N-acetylaspartate is an axon-specific marker of mature white matter in vivo: a biochemical and immunohistochemical study on the rat optic nerve.

Axonal pathology is a major cause of neurological disability in multiple sclerosis. Axonal transection begins at disease onset but remains clinically silent because of compensatory brain mechanisms. Noninvasive surrogate markers for axonal injury are therefore essential to monitor cumulative disease burden in vivo. The neuronal compound N-acetylaspartate, as measured by magnetic resonance spectroscopy, is currently the best and most specific noninvasive marker of axonal pathology in multiple sclerosis. The possibility has been raised, however, that N-acetylaspartate is expressed also by oligodendroglial lineage cells. In order to investigate N-acetylaspartate specificity for white matter axons, transected rat optic nerves were analyzed by high-performance liquid chromatography and immunohistochemistry. In transected adult nerves, N-acetylaspartate and N-acetyl aspartylglutamate decreased in concordance with axonal degeneration and were undetectable 24 days posttransection. Nonproliferating oligodendrocyte progenitor cells, oligodendrocytes, and myelin were abundant in these axon-free nerves. At 24 days posttransection, N-acetylaspartate was increased (42%; p = 0.02) in nontransected contralateral nerves. After transection at postnatal day 4, total N-acetylaspartate decreased by 80% (P14; p = 0.002) and 94% (P20; p = 0.003). In these developing axon-free nerves, 25 to 33% of oligodendrocyte progenitor cells were proliferating. These data validate magnetic resonance spectroscopy measurements of N-acetylaspartate as an axon-specific monitor of central nervous system white matter in vivo. In addition, the results indicate that neuronal adaptation can increase N-acetylaspartate levels, and that 5 to 20% of the N-acetylaspartate in developing white matter is synthesized by proliferating oligodendrocyte progenitor cells.     

Body pain and treatment response in late-life depression.

OBJECTIVE: The authors investigated the influence of body pain on 1) time to treatment response and 2) suicidal ideation, in late-life depression. They hypothesized that higher levels of body pain would predict a longer time to and lower likelihood of response, and increased levels of suicidal ideation. METHODS: Subjects (N=187) were older adult outpatients (age > or =69 years), with current episodes of major depression, who were openly treated with paroxetine up to 40 mg daily and weekly interpersonal psychotherapy. Response was defined as 3 consecutive weeks of Hamilton Rating Scale for Depression at < or =10. Body pain was measured with the Bodily Pain Index of the SF-36 quality-of-life assessment. Authors used survival-analysis models on the responder sample to test the effect of body pain on response, after controlling for severity of depression. RESULTS: Overall response rate was 75.4%. Nonresponders reported more severe pain at baseline. After covarying for severity of baseline depression, no effect was found for physical pain on time-to-response or degree of suicidality. Bodily pain remained stable during acute treatment for responders, independent of depression response to combination psychotherapy and antidepressant treatment. CONCLUSIONS: Older adult patients with higher levels of physical pain can still respond to antidepressant treatment; however, reported bodily pain may be associated with a more difficult-to-treat depression.     

Alpha-contingent EEG feedback reduces SPECT rCBF variability.

EEG feedback methods, which link the occurrence of alpha to the presentation of repeated visual stimuli, reduce the relative variability of subsequent, alpha-blocking event durations. The temporal association between electro-cortical field activation and regional cerebral blood flow (rCBF) led us to investigate whether the reduced variability of alpha-blocking durations with feedback is associated with a reduction in rCBF variability. Reduced variability in the rCBF response domain under EEG feedback control might have methodological implications for future brain-imaging studies. Visual stimuli were randomly presented to seven subjects, contingent upon the occurrence of alpha (alpha-contingent stimulation (ACS)) or alpha-blocking (not-alpha-blocking-contingent stimulation (NACS)) events. We employed a within-subjects design. rCBF was measured from multiple, cortical and sub-cortical regions. The primary dependent variables were the Mean, Standard Deviation and the ratio of Mean/Standard Deviation of: 1) the alpha-blocking response durations and 2) the temporally summated rCBF responses within the Visual Associative regions of interest (ROIs). Additional within-subjects rCBF measures were derived to quantify the variance-reducing effects of ACS across multiple, distributed areas of the brain. Both EEG and rCBF measures demonstrated decreased variability under ACS. This improved control was seen for localized as well as anatomically distributed rCBF measures.     

Developing a Peer Review Process for Web-based Curricula

The World Wide Web creates new challenges and opportunities for medical educators. Prominent among these are the lack of consistent standards by which to evaluate web-based educational tools. We present the instrument that was used to review web-based innovations in medical education submissions to the 2003 Society of General Internal Medicine (SGIM) national meeting, and discuss the process used by the SGIM web-based clinical curriculum interest group to develop the instrument. The 5 highest-ranked submissions are summarized with commentary from the reviewers.     

A sexually dimorphic ratio of orbitofrontal to amygdala volume is altered in schizophrenia.

BACKGROUND: Neuroanatomic sexual dimorphisms have been correlated with behavioral differences between healthy men and women. We have reported higher orbitofrontal cortex to amygdala ratio (OAR) in women than men. Although gender differences in schizophrenia are evident clinically and correlate with neuroanatomic measures, their relationship to OAR has not been examined. METHODS: Magnetic resonance imaging was performed in 31 neuroleptic-na?ve schizophrenic patients (16 men) and 80 healthy volunteers (34 men), aged less than 50 years. An automated tissue segmentation procedure was combined with expert-guided parcellation of orbitofrontal and amygdala volumes. RESULTS: Men with schizophrenia had increased OAR relative to healthy men, whereas women had decreased OAR. Increased OAR in men with schizophrenia reflected abnormally low amygdala volumes, whereas decreased OAR in women reflected abnormally low orbitofrontal volumes. Less severe negative symptoms were associated with increased OAR in men but with decreased OAR in women. In men, increased amygdala volume was associated with greater symptom severity, whereas in women higher volumes of both amygdala and orbitofrontal regions were associated with lesser severity of negative symptoms. CONCLUSIONS: These opposite OAR abnormalities, whereby men show feminization and women masculinization, suggest gender-mediated effects of the underlying neuropathologic processes. The correlations with symptom severity suggest that neuroanatomic abnormalities in OAR reflect compensatory brain changes.     

Development of nitric oxide synthase-defined neurons in the sea urchin larval ciliary band and evidence for a chemosensory function during metamorphosis.

We previously reported that initiation of metamorphosis of larvae of Lytechinus pictus is negatively regulated by nitric oxide (NO) and cGMP. We have examined the expression of nitric oxide synthase (NOS) and cGMP in cells of the developing larva. A section of the post-oral ciliary band of feeding larvae includes neural cells defined by their expression of both NOS and the echinoderm neural-specific antibody 1E11. These neurons project processes to the pre-oral neuropile during larval development. Larvae regenerated this section of the ciliary band after its excision, complete with NOS-defined neurons that projected again to the pre-oral neuropile. Excision of ectoderm containing the post-oral ciliary band prevented a behavioral and morphogenetic response of competent larvae to biofilm, and delayed initiation of metamorphosis. Elevated cGMP levels were detected in several larval and juvenile cell types prior to metamorphosis. Treatment of larvae with ODQ, an inhibitor of soluble guanylate cyclase, decreased cGMP levels and induced metamorphosis while a generator of NO counteracted this effect, indicating inhibition of metamorphosis by NO operates via interaction with soluble guanylate cyclase. We discuss these observations, proposing that the NOS-defined neurons in the post-oral ciliary band have a chemosensory function during settlement and metamorphosis that involves morphologically specialized ectoderm and manipulation of fluid flow. We provide a tentative cellular model of how environmental signals may be transduced into a metamorphic response.