Acute and chronic changes in dorsal horn innervation by primary afferents and descending supraspinal pathways after spinal cord injury

Sprouting of peptidergic nociceptive and descending supraspinal projections to the dorsal horn following spinal cord injury (SCI) has been proposed as a mechanism of neuropathic pain. To identify structural changes that could initiate or maintain SCI pain, we used a complete transection model in rats to examine how structural remodeling in the dorsal horn rostral to the lesion relates to distance from injury, laminar region, and duration of injury. The major classes of C-fiber primary afferents differed greatly in their susceptibility to structural and chemical changes and their ability to undergo plasticity. Peptidergic primary afferents showed a widespread loss throughout the dorsal horn of segments approaching the injury site. Some of this loss may have been due to decreased neuropeptide expression. The reduction in peptidergic fibers was transient, indicating compensatory sprouting and perhaps also increased neuropeptide expression within the cord. Nonpeptidergic afferents expressing GFRalpha1 were largely unaffected by SCI. In contrast, in GFRalpha2-expressing nonpeptidergic afferents SCI caused a permanent loss of dorsal horn innervation. Unexpectedly, GFRalpha2 was transiently induced throughout deeper laminae but this was not due to upregulation of GFRalpha2 in dorsal root ganglia. We also observed permanent sprouting of catecholamine terminals of supraspinal origin. This was restricted to the superficial laminae. Our results show that SCI caused a loss of sensory input as well as structural remodeling such that the balance of nociceptive inputs and descending modulation was permanently altered. These changes may contribute to mechanisms rostral to the site of SCI that trigger and maintain neuropathic pain.     

Normal sexual dimorphism in theory of mind circuitry is reversed in Schizophrenia

ABSTRACT

The ability to mentalize, or theory of mind (ToM), is sexually dimorphic in humans and impaired in schizophrenia. This sex-stratified study probed cognitive (indexed by intelligence) and affective (indexed by olfactory tasks) contributions to ToM performance in 37 individuals with schizophrenia and 31 healthy controls. The schizophrenia group showed impairments in mental state identification and inferring intentions compared to controls. Higher intelligence was correlated with mental state identification and inferring intentions in healthy females, whereas better smell identification was associated with mental state identification in healthy males. Conversely, higher intelligence was associated with mental state identification and inferring intentions in schizophrenia males, while better smell identification was correlated with mental state identification in schizophrenia females. These findings suggest that for ToM circuitry, the cognitive influences in healthy females and affective influences in healthy males are reversed in schizophrenia and may be displaced to lower circuitries by disease pathology. Symptom associations with emotion and cognition are also dimorphic, plausibly due to similar pathology superimposed on normal sex-specific circuitries. Males appear to rely on limbic processing for ToM, and disruption to this circuitry may contribute to development of negative symptoms. These findings highlight the importance of utilizing sex-stratified designs in schizophrenia research.     

The controversy about a sexual dimorphism of the human corpus callosum

A sexual dimorphism of the splenium corporis callosi in man was reported in 1982. The authors described the posterior part of the female corpus callosum to be larger and more bulbous than its male counterpart. From the lateralization research, it has previously been stated that the female brain is less well lateralized for visuospatial functions than the male. The authors postulated that a larger splenium implies a larger number of fibers and that the number of interhemispheric fibers correlates inversely with lateralization of function. However, their sample was very small and not adequately matched for sex. Therefore, we reinvestigated this question. A standardized computer assisted program will be presented. With this program the "classical" parameters have been evaluated and the "rotatory diameter measurement" was performed. No differences between the sexes were seen either for the splenium corporis callosi or for the other parts of the corpus callosum.     

The expression of brain sexual dimorphism in artificial selection of rat strains

Central nervous system sex differences have two morphological patterns. In one pattern, males show larger measurements (volume, number of neurons) than females (male > female; m > f) and, in the other, the opposite is true (female > male; f > m). The bed nucleus of the stria terminalis (BST) is a unique model for the study of sex differences because it has dimorphic and isomorphic subdivisions, with the former showing the two sexually differentiated morphological patterns. Meanwhile, other CNS structures, like the locus coeruleus (LC), present the f > m pattern. The philogenetic maintenance of the two patterns of sexual differentiation can help to disentangle the functional meaning of sex differences. Laboratory rat strains, whether albino or pigmented, descend from the Wistar strain through artificial selection. The present work compares the BST and LC of Wistar and Long-Evans rats. The medial posterior subdivision of the BST (BSTMP) is sexually dimorphic (m > f pattern) in the original (Wistar) and derived (Long-Evans) strains, while the lateral anterior and medial anterior subdivisions of the BST and the LC only present sex differences (f > m pattern) in the ancestor Wistar strain. Isomorphic BST regions are the same in both strains. The fact that the BSTMP, which is implicated in male copulatory behavior, is sexually dimorphic in both strains, as well as in other species, including humans, indicates the relevance of this structure in male sexual behavior in mammals.     

Descending supraspinal effect in tetanus intoxication of the spinal cord

In experiments performed on cats under Nembutal-chloralose anesthesia it was established that in development of local tentanus there occurs a strengthening of facilitatory and weakening of inhibitory descending effects on the side of toxin injection. At stimulation of facilitatory structures of the medulla oblongata (parvocellular and ambigus nuclei) strengthening of extensor and flexor monosynaptic reflexes and appearance of polysynaptic activity were observed. Stimulation of structures which in the normal state evokes inhibition (gigantocellular and raphe nuclei) in local tetanus produced facilitation instead of inhibition of extensor and flexor monosynaptic reflexes and appearance of polysynaptic activity on the side of toxin injection. On the contralateral side at stimulation of the same nuclei usual inhibitory effects are observed. The intracellular recording of motoneurones potentials showed abolishment of IPSP in tetanus at stimulation of different brain stem structures and their replacement with EPSP. The study of temporal course of suprasegmental inhibition of monosynaptic and early polysynaptic reflexes in normal state and on the side of toxin injection has shown that there are two components. The first short-lasting component (20–60 msec) and the second-later with a maximum about 160 msec. In local tetanus the short-lasting inhibition which is apparently of postsynaptic origin was abolished. The late inhibition was maintained, but slightly weakened. Inhibition of late polysynaptic relfexes belonging by their characteristics to spinobulbo-spinal ones were not abolished but even strengthened in local tetanus. The possible mechanism of appearance of excitatory responses instead of inhibitory ones in local tetanus are discussed.     

Re-evaluation of sexual dimorphism in human corpus callosum.

To study the sexual dimorphism of human corpus cauosum (CC), we analyzed the midsaggital magnetic resonance imaging (MRI) morphometry in 67 adults aged (mean+/-s.d.) 36.82+/-9.35 years. Four specific angles of the CC were determined. All four angles in 34 females and 33 age-matched males showed a significant difference between females and males. These morphometric findings confirm a gender difference in the orientation of corpus callosum.     

Voluntary supraspinal suppression of spinal reflex activity in paralyzed muscles of spinal cord injury patients

Having previously demonstrated that residual facilitatory brain influence on segmental structures occurs in paralyzed spinal cord injury patients, we sought evidence of suprasegmental suppression in such patients. By recording EMG activity from leg muscles, we studied changes in segmental excitability of the plantar reflex elicited by cutaneous stimulation of the plantar surface. Using surface EMG recordings, 50 paralyzed spinal cord injury patients were examined for their ability to volitionally suppress the plantar reflex on three repeated trials after three baseline trials. The patients, who had no voluntary EMG activity in the monitored muscles, were able to volitionally suppress the plantar reflex responses by 45% in the tibialis anterior, hamstring, and triceps surae muscles and to suppress the quadriceps response by 72%. In this patient group, 73 of 100 tibialis anterior muscle groups showed suppression of more than 20% compared with the control response. On reexamination, these findings were consistent during a period of 2 years in six patients. We conclude that suprasegmental suppression of segmental activity does occur in paralyzed spinal cord injury patients, and that in clinically complete patients, neurological evaluation should include assessment of the degree of preservation of suprasegmental neurocontrol on segmental activity below the lesion.     

Neurophysiological correlates for the perception of facial sexual dimorphism

Neural correlates for the processing of face identity, expression, gaze direction and attractiveness are well described, but neurophysiological correlates for the perception of face gender are less understood. Here, we used morphing techniques to produce synthetic faces with graded perceivable gender and independent component analysis (ICA) of multifocal EEG to unravel neural signals correlated to processing and perception of face gender. We investigate possible neural correlates of face perception using scalp event-related potentials (ERPs) and dipole source analysis in a group of health observers. We isolated one signal source localised to the right parieto-temporal region with a latency of about 170 ms, whose latency correlates with perceived facial masculinity. In conclusion, our data prove that the right parieto-temporal regions play a fundamental role in face gender masculinity processing and perception in humans.     

Neurobehavioral hemispheric preferences: a case of sexual dimorphism

Ninety subjects (47 females and 43 males) with age ranging from 17 to 25 completed a neurobehavioral inventory of hemispheric preference. The inventory (Wagner & Wells, 1985) consists of 12 items, each of which has 4 statements that relate to four different functions of the two hemispheres namely: (a) Left-logical (b) Left-verbal (c) Right-manipulative/spatial and (d) Right-creative. The results indicated an overall preference for verbal-logical tasks. This preference pattern was more pronounced in males than in the female subjects. Also, the female subjects exhibited greater preference for creative tasks (activities), whereas the males showed preference for verbal tasks. These results suggests that proficiency and preference may not necessarily follow the similar pattern.     

Reversal of hippocampal sexual dimorphism by gonadal steroid manipulation

Hippocampal slices display a sexually dimorphic pattern of physiological neuromodulation to gonadal steroid administration. To determine if this is the result of organizational or activational hormone action, plasma steroid levels of adult male rats were manipulated. The results support an activational mechanism since steroid levels can be manipulated to abolish, reverse, or maintain the functional dimorphism. The results suggest a role for gonadal steroid action in rapid neuromodulation of brain function.     

The acute effects of capsaicin on rat primary afferents and spinal neurons

Capsaicin applied to the soma of fast and slow conducting primary afferent fibers had a depolarizing action associated with an increase in membrane conductance. The depolarizing effect desensitized rapidly and was only partially reversible in slow conducting fibers.Capsaicin application to the entry zone of the appropriate dorsal rootlets led to strong excitation of dorsal horn neurons receiving multimodal input. After acute capsaicin treatment the response to noxious heat was attenuated or totally absent, while other noxious stimuli were still effective. The present data suggest that capsaicin exerts its specific degenerative action by a long-lasting depolarizing action on small-calibre fibers.     

Dissociation of supraspinal and spinal actions of morphine: A quantitative evaluation

Opiate suppression of spinal withdrawal reflexes was tested in rats with lesions of several spinal funiculi to determine the relative contribution of supraspinal descending systems. The latency of tail-flick to noxious heat was used to assess "analgesia". The effect of lesions of dorsolateral funiculus (DLF), dorsal columns (DC) and ventral quadrant (VQ) were compared to that of sham operations. None of the lesions produced a change in baseline latency. Each animal was tested with varying doses of morphine sulfate over several weeks. Only DLF lesions consistently antagonized tail-flick suppression by morphine across the dose range studied (5-15 mg/kg i.p.), although VQ lesions were somewhat effective. The reduction of morphine's action was proportionally greater for lower doses. The results indicate that both spinal and supraspinal sites contribute significantly to the analgesia produced by systemic administration of opiates.     

Hypothalamic resetting at puberty and the sexual dimorphism of migraine

It is well known that migraine is far more represented in females than in males. However, this gender-related difference is present only during reproductive life since in prepubertal children, migraine prevalence figures are independent of sex. Thus, transition to puberty accounts for changes which render females more susceptible to migraine attacks. In females, the main driver of the hormonal events allowing sexual maturation is the pulsatile secretion of hypothalamic LHRH modulated by opioid activity. Clinical reports suggest that migraine attacks could be prevented by the abolition of this neurohormonal secretion. On the other hand, several clinical and experimental observations have focused on neuroendocrine systems (opiatergic, serotonergic, adrenergic) as participating in the constitution of the so-called "migraine trait", the biological predisposition in patients that would explain their sensitivity to migraine triggers. Such neuroendocrine secretions are mainly dependent upon hypothalamic activity where a sexual dimorphic nucleus has been discovered in the preoptic area. We suggest that the sexual dimorphism of migraine should be sought in hypothalamic networks related to LHRH secretion.     

Inhibition of spinal opioid analgesia by supraspinal administration of selective opioid antagonists

The effect of intracerebroventricular administration of a selective mu- (CTOP) or delta- (ICI 174,864) opioid receptor antagonist on the antinociceptive effects produced by intrathecal administration of selective mu- (DAMGO), delta- (DPDPE) and kappa- (U50-488H) opioid receptor agonists was evaluated using the Randall-Selitto paw-withdrawal test, in the rat. While the intracerebroventricular administration of CTOP or ICI 174,864, alone, had no effect on nociceptive thresholds, intracerebroventricular administration of CTOP and ICI 174,864 produced marked antagonism of the antinociceptive effects of intrathecal DAMGO. The antinociceptive effects of intrathecal administration of DPDPE or U50,488H were not antagonized by intracerebroventricular administration of CTOP or ICI 174,864. These data suggest that, in the rat, along with the established descending antinociceptive pathways, there is an ascending antinociceptive control mechanism projecting from the spinal cord to the brainstem. The ascending antinociceptive control involves mu- and delta-opioid agonism at supraspinal sites and appears to be mediated selectively by mu-, but not by delta- or kappa-opioid agonism at the spinal level.     

The induction of heterotypical sexual behavior in the rat

(1) In the laboratory rat, the behavioral responsiveness of the brain to hormones is sexually dimorphic. An important factor in that dimorphism is the exposure of the developing brain, perhaps both pre- and post-natally, to gonadal steroids. (2) Androgen and/or estrogen suppress lordosis behavior in both sexes and appear to potentiate masculine behavior in the female and presumably the male. (3) To the extent that sexual behavior in the human is dependent on gonadal hormone activation, the hormonal milieu during development would be expected to modify adult behavior. (4) The view that the adult brain is in a static state is challenged by lesion studies. After destruction of the lateral septum plus exposure to estrogen or a hypothyroid condition, the adult male regains his inherent potential to exhibit lordosis behavior. (5) Further study of this adult model of behavior organization may contribute to our understanding of behavioral differences.     

Spinal vs supraspinal actions of morphine on cat spinal cord multireceptive neurons

To examine whether morphine elicits a supraspinal mediated spinal inhibition of nociceptive transmission, several investigators have compared the effects of morphine on nociceptive transmission in animals with the spinal cord intact vs transected or cold-blocked. The results have been conflicting, possibly due to different methods of analysis. For example, some investigators have found i.v. administered morphine produces a greater percentage decrease in nociceptive transmission when the spinal cord is intact compared to the transected state. Therefore, they concluded that morphine elicits a supraspinal-mediated inhibition. Conversely, others have reported that the increase in noxious stimulus-evoked responses of dorsal horn neurons upon cold blocking the spinal cord was reduced by i.v. morphine. They therefore concluded that morphine decreases descending inhibition. We tested the effects of i.v. morphine on spinal cord multireceptive neurons in the presence and absence of descending inhibition. Using the above methods of analysis, our results were found to be consistent with their findings which indicate that the method of analysis used is critical to the interpretation reached. To determine how these calculations would be affected by a depressant effect on the spinal cord neurons only, we performed similar experiments iontophoresing gamma-aminobutyric acid (GABA) onto these dorsal horn neurons. The similarity between the morphine and GABA data suggests that the effects of systemically administered morphine on multireceptive dorsal horn neurons can be adequately explained by a spinal cord site of action.