Patricia S. Goldman

Columnar Distribution of Cortico-Cortical Fibers in the Frontal Association, Limbic, and Motor Cortex of the Developing Rhesus Monkey

The terminal distribution of cortico-cortical connections was examined by autoradiography 7-8 days following injections of tritium labeled amino acids into the dorsal bank of the principal sulcus, the posterior part of the medial orbital gyrus, or the hand and arm area of the primary motor cortex in monkeys ranging in age from 4 days to 5.5 months. Labeled axons originating in these various regions of the frontal lobe have topographically diverse ipsilateral and contralateral destinations but virtually all of these projections share a common mode of distribution: they terminate in distinct vertically oriented columns, 200-500 mum wide, that extend across all layers of cortex and alternate in regular sequence with columns of comparable width in which grains do not exceed background. Spatial periodicity in the pattern of transported label in such regions as the prefrontal association cortex, the retrosplenial limbic cortex and the motor cortex indicates that columination in the intracortical distribution of afferent fibers is not unique to sensory specific cortex but is instead a general feature of neocortical organization. A columnar mode of distribution of cortico-cortical projections is present in monkeys at all ages investigated but is especially well delineated in the youngest of them. Thus, grain concentrations within columns are very high in monkeys injected at 4 days of age, somewhat lower in monkeys injected at 39-45 days of age, and least dense in those injected at 5.5 months. The distinctness of the spatially segregated pattern of innervation in the cortex of neonates indicates that the columnar organization of association-fiber systems in the frontal and limbic cortex is achieved before or shortly after birth.

Regional distribution of monoamines in the cerebral cortex and subcortical structures of the rhesus monkey: concentrations and in vivo synthesis rates.

Endogenous monoamine concentrations and turnover rates vary markedly in different regions of neocortex as well as in various subcortical structures of young adult rhesus monkeys. Monoamine levels and synthesis rates in amygdala, hippocampus, neostriatum, thalamus and brain stem are generally similar to comparable measures previously reported in a variety of species. However, extending and confirming the results of an earlier study, cortical monoamines exhibit topographically specific patterns of distribution. Thus, dopamine concentration is highest in the prefrontal and temporal neocortex; it decreases along the fronto-occipital axis and only trace amounts are detectable in the visual cortex. The distribution of norepinephrine is similar to that of dopamine except that the highest concentrations of norepinephrine are found in somatosensory cortex instead of prefrontal cortex. The pattern of distribution of serotonin is more uniform. However, the distribution of its metabolite, 5-hydroxyindoleacetic acid, is complementary to that of dopamine: the concentration is lowest in prefrontal cortex and highest in posterior regions of the telencephalon. Synthesis of catecholamines as measured by DOPA accumulation in monkeys treated with an aromatic amino acid decarboxylase inhibitor, NSD 1015, generally parallels the distribution of the catecholamines while indoleamine synthesis, as measured by 5-HTP accumulation, is similar to the distribution of 5-hydroxyindoleacetic acid. It may be significant that synthesis rates for the catecholamines are especially high in various areas of association cortex.

Prenatal removal of frontal association cortex in the fetal rhesus monkey: anatomical and functional consequences in postnatal life.

Anatomical and behavioral consequences were examined following bilateral or unilateral resections of the presumptive dorsolateral prefrontal cortex in 4 rhesus monkey fetuses at E102 (102nd embryonic day), E104, E106 and E119, with subsequent replacement in utero and delivery at later stages of development. Unoperated monkeys of appropriate pre- and postnatal ages served as controls for certain features of morphogenesis and tectogenesis. Monkeys given comparable unilateral or bilateral lesions at selected postnatal ages were used as controls for the behavioral effects of prenatal resection as well as for neuropathological examination. The behavioral evaluation provided evidence for extraordinary preservation of function after frontal cortical resection in the prenatal period. During the entire course of its postnatal development, a monkey that sustained bilateral resection as a fetus at E106 performed surprisingly well and clearly with the competence of unoperated monkeys of identical or older ages on tasks selective for dorsolateral prefrontal cortical function; it did not exhibit deficits characteristic of animals that have comparable or even smaller resections as juveniles or adults. Following either unilateral or bilateral resection prior to E106, ectopic sulci and gyri appeared in intact regions of the frontal lobe of each hemisphere, as well as in locations at a considerable distance from the lesions, such as the temporal and occipital lobes. The cytoarchitectonic characteristics of the cortex in these anomalous gyri were typical of adjacent cortex in the regions in which they appeared. Examination of the parvocellular subdivision of the mediodorsal thalamic nucleus yielded the novel finding that this principal source of essential projections to the dorsolateral prefrontal cortex contained a virtually normal number of neurons in postnatal monkeys, following unilateral or bilateral lesions performed at or before E106, and exhibited only a partial loss of neurons after surgery at E119. The same cells regularly degenerate following comparable resections in the postnatal period. The survival of these neurons in prenatally operated monkeys is unprecedented, and can be explained by several hypotheses, including the possibility that their axons become rerouted to their structures in the absence of their normal targets. The present results thus demonstrate that ablation of a circumscript area of the frontal cortex in a non-human primate a full two months before birth may leave the functions later to be subserved by that area unaffected. Such early surgical intervention results in significant alteration in the gross morphological characteristics of the cortex, and apparently induces a functionally compensatory reorganization of thalamocortical connections. Similar principles may account for sparing of function following early damage to the human brain.

Sex-Dependent Behavioral Effects of Cerebral Cortical Lesions in the Developing Rhesus Monkey

Male rhesus monkeys with orbital prefrontal lesions were imtpaired on behavioral tests at 2� months of age whereas similar deficits were not detected in females with comparable lesions until 15 to 18 months of age. The results suggest that the maturation of a cortical region in the primate brain proceeds at different tempos in males and females.

The effects of selective caudate lesions in infant and juvenile Rhesus monkeys.

Summary Monkeys given selective caudate lesions in infancy were compared with monkeys given comparable lesions as juveniles on a variety of behavioral tests beginning 10 months after surgery. The monkeys operated upon in infancy were impaired on all of the tests on which the monkeys operated upon as juveniles were impaired, and to no less degree. The results underscore the importance of the site of injury in determining future recovery from brain damage, however early in life that damage occurs. The present results obtained in monkeys with caudate lesions were also compared with previous results on the effects of prefrontal cortical injury in infancy. The finding that the early caudate lesions impair exactly those functions that the early prefrontal lesions spare, led to the conclusion that the caudate nucleus becomes functional earlier in ontogeny than the cortex and can mediate the functions that the cortex will ultimately assume.

Functional development of the dorsolateral prefrontal cortex: An analysis utilizing reversible cryogenic depression

The dorsolateral prefrontal cortex of rhesus monkeys was functionally inactivated by local hypothermia as the monkeys performed spatial delayed-response and spatial delayed-alternation tasks at different stages of postnatal development. Cryogenic depression of prefrontal cortex at a temperature sufficient to induce 21--25% decrements in delayed-response performance in 34--36-month-old-monkeys, produced deficits of only 7--8% in 19--31-month-old and no detectable loss in younger monkeys, 9--16 months of age. Delayed-alternation performance was impaired by local hypothermia as early as 8.5 months of age, but maximal cooling-induced deficits on this task were not observed before 33 months of age. Thermal gradients mapped in representative monkeys at different stages of development were remarkable similar, indicating that the age-dependent differences in behavior were not attributable to technical factors. The results obtained in the present study on normal developing monkeys confirm the interpretation of previous research on brain-damaged infants that functional maturation of the dorsolateral prefrontal cortex is protracted over several years of postnatal life, and extends the earlier studies by indicating that the lower limit for maturity of dorsolateral function is close to puberty in this species. Further, the present study revealed that delayed-response and delayed-alternation performance are dissociable dorsolateral functions which achieve maturity at different rates. The convergence of evidence from reversible neural depression and permanent lesion methods provides strong validation for neurobehavioral analysis as a general approach to the study of regional maturation of the brain.

Delayed Recovery of Function follwing Orbital Prefrontal Lesions in Infant Monkeys

Monkeys given orbital prefrontal lesions at 1, 4, or 8 weeks of age exhibited a severe learning disability when they were tested at 1 year of age, but showed substantial recovery by the time they were 2 years old. These results suggest that the protracted maturation of intact cortical regions is important in recovery of function after early brain injury.

DEVELOPMENTAL CHANGES IN CATECHOLAMINE CONTENT AND ACTIVITY IN CIRCUMSCRIBED REGIONS OF THE CEREBRAL CORTEX IN THE RHESUS MONKEY

ABSTRACT Concentrations and turnover of endogenous catecholamines and serotonin in the cerebral cortex of rhesus monkeys change considerably from birth through adulthood. The time-table, magnitude, and direction of such changes depend upon the specific amine and cortical region examined.