James L. O'Leary

The effects of polarizing currents on cell potentials and their significance in the interpretation of central nervous system activity

Abstract Since no potential could be recorded from the medium surrounding a cell which was uniformly and synchronously active over its whole surface, potentials recorded across cell layers represent the difference in activity at apical and basal regions. Since potentials led from simple cell layers are effectively monophasic, the conduction time along the soma is a minor factor in determining the form of the record. Diphasic records are inferred to be summations of cell discharges some of which, represented predominantly in one phase, have a difference of potential of one polarity, others represented chiefly in the other phase having a potential difference of opposite polarity. If this is valid, potential differences of opposite polarity must be exhibited by cortical pyramids with a uniform anatomical orientation. A difference in the distribution or intensity of response of apical and basal dendrites is suggested as a possible factor. Polarization from an external source across a simple cell layer may either increase the amplitude of the monophasic difference of potential led from across it, or decrease and finally reverse its sign; presumably by altering the relative amplitudes of electrical activity at the two poles of the cells, but without blocking conduction from pre- to post-synaptic axons. The interpretation of this fact involves that polarizing currents act on cells essentially as they do on peripheral nerve axons. The change in polarity of record is in a direction opposite to the sign of the polarizing current. Polarization of optic tract axons may result in prolonged after-effects, negative under anodal polarization and positive under cathodal. This is interpreted as representing a repolarization, after discharge during the spike of the externally applied component of membrane charge, along with its resting metabolically induced component. This effect also occurs at axon end-arborizations, and changes in synaptic conduction may be assigned to such effects of sufficient intensity as well as to polarization of post-synaptic dendrites in the same region. Under polarizing currents the changes in amplitude and reversals of sign of the cortical alpha rhythm, of evoked potentials from shocks to the optic nerve including the evoked alpha waves, evoked potentials from the superior colliculus, strychnine spikes, and paroxysmal spikes of cortex set up by repetitive stimulation or otherwise all may be accounted for by the interpretation offered for the effects of polarization at the geniculate.

Cortical D.C. changes incident to midline thalamic stimulation

Abstract 1. 1. Cortical D.C. changes occur incident to stimulation of the mid-line thalamus of rabbit and cat. 2. 2. At stimulating frequencies which elicit recruiting a negative D.C. shift ordinarily occurs in the rabbit. In the cat there is no shift or a minor positive one may occur. 3. 3. In the rabbit with high frequency stimulation a negative D.C. shift results which may obtain an amplitude of 1.5 mV. and persist for several seconds into the post-stimulatory period. In the cat there is also a negative shift, but it is usually less manifest than the rabbit. 4. 4. The D.C. shift with low frequency stimulation results from summation of after-effect. At high frequency stimulation the D.C. shift is accounted for by summation of transients as well as summation of after-effects and is regarded as a steady state of activity in dendrites. 5. 5. Prolonged stimulation (10–15/sec) may introduce other effects which occasion the return of the D.C. shift to the pre-stimulatory base line and post-stimulatory positivity. 6. 6. The after-effect following the initial response of a recruiting series is associated with increased excitability. The negative D.C. shift following brief repetitive stimulation and the positive one following prolonged (10–15 sec.) stimulation are associated with decreased excitability for a test recruiting series. 7. 7. Intense repetitive stimulation in the relay nuclei of the thalamus may occasion cortical paroxysm on a base line indicative of positive D.C. shift, whereas corresponding stimulation in the mid-line thalamus has been shown to relate to negative D.C. shift. At present no explanation can be offered for this difference.

Correlation between steady transcortical potential and evoked response

In 9 cats and 3 rabbits we investigated the effects of veratrine hydrochloride, weak strychnine, 1 per cent novocaine and 1 per cent KCl upon the steady potential, evoked response, and spontaneous ECG of the somatic receiving area. Under 10−4 veratrine cyclic intense negative shifts of steady potential commence to recur immediately after its application to the cortical surface. In the negative troughs there is depression of evoked response; upon the plateaus between, the initial positive phase is markedly exaggerated and lengthened. Barbiturate spindles also change through exaggeration of their positively directed components. The SP shift which accompanies and follows barbiturate spindles of normal cortex is negative; after veratrine it becomes positive. With time spontaneous spikes of positive polarity appear upon the plateaus of veratrinized cortex, and recur after the steady potential has stabilized again. Such spikes, as well as evoked responses, acquire prolonged after-positivities with time. With 10−3 strychnine we noted exaggeration of the negatively directed components of evoked responses and of barbiturate spindles. The action of veratrine was observed to supercede that of strychnine; that is, after its application the previous effects of strychnine upon the evoked response and upon the barbiturate spindles disappeared, to be succeeded by typical veratrine effect. One per cent novocaine occasions at first an increase in amplitude and duration of the initial positive phase of the evoked response comparable with the earliest noted effect of veratrine. However, no steady potential shifts occur, and this initial effect of novocaine is followed by one of depression of the amplitude of the evoked response. After novocaine is washed off and replaced by veratrine a typical veratrine effect develops with marked exaggeration of the positive component of the evoked response. Veratrine spikes and SP negative shifts also occur. KC1 gives SP negative shifts, occasions only depression in amplitude of the evoked response. Followed by vetratrine, the effect of veratrine on the evoked response while still evident is reduced.

Study of a somatic evoked response of midbrain reticular substance.

Using 36 lightly anesthetized cats we studied the characteristics of a quite brief duration evoked midbrain potential. This was recorded from a discrete region of the reticular substance caudal and ventral to centre median, lateral to the oculomotor nucleus and dorsal to the rostral nucleus ruber. It was found to have a latency approximating that of the centre median potential previously identified and studied by Magoun and McKinley (1942), though the latter has a significantly longer duration. The midbrain potential we describe has a threshold corresponding to that of the gamma axons of the superficial radial nerve and is activated through the contralateral ventrolateral sector of the cord principally. The fastest peripheral axons that activate it have a conduction rate of about 45 m/sec. as compared with 85 for the posteroventral thalamic potential. Like the centre median potential (French, Verzeano and Magoun 1953b) it is sensitive to anesthesia. It tends to potentiation by noxious stimuli applied by natural means. Other data upon centre median and posteroventral thalamic potentials obtained in the same animals is presented for comparison.

Ocular motor dysfunction in total and hemicerebellectomized monkeys.

Studies of ocular motor function in monkeys undergoing either total or hemicerebellectomies has revealed the following abnormalities which can be attributed to cerebellar dysfunction: 1. Loss of smooth pursuit movements 2. Gaze-fixation nystagmus 3. Loss of inhibitory input on the vestibular apparatus reflected in a decreased latency and prolonged response to caloric stimuli. It is intimated that the role of the hemicerebellum deals with ipsilateral tone and its effect on eye movements.

Summation of certain enduring sequelae of cortical activation in the rabbit

Abstract In 32 rabbits, carried under high cord transection and infiltration of sensitive areas with novocaine, steady potential (SP) was studied using transcortical recording from the visual cortex by calomel half-cells and a “chopper” system. From immediately adjoining silver-silver chloride wire electrodes the usual ECG was recorded. Strychnine in different concentrations was applied to the surface of the cortex in some animals; in others primary visual responses were elicited by single and repetitive stimuli at different intensities applied to the contralateral optic nerve and the homolateral geniculate nucleus. 1. 1. Relatively long enduring (1–4 sec.) after-effects detected by the chopper method commonly followed the strychnine spikes and primary visual responses. 2. 2. Clusters of strychnine spikes produced somewhat longer and higher amplitude after-effects than single ones, suggesting summation. Trains of 2–3 primary visual responses evoked by very brief electrical stimulation did not summate, however. 3. 3. Repetitive stimulation of optic nerve for 2–10 sec. led to complex summations. Early in experiments the predominant polarity of the summated after-effect resulting from repetitive stimulation of the nerve was negative regardless of stimulus strength. Later under identical conditions of stimulation but following any major long-lasting SP shift, the summated after-effect was positive. 4. 4. Repetitive stimulation of the lateral geniculate nucleus caused somewhat different changes. At a stimulus strength maximal for the primary visual response the negative summation was replaced by a positive one, which was frequently accompanied by paroxysm. As with the optic nerve, following any major SP shift the summated after-effect changed and was positive at any stimulus strength. At this time repetitive stimulation of the lateral geniculate nucleus at maximum for the primary visual response resulted in a marked positive shift in SP which was most always accompanied by a sustained after discharge in the ECG. As the after-discharge continued to increase in voltage, the surface-positivity became more marked, and the latter did not disappear in a negative shift until the termination of the paroxysm. This pattern of SP shift with paroxysm was observed many times, and the only exception we have observed relates to the occasional appearance of fast spiky paroxysm associated with negativity in SP. 5. 5. It was concluded that relatively long-enduring positive and negative after-effects of primary visual response and of strychnine spikes occur more or less concomitantly, and the dominant polarity as detected in the records is determined by the algebraic summation of the opposing disturbances. 6. 6. Although summation of positive after-effects may account for the accumulation of positivity during paroxysm, and the summation of the opposing after-effects for the subsequent negative change that develops rapidly as paroxysm disappears, significant exceptions occur suggesting the existence of yet undiscovered factors. One such exception occurs when significant positive shift precedes the development of paroxysm.

Experimental modification of dendritic and recruiting processes and their DC after-effects☆

Abstract The study concerns agents that modify evoked cortical potentials of rabbit and cat in a predictable way and at the same time change the DC accompaniments of the activation process. Recruiting, surface-activated (dendritic) and subcortically activated (radiation) potentials were studied, both as responses to single stimuli and in repetitive series. In one set of experiments a variety of agents (1 per cent procaine, 0.01 per cent veratrine, 0.1 per cent GAB, and boiling water as a control) were applied to the cortical surface. In another, modifications were induced by the increasing injection of a barbiturate into artificially respired cats (immobilized with Flaxedil), leading to very deep anesthesia. Of the agents applied to the cortical surface all occasioned reversal (transcortical lead) of the ordinarily negative sign of the recruiting transient to positive, the summated after-effects evident during stimulation being augmented at the same time. Reversal in sign occurred in the transcortical lead even though the negative potentials remained in a lead from a superficial intracortical position to the subcortical white matter. Thus, the reversal could be attributed to a block in activity very close to the cortical surface, with continuation of activity of usual sign in the deeper cortical fraction. Dendritic and radiation activated responses behaved similarly. In the cat prior to the intravenous injection of Nembutal (0.15 – 0.3 g.), the negative dendritic response shows a short-lived negative after-effect followed by a longer lasting positive one. With repetitive stimulation the positive after-effect disappears, the negative one increasing and showing summation. Intravenous Nembutal occasions the disapperance of the positive after-effect which follows the response to a single stimulus and also augments the negative one which then lasts for a much longer time. With deepening anesthesia and repetitive stimulation transients no longer follow each of successive stimuli, a series of shocks then giving rise to a summation of negative after-effect alone. This is comparatively large and outlasts the stimulus series by several seconds. During deepening anesthesia the recruiting response fails earlier than the dendritic and radiation activated ones, the latter two being lost nearly simultaneously.

Caudate-Induced Cortical Potentials: Comparison between Monkey and Cat

The segment of the internal capsule which carries axons relating to the sensorimotor cortex does not closely adjoin the caudate in the monkey as it does in the cat. Therefore, in seeking evidence for caudate-induced cortical responses, activation of the adjoining internal capsule by stimulus spread can be avoided. In the monkey, caudate stimulation never produced cortical responses, and only capsule stimulation evoked the potential complex which has been attributed to caudate stimulation in the cat.

The thalamic source of cortical recruiting in the rodent

Abstract Cortical recruiting activated from the midline thalamus was studied in 80 animals, including (1) distribution elicited at different stimulus positions in the AP and transverse planes, (2) comparative latencies from parasagittal points to the cortices of the two hemispheres, and (3) the effects of acute and pf chronic lesions involving conceivable sources and routes of activation. The following are our significant conclusions: 1. 1. Using stimulus trains (with stimuli 5 msec. apart) to replace usual single stimuli, the negative phase of the single response evoked from a recruiting region is progressively extended as the length of a train increases. When trains at 6 per sec. recurrence replace the usual recruiting stimulus, the wave durations are also prolonged, although with longer trains the response ordinarily falls off rapidly past 25 stimuli. 2. 2. From parasagittal stimulation there is a significant latency difference to ipsi- and contralateral recording points, only midline stimulation resulting in nearly equal latency. Parasagittal placement shortens latency to the ipsilateral and lengthens it to the contralateral cortex. 3. 3. Neither acute nor chronic lesions of the corpus callosum influence recruiting activated from the midline thalamus. Lesions of the anterior limb of the internal capsule reduce the responsiveness of the rostral cortex of that hemisphere significantly. If a large area of retrograde change is produced by a chronic lesion, the effect upon recruiting is more pronounced than with a smaller area. Parasagittal lesions which do not affect the internal capsule or penetrate the thalamic peduncle interfere with recruiting much less significantly. Combinations of the two nearly abolish ipsilateral recruiting. 4. 4. Very active recruiting can be obtained from midline nuclei after destruction of both dorsomedial nuclei. Lesions on the raphe involving centralis medialis and rhomboideus nuclei significantly affect recruiting from electrode penetrations in the neighborhood of the lesion. Due to destruction of commissural connections the effect is more pronounced contralaterally. Active ipsilateral recruiting can still be elicited from rostral stimulating positions in the midline thalamus when a large lesion has destroyed the centralis medialis. Small dorsal lesions of the raphe reduce contralateral recruiting and elevate its threshold, indicating that the commissural system concerned with recruiting does not occupy a restricted part of the raphe. 5. 5. Section of the anterior limb of the internal capsule effectively abolishes the repetitive cortical spindles that follow single stimuli to the intralaminar nuclei. 6. 6. The findings are in general accord with prevailing opinion, give direct confirmation of the importance of the midline nuclei, and show that the dorsomedial nuclei, at least, are not essential to recruiting.

Supravital Staining of Mammalian Brain with Intraarterial Methylene Blue Followed by Pressurized Oxygen

In 25-day-old rats, injected intraperitoneally with 0.2 ml aliquots of 6% methylene blue in saline over 1 hr followed by a single 4–6 ml intra-arterial injection; O2 pressurized to 45 lb/in2 was used to improve reblueing of 1.5–2 mm slices of cerebellum, thus increasing staining selectivity. Factors believed to influence this selectivity for axonal elements and fine dendrites are the rapidity and pressure (about 300 mm Hg) of the terminal intra-arterial injection, the hyperbaric O2 treatment of tissue slabs for 1 hr as a substiute for room air, and immersion in 6% ammonium molybdate for 1 hr before return to atmospheric conditions.