Early brain pathology and its relation to cognitive impairment: the role of quantitative magnetic resonance techniques.
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Aging↗
Biomedical subjects
M Mishkin
Publications and source records attributed to M Mishkin.
Neural basis of an inherited speech and language disorder.
Investigation of the three-generation KE family, half of whose members are affected by a pronounced verbal dyspraxia, has led to identification of their core deficit as one involving sequential articulation and orofacial praxis. A positron emission tomography activation study revealed functional abnormalities in both cortical and subcortical motor-related areas of the frontal lobe, while quantitative analyses of magnetic resonance imaging scans revealed structural abnormalities in several of these same areas, particularly the caudate nucleus, which was found to be abnormally small bilaterally. A recent linkage study [Fisher, S., Vargha-Khadem, F., Watkins, K. E., Monaco, A. P. & Pembry, M. E. (1998) Nat. Genet. 18, 168-170] localized the abnormal gene (SPCH1) to a 5. 6-centiMorgan interval in the chromosomal band 7q31. The genetic mutation or deletion in this region has resulted in the abnormal development of several brain areas that appear to be critical for both orofacial movements and sequential articulation, leading to marked disruption of speech and expressive language.
Brain↗
Object recognition and location memory in monkeys with excitotoxic lesions of the amygdala and hippocampus.
Earlier work indicated that combined but not separate removal of the amygdala and hippocampus, together with the cortex underlying these structures, leads to a severe impairment in visual recognition. More recent work, however, has shown that removal of the rhinal cortex, a region subjacent to the amygdala and rostral hippocampus, yields nearly the same impairment as the original removal. This raises the possibility that the earlier results were attributable to combined damage to the rostral and caudal portions of the rhinal cortex rather than to the combined amygdala and hippocampal removal. To test this possibility, we trained rhesus monkeys on delayed nonmatching-to-sample, a measure of visual recognition, gave them selective lesions of the amygdala and hippocampus made with the excitotoxin ibotenic acid, and then assessed their recognition abilities by using increasingly longer delays and list lengths, including delays as long as 40 min. Postoperatively, monkeys with the combined amygdala and hippocampal lesions performed as well as intact controls at every stage of testing. The same monkeys also were unimpaired relative to controls on an analogous test of spatial memory, delayed nonmatching-to-location. It is unlikely that unintended sparing of target structures can account for the lack of impairment; there was a significant positive correlation between the percentage of damage to the hippocampus and scores on portions of the recognition performance test, suggesting that, paradoxically, the greater the hippocampal damage, the better the recognition. The results show that, within the medial temporal lobe, the rhinal cortex is both necessary and sufficient for visual recognition.
Amygdala↗
Amnesia and the organization of the hippocampal system.
Early hippocampal injury in humans has been found to result in a limited form of global anterograde amnesia. At issue is whether the limitation is qualitative, with the amnesia reflecting substantially greater impairment in episodic than in semantic memory, or only quantitative, with both episodic and semantic memory being partially and equivalently impaired. Evidence from neuroanatomical and lesion studies in animals suggests that the hippocampus and subhippocampal cortices form a hierarchically organized system, such that the greatest convergence of information (and, by implication, the richest amount of association) takes place within the hippocampus, located at the top of the hierarchy. On the one hand, this evidence is consistent with the view that selective hippocampal damage produces a differential impairment in context-rich episodic memory as compared with context-free semantic memory, because only the latter can be supported by the subhippocampal cortices. On the other hand, given the system's hierarchical form of organization, this dissociation of deficits is difficult to prove, because a quantitatively limited deficit will nearly always be a viable alternative. A final choice between the alternative views is therefore likely to depend less on further evidence gathered in brain-injured patients than on which view accounts for more of the data gathered from converging approaches to the problem.
Amnesia↗
Effects of muscarinic blockade in perirhinal cortex during visual recognition.
Stimulus recognition in monkeys is severely impaired by destruction or dysfunction of the perirhinal cortex and also by systemic administration of the cholinergic-muscarinic receptor blocker, scopolamine. These two effects are shown here to be linked: Stimulus recognition was found to be significantly impaired after bilateral microinjection of scopolamine directly into the perirhinal cortex, but not after equivalent injections into the laterally adjacent visual area TE or into the dentate gyrus of the overlying hippocampal formation. The results suggest that the formation of stimulus memories depends critically on cholinergic-muscarinic activation of the perirhinal area, providing a new clue to how stimulus representations are stored.
Animals↗
Hierarchical organization of cognitive memory.
This paper addresses the question of the organization of memory processes within the medial temporal lobe. Evidence obtained in patients with late-onset amnesia resulting from medial temporal pathology has given rise to two opposing interpretations of the effects of such damage on long-term cognitive memory. One view is that cognitive memory, including memory for both facts and events, is served in a unitary manner by the hippocampus and its surrounding cortices; the other is that the basic function affected in amnesia is event memory, the memory for factual material often showing substantial preservation. Recent findings in patients with amnesia resulting from relatively selective hippocampal damage sustained early in life suggest a possible reconciliation of the two views. The new findings suggest that the hippocampus may be especially important for event as opposed to fact memory, with the surrounding cortical areas contributing to both. Evidence from neuroanatomical and neurobehavioural studies in monkeys is presented in support of this proposal.
Amnesia↗
Differential effects of early hippocampal pathology on episodic and semantic memory.
Global anterograde amnesia is described in three patients with brain injuries that occurred in one case at birth, in another by age 4, and in the third at age 9. Magnetic resonance techniques revealed bilateral hippocampal pathology in all three cases. Remarkably, despite their pronounced amnesia for the episodes of everyday life, all three patients attended mainstream schools and attained levels of speech and language competence, literacy, and factual knowledge that are within the low average to average range. The findings provide support for the view that the episodic and semantic components of cognitive memory are partly dissociable, with only the episodic component being fully dependent on the hippocampus.
Adolescent↗
Serial and parallel processing in rhesus monkey auditory cortex.
Auditory cortex on the exposed supratemporal plane in four anesthetized rhesus monkeys was mapped electrophysiologically with both pure-tone (PT) and broad-band complex sounds. The mapping confirmed the existence of at least three tonotopic areas. Primary auditory cortex, AI, was then aspirated, and the remainder of the cortex on the supratemporal plane was remapped. PT-responses in the caudomedial area, CM, were abolished in all animals but one, in which they were restricted to the high-frequency range. Some CM sites were still responsive to complex stimuli. In contrast to the effects on CM, no significant changes were detectable in the rostral area, R. After mapping cortex in four additional monkeys, injections were made with different tracers into matched best-frequency regions of AI, R, and CM. Injections in AI and R led to retrograde labeling of neurons in all three subdivisions of the medial geniculate (MG) nucleus (MGv, MGd, and MGm), as well as nuclei outside MG, whereas CM injections led to only sparse labeling of neurons in a restricted zone of the lateral MGd and, possibly, MGm, in addition to labeling in non-MG sites. The combined results suggest that MGv sends direct projections in parallel to areas AI and R, which drive PT-responses in both areas. PT-responses in area CM, however, appear to be driven by input relayed serially from AI. The direct input to CM from MGd and other thalamic nuclei may thus be capable of mediating responses only to broad-band sounds.
Acoustic Stimulation↗
Socioemotional behavior in adult rhesus monkeys after early versus late lesions of the medial temporal lobe.
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Aging↗
Effects of orbital frontal and anterior cingulate lesions on object and spatial memory in rhesus monkeys.
Object memory processes, evaluated in rhesus monkeys by delayed nonmatching-to-sample with trial-unique stimuli and object reversal learning, were more severely impaired by orbital frontal than by anterior cingulate lesions. Spatial memory processes, assessed by spatial delayed response and spatial reversal learning, showed a weak trend in the opposite direction, though on these tasks neither lesion produced a serious loss. Comparison of the present results with those of earlier studies on the effects of various limbic system lesions suggests that object memory processes, including object recognition and object-reward association, are served by a circuit consisting mainly of the rhinal cortex, orbitofrontal cortex, and the magnocellular division of the medial dorsal thalamic nucleus. Although both the rhinal and orbitofrontal components of this circuit appear to participate in both functions, evidence from the present and earlier studies suggests that the orbitofrontal component is the more important one for associative memory, i.e. the formation across trials of associations between particular objects or classes of objects and reward, whereas the rhinal component is the more critical one for recognition memory, i.e. the storage and retrieval within trials of the representations of particular objects.
Animals↗
Onset of speech after left hemispherectomy in a nine-year-old boy.
Case Alex, with Sturge-Weber Syndrome affecting the left hemisphere, failed to develop speech throughout early boyhood, and his comprehension of single words and simple commands remained stagnant at an age equivalent of 3-4 years. But then, following left hemidecortication at age 8.5 years and withdrawal of anticonvulsants when he was more than 9 years old, Alex suddenly began to acquire speech and language. He also showed an unusual degree of residual motor capacity on his right side. Alex's remarkable progress in learning speech and language, and the development of his other cognitive abilities, were measured periodically from the age of 9 to 15 years. His most recent scores on tests of receptive and expressive language place him at an age equivalent of 8-10 years. Comparison with the level of function attained in these domains by nine other left hemispherectomized patients with early onset of disease and comparable IQ (range, 40-68) but with early development of speech and language, suggests that, surprisingly, Alex has suffered no permanent disadvantage from his protracted period of mutism and severely limited comprehension. Although the findings in Alex, as in other left-hemispherectomized patients, indicate define limits to the cognitive and linguistic capacity of the isolated right hemisphere, Alex's achievements appear to challenge the widely held view that early childhood is a particularly critical period for acquisition of speech and language or any of their selective aspects, including phonology, grammar, prosody and semantics. It is concluded that clearly articulated, well structured, and appropriate language can be acquired for the first time as late as age 9 years with the right hemisphere alone.
Adolescent↗
Cortical projections of area V2 in the macaque.
To determine the locus, extent and topograhic organization of cortical projections of area V2, we injected tritiated amino acids under electrophysiological control into 15 V2 sites in 14 macaques. The injection sites included the foveal representation and representations ranging from central to far peripheral eccentricities in both the upper and lower visual fields. The results indicated that all V2 sites project topographically back to V1 and forward to V3, V4 and MT. There is also a topographically organized projection from V2 to V4t, but this projection is limited to the lower visual field representation. V2 thus appears to project to virtually all the visual cortex within the occipital lobe. In addition to these projections to occipital visual areas, V2 sites representing eccentricities of approximately 30 degrees and greater project to three visual areas in parietal cortex-the medial superior temporal (MST), parieto-occipital (PO) and ventral intraparietal (VIP) areas. This peripheral field representation of V2 also projects to area VTF, a visual area located in area TF on the posterior parahippocampal gyrus. Projections from the peripheral field representation of V2 of parietal areas could provide a direct route for rapid activation of circuits serving spatial vision and spatial attention.
Amino Acids↗
Positive correlations between cerebral protein synthesis rates and deep sleep in Macaca mulatta.
Local rates of cerebral protein synthesis (ICPSleu) were determined with the autoradiographic L-[1-14C]leucine method in seven awake and seven asleep, adult rhesus monkeys conditioned to sleep in a restraining chair in a darkened, ventilated chamber while EEG, EOG, and EMG were monitored. Prior to the period of measurement all animals slept for 1-4 h. Controls were awakened after at least one period of rapid-eye-movement (REM) sleep. Experimental animals were allowed to remain asleep, and they exhibited non-REM sleep for 71-99% of the experimental period. Statistically significant differences in ICPSleu between control and experimental animals were found in four of the 57 regions of brain examined, but these effects may have occurred by chance. In the sleeping animals, however, correlations between ICPSleu and percent time in deep sleep were positive in all regions and were statistically significant (P < or = 0.05) in 35 of the regions. When time in deep sleep was weighted for the integrated specific activity of leucine in grey matter, positive correlations were statistically significant (P < or = 0.05) in 18 regions in the experimental animals. These results suggest that rates of protein synthesis are increased in many regions of the brain during deep sleep compared with light sleep.
Animals↗
Effects of hemispheric side of injury, age at injury, and presence of seizure disorder on functional ear and hand asymmetries in hemiplegic children.
Dichotic listening, manual functions, and IQ were measured in a large group of hemiplegic children with unilateral hemispheric damage. In the children without a history of seizure disorder, only manual functions were impaired, but in those with such a history (and hence a regime of anticonvulsant medication), all measures were affected. Some children with congenital left hemisphere lesions (with and without siezure disorder) showed a left ear advantage for dichotic digits as well as greater impairment in right hand function than those who showed the usual right ear advantage. The latter result suggests that the hemipheric damage in the subgroup with altered ear asymmetry was greater than in the others and extensive enough to encroach on language areas, shifting language representation to the right.
Adolescent↗
Visually guided reaching with the forelimb contralateral to a "blind" hemisphere in the monkey: contribution of the cerebellum.
Metabolic activity was mapped in the cerebellar cortex and its major inputs and projection targets in monkeys performing visually guided reaching with the left forelimb. Normal monkeys and monkeys deprived of visual input to the right cerebral hemisphere by right optic tract section, combined in some cases with forebrain commissurotomy, were studied. We reported previously that visually guided reaching with the left forelimb activated the motor cortex of the right hemisphere equally in all these monkeys, indicating that reaching was controlled by the right hemisphere whether it was visually intact or "blind" [Savaki H.E. et al. (1993) J. Neurosci. 13, 2772-2789]. In the present study, metabolic activations were observed in the left cerebellar hemispheric extensions of vermian lobules V, VI and VIII, again regardless of whether the right hemisphere was visually intact or "blind". In intact monkeys, however, the activations were significantly smaller in the lateral than in the paravermal zone of these hemispheric extensions, whereas in tractotomized/commissurotomized monkeys the activations were equal in the two zones. The greater activations in the left lateral zone in tractotomized/commissurotomized monkeys may represent compensation in part for the visual deafferentation of the right cerebral hemisphere. Also observed were metabolic activation in the left dorsolateral pontine nucleus in tractotomized/commissurotomized monkeys and metabolic depression in the left dentate nucleus in visually intact monkeys. This pattern of results suggests the following conclusions. The activated loci in the left cerebellar cortex combine (i) visual information about the target relayed by seeing cerebral hemispheres, and (ii) sensorimotor information concerning intended and actual movements of the left forelimb relayed by the right cerebral hemisphere and the limb, respectively, and then (iii) send this integrated information back to the motor cortex of the right cerebral hemisphere, thus enabling it to guide the left forelimb to the target whether the hemisphere is visually intact or "blind".
Animals↗
Protein kinase C in the hippocampus is altered by spatial but not cued discriminations: a component task analysis.
The exact role of the mammalian hippocampus in memory formation remains essentially as an unanswered question for cognitive neuroscience. Experiments with humans and with animals indicate that some types of mnemonic associative processes involve hippocampal function while others do not. Support for the spatial processing hypothesis of hippocampal function has stemmed from the impaired performance of rats with hippocampal lesions in tasks that require spatial discriminations, but not cued discriminations. Previous procedures, however, have confounded the interpretation of spatial versus cued discrimination learning with the number and kinds of irrelevant stimuli present in the discrimination. An empirical set of data describing a role of protein kinase C (PKC) in different mnemonic processes is similarly being developed. Recent work has implicated the activation of this serine-threonine kinase in a variety of learning paradigms, as well as long-term potentiation (LTP), a model system for synaptic plasticity which may subserve some types of learning. The present study employs the principles of component task analysis to examine the role of membrane-associated PKC (mPKC) in hippocampal-dependent memory when all factors other than the type of learning were equivalent. The results indicate that hippocampal mPKC is altered by performance in hippocampally-dependent spatial discriminations, but not hippocampally-independent cued discriminations and provide a general experimental procedure to relate neural changes to specific behavioral changes.
Animals↗
Long-term effects of selective neonatal temporal lobe lesions on learning and memory in monkeys.
Rhesus monkeys with neonatal damage to either the medial temporal lobe or the inferior temporal cortical area TE, and their normal controls, were reassessed in visual habit formation (24-hour intertrial interval task) and visual recognition (delayed nonmatching to sample; DNMS) at 4-5 years of age and then tested on tactile and spatial DNMS. Results on the two visual tasks were the same as those obtained when the monkeys were under 1 year of age. Specifically, early medial temporal lesions, like late lesions, left habit formation intact but severely impaired recognition memory. Furthermore, the memory deficit extended to the tactile and spatial modalities. By contrast, early damage to TE, unlike late damage to it, yielded only mild deficits on both visual tasks and had no effect on tactile or spatial DNMS. Compensatory mechanisms that promote substantial and permanent recovery thus appear to be available after neonatal TE lesions but not after neonatal medial temporal lesions.
Animals↗
Responses of cells in the tail of the caudate nucleus during visual discrimination learning.
1. The tail of the caudate nucleus and adjacent ventral putamen (ventrocaudal neostriatum) are major projection sites of the extrastriate visual cortex. Visual information is then relayed, directly or indirectly, to a variety of structures with motor functions. To test for a role of the ventrocaudal neostriatum in stimulus-response association learning, or habit formation, neuronal responses were recorded while monkeys performed a visual discrimination task. Additional data were collected from cells in cortical area TF, which serve as a comparison and control for the caudate data. 2. Two monkeys were trained to perform an asymmetrically reinforced go-no go visual discrimination. The stimuli were complex colored patterns, randomly assigned to be either positive or negative. The monkey was rewarded with juice for releasing a bar when a positive stimulus was presented, whereas a negative stimulus signaled that no reward was available and that the monkey should withhold its response. Neuronal responses were recorded both while the monkey performed the task with previously learned stimuli and while it learned the task with new stimuli. In some cases, responses were recorded during reversal learning. 3. There was no evidence that cells in the ventrocaudal neostriatum were influenced by the reward contingencies of the task. Cells did not fire preferentially to the onset of either positive or negative stimuli; neither did cells fire in response to the reward itself or in association with the motor response of the monkey. Only visual responses were apparent. 4. The visual properties of cells in these structures resembled those of cells in some of the cortical areas projecting to them. Most cells responded selectively to different visual stimuli. The degree of stimulus selectivity was assessed with discriminant analysis and was found to be quantitatively similar to that of inferior temporal cells tested with similar stimuli. Likewise, like inferior temporal cells, many cells in the ventrocaudal neostriatum had large, bilateral receptive fields. Some cells had "doughnut"-shaped receptive fields, with stronger responses in the periphery of both visual fields than at the fovea, similar to the fields of some cells in the superior temporal polysensory area. Although the absence of task-specific responses argues that ventrocaudal neostriatal cells are not themselves the mediators of visual learning in the task employed, their cortical-like visual properties suggest that they might relay visual information important for visuomotor plasticity in other structures. (ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗