Reorganization of remote cortical regions after ischemic brain injury: a potential substrate for stroke recovery.

Although recent neurological research has shed light on the brain's mechanisms of self-repair after stroke, the role that intact tissue plays in recovery is still obscure. To explore these mechanisms further, we used microelectrode stimulation techniques to examine functional remodeling in cerebral cortex after an ischemic infarct in the hand representation of primary motor cortex in five adult squirrel monkeys. Hand preference and the motor skill of both hands were assessed periodically on a pellet retrieval task for 3 mo postinfarct. Initial postinfarct motor impairment of the contralateral hand was evident in each animal, followed by a gradual improvement in performance over 1-3 mo. Intracortical microstimulation mapping at 12 wk after infarct revealed substantial enlargements of the hand representation in a remote cortical area, the ventral premotor cortex. Increases ranged from 7.2 to 53.8% relative to the preinfarct ventral premotor hand area, with a mean increase of 36.0 +/- 20.8%. This enlargement was proportional to the amount of hand representation destroyed in primary motor cortex. That is, greater sparing of the M1 hand area resulted in less expansion of the ventral premotor cortex hand area. These results suggest that neurophysiologic reorganization of remote cortical areas occurs in response to cortical injury and that the greater the damage to reciprocal intracortical pathways, the greater the plasticity in intact areas. Reorganization in intact tissue may provide a neural substrate for adaptive motor behavior and play a critical role in postinjury recovery of function.

Role of adaptive plasticity in recovery of function after damage to motor cortex.

Based upon neurophysiologic, neuroanatomic, and neuroimaging studies conducted over the past two decades, the cerebral cortex can now be viewed as functionally and structurally dynamic. More specifically, the functional topography of the motor cortex (commonly called the motor homunculus or motor map), can be modified by a variety of experimental manipulations, including peripheral or central injury, electrical stimulation, pharmacologic treatment, and behavioral experience. The specific types of behavioral experiences that induce long-term plasticity in motor maps appear to be limited to those that entail the development of new motor skills. Moreover, recent evidence demonstrates that functional alterations in motor cortex organization are accompanied by changes in dendritic and synaptic structure, as well as alterations in the regulation of cortical neurotransmitter systems. These findings have strong clinical relevance as it has recently been shown that after injury to the motor cortex, as might occur in stroke, post-injury behavioral experience may play an adaptive role in modifying the functional organization of the remaining, intact cortical tissue.

Somatosensory and motor representations in cerebral cortex of a primitive mammal (Monodelphis domestica): a window into the early evolution of sensorimotor cortex.

To examine the potential early stages in the evolution of sensorimotor cortex, electrophysiological studies were conducted in the primitive South American marsupial opossum, Monodelphis domestica. Somatosensory maps derived from multiunit microelectrode recordings revealed a complete somatosensory representation of the contralateral body surface within a large region of midrostral cortex (primary somatosensory cortex, or S1). A large proportion ( approximately 51%) of S1 was devoted to representation of the glaborous snout, mystacial vibrissae, lower jaw, and oral cavity (the rostrum). A second representation, the second somatosensory area (or S2), was found adjacent and caudolateral to S1 as a mirror image reversed along the representation of the glabrous snout. A reversal of somatotopic order and an enlargement of receptive fields marked the transition from S1 to S2. Mapping of excitable cortex was conducted by using intracortical microstimulation (ICMS) techniques, as well as low-impedance depth stimulation and bipolar surface stimulation. In all three procedures, electrical stimulation resulted in movements confined strictly to the face. Specifically, at virtually all sites from which movements could be evoked, stimulation resulted in only vibrissae movement. ICMS-evoked vibrissae movements typically occurred at sites within S1 with receptive fields of the mystacial vibrissae, lower jaw, and glaborous snout. Results were similar using low-impedance depth stimulation and bipolar surface stimulation techniques except that the motor response maps were generally larger in area. There was no evidence of a motor representation rostral to S1. Examination of the cytoarchitecture in this cortical region (reminiscent of typical mammalian somatosensory cortex) and the high levels of stimulation needed for vibrissae movement suggest that the parietal neocortex of Monodelphis is representative of a primitive sensorimotor condition. It possesses a complete S1 representation with an incomplete motor component overlapping the S1 representation of the face. It contains no primary motor representation. Completion of the motor representations within S1 (trunk, limbs, tail) as well as the emergence of a primary motor cortex rostral to S1 may have occurred relatively late in mammalian phylogeny.

Hearing in primitive mammals: Monodelphis domestica and Marmosa elegans.

Although opossums of the Family Didelphidae usually serve as a parsimonious starting point for tracing the otological and neurological evolution of modern mammals, audiological data for Didelphid opossums is available only for the North American opossum (Didelphis virginiana) which because of its large size, may be one of the least representative genera of the family. The present report extends the audiological data to two other species of Didelphid opossums, Monodelphis domestica, and Marmosa elegans. At 60 dB SPL, the hearing of Monodelphis extends from 3.6 kHz to 77 kHz, with a range of best sensitivity from 8 to 64 kHz while the hearing of Marmosa extends from 3.8 kHz to 80 kHz, with a range of best sensitivity from 8 to 64 kHz. Neither species was found to be particularly sensitive to tones, with the average lowest threshold near 20 dB SPL for Monodelphis and 33 dB SPL for Marmosa. These results indicate that like the North American opossum both genera are sensitive to high frequencies yet relatively insensitive to sound. Because the hearing of the three genera of Didelphids agree in several respects, it can be concluded that sensitivity to high frequencies almost certainly was present in ancient mammals, probably following quickly after the acquisition of a 3 ossicle middle ear linkage. It is not unlikely that the utility value of high frequency hearing, rather than highly sensitive hearing, may have been a primary source of selective pressure for this morphological transformation.

Origin of mammalian thalamocortical projections. I. Telencephalic projections of the medial geniculate body in the opossum (Didelphis virginiana).

Telencephalic projections from the medial geniculate nucleus (MG) in opossum were traced with tritiated leucine autoradiography and by horseradish peroxidase and fluorescent dye retrograde labeling techniques. The results show that the opossum's MG contains two separate populations of neurons-one in the anterior two-thirds of MG projecting to auditory neocortex, the other occupying the entire caudal one-third of MG and projecting mostly to lateral amygdala and putamen. Because the subcortical projection of the MG in opossum is larger than that seen in any other mammal to date, it is reminiscent of the subcortical projections of the MG in reptiles and birds. Furthermore, when the subcortical projections of the MG in reptiles and opossums are compared with similar subcortical projections of the MG in rats, cats, and monkeys, the proportion of the MG neurons projecting to subcortical structures is seen to be inversely related to the recency of each animal's common ancestry with primates. The possibility that the subcortical projection of the MG in mammals is homologous with that seen in reptiles or birds implies that it might be a dwindling vestige of the projection present in the common ancestry of reptiles and mammals.

Studies of the effects of alpha-difluoromethylornithine and ethanol on the pathogenesis of bleomycin-induced pulmonary fibrosis in mice.

Both DL-alpha-difluoromethylornithine (DFMO) and ethanol have been reported to inhibit the growth of fibroblasts in cell culture. The objectives of the present study were to determine whether these compounds could be used to inhibit the growth of fibroblasts in vivo, with a bleomycin-induced mouse model of pulmonary fibrosis. DBA/2J mice were given a single endotracheal injection of bleomycin, 10 nmol. In addition to bleomycin (BLM), groups of animals received 2% DFMO in drinking water for 4 days prior to BLM and 18 days after (BLM DFMO), 6% ethanol in drinking water for 7 days prior to BLM and 21 days after (BLM E7), 6% ethanol in drinking water for 21 days initiated on the day of BLM intubation (BLM E), or DFMO, E7, and BLM in combination (BLM DFMO E7). Animals died or were killed 21 days after bleomycin treatment and lungs were evaluated by histopathologic criteria. DFMO failed to alter the incidence or severity of fibrotic lesions, increased the severity of epithelial metaplasia (p less than 0.05), and reduced the lung disease index (from 56.3 to 42.1%, p less than 0.05) and mortality from 83.3 to 41.7% (p less than 0.025). In contrast to the unsatisfactory response to DFMO, pretreatment with ethanol (BLM E7) reduced the incidence of interstitial fibrosis from 91.3 to 71.4% (p less than 0.05) and confluent fibrosis from 73.9 to 20.0% (p less than 0.005). The severity of lesions was also reduced by ethanol, resulting in an 18.5% decrease in interstitial fibrosis, a 25.9% decrease in epithelial metaplasia, and a 55.4% reduction in the lung disease index (all p less than 0.01). However, when ethanol and DFMO were administered in combination, the beneficial effects of ethanol alone were not observed, and only the lung disease index was decreased.