Eye position-sensitive units in hippocampal formation and in inferotemporal cortex of the macaque monkey.

The activity of 330 hippocampal and inferotemporal cells was recorded while seated monkeys with fixed heads worked in a visual discrimination task. Monkeys had to move their eyes to one of five different positions to maintain gaze on an image. The image was then extinguished and the monkeys maintained a fixed gaze on the target position in darkness to obtain a reward. The five positions of image presentation were on a horizontal line, consisting of a centre position and lateral positions which were 10 and 20 degrees right and left of it. Twenty-two per cent of single units recorded from the hippocampus showed statistically significant sensitivity to target position in complete darkness. A similar fraction (23%) was significantly affected by target position in the light. Position sensitivity was also found among cells recorded from the inferotemporal cortex. Eye position significantly influenced the activity of 19% of inferotemporal units in darkness and 28% of inferotemporal units in the light. Interestingly, the populations of cells showing position effect in the light and in darkness were independent.

Activity linked to externally cued saccades in single units recorded from hippocampal, parahippocampal, and inferotemporal areas of macaques.

We studied whether target-directed, externally commanded saccadic eye movements (saccades) induced activity in single units in inferotemporal cortex, the hippocampal formation, and parahippocampal gyrus. The monkeys first were required to fix their gaze on a small cross presented to the left or right of center on the monitor screen. The cross was extinguished, and a random 600-1,000 ms thereafter, a small dot was presented for 200 ms. The dot was located either 10 degrees above, below, right, or left of the position on which the fixation cross had been. The monkey made a saccadic eye movement to this dot (in darkness). The neuronal activity around this goal-directed saccade was analyzed. In addition, control conditions were imposed systematically in which similar dots were presented, but the monkey's task was to withhold the saccade. We recorded 290 units from two monkeys. From this group, 134 met two criteria, they did not show visual response in control trials and they had spike rates >2 Hz. These were analyzed further; 53% (71/134) showed modulation related to the target directed saccade, and 29% (39/134) showed saccadic modulation during spontaneous eye movements. These two groups were correlated only weakly. Of the units with significant saccadic modulation, 17% (12/71) showed significant directional selectivity, and 13% (9/71) showed significant position selectivity (P < 0.01). At a lower criterion (P < 0.05), almost one-half (33/71) showed one or the other spatial selectivity. Primates use saccades to acquire visual information. The appearance of strong saccadic modulation in brain structures previously characterized as mnemonic suggests the possibility that the mnemonic circuitry uses an extraretinal signal linked to saccades to control visual memory processes, e.g., synchronizing mnemonic processes to the pulsatile visual data inflow.

Saccadic eye movements, even in darkness, generate event-related potentials recorded in medial sputum and medial temporal cortex.

Saccadic eye movements (saccades) in primates organize the visual information about the environment into a pulsatile course. Recent studies from our laboratory have found substantial single unit activity, of extra-retinal origin, in medial temporal and inferotemporal cortex with each saccade (even in the dark). In the current experiment we studied event-related potentials to spontaneous saccades from electrodes in medial temporal cortex as well as medial septum. Significant event-related potentials were recorded in both regions (again even in the dark). These data suggest that higher-level processing itself may synchronize with saccades.

Mnemonic responses of single units recorded from monkey inferotemporal cortex, accessed via transcommissural versus direct pathways: a dissociation between unit activity and behavior.

Three macaques were trained on a task in which a sequence of single visual images was presented serially, and the monkeys signaled whether the image was a new or a repeated one. The optic chiasm and splenium of the corpus callosum were transected, leaving the anterior commissure as the only path for cortical interhemispheric transfer. Images were presented to only one eye at a time. Re-presentations of images to the same eye were recognized correctly in >95% of trials. A robust stimulus-specific adaptation (i.e., a reduced response to a repeated image) was seen in the population of single units recorded from inferotemporal cortex during these same trials. When an interhemispheric transfer was demanded of the animals (i.e., the re-presentation was made to the other eye), recognition performance was somewhat reduced, to 86% correct. Interestingly, in this situation the stimulus-specific adaptation disappeared completely. The disappearance occurred regardless of whether the transfer direction was from the hemisphere ipsilateral to the recording site to the hemisphere contralateral to the recording site, or vice versa. Thus, stimulus-specific adaptation in inferotemporal cortex units is not required for recognition.

Brevity of processing in a mnemonic task.

1. A burst of from one to four current pulses of 0.2 ms at 100 Hz was administered bilaterally to medial temporal lobe areas while monkeys worked in a delayed matching-to-sample visual memory task. The brief electrical stimulation was used as a probe to determine when, around the 20 or 50 ms sample presentation, the disruption was most severe. 2. Stimulation within about 200 ms of the sample image onset severely perturbed the animals' ability subsequently to recognize that image. Identical stimulation at other times did not. 3. Thus, the processing during encoding, that is accessible to the implanted medial temporal lobe electrodes, appears to occur only in a brief interval associated with receipt of the sensory input.

Interhemispheric sharing of visual memory in macaques.

(1) In macaques with the optic chiasm transected, and forebrain commissural communication limited to the anterior commissure or the posterior 5 mm of the splenium of the corpus callosum, visual patterns viewed initially by only one eye (hemisphere) are subsequently recognized by the other with normal accuracy. (2) The efficiency of these commissural paths is further indicated by the fact that even when as many as six "target" images are presented for memorization to only one hemisphere, it makes essentially no difference as to accuracy or latency of performance which hemisphere is then required to distinguish "target" from "non-target" images. (3) By electrically tetanizing structures in one or the other temporal lobe at various times in relation to visual input and/or mnemonic testing it could be shown: (a) that a memory trace restricted in its formation to a single hemisphere was available to the other via either forebrain commissure, and (b) that the memory is formed bilaterally despite unilateral input. (4) When the chiasm is split but the commissures are intact, simultaneous presentation of disparate images to each hemisphere severely perturbs performance, suggesting that the callosal system operates continuously to unify visual percepts; but when only the anterior commissure is intact, the two hemispheres accept incongruent images without perturbation. (5) In the fully "split-brain" condition, when one hemisphere cannot access memories held in the other, the accuracy of performance by each hemisphere is nevertheless burdened by the memory load of its neocortically disconnected partner. It can thus be inferred that the brainstem plays a critical, unifying role in this mnemonic process.

Time is of the essence: a conjecture that hemispheric specialization arises from interhemispheric conduction delay.

Tomasch (1954) and Aboitiz et al. (1992) found the majority of the fibers of the human corpus callosum are under 1 micron in diameter. Electron microscopic studies of Swadlow et al. (1980) and the detailed study of LaMantia and Rakic (1990a) on macaques show the average size of the myelinated callosal axons also to be less than 1 micron. In man, the average-sized myelinated fiber interconnecting the temporal lobes would have a one-way, interhemispheric delay of over 25 msec. Thus, finely detailed, time-critical neuronal computations (i.e., tasks that strain the capacity of the callosum and hence could not be handled by just the larger fibers) would be performed more quickly via shorter and faster intrahemispheric circuits. While one transit across the commissural system might yield tolerable delays, multiple passes as in a system involving "setting" would seem prohibitively slow. We suggest that these temporal limits will be avoided if the neural apparatus necessary to perform each high-resolution, time-critical task is gathered in one hemisphere. If the, presumably overlapping, neural assemblies needed to handle overlapping tasks are clustered together, this would lead to hemispheric specialization. The prediction follows that the large brains of mammals such as elephants and cetaceans will also manifest a high degree of hemispheric specialization.

Stimulus specific adaptation in excited but not in inhibited cells in inferotemporal cortex of macaque.

Many cells in inferotemporal cortex respond more actively to a novel presentation than to a subsequent re-presentation of the same image, exhibiting stimulus specific adaptation (SSA). Previously, analysis of this adaptation was limited to visually excited cells, excluding visually inhibited cells. In the present experiment we studied 654 cells in four macaques performing visual tasks. Strong SSA (P < 0.0001) was observed in those cells which were excited by visual stimuli. This adaptation was also seen in the subset of such cells which, though excited by visual stimuli, failed to show visual specificity in their responses. Interestingly, no SSA (P > 0.1) was observed in the group of cells inhibited by visual stimuli. Furthermore, most inhibited cells failed to show visual specificity. This lack of visual specificity and SSA suggests that the visually inhibited cells have a limited role in the detailed information processing of visual perception and memory activated by the tasks used in the present experiments.

Eye movements modulate activity in hippocampal, parahippocampal, and inferotemporal neurons.

1. Inferotemporal, hippocampal, and parahippocampal units were recorded while monkeys were alert (as judged by eye movements) but resting, in both light and dark. 2. Spontaneous saccadic eye movements produced significant changes in unit activity for 108 of 308 cells. This activity is shown to be extraretinal either because it occurred in complete darkness or because of its timing relative to the eye movement. 3. The total saccadic modulation in the ventral temporal lobe is estimated to be over ten million action potentials.

Indirect inputs to ventral temporal cortex of monkey: the influence of unit activity of alerting auditory input, interhemispheric subcortical visual input, reward, and the behavioral response.

1. This study examined nonvisual and indirect inputs to 1,021 single units recorded in inferotemporal and parahippocampal cortex of behaving macaques. 2. To better isolate these influences, a fully split-brain, split-chiasm preparation was used. Extracellular single-unit activity was recorded while the ipsilateral eye was covered. During the recordings the monkeys worked on a visual discrimination task that consisted of a series of presentations of single images. 3. When the interval between presentations was varied randomly (usually between 4 and 15 s) about one-quarter of these cells responded to an alerting tone sounded 500 ms before the onset of the visual image. That this response is due to the warning value of the tone was shown by finding that an identical tone sounded at the end of each trial produced no response from these cells. Use of an exchange between pairs of light-emitting diodes as a warning signal (one turned on as the other was turned off, also 500 ms before the visual stimulus onset) produced a similar response in many units. This indicates a subcortical route for the alerting signal. In most cases, warning responses were inhibitory, often delayed with respect to the warning signal occurrence to more nearly match the image arrival time. 4. Surprisingly, and despite the monkeys' confirmed split-brain status, occasional cells (approximately 2%) showed a response from a visual presentation limited to the other hemisphere. Although this subcortical visual input was far weaker than direct visual input, it was nonetheless statistically reliable. Importantly, the indirect input was stimulus specific and could form the neural basis for a limited interhemispheric visual transfer of the sort seen in human split-brain patients. 5. Also rarely, cells showed activity time locked to the animal's behavioral response.

Spared short-term memory in monkeys following medial temporal lobe lesions is not yet established: a reply to Alvarez-Royo, Zola-Morgan and Squire.

It is important to know whether or not short-term memory (STM) is preserved in monkeys, as sometimes claimed, following lesions to medial temporal lobe that disrupt longer term memory. As examined herein, the magnitude of the longer term deficit in the delayed matching-to-sample task is well correlated with slower learning at short delays. This learning deficiency with short delays can be severe, e.g., failure to reach criterion despite ten times the number of trials required by control animals, yet the same animals can perform some visual discriminations normally. Such slow learning may thus be most parsimoniously attributed to a STM deficit. Studies are also reviewed which compare delayed (non)matching-to-sample performance in lesioned monkeys at short and long delays. For those groups that received equal training at all delays, the short-term deficit is as large as the longer term deficit. For those groups trained only at the short delay the short-term deficit is small. Caveats for future studies are discussed.

Investigation of long-term recognition and association memory in unit responses from inferotemporal cortex.

We investigated recognition and association memory in the responses of single units isolated in the inferior temporal cortex of a macaque while it performed a visual discrimination task. The unit responses showed significant recognition memory (a decreased response upon image repetition). Furthermore, a recognition memory appeared to be a permanent feature in these units. Such memory was evident in responses recorded at least 1 h after the most recent presentations of the more familiar images and may have been built up over the months of training. For these cells, the shorter-term recognition memory (seconds) and the longer-term recognition memory (hour plus) were significantly correlated (0.68). In these same cells associative memory was investigated with ten abstract images which had been randomly and permanently paired. The monkey had been taught to discriminate these five pairs from other similar pairs of images. Neither the spike count nor temporal response shape (as determined by a principal-components analysis) showed increased similarity for the images that had been paired. The cells that had both short-term and long-term recognition memory had responses to previously paired stimuli that were no more similar than expected by chance.

The medial temporal lobe in encoding, retention, retrieval and interhemispheric transfer of visual memory in primates.

Low-level electrical stimulation through electrodes in the medial temporal lobe (MTL) was used to disrupt the performance of chiasm-split macaques working in a delayed matching-to-sample (DMS) visual memory task. The stimulation was below afterdischarge threshold and did not distract the animals. Nonetheless, stimulation caused severe deficits when delivered either during encoding or retrieval stages. Substantially less deficit appeared when stimulation was delivered during the retention interval. Stimulation levels which led to significant disruption on the DMS task had no effect on a discrimination task using the same kinds of images. Unilateral electrical stimulation delivered to MTL in one hemisphere during encoding and to MTL in the other hemisphere during retrieval produced an effective disruption, suggesting that the unilateral stimulation during the encoding period disrupts the encoding on that side while unilateral stimulation delivered to the opposite side during the retrieval period prevents the retrieval of the (now unilateral) memory. This suggestion is supported by control experiments in which significantly less disruption was caused by unilateral electrical stimulation delivered during both the encoding and the retrieval period if the stimulation was delivered to the same side in both periods. The electrical stimulation was further used to determine that interhemispheric access by one hemisphere to memories placed in the other was excellent. This was done, in these split-chiasm monkeys, by using unilateral stimulation to limit memory formation to just one hemisphere, then testing interhemispheric access by routing the test through the "ignorant" hemisphere (using just the ipsilateral eye). Successful interhemispheric access was obtained with either the anterior commissure or with the splenium of the corpus callosum (the other interhemispheric forebrain pathways having been cut). The electrical stimulation was also used to determine that the visual inputs even though entering via just one eye and one hemisphere, lead to bilateral memory formation. In this case each hemisphere was tested separately during retrieval by delivering disruptive levels of the electrical stimulation to the MTL of the other hemisphere.

Memory decays at the same rate in macaques with and without brain lesions when expressed in d' or arcsine terms.

Data from the literature on the effect of lesions upon recognition memory in the monkey have been examined. On the basis of percentage scores the published data can be interpreted as showing that the ability to recognize a previously seen object decays faster in macaques with brain lesions than it does in normal animals. A reanalysis of the extensive data in terms of d' of Signal Detection Theory or by arcsine transform suggests, on the contrary, that the rate of decay from 0 to 600 s, is essentially the same in normal animals and in those with lesions (particularly temporal lobe lesions). Indeed, in d' or arcsine terms, the effect of the lesions is fully developed at the shortest times used, and shows no increase as a function of the delay between initial presentation and test. Thus, very different conclusions stem from the choice of scale.

Neuronal interconnection as a function of brain size.

The effect of increasing brain size upon the degree of interconnection between neurons is analyzed. An explicit model suggests that as the brain is scaled up there must be a corresponding fall in percent connectedness (the fraction of cells with which any one cell communicates directly). The reason for this is that if the percent connectedness is to be maintained in the face of increased neuron number, than a large fraction of any brain size increase would be spent maintaining such interconnection while the increasing axon lengths would reduce neural computational speed. One implication is that larger brains, being necessarily limited in allowable interconnectedness, may tend to show more specialization.

Bi-versus monohemispheric performance in split-brain and partially split-brain macaques.

Experiments comparing binocular with monocular abilities of monkeys working on visual mnemonic tasks were performed. First, it was shown that even in split-brain monkeys performance was more accurate when both hemispheres were utilized than when the task was performed with only the single (better) hemisphere. Some form of noncommissural integration is thus possible. However, when the forebrain commissures are present, as in four other animals (with only optic chiasm transected) it was shown that integration occurs via callosal mechanisms as well. This was demonstrated by the fact that here, too, binocular performance was normally more accurate than monocular performance, but when different images to be remembered were presented concurrently to the two eyes, the binocular advantage was lost. Finally, in three monkeys with only the anterior commissure allowing interhemispheric communication the superiority of binocular assessment remained even when the two hemispheres simultaneously received such differing images.

Interhemispheric transfer of visual discriminations in split-chiasm monkeys (Macaca nemestrina) and its measurement.

The interhemispheric transfer of visual discriminations in split-chiasm monkeys (Macaca nemestrina) was assessed by training with one eye to a criterion level, then testing either with that same eye (control) or with the other eye (transfer). The difference between these two values was the loss due to transfer. A computer simulation suggested that the usual savings score could grossly misestimate transfer ability. In addition, stimuli with comparable left and right halves were used to minimize the effect of the bilateral hemianopia caused by chiasm section. Performance with the untrained eye was slightly, but statistically significantly, poorer than with the trained eye. No evidence of the phenomena of "learning to transfer" was found (i.e., there was no improvement in transfer ability in relation to concurrent intrahemispheric controls).

Amnesia for the McCollough effect following unilateral electroconvulsive therapy: implications for laterality.

The hemispheric lateralization of retrograde amnesia following unilateral electroconvulsive therapy (ECT) was measured by a novel nonverbal probe, the McCollough effect, which allowed equal and exclusive access to each hemisphere. Alternating exposure to perpendicular gratings of complementary colors (e.g., red vertical stripes alternated with green horizontal stripes) will cause subsequently presented black and white gratings to appear colored hours or even days later (the McCollough effect). Three of the patients examined (3 of 10) lost the effect in just the half visual field contralateral to the treatment side when unilateral nondominant ECT was interposed between the induction of the effect and the its test. Six patients lost the effect bilaterally following unilateral ECT. One patient retained a bilateral aftereffect. This patient had by far the shortest seizure (18 sec). Nine of 10 comparison patients, also suffering from major depression but without ECT intervening between induction and test, showed good bilateral retention of the McCollough effect. The remaining comparison patients showed no retention. These results imply that despite bilateral cortical spread of seizure activity, unilateral nondominant ECT has effects that are most pronounced over the stimulated hemisphere.

Forebrain commissures and visual memory: a new approach.

The primary purpose of these exploratory experiments was to determine: (1) whether the forebrain commissures can provide full accessibility of the mnemonic store to either hemisphere when the taks involves memory for 'events' (images) rather than, as in essentially all previous tests on split-brain animals, memory for 'rules' (discrimination habits); and (2) whether the anterior commissure (AC) alone is capable of such function. Macaques, with optic chiasm transected to allow limitation of direct visual input to one or the other hemisphere, were trained on tasks requiring recognition of previously viewed photographic slides. For one task, delayed-matching-to-sample (DMTS), the animal was presented with a 'sample' image, and then 0-15s later was required to choose that image in preference to a second image concurrently displayed. On the other task, running recognition (RR), a series of images was presented, some of which were repetitions of images previously seen in that session, and the animal was required to signal its recognition of these repetitions. For either task the initial presentation could be made to one eye and hemisphere, and subsequent recognition required of the other. In such circumstance, if all forebrain commissures were divided, such interhemispheric recognition was no longer possible. For the DMTS task if either the AC or 5 mm of the splenium of the corpus callosum were available, interhemispheric recognition was basically equivalent to that using the same eye and hemisphere. However, interhemispheric accuracy with the RR task, while well above chance levels, was consistently inferior to that achieved intrahemispherically when complex scenes or objects were viewed. This is probably a consequence mostly of the differing visual fields of the two eyes, since interhemispheric accuracy was greatly improved by use of images having approximately identical right and left halves. No consistent hemispheric specialization nor difference in direction of interhemispheric communication was observed despite the use of different types of material and the different mnemonic tasks. It is concluded that the AC in macaques can achieve full and continuously operative neural unification of the mnemonic traces of past experience.