In a prospective study 58 patients undergoing limb amputation were interviewed the day before operation about their pre-amputation limb pain and 8 days, 6 months and 2 years after limb loss about their stump and phantom limb pain. All but one patient had experienced pain in the limb prior to amputation. Pre-amputation limb pain lasted less than 1 month in 25% of patients and more than 1 month in the remaining 75% of patients. At the first examination the day before amputation 29% had no limb pain. The incidence of phantom pain 8 days, 6 months and 2 years after amputation was 72, 65 and 59%, respectively. Within the first half year after limb loss phantom pain was significantly more frequent in patients with long-lasting pre-amputation limb pain and in patients with pain in the limb immediately prior to amputation. Phantom pain and pre-amputation pain were similar in both localization and character in 36% of patients immediately after amputation but in only 10% of patients later in the course. Both the localization and character of phantom pain changed within the first half year; no further change occurred later in the course. The incidence of stump pain 8 days, 6 months and 2 years after limb loss was 57, 22 and 21%, respectively. It is suggested that preoperative limb pain plays a role in phantom pain immediately after amputation, but probably not in late persistent phantom pain.

The incidence and clinical picture of non-painful and painful phantom limb sensations as well as stump pain was studied in 58 patients 8 days and 6 months after limb amputation. The incidence of non-painful phantom limb, phantom pain and stump pain 8 days after surgery was 84, 72 and 57%, respectively. Six months after amputation the corresponding figures were 90, 67 and 22%, respectively. Kinaesthetic sensations (feeling of length, volume or other spatial sensation of the affected limb) were present in 85% of the patients with phantom limb both immediately after surgery and 6 months later. However, 30% noticed a clear shortening of the phantom during the follow-up period; this was usually among patients with no phantom pain. Phantom pain was significantly more frequent in patients with pain in the limb the day before amputation than in those without preoperative limb pain. Of the 67% having some phantom pain at the latest interview 50% reported that pains were decreasing. Four patients (8%), however, reported that phantom pains were worse 6 months after amputation than originally. During the follow-up period the localization of phantom pains shifted from a proximal and distal distribution to a more distal localization. While knifelike, sticking phantom pains were most common immediately after surgery, squeezing or burning types of phantom pain were usually reported later in the course. Possible mechanisms for the present findings either in periphery, spinal cord or in the brain are discussed.

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Functional hyperemia reduces oxygen extraction efficacy unless counteracted by a reduction of capillary transit-time heterogeneity of blood. We adapted a bolus tracking approach to capillary transit-time heterogeneity estimation for two-photon microscopy and then quantified changes in plasma mean transit time and capillary transit-time heterogeneity during forepaw stimulation in anesthetized mice (C57BL/6NTac). In addition, we analyzed transit time coefficient of variance = capillary transit-time heterogeneity/mean transit time, which we expect to remain constant in passive, compliant microvascular networks. Electrical forepaw stimulation reduced, both mean transit time (11.3% ± 1.3%) and capillary transit-time heterogeneity (24.1% ± 3.3%), consistent with earlier literature and model predictions. We observed a coefficient of variance reduction (14.3% ± 3.5%) during functional activation, especially for the arteriolar-to-venular passage. Such coefficient of variance reduction during functional activation suggests homogenization of capillary flows beyond that expected as a passive response to increased blood flow by other stimuli. This finding is consistent with an active neurocapillary coupling mechanism, for example via pericyte dilation. Mean transit time and capillary transit-time heterogeneity reductions were consistent with the relative change inferred from capillary hemodynamics (cell velocity and flux). Our findings support the important role of capillary transit-time heterogeneity in flow-metabolism coupling during functional activation.

Brain imaging in Klinefelter syndrome (47, XXY) (KS), a genetic disorder characterized by the presence of an extra X chromosome, may contribute to understanding the relationship between gene expression, brain structure, and subsequent cognitive disabilities and psychiatric disorders.We conducted the largest to date voxel-based morphometry study of 65 KS subjects and 65 controls matched for age and education and correlated these data to neuropsychological test scores. The KS patients had significantly smaller total brain volume (TBV), total gray matter volume (GMV) and total white matter volume (WMV) compared to controls, whereas no volumetric difference in cerebral spinal fluid (CSF) was found. There were no differences in TBV, GMV, WMV or CSF between testosterone treated KS (T-KS) and untreated KS (U-KS) patients. Compared to controls, KS patients had significantly decreased GMV bilaterally in insula, putamen, caudate, hippocampus, amygdala, temporal pole and frontal inferior orbita. Additionally, the right parahippocampal region and cerebellar volumes were reduced in KS patients. KS patients had significantly larger volumes in right postcentral gyrus, precuneus and parietal regions. Multivariate classification analysis discriminated KS patients from controls with 96.9% (p < 0.001) accuracy. Regression analyses, however, revealed no significant association between GMV differences and cognitive and psychological factors within the KS patients and controls or the groups combined. These results show that although gene dosage effect of having and extra X-chromosome may lead to large scale alterations of brain morphometry and extended cognitive disabilities no simple correspondence links these measures.

We found evidence that MDMA but not hallucinogen use is associated with changes in the cerebral presynaptic serotonergic transmitter system. Because hallucinogenic drugs primarily have serotonin(2A) receptor agonistic actions, we conclude that the negative association between MDMA use and cerebral SERT binding is mediated through a direct presynaptic MDMA effect rather than by the serotonin(2A) agonistic effects of MDMA. Our cross-sectional data suggest that subcortical, but not cortical, recovery of SERT binding might take place after several months of MDMA abstinence.

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The interpretation of regional blood flow and blood oxygenation changes during functional activation has evolved from the concept of 'neurovascular coupling', and hence the regulation of arteriolar tone to meet metabolic demands. The efficacy of oxygen extraction was recently shown to depend on the heterogeneity of capillary flow patterns downstream. Existing compartment models of the relation between tissue metabolism, blood flow, and blood oxygenation, however, typically assume homogenous microvascular flow patterns. To take capillary flow heterogeneity into account, we modeled the effect of capillary transit time heterogeneity (CTH) on the 'oxygen conductance' used in compartment models. We show that the incorporation of realistic reductions in CTH during functional hyperemia improves model fits to dynamic blood flow and oxygenation changes acquired during functional activation in a literature animal study. Our results support earlier observations that oxygen diffusion properties seemingly change during various physiologic stimuli, and posit that this phenomenon is related to parallel changes in capillary flow patterns. Furthermore, our results suggest that CTH must be taken into account when inferring brain metabolism from changes in blood flow-or blood oxygenation-based signals. Keywords: blood oxygen level-dependent contrast; capillaries; capillary transit time heterogeneity; hemodynamics; neurovascular coupling INTRODUCTION Brain function depends critically on a steady supply of oxygen. During rest, the central nervous system receives 420% of the cardiac output, and consciousness is lost within seconds after circulatory arrest. Although functional activation is typically associated with a modest 10% to 30% increase in local cerebral metabolic rate of oxygen (CMRO 2 ), regional cerebral blood flow (CBF) typically increases by 20% to 80%, with δCBF/δCMRO 2 coupling ratios consistently larger than unity. 1,2 This functional hyperemia permits the localization of brain activity by imaging techniques such as positron emission tomography and functional magnetic resonance imaging. Today, arterial spin labeling functional magnetic resonance imaging and blood oxygen leveldependent (BOLD) functional magnetic resonance imaging are the preferred tools in human brain mapping. 3,4 The interpretation of regional blood flow and blood oxygenation changes during functional activation has evolved from the concept of 'neurovascular coupling': mechanisms that converge on cerebral arterioles to adjust CBF according to changing metabolic needs. The subsequent distribution of blood across the capillary bed, and the oxygen diffusion from the microcirculation to active cells, is extremely complex, and so far biophysical models have been unable to establish with certainty whether the increase in oxygen supply during functional hyperemia is matched to the increased metabolic demands. 5 Buxton and Frank 6 derived the so-called 'oxygen limitation model', which relates CBF and CMRO 2 through the flow diffusion