"Cinderella was attacked by the big bad wolf, but the police saved her": intrusions and confabulations on story recall in Korsakoff's syndrome and alcohol-related cognitive impairments.

BACKGROUND: The relation between confabulations and intrusions in patients with Korsakoff's syndrome (KS) and patients with alcohol-related cognitive impairments (ARCI) remains under debate. This study examines (1) differences in the production of confabulations and intrusions between patients with KS and ARCI, (2) whether an altered fairy tale induces more intrusions, and (3) whether different types of intrusions were significantly related to confabulations. METHODS: Twenty-three patients with KS and twenty-two patients with ARCI recalled three different types of stories: a novel story, a fairy tale, and a modified fairy tale. Different types of intrusions were correlated with confabulation measures. RESULTS: Patients with KS produced more intrusions in the modified fairy tale condition than patients with ARCI, but these were unrelated to confabulations. Only unrelated intrusions were related to provoked confabulations. CONCLUSIONS: The results of this study indicate that researchers and clinicians must be aware that in general, intrusions on memory tests should not be interpreted as confabulations. Especially spontaneous confabulations appear to be something completely different from intrusions on any type of story recall. When measuring confabulations it is crucial to use validated instruments.

Personal semantic and episodic autobiographical memories in Korsakoff syndrome: A comparison of interview methods.

OBJECTIVE: The temporal gradient in patients with Korsakoff's syndrome has been of particular interest in the literature, as many studies have found evidence for a steep temporal gradient, but others have observed more uniform remote memory impairment across all past time periods. Inconsistencies might be the result of the nature of remote memory impairment under study (i.e., nonpersonal or autobiographical memory) and of methodological differences in the examination of remote memory loss. The aim of this study was to examine whether differences between autobiographical memory interview (AMI) and autobiographical interview (AI) procedures influence the presence of a temporal gradient in semantic and episodic autobiographical memory in Korsakoff patients. METHOD: The procedure used in the present study combined the AMI and AI into one study session. We compared the performance of 20 patients with Korsakoff's syndrome and 27 healthy controls. First, participants were asked to recall knowledge from different life periods. Second, participants were asked to recall memories from five life periods. Thirdly, participants were asked to rate their subjective experience of each event recalled on a 5-point scale. Finally, we analyzed the findings in terms of all the memories recalled versus the first memory from each life-period only. RESULTS: Both the AMI and the AI showed a temporally graded retrograde amnesia in the Korsakoff patients for personal semantic and episodic autobiographical memories. The pattern of amnesia in Korsakoff patients was not affected by examining only one event per life-period. Subjective ratings of recalled memories were largely comparable between the groups. CONCLUSIONS: The findings were generally consistent across the AMI and AI. Varying the number of events did not affect the pattern of the gradient. Hence, the temporal gradient in Korsakoff patients is not an artefact of either the AMI or the AI method.

Intrusions and provoked and spontaneous confabulations on memory tests in Korsakoff's syndrome.

INTRODUCTION: Intrusions on verbal memory tests have been used as an index for clinical confabulation. Severe memory impairments in combination with executive dysfunction have been suggested to be the underlying mechanism of confabulation, but to date, this relation is unclear. The aim of this study was (a) to examine the relation between (different types of) intrusions and confabulations in a large sample of confabulating patients with Korsakoff's syndrome (KS) and (b) to investigate whether different measures of executive functioning and memory performance are related to provoked and spontaneous confabulation. METHOD: The Dutch version of the California Verbal Learning Test (CVLT) and various executive function and memory tests were administered to a group of 51 confabulating patients with KS. Professional caregivers rated the severity of provoked and spontaneous confabulation behavior of the patients using the Nijmegen-Venray Confabulation List-20 (NVCL-20). RESULTS: The total number of intrusions on the CVLT was not related to either provoked or spontaneous confabulation scores. None of the CVLT intrusion scores correlated significantly with any of the confabulation scores, but we did find small-to-medium, positive correlations between unrelated intrusions and both provoked confabulations and spontaneous confabulation. Provoked confabulation behavior was associated with executive dysfunction and poorer memory performances. Spontaneous confabulation was not related to performance on measures of executive function and memory. CONCLUSIONS: The total number of intrusions on verbal memory tests and clinical confabulations appear to be different phenomena. Only unrelated intrusions produced on the CVLT might possibly be related to confabulations. The production of provoked, but not spontaneous, confabulation is associated with executive dysfunction and memory deficits.

Simple and complex rule induction performance in young and older adults: contribution of episodic memory and working memory.

This study tested the hypothesis that part of the age-related decline in performance on executive function tasks is due to a decline in episodic memory. For this, we developed a rule induction task in which we manipulated the involvement of episodic memory and executive control processes; age effects and neuropsychological predictors of task performance were investigated. Twenty-six younger (mean age, 24.0; range, 19-35 years) and 27 community-dwelling older adults (mean age, 67.5; range, 50-91 years) participated. The neuropsychological predictors consisted of the performance on tests of episodic memory, working memory, switching, inhibition and flexibility. Performance of the older adults was worse for the learning and memorization of simple rules, as well as for the more demanding executive control condition requiring the manipulation of informational content. Episodic memory was the only predictor of performance on the simple learning and memorization task condition whereas an increase in rule induction complexity additionally engaged working memory processes. Together, these findings indicate that part of the age-related decline on rule induction tests may be the result of a decline in episodic memory. Further studies are needed that examine the role of episodic memory in other executive function tasks in aging.

On the relationship between autistic traits and executive functioning in a non-clinical Dutch student population.

We examined the association between autistic traits and different aspects of executive functioning (EF), using non-clinical Social Science and Science students as participants. Autistic traits, and associated personality traits, were measured using the Autism Quotient (AQ) and the Temperament and Character Inventory (TCI), respectively. EF was examined by means of a random number generation test and a phonemic fluency test. Using appropriate dependent measures, the following EF components were examined: 1) inhibition of prepotent responding, 2) simple output inhibition, 3) working memory monitoring and updating, and 4) switching. No significant relationship was found between the AQ and each of the four components of EF. However, two TCI subscales were reliably correlated with either the working memory or the shifting component. These results were discussed in view of the concept of an autism spectrum with respect to executive abilities.

An investigation of different aspects of overgeneralization in patients with major depressive disorder and borderline personality disorder.

OBJECTIVE: The aim of this study was to investigate whether (a) overgeneralization is restricted to negative attributions directed at the self; or whether it also extends to positive self-attributions and to attributions of situations in the outside world, and (b) whether the valence and direction (positively or negatively, to the self- or across situations) of overgeneralization processes vary among different patient populations. METHODS: Patients with major depressive disorder (MDD, n = 34), borderline personality disorder (BPD, n = 18), or both (n = 35), and never-depressed non-patients (NPs; n = 50) completed various measures of overgeneralization. RESULTS: Patients with MDD show higher levels of negative overgeneralization but lower levels of positive overgeneralization to the self- and across situations than NPs. Patients with MDD show more negative than positive overgeneralization to the self: a negative bias. They, however, do show higher levels of positive than negative overgeneralization across situations. Patients with BPD show the same pattern for overgeneralization to the self, but their higher levels of negative overgeneralization across situations are not exceeded by their positive counterpart. CONCLUSIONS: Results indicate that patient groups differ from NPs not only with respect to negative, but also with respect to positive overgeneralization. Furthermore, the valence and direction of overgeneralization processes vary among MDD and BPD patient populations. More specifically, findings suggest that, as compared to never-depressed individuals, patients with BPD and patients with MDD alike, lack a buffer against negative overgeneralization directed at the self. In patients with BPD, not only the high level of overgeneralization to the self, but also the high level of overgeneralization across situations seems to be problematic, since both types of overgeneralization appear not to be buffered by their positive counterparts.

Chronic activation of corticotropin-releasing factor type 2 receptors reveals a key role for 5-HT1A receptor responsiveness in mediating behavioral and serotonergic responses to stressful challenge.

BACKGROUND: The corticotropin-releasing factor type 2 receptor (CRFR2) is suggested to play an important role in aiding recovery from acute stress, but any chronic effects of CRFR2 activation are unknown. CRFR2 in the midbrain raphé nuclei modulate serotonergic activity of this key source of serotonin (5-HT) forebrain innervation. METHODS: Transgenic mice overexpressing the highly specific CRFR2 ligand urocortin 3 (UCN3OE) were analyzed for stress-related behaviors and hypothalamic-pituitary-adrenal axis responses. Responses to 5-HT receptor agonist challenge were assessed by local cerebral glucose utilization, while 5-HT and 5-hydroxyindoleacetic acid content were quantified in limbic brain regions. RESULTS: Mice overexpressing urocortin 3 exhibited increased stress-related behaviors under basal conditions and impaired retention of spatial memory compared with control mice. Following acute stress, unlike control mice, they exhibited no further increase in these stress-related behaviors and showed an attenuated adrenocorticotropic hormone response. 5-HT and 5-hydroxyindoleacetic acid content of limbic nuclei were differentially regulated by stress in UCN3OE mice as compared with control mice. Responses to 5-HT type 1A receptor challenge were significantly and specifically reduced in UCN3OE mice. The distribution pattern of local cerebral glucose utilization and 5-HT type 1A receptor messenger RNA expression levels suggested this effect was mediated in the raphé nuclei. CONCLUSIONS: Chronic activation of CRFR2 promotes an anxiety-like state, yet with attenuated behavioral and hypothalamic-pituitary-adrenal axis responses to stress. This is reminiscent of stress-related atypical psychiatric syndromes such as posttraumatic stress disorder, chronic fatigue, and chronic pain states. This new understanding indicates CRFR2 antagonism as a potential novel therapeutic target for such disorders.

Assessing executive functioning: on the validity, reliability, and sensitivity of a click/point random number generation task in healthy adults and patients with cognitive decline.

In random number generation (RNG) tasks, used to assess executive functioning, participants are asked to generate a random sequence of digits at a paced rate, either verbally or by writing. Some previous studies used an alternative format in which participants had to randomly press different response keys, assuming that this task version demands the same cognitive processes as those implied in the standard version. The present study examined the validity of this assumption. To this end, the construct validity, reliability, and sensitivity of a conceptually similar task version of the key-press task were examined. Participants had to randomly click on, or point to, the digits 1-9, laid out orderly in a 3 × 3 grid on a computer screen. Psychometric properties of this task were examined, based on the performance of 131 healthy participants and 80 patients with cognitive decline. The results suggest that the click/point RNG task version can be used as a reliable and valid substitute for standard task versions that use the same response set and response pacing rate as those used in the present study. This task might be a useful alternative, demanding no separate recording and recoding of responses, and being suitable for use with patients with speech or writing problems.

Rose or black-coloured glasses? Altered neural processing of positive events during memory formation is a trait marker of depression.

BACKGROUND: Valence-specific memory enhancement is one of the core cognitive functions that causes and maintains Major Depressive Disorder (MDD). While previous neuroimaging studies have elucidated the neural underpinnings of this emotional enhancement effect in depressed patients, this study aimed at detecting processing biases that are maintained throughout remission while patients were euthymic. METHODS: Fourteen medication-free women remitted from unipolar MDD and 14 matched controls were scanned while learning negative, positive, and neutral words, which were subsequently tested with free recall. RESULTS: The two groups did not differ in memory performance and showed no neural differences during successful encoding of neutral or negative words. However, during successful encoding of positive words, patients exhibited a larger recruitment of a set of areas, comprising cingulate gyrus, right inferior- and left medial-frontal gyrus as well as the right anterior hippocampus/amygdala. LIMITATIONS: Restriction to female participants may limit the generalization of the findings. CONCLUSION: Female MDD patients in clinical remission exert greater neural recruitment of memory-related brain regions when successfully encoding positive words, suggesting that neural biases related to memory formation of positive information do not entirely normalize. Further research is needed to establish whether this processing bias during successful memory formation of positive information is predictive for future relapse thereby offering the possibility to develop more focused therapeutic interventions to specifically target these processes.

Attentional set shifting in autism spectrum disorder: differentiating between the role of perseveration, learned irrelevance, and novelty processing.

Autism spectrum disorders (ASD) are associated with impaired attentional set shifting, which may reflect enhanced perseverative responding, enhanced learned irrelevance, and/or reduced novelty processing. We assessed the contribution of these potential error sources in ASD adults. A total of 17 ASD and 19 matched comparison individuals first solved a discrimination learning task. Thereafter, the participants faced three types of attentional shift, specifically designed to isolate the effect of the three possible error sources. ASD participants made more errors than comparison individuals in a shift implying a choice between a novel relevant stimulus attribute and a familiar attribute that was previously relevant but now irrelevant. However, they made fewer errors in a shift involving a choice between a novel irrelevant attribute and a familiar, previously irrelevant but now relevant attribute. The results in combination suggest that the performance difference, at least in the present shift task, is caused by reduced novelty processing in ASD participants.

Working memory in schizophrenia: a systematic study of specific modalities and processes.

Although many researchers agree that working memory (WM) impairments are a core symptom of schizophrenia, it remains unclear how the disturbances on specific WM components relate to one another. In this study, we presented a Delayed-Matching-To-Sample task to 24 schizophrenia patients and 24 healthy controls, matched on demographical variables. Verbal and visuospatial WM performance was investigated with pseudowords and Chinese characters as stimuli, respectively. Processing demands (maintenance and manipulation, measured with delay and mental rotation) were low or high. Reaction time and accuracy were recorded. All experimental factors had significant effects. In general, patients were slower and less accurate than controls. Patients were especially slower on verbal tasks but they were not less accurate. Accuracy differences did not increase when either maintenance or manipulation demands increased alone but they did when both maintenance and manipulation demands increased simultaneously. These findings indicate that performance impairment in patients was non-specific and that no specific deficit of any WM component was observed.

Cerebral metabolic responses to 5-HT2A/C receptor activation in mice with genetically modified serotonin transporter (SERT) expression.

Variation in the human serotonin transporter gene (hSERT; 5-HTT) resulting in a life-long alteration in SERT function influences anxiety and the risk of developing affective disorders. The mechanisms underlying the influence of the hSERT gene on these phenotypes remain unclear but may involve altered 5-HT receptor function. Here we characterise the cerebral metabolic response to 5-HT(2A/C) receptor activation in two transgenic mouse models of altered SERT function, SERT knock-out (SERT KO) and hSERT over-expressing (hSERT OE) mice, to test the hypothesis that genetically mediated variability in SERT expression alters 5-HT(2A/C) function. We found that a constitutive increase in SERT expression (hSERT OE) enhanced, whereas a constitutive decrease in SERT expression (SERT KO) attenuated, 5-HT(2A/C) function. Therefore, altered 5-HT(2A/C) receptor functioning in response to hSERT gene variation may contribute to its influence on affective phenotypes.

Elevated BDNF protein level in cortex but not in hippocampus of MDMA-treated Dark Agouti rats: a potential link to the long-term recovery of serotonergic axons.

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a widely used recreational drug known to cause selective long-term serotonergic damage. In this study, we examined the pattern of BDNF protein expression 1 day, 3, 8, 12 and 24 weeks after a single 15mg/kg i.p. dose of MDMA to adolescent Dark Agouti rats. In parallel, we measured either tryptophan-hydroxylase immunoreactive (TpH IR) axon density, or [(3)H]-paroxetine-binding in parietal cortex and hippocampus, two brain areas known to have different recovery capacity after MDMA, to test whether BDNF-levels were associated with the long-term recovery of serotonergic fibers after a neurotoxic dose of MDMA. Both TpH IR axon density and [(3)H]-paroxetine-binding were significantly decreased 3 weeks after the treatment in both brain areas but while normalization in both parameters was found in parietal cortex 24 weeks after treatment, significant decreases remained evident in the hippocampus. In the parietal cortex, a significant reduction in BDNF protein levels was found in the acute phase after treatment (1 day), which was followed by a robust increase 8 weeks later and a return to control levels by 12 weeks. In contrast, no significant alteration of BDNF protein level was found in the hippocampus at any time points. This absence of any significant increase in BDNF protein levels in the hippocampus, and the persistence in this region of decreases in TpH IR axon density and [(3)H]-paroxetine-binding, raises the possibility that BDNF has an important role in the long-term recovery of serotonergic axons after MDMA treatment.

Apoptosis inducing activity of steroidal constituents from Solanum xanthocarpum and Asparagus racemosus.

A series of Sarsapogenin and Diosgenin derived steroidal constituents (1-12), isolated from Solanum xanthocarpum and Asparagus racemosus were screened for their ability to induce cell death and apoptosis of colon carcinoma cells. The carbohydrate moieties linked to the steroid backbones were found to strongly influence cytotoxic activity and cell death mode (apoptosis or necrosis). Compound 10, from A. racemosus was found to be a potent inducer of apoptosis.

Acute tryptophan depletion in C57BL/6 mice does not induce central serotonin reduction or affective behavioural changes.

Acute tryptophan depletion is extensively used to investigate the implication of serotonin in the onset of depressive disorders. In rats, it lowers peripheral tryptophan and decreases central serotonin concentrations. We aimed to establish the rat model of acute tryptophan depletion in the mouse for potential application as serotonin challenge tool in genetic mouse models of depression. Pharmacokinetic and behavioural effects of a tryptophan-free diet were examined in Swiss and C57BL/6 mice. Peripheral amino acids were measured and central tryptophan and serotonin concentrations were compared with anxiety and depression-like behaviour in the elevated zero-maze, forced swimming test or tail suspension test. While acute tryptophan depletion resulted in a 74% reduction of the plasma ratio tryptophan to the sum of other large neutral amino acids in Swiss mice 1h after administration (2x10 ml/kg, 30 min interval), there was only a 40% reduction in C57BL/6 mice. The latter did not show anxiety in the elevated zero-maze or increased immobility in the forced swimming test or tail suspension test. A higher dose (2x20 ml/kg) with a longer interval (60 min) reduced the ratio with 68% in C57BL/6 mice, lowered hippocampal serotonin turnover and had no functional effect when tested in the elevated zero-maze and forced swimming test. These findings have important implications for the use of acute tryptophan depletion in general and in particular for its application in mice. Although in healthy mice no clear central serotonin or functional effects were observed, further research is indicated using mice with pre-existing serotonin dysfunction, as they might be more vulnerable to acute tryptophan depletion.

Acute tryptophan depletion potentiates 3,4-methylenedioxymethamphetamine-induced cerebrovascular hyperperfusion in adult male Wistar rats.

The serotonergic (5-hydroxytryptamine; 5-HT) dysfunction found in depression may affect not only brain function (mood) but also cerebrovascular control. Similar, but possibly occult, disturbances may also be induced by 3,4-methylenedioxymethamphetamine-induced neurotoxicity (MDMA, or "ecstasy"). Acute tryptophan depletion (ATD) is widely used to identify vulnerability to depression, and we hypothesized that repeated MDMA administration would increase the sensitivity of rats to this acute serotonergic challenge. In this study, male Wistar rats were injected with MDMA (20 mg kg(-1), twice daily for 4 days) and challenged 3 weeks later with ATD, induced by intragastric administration of a nutritional mixture with tryptophan (TRP) removed. Cerebral metabolism (CMRG) and blood flow (CBF) were measured in parallel groups of animals following ATD by using quantitative [(14)C]2-deoxyglucose and [(14)C]iodoantipyrine autoradiographic techniques, respectively. A significant reduction in paroxetine binding to 5-HT transporter sites in MDMA-treated rats indicated 5HT terminal depletion, whereas the plasma TRP/sum large neutral amino acids ratio was reduced by 40% following ATD. Under all experimental conditions, the normal close correlation between CBF and metabolic demand was maintained. However, a global analysis of all brain regions revealed a significant decrease in the overall ratio of CBF to CMRG after ATD in control animals, whereas a higher ratio was observed after ATD in the MDMA-treated group. This increase in blood flow relative to cerebral metabolism suggests an ATD-induced loss of cerebrovascular tone in MDMA-treated animals that could have pathophysiological consequences and might conceivably contribute to the behavioral dysfunction of depression.

Acute SSRI-induced anxiogenic and brain metabolic effects are attenuated 6 months after initial MDMA-induced depletion.

To assess the functional state of the serotonergic system, the acute behavioural and brain metabolic effect of SSRI antidepressants were studied during the recovery period after MDMA-induced neuronal damage. The effects of the SSRI fluoxetine and the serotonin receptor agonist meta-chloro-phenylpiperazine (m-CPP) were investigated in the social interaction test in Dark Agouti rats, 6 months after treatment with a single dose of MDMA (15 or 30 mg kg(-1), i.p.). At earlier time points these doses of MDMA have been shown to cause 30-60% loss in axonal densities in several brain regions. Densities of the serotonergic axons were assessed using serotonin-transporter and tryptophan-hydroxylase immunohistochemistry. In a parallel group of animals, brain function was examined following an acute challenge with either fluoxetine or citalopram, using 2-deoxyglucose autoradiographic imaging. Six months after MDMA treatment the densities of serotonergic axons were decreased in only a few brain areas including hippocampus and thalamus. Basal anxiety was unaltered in MDMA-treated animals. However, the acute anxiogenic effects of fluoxetine, but not m-CPP, were attenuated in animals pretreated with MDMA. The metabolic response to both citalopram and fluoxetine was normal in most of the brain areas examined with the exception of ventromedial thalamus and hippocampal sub-fields where the response was attenuated. These data provide evidence that 6 months after MDMA-induced damage serotonergic axons show recovery in most brain areas, but serotonergic functions to challenges with SSRIs including anxiety and aggression remain altered.

Sex influences the effect of a lifelong increase in serotonin transporter function on cerebral metabolism.

Polymorphic variation in the human serotonin transporter (SERT; 5-HTT) gene resulting in a lifelong increase in SERT expression is associated with reduced anxiety and a reduced risk of affective disorder. Evidence also suggests that sex influences the effect of this polymorphism on affective functioning. Here we use novel transgenic mice overexpressing human SERT (hSERT OVR) to investigate the possible influence of sex on the alterations in SERT protein expression and cerebral function that occur in response to increased SERT gene transcription. SERT binding levels were significantly increased in the brain of hSERT OVR mice in a region-dependent manner. The increased SERT binding in hSERT OVR mice was more pronounced in female than in male mice. Cerebral metabolism, as reflected by a quantitative index of local cerebral glucose utilization (iLCMRglu), was significantly decreased in many brain regions in hSERT OVR female as compared with wild-type female mice, whereas there was no evidence for a significant effect in any region in males. The ability of hSERT overexpression to modify cerebral metabolism was significantly greater in females than in males. This effect was particularly pronounced in the medial striatum, globus pallidus, somatosensory cortex, mamillary body, and ventrolateral thalamus. Overall, these findings demonstrate that the influence of a lifelong increase in SERT gene transcription on cerebral function is greater in females than in males and may relate, in part, to the influence of sex on genetically driven increases in SERT protein expression.

Novel analysis for improved validity in semi-quantitative 2-deoxyglucose autoradiographic imaging.

The original [(14)C]-2-deoxyglucose autoradiographic imaging technique allows for the quantitative determination of local cerebral glucose utilisation (LCMRglu) [Sokoloff L, Reivich, M, Kennedy C, Desrosiers M, Patlak C, Pettigrew K, et al. The 2-deoxyglucose-C-14 method for measurement of local cerebral glucose utilisation-theory, procedure and normal values in conscious and anestherized albino rats. J Neurochem 1977;28:897-916]. The range of applications to which the quantitative method can be readily applied is limited, however, by the requirement for the intermittent measurement of arterial radiotracer and glucose concentrations throughout the experiment, via intravascular cannulation. Some studies have applied a modified, semi-quantitative approach to estimate LCMRglu while circumventing the requirement for intravascular cannulation [Kelly S, Bieneman A, Uney J, McCulloch J. Cerebral glucose utilization in transgenic mice over-expressing heat shock protein 70 is altered by dizocilpine. Eur J Neurosci 2002;15(6):945-52; Jordan GR, McCulloch J, Shahid M, Hill DR, Henry B, Horsburgh K. Regionally selective and dose-dependent effects of the ampakines Org 26576 and Org 24448 on local cerebral glucose utilisation in the mouse as assessed by C-14-2-deoxyglucose autoradiography. Neuropharmacology 2005;49(2):254-64]. In this method only a terminal blood sample is collected for the determination of plasma [(14)C] and [glucose] and the rate of LCMRglu in each brain region of interest (RoI) is estimated by comparing the [(14)C] concentration in each region relative to a selected control region, which is proposed to demonstrate metabolic stability between the experimental groups. Here we show that the semi-quantitative method has reduced validity in the measurement of LCMRglu as compared to the quantitative method and that the validity of this technique is further compromised by the inability of the methods applied within the analysis to appropriately determine metabolic stability in the selected standard region. To address these issues we have developed a novel form of analysis that provides an index of LCMRglu (iLCMRglu) for application when using the semi-quantitative approach. Provided that the methodological constraints inherent in 2-deoxyglucose autoradiography (e.g. normoglycaemia) are met this analytical technique both increases the validity of LCMRglu estimation by the semi-quantitative method and also allows for its broader experimental application.

The debt of nations and the distribution of ecological impacts from human activities.

As human impacts to the environment accelerate, disparities in the distribution of damages between rich and poor nations mount. Globally, environmental change is dramatically affecting the flow of ecosystem services, but the distribution of ecological damages and their driving forces has not been estimated. Here, we conservatively estimate the environmental costs of human activities over 1961-2000 in six major categories (climate change, stratospheric ozone depletion, agricultural intensification and expansion, deforestation, overfishing, and mangrove conversion), quantitatively connecting costs borne by poor, middle-income, and rich nations to specific activities by each of these groups. Adjusting impact valuations for different standards of living across the groups as commonly practiced, we find striking imbalances. Climate change and ozone depletion impacts predicted for low-income nations have been overwhelmingly driven by emissions from the other two groups, a pattern also observed for overfishing damages indirectly driven by the consumption of fishery products. Indeed, through disproportionate emissions of greenhouse gases alone, the rich group may have imposed climate damages on the poor group greater than the latter's current foreign debt. Our analysis provides prima facie evidence for an uneven distribution pattern of damages across income groups. Moreover, our estimates of each group's share in various damaging activities are independent from controversies in environmental valuation methods. In a world increasingly connected ecologically and economically, our analysis is thus an early step toward reframing issues of environmental responsibility, development, and globalization in accordance with ecological costs.