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Traumatic brain injury (TBI) results in well-known, significant alterations in structural and functional connectivity. Although this is especially likely to occur in areas of pathology, deficits in function to and from remotely connected brain areas, or diaschisis, also occur as a consequence to local deficits. As a result, consideration of the network wiring of the brain may be required to design the most efficacious rehabilitation therapy to target specific functional networks to improve outcome. In this work, we model remote connections after controlled cortical impact injury (CCI) in the rat through the effect of callosal deafferentation to the opposite, contralesional cortex. We show rescue of significantly reaching deficits in injury-affected forelimb function if temporary, neuromodulatory silencing of contralesional cortex function is conducted at 1 week post-injury using the γ-aminobutyric acid (GABA) agonist muscimol, compared with vehicle. This indicates that subacute, injury-induced remote circuit modifications are likely to prevent normal ipsilesional control over limb function. However, by conducting temporary contralesional cortex silencing in the same injured rats at 4 weeks post-injury, injury-affected limb function either remains unaffected and deficient or is worsened, indicating that circuit modifications are more permanently controlled or at least influenced by the contralesional cortex at extended post-injury times. We provide functional magnetic resonance imaging (MRI) evidence of the neuromodulatory effect of muscimol on forelimb-evoked function in the cortex. We discuss these findings in light of known changes in cortical connectivity and excitability that occur in this injury model, and postulate a mechanism to explain these findings.

Clinical studies have indicated an association between acute hyperglycemia and poor outcomes in patients with traumatic brain injury (TBI), although optimal blood glucose levels needed to maximize outcomes for these patients' remain under investigation. Previous results from experimental animal models suggest that post-TBI hyperglycemia may be harmful, neutral, or beneficial. The current studies determined the effects of single or multiple episodes of acute hyperglycemia on cerebral glucose metabolism and neuronal injury in a rodent model of unilateral controlled cortical impact (CCI) injury. In Experiment 1 , a single episode of hyperglycemia (50% glucose at 2 g/kg, i.p.) initiated immediately after CCI was found to significantly attenuate a TBI-induced depression of glucose metabolism in cerebral cortex (4 of 6 regions) and subcortical regions (2 of 7) as well as to significantly reduce the number of dead/dying neurons in cortex and hippocampus at 24 h post-CCI. Experiment 2 examined effects of more prolonged and intermittent hyperglycemia induced by glucose administrations (2 g/kg, i.p.) at 0, 1, 3 and 6 h post-CCI. The latter study also found significantly improved cerebral metabolism (in 3 of 6 cortical and 3 of 7 subcortical regions) and significant neuroprotection in cortex and hippocampus 1 day after CCI and glucose administration. These results indicate that acute episodes of post-TBI hyperglycemia can be beneficial and are consistent with other recent studies showing benefits of providing exogenous energy substrates during periods of increased cerebral metabolic demand.

Sodium pyruvate (SP) treatment initiated within 5 min post-injury is neuroprotective in a rat model of unilateral cortical contusion injury (CCI). The current studies examined: (1) effects of delayed SP treatments (1000 mg/kg, i.p., at 1, 12 and 24 h), (2) effects of single (1 h) or multiple (1, 12 and 24 h) ethyl pyruvate treatments (EP; at 20 or 40 mg/kg, i.p.), and (3) mechanisms of action for pyruvate effects after CCI. In Experiment 1, both SP and EP treatment(s) significantly reduced the number of dead/dying cells in the ipsilateral hippocampus (dentate hilus+CA3c and/or CA3a-b regions) at 72 h post-CCI. Pyruvate treatment(s) attenuated CCI-induced reductions of cerebral cytochrome oxidase activity at 72 h, significantly improving activity in peri-contusional cortex after multiple SP or EP treatments. Optical density measures of ipsilateral CD11b immuno-staining were significantly increased 72 h post-CCI, but these measures of microglia activation were not different from sham injury values in SP and EP groups with three post-CCI treatments. In Experiment 2, three treatments (1, 12 and 24 h) of SP (1000 mg/kg) or EP (40 mg/kg) significantly improved recovery of beam-walking and neurological scores in the first three weeks after CCI, and EP treatments significantly improved spatial working memory one week post-CCI. Ipsilateral CA3b neuronal loss, but not cortical tissue loss, was significantly reduced one month post-CCI with pyruvate treatments begun 1 h post-CCI. Thus, delayed pyruvate treatments after CCI are neuroprotective and improve neurobehavioral recovery; these effects may be mediated by improved metabolism and reduced inflammation.

Having reported that traumatic brain injury (TBI), produced by moderate lateral controlled cortical impact (CCI), causes long-term dysregulation of the neuroendocrine stress response, the aim of this study was to assess short- and long-term effects of both moderate and mild CCI on stress-induced hypothalamic-pituitary-adrenal (HPA) function. TBI was induced to the left parietal cortex in adult male rats with a pneumatic piston, at two different impact velocities and compression depths to produce either a moderate or mild CCI. Controls underwent sham surgery without injury. Commencing at one week after recovery from surgery, rats were exposed to stressors: 30-min restraint (days 7, 34, and 70) or 15-min forced swim (days 21 and 54). Tail vein blood was analyzed for corticosterone (CORT) content by radioimmunoassay. On days 7 and 21, the stress-induced HPA responses were significantly attenuated by both mild and moderate CCI. Significant attenuation of the CORT response to stress persisted through day 70 after moderate CCI. In contrast, stress-induced CORT levels on days 34, 54, and 70 were significantly enhanced after mild CCI. Differential effects of injury severity were also observed on motor function in a forelimb test on post-injury day 12 and on cortical lesion volume and hippocampal cell loss at day 70, but not on working memory in a radial maze on day 15. The differing short- and long-term stress-induced HPA responses may be mediated by differential effects of moderate and mild CCI on the efficiency of glucocorticoid negative feedback or signaling among hypothalamic and extrahypothalamic components of the neuroendocrine stress-response system.

The impact of hyperglycemia after traumatic brain injury (TBI), and even the administration of glucose-containing solutions to head injured patients, remains controversial. In the current study adult male Sprague-Dawley rats were tested on behavioral tasks and then underwent surgery to induce sham injury or unilateral controlled cortical impact (CCI) injury followed by injections (i.p.) with either a 50% glucose solution (Glc; 2g/kg) or an equivalent volume of either 0.9% or 8% saline (Sal) at 0, 1, 3 and 6h post-injury. The type of saline treatment did not significantly affect any outcome measures, so these data were combined. Rats with CCI had significant deficits in beam-walking traversal time and rating scores (p's < 0.001 versus sham) that recovered over test sessions from 1 to 13 days post-injury (p's < 0.001), but these beam-walking deficits were not affected by Glc versus Sal treatments. Persistent post-CCI deficits in forelimb contraflexion scores and forelimb tactile placing ability were also not differentially affected by Glc or Sal treatments. However, deficits in latency to retract the right hind limb after limb extension were significantly attenuated in the CCI-Glc group (p < 0.05 versus CCI-Sal). Both CCI groups were significantly impaired in a plus maze test of spatial working memory on days 4, 9 and 14 post-surgery (p < 0.001 versus sham), and there was no effect of Glc versus Sal on this cognitive outcome measure. At 15 days post-surgery the loss of cortical tissue volume (p < 0.001 versus sham) was significantly less in the CCI-Glc group (30.0%; p < 0.05) compared to the CCI-Sal group (35.7%). Counts of surviving hippocampal hilar neurons revealed a significant (~40%) loss ipsilateral to CCI (p < 0.001 versus sham), but neuronal loss in the hippocampus was not different in the CCI-Sal and CCI-Glc groups. Taken together, these results indicate that an early elevation of blood glucose may improve some neurological outcomes and, importantly, the induction of hyperglycemia after isolated TBI did not adversely affect any sensorimotor, cognitive or histological outcomes.

The metabolic fate of [1,2 13C]-labeled glucose was determined in male control and unilateral controlled cortical impact (CCI) injured rats at 3.5 and 24 h after surgery. The concentration of 13C-labeled glucose, lactate, glutamate and glutamine were measured in the injured and contralateral cortex. CCI animals showed a 145% increase in 13C lactate in the injured cortex at 3.5 h, but not at 24 h after injury, indicating increased glycolysis in neurons and/or astrocytes ipsilateral to CCI. Total levels of 13C glutamate in cortical tissue extracts did not differ between groups. However, 13C glutamine increased by 40% in the left and 98% in the right cortex at 3.5 h after injury, most likely resulting from an increase in astrocytic metabolism of glutamate. Levels of 13C incorporation into the glutamine isotopomers had returned to control levels by 24 h after CCI. The singlet to doublet ratio of the lactate C3 resonances was calculated to estimate the flux of glucose through the pentose phosphate pathway (PPP). CCI resulted in bilateral increases (9-12%) in the oxidation of glucose via the PPP, with the largest increase occurring at 24 h. Since an increase in PPP activity is associated with NADPH generation, the data suggest that there was an increasing need for reducing equivalents after CCI. Furthermore, 13C was incorporated into glutamate and glutamine isotopomers associated with multiple turns of the tricarboxylic acid (TCA) cycle, indicating that oxidative phosphorylation of glucose was maintained in the injured cortex at 3.5 and 24 h after a moderate to severe CCI injury.

The present review highlights critical issues related to cerebral metabolism following traumatic brain injury (TBI) and the use of (13)C labeled substrates and nuclear magnetic resonance (NMR) spectroscopy to study these changes. First we address some pathophysiologic factors contributing to metabolic dysfunction following TBI. We then examine how (13)C NMR spectroscopy strategies have been used to investigate energy metabolism, neurotransmission, the intracellular redox state, and neuroglial compartmentation following injury. (13)C NMR spectroscopy studies of brain extracts from animal models of TBI have revealed enhanced glycolytic production of lactate, evidence of pentose phosphate pathway (PPP) activation, and alterations in neuronal and astrocyte oxidative metabolism that are dependent on injury severity. Differential incorporation of label into glutamate and glutamine from (13)C labeled glucose or acetate also suggest TBI-induced adaptations to the glutamate-glutamine cycle.

The beneficial effect of interventions with chondroitinase ABC enzyme to reduce axon growth-inhibitory chondroitin sulphate side chains after central nervous system injuries has been mainly attributed to enhanced axonal sprouting. After traumatic brain injury (TBI), it is unknown whether newly sprouting axons that occur as a result of interventional strategies are able to functionally contribute to existing circuitry, and it is uncertain whether maladaptive sprouting occurs to increase the well-known risk for seizure activity after TBI. Here, we show that after a controlled cortical impact injury in rats, chondroitinase infusion into injured cortex at 30 min and 3 days reduced c-Fos+ cell staining resulting from the injury alone at 1 week postinjury, indicating that at baseline, abnormal spontaneous activity is likely to be reduced, not increased, with this type of intervention. c-Fos+ cell staining elicited by neural activity from stimulation of the affected forelimb 1 week after injury was significantly enhanced by chondroitinase, indicating a widespread effect on cortical map plasticity. Underlying this map plasticity was a larger contribution of neuronal, rather than glial cells and an absence of c-Fos+ cells surrounded by perineuronal nets that were normally present in stimulated naïve rats. After injury, chondroitin sulfate proteoglycan digestion produced the expected increase in growth-associated protein 43–positive axons and perikarya, of which a significantly greater number were double labeled for c-Fos after intervention with chondroitinase, compared to vehicle. These data indicate that chondroitinase produces significant gains in cortical map plasticity after TBI, and that either axonal sprouting and/or changes in perineuronal nets may underlie this effect. Chondroitinase dampens, rather than increases nonspecific c-Fos activity after brain injury, and induction of axonal sprouting is not maladaptive because greater numbers are functionally active and provide a significant contribution to forelimb circuitry after brain injury.

Despite various lines of evidence pointing to the compartmentation of metabolism within the brain, few studies have reported the effect of a traumatic brain injury (TBI) on neuronal and astrocyte compartments and/or metabolic trafficking between these cells. In this study we used ex vivo 13C NMR spectroscopy following an infusion of [1-13C] glucose and [1,2-13C2] acetate to study oxidative metabolism in neurons and astrocytes of sham-operated and fluid percussion brain injured (FPI) rats at 1, 5, and 14 days post-surgery. FPI resulted in a decrease in the 13C glucose enrichment of glutamate in neurons in the injured hemisphere at day 1. In contrast, enrichment of glutamine in astrocytes from acetate was not significantly decreased at day 1. At day 5 the 13C enrichment of glutamate and glutamine from glucose in the injured hemisphere of FPI rats did not differ from sham levels, but glutamine derived from acetate metabolism in astrocytes was significantly increased. The 13C glucose enrichment of the C3 position of glutamate (C3) in neurons was significantly decreased ipsilateral to FPI at day 14, whereas the enrichment of glutamine in astrocytes had returned to sham levels at this time point. These findings indicate that the oxidative metabolism of glucose is reduced to a greater extent in neurons compared to astrocytes following a FPI. The increased utilization of acetate to synthesize glutamine, and the acetate enrichment of glutamate via the glutamate-glutamine cycle, suggests an integral protective role for astrocytes in maintaining metabolic function following TBI-induced impairments in glucose metabolism.

Traumatic brain injury (TBI) results in enduring functional deficits. Strategies aimed at promoting plasticity within the injured brain may aid in enhancing functional outcome. We have previously shown that spontaneous pericontusional axon sprouting occurs within 7–14 days after controlled cortical impact injury in the adult rat, but ultimately fails due to an increasingly growth-inhibitory environment. We therefore sought to determine whether acute infusion of chondroitinase ABC into the site of the cortical contusion, to further reduce pericontusional growth-inhibitory chondroitin sulfate proteoglycans (CSPGs), would enhance and prolong the sprouting response. We also wanted to determine if chondroitinase-enhanced sprouting would ameliorate the behavioral deficits in forelimb function that occur in this model. Acute chondroitinase infusion decreased intact CSPGs and significantly increased pericontusional cortical grey and white matter growth-associated protein 43 (GAP43)-positive axon sprouting at 7 days post-injury. A return of intact CSPGs at later time points likely contributed to the absence of persistently increased levels of axon sprouting by 14–21 days post-injury. There was no overall benefit on forelimb function during the time of maximal sprouting or at any subsequent times in three of four behavioral outcome measures. However, there was a chondroitinase-induced improvement in recovery from unskilled limb use deficits on the staircase forelimb reaching test toward sham-injured values at 28 days, which was not achieved by the vehicle-treated rats, indicating that there is some minor functional benefit of the increased sprouting induced by chondroitinase treatment. The current results, together with data from spinal cord injury models after chondroitinase intervention, suggest that a combinatorial approach with the addition of neurotrophins and rehabilitation would result in more robust axon sprouting and consequently improve behavioral outcome.

We previously reported that pericontusional extracellular chondroitin sulfate proteoglycans (CSPGs) are profoundly reduced for 3 weeks after experimental traumatic brain injury, indicating a potential growth-permissive window for plasticity. Here, we investigate the extracellular environment of sprouting neurons after controlled cortical impact injury in adult rats to determine the spatial and temporal arrangement of inhibitory and growth-promoting molecules in relation to growth-associated protein 43-positive (GAP43+) neurons. Spontaneous cortical sprouting was maximal in pericontused regions at 7 and 14 days after injury but absent by 28 days. Perineuronal nets containing CSPGs were reduced at 7 days after injury in the pericontused region (p0.05), which was commensurate with a reduction in extracellular CSPGs. Sprouting was restricted to the perineuronal nets and CSPG-deficient regions at 7 days, indicating that the pericontused region is temporarily and spatially permissive to new growth. At this time point,GAP43+ neurons were associated with brain regions containing cells positive for polysialic acid neural cell adhesion molecule but not with fibronectin-positive cells. Brain-derived neurotrophic factor was reduced in the immediate pericontused region at 7 days. Along with prior Western blot evidence, these data suggest that a lowered intrinsic growth stimulus, together with a later return of growth-inhibitory CSPGs, may contribute to the ultimate disappearance of sprouting neurons after traumatic brain injury.

The maturation of brain oxidative capacity was studied in kittens, using cytochrome oxidase histochemistry, at different ages throughout development. Optical densitometry values of reacted tissue were obtained for 50 different structures of the brain. In general, most structures reached adult levels of oxidative capacity by 30 days of age with some motor areas (e.g., cerebellum, red nucleus) exhibiting adult values as early as 7 days of age. Thereafter, some structures (e.g., basal ganglia, thalamus) exhibited levels of cytochrome oxidase activity that exceeded adult values for varying periods of time. These findings indicate regional heterogeneity in the maturation of cerebral oxidative capacity. Furthermore, these maturational patterns appear to correlate well with previous observations from anatomical, physiological and neuro-behavioral studies.

Traumatic brain injury (TBI) is associated with significant neurological deficits that in most cases do not completely resolve with time. Because axonal injury produced by shearing impact forces is a major hallmark of TBI (Adams et al., 1989), it seems likely that therapies directed toward enhancing axon repair and connectivity have the potential to improve functional outcomes after TBI. However, there is a large amount of literature that describes a significant axon growth inhibitory environment after central nervous system (CNS) lesions (Asher et al., 2000, 2002; Levine et al., 2001; Chen et al., 2003; Dobbertin et al., 2003; Sandvig et al., 2004; Silver and Miller, 2004; Dubreuil et al., 2006; Marklund et al., 2006; Thompson et al., 2006). This environment consists of increases in axon growth inhibitory extracellular matrix and myelin-associated molecules (growth-IMs) as well as increases in reactive astrocytes, microglia, and oligodendrocytes, all of which are associated with glial scar formation and can contribute to prevention of axon plasticity or synapse formation (Fawcett and Asher, 1999). Unfortunately, there has been little research to determine how the brain responds to TBI in terms of the glial scar and the local brain environment for growth inhibition. By addressing this gap in our knowledge, it should be possible to determine whether axon sprouting could underlie some spontaneous recovery of function after CNS injury, as some studies suggest (Castro-Alamancos and Borrell, 1995; Christman et al., 1997; Hulsebosch et al., 1998; Emery et al., 2000), and then proceed to determine whether this might be enhanced through therapeutic measures. The major growth-IMs so far identified consist of myelin-associated glycoprotein, oligodendrocyte myelin glycoprotein, chondroitin sulfate proteoglycans (CSPGs), and NOGO, and these growth-IMs are generally, but not always, up-regulated after CNS injury (Fawcett and Asher, 1999; Sandvig et al., 2004; Silver and Miller, 2004). The CSPGs are extracellular molecules composed of secreted and transmembrane forms. They have a central protein core attached to glycosaminoglycan side chains containing repeating dissacharide units. The members of the CSPG family, versican, neurocan, phosphacan, brevican, neurocan, and NG2, differ in the protein core and the number and length of sulfation of the side chains (Morgenstern et al., 2002), which confers binding properties and hence function (Properzi et al., 2003). CSPGs undergo proteolytic cleavage to create additional forms (Morgenstern et al., 2002), and most are normally expressed by astrocytes, although there is now good evidence that immature oligodendrocytes either produce and/or associate with neurocan, versican, and NG2 (Ong and Levine, 1999; Asher et al., 2000, 2002) and that neurons produce at least some species of aggrecan, brevican, and neurocan (Oohira et al., 1994; Lander et al., 1998; Seidenbecher et al., 2002). The CSPGs are present in normal brain, either within the extracellular space or aggregated as perineuronal nets that encase or surround neurons (Lander et al., 1998). They have been shown to be up-regulated after spinal cord injury (Lemons et al., 1999; Jones et al., 2003; Tang et al., 2003), stroke (Carmichael et al., 2005), hypoxic-ischemic injury (Aya-ay et al., 2005), or nigrostriatal lesion (Moon et al., 2002), and they are major inhibitory components of the resulting glial scar (Fawcett and Asher, 1999). A CSPG receptor site has not been identified, but Rho GTPase, which is increased after TBI (Dubreuil et al., 2006), appears to play a role (Jain et al., 2004) as does the epidermal growth factor receptor (Koprivica et al., 2005). The idea that all CSPGs are largely up-regulated after CNS injury and that they are all inhibitory to axon outgrowth is an oversimplification. Individual CSPGs have differential and even opposing effects on outgrowth, depending on the specific neuronal population and the developmental state of the neuron (Maeda and Noda, 1996). Previous reports suggest that the CSPG response to injury is quite heterogenous and may vary as a function of injury model or clinical disease state, temporal factors, or the specific species of growth-IMs (Levine, 1994; Jaworski et al., 1999; Asher et al., 2000, 2002; Lemons et al., 2001; Garwood et al., 2003; Dobbertin et al., 2003; Okamoto et al., 2003; Miyata et al., 2004). Although on the face of it one might anticipate similar pathophysiology after TBI and other CNS injuries such as stroke, the initial insult very clearly differs between these two injuries, especially with regard to the mechanism of primary axonal damage (Bramlett and Dietrich, 2004). Differences might therefore be expected in the temporal and/or spatial expression of molecules that affect axonal repair as a function of injury model. We reasoned that a study designed to investigate CSPGs associated with the glial scar after TBI would be an important first step for future efforts to design therapies that might enhance axon repair and functional outcome following TBI. The current study was designed to determine temporal changes in mRNA and protein expression levels of the CSPGs aggrecan, phosphacan, versican, and neurocan and to determine their regional localization and cellular association by using immunohistochemistry, in a controlled cortical impact (CCI) model of mild-to-moderate TBI.

We investigated whether a learning impairment after a controlled cortical impact (CCI) injury was associated with alterations in molecules involved in synaptic plasticity and learning and memory. Adult male rats with moderate CCI to the left parietal cortex, tested in a Morris water maze (MWM) beginning at postinjury day 10, showed impaired cognitive performance compared with sham-treated rats. Tissue was extracted for mRNA analysis on postinjury day 21. The expression of brain-derived neurotrophic factor (BDNF), synapsin I, cyclic-AMP response element binding protein (CREB), and calcium-calmodulin-dependent protein kinase II (alpha-CAMKII) were all significantly decreased compared with sham injury levels within the ipsilateral hippocampus after CCI. No significant molecular level changes were found in the contralateral hippocampus. Decreased expression of BDNF and synapsin I was also found within the ipsilateral parietal cortex of CCI-injured rats compared with shams. However, BDNF and synapsin I expressions were significantly increased in the contralateral parietal cortex of the CCI rats. CREB expression was significantly decreased within the contralateral cortex of the CCI group. These findings show enduring reductions in the expression of BDNF, synapsin I, CREB, and alpha-CAMKII ipsilateral to a CCI injury, which seem associated with the spatial learning deficits observed in this injury model. In addition, the delayed increase in the expression of BDNF and synapsin I within the cortex contralateral to CCI may reflect restorative processes in areas homotypical to the injury.

Secondary ischemia (SI) following traumatic brain injury (TBI) increases damage to the brain in both animals and humans. The current study determined if SI after TBI alters the extent or duration of reduced energy production within the first 24 h post-injury and hippocampal cell loss at one week post-injury. Adult male rats were subjected to sham injury, lateral (LFPI) or central fluid percussion injury (CFPI) only, or to combined LFPI or CFPI with SI. The SI was 8 min of bilateral forebrain ischemia combined with hemorrhagic hypotension, applied at 1 h following FPI. After LFPI alone adenosine triphosphate (ATP) levels within the ipsilateral CA1 were reduced at 2 h (p

Rats with contusion injury to the right cortex exhibited significant formation of edema 6 and 24 hours after injury which resolved by 8 days and was replaced by cavitation necrosis. The contusions produced hyperglycolysis and ischemia in the impacted cortical tissue and underlying hippocampus immediately through 30 minutes post-injury. Glucose utilization was depressed throughout the contused cortex and in ipsilateral subcortical regions, as was blood flow, at chronic (1 and 10 days) periods after injury.

After thermal cauterization of the area postrema in rats the absence of conditioned taste aversion to sucrose paired with lithium chloride (0.15 M, 3.3 ml/kg) was used as a pharmacologic/behavioral index of area postrema damage. In a subsequent experiment the effects of area postrema lesions on three measures proposed as species-relevant measures of motion sickness were studied, using off-vertical rotation at 150 degrees/s for either 30 or 90 min. Lesions of area postrema did not alter postrotational suppression of drinking or amount of defecation during motion. The initial acquisition of conditioned taste aversion to a novel cider vinegar solution paired with motion was not affected by lesioning of the area postrema, but these taste aversions extinguished more slowly in lesioned rats than in sham-operates or intact controls. Results are discussed in terms of proposed humoral factors which may induce motion sickness and in light of recent data on the role of the area postrema in similar measures in species possessing the complete emetic reflex.

Corticorubral (CR) connections are reorganized after the red nucleus is deafferented by neonatal hemispherectomy. Our objective was to determine if the new decussating CR axons establish synaptic junctions with their target neurons. The ultrastructure of CR axonal terminal arbors was identified by the anterograde transport and histochemical labeling of wheat germ agglutinin lectin-bound horseradish peroxidase injected unilaterally into the pericruciate neocortex of adult cats that received unilateral neonatal hemispherectomy (HEMI cases) and normal adult cats (control cases). The regional organization of undecussated and decussated CR arbors was nearly equivalent in the HEMI cases. The fine structure of both connections was uniform. Asymmetrical synaptic junctions were observed in frequent axodendritic and infrequent axosomatic boutons en passage and boutons terminaux. The undecussated arbors formed the principal connection in the control cases. However, the fine structures of the decussated and undecussated arbors were comparable and matched the arrangements in the HEMI cases. We conclude that developmental deafferentation redirects CR axons to provide stable synaptic afferents to new targets. The reinnervation is homotypical in terms of regional and fine structure organization. It is likely to be an important factor in chemically mediated neurotransmission that contributes to the sparing/recovery of function after brain damage.

Cerebral metabolic effects of locus coeruleus (LC) lesion or drugs affecting LC were investigated after unilateral injury of sensorimotor cortex in rats. Sensoriomotor cortex ablation produced a widespread depression of cerebral 14C-2-deoxyglucose utilization which was reversed by amphetamine (AMP, 2 mg/kg) and worsened by haloperidol (HAL, 0.4 mg/kg). Lesion of LC alone did not affect cerebral oxidative metabolism, measured by a stain for the enzyme alpha-glycerophosphate dehydrogenase (α-GPDH). Lesion of LC prior to undercut laceration of motor cortex shortened time to onset of α-GPDH cortical paling. Treatment with AMP (2 mg/kg) blocked cortical paling of the enzyme stain at 4 days postinjury, an effect prevented by concomitant HAL (0.3 or 0.6 mg/kg). Apomorphine (1 mg/kg) did not block cortical paling. These data parallel effects of these drugs on recovery of function. The results suggest that a metabolic “remote functional depression” (RFD) is alleviated by catecholamine activation after cortical injury, whereas onset of RFD is accelerated by LC lesions and exacerbated by catecholamine blockade.

After bilateral visual cortex ablation, cats show a transient deficit in tactile placing and a permanent deficit in visual placing of both forelimbs. Amphetamine administration (four doses, 5 mg/kg, i.p., spaced at 4-day intervals beginning 10 days after surgery) accelerated the rate of recovery of tactile placing compared with saline controls whereas visual placing was not affected. The catecholamine antagonist, haloperidol (0.4 mg/kg, i.p.), blocked the amphetamine-enhanced recovery of tactile placing. Additionally, the visual cortex lesions produced a depression of oxidative metabolism, measured by cytochrome oxidase histochemistry, in subcortical regions remote from the injury. Animals treated with amphetamine exhibited an alleviation of this metabolic depression in the superior colliculus but not in other regions.

Although Cottle 1 described a case of what we now believe to have been angiokeratoma as early as 1877, and Crocker, 2 Colcott Fox 3 and Dubreuilh 4 reported examples of the disease as instances of unusual varieties of verruca a few years later, it was not until the publication of Mibelli's 5 classical description, in September, 1889, that a careful and accurate delineation of the clinical and pathologic features of the malady was available. Mibelli's case was in a young girl, and the disease, which had been present for about five years, involved the dorsal surfaces of the fingers and toes. The lesions varied in size from that of a hemp-seed to that of the head of a large pin, and were distributed along the course of the superficial capillaries, which were slightly dilated and more prominent than usual. The patient had for several years suffered from recurring attacks

To the Editor:— Regarding angiomas of the scrotum (angiokeratoma, Fordyce), Robinson and Tasker (Arch. Dermat. & Syph. 54 :667-674 [Dec.] 1946) concluded that their "reported case is the first in which angiomas of the tongue were associated with those of the scrotum..." I call attention to a statement I (Sutton, R. L., and Sutton, R. L., Jr.: Diseases of the Skin, ed. 10, St. Louis, C. V. Mosby Company, 1939, p. 668) published in 1939, that "in all such cases seen by the junior author, the tongue showed beneath it and along its border the telangiectases which characterize Osler's disease, one manifestation of which vascular anomaly we believe scrotal angiokeratoma to be." That sentence ought by now to be revised to read, "In several such cases..." I hesitantly claim priority for my observation, which—if Robinson and Tasker saw it—was not, they could correctly rebut, a formal report of a case.

A rare but typical form of recurrent, scarring, painful aphthae is recognized under many names, one of which is periadenitis mucosa necrotica recurrens. 1 Cases of such aphthae are all alike and like nothing else, but their cause, which I think must be a specific one, is entirely unknown. Three cases were reported by Sibley 2 in 1899 as of "neurotic" origin, and Sibley cited Jacobi as having described 3 cases in 1894. These are the earliest reports I have found. Commencing as a small nodule within and beneath the mucous membrane of the lip, cheek or tongue, a lesion increases in size, sloughs and causes severe pain, becomes a crateriform ulcer with inflamed, firm borders, runs a course uninfluenced by local treatment and eventually heals, leaving a soft, pliable, depressed, whitish scar. Several lesions may be present simultaneously. The patient, suffering over a period sometimes of many years, can

Olive oil, Olea europaea sativa (Oleum olivae, U. S. P.), is generally believed completely bland on topical application. Many a dermatologic prescription contains it. I have, however, observed trouble resulting from its use. When it is applied to "dry scalp" (seborrheic dermatitis of the scalp) the dandruff is regularly made worse. When it is applied to senile pruritus the result is often unfavorable. Olive oil is not different from any other greasy substance when applied to superficial, vesiculating, autoinoculable, staphylococcic dermatitis, generally known as "infectious eczematoid dermatitis." In this condition any unguent smears the parasites about, prevents their drying and promotes spread of the disease. In the case which I report here the dermatitis was present for more than ten years and its maintenance was evidently due solely to olive oil, for interdiction of its use was followed by prompt cure. As I 1 have emphasized previously, the cure of

In January, 1921, while delivering a clinical lecture before the Douglas County Medical Society, at Lawrence, Kansas, I encountered a case of nail disorder which was entirely new to me. REPORT OF CASES Case 1.— The patient was a young woman, under the care of my friend, Dr. H. L. Chambers, and the affection, which involved the nail of the left thumb, had been present for about one year. There was no history of injury, and, in so far as could be demonstrated, the patient was free from syphilis and tuberculosis. The earliest noticeable manifestation was a small, hard, rounded, painless tumor at the base of the nail. The growth had increased gradually in size until it was about 0.5 cm. in height, and 0.7 cm. in width. Coincident with its development, a V-shaped groove had appeared in the nail, extending from the matrix to the free margin, and gradually

To the uninitiated, the successful treatment of early, superficial carcinoma of the external ear may seem a comparatively simple matter; but after one has acquired a little experience in combating even the milder type of the disorder in this region, a pessimistic attitude generally replaces the former optimistic one. The difficulty of bringing about a cure in these cases is largely due to the fact that the skin lies very close to the cartilage; and even if the latter escapes direct cancerous involvement, the chronic inflammatory changes to which it is subjected, together with the poor blood supply, prevent prompt healing, even after the removal of the parent cause of the trouble. During the past two years, I have had opportunity to study seventeen cases of carcinoma of the ear. All the patients were men. The youngest was 28, the oldest 81 years of age. In five cases studied microscopically

Erosive and gangrenous balanitis, the balanoposthite erosive circinee of Berdal and Bataille, 1 is a fairly uncommon affection, even in large venereal clinics, but its serious character when unrecognized entitles it to more frequent and extended notice in medical literature than it has received up to the present time. The disease is due to the symbiosis of a fusiform bacillus and a spirochete, which structurally resemble those found in Vincent's angina. The causative organisms were originally described by Muller and Scherber. 2 Culturally, they are anaerobic, and both stain readily with dilute carbolfuchsin, a tinctorial reaction which distinguishes the vibrio from the Spirochaeta pallida of Schaudinn and Hoffmann. The lesions, which develop quickly on the glans or foreskin, usually are single, in contradistinction to chancroid, and do not give rise to inguinal adenitis. The pus is of a characteristic, foul odor. The local and constitutional symptoms vary with the severity

The late R. W. Taylor 1 held that the color changes occurring in the skin as a result of syphilis could be separated into two distinct groups, true pigmentary syphilodermas, and pigmentations and leukodermatous conditions developing in the course of syphilis, as relics or sequelae of lesions, chiefly secondary, and which might be considered as dyschromatous accidents. Taylor believed, with Maieff, 2 that the pigmentary syphiloderm was due to a chronic specific inflammation of the capillaries of the skin, with ensuing endarteritis and occlusion of the affected vessels. As a result of this circulatory disturbance, the red cells lost their pigment, and the escaping coloring matter permeated not only the walls and adventitia of the vessels, but the connective tissue cells, and those of the derma and malpighian layer as well. In view of the fact that this attractive theory of the hematogenous origin of pigment has been generally abandoned

A transverse band in a nail is caused by a temporary alteration in the normal production of nail substance as it is produced by the nail matrix that underlies the proximal nail fold. 1 A fingernail band that is concave distally is usually caused by the trauma of manicuring, the nail being temporarily damaged by the instrument as it pushes back and follows the curve of the proximal nail fold. A distally convex band is generally caused by a temporary abnormality of the skin of the dorsum of the terminal phalanx. Contact or parasitic dermatitis of a digit will produce this in one nail; systemic disease, such as lobar pneumonia, is capable of producing transverse bands in the nails of both the hands and the feet. When a patient has distally convex, transverse bands only of all nails of the hands, the conditions leading to the abnormality are uncommon. Pigmentation

It is probable that the true nature of synovial lesions of the skin was first discovered by Sidney Jones and G. H. Makins 1 of London, but it is to the late James Nevins Hyde 2 that the general profession is indebted for a classical description of the disorder. In the first edition of his treatise on diseases of the skin, he states that lesions of this type Occur in the form of wart-like projections from the skin, pseudovesicles, and bullae, always over the sites of bursae connected with tendons, traversing the small articulations of the hand and foot. They are seen over the metatarsophalangeal articulations; and in the hand most frequently over the dorsal face of the articulation between the distal and adjacent phalanges of the index finger and thumb. The first form is that of a roundish, corneous, pea-sized wart with a yellowish center, of long duration, usually

"I write this book about acne," says Dr. Bobroff, "because I am shocked at the enormous disfigurement, scarring, and facial destruction among young people. Acne is, in most cases, an easily curable disorder. What is more, it can be controlled before it disfigures . . . I am not satisfied with conventional dermatological practice as regards acne . . . The dermatological practice in which I was indoctrinated . . . has proved to be irrelevant to the need, and that is why I am setting out to make some changes . . . It will be my aim in this book to simplify . . . to deprofessionalize and simplify the subject as much as possible. [Acne] belongs, not in medical practice, but in the realm of school health . . . under the head of educational preventive medicine. [An] adolescent has a right to simple hygienic instruction and guidance that will free him from the common yet needless disfigurement of adolescence." "Over the past dozen years

Two instances of a fissured, granulomatous growth are here noted. The lesions occurred in the superior labio-alveolar sulcus in both cases, and are significant because they might easily have been mistaken for epitheliomas. The similarity of the two cases, which were seen only a few months apart, and the failure to find descriptions of a disturbance of such well-defined character justify this report. These two solitary tumors were roughly circular, arising from the mucous membrane at the juncture of the upper lip and the gum. They were about 1 cc. in diameter, raised 2 to 3 mm. from the general level and conspicuously indented by a fissure in the coronal plane which divided the tumor in half and which continued at either extremity into the normal mucosa of the unaffected part of the sulcus. The shape of the tumors was that of a folded coin, the fissure being within the

As a carcinoma grows, it expands laterally as well as in depth. Starting in known cancerous tissue near the middle of a lesion and moving radially outward, one must reach eventually an external region where all epithelium is known to be normal; hence transition zones must exist. My study concerns these zones where neoplastic and normal epithelium lie close together. The question is considered whether there occurs intergradient transition of cell type between obviously normal and obviously neoplastic cells or, alternatively, whether the normal cells are of one kind, the neoplastic ones of another kind and their spacial relation merely juxtaposition. Does "progressive cancerization" of normal epithelium occur at the boundary of a growing carcinoma? MATERIALS AND METHODS My material consists of whole tumor sections of some sixteen hundred cutaneous lesions. Most of the tumors were excised along with margins of normal skin by means of the actual cautery. Fixed

Recently I have been impressed by the frequency with which the dermatologist is consulted regarding simple fissures of the anterior nares. The condition must be a comparatively common one, for I have seen twenty-seven cases within a period of less than five years. Practically all (twenty-six) of my patients were women, between the ages of 35 and 55 years. In the majority of instances, only one side of the nose was involved. The lesions occur at the anterior angle of the opening, and, while scarcely perceptible to the eye of the examiner, are very persistent, and give rise to considerable pain and discomfort. Not infrequently there is a secondary, streptococcic involvement, which may cause slight fever and some intermittent redness of the tip of the organ. Dryness of the nasal mucosa and rosacea probably are provocative factors, but why the condition is almost wholly limited, at least