Neurol Sci (2005) 26:s225–s232 DOI 10.1007/s10072-005-0492-8
C.A. Tassinari • G. Rubboli • E. Gardella • G. Cantalupo • G. Calandra-Buonaura • M. Vedovello M. Alessandria • G. Gandini • S. Cinotti • N. Zamponi • S. Meletti
Central pattern generators for a common semiology in fronto-limbic seizures and in parasomnias. A neuroethologic approach
Abstract Central pattern generators (CPGs) are genetically determined neuronal aggregates in the mesencephalon, pons and spinal cord subserving innate motor behaviours essential for survival (feeding, locomotion, reproduction etc.). In higher primates CPGs are largely under neocortical control. We describe how certain motor events observed in parasomnias and epileptic seizures could have similar features and resemble motor behaviours, which can be the expression of the same CPG. Both epilepsy and sleep can lead to a temporary loss of control of neomammalian cortex that facilitates through a common platform (arousal) the emergences of stereotyped inborn fixed action patterns. Therefore we suggest that, independently from the nature of the trigger, be it a seizure or a parasomnia, the same CPGs can be involved, “caught up”, leading to a common motor semiology (the “Carillon theory”). Key words Central pattern generators Epilepsy • Arousal
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Parasomnias
C.A. Tassinari () • G. Rubboli • E. Gardella • G. Cantalupo G. Calandra-Buonaura • M. Vedovello • M. Alessandria S. Meletti Division of Neurology, Department of Neurosciences Bellaria Hospital, University of Bologna, Italy Via Altura 3, I-40139 Bologna, Italy e-mail:
[email protected] G. Gandini • S. Cinotti Department of Clinical Veterinary University of Bologna, Italy N. Zamponi Department of Pediatric Neurology Children’s Hospital G. Salesi, Ancona, Italy
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Introduction In our analysis we will consider exclusively the motor expression of events related to epileptic seizures and parasomnias. Other components, albeit relevant, such as the subjective feelings, the impairment – if any – of consciousness or of memory and the variations of vegetative functions, are not considered. We analyse seizures of a proven epileptic nature, recorded by intensive video-polygraphic monitoring of patients, with drug-resistant epilepsy, evaluated for epilepsy surgery treatment in the “C. Munari” Centre of Niguarda (Milan) and in the Bellaria Hospital (Bologna). For each recorded seizure we focused our attention on movements involving the limbs, the trunk and particularly the face. Kinematic analysis of these videorecorded motor events was performed frame-by-frame with dedicated computer software. The great majority of our patients suffered from “frontal nocturnal hypermotor seizures” (discussed in this Symposium) or seizures related to mesial temporal/frontotemporal networks. Our main purposes according to our previous works [1–4] are: - to suggest that some “motor events” – related to epileptic seizures or to certain “parasomnias” – are stereotyped inborn fixed action patterns; - to stress that such “motor events” – independently from their aetiology and nature – can be the expression of the same genetically determined central pattern generators (CPGs); - to suggest that there can be a continuum of stereotyped motor sequences, ranging from physiological movement in foetuses and newborn, to motor behaviours in physiological sleep, in parasomnias and some epileptic seizures; - to show that the motor sequences can often be viewed as “behaviours” or “ethograms”, similar and comparable with “nonhuman” behaviours.
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The motor behaviours considered here have the following features: They have stereotyped features as “fixed action patterns” in relation to a common network referred to as “central pattern generators”. When they occur during sleep they stem from a common platform: the arousal network.
The central pattern generators From Grillner [5]: “Movements are generated by dedicated network of nerve cells that contain the information that is necessary to activate different motor neurons in the appropriate sequence and intensity to generate motor patterns. Such networks are referred to as ‘Central Pattern Generators’”. We are particularly interested in CPGs (Fig. 1) that (a) “generate rhythmic movements” and (b) “express speciesspecific innate emotions” [5].
The motor expression of the arousal Since Broughton’s seminal paper [6], arousal has been considered a common platform for the appearance of various parasomnias and paroxysmal epileptic discharges and seizures during sleep [7, 8].
Motor arousal, with all the question marks related to our scanty data, is variously described as a head movement, an opening of the eyes, occasionally with a deviation on one side as in a searching behaviour; one hand frequently is raised toward the head. Such motor behaviour is observed in normal subjects during physiological sleep, and it occurs in the onset of various parasomnias and in various sleeprelated epileptic seizures (such as the tonic “a minima” seizures in Lennox Gastaut syndrome or in hypermotor seizure onset in Wada’s [9] first classical description). Surface EEG can help in finding if the event is epileptic or not in nature [10], but at times intracerebral recording necessary to find the precise nature (epileptic or nonepileptic) of the event [11, 12]. For these reasons it is difficult to know whether arousal is different in a physiological event or when it introduces a parasomnia or is the initial fragment of an epileptic seizure. We report here some conditions where motor behaviour is the same, and yet the aetiology can be an epileptic seizure or an event of a non-epileptic nature such as a parasomnia (Fig. 2). Bruxism. It is a parasomnia characterised by stereotyped grinding or clenching of the teeth, a masticatory activity related to brainstem CPG [13] and secondary to periodic microarousal [14, 15]. We have reported [16] clinical and video polygraphic evidence of rhythmic teeth grinding as the predominant symptom related to temporal lobe seizures during sleep (Fig. 3). After a left temporal lobectomy both seizures and the related bruxism disappeared after a two-year follow-up.
Fig. 1 Modified from Grillner [5] (with permission). Location of different central pattern generators that coordinate different motor patterns/behaviours in vertebrates (on the right). The vertebrate control scheme for locomotion (on the left). The basal ganglia exert a tonic inhibitory influence on motor centres that is released when a motor pattern is selected. Locomotion is initiated by activity in reticulospinal neurons of the brainstem locomotor centre, which produces locomotor pattern modulated in the central spinal network
C.A. Tassinari et al.: CPGs in fronto-limbic seizures and parasomnias
We considered that one common CPG involved in the masticatory rhythmic activity could be “activated” or “released” by different conditions, be it a physiologic masticatory activity, a sleep-related parasomnia or a seizure-related event. Masticatory swallowing and lip smacking activities are frequently related to seizures involving the mesiotemporal structures, which likely activate a set of coordinated, stereotyped movements related to alimentary behaviour. Seizure-related bruxism, present in 10 of 10 recorded seizures of our patient [16], was also accompanied by rhythmic myoclonus of the left leg in 5 out 10 seizures: in four the leg myoclonus occurred simultaneously with the bruxism, and in the other the leg movements preceded the onset of bruxism by two seconds (see the supplementary material on the Neurology Website, www.neurology.org). End of bruxism and myoclonus could also be in various relationships (Fig. 3). These data suggest two different rhythmic CPG in the brain stem: one for the bruxism [13, 17] and the other for rhythmic leg movements (Fig. 3 and see also Discussion). Biting/flybiting and facio-mandibular myoclonus. Faciomandibular myoclonus during sleep, responsible for repeated self-biting with bleeding of the oral tissues, has been documented by Vetrugno [18] in non-epileptic patients. Biting in relation to epileptic partial seizures in dogs constitute a frequent and well known phenomena referred to as “fly-biting seizures”, a self-descriptive term (Fig. 4). Faciomandibular myoclonus during sleep in man and the fly-biting in dogs in relation to epileptic seizures are very similar – in our judging of video recordings of Vetrugno’s [18] cases
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and of “fly biting seizures” documented in dogs (Fig. 4). Biting can also occur in strict relationship with an epileptic seizure in man [19]: the act of biting is most frequently observed as evoked by an intrusion of the examiner’s hand in the peripersonal, particular facial, “territorial” space of the patient. However it can also occur albeit rarely “spontaneously” not as a reflex biting but as an urge, a need to bite (Fig. 4). Epileptic biting in man occurs in frontal and temporal seizures [20, 21]; intracranial deep stereotaxic recording, SEEG, in one subject explored at the Munari Centre for Epilepsy in Milan, showed that the amygdalohippocampal and the orbitomedial prefrontal networks were involved when the biting behaviour occurred [20]. These data indicate that the act of biting can be related to an epileptic event as well as non-epileptic behaviour during sleep, suggesting a common CPG. Emotions: facial expressions and vocalisations. The ability to accurately interpret facial expressions is of primary importance for humans to socially interact with one another. Facial expressions communicate information from which one can quickly infer the state of mind of one’s peers, and adjust one’s behaviour accordingly. From this point of view, the human face can be viewed as a transmitter of expression signals and the brain as a decoder of these expression signals. It follows that facial expressions and the underlying motor circuitry (the brain CPG, the facial nerve and facial musculature) have evolved to optimise the transmission of such signals [23, 24]. During seizures, in addition to a number of non-emotional facial displays, a coherent pattern of muscular activa-
Fig. 2 Since 1952 the neurologist Paul MacLean proposed that our skull holds not one brain, but three (neomammalian, paleomammalian and reptilian), each representing a distinct evolutionary stratum formed upon the older layer before it, like an archaeological site. He calls it the “triune brain” (shown on the left) [22]. Both epilepsy and sleep can lead to a temporary loss of control of neomammalian cortex that facilitates through a common platform (arousal) the emergences of motor events (in the middle) referable to stereotyped inborn fixed action patterns (behaviors on the right)
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Fig. 3a Polygraphic recording of one seizure showing bilateral rhythmic masseter (Mass.) activity associated with rhythmic contraction of the left tibialis anterior (Tib. Ant.) muscle. In the first channel the left anterior temporal EEG derivation (F7-T3) is recorded, showing rhythmic muscular artefacts. b Detail from previous. Note the longer duration of electromyographic bursts in the left tibialis anterior muscle compared with masseter activity and the different burst frequency. c Scheme of the time course of the seizure’s manifestations. (a and b modified from [16] with permission)
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Fig. 4a Epileptic fly-biting behaviour in the ictal period of a partial seizure in a dog. b Spontaneous (not evoked) biting behaviour. Here the patient with a right hippocampal sclerosis is biting a thermometer during a seizure
tion comparable to that observed in genuine “universal” facial emotions in normal subjects was observed [25, 26]. Coherent patterns of facial emotions during the ictal event (Fig. 5) were preferentially observed during seizures with involvement of medial temporal, cingular and orbital-frontal cortex. On the other hand, “emotional parasomnias” such as pavor nocturnus, nightmares and sleep terror clearly indicate a high level of emotional arousal. However studies of facial expression during these emotional sleep-related
events are unfortunately lacking to our knowledge. Is facial expression of basic emotions the same whether related to an epileptic event (limbic-hypothalamic network) or non-epileptic “emotional parasomnias”? Finally, it is relevant that decoding recognition of facial emotions is significantly impaired in epileptic patients with damage to the medial temporal lobe network occurring early in infancy [27, 28]. Repetitive “vocalisations”, consisting of intense acoustic production (“wild screaming”), can occur concomitantly
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Fig. 5a, b Two examples of facial expression of emotion during epileptic seizures: fear (a) and sadness (b) (FACS analysis performed by Prof. P.E. Ricci Bitti and Dr. M. Costa, Department of Psychology, University of Bologna). Image a from [24] (the reproduction of the images of the patients is approved either by the patient herself or by her legal representative)
with bimanual, bipedal rocking and pelvic thrusting behaviours in nocturnal frontal hypermotor seizures. In each patient the wave form and the spectrogram of the sequence of acoustic events during the whole epileptic seizure showed a temporal and morphologic pattern, quite constant for the same patient in various seizures, even for those recorded at intervals of several years. Acoustic manifestations produced during hypermotor epileptic seizures can be stereotyped, supporting the hypothesis that the vocalisations could be related to a pre-encoded acoustic (instinctive?) behaviour [29]. Unfortunately we do not have equivalent studies to compare a facial expression of emotions and the vocal emissions during parasomnias with emotional expression. Locomotor activity is present in frontal nocturnal hypermotor seizures ([9] and this symposium) and in various parasomnias (as indicated in Figure 2) and variously referred to as “wandering” “circling”, “repetitive legs movements”. Three points should be considered: a. The stereotypic motor sequence in the same subject (Fig. 6) is well in agreement with the definition of Central Pattern Generators and related “fixed action patterns”. b. A stereotyped locomotor activity can be observed by stimulation of the mesencephalic-diencephalic locomotor regions and by stimulation of the spinal cord not only in animal but also in man [5]. c. As a confounding issue on this matter is the fact that motor behaviors, variously described as parasomnias, can indeed be undiagnosed epileptic seizures.
Discussion and conclusions On the basis of video and polygraphic analysis of movements we suggested that in some seizures (mainly fronto-
nocturnal hypermotor and temporal-limbic), the epileptic discharge acts as a trigger for the appearance of behaviours which are the expression of inborn motor patterns, related to CPG, mainly located outside the cerebral cortex in the meso-diencephalic-pontine regions and the spinal cord. That is to say that a certain number of motor behaviours or automatisms referred to as epileptic are not the direct consequence of the paroxysmal discharge of the cortical neurons (as jerks related to a contralateral cortical spike can be); they are an indirect effect of the cortical discharges on far away CPG, responsible for stereotyped (Fig. 6) and cyclically repeated behaviours (ambulatory, masticatory). We are extending this concept to parasomnias, whose motor expression is the same as in epileptic seizure, as they result from the activity of the same CPG. Moreover the same association of two different CPG, as for example those responsible for teeth grinding and rhythmic leg movements, can occur in both epileptic (Fig. 3) [16] and in non-epileptic events [17]. Still relevant in this context is the observation of masticatory oroalimentary automatism closely mimicking those observed in partial seizures precipitated by a cerebral anoxia (syncopal attacks) [30]. The Authors appropriately conclude that “masticatory automatism” may represent a release phenomenon resulting from inactivation of neocortical structures by cerebral anoxia or reticular disconnection. The aetiology seems irrelevant: the motor symphony is the same as we suggested in the carillon theory [1, 2]. We consider now the hypothesis that the fixed action pattern leading to the same motor behaviour in different aetiological conditions (a seizure, a parasomnia) can be considered a release [31–33], loss of control of the “neomammalian cortex on the CPG located in the “paleomammalian” or “reptilian brain” (Fig. 2). Ethologists have no doubts: “it is easy to demonstrate that not only in worms but also in man there are automatic
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Fig. 6 Stereotyped locomotory behaviour (in supine position) in frontal hypermotor nocturnal seizures throughout 10 years of evolution in a patient with right frontal paracentral dysplasia. The seizure frames are taken after the same delay from the seizure onset recorded in 1993, 1996 and 2003. Note: right hand toward the head; flexion of the left leg with right leg in extension; grasping of the left thigh by the left hand. (the reproduction of the images of the patients is approved by the patient himself)
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Fig. 7a-c Frontal nocturnal “hypermotor seizures”: the boy (c) previously in supine position had “the need to pronate” at the seizure onset and in this position presented coordinated locomotory movements such as occur in neonates (b) [34] and in general in vertebrates progression (a) [35] (frames from free downloadable “Trotting salamander” animation by Ecole Polytechnique Fédérale de Lausanne)
movements of endogenous origin, centrally coordinated, who would be continuous if not ‘braked’ by a central inhibition when they are not needed” [31]. With regards to higher level control for locomotion and referring to Figure 1, Grillner states “it seems likely that the basal ganglia can contribute to the initiation of the locomotion through disinhibition of either of the two
(mesopontine and diencephalic) locomotor regions” [5]. Similarly, inactivation or true inhibition may have an important role in the genesis of various forms of epileptic automatism, which Penfield has called “psychoparetic” rather than psychomotor [32]. Grasping, for instance, frequently observed in nocturnal hypermotor seizures, is interpreted as a “release” motor behaviour [33]. Otherwise
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automatisms can occur in different conditions that lead to inactivation of neocortical structures like cerebral anoxia [29]. In conclusion we imply (Fig. 2) that loss of control of neomammalian cortex due to an event (a seizure, an arousal disorder) can facilitate the emergence of innate behaviours. If so, many of these behaviours should be automatically present when the neomammalian cortex is still “in progress”. Indeed alimentary, locomotory (Fig. 7) and grasping behaviours occur “spontaneously” in foetuses and newborns. Acknowledgements This work was supported by a grant of the Ministero Italiano dell’Università e della Ricerca Scientifica (MIUR, ex-40%) and by Fondazione CARISBO in Bologna. We thank Prof. Paolo Nichelli (Dept. of Neurosciences, University of Modena and Reggio Emilia), Prof. Pio Enrico Ricci-Bitti (Dept. of Psychology, University of Bologna), and Prof. Anna Esposito (Speech Communication Group, Research Laboratory of Electronic (RLE), MIT, Boston), the Epilepsy Surgery Centre “C Munari”, Dept. of Neuroscience - Niguarda Hospital, Milan, and the Division of Neurology - Bellaria Hospital, Bologna (Drs. Roberto Michelucci, Roberta Pantieri, Rosaria Plasmati, Patrizia Riguzzi, Fabrizio Salvi, Franco Valzania, and Lilia Volpi). Finally we also thank Mrs Clementina Giardini for editorial assistance.
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