Brain Function in Epilepsy: Midbrain, Medullary, and Cerebellar Interaction with the Rostral Forebrain

Home , Dentate nucleus, Fastigial nucleus

J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.11.1037 on 1 November 1976. Downloaded from

Journal ofNeurology, Neurosurgery, and Psychiatry, 1976, 39, 1037-1051

Brain function in epilepsy: midbrain, medullary, and cerebellar interaction with the rostral forebrain

R. G. HEATH1 From the Department ofPsychiatry and Neurology, Tulane University School ofMedicine, USA

SYNOPSIS Against the background of previous findings in epileptic patients, in whom electroencephalographic recordings were obtained from numerous deep and surface brain sites during seizures, rhesus monkeys with electrodes implanted into specific brain sites were used to demonstrate anatomical connections by evoked potential techniques and to serve as models of experimental epilepsy. In the animals, many monosynaptic connections were revealed between forebrain sites consistently involved in seizures in patients and more caudal brain sites subserving functions of sensory perception, eye movement, synaptic chemical transmission, and motor coordination. Further, the guest. Protected by copyright. participation of these interrelated sites during seizures was demonstrated. The findings provide an anatomical-physiological explanation for many of the clinical phenomena observed in epileptic patients and a rationale for the use ofcerebellar stimulation as a treatment.

That epileptic seizures are associated with distinct trol certain types of epilepsy (Cooper et al., 1973; and characteristic electroencephalographic (EEG) Cooper and Snider, 1974). Anatomical and physio- changes in the cerebral cortex has been well estab- logical studies in our laboratories indicate that lished. In our programme at Tulane, data from forebrain seizural transmission sites (hippocampus- epileptic patients prepared with brain electrodes for amygdala-septal region) have monosynaptic anatom- treatment of intractable neurological disorders re- ical connections with the cerebellum as well as with vealed pathological recordings from specific deep many other specific subcortical nuclei through the brain structures when cortical and scalp recordings midbrain and lower brain stem. We have reported were normal. These recording aberrations occurred some of these connections (Heath, 1972, 1973, 1976; during interictal periods. Moreover, before the ap- Harper and Heath, 1973; Paul et al., 1973; Harper and pearance ofcharacteristic seizural EEG activity in the Heath, 1974; Heath and Harper, 1974, 1976); but cortical recordings at the onset of the clinical seizure, many others have not been described previously. chronological spread of seizural activity was con- In most instances, the connections are two-way, the sistently noted from the hippocampus and amygdala more caudal structures projecting rostrally to the to the septal region (Mickle and Heath, 1957; Heath, forebrain seizural transmission sites. http://jnnp.bmj.com/ 1962, 1963). Because the functional involvement of In the present report of findings obtained in these subcortical structures is so consistent in the monkeys made epileptic by several experimental genesis of the seizure, we group them together as methods, principal caudal connections are grouped forebrain seizural transmission sites. roughly according to function under the following For several years, investigators have been accumu- headings: sensory relay nuclei, chemical transmitter lating data that suggest the influence ofthe cerebellum sites, sites for facial expression and eye movement, on epileptic seizures (Snider and Magoun, 1949). nuclei involved in motor coordination, and non- Recently, electrical stimulation of the surface of the specific sites. Recordings from these numerous deep on October 1, 2021 by anterior lobe of the cerebellum has been used to con- brain sites of animals made epileptic indicate the anatomical connections that are significant in epilepsy. The recordings show the manner in which the ' Address for reprint requests: Dr Robert G. Heath, Tulane University caudal sites are School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana more functional interrelated with the 70112, USA. forebrain seizural transmission sites in the genesis ofa (Accepted 13 July 1976.) seizure. 1037 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.11.1037 on 1 November 1976. Downloaded from

1038 R. G. Heath

METHODS between the two leads ofan implanted electrode while bipolar recordings were made between the pairs of an Young adult rhesus monkeys with electrodes im- electrode at one of the other implanted sites. The planted into specific brain sites were used to demon- stimulus consisted of a rectangular bidirectional strate anatomical connections by evoked potential pulse of 0.1 to 0.25 ms duration at currents varying techniques and to serve as models of experimental from 2 to 5 mA. All studies were conducted with the epilepsy. The findings presented in the current report monkeys awake. Evoked reponses were recorded on a are from 50 monkeys in which electrode sites were Tektronix dual-channel 502A oscilloscope, with confirmed histologically and from which evoked Tektronix low-level preamplifiers to which a Polaroid potential data were gathered. Twenty-four of the C- 12 camera was mounted to obtain permanent animals were also used to determine the spread of photographic records. For each study, recordings epileptic seizures. were obtained of a single response, a superimposition of 30 responses delivered at one-second intervals ELECTRODE IMPLANTATION PROCEDURE (which will be used in the current report to demon- By previously described methods (Heath et al., 1968, strate connections), and a high-frequency stimulation 1976) and with the Atlas of Snider and Lee (1961) as a between 50 and 145 Hz. guide, each monkey had electrodes implanted into the anterior septal region (Heath, 1954), mid-septal region, fastigial nucleus of the cerebellum, hippo- MODELS OF EXPERIMENTAL EPILEPSY campus, amygdala, and bilaterally on the temporal Three methods were used to induce experimental

cortex. In addition, electrodes were implanted into at epilepsy in monkeys: focal electrical stimulation, guest. Protected by copyright. least one of the following brain sites of several implantation of cobalt, and administration of con- monkeys in the group: ventroposterior lateral thala- vulsant drugs. mus, medial and lateral geniculate nuclei, hypothalamus, mesencephalic reticulum, substantia nigra, locus coeruleus, raphe nucleus, nucleus cuneiformis, Focal electrical stimulation To induce an after- red nucleus, dentate nucleus of the cerebellum, in- discharge, we delivered an electrical stimulus (0.5 ms ferior olive, superior colliculus, caudate nucleus, and biphasic pulse, 60 Hz, at 2 mA for two seconds) to the over the frontal and occipital cortices. The subcortical hippocampus of the monkey. Recordings from all bipolar silver-ball electrodes, each 0.5 mm in dia- deep sites were bipolar, between the two leads of a meter, were each separated by 2.0 mm. Cortical im- subcortical electrode. Cortical recordings were also plants were single silver-ball electrodes, each 0.5 mm bipolar between combinations of single-ball leads in diameter, and scalp electrodes were silver discs. under the bone. Scalp leads were bipolar between The implantation procedure was accompanied by silver disc leads fixed to the scalp. radiological visualisation with air in the ventricular system to ensure accuracy ofplacement. At the end of Subcortical implantation of cobalt Introduction of the studies, the monkeys were killed, and the brains an irritant into a specific brain site of an animal has were fixed in 10 % formalin for histological study and proved effective in studying functional relations confirmation ofelectrode placements. among various brain sites. For this study, metallic Each monkey was allowed to rest for two to three cobalt was introduced, by a procedure previously weeks after implantation to allow all postoperative described, into deep nuclear brain sites into which recording artefacts to disappear. electrodes had previously been implanted (Guerrero- http://jnnp.bmj.com/ Figueroa et al., 1963). Recordings were obtained one ELECTROENCEPHALOGRAMS hour after cobalt implantation and at intervals there- Electroencephalograms (EEGs) were obtained on a after for days or weeks, depending on responses and 16-channel Grass Model 6 electroencephalograph. developing foci. Sometimes, in order to obtain additional channels of recordings, an 8-channel Grass Model electro- Use of convulsant drugs Three drugs, d-LSD, phen- encephalograph was also used, the two machines cyclidine, and leptazol (Metrazol), were used for this on October 1, 2021 by synchronised by a time code generator. study. The d-LSD was given intravenously at a dose of 100 1tg/kg, whereas phencyclidine was given intra- EVOKED POTENTIALS muscularly at a dose of 0.25 mg/kg. Metrazol was To demonstrate anatomical-physiological connec- administered intravenously in one ml (10 mg) incre- tions between various specific sites, we evoked ments at 30-second intervals until epileptiform potentials in the monkeys by applying a stimulus activity appeared in the monkey's recordings. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.11.1037 on 1 November 1976. Downloaded from

Brain function in epilepsy: midbrain, medullary, and cerebellar interaction with the rostralforebrain 1039

RESULTS Cobalt-induced experimental epilepsy After implantation of cobalt into certain specific subcortical ANATOMICAL CONNECTIONS REVEALED BY EVOKED nuclei presumed to be implicated in epilepsy, epilepti- POTENTIALS form activity usually developed at the implanted site In monkeys, monosynaptic connections in the brain within a few hours. Spreading from the primary focus were denoted by short delay time between stimulus (site of implantation) to directly-connected nuclei and response. Responses evoked at various brain (that can be functionally grouped together as pre- sites by electrical stimulation of the rostral septal viously described), the activity gradually intensified region are shown in Fig. 1 .2 The short delay times over the next 12 to 24 hours. Regardless ofthe nuclear suggest monosynaptic connections from the septal site implanted with cobalt, the directly-connected region to these sites. In Tables 1-5 direct connections sites were also implicated. In Fig. 4, serial recordings among brain sites, demonstrated by evoked res- from a monkey with cobalt implanted into the right ponses in the monkeys, are grouped according to anterior septal region demonstrate this phenomenon. functions considered relevant in epilepsy. Responses As the hours passed, epileptiform activity was trans- evoked in various sites with stimulation of forebrain mitted from the right anterior septal region to the transmission sites are listed in Table 1. Table 2 lists contralateral septal region, amygdala, and hippo- the delay responses obtained in numerous sites with campus. Before long, the spread involved the sub- stimulation of sensory relay nuclei, and Table 3 lists stantia nigra and inferior olive. By 18 hours after those obtained when stimuli were applied to various cobalt implantation, the sensory relay nuclei (ventro- transmitter chemical reservoir nuclei. Responses ob- posterior lateral thalamus and deep cerebellar nuclei) tained with stimulation to nuclei influencing motor were also involved with the seizural activity which guest. Protected by copyright. coordination and expression (facial and eyes) are continued in the amygdala, hippocampus, and septal shown in Table 4, and those obtained with stimulation region. At this point, the continuous discharge ofnon-specific brain sites are listed in Table 5. migrating among forebrain structures and sensory relay nuclei also involved nuclei controlling the eyes FUNCTIONAL RELATIONSHIPS REVEALED BY 'MODEL (superior colliculus), and structures controlling co- EPILEPSY' TECHNIQUES ordination (inferior olive and dentate nucleus of the After-discharge induced by electrical stimulation cerebellum), as well as a transmitter chemical site Deep and surface recordings from a wide variety of (substantia nigra containing dopaminergic neurones). brain sites of a rhesus monkey were made before By 24 hours after cobalt implantation, midbrain and (Fig. 2) and after (Fig. 3) stimulation of the hippo- hindbrain structures showed intermittent seizural campus. The after-discharge immediately involved activity. Clinical manifestations of the seizure oc- the septal region, medial geniculate body, and su- curred, however, only after the forebrain transmission perior colliculus. It then spread to include the sub- sites (hippocampus, amygdala, septal region) and stantia nigra and dentate nucleus of the cerebellum. then the cortex had developed continuous rhythmical Whereas seizural activity did not implicate cortical seizural activity. leads, the extraoculogram (EOG) indicated nystag- Recordings from another monkey show the seizural mus throughout the time the subcortical seizural dis- activity induced with cobalt implanted into the charge was recorded. During this period the monkey fastigial nucleus of the cerebellum (Fig. 5). In this had no tonic and clonic movements, but he showed example, intermittent spiking activity first involved 'absence behaviour' characterised by searching move- the contralateral dentate nucleus of the cerebellum, http://jnnp.bmj.com/ ments ofthe eyes and lip-smacking. the hippocampus, and the temporal cortex. Seizural activity then encompassed the hippocampus, septal region, and temporal cortex concomitant with slow activity in the ventroposterior lateral thalamus. (As 2 Abbreviations The following abbreviations are used in the Tables the nucleus of the and Figures: A: anterior. Amy, Amyg: amygdala. Cau: caudate previously described, fastigial nucleus. Cbl den: dentate nucleus of the cerebellum. Cbl fas: fastigial cerebellum projects monosynaptically to all these nucleus of the cerebellum. Cen med: centromedian nucleus of the structures.) Only after seizural activity spread to the thalamus. Cuneif: cuneiformis nucleus. Dor cau: dorsal caudate nucleus. ECG: electrocardiogram. EOG: extraoculogram. F: frontal. septal region did the cortical mantle become com- H: highest of three electrodes implanted into structure. Hip, Hippo: pletely involved and the animal develop a grand mal on October 1, 2021 by hippocampus. Hypo: hypothalamus. Inf olive: inferior olive. L: left or lowest of three electrodes implanted into structure. Lat: lateral. Lat seizure. gen: lateral geniculate nucleus. Loc coer: locus coeruleus. M: middle of When cobalt was implanted into the hippocampus, three electrodes implanted into structure. Med: medial. Med gen: medial geniculate nucleus. Mes ret: mesencephalic reticulum. P: epileptiform activity spread similarly to implicate posterior. PVL THAL: ventroposterior lateral nucleus ofthe thalamus. interconnected subcortical sites. In the recordings Raphe: raphe nucleus. Red nuc: red nucleus. Sep, Septal: septal region. shown in 6, activity appeared first Sub nigra: substantia nigra. Sup col, coll: superior colliculus. TCG: Fig. epileptiform time code generator. Tem, Temp cx: temporal cortex. at theprimary siteand then spread to the septal region. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.11.1037 on 1 November 1976. Downloaded from

1 040 R. G. Heath

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CBL DEN 4 i50uv 2-ms FIG. 1 Potentials evoked at various brain sites with stimulation ofthe septal region. The potentials shown represent 30 superimposed responses. In every instance, high-frequency stimulation (100 Hz) abolished the response. The short delay times indicate monosynaptic connections from the septal region to these sites. Sites from which recordings were obtained are grouped roughly according to function: Amygdala, hippocampus, septal region- forebrain transmission sites; raphe, substantia nigra, locus coeruleus-transmitter chemical reservoirs; superior colliculus, inferior olive, dentate nucleus ofthe cerebellum-motor coordination andexpression; medialgeniculate, lateral geniculate, ventroposterior lateral thalamus, fastigial nucleus of the cerebellum-sensory relay nuclei; temporal cortex, dorsal caudate nucleus-non-specificsites. http://jnnp.bmj.com/ Four hours after cobalt implantation, the substantia region, hippocampus, and caudate nucleus), and then nigra and dentate nucleus of the cerebellum were also soon implicated the substantia nigra. By four minutes involved. Bysix hours after implantation, epileptiform after the injection, epileptiform activity had intensified activity had increased at these sites and also had en- and spread to involve other more caudal, intercon- compassed the ventroposterior lateral thalamus and nected structures (superior colliculus and deep the amygdala. cerebellar nuclei). The effects of phencyclidine were somewhat dif- Drug-induced seizural activity Figure 7 shows EEGs ferent. As shown in Fig. 8, not only did EEG changes on October 1, 2021 by obtained from a monkey before (baseline) and after develop promptly in forebrain structures (hippo- intravenous administration of d-LSD. Because the campus, amygdala, septal region), but significant rhesus monkey has a high threshold for d-LSD, it changes also rapidly appeared in cortical structures requires a dose equal to that given to a man to induce and sensory relay nuclei (medial geniculate and a response. Thirty seconds after the injection, initial ventroposterior lateral thalamus). Likewise, as evi- changes were noted in forebrain structures (septal denced by the EEGs, the fastigial nucleus of the J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.11.1037 on 1 November 1976. Downloaded from

Brainfunction in epilepsy: midbrain, medullary, and cerebellar interaction with the rostral/forebrain 1041

TABLE 1 FOREBRAIN TRANSMISSION SITES

Site of evoked response and latency (ms) Site of Forebraini Sensory Transmitter Motor coordination Non-specific stimulation transmission sites relay nuclei chemical reservoirs and expression sites

I C I C I C I C I C Septal Amyg 1.0 1.0 Med gen 1.0 0.8 Loc coer NR 1.0 Inf olive 1.2 NR Hypo 5.0 NR Hippo 2.0 2.0 Lat gen 1.0 NR Sub nigra 1.5 NR Cbl den 1.0 1.0 Red nuc 3.0 NR Septal NT 0.6 VPLT 1.5 NR Raphe 3.5 3.0 Sup coll 0.8 0.8 Dor cau 1.5 1.0 Cbl fas 1.5 0.8 Cen med NT NT Temp cx 2.0 2.0 Hippu Amyg 0.5 0.8 Med gen 0.5 1.5 Loc coer 1.0 0.6 Inf olive 0.5 2.5 Hypo 0.8 NR Hippo NT 1.0 Lat gen 1.0 1.0 Sub nigra 0.8 NR Cbl den 1.0 0.6 Red nuc 0.5 0.8 Septal 0.5 0.8 VPLT 0.8 1.0 Raphe 1.0 NR Sup coll 0.8 NR Dor cau 0.6 0.6 Cbl fas 0.8 0.5 Cen med 1.0 1.0 Temp cx 1.0 0.5 Amyg Amyg 1.5* 1.5 Med gen NT 1.0 Loc coer 1.0 NR Inf olive NR 0.8 Hypo NR NR Hippo 2.0 1.0 Lat gen NT NR Sub nigra NR NR Cbl den NR 1.0 Red nuc NR 0.8 Septal 0.5 1.0 VPLT 0.5 NR Raphe 0.5 NR Sup coll 4.0 1.2 Dor cau NR 2.0 Cbl fas NR 0.8 Cen med NT NT

Temp cx 1.0 1.0 guest. Protected by copyright.

*Local evoked response recorded from other leads at this site. Tables 1-5 summarise evoked potential data in monkeys. The latency response listed is the shortest one obtained for the site in the series of monkeys that were studied. I: Ipsilateral. C: Contralateral. NR: No response obtained. NT: Site not tested.

TABLE 2 SENSORY RELAY NUCLEI SITES

Site of evoked response and latency (ms) Site of Sensory Forebrain Tranismitter Motor coordination Non-specific stimulation relay nuclei transmission sites chemical reservoirs and expression sites

I C I C I C I C I C Med gen Med gen NT NR Amyg 1.5 0.8 Loc coer NR 1.0 Inf olive NR NR Hypo NR NR Lat gen 1.0 NR Hippo 0.5 1.5 Sub nigra 1.0 NR Cbl den NR 0.5 Red nuc NR NR

VPLT 1.0 0.5 Septal 0.6 1.0 Raphe NR NR Sup coll 0.5 NR Dor cau 3.0 1.0 http://jnnp.bmj.com/ Cbl fas 0.5 NR Cen med NR NR Temp cx 0.8 1.0 Lat gen Med gen NR 2.0 Amyg 2.0 NR Loc coer NR NR Inf olive 5.0 NR Hypo 3.0 2.0 Lat gen NT NR Hippo NR 2.5 Sub nigra NR NR Cbl den NR NR Red nuc NR 0.8 VPLT 2.0 4.0 Septal 0.5 1.0 Raphe NR NR Sup coll 2.0 NR Dor cau 1.0 1.0 Cbl fas 2.0 1.5 Cen med NR NR Temp cx 1.0 1.0 VPLT Med gen NR 1.2 Amyg 2.0 NR Loc coer 2.0 NR Inf olive NR 0.8 Hypo NR NR Lat gen 0.8 NR Hippo 0.4 0.8 Sub nigra 1.0 1.0 Cbl den 1.2 1.0 Red nuc NR 1.0 VPLT NT NR Septal 1.0 0.8 Raphe NR NR Sup coll NR 5.0 Dor cau 1.0 NR on October 1, 2021 by Cbl fas 6.0 0.6 Cen med NR NR Temp cx 1.5 1.5 Cbl fas Med gen 1.0 NR Amyg 0.8 1.0 Loc coer NR 0.8 Inf olive 1.0 NR Hypo NR 1.0 Lat gen 1.0 NR Hippo 0.8 1.5 Sub nigra 1.2 NR Cbl den 0.8 0.8 Red nuc NR 3.0 VPLT 0.8 0.8 Septal 0.6 0.8 Raphe NR 0.6 Sup coll 0.8 NR Dor cau NR 1.5 Cbl fas NT 1.5 Cen med NR NR Tempcx 1.0 1.0 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.11.1037 on 1 November 1976. Downloaded from

1042 R. G. Heath

TABLE 3 TRANSMITTER CHEMICAL RESERVOIRS

Site of evoked response and latency (ms) Site of Transmitter Forebrain Sensory Motor coordination Non-specific stimulation chemical reservoirs transmission sites relay nuclei and expression sites

I C I C I C I C I C Loc coer Loc coer NR NR Amyg 0.5 NR Med gen 0.8 0.8 Inf olive NR 1.0 Hypo NR NR Sub nigra NR 0.5 Hippo 1.0 2.5 Lat gen 1.0 NR Cbl den 1.0 NR Red nuc NR NR Raphe NR NR Septal 0.8 0.8 VPLT 1.0 NR Sup coll 1.8 NR Dor cau 1.0 NR Cbl fas 0.6 0.8 Cen med NR NR Temp cx 1.0 1.0 Sub nigra Loc coer NR 0.8 Amyg NR NR Med gen 1.0 NR Inf olive 0.4 NR Hypo NR NR Sub nigra NT 2.0 Hippo 1.2 3.0 Lat gen NR NR Cbl den NR 0.8 Red nuc NR NR Raphe NR NR Septal 0.6 0.8 VPLT NR 0.8 Sup coll 0.8 NR Dor cau 1.5 0.8 Cbl fas 1.0 NR Cen med NR NR Temp cx 2.5 2.5 Raphe Loc coer NR NR Amyg NR 1.0 Med gen NR NR Inf olive NR NR Hypo NR NR Sub nigra NR NR Hippo 1.5 NR Lat gen NR NR Cbl den 0.8 NR Red nuc NR NR Raphe NT NT Septal 1.0 NR VPLT NR NR Sup coil NR NR Dor cau 1.2 NR Cbl fas NR 1.0 Cen med NR NR Temp cx 1.0 1.0 guest. Protected by copyright.

TABLE 4 SITES FOR MOTOR COORDINATION AND EXPRESSION

Site of evoked response and latency (ms) Site of Motor coordination Forebrain Sensory Transmitter Non-specific stimulation and expression transmission sites relay nuclei chemical reservoirs sites

I C I C I C I C I C Inf olive Inf olive NT NR Amyg 1.0 0.8 Med gen 0.6 NR Loc coer NR 1.0 Hypo 0.8 NR Cbl den 0.4 0.6 Hippo 0.8 1.5 Lat gen 0.8 NR Sub nigra 0.8 NR Red nuc 1.0 NR Sup coll 1.0 NR Septal 0.8 1.5 VPLT 0.5 0.8 Raphe NR NR Dor cau NR 2.3 Cbl fas 0.5 NR Cent med NR NR Temp cx 1.0 1.0 Cbl den Inf olive 1.0 0.8 Amyg 1.0 1.2 Med gen NR 0.8 Loc coer 1.0 NR Hypo NR NR Cbl den NT NR Hippo 1.0 1.0 Lat gen NR NR Sub nigra 0.6 1.5 Red nuc 1.0 NR Sup coll 0.8 0.5 Septal 1.0 1.0 VPLT 1.0 1.0 Raphe 2.5 NR Dor cau 1.0 NR Cbl fas 1.0 0.6 Cen med NR NR Tempcx 1.0 1.0

Sup coll Inf olive NR NR Amyg 1.0 0.8 Med gen NR NR Loc coer NR NR Hypo NR NR http://jnnp.bmj.com/ Cbl den 1.5 1.5 Hippo 9.0 NR Lat gen NR NR Sub nigra NR NR Red nuc NR NR Sup coll NT NT Septal 0.5 0.6 VPLT NR 2.0 Raphe 0.8 NR Dor cau NR 0.8 Cbl fas 1.4 NR Cen med NR NR Temp cx 2.0 2.0

cerebellum and the substantia nigra were quickly phencyclidine, they were different in form, and involved. For as long as one hour after the intra- seizural activity did not spread subsequently through on October 1, 2021 by muscular injection of phencyclidine, epileptiform the septal region to encompass the cortex, as occurred activity continued to migrate, intensifying and dim- consistently with the clinical seizure. inishing, through these brain structures. Intravenous use of Metrazol invariably induced Clinical seizures did not occur with use of d-LSD or grand mal seizures in the monkeys (Fig. 9). Con- phencyclidine. Although significant cortical electro- sistent with the EEGs we have obtained from epileptic graphic changes developed after administration of patients during clinical seizures, and from monkeys J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.11.1037 on 1 November 1976. Downloaded from

Brain Junction in epilepsy: midbrain, medullary, and cerebellar interaction with the rostra/forebrain 1043

TABLE 5 NON-SPECIFIC SITES

Site of evoked response and latency (ins) Site of' Non-specific Forebrain Sensory Transmitter Motor coordination stimulation sites transmission sites relay nuclei chemical reservoirs and expression I C I C I C I C I C Hypo H-ypo NT NR Amyg NR NR Med gen NR NR Loc coer NR NR Inf olive 1.2 NR Red nuc 1.0 NR Hippo 1.0 NR Lat gen NR 1.0 Sub nigra NR NR Cbl den NR NR Dor cau NR NR Septal 0.8 3.0 PVLT NR NR Raphe 1.0 NR Sup coil NR NR Cen med NR NR Cbl fas NR 1.0 Temp cx 1.0 1.0 Red nuc Hypo 0.5 NR Amgy NR NR Med gen NR NR Loc coer NR NR Inf olive 0.8 NR Red nuc NT NR Hippo 0.5 4.0 Lat gen NR NR Sub nigra NR NR Cbl den 5.0 8.0 Dor cau 5.0 2.0 Septa] 0.8 1.0 PVLT NR NR Raphe 1.5 NR Sup coIl NR NR Cen mcd NR NR Cbl fas 1.0 3.0 Temp cx 1.0 1.0 Dor cau Hypo 1.5 NR Amyg NR NR Med gen NR 1.0 Loc coer 1.0 NR Inf olive NR NR Red nuc 8.0 8.0 Hippo 7.0 1.0 Lat gen NR NR Sub nigra NR 0.6 Cbl den NR 20.0 Dor cau NR NR Septal 4.0 NR PVLT 3.0 0.6 Raphe NR NR Sup coil NR 4.0 Cen med NR NR Cbi fas 4.0 1.2 Temp cx 7.0 7.0

Cen med Hypo NR NR Amyg NR NR Med gen NR NR Loc coer NR NR Inf olive NR NR guest. Protected by copyright. Red nuc NR NR Hippo NR NR Lat gen NR NR Sub nigra NR NR Cbl den NR NR Dor cau NR NR Septal NR NR PVLT 1.5 NR Raphe NR NR Sup coll NR NR Cen med NR NR Cbl fas NR NR Temp cx NR NR Temp cx Hypo NR NR Amyg NR 1.0 Med gen NR NR Loc coer 5.0 5.0 Inf olive NR NR Red nuc NR NR Hippo NR NR Lat gen NR NR Sub nigra 1.0 1.0 Cbl den 1.0 1.0 Dor cau 2.5 2.5 Septal 0.5 NR PVLT 1.0 1.0 Raphe NR NR Sup coil NR NR Cen med NR NR Cbl fas 1.0 1.0 Temp cx NT 1.5

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1044 R. G. Heath

BASELINE 4HR POST I8 HR POST R.HIP 0'/\N*NNA,9, /V { L MED AMY I Ir\vidv4l R MED GEN -- R A SEP 'r : L P SEP '--. Vvvv' Y L P V L THAL -r' R SUB NIGRA Aow R INF OLIVE - 4 9At'A^ 90 R SUP COL - L CBL DEN e :I FIG. 4 Electroencephalograms from a rhesus monkey before R CBL fAS N 5owECo'"Xil^, (baseline) andafter ECG implantation ofcobalt into the right anterior septal region. IS HR POST IS HR POST 24 HR. POST The electrocardiogram (ECG) with a slightly different R HIP frequency establishes that the L MED AMY rhythmical brain discharges guest. Protected by copyright. R MED GEN do not represent heart beat. R A SEP IIV L P SEP I,< I VW L PV LTHAL R SUB NIGRA i ______tJ^45'*j'/^ 4 R INF OLIVE R SUP COL xJ*skwto,-~ag-gsw<% X,p.______L CBL DEN R CBL FAS A,/WN~~~~~~~~~~v ECG

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FIG. 5 Electroencephalograms from a rhesus monkey before (baseline) and 24 hours after implantation ofcobalt into the leftfastigialnucleus ofthe cerebellum. Migration ofseizural activity. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.11.1037 on 1 November 1976. Downloaded from

Brain jiunction in epilepsy: midbrain, mtiedullary, an1d cerebellar interaction with the rostralforebrain 1045

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in which seizural activity was induced by other tech- monkeys that artefacts from the consequent move- http://jnnp.bmj.com/ niques, epileptiform activity migrated through ment made surface recordings worthless. forebrain transmission sites (hippocampus, amyg- A phenomenon we have observed consistently in dala, septal region) and encompassed the cortex as the epileptic monkeys during seizures and during the clinical seizure began. These recordings from a postictal periods is illustrated in the recordings from monkey with electrodes in several deep sites in ad- the fastigial nucleus of the cerebellum of the monkey dition to the forebrain nuclei, and at surface sites as that received Metrazol (Fig. 9). After the seizure has well, further demonstrated the way in which seizural passed its peak, high-amplitude cerebellar activity activity encompasses other nuclei associated with appears. It continues rhythmical as the seizure ends on October 1, 2021 by specific neural functions. In this example, the hypo- and it persists well into the postictal period. (In the thalamus and cuneiform nucleus were implicated epileptic monkeys, this phenomenon has been ob- early, along with the hippocampus. Epileptiform served in both the fastigial and dentate nuclei.) This activity, after appearing in septal leads, spread to recording pattern indicates that activation of the deep involve the raphe nuclei and fastigial nucleus of the cerebellar iiuclei correlates with cessation of the cerebellum. Metrazol created so much agitation in the seizure (Figs. Sand 9). J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.11.1037 on 1 November 1976. Downloaded from

1046 R. G. Heath

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LCAUJRA S5R~~ 1P5'±;v z TCG fffi 0mIflTTOW W~!TWPgm1¶~flDflI ThTflThTT ri.T7 . FIG. 7 Electroencephalograms from a rhesus monkey before (baseline) and after intravenous administration of d-LSD (100 ltg/kg).

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Brainfunction in epilepsy: midbrain, medullary, and cerebellar interaction with the rostralforebrain 1047

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iOf= ZFia wM-W.TH? LW UN-WP- RAPH- CUL f CaL FAN RHYTHUCAL KINS FIG. 9 Electroencephalograms from a rhesus monkey before (baseline) and after intravenous administration of Metrazol. Generalisedseizure.

DISCUSSION Heath, 1973, 1974; Paul et al., 1973; Heath and Harper, 1974, 1976; Clark, Ellison, and Heath, in These studies in monkeys extend observations made preparation). in patients concerning the organisation of the brain in epileptic patients. In addition to altered consciousness In our patients with depth electrodes, the forebrain and motor manifestations, both consistent features of transmission sites were always involved, in a uniform seizures, other functions are often affected. For ex- chronology, during interictal periods and seizures ample, variable signs and symptoms occur with aura. (Figs. 10 and 11). Not only are these sites intercon- Some of the most common are changes in emotional nected, but each is connected, back-and-forth, with state, alterations in sensory perception, changes in caudal sites (grouped together arbitrarily by virtue of facial expression and eyes, and impairment of motor subserving special functions). In the monkeys in coordination. The brief delay times in evoked poten- which experimental epilepsy was induced, electrodes tials suggested direct anatomical connections among were implanted into these caudal sites. The recordings http://jnnp.bmj.com/ nuclei subserving these functions. Even when elec- show that seizural EEG activity not only occurred at trode placements are verified histologically, the forebrain sites (where it had been recorded in epileptic evoked potential technique for demonstrating ana- patients), but spread to more caudal sites, migrating tomical pathways lacks precision, as the eliciting among these sites interictally. Before a clinical stimulus can activate nearby structures and the seizure, build-up of epileptiform activity occurred at recorded response can be from a site near the record- these various sites, but immediately before a seizure, ing electrode. The technique serves as a satisfactory, the same chronological dispersion that we have ob- quick screening method, but it is desirable further to served in patients spread through the hippocampus on October 1, 2021 by establish the connections by histological methods. and amygdala, then to the septal region, and finally to Many of the principal connections revealed by the cortex. evoked potentials have been verified by Fink-Heimer In epileptic patients with depth electrodes, we have axonal degeneration studies and horseradish peroxi- previously observed that intensified epileptiform dase methods for demonstrating afferent connections activity in forebrain transmission sites correlated with to a given site (Heath, 1972, 1973, 1976; Harper and altered emotionality (Heath, 1962, 1975, 1976; Heath J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.11.1037 on 1 November 1976. Downloaded from

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PATIENT A.V. :WUV UL. and Gallant, 1964). The same sites and complex path- and psychosis. Electroencephalographic activity re- ways have been shown to be basic to emotional ex- corded from the involved brain sites of epileptic pression, and they are thus significantly involved in patients during seizures is different from that re- healthy and pathological behaviour (Heath, 1964, corded in patients with profound behavioural path- 1966, 1972, 1975, 1976; Heath etal., 1974). In epileptic ology who are seizure-free. In the epileptic patients http://jnnp.bmj.com/ patients, behavioural concomitants ranging from with depth electrodes, who had psychotic episodes as mildly inappropriate emotionality (usually adverse, well as seizures, both kinds of EEG recordings were rarely pleasurable) to irrational psychotic behaviour, obtained depending on clinical state. During their which sometimes occur interictally and frequently psychotic behaviour, recordings often closely re- occur as part ofan aura, have been correlated with the sembled those of other psychotic patients-for aberrant EEG activity in forebrain transmission example, schizophrenic patients-whereas, during sites. This finding that the same interconnected seizures, recordings were characteristic of the neural structures are involved in behavioural phe- epileptic. on October 1, 2021 by nomena and seizures also provides an anatomical- The animal data reported herein demonstrate that physiological basis for the observation that aberrant the ro3tral forebrain structures, where reCordings in behaviour can be ameliorated by the induction of patients correlated with the clinical phenomena of seizures, as in electroconvulsive or Metrazol therapy. seizures and emotionality, are directly connected with These treatments evolved from clinical observations several brain sites subserving other functions. Further, of an occasional inverse relationship between epilepsy the animal data reveal the involvement of these J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.11.1037 on 1 November 1976. Downloaded from

Brain fiunction in epilepsy: midbrain, medullary, and cerebellar interaction with the rostralforebrain 1049

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W fM http://jnnp.bmj.com/ on October 1, 2021 by FIG. 1 1 Deep and surface recordings from an epileptic patient during a psychomotor seizure. The three 16-channel recordings (sample) show diffierent sequences in the onset of the seizure. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.11.1037 on 1 November 1976. Downloaded from

1050 R. G. Heath remote sites in clinical seizures. In the experimental Many of these same brain structures and pathways epileptic animals, recordings show that electrical -the septal region, hippocampus, and amygdala of seizural activity can spread over direct pathways to the rostral forebrain; the thalamic nuclei; the relay involve other interconnected sites, the sequence nuclei for sensory perception; the midbrain nuclei for varying from one seizure to the next. This finding various chemical transmitters and for eye movement could account for the variability in aura and sequelae -all interrelated with the hind-brain through the ofseizures. cerebellar-inferior olive system, have been shown to Involvement ofthe sensory relay nuclei (medial and be implicated in dyskinesia. Physiological interven- lateral geniculates, ventroposterior lateral thalamus, tion at some of these sites (by different treatment and fastigial nucleus ofthe cerebellum) in the seizural methods) has proved effective in alleviating signs and spread could explain the disturbances in sensory per- symptoms of dyskinesia (Cooper, 1969). Drugs bene- ception that often occur during aura ofthe seizure and ficial in treating behavioural disorders often induce could also account for the observation that sensory dyskinesia. On the other hand, drugs used for treating stimuli sometimes precipitate a seizure. dyskinesia sometimes induce or aggravate pathologi- Ocular involvement in seizures, such as the blank cal behaviour. The complicated anatomical- stare during a psychomotor attack and the gross functional relationship among systems subserving aberrations associated with a grand mal seizure, is these different functions offers a basis for under- probably due in part to involvement of the superior standing clinical observations and may ultimately colliculus and third nerve nuclei. The consistent input open the way for other therapeutic procedures. from the inferior olive and dentate nucleus in per-

petuating the seizural discharge provides an explana- guest. Protected by copyright. tion for changes in coordination during seizures Supported in part by grants from the Ittleson Family (Llinas et al., 1975). Foundation and J. Aron Foundation, New York, The functional role of various putative neurotrans- NY, and from the Zemurray Foundation, New mitters in epilepsy is by no means clear. Underscoring Orleans, La. The author wishes to acknowledge the the complexity of this phenomenon is the finding that technical assistance of Charles J. Fontana and cell reservoirs for several transmitters are involved in Herbert J. Daigle. the interconnected pathways implicated in the de- velopment of an epileptic seizure. The chemical synaptic transmitters involved are probably the basic determinants of whether activity at these neural REFERENCES structures results in seizures or pathological behaviour. Cooper, I. S. (1969). Involuntary Movement Disorders. Participation of the deep cerebellum in the course Harper and Row: New York. of a seizure appears unique. Although epileptiform Cooper, I. S., Crighel, E., and Amin, I. (1973). Clinical and physiolo-gical effects of stimulation of the paleocerebel- activity in the deep cerebellar nuclei occurred during lum in humans. Journal of the American Geriatric build-up to seizure, rhythmical full-blown seizural Society, 21,40-43. activity did not begin there until the clinical seizure Cooper, 1. S., and Snider, R. S. (1974). The effect ofvarying had passed its peak. High-amplitude rhythmical the frequency of cerebellar stimulation upon epilepsy. cerebellar discharges then continued for some time In The Cerebellum, Epilepsy, andBehavior, pp. 245-256. postictally while recordings from other sites were Edited by I. S. Cooper, M. Riklan, and R. S. Snider. virtually isoelectric, suggesting that enhanced activity Plenum: New York. http://jnnp.bmj.com/ of the deep cerebellar nuclei correlated with cessation Grabow, J. D., Ebersold, M. J., Albers, J. W., and Schima. of the seizure. One can only speculate on the relation E. M. (1974). Subject review-Cerebellar stimulation between this finding and the beneficial results that for the control of seizures. Mayo Clinic Proceedings, 40, have been obtained with use of surface cerebellar 759-774. stimulation for control of seizures (Grabow et al., Guerrero-Figueroa, R., Barros, A., deBalbian Verster, F., 1974). Since the Purkinje cells of the cerebellar cortex and Heath, R. G. (1963). Experimental petit mal in inhibit activity in the deep nuclei, the assumption that kittens. Archives ofNeurology (Chic.), 9, 297-306. cerebellar stimulation is beneficial by virtue of Harper, J. W., and Heath, R. G. (1973). Anatomic con- on October 1, 2021 by activating Purkinje cells would be irreconcilable with nections of the fastigial nucleus to the rostral forebrain our findings. An alternative explanation might be in the cat. ExperimentalNeurology, 39, 285-292. more feasible. Conceivably, the slow-frequency Harper, J. W., and Heath, R. G. (1974). Ascending projec- stimulation may inhibit Purkinje cells or a mechanism tions of the cerebellar fastigial nuclei: Connections to not involving the Purkinje cells may facilitate activity the ectosylvian gyrus. Experimental Neurology, 42, in the deep nuclei to control the seizure. 241-247. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.39.11.1037 on 1 November 1976. Downloaded from

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Heath, R. G. (1954). Definition of the septal region. In Pleasure in Behavior, pp. 83-106. Edited by R. G. Heath. Studies in Schizophrenia, pp. 3-5. Harvard University Harper and Row: New York. Press: Cambridge, Mass. Heath, R. G., and Harper, J. W. (1974). Ascending pro- Heath, R. G. (1962). Common characteristics of epilepsy jections of the cerebellar fastigial nucleus to the hippo- and schizophrenia: Clinical observation and depth campus, amygdala, and other temporal lobe sites: electrode studies. American Journal ofPsychiatry, 118, evoked potential and histological studies in monkeys 1013-1026. and cats. Experimental Neurology, 45, 268-287. Heath, R. G. (1963). Closing remarks, with commentary Heath, R. G., and Harper, J. W. (1976). Descending on depth electroencephalography in epilepsy and schizo- projections of the rostral septal region: an electro- phrenia. In EEG and Behavior, pp. 377-393. Edited by physiological-histological study in the cat. Experimental G. H. Glaser. Basic Books: New York. Neurology, 50,536-560. Heath, R. G. (1964). Pleasure response of human subjects Heath, R. G., John, S. B., and Fontana, C. J. (1968). The to direct stimulation of the brain: physiologic and pleasure response: studies by stereotaxic technics in psychodynamic considerations. In The Role ofPleasure patients. In Computers and Electronic Devices, pp. in Behavior, pp. 219-243. Edited by R. G. Heath. 178-189. Edited by N. Kline and E. Laska. Grune and Harper and Row: New York. Stratton: New York. Heath, R. G. (1966). Schizophrenia: biochemical and Heath, R. G., John, S. B., and Fontana, C. J. (1976). physiologic aberrations. International Journal ofNeuro- Stereotaxic implantation of electrodes in the human psychiatry, 2, 597-610. brain: A method for long-term study and treatment. Heath, R. G. (1972). Physiologic basis of emotional ex- IEE Transactions on Biomedical Engineering, vol. BME- pression: evoked potential and mirror focus studies in 23, no. 4, 296-304. rhesus monkeys. BiologicalPsychiatry, 5, 15-31. Llinas, R., Walton, K., and Hillman, D. E. (1975). In- guest. Protected by copyright. Heath, R. G. (1973). Fastigial nucleus connections to the ferior olive: Its role in motor learning. Science, 190, septal region in monkey and cat: a demonstration with 1230-1231. evoked potentials of a bilateral pathway. Biological Mickle, W. A., and Heath, R. G. (1957). Electrical activity Psychiatry, 6, 193-196. from subcortical, cortical, and scalp electrodes before and during clinical epileptic seizures. Transactions ofthe Heath, R. G. (1975). Brain function and behavior: I. American Neurological Association, 82, 63. Emotion and sensory phenomena in psychotic patients and in experimental animals. Journal of Nervous and Paul, S. M., Heath, R. G., and Ellison, J. P. (1973). Histo- Mental Disease, 160,159-175. chemical demonstration of a direct pathway from the fastigial nucleus to the septal region. Experimental Heath, R. G. (1976). Correlation of brain function with Neurology, 49,798-805. emotional behavior. Biological Psychiatry, 11, 463-480. Snider, R. S., and Lee, J. C. (1961). A Stereotaxic Atlas of Heath, R. G., Cox, A. W., and Lustick, L. S. (1974). Brain the Monkey Brain (Macaca mulatta). University of activity during emotional states. American Journal of Chicago Press: Chicago, Ill. Psychiatry, 131, 858-862. Snider, R. S., and Magoun, H. (1949). Facilitation pro- Heath, R. G., and Gallant, D. M. (1964). Activity of the duced by cerebellar stimulation. Journal of Neuro- human brain during emotional thought. In The Role of physiology, 12,335-345. http://jnnp.bmj.com/ on October 1, 2021 by