Brain Research, 169 (1979) 173-177 © Elsevier/North-HolandBiomedicalPress

173

Non-burst epileptic firing patterns of neurons in chronic epileptic foci

ALLEN R. WYLER, CAROL A. ROBBINS and STEVEN KLEIN Department of Neurological Surgery, University of Washington, Seattle, Wash. 98195 (U.S.A.)

(Accepted February 15th, 1979)

Since Hughlings Jackson's prediction that focal epilepsy emanates from neurons which are in a 'hyperphysiologic' state, research into the epilepsies' basic mechanisms has been directed at neuronal pathophysiology. Studies of single neurons from chronic epileptogenic cortex have demonstrated that their firing behavior can be characterized by bursts of action potentials (APs) with extremely short interspike intervals (ISis) a-7. Most studies, however, have been qualitative and as such may miss subtle differences between the firing behavior of neurons in epileptogenic and normal cortex. Monkeys may be operantly conditioned to control the firing patterns of single neurons 2,a. The applications of this technique to study single neurons can yield subtle differences between firing patterns of units in epileptogenic and normal cortex. We report an abnormal neuronal firing pattern within alumina foci which has not been acknowledged previously. Data are from 5 male Macaca mulatta monkeys. Epileptic foci were produced by the Ward e modification of the Kopeloff8 technique in 3 monkeys, and 2 remained normal. Chronic recording chambers were placed over precentral cortex bilaterally and chronic pyramidal tract (PT) electrodes placed in each medullary pyramid. The methods for 24 h seizure monitoring extracellular neuronal recording, and PT stimulation are detailed elsewhere 7-9. The operant task is for the monkey to change the neuron's firing pattern from phasic to tonics and requires the monkey to produce consecutive ISis within a requisite range of 30--60 msec. Each 5 min operant period is termed 'differential reinforcement of tonic patterns' (DRTP) and is numbered sequentially. DRTP periods are alternated with 5 min time-out (T.O.) periods. Single neuronal epileptic activity is quantified by the burst index (BI), which is the per cent of ISis less than 5 msec per 15 sec. Epileptic neurons are divided into 2 groups on the basis of the BI magnitude and variability. Group 1 neurons (highly epileptic) have a variability less than -/-10, whereas Group 2 neurons (weakly epileptic) have a variability greater than ± 10. Neurons with a BI less than 10 are considered normal. Each cell is judged normal or epileptic by the mean BI of the preconditioning period. Unit recordings were accepted only if the following criteria were met: (a) APs were negative-positive; (b) APs were recorded from non-injured neurons; (c) the unit

174

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Fig. 1. Action potentials and interspike intervals from a normal PTN (A) and a Group 1 epileptic PTN (B). For APs negativity is up and calibration bars are 100 #V and 200 reset; band pass is 300 Hz-10 kHz. Histogram bin-width, 2 msec; cursors mark 30 and 60 msec.

had been recorded through 4 operant periods; (d) was fromprecentralcortex, and (e) had a preconditioning firing rate greater than 2 APs/sec. Three hundred precentral neurons were selected for analysis; 150 neurons were from normal cortex either contralateral to alumina foci or were from non-epileptic monkeys. The remaining 150 neurons were from chronic alumina foci. An example of a tonically firing P T N from normal cortex is shown in Fig. 1A. In contrast, the firing pattern of a G r o u p 1 epileptic neuron is demonstrated in Fig. lB. This neuron fired high frequency AP bursts (unresolved at the slow sweep speed), a characteristic epileptic firing pattern. F o r this G r o u p 1 epileptic neuron, the modal ISI is between 2-4 msec and indicates that the majority of ISis are associated with burst firing. It should be emphasized that in both examples in Fig. 1, 10-18 msec ISis are not predominant. O f the 150 precentral neurons studied within alumina foci, 87 were normal and 63 epileptic by the BI criterion. Of the 87 normal neurons, 39 showed firing patterns which are decidedly abnormal in comparison to other normal neurons 1. Characteristically, these neurons generate bimodal ISI histograms which have an ISI peak between

175 10 and 18 msec. A series of histograms from a representative neuron are shown in Fig, 2. As the monkey attempted to operantly control this neuron, the histograms became unimodal with an ISI peak between 12 and 16 msec. Although this precentral neuron was considered 'normal' by the BI criteria, the histograms demonstrate an abnormal DnTP~

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Fig. 2. Interspike interval histograms of all ISis during 5 rain behavioral periods of an operant conditioning experiment involving a PTN within an alumina focus (not all periods are shown). DRTP and time-out (T.O.) periods are numbered consecutively. Bin-width, 2 reset; cursors mark 30-60 msec target.

176 firing pattern. Inspection of the raw data indicated the 12-16 msec intervals were actually doublets rather than characteristic epileptiform bursts. It should be emphasized that the 150 PTNs from normal cortex did not have such predominant modal ISI peaks within the 10-18 msec range. It has been postulated 9 that chronic epileptic foci are comprised of a spectrum of neurons which range from those which are completely normal to those which are grossly epileptic. By the BI criteria the spectrum was divided into two groups. Group 2 (weakly epileptic) neurons had relatively low BIs which, more importantly, were extremely variable and fluctuated with the animal's state of consciousness and activity. On the other hand, Group 1 (highly epileptic) neurons had higher and less variant Bls which were relatively unaffected by the animals's state of arousal. However, since the BI is determined by the percentage of ISis less than 5 msec, it may neglect more subtle inherent neuronal firing abnormalities. We propose that one such abnormality is demonstrated by those precentral neurons (especially PTNs) which generate predominant ISis between 10 and 18 msec. Although normal precentral PTNs may show ISis between 10 and 18 msec, our data indicates this is not characteristically a model ISI when firing is faster than 2/sec during wakefulness. In addition, we have been unsuccessful in conditioning monkeys to produce such doublets from normal PTNs in non-epileptic cortex (unpublished data). That the doublets increased their occurrence as the monkey attempted to produce consecutive 30-60 msec implies the doublets are synaptically initiated obligatory events. It would appear, therefore, that these 10-18 msec doublets represent a subtle abnormal firing pattern characteristic of some precentral neurons in chronic foci. A peculiarly structured burst pattern has been recorded from epileptic PTNs within chronic foci: the long first-interval (LFI) burst 2,6,7. This burst is typified by an initial AP, followed by a relatively long ISI that is terminated by a stereotyped burst. The modal first interval of LF1 bursts is 8 msec 7, whereas the afterburst intervals are between 3-5 msec. Therefore, the total duration of the average LFI burst would be approximately 18 msec. We propose that PTNs which fire predominantly 10-18 msec doublets may represent a transition state between normal and pathologic physiology; i.e., the second AP of the doublet represents an incompletely developed 'afterburst'. Although this concept is speculative, there are analogies between the doublets and LFI bursts: (a) both appear to be obligatory events which are synaptically initiated; (b) when monkeys operantly increase the firing rate of LFI burst generating PTNs, they do so by increasing burst occurrence z, and this is similar to the increased doublets that occur when the monkey attempts to fire PTNs tonically within the 30-60 msec range; and (c) the LFI afterburst attenuates and becomes less variable with interburst intervals less than 100 msec7; this is similar to the sharper doublet modal ISI peak as the monkey increases ISis within the 30-60 msec target (as seen in Fig. 2). The relationship between LFI bursts and 10-18 msec doublets remains speculative. However, it appears that such doublets represent a definitely abnormal firing pattern recorded from neurons within alumina foci. Therefore, it is logical to suggest that this subtle abnormal firing behavior falls within the spectrum of epileptic firing

177 patterns c o m m o n l y associated with chronic foci, and most likely represents a transition between normal and G r o u p 2 epileptic neurons. This research was supported by G r a n t s NS 04053, NS 14590 and Teacher Investigator A w a r d (A.R.W.) NS-00195 awarded by the N a t i o n a l Institute o f Neurological and Communicative Disorder and Stroke, P H S / D H E W . S.K. was supported by an Epilepsy F o u n d a t i o n o f America Medical Student S u m m e r Fellowship. A . R . W . is an Affiliate of the Child Development and Mental Retardation Center, University o f Washington, Seattle, Wash. 1 Evarts, E. V., Temporal patterns of discharge of pyramidal tract neurons during sleep and waking in the monkey, J. Neurophysiol., 27 (1964) 152-171. 2 Fetz, E. E. and Wyler, A. R., Operantly conditioned firing patterns of epileptic neurons in motor cortex of chronic monkey, Exp. NeuroL, 40 (1973) 586-607. ] Kopeloff, L. M., Chusid, J. C. and Kopeloff, N., Chronic experimental epilepsy in Macaca mulatta, Neurology (Minn.), 4 (1954) 218-227. 4 Prince, D. A. and Futamaehi, K. J., Intracellular recordings from chronic epileptogenic foci in monkey, Electroenceph. clin. Neurophysiol., 29 (1970) 496-510. 5 Schmidt, R. P., Thomas, L. B. and Ward, A. A., Jr., The hyperexcitable neuron: microelectrode studies of chronic epileptic loci in monkey, J. NeurophysioL, 22 (1959) 285-302. 6 Ward, A. A., Jr., The epileptic neuron: chronic foci in animals and man. In H. H. Jasper, A. A. Ward, Jr. and A. Pope (Eds.), The Basic Mechanisms of the Epilepsies, Little and Brown, Boston, 1969, pp. 263-289. 7 Wyler, A. R., Fetz, E. E. and Ward, A. A., Jr.,Spontaneous firing patterns of epileptic neurons in motor cortex of chronic monkey, Exp. NeuroL, 40 (1973) 567-585. 8 Wyler, A. R. and Finch, C. A., Operant conditioning of tonic firing patterns from precentral neurons in monkey neocortex, Brain Research, 146 (1978) 51-68. 9 Wyler, A. R., Burchiel, K. J. and Ward, A. A., Jr., Chronic epileptic foci in monkeys: correlation between seizure frequency and proportion of pacemaker epileptic neurons, Epilepsia, 19 (1978) 475-484.

Non-burst epileptic firing patterns of neurons in chronic epileptic foci.

Brain Research, 169 (1979) 173-177 © Elsevier/North-HolandBiomedicalPress 173 Non-burst epileptic firing patterns of neurons in chronic epileptic fo...
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