Anatomical and neurobehavioral investigations concerning the thalamo-cortical organization of the rat's visual system.

The organization of thalamic afferents to the rat's visual cortex was investigated autoradiographically and through the retrograde transport of horseradish peroxidase (HRP) following infections into striate and peristriate cortex. The results revealed that Nucleus lateralis posterior (NLP) projects to a large peristriate cortical field that includes areas 18A, 7, and the anterior portion of area 18, and to a circumscribed temporal area corresponding to Krieg's ('46a,b) area 20. The dorsal lateral geniculate nucleus (LGNd) was shown to project to two spatially discontinuous cortical areas. The largest geniculate receiving area is partially coextensive with Krieg's area 17, but an extension of this projection posterior and medial to the striate cortex was found. In addition, a geniculate projection to a restricted field located in the lateral peristriate cortex was identified. Concurrent investigations were designed to assess the pattern discrimination abilities of rats prepared with striate cortical ablations, lesions in NLP and combined striate-cortical and thalamic ablations. Comparison of these animals with normal control subjects revealed that the striate cortex in the rat (as in the cat [Doty, '71; Sprague et al., '77] and the tree shrew [Killackey and Diamond, '71; Ware et al., '74]) is not necessary for successful pattern discrimination, and that the geniculo-striate and NLP-extra-striate projection systems are both involved in mediating the visual discriminative abilities of the rat. The results add species generality to the concept that the central connections to the visual cortex are characterized by parallel-conducting thalamic channels and contribute to the growing number of demonstrations that the extra-striate cortex and associated thalamic cell groups contribute significantly to the process of visual-pattern recognition.

Natural boundaries for the spatial spread of directed visual attention.

The spatial characteristics of directed attention were studied using spatial precues in a suprathreshold luminance detection task. Visual response times to probe flashes presented at various distances from the presumed focus of attention provided the dependent measure. The variation in response times with distance from the attentional focus was used to create spatial maps of the expectancy effect. The results indicate that, in an uncluttered visual field, the effects of precuing are widely distributed, and that the principal transitions in performance tend to occur either at the horizontal meridian, the vertical meridian, or both meridians, depending on the locus of the observers' expectancy.

Effects of excess glucose and insulin on glycolytic metabolism during experimental myocardial ischemia.

The selective metabolic effects of glucose and insulin were tested in an intact working swine heart preparation. Supplements of glucose (26.6 millimolar [mM] and insulin (0.025 units/ml) were provided to 18 hearts, 9 control hearts (coronary flow 151 ml/min) and 9 hearts rendered globally ischemic (coronary flow reduced from 167 to 85 ml/min). These hearts were compared with 14 additional hearts (6 control and 8 ischemic) given no supplements (glucose 8.6 mM, no excess insulin). In hearts without supplements, ischemic significantly decreased mechanical performance, myocardial oxygen consumption, fatty acid oxidation and tissue high energy phosphate stores. Glucose consumption was reduced from 133 micromoles (mumol)/hr per g (before ischemia) to 58 mumol/hr per g (P less than 0.05), presumably from inhibition at glyceraldehyde-3-phosphate dehydrogenase. Data for control hearts with excess glucose and insulin were similar to data in control hearts without supplements except that glucose consumption and glycolytic flux were increased. Ischemia in treated hearts, as compared with untreated ischemic hearts, effected similar significant decreases in myocardial oxygen consumption, fatty acid oxidation and high energy phosphate stores and resulted in greater reductions in mechanical performance and in 10 minutes' less average survival time. Glucose consumption was reduced from 483 (before ischemia) to 242 mumol/hr per g (P less than 0.005) and inhibition at glyceraldehyde-3-phosphate dehydrogenase was again noted. Thus, excess carbohydrate and insulin hormone, when infused directly into the ischemic myocardium, did not provide an efficacious increase in either glycolytic flux or energy production. These findings suggest that an alternative explanation for the reported efficacy of glucose-insulin-potassium infusions must be sought.

Rechargeable silver-modified mercuric oxide-zinc cell for cardiac pacemakers.

Tests were conducted on rechargeable mercury-zinc pacemaker batteries under simulated and actual biologic conditions, using a variety of discharge rates and charging schedules. In tests on 96 cells at a 6.4 milliampere (ma) discharge, recharging once every 15 months of simulated pacing at a 25 microampere (mua) drain, the earliest cell failure occurred after an equivalent of 50 years of pacing. The mean pacing equivalent for all 96 cells was more than 140 years. In 6.4 ma discharge tests on 24 cells, recharging once every 8 days of simulated pacing, only 1 cell in 24 failed after an equivalent of more than 500 years of pacing (actual time 2 years). In tests on 13 cells pacing at a 200 mua drain without recharging, the simulated mean duration of pacing before total discharge was 4.8 years. Seven other cells at a 200 mua drain with periodic recharging continue to function normally after more than 7 years of actual time, simulating 56 years of pacing at a 25 mua drain. Cardiac pacemakers using the rechargeable mercury-zinc cell have been implanted in animals for more than 2 1/2 years and in patients for more than 1 year with all units continuing to function satisfactorily. It has been demonstrated unequivocally that a rechargeable mercury-zinc pacemaker will function continuously for more than 4 years without recharging and that periodic recharging will extend pacing life far beyond that predicted for lithium and nuclear primary power sources.

Functional reductions in left ventricular volume. Minimum chamber size consonant with effective hemodynamic performance.

A heart model in dogs was developed to evaluate quantitatively the extent to which left ventricular chamber size could be reduced and yet retain residual mechanical function to perform adequately as a pump. In 9 animals placed on right heart bypass perfusion to control systemic flows; left ventricular performance was estimated from high-fidelity left ventricular pressure and aortic flowmeter recordings and from lateral plane left ventricular angiograms. Studies were made during unrestricted left ventricular filling at varying cardiac outputs and with inflation of a balloon in the left ventricular cavity at a physiological cardiac output. As compared with control data (cardiac output 1.4 L. per minute), balloon inflation to 18.7 ml. caused an increase in total left ventricular end-diastolic volume (from 35.4 to 44.3 ml., p less than 0.001) and left atrial pressure (from 7.8 to 21.2 mm. Hg; p less than 0.001); it also caused a reduction in left ventricular stroke work (from 12.5 to 8.1 Gm.-M., P LESS THAN 0.005) ANd max. dp/dt (from 2,487 to 1,320 mm. Hg per second, p less than 0.05). Importantly, left ventricular stroke volume was unchanged. When compared with preload augmentation (with the balloon deflated), the magnitude of depression of cardiac performance caused by balloon inflation was more fully appreciated (left ventricular stroke work, max. dp/dt, and ejection fraction reduced 69, 61, and 45 per cent, respectively). Even so, with appropriate compensations, principally by the Frank-Starling mechanism, up to 42 per cent of the left ventricular cavity volume could be functionally eliminated with retention of adequate mechanical performance. Such data may have implications regarding the extent of resections possible in patients undergoing surgery for left ventricular aneurysm.

Ischemic injury to the conducting system of the heart. Involvement of myocardial lysosomes.

The conducting system was studied in an in situ perfused swine heart preparation with reduced coronary flow (ischemia) using perfusate containing high and low levels of glucose (26.6 versus 8.6mM) with and without insulin. Coronary flow was maintained at normal levels for 60 minutes in control hearts. In ischemic hearts flow was reduced to about 50 percent of control levels for 30 minutes. Ultrastructural studies documented only subtle modifications of Purkinje fibers in ischemic hearts. Glycogen depletion and disruption of cell junctions were observed in some fibers. One consistent finding was the activation of the lysosomal system. The outer membranes of primary lysosomes appeared herniated and in some cases disrupted, and small vesicles containing hydrolytic enzymes were seen in association with the Golgi apparatus and larger primary lysosomes. Specimens prepared for the demonstration of acid phosphatase indicated a redistribution of hydrolytic enzymes in Purkinje fibers with a depostion of acid hydrolases in smaller lysosomal vesicles, the transverse and side-to-side junctions between cells, and occasionally in the sarcoplasmic reticulum. Enriched perfusate containing high levels of glucose with insulin appeared to have no therapeutic effects in terms of the structure of the Purkinje fibers. The results suggest that alterations in the lysosomal system may be one of the earliest structural changes which occur in oxygen-deficient hearts.

An experimental model for studying myocardial ischemia. Correlation of hemodynamic performance and metabolism in the working swine heart.

An intact, working swine heart preparation with controlled coronary perfusion is described. In this model, hemodynamic and metabolic functions were correlated in control and ischemic myocardium. A closed-loop, extracorporeal coronary perfusion circuit in series with a perfusion pump and oxygenator was designed to return reoxygenated coronary venous blood at controlled flow rates to the left and right coronary arteries. In 9 swine at normal flows (232 plus or minus 17 ml. per minute), the preparation maintained stable hemodynamic performance and oxygen consumption for a 1 hour period, after which ischemia was induced by reducing coronary flow by 50 per cent. As a result, left ventricular end-diastolic pressure (LVEDP) rose by 227 per cent, whereas heart rate (-17 per cent), aortic pressure (-9 per cent), pressure time/minute (PTM) (-28 per cent), left ventricular work (-47 per cent), and oxygen consumption (-39 per cent) all decreased. The ischemic myocardium shifted from lactate extraction to production. With this model, we can define, over a period of time, several mechanical and metabolic collations as a function of total coronary blood flow in an intact, large animal. We can also test interventions during the acute phases of ischemia in an effort to reduce myocardial damage.

The effect of different methods of protecting the myocardium on lysosomal activation and acid phosphatase activity in the dog heart after one hour of cardiopulmonary bypass.

The present study was undertaken to determine the involvement of cardiac lyososomes in injury to the myocardium after cardiopulmonary bypass. Twenty conditioned mongrel dogs, weighing 15 to 18 kilograms, were fasted overnight, anesthetized with sodium pentobarbital (30 mg. per kilogram), intubated, and maintained on positive-pressure ventilation. The femoral artery and femoral vein were cannulated for pressure measurements. After median sternotomy, intravenous heparin was administered (3 mg. per kilogram) before the aorta and the superior and inferior venae cavae were cannulated for bypass. Bypass was instituted with a Travenol modular pump and a Bentley pediatric bubble oxygenator and heat exchanger. The ultrastructural effects on the myocardium and the acid phosphatase activity in the left ventricle were compared in dogs exposed to bypass for 1 hour with varying types of myocardial support: perfusion of the coronary arteries, normothermic ischemic arrest, or selective cardiac hypothermia. The morphology of control hearts and hearts fixed after 1 hour of coronary perfusion were similar. The distribution and structure of subcellular lysosomes were the same and showed identical patterns of acid phosphatase activity. Normothermic ischemic arrest was associated with a loss of glycogen stores, disrupted sarcoplasmic reticulum and T tubules, vacuolization and decrease in matrix density of mitochondria, and separation of the intercalated discs. Lysosomal activity was absent except for occasional residual bodies in the nuclear pole zone of the myocardial cells. Selective cardiac hypothermia produced results superior to those from normothermic ischemic arrest. Although these hearts showed proliferation of the lysosomal compartment, the organelles responsible for excitation-contraction coupling were spared.

Effect of perfusate temperature on myocardial protection from ischemia.

During reperfusion, functional and metabolic recovery of the isolated working rat heart from one hour of ischemia was best in hearts selectively cooled at the onset of the ischemic interval by perfusion with 5 to 10 ml. of 10 degrees C. or 15 degrees C. Krebs-Henseleit buffer. Hearts similarly perfused at 4 degrees C., 20 degrees C. recovered significantly less well or not at all. Immediately after the hour of ischemia and prior to reperfusion, the absolute levels of glycogen and high-energy phosphates were best in the hearts perfused at 4 degrees C. However, metabolic function was best preserved in those perfused at 10 degrees C. and 15 degrees C., as evidenced by rapid recovery of high-energy phosphates and glycogen to control levels compared to metabolic deterioration in the 4 degrees C. group.

The advantages of transthoracic placement of permanent cardiac pacemaker electrodes.

To determine the effect of stimulation site on cardiac pacing thresholds, identical, small-surface area, cathodal, Elgiloy electrodes were placed intramyocardially on the left and right ventricular apices and transvenously into the right ventricular apex of 20 dogs in complete heart block. At seven stimulus durations, threshold voltage and current were measured directly with an oscilloscope and current probe. Left ventricular intramyocardial pacing required less threshold stimulus energy than right ventricular intramyocardial or right ventricular endocardial pacing. Previous studies that determined lower thresholds with transvenous right ventricular endocardial leads than with directly placed myocardial leads used stimulating electrodes of differing configuration, surface area, and materials at the different sites and/or used epicardial rather than intramyocardial electrodes. These factors biased the results in favor of the endocardial site. When all clinical and electrophysiological facotrs are considered, direct intramyocardial placement of electrodes deserves a much wider acceptance and application than it now enjoys.

Chronic testing of a pacemaker that needs recharging only once every four years.

Since 1967, three series of rechargeable single-cell silver-mercuric oxide-zinc pacemakers have been implanted in dogs with complete heart block. The five nonhermetic units in series 1 failed after less than or equal to 18 months, primarily due to prototype cell deficiencies, although one cell functioned for eight years. The six units in series II contained improved cells, but failed due to gradual transepoxy fluid absorption after less than or equal to 31 months. All rechargeable cells were salvaged and dried, and, seven years after their manufacture, they continue to power pacing circuits. Series III now totals 20 doubly hermetically sealed units, tested for up to three years (total more than 300 months or 26 years), with no pacemaker failures. Accelerated tests indicate a minimum life of more than 50 years. A clinical trial is in progress.

Myocardial stimulation impedance: the effects of electrode, physiological, and stimulus variables.

With exposed metal at the electrode tissue interface (8 mm2, 28 mm2, 57 mm2), myocardial threshold stimulation impedance increased as pulse duration was lengthened, with left ventricular intramyocardial stimulation, and with the smaller surface area electrode. An 0.5 mm2 differential-current-density electrode, which eliminated direct metal-to-tissue contact at the electrode-myocardial interface, was associated with notably higher impedances than each of the three metal tip electrodes and did not show increasing impedance levels with changes in pulse duration, confirming the minimization of polarization energy losses with this device. The majority of electrode, electrode tissue interface, and myocardial variables that are characterized by high threshold stimulation impedance are associated with low threshold energy requirements for pacing and reduced pacemaker power source drain. No accurate information about sensing impedances can be derived from current knowledge of pacing impedance.

The organization of reticulo-olivo-cerebellar circuits in the North American opossum.

By employing the autoradiographic method we have determined that the inferior olivary nucleus receives input from the reticular formation of the midbrain, pons and, probably, the medulla. The remarkable thing about such connections is that they are not diffuse, but targeted in large part on restricted portions of the caudal acessory nuclei. From our previous studies it is clear that some of the olivary regions receiving reticular input also receive projections from the cerebral cortex, the spinal cord and the dorsal column nuclei. In addition, the HRP technique reveals that these same olivary regions relay to parts of the spinal cerebellum, i.e. to restricted zones of the anterior lobe (present study). Taken together these observations suggest that some reticulo-olivo-cerebellar connections provide indirect routes through which cortical and spinal information gains access to the spinal cerebellum. Such circuits have also been suggested by the physiological literature. Of particular interest, however, was our finding that several reticular areas of the midbrain and pons project to the portion of the medial acessory nucleus which relays in turn to auditory-visual areas of the cerebellar vermis (declive, folium and tuber). It would appear that at least some reticulo-olivo-cerebellar circuits are significant in the organization of motor responses to visual and/or auditory stimuli.

Effects of successive unilateral ablations of principalis cortex upon performances of delayed alternation and delayed response by monkeys.

Monkeys were trained on delayed alternation (DA), and were then subjected to serial unilateral or simultaneous bilateral ablations of the banks of the sulcus principalis of each frontal lobe. When subjects with unilateral lesions were retrained on DA, their performances were intermediate to those of normal and bilateral animals. This interoperative training failed to protect the serially operated monkeys from losses of DA following their second-stage ablations, for they then performed as poorly as one-stage subjects and subjects prepared with serial ablations that were not given practice on the task between the two operations. Additional postoperative tests of delayed responding (DR) showed that both serially and simultaneously ablated subjects also had severe impairments of performance of DR. This result confirmed, in principle, a finding that monkeys with large unilateral ablations, if reoperated after many months for the removal of the contralateral dorsolateral perfrontal cortex, will thereafter exhibit DR deficits that are both severe and endure for a period of years. It contrasted sharply with a recent observation that DR is retained by monkeys subjected to two-stage symmetrical ablations of the principalis cortex, which suggests that recoveries of frontal-lobe functions are powerfully affected by the orders in which serial extirpations are performed.

Antenatal sex determination in Macaca arctoides.

Transabdominal amniocentesis was performed on 11 Macaca arctoides, between the 10th and 20th weeks of gestation, for the purpose of antenatal sex determination. The technique employing Y-chromatin fluorescence was unsuccessful in predicting sex, but the sexes were differentiated with complete accuracy by examining amniotic cells stained by a modified Papanicolaou technique. Of the cells from male fetuses, fewer than 10% contained X-chromatin (Barr bodies); of those from females, more than 45% contained X-chromatin.

PIP: A modified Papanicolaou technique for staining amniotic cells obtain ed by transabdominal amniocentesis in Macaca arctoides between the 10th-20th weeks of gestation is described. The purpose was antenatal sex determination. The method was based on the fluorescent 7-chromatin in human male interphase cells discovered by Pearson et al. in 1970; the Y-chromatin fluorescence method was unsuccessful in predicting sex in the M. arctoides, but the stained slides showed that fewer than 10% of cells from male fetuses contained X-chromatin (Barr bodies) while more than 45% of cells from females contained X-chromatin. It is concluded that this monkey does not have a Y-chromosome sufficiently large to bind an adequate amount of quinacrine dye to brightly fluoresce while there is not the overlap between the high normal X-chromatin frequency in males and low normal in females which causes problems in humans. It is hoped this technique will aid in management of primate colonies by allowing female fetuses to develop to term while only male-carrying animals are used for experiments.

Spatial maps of directed visual attention.

Simple reaction times (RTs) to a visual target are facilitated when the target occurs at a location expected by an observer, and are slowed when the target occurs at the mirror-symmetric location contralateral to the expectancy (e.g., Posner, 1978; Posner, Snyder, & Davidson, 1980). The spatial extent of this attention effect was examined by inducing subjects to expect the target at one location and introducing occasional probe flashes at other locations throughout the visual field. The results indicated that RTs to these probes were equivalent to those obtained at the expected location so long as the probe was in the same hemifield as the subject's expectancy. Conversely, RTs to probes in the hemifield opposite the expectancy generated uniformly slower response times. These results were obtained when the expected location varied in eccentricity from 2 degrees to 16 degrees along the horizontal meridian. In addition, when the expected and unexpected locations were within the same hemifield, no expectancy effects were observed. Under these conditions, the frequently used metaphor that directed visual attention operates like a spatially restricted "beam" appears inaccurate. The implications of these findings for current views of directed attention are considered.

Visual-auditory interactions in sensorimotor processing: saccades versus manual responses.

Reaction times (RTs) to bimodal (visual and auditory) stimuli were examined using 3 different response systems: saccades, directed manual responses, and simple manual responses. The observed levels of intersensory facilitation exceeded race model predictions and therefore support summation (coactivation) models of bimodal processing. However, response-dependent differences suggest that the processing of bimodal targets also depends on the relevant sensorimotor pathways and requirements of the task. Coactivation of response mechanisms might account for the effects found using simple RTs. The results for saccades are consistent with known patterns of auditory-visual convergence in the oculomotor system.

Fate of neglected targets: a chronometric analysis of redundant target effects in the bisected brain.

The authors examined some of the sensorimotor effects of the split-brain operation to understand how a "dual mind" can produce unified behavior. They report psychophysical evidence of extinction to bilateral simultaneous stimulation in callosotomy patient J.W.: Although he could verbally report the occurrence of a unilateral left or right visual field target, left field report accuracy dropped by 34% when targets occurred bilaterally. Paradoxically, the same stimulus conditions produced abnormally robust redundant signal effects on simple manual and vocal reaction times, which exceeded predictions that were based on probability summation. Neural summation is often inferred from redundancy gain of this magnitude. Because this seems less likely after callosotomy, the authors suggest a model that is based on response competition between the disconnected hemispheres to account for J.W.'s redundant target effects. The dissociation between explicit report and motor performance is discussed.

Afferent delays and the mislocalization of perisaccadic stimuli.

Determining the precise moment a visual stimulus appears is difficult because visual response latencies vary. This temporal uncertainty could cause localization errors to brief visual targets presented before and during eye movements if the oculomotor system cannot determine the position of the eye at the time the stimulus appeared. We investigated the effect of varying neural processing time on localization accuracy for perisaccadic visual targets that differed in luminance. Although systematic errors in localization were observed, the effect of luminance was surprisingly small. We explore several hypotheses that may explain why processing delays are not more disruptive to localization performance.

Spatial characteristics of visual-auditory summation in human saccades.

Bimodal (auditory + visual) stimuli reduce saccade latencies in human observers to a degree that exceeds levels predictable by probabilistic summation between parallel, independent unimodal pathways. These interactions have been interpreted in terms of converging visual and auditory afferents within the oculomotor pathways, specifically within the superior colliculus (SC). The present work describes the spatial tuning of auditory-visual summation in human saccades, using diagnostics derived from stochastic models of information processing. Consistent with expectations based on the electrophysiology of the SC, the magnitude of facilitation varied with the degree of spatial correspondence, and the spatial tuning was quite coarse.