Charles J. Hodge

Biological plasticity: the future of science in neurosurgery.

THE FUTURE OF neurosurgery is intimately related to the future of neuroscientific research. Although the field of neuroscience is immense and not subject to brief review, it is clear that certain trends have become critical to future thinking regarding neurosurgery. An important theme that recurs in much of the current research and that will become more prominent in the future is the concept of plasticity. This refers not only to the changes in cortical representation that can occur after a variety of perturbations but also to a wide variety of neurologically relevant biological processes. In this review, we describe three areas of plasticity, i.e., the response of the brain to ischemia, cortical representational changes, and the potential for stem cell biological processes to allow us to manipulate plasticity. We posit that these trends will be crucial to the future of our specialty.

Use-dependent plasticity in barrel cortex: Intrinsic signal imaging reveals functional expansion of spared whisker representation into adjacent deprived columns

We used optical imaging of intrinsic cortical signals, elicited by whisker stimulation, to define areas of activation in primary sensory cortex of normal hamsters and hamsters subjected to neonatal follicle ablation at postnatal day seven (P7). Follicle ablations were unilateral, and spared either C-row whiskers or the second whisker arc. This study was done to determine if the intrinsic cortical connectivity pattern of the barrel cortex, established during the critical period, affects the process of representational plasticity that follows whisker follicle ablation. Additionally, we tested the ability to monitor such changes in individual cortical whisker representations using intrinsic signal imaging. Stimulation of a single whisker yielded peak activation of a barrel-sized patch in the somatotopically appropriate location in normal cortex. In both row and arc-spared animals, functional representations corresponding to spared follicles were significantly stronger and more oblong than normal. The pattern of activation differed in the row-sparing and arc-sparing groups, in that the expansion was preferentially into deprived, not spared areas. Single whisker stimulation in row-spared cases preferentially activated the corresponding barrel arc, while stimulation of one whisker in arc-spared cases produced elongated activation down the barrel row. Since whisker deflection normally has a net inhibitory effect on neighboring barrels, our data suggest that intracortical inhibition fails to develop normally in deprived cortical columns. Because thalamocortical projections are not affected by follicle ablation after P7, we suggest that the effects we observed are largely cortical, not thalamocortical.

Effects of hyperoxia on human sensorimotor cortex activity produced by electrical stimulation of the median nerve: a functional magnetic resonance imaging study.

This study investigated the effect of hyperoxia on sensorimotorcortical activity resulting from electrical stimulation of the median nerve, using functional magnetic resonance imaging (fMRI). Nine volunteers underwent stimulation at 5 and 100 Hz while breathing 21% FIO(2) (fraction of inspired oxygen) or 100% FIO(2). fMRI data were correlated with a stimulus predictor curve, transformed into Talairach space and averaged by group. Normoxic (21% FIO(2)) and hyperoxic (100% FIO(2)) sensorimotor activation volumes were compared using Students t-test. There were no significant differences between the primary somatosensory/primary motor/Brodmann area 40 (SI/MI/Ba40) and secondary somatosensory cortex (SII) activation volumes for normoxia and hyperoxia. (P>0.05). There was no difference between SI/MI/Ba40 and SII activations at 5 and 100 Hz. In contrast to results previously reported for primary visual cortex (V1), hyperoxia did not enhance sensorimotor cortical activation in area SI/MI/Ba40 or SII. These results indicate that there is regional heterogeneity of the fMRI response to hyperoxia in the cerebral cortex.

Reorganization of adult rat barrel cortex intrinsic signals following kainic acid induced central lesion.

A plasticity model studying the adult rat barrel cortex intrinsic signal after a central lesion was developed. Repeated optical imaging studies of the barrel cortex of five rats were performed over variable periods of time (2 days to 6 weeks) after intracortical injection of kainic acid. The signal of the elicited principal whisker corresponding to the injected barrel in the repeat studies relocated to the perimeter of the lesion. The area of the signals of this principal whisker and of surrounding whiskers were larger in the first two weeks studies than those obtained before injection (P<0.01) resulting in increase overlapping of adjacent signals (P=0.01). Even though the signal of the PW remains relocated in the later studies (>2 weeks), all the signals returned to normal size. These findings demonstrate recovery and reorganization of sensory representation in the somatosensory cortex following a central lesion.

Anomalous functional organization of barrel cortex in GAP-43 deficient mice.

Growth associated protein 43 (GAP-43), found only in the nervous system, regulates the response of neurons to axon guidance signals. It is also critical for establishing normal somatotopy. Mice lacking GAP-43 (KO) show aberrant pathfinding by thalamocortical afferents, and do not form cortical whisker/barrels. GAP-43 heterozygous (HZ) mice show more subtle deficits--delayed barrel segregation and enlarged barrels at postnatal day 7. Here, we used cortical intrinsic signal imaging to characterize adult somatotopy in wildtype (WT), GAP-43 KO, and HZ mice. We found clear foci of activation in GAP-43 KO cortex in response to single-whisker stimulation. However, the KO spatial activation patterns showed severe anomalies, indicating a loss of functional somatotopy. In some cases, multiple foci were activated by single whiskers, while in other cases, the same cortical zone was activated by several whiskers. The results are consistent with our previous findings of aberrant pathfinding and clustering by thalamocortical afferent axons, and absence of barrel patterning. Our findings indicate that cortex acts to cluster afferents from a given whisker, even in the absence of normal topography. By contrast, single-whisker stimulation revealed normal adult topographic organization in WT and HZ mice. However, we found that functional representations of adult HZ barrels are larger than those found in WT mice. Since histological HZ barrels recover normal dimensions by postnatal day 26, the altered circuit function in GAP-43 HZ cortex could be a secondary consequence of the rescue of barrel dimensions.

Impact of the number of metastatic brain lesions on survival after Gamma Knife radiosurgery

Effectiveness of Gamma Knife radiosurgery (GKRS: Elekta AB, Stockholm, Sweden) for patients with metastatic brain disease and the prognostic factors influencing their survival were analyzed in a 5 year retrospective data analysis (July 2001 to June 2006). Kaplan-Meier survival curves were constructed using univariate and multivariate analyses with the respective salient prognostic factors. This study analyzed data on 330 patients with brain metastases who underwent GKRS. Lung carcinoma (55%) was the most common primary cancer followed by breast (17.8%), melanoma (9.4%), colorectal (4.8%) and renal (3.9%). The median survival for all patients was 8 months. Survival ranged from 13 months for breast metastases, 10 months for renal, and 8 months for lung to 5 months for colorectal and melanoma. Mean age of patients was 58.5 years (range 18-81). Melanoma patients were younger with a mean age of 49 and also had the highest number of lesions (3.8) when compared to patients with renal (2.5), lung (2.8), colorectal (3) and breast (3.6). When stratified according to the number of lesions patient survival was 8 months (one to three lesions), 7.5 months (four or five lesions) and 7 months (six lesions or more). Mean Karnofsky Performance Status score (KPS) was 77 and survival dropped significantly from 8 months to 4.5 months if KPS was less than 70. Survival improved with a KPS of 70 or more, regardless of the number of lesions treated. Selection of patients based on the number of lesions may not be justified. A prospective trial is required to further define the prognostic factors affecting survival.

A new model of cortical plasticity using rat whisker barrel cortex

Abstract Each snout whisker of the rat is represented in the contralateral cortex by a group of cells which, because of the group shape, is called a barrel. The barrel cortex represents invariant somatotopy and function from animal to animal. This model has been used frequently in animals with whisker trimming or removal to study use-dependent cortical plasticity. We have developed a model more relevant to clinical brain injury. Imaging of the cortical intrinsic signal evoked by single movement was used to define the somatotopy of the barrel cortex. A single barrel was then destroyed by injection of 0.1 μl of kainic acid (KA). Repeated maps of the barrel cortex were then made using optical imaging techniques. The whisker projecting to the barrel, which had been destroyed, became represented in nearby cortex. Additionally, the surrounding barrels had increased size which, over a period of several months, returned towards control levels. The lesions were associated with increases in both GAP-43 and brain derived neurotrophic factor (BDNF). Further investigation of the role that GAP-43 might play in cortical organization was evaluated using GAP-43 knockout mice. These mice had dramatically disrupted cortical organization. Preliminary results indicate that injection of pluripotential neural precursor cells into the area of the destroyed barrel appeared to result in restoration of the somatotopic organization of the cortex. We conclude that the original changes in cortical organization are likely related to decrease in surround inhibition and that intracortical sprouting completes this process. The mechanisms of the effects seen with precursor injection remain uncertain but are under further investigation.