used to synchronize behavioral changes and EEG data. Mild sound-induced running seizures were associated with minimal movement artifacts and our EEG registration system allowed relatively artifact-free recording (see the Section 2). Electrical activity (band pass 0–500 Hz) was registered with a six-channel, high-input impedance (1 g Ω) dc amplifier and A/D converter (E14-440, L-Card, Russia). The data were digitized at 2 kHz sample rate and stored on PC. Recordings were band-pass filtered (1–45 Hz) and analyzed off-line. The severity of limbic seizures was scored according to the scale of Racine (1972): 1 – facial/ear clonus; 2 – head nodding; 3 – forelimb clonus; 4 – forelimb clonus with rearing; 5 – forelimb clonus with rearing and falling (generalized tonic–clonic seizures).
frequency and power of theta cortical oscillations in epileptic and non-epileptic rats. The level of significance was accepted to be po0.05. A peak frequency and its power for bandpass-filtered (4– 12 Hz) oscillations were calculated to estimate cortical theta activity during audiogenic running seizures. Two-second artifact-free epochs were analyzed using a fast Fourier transform procedure. The signal epochs were selected (1) during the background period, (2) immediately after the onset of sound stimulation and (3) during seizure behavior in epileptic rats or rapid locomotion in non-epileptic rats.
r e f e r e nc e s
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Please cite this article as: Vinogradova, L.V., Grinenko, O.A., Ictal electrographic pattern of focal subcortical seizures induced by sound in rats. Brain Research (2016), http://dx.doi.org/10.1016/j.brainres.2016.01.027
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Munari, C., Kahane, P., Francione, S., Hoffmann, D., Tassi, L., Cusmani, R., Vigevano, F., Pasquier, B., Betti, O.O., 1995. Role of the hypothalamic hamartoma in the genesis of gelastic fits (a video-stereo-EEG study). Electroencephalogr. Clin. Neurophysiol. 95, 154–160. Naritoku, D.K., Mecozzi, L.B., Aiello, M.T., Faingold., C.L., 1992. Repetition of audiogenic seizures in genetically epilepsyprone rats induces cortical epileptiform activity and additional seizure behaviors. Exp. Neurol. 115, 317–324. Parvizi, J., Le, S., Foster, B.L., Bourgeois, B., Riviello, J.J., Prenger, E., Saper, C., Kerrigan, J.F., 2011. Gelastic epilepsy and hypothalamic hamartomas: neuroanatomical analysis of brain lesions in 100 patients. Brain 134, 2960–2968. Paxinos, G., Watson, C., 1986. The Rat Brain in Stereotaxic Coordinates. Academic Press, New-York. Pontes-Neto, O.M., Wichert-Ana, L., Terra-Bustamante, V.C., Velasco, T.R., Bustamante, G.O., Fernandes, R.M.F., AzevedoMarques, P.M., Oliveira, L.F., Santos, A.C., Kato, M., Inuzuka, L. M., Machado, H.R., Sakamoto, A.C., 2006. Pontine activation during focal status epilepticus secondary to hamartoma of the floor of the fourth ventricle. Epilepsy Res. 68, 265–267. Racine, R.J., 1972. Modification of seizure activity by electrical stimulation: II. Motor seizure. Electroencephalogr. Clin. Neurophysiol. 32, 281–294. Simler, S., Vergnes, M., Marescaux, C., 1999. Spatial and temporal relationships between c-fos expression and kindling of audiogenic seizures in Wistar rats. Exp. Neurol. 157, 106–119. Troester, M., Haine-Schlagel, R., Ng, Y., Chapman, K., Chung, S., Drees, C., Prenger, E., Rekate, H., Kerrigan, J.F., 2011. EEG and video-EEG seizure monitoring has limited utility in patients with hypothalamic hamartoma and epilepsy. Epilepsia 52, 1137–1143. Vinogradova, L.V., 2008. Audiogenic kindling in Wistar and WAG/ Rij rats: kindling-prone and kindling-resistant subpopulations. Epilepsia 49, 1665–1674. Vinogradova, L.V., 2015. Audiogenic kindling and secondary subcortico-cortical epileptogenesis: Behavioral correlates and electrophysiological features. Epilepsy Behav.http://dxdoi.org/ 10.1016/j.yebeh.2015.06.14. Vinogradova, L.V., Sharskova, A.B., 2012. Lateral asymmetry of early seizure manifestations in experimental generalized epilepsy. Neuroscience 213, 133–143. Ward, R., 1971. Unilateral susceptibility to audiogenic seizure impaired by contralateral lesions of the inferior colliculus. Exp. Neurol. 32, 313–316. Ward, R., Collins, R.L., 1971. Asymmetric audiogenic seizures in mice: a possible analogue of focal epilepsy. Brain Res. 31, 207–210. Zifkin, B.G., Guerrin, R., Plouin, P., 2008. Reflex seizures. In: Engle, Q7 Jr., Pedley, T. (Eds.), Epilepsy: A Comprehensive Textbook. Lippincott Williams & WilkinsUSA, pp. 2559–2695.
Please cite this article as: Vinogradova, L.V., Grinenko, O.A., Ictal electrographic pattern of focal subcortical seizures induced by sound in rats. Brain Research (2016), http://dx.doi.org/10.1016/j.brainres.2016.01.027
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Research Report
Ictal electrographic pattern of focal subcortical seizures induced by sound in rats Lyudmila V. Vinogradovaa,n, Olesya A. Grinenkob a
Institute of Higher Nervous Activity and Neurophysiology Russian Academy of Sciences, Moscow, Russia Burdenko Neurosurgery Institute, Moscow, Russia
b
art i cle i nfo
ab st rac t
Article history:
It is now recognized that both generalized and focal seizures may originate in subcortical
Accepted 18 January 2016
structures. The well-known types of focal subcortically-driven seizures are gelastic seizures in patients with the hypothalamic hamartoma and sound-induced seizures in
Keywords:
rodents with audiogenic epilepsy. The seizures are generated by subcortical intrinsically
Epilepsy
epileptogenic focus, the hamartoma in humans and the inferior colliculus (IC) in rodents.
Secondary epileptogenesis
In patients with gelastic epilepsy additional seizure types may develop with time that are
Audiogenic seizure
supposed to result from secondary epileptogenesis and spreading of epileptic discharges to
Kindling
the cortex. Repeated audiogenic seizures can also lead to development of additional
EEG
seizure behavior and secondary epileptic activation of the cortex. This process, named
Hamartoma
audiogenic kindling, may be useful for studying secondary subcortico-cortical epileptogenesis. Using intracollicular and intracortical recordings, we studied an ictal electrographic pattern of focal subcortical seizures induced by repeated sound stimulation in Wistar audiogenic-susceptible rats. The audiogenic seizures, representing brief attacks of paroxysmal unidirectional running, were accompanied by epileptiform abnormalities in the IC, mostly on the side ipsilateral to run direction, and enhanced rhythmic 8–9 Hz activity in the cortex. With repetition of the subcortical seizures and kindling development, a secondary cortical discharge began to follow the IC seizure. The secondary discharge initially involved the cortex homolateral to the side of dominant subcortical epileptiform abnormalities and behaviorally expressed as limbic (partial) clonus. Kindling progression was associated with bilateralization of the secondary cortical discharge, an increase in its amplitude and duration, intensification of associated behavioral seizures (from partial clonus to generalized tonic–clonic convulsions). Thus, ictal recordings during brief audiogenic running seizures showed their focal subcortical origin. Repetition of the subcortical seizures may result in secondary subcortico-cortical epileptogenesis manifested by emergence and progressive intensification of epileptiform discharges in the cortex. & 2016 Published by Elsevier B.V.
n Correspondence to: Institute of Higher Nervous Activity and Neurophysiology Russian Academy of Sciences, 117485 Moscow Butlerova Street 5A. Fax: þ7 499 7430056. E-mail address: [email protected] (L.V. Vinogradova).
http://dx.doi.org/10.1016/j.brainres.2016.01.027 0006-8993/& 2016 Published by Elsevier B.V.
Please cite this article as: Vinogradova, L.V., Grinenko, O.A., Ictal electrographic pattern of focal subcortical seizures induced by sound in rats. Brain Research (2016), http://dx.doi.org/10.1016/j.brainres.2016.01.027
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1.
Introduction
Although human epilepsy is traditionally considered as a result of cortical pathology, it is now recognized that some seizure types may have subcortical origin (Berg et al., 2010), for example, gelastic seizures in patients with hypothalamic hamartoma. These seizures arise directly from the focal subcortical lesion associated with hamartoma (Munari et al., 1995; Kuzniecky et al., 1997) that exhibits intrinsic epileptogenicity (Fenoglio et al., 2007). With time, patients with hypothalamic hamartoma begin to show epileptiform abnormalities in the cortex and additional seizure types, i.e. partial and generalized tonic–clonic seizures (Berkovic et al., 1988). Since the appearance of multiple non-gelastic seizures highly depends on the disease duration, involvement of kindling-like mechanisms and secondary subcortico-cortical epileptogenesis has been suggested to underlie the disease progression (Parvizi et al., 2011). In the course of the hamartoma-related epilepsy, repetitive ictal discharges are supposed to spread from a subcortical lesion to the cerebral cortex, leading to appearance of secondary cortical seizure foci (Kahane et al., 2003; Kerrigan et al., 2005). However, there is no experimental evidence for this hypothesis. The best characterized experimental model for primary subcortical seizures and secondary subcortico-cortical epileptogenesis is audiogenic epilepsy in rodents (Krushinsky et al., 1970; Jobe et al., 1973; Ludvig and Moshe, 1989; Faingold, 2002, 2004; Garcia-Cairasco, 2002; Jobe and Browning, 2006; Vinogradova, 2015). Audiogenic seizures induced by sound in susceptible animals are driven by brainstem networks with a primary focus in the inferior colliculus (IC), the subcortical auditory nucleus showing intrinsic epileptogenicity in rodents with audiogenic epilepsy (Faingold, 2002). Soundinduced seizures may be focal or widely generalized within brainstem networks. Full-blown audiogenic seizures, i.e. running followed by generalized tonic/clonic convulsion, are associated with widespread epileptic activation of the brainstem (Krushinsky et al., 1970; Garcia-Cairasco, 2002; Faingold, 2004; Jobe and Browning, 2006). The initial running component of audiogenic seizures is thought to reflect early focal brainstem excitation (Jobe and Browning, 2006). Rats with high genetic susceptibility to audiogenic seizures (Genetically Epilepsy-prone Rats (GEPRs), Wistar Audiogenic Rats (WARs), KM rats) express explosive running/myoclonic trusts before the onset of severe sound-induced tonic–clonic seizures. In rats with low seizure susceptibility (audiosensitive rats of Wistar and Sprague-Dawley outbred strains) audiogenic seizures usually start with one or two episodes of mild running behavior. Motor asymmetry of the latter running behavior has been described recently Vinogradova and Sharskova, 2012), further supporting the focal nature of the seizure. With repetition of audiogenic seizures, epileptic activity spreads to the forebrain (the amygdala, cortex and hippocampus) and additional forebrain-driven seizure types develop (Marescaux et al., 1987; Naritoku et al., 1992; Simler et al., 1999; Dutra Moraes et al., 2000). During this epileptogenic process, named audiogenic kindling, recurrent subcortical seizures elicit a trans-synaptic and long-lasting increase in excitability of cortico-limbic regions that finally leads to
development of secondary epileptiform discharges in the cortex. Evidence obtained in the kindling model, in which epileptogenesis is determined by expansion of the seizure network from a primary subcortical focus to the cerebral cortex, may be useful for understanding secondary subcortico-cortical epileptogenesis in the human brain. Audiogenic kindling can be produced by repetition of either focal or full-blown generalized seizures. Behavioral and electrographic profiles of the latter kindling paradigm produced by generalized brainstem seizures have been studied previously (Marescaux et al., 1987; Naritoku et al., 1992; Faingold, 2004; Dutra Moraes et al., 2000). Epileptic activation of the cerebral cortex has been reported during the seizures not only in kindled but even in non-kindled animals (Moraes et al., 2005; Carballosa-Gonzales et al., 2013). This suggests co-activation of subcortical and cortical networks during full-blown audiogenic seizures irrespectively of kindling development. Mild paradigm of audiogenic kindling produced by repetition of focal running seizures (in fact the first manifestation of audiogenic seizures) may model epilepsy related with a local subcortical epileptogenic lesion, such as in case of patients with hamartoma. Though a behavioral pattern of the kindling has been characterized previously (Vinogradova, 2008), little is known about electrographic manifestations of the focal audiogenic seizures and secondary kindling-induced epileptogenic changes in the cortex. The present study examined the relationship between the behavioral expression of repeated audiogenic running seizures and ictal electrical activity in the primary subcortical focus (the IC) and in the cerebral cortex secondarily involved in the seizure network. Because a motor asymmetry is a common feature of the audiogenic running seizures in Wistar rats (Vinogradova and Sharskova, 2012), ictal electrographic activity was recorded in both sides of the brain.
2.
Results
In Wistar rats with audiogenic epilepsy, sound stimulation initially evoked only brief running seizures (focal subcortical seizures), i.e., stage-1 seizures according to the scale of Jobe (Jobe et al., 1973). In 6–18 s after the onset of sound stimulation (a latent period of a seizure), rats expressed one or two brief episodes of mild motor behavior (running) without jumps and tonic–clonic convulsions. After interruption of sound stimulation with the seizure onset, self-sustained running behavior continued for 2–11 s. The pattern of the seizure behavior in non-kindled animals varied from a forced unidirectional turning/lateroflexion to rapid locomotion/slow running. In repeated tests the running seizures began to be accompanied by jumping. The sound-induced running had an asymmetric (unidirectional) pattern and its individual directionality was consistent in repeated tests, confirming our previous findings (Vinogradova and Sharskova, 2012). The running seizure was preceded and followed by freezing behavior. The characteristic pattern and latency of repeated running seizures allowed distinguishing the seizure behavior from any non-epileptic locomotion. Electrographic recordings during the initial focal audiogenic seizures in non-kindled rats revealed epileptiform
Please cite this article as: Vinogradova, L.V., Grinenko, O.A., Ictal electrographic pattern of focal subcortical seizures induced by sound in rats. Brain Research (2016), http://dx.doi.org/10.1016/j.brainres.2016.01.027
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Fig. 1 – Ictal electrographic patterns of audiogenic running seizures in non-kindled Wistar rats. Recordings from the right (R) and left (L) parietal cortices (Cx) and inferior colliculi (IC) during sound-induced forced leftward lateroflexion (A and B) and rightward running (C) are presented. B is an expanded fragment marked by rectangle in A. Lines below fragments mark episodes of motor behavior – running seizure (black lines) and non-seizure locomotion (white line in A). Audiogenic seizures are accompanied by rhythmic activity in the cortex and unilateral (A and B) or bilateral asymmetric (C) epileptiform abnormalities in the IC. A lack of movement artifacts during non-seizure locomotion (A) indicates relatively artifact-free EEG recording. Negativity is directed downward. Calibration: 0.2 mV, 5 s (A) or 2 s (B and C).
Fig. 2 – Rhythmic activity in the cortex during sound-induced running seizures. A – typical ictal activity in the parietal cortex of the right (R) and left (L) hemispheres during episode of audiogenic running. Period of running behavior is marked below the recording. Calibration: 0.2 mV, 2 s. B and C – frequency and power of cortical activity in the theta frequency band (4–12 Hz) during the background period (bg), after the onset of sound stimulation (sound stimulation) and during sound-induced motor activity (running seizures in epileptic rats or rapid locomotion in non-epileptic rats). ***po0.001 – significant difference between epileptic (open bars) and non-epileptic (filled bars) rats. Please cite this article as: Vinogradova, L.V., Grinenko, O.A., Ictal electrographic pattern of focal subcortical seizures induced by sound in rats. Brain Research (2016), http://dx.doi.org/10.1016/j.brainres.2016.01.027
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abnormalities in the IC but not in the cortex. Usually mild motor activity during the seizures allowed us to avoid significant movement artifacts in EEG recording. Depth recordings showed the presence of sharp waves, spikes and polispikes in the IC even during the subtle seizure behavior (Fig. 1). The intracollicular epileptiform activity was evident in 23 of 27 artifact-free episodes of mild audiogenic seizures recorded in five rats. The ictal IC discharges had lateralized patterns and were expressed as unilateral (Fig. 1A and B) or bilateral asymmetric (Fig. 1C) activity. The collicular epileptiform activity was predominantly or exclusively recorded on the side ipsilateral to run direction. In the cortex of non-kindled rats, no obvious epileptiform activity was observed during the running seizures. The accentuated oscillations in the theta frequency band were the only and reliable feature of cortical activity during the mild focal audiogenic seizures across rats and in the same animal (Fig. 2A). The period of enhanced rhythmic activity of 8–9 Hz always coincided with sound-induced seizure behavior. ANOVA for repeated measures has shown that both frequency and power of theta cortical oscillations was significantly higher during the ictal behavior as compared to background and sound-induced arousal (po0.001) as well as to rapid locomotion in non-epileptic rats (Fig. 2B and C). In rats that developed audiogenic kindling with repeated running seizures (n¼ 6), epileptiform activity appeared in the cortex, indicating secondary epileptogenic changes in the cortex. Fig. 3 shows a typical example of the first cortical epileptiform discharge recorded after repeated running seizures. The cortical seizure represented a low-frequency (2–4 Hz) selfsustained spike discharge in the hemisphere homolateral to the side of the subcortical seizure. The cortical spiking started with the end of IC-driven seizure (running), continued during the limbic clonus (kindled forebrain-driven seizure behavior) and terminated simultaneously with the end of the clonus. The limbic clonus, that is accepted to model complex partial
Fig. 3 – The first epileptiform discharge recorded in the cortex after the 16th episode of running seizure. The discharge represents unilateral spiking in the right cortex associated with facial clonus (open line) that follows rightward running (filled line below the fragment). Thus sound evokes subsequent activation of the IC (unilateral highamplitude spikes) and cerebral cortex. Abbreviations and calibration are identical to those on Fig. 1.
seizures in patients (Racine, 1972), was initially expressed as eye blinking, facial clonus or unilateral clonic jerking of the pinna contralateral to the cortical discharge. With further sound stimulation and induction of running seizures, the kindled cortical discharge became bilateral and progressively increased in amplitude and duration (Fig. 4A–C). The intensification of the secondary electrographic seizures in the cortex was accompanied by an increasingly severe clonic seizure behavior, evolving in repeated tests from mild limbic (partial) clonus to generalized clonus with rearing and falling (Fig. 4D). The severity of initial running (subcortical) seizure component did not change in repeated tests. At the late kindling stages sound elicited complex two-component seizures consisting of an initial short-lasting (9.270.4 s) subcortical discharge behaviorally manifested as a brief episode of running (Jobe's stage 1 brainstem seizure) and a subsequent prolonged (42.6719.8 s) cortical spike-wave discharge associated with generalized clonic convulsions (Racine's stage 5 limbic seizures).
3.
Discussion
The present study for the first time describes an electrographic pattern of minimal focal subcortical seizures (brief running episodes): their close association with epileptiform abnormalities in the IC and rhythmic activity in the cortex. The epileptogenic zone in audiogenic epilepsy localizes in the IC, the main subcortical area of the auditory system (GarciaCairasco, 2002; Faingold, 2002, 2004). Removal or disconnection of the IC prevents occurrence of audiogenic seizures in susceptible rodents (Browning, 1986), while stimulation of the subcortical nucleus evokes audiogenic seizure-like response in normal rats (Hirsch et al., 1993). The cortex is not involved in the expression of acute audiogenic seizures (Marescaux et al., 1987; Garcia-Cairasco, 2002; Faingold, 2002) and cortical ablation does not influence the incidence and pattern of the seizures (Browning, 1986). Epileptiform activity in the IC during full-blown audiogenic seizures has been reported previously (Ludvig and Moshe, 1989; Dutra Moraes et al., 2000; Moraes et al., 2005). In rodents with high genetic susceptibility to audiogenic seizures (GEPRs, WARs, hamster GASH:Sal), high-amplitude spikes are recorded during the initial running phase of the seizures while electrodecremental and/or spike-wave activity is observed during subsequent tonic and tonic–clonic convulsions (Marescaux et al., 1987; Naritoku et al., 1992; Dutra Moraes et al., 2000; Moraes et al., 2005; Carballosa-Gonzales et al., 2013). In the severe audiogenic seizures, the cortex shows similar electrographic patterns, i.e. spikes during running and electrodecremental pattern during tonic convulsions. The similarity in the electrographic seizure manifestations at the subcortical and cortical levels suggests simultaneous activation of brainstem and cortical substrates during severe generalized audiogenic seizures, including the initial running phase (Dutra Moraes et al., 2000; Moraes et al., 2005). As the current study shows, minimal non-kindled audiogenic seizures (brief running episodes) induced by short sound in Wistar outbred rats are accompanied by epileptiform activation of the IC but not the cortex. Spike activity
Please cite this article as: Vinogradova, L.V., Grinenko, O.A., Ictal electrographic pattern of focal subcortical seizures induced by sound in rats. Brain Research (2016), http://dx.doi.org/10.1016/j.brainres.2016.01.027
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Fig. 4 – Progressive intensification of repeated secondary cortical discharges and associated behavioral seizures during kindling. A – epileptiform discharges recorded in symmetrical sites of the right (upper trace) and left (lower trace) cortex in the same rat after repeated leftward running seizures. The beginning of each trace coincides with the end of a running attack. Negativity is directed downward. Calibration: 0.1 mV, 2 s. B–D – a progressive increase in the mean amplitude (B, po0.05) and duration (C, po0.05) of repeated cortical discharges and in severity of associated limbic seizures (D, po0.0005). D: severity of kindled limbic seizures (circles) was scored according to the 5-point scale of Racine (1972); severity of an initial subcortical (brainstem) component of audiogenic seizures (squares) was scored according to the 9-point scale of Jobe et al. (1973).
recorded in the IC during the mild running seizures is similar to patterns of the IC activity observed during explosive running in rodents with genetic audiogenic epilepsy (Ludvig and Moshe, 1989; Moraes et al., 2005). But the violent running behavior observed in the later rats before tonic–clonic convulsions is accompanied by high-amplitude spikes/polyspikes not only in the IC but in the cortex too (Moraes et al., 2005; Carballosa-Gonzales et al., 2013). The present study in Wistar outbred rats shows a lack of epileptiform activity in the cortex during isolated episodes of running seizures that represents a characteristic feature of primary subcortical seizures. Rhythmic theta activity described in the cortex during the focal audiogenic seizures may result from changes in the activity in the ascending arousal system during soundinduced hyperexcitation of subcortical networks. Theta
oscillations observed in the parietal cortex may reflect activity of hippocampal generators because monopolar EEG recording used in the present study is vulnerable to volume conduction. Remarkably, in patients with the hamartoma of the floor of the fourth ventricle during subcortical seizures the cortex also shows excessive theta activity without epileptic discharges (Pontes-Neto et al., 2006; Delalande et al., 2001). Non-symmetric pattern of the ictal activity of the cortical IC nucleus during audiogenic running seizures described in the present study may indicate lateralized epileptogenicity of subcortical seizure substrates. The ictal electrographic asymmetry of audiogenic running seizures and its relationship with motor asymmetry of the seizures are consistent with the data on unilateral pattern of the IC activation during running seizures induced by direct electrical stimulation of the IC (McCown et al.,
Please cite this article as: Vinogradova, L.V., Grinenko, O.A., Ictal electrographic pattern of focal subcortical seizures induced by sound in rats. Brain Research (2016), http://dx.doi.org/10.1016/j.brainres.2016.01.027
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1991) or by monaural audiogenic priming (Ward, 1971; Ward and Collins, 1971) in Sprague-Dawley and Wistar outbred rats. The finding deserves further investigation. Audiogenic kindling produced by recurrent subcortical seizures leads to secondary epileptic activation of the cerebral cortex (Marescaux et al., 1987; Naritoku et al., 1992; Dutra Moraes et al., 2000). The secondary cortical seizures represent rhythmic spike- or spike-wave discharges starting immediately after the termination of the subcortical IC-driven seizures and accompanied by limbic clonus. Thus, in rats kindled with recurrent running seizures, sound elicits subsequent activation of brainstem and cortical seizure substrates instead of their simultaneous activation observed in rats kindled with repeated full-blown audiogenic seizures (Moraes et al., 2005). During the ictal episodes, a kindled audiogenic running seizure begins as a subcortical event involving the IC and later spreads to the cortex as a running behavior progresses into a limbic clonus. This seizure evolution reflects propagation of seizure discharge from the primary subcortical focus to the cortex. Secondary cortical discharges first appear in the cortex homolateral to the dominant subcortical epileptiform abnormalities. That is primary subcortical seizures and first cortical discharges involve the same hemisphere, suggesting that repetition of focal subcortical seizures may lead to intrahemispheric bottom-up seizure propagation to the cortex. The result reminds clinical evidence obtained in patients with unilateral hamartoma (i.e., lateralized subcortical epileptogenic focus) in which ictal onset of additional seizure types may be asymmetric and lateralized to the side ipsilateral to the hamartoma (Kahane et al., 2003; Troester et al., 2011). The features of focal subcortical seizures induced by sound in animals have many similarities with those of subcortical seizures in patients with hamartoma. Both the IC in rats with audiogenic epilepsy (Faingold, 2002) and the hypothalamic hamartoma in patients (Fenoglio et al., 2007) are intrinsically epileptogenic and could generate brief stereotyped epileptic attacks characterized by paroxysmal running in rats (Garcia-Cairasco, 2002; Faingold, 2002) or laughing in patients (Munari et al., 1995; Kuzniecky et al., 1997). In both animals and humans, only resection of the subcortical focus, but not neocortical ablation, is effective in abolishing the epileptic attacks (Browning, 1986; Delalande et al., 2001; Cascino et al., 1993). Electrical stimulation of the IC or hamartoma elicits seizures similar in their pattern to audiogenic seizures (Hirsch et al., 1993) and hamatromadriven seizures (Kahane et al., 2003) respectively. In patients with the hamartoma of the floor of the fourth ventricle attacks of hemifacial spasms are also supposed to reflect epileptic activation of a subcortical network involving brainstem nuclei (Delalande et al., 2001). Excessive theta activity and no epileptic discharges in the cortex have been described during subcortical seizures in patients with the hamartoma of the floor of the fourth ventricle (Pontes-Neto et al., 2006; Delalande et al., 2001) and hypothalamic hamartoma (Leal et al., 2006). Epilepsy associated with the hypothalamic hamartoma is characterized by progressive evolution. Several years after onset of gelastic seizures patients demonstrate new seizure
types: tonic, complex partial and generalized tonic–clonic (Brandberg et al., 2004; Arzimanoglou et al., 2003). This coincides with progressive EEG epileptiform changes (Arzimanoglou et al., 2003). Partial and generalized seizures can occur separately or with preceding gelastic episodes (Kahane et al., 2003; Arzimanoglou et al., 2003, Berkovic et al., 1988). Berkovic et al. (1988) hypothesized that seizures starting in the intrinsically epileptogenic hamartoma spread by ascending connections to produce cortical ictal discharges. Similar secondary propagation of subcortical seizures to the cerebral cortex with development of cortical ictal discharges and emergence of increasingly complex seizures (running, limbic/partial, generalized tonic–clonic) occurs in audiogenic kindling (Marescaux et al., 1987; Naritoku et al., 1992; Simler et al., 1999; Garcia-Cairasco, 2002; Faingold, 2004; Vinogradova and Sharskova, 2012). That is progressive course of both human gelastic epilepsy and audiogenic kindling is determined by secondary subcortico-cortical epileptogenesis. Despite different neuroanatomical substrates and ictogenic mechanisms of audiogenic and hamartoma-generated seizures, the close similarity in patterns of reflex and spontaneous seizures (Zifkin et al., 2008) allows considering reflex Q5 epilepsy as a valuable tool for studying ictogenesis and epileptogenesis associated with spontaneous seizures. The model of kindling produced by focal reflex subcorticallydriven seizures may be relevant for identification of basic mechanisms of secondary subcortico-cortical epileptogenesis in hamartoma-related epilepsy and searching pharmacological treatments for the medically intractable epileptic syndrome. We believe that audiogenic kindling may be a useful model for studying secondary subcortico-cortical epileptogenesis in patients with symptomatic subcortical epilepsy. This is of interest because clinical data usually do not allow distinguishing between multifocal epilepsies and focal ones with secondary epileptogenesis (Morrell. 1989). Audiogenic kindling, in which primary subcortical epileptogenic zone and secondary cortical foci are clearly separated in time and space, provides unique possibility to study secondary subcortico-cortical epileptogenesis.
4.
Experimental procedures
4.1.
Animals
Adult male Wistar rats (3–5 months, 350–450 g) were used for the experiments. Rats were housed in individual cages under the controlled environmental conditions (a 12-h light-dark cycle, lights on at 7:00 A.M., 20–23 1C) with free access to food and water. The experiments were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and our protocol was approved by the Institutional Animal Care Committee. All efforts were made to minimize animal suffering. Rats susceptible (n ¼20) and unsusceptible (n ¼5) to audiogenic seizures were selected during preliminary screening procedure (three sound stimulations at a week intervals). Wistar rats that reproducibly displayed running seizures in response to three subsequent sound stimulations were
Please cite this article as: Vinogradova, L.V., Grinenko, O.A., Ictal electrographic pattern of focal subcortical seizures induced by sound in rats. Brain Research (2016), http://dx.doi.org/10.1016/j.brainres.2016.01.027
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referred to as susceptible to audiogenic seizures. Rats never showing paroxysmal response to repeated sound stimulation were considered as unsusceptible to audiogenic seizures.
4.4.
7
Data analysis
Data were expressed as mean7SEM. ANOVA for repeated measures was used to evaluate changes in the amplitude and
4.2.
Surgery
duration of electrographic cortical discharges and in severity of seizure behavior in repeated tests as well as to compare
Rats were anesthetized with chloral hydrate (360 mg/kg, i.p.) and treated locally with 2% novocaine. Rats were equipped with both cortical and subcortical electrodes (n¼ 10) or with only cortical electrodes (n ¼10). Depth electrodes, made of vanished nichrome wire (0.5 mm diameter) and insulated except for their cut tips, were implanted bilaterally in the dorsal portion (dorsal cortical nucleus) of the inferior colliculus (stereotaxic coordinates: anteroposterior 9.3–9.5 mm; mediolateral 1–1.5 mm; dorsoventral 3–3.5 mm) (Paxinos and Watson, 1986). Cortical electrodes (stainless steel screws) were placed over the parietal cortex in symmetrical points of the two hemispheres. A stainless-steel screw over the cerebellum was used as a reference electrode. All electrodes were soldered to a pin connector and secured with acrylic cement. The experiment began two weeks after surgery.
4.3.
Experimental design
Audiogenic seizures were induced by standard broad-band sound stimulation (key ringing produced by a purpose-made mechanical vibro-device). Repeated measuring spectral characteristics of the sound with the wide-band spectrum analyzer (Oktava-110A, Digital Instruments, Russia) has shown their high reproducibility (50–60 dB, 13–85 kHz). The sound lasted until the onset of distinct running behavior. If no convulsions occurred, the sound was applied for 60 s. In audiosensitive Wistar rats, the sound stimulation induced minimal seizure response – one or two episodes of running without tonic–clonic convulsions. Each rat was exposed to the sound stimulation once a day at 3– 4-day intervals between repetitions. Twenty five running episodes were induced in each audiosensitive rat. Non-epileptic rats were subjected to 25 sound stimulations. Each animal was individually placed in a shielded chamber (60 50 40 cm3) with a frontal transparent wall and the implanted connector was attached to the recording cable. Swivel system allowed avoiding cable twisting during running behavior. Simultaneous EEG recording and video monitoring (DCR-DVD7E, Sony, Japan; 24 fps) were continuously performed since 1 h before till 1 h after sound stimulation. Synchronous event markers were used to synchronize behavioral changes and EEG data. Mild sound-induced running seizures were associated with minimal movement artifacts and our EEG registration system allowed relatively artifact-free recording (see the Section 2). Electrical activity (band pass 0–500 Hz) was registered with a six-channel, high-input impedance (1 g Ω) dc amplifier and A/D converter (E14-440, L-Card, Russia). The data were digitized at 2 kHz sample rate and stored on PC. Recordings were band-pass filtered (1–45 Hz) and analyzed off-line. The severity of limbic seizures was scored according to the scale of Racine (1972): 1 – facial/ear clonus; 2 – head nodding; 3 – forelimb clonus; 4 – forelimb clonus with rearing; 5 – forelimb clonus with rearing and falling (generalized tonic–clonic seizures).
frequency and power of theta cortical oscillations in epileptic and non-epileptic rats. The level of significance was accepted to be po0.05. A peak frequency and its power for bandpass-filtered (4– 12 Hz) oscillations were calculated to estimate cortical theta activity during audiogenic running seizures. Two-second artifact-free epochs were analyzed using a fast Fourier transform procedure. The signal epochs were selected (1) during the background period, (2) immediately after the onset of sound stimulation and (3) during seizure behavior in epileptic rats or rapid locomotion in non-epileptic rats.
r e f e r e nc e s
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Please cite this article as: Vinogradova, L.V., Grinenko, O.A., Ictal electrographic pattern of focal subcortical seizures induced by sound in rats. Brain Research (2016), http://dx.doi.org/10.1016/j.brainres.2016.01.027
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