An illustration of the modelling of cost and efficacy data from a clinical trial

Health care providers, purchasers and policy makers need to make informed decisions regarding the provision of cost-effective care. When a new health care intervention is to be compared with the current standard, an economic evaluation alongside an evaluation of health benefits provides useful information for the decision making process. We consider the information on cost-effectiveness which arises from an individual clinical trial comparing the two interventions. Recent methods for conducting a cost-effectiveness analysis for a clinical trial have focused on the net benefit parameter. The net benefit parameter, a function of costs and health benefits, is positive if the new intervention is cost-effective compared with the standard. In this paper we describe frequentist and Bayesian approaches to cost-effectiveness analysis which have been suggested in the literature and apply them to data from a clinical trial comparing laparoscopic surgery with open mesh surgery for the repair of inguinal hernias. We extend the Bayesian model to allow the total cost to be divided into a number of different components. The advantages and disadvantages of the different approaches are discussed. In January 2001, NICE issued guidance on the type of surgery to be used for inguinal hernia repair. We discuss our example in the light of this information. Copyright © 2003 John Wiley & Sons, Ltd.

Restricted expression of NADPH oxidase/peroxidase gene (Duox) in zone VII of the ascidian endostyle

The ascidian Ciona intestinalis, a marine invertebrate chordate, is an emerging model system for developmental and evolutionary studies. The endostyle, one of the characteristic organs of ascidians, is a pharyngeal structure with iodine-concentrating and peroxidase activities and is therefore considered to be homologous to the follicular thyroid of higher vertebrates. We have previously reported that a limited part of the endostyle (zone VII) is marked by the expression of orthologs of the thyroid peroxidase (TPO) and thyroid transcription factor-2 (TTF-2/FoxE) genes. In this study, we have identified the Ciona homolog of NADPH oxidase/peroxidase (Duox), which provides hydrogen peroxide (H2O2) for iodine metabolism by TPO in the vertebrate thyroid. Expression patterns assessed by in situ hybridization have revealed that Ciona Duox (Ci-Duox) is predominantly expressed in the dorsal part of zone VII of the endostyle. Furthermore, two-color fluorescent in situ hybridization with Ci-Duox and Ciona TPO (CiTPO) has revealed that the ventral boundary of the Ci-Duox domain of expression is more dorsal than that of CiTPO. We have also characterized several genes, such as Ci-Fgf8/17/18, 5HT7, and Ci-NK4, which are predominantly expressed in the ventral part of zone VII, in a region complementary to the Ci-Duox expression domain. These observations suggest that, at the molecular level, zone VII has a complex organization that might have some impact on the specification of cell types and functions in this thyroid-equivalent element of the ascidian endostyle.

Plumatella geimermassardi, a newly recognized freshwater bryozoan from Britain, Ireland, and continental Europe (Bryozoa : Phylactolaemata)

Plumatella geimermassardi is a newly recognized species of phylactolaemate bryozoan. Its known range extends from Ireland east through southern Norway and south into Italy. Colonies grow close to the substrate with little free branching; the body wall is mostly transparent and without an obvious raphe. Floatoblasts are broadly oval and relatively small, with distinctively large dorsal fenestra and uniformly narrow ventral annulus. The sessoblast basal valve is low and dish-shaped; the annulus bears tubercles which vary in their prominence. This species brings to 14 the number of phylactolaemate bryozoans known in the region.

Learning associations between places and visual cues without learning to navigate: neither fornix nor entorhinal cortex is required

Rats with fornix transection, or with cytotoxic retrohippocampal lesions that removed entorhinal cortex plus ventral subiculum, performed a task that permits incidental learning about either allocentric (Allo) or egocentric (Ego) spatial cues without the need to navigate by them. Rats learned eight visual discriminations among computer-displayed scenes in a Y-maze, using the constant-negative paradigm. Every discrimination problem included two familiar scenes (constants) and many less familiar scenes (variables). On each trial, the rats chose between a constant and a variable scene, with the choice of the variable rewarded. In six problems, the two constant scenes had correlated spatial properties, either Alto (each constant appeared always in the same maze arm) or Ego (each constant always appeared in a fixed direction from the start arm) or both (Allo + Ego). In two No-Cue (NC) problems, the two constants appeared in randomly determined arms and directions. Intact rats learn problems with an added Allo or Ego cue faster than NC problems; this facilitation provides indirect evidence that they learn the associations between scenes and spatial cues, even though that is not required for problem solution. Fornix and retrohippocampal-lesioned groups learned NC problems at a similar rate to sham-operated controls and showed as much facilitation of learning by added spatial cues as did the controls; therefore, both lesion groups must have encoded the spatial cues and have incidentally learned their associations with particular constant scenes. Similar facilitation was seen in subgroups that had short or long prior experience with the apparatus and task. Therefore, neither major hippocampal input-output system is crucial for learning about allocentric or egocentric cues in this paradigm, which does not require rats to control their choices or navigation directly by spatial cues.

Motor brain regions are involved in the encoding of delayed intentions: a fMRI study

In studies of prospective memory, recall of the content of delayed intentions is normally excellent, probably because they contain actions that have to be enacted at a later time. Action words encoded for later enactment are more accessible from memory than those encoded for later verbal report [Freeman, J.E., and Ellis, J.A. 2003a. The representation of delayed intentions: A prospective subject-performed task? Journal of Experimental Psychology: Learning, Memory, and Cognition, 29, 976-992.]. As this higher assessibility is lost when the intended actions have to be enacted during encoding, or when a motor interference task is introduced concurrent to intention encoding, Freeman and Ellis suggested that the advantage of to-be-enacted actions is due to additional preparatory motor operations during encoding. Accordingly, in a fMRI study with 10 healthy young participants, we investigated whether motor brain regions are differentially activated during verbal encoding of actions for later enactment with the right hand in contrast to verbal encoding of actions for later verbal report. We included an additional condition of verbal encoding of abstract verbs for later verbal report to investigate whether the semantic motor information inherent in action verbs in contrast to abstract verbs activates motor brain regions different from those involved in the verbal encoding of actions for later enactment. Differential activation for the verbal encoding of to-be-enacted actions in contrast to to-be-reported actions was found in brain regions known to be involved in covert motor preparation for hand movements, i.e. the postcentral gyrus, the precuneus, the dorsal and ventral premotor cortex, the posterior middle temporal gyrus and the inferior parietal lobule. There was no overlap between these brain regions and those differentially activated during the verbal encoding of actions in contrast to abstract verbs for later verbal report. Consequently, the results of this fMRI study suggest the presence of preparatory motor operations during the encoding of delayed intentions requiring a future motor response, which cannot be attributed to semantic information inherent to action verbs. (c) 2006 Elsevier B.V. All rights reserved.

Maturation of limbic corticostriatal activation and connectivity associated with developmental changes in temporal discounting

Temporal discounting (TD) matures with age, alongside other markers of increased impulse control, and coherent, self-regulated behaviour. Discounting paradigms quantify the ability to refrain from preference of immediate rewards, in favour of delayed, larger rewards. As such, they measure temporal foresight and the ability to delay gratification, functions that develop slowly into adulthood. We investigated the neural maturation that accompanies the previously observed age-related behavioural changes in discounting, from early adolescence into mid-adulthood. We used functional magnetic resonance imaging of a hypothetical discounting task with monetary rewards delayed in the week to year range. We show that age-related reductions in choice impulsivity were associated with changes in activation in ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), ventral striatum (VS), insula, inferior temporal gyrus, and posterior parietal cortex. Limbic frontostriatal activation changes were specifically associated with age-dependent reductions in impulsive choice, as part of a more extensive network of brain areas showing age-related changes in activation, including dorsolateral PFC, inferior parietal cortex, and subcortical areas. The maturational pattern of functional connectivity included strengthening in activation coupling between ventromedial and dorsolateral PFC, parietal and insular cortices during selection of delayed alternatives, and between vmPFC and VS during selection of immediate alternatives. We conclude that maturational mechanisms within limbic frontostriatal circuitry underlie the observed post-pubertal reductions in impulsive choice with increasing age, and that this effect is dependent on increased activation coherence within a network of areas associated with discounting behaviour and inter-temporal decision-making.

Automatic imitation of intransitive actions

Previous research has indicated a potential discontinuity between monkey and human ventral premotor-parietal mirror systems, namely that monkey mirror systems process only transitive (object-directed) actions, whereas human mirror systems may also process intransitive (non-object-directed) actions. The present study investigated this discontinuity by seeking evidence of automatic imitation of intransitive actions—hand opening and closing—in humans using a simple reaction time (RT), stimulus–response compatibility paradigm. Left–right and up–down spatial compatibility were controlled by ensuring that stimuli were presented and responses executed in orthogonal planes, and automatic imitation was isolated from simple and complex orthogonal spatial compatibility by varying the anatomical identity of the stimulus hand and response hemispace, respectively. In all conditions, action compatible responding was faster than action incompatible responding, and no effects of spatial compatibility were observed. This experiment therefore provides evidence of automatic imitation of intransitive actions, and support for the hypothesis that human and monkey mirror systems differ with respect to the processing of intransitive actions.

Turning on the alarm: the neural mechanisms of the transition from innocuous to painful sensation

The experience of pain occurs when the level of a stimulus is sufficient to elicit a marked affective response, putatively to warn the organism of potential danger and motivate appropriate behavioral responses. Understanding the biological mechanisms of the transition from innocuous to painful levels of sensation is essential to understanding pain perception as well as clinical conditions characterized by abnormal relationships between stimulation and pain response. Thus, the primary objective of this study was to characterize the neural response associated with this transition and the correspondence between that response and subjective reports of pain. Towards this goal, this study examined BOLD response profiles across a range of temperatures spanning the pain threshold. 14 healthy adults underwent functional magnetic resonance imaging (fMRI) while a range of thermal stimuli (44-49oC) were applied. BOLD responses showed a sigmoidal profile along the range of temperatures in a network of brain regions including insula and mid- cingulate, as well as a number of regions associated with motor responses including ventral lateral nuclei of the thalamus, globus pallidus and premotor cortex. A sigmoid function fit to the BOLD responses in these regions explained up to 85% of the variance in individual pain ratings, and yielded an estimate of the temperature of steepest transition from non-painful to painful heat that was nearly identical to that generated by subjective ratings. These results demonstrate a precise characterization of the relationship between objective levels of stimulation, resulting neural activation, and subjective experience of pain and provide direct evidence for a neural mechanism supporting the nonlinear transition from innocuous to painful levels along the sensory continuum.

Combined phylogenetic analyses reveal interfamilial relationships and patterns of floral evolution in the eudicot order Fabales

Relationships between the four families placed in the angiosperm order Fabales (Leguminosae, Polygalaceae, Quillajaceae, Surianaceae) were hitherto poorly resolved. We combine published molecular data for the chloroplast regions matK and rbcL with 66 morphological characters surveyed for 73 ingroup and two outgroup species, and use Parsimony and Bayesian approaches to explore matrices with different missing data. All combined analyses using Parsimony recovered the topology Polygalaceae (Leguminosae (Quillajaceae + Surianaceae)). Bayesian analyses with matched morphological and molecular sampling recover the same topology, but analyses based on other data recover a different Bayesian topology: ((Polygalaceae + Leguminosae) (Quillajaceae + Surianaceae)). We explore the evolution of floral characters in the context of the more consistent topology: Polygalaceae (Leguminosae (Quillajaceae + Surianaceae)). This reveals synapomorphies for (Leguminosae (Quillajaceae + Surianaceae)) as the presence of free filaments and marginal/ventral placentation, for (Quillajaceae + Surianaceae) as pentamery and apocarpy, and for Leguminosae the presence of an abaxial median sepal and unicarpellate gynoecium. An octamerous androecium is synapomorphic for Polygalaceae. The development of papilionate flowers, and the evolutionary context in which these phenotypes appeared in Leguminosae and Polygalaceae, shows that the morphologies are convergent rather than synapomorphic within Fabales.

Individual differences in brain structure underpin empathizing–systemizing cognitive styles in male adults

Individual differences in cognitive style can be characterized along two dimensions: ‘systemizing’ (S, the drive to analyze or build ‘rule-based’ systems) and ‘empathizing’ (E, the drive to identify another's mental state and respond to this with an appropriate emotion). Discrepancies between these two dimensions in one direction (S > E) or the other (E > S) are associated with sex differences in cognition: on average more males show an S > E cognitive style, while on average more females show an E > S profile. The neurobiological basis of these different profiles remains unknown. Since individuals may be typical or atypical for their sex, it is important to move away from the study of sex differences and towards the study of differences in cognitive style. Using structural magnetic resonance imaging we examined how neuroanatomy varies as a function of the discrepancy between E and S in 88 adult males from the general population. Selecting just males allows us to study discrepant E-S profiles in a pure way, unconfounded by other factors related to sex and gender. An increasing S > E profile was associated with increased gray matter volume in cingulate and dorsal medial prefrontal areas which have been implicated in processes related to cognitive control, monitoring, error detection, and probabilistic inference. An increasing E > S profile was associated with larger hypothalamic and ventral basal ganglia regions which have been implicated in neuroendocrine control, motivation and reward. These results suggest an underlying neuroanatomical basis linked to the discrepancy between these two important dimensions of individual differences in cognitive style.

Disrupted white matter in language and motor tracts in developmental stuttering

White matter tractsc onnecting areas involved in speech and motor control were examined using diffusion-tensor imagingingin a sample of peoplewhostutter (n=29) who were heterogeneous with respect to age, sex, handedness and stuttering severity. The goals were to replicate previous findings in developmental stuttering and to extend ourknowledge by evaluating the relationship between white matter differences in people who stutter and factors such as age, sex, handedness and stuttering severity. We replicated previous findings that showed reduced integrity in white matter underlying ventral premotorcortex, cerebral peduncles and posteriorcorpus callosum in people who stutter, relative to controls. Tractography analysis additionally revealed significantly reduced white matter integrity in the arcuate fasciculus bilaterally and the left corticospinal tract and significantly reduced connectivity within theleft corticobulbar tract in people who stutter. Region-of-interest analyses revealed reduced white matter integrity in people whostutter in the three pairs ocerebellar peduncles thatcarry the afferent and efferent fibers of the cerebellum. Within thegroup of people who stutter, the higher the stuttering severity index, the lower the white matter integrity in the leftangular gyrus but the greater the white matter connectivity in theleft corticobulbartract. Also,in people who stutter, handedness and age predicted the integrity of the corticospinal tract and peduncles, respectively. Further studies are needed to determine which of these white matter differences relate to the neural basis of stuttering and which reflect experience-dependent plasticity.

Whole-brain functional connectivity during emotional word classification in medication-free Major Depressive Disorder: abnormal salience circuitry and relations to positive emotionality

Major Depressive Disorder (MDD) has been associated with biased processing and abnormal regulation of negative and positive information, which may result from compromised coordinated activity of prefrontal and subcortical brain regions involved in evaluating emotional information. We tested whether patients with MDD show distributed changes in functional connectivity with a set of independently derived brain networks that have shown high correspondence with different task demands, including stimulus salience and emotional processing. We further explored if connectivity during emotional word processing related to the tendency to engage in positive or negative emotional states. In this study, 25 medication-free MDD patients without current or past comorbidity and matched controls (n=25) performed an emotional word-evaluation task during functional MRI. Using a dual regression approach, individual spatial connectivity maps representing each subject’s connectivity with each standard network were used to evaluate between-group differences and effects of positive and negative emotionality (extraversion and neuroticism, respectively, as measured with the NEO-FFI). Results showed decreased functional connectivity of the medial prefrontal cortex, ventrolateral prefrontal cortex, and ventral striatum with the fronto-opercular salience network in MDD patients compared to controls. In patients, abnormal connectivity was related to extraversion, but not neuroticism. These results confirm the hypothesis of a relative (para)limbic-cortical decoupling that may explain dysregulated affect in MDD. As connectivity of these regions with the salience network was related to extraversion, but not to general depression severity or negative emotionality, dysfunction of this network may be responsible for the failure to sustain engagement in rewarding behavior.

Neural and psychological maturation of decision-making in adolescence and young adulthood

We examined the maturation of decision-making from early adolescence to mid-adulthood using fMRI of a variant of the Iowa gambling task. We have previously shown that performance in this task relies on sensitivity to accumulating negative outcomes in ventromedial PFC and dorsolateral PFC. Here, we further formalize outcome evaluation (as driven by prediction errors [PE], using a reinforcement learning model) and examine its development. Task performance improved significantly during adolescence, stabilizing in adulthood. Performance relied on greater impact of negative compared with positive PEs, the relative impact of which matured from adolescence into adulthood. Adolescents also showed increased exploratory behavior, expressed as a propensity to shift responding between options independently of outcome quality, whereas adults showed no systematic shifting patterns. The correlation between PE representation and improved performance strengthened with age for activation in ventral and dorsal PFC, ventral striatum, and temporal and parietal cortices. There was a medial-lateral distinction in the prefrontal substrates of effective PE utilization between adults and adolescents: Increased utilization of negative PEs, a hallmark of successful performance in the task, was associated with increased activation in ventromedial PFC in adults, but decreased activation in ventrolateral PFC and striatum in adolescents. These results suggest that adults and adolescents engage qualitatively distinct neural and psychological processes during decision-making, the development of which is not exclusively dependent on reward-processing maturation.

Increased neural processing of rewarding and aversive food stimuli in recovered anorexia nervosa

Background Recent evidence has shown that individuals with acute anorexia nervosa and those recovered have aberrant physiological responses to rewarding stimuli. We hypothesized that women recovered from anorexia nervosa would show aberrant neural responses to both rewarding and aversive disorder-relevant stimuli. Methods Using functional magnetic resonance imaging (fMRI), the neural response to the sight and flavor of chocolate, and their combination, in 15 women recovered from restricting-type anorexia nervosa and 16 healthy control subjects matched for age and body mass index was investigated. The neural response to a control aversive condition, consisting of the sight of moldy strawberries and a corresponding unpleasant taste, was also measured. Participants simultaneously recorded subjective ratings of “pleasantness,” “intensity,” and “wanting.” Results Despite no differences between the groups in subjective ratings, individuals recovered from anorexia nervosa showed increased neural response to the pleasant chocolate taste in the ventral striatum and pleasant chocolate sight in the occipital cortex. The recovered participants also showed increased neural response to the aversive strawberry taste in the insula and putamen and to the aversive strawberry sight in the anterior cingulate cortex and caudate. Conclusions Individuals recovered from anorexia nervosa have increased neural responses to both rewarding and aversive food stimuli. These findings suggest that even after recovery, women with anorexia nervosa have increased salience attribution to food stimuli. These results aid our neurobiological understanding and support the view that the neural response to reward may constitute a neural biomarker for anorexia nervosa.

Diminished neural processing of aversive and rewarding stimuli during selective serotonin reuptake inhibitor treatment

Background Selective serotonin reuptake inhibitors (SSRIs) are popular medications for anxiety and depression, but their effectiveness, particularly in patients with prominent symptoms of loss of motivation and pleasure, has been questioned. There are few studies of the effect of SSRIs on neural reward mechanisms in humans. Methods We studied 45 healthy participants who were randomly allocated to receive the SSRI citalopram, the noradrenaline reuptake inhibitor reboxetine, or placebo for 7 days in a double-blind, parallel group design. We used functional magnetic resonance imaging to measure the neural response to rewarding (sight and/or flavor of chocolate) and aversive stimuli (sight of moldy strawberries and/or an unpleasant strawberry taste) on the final day of drug treatment. Results Citalopram reduced activation to the chocolate stimuli in the ventral striatum and the ventral medial/orbitofrontal cortex. In contrast, reboxetine did not suppress ventral striatal activity and in fact increased neural responses within medial orbitofrontal cortex to reward. Citalopram also decreased neural responses to the aversive stimuli conditions in key “punishment” areas such as the lateral orbitofrontal cortex. Reboxetine produced a similar, although weaker effect. Conclusions Our findings are the first to show that treatment with SSRIs can diminish the neural processing of both rewarding and aversive stimuli. The ability of SSRIs to decrease neural responses to reward might underlie the questioned efficacy of SSRIs in depressive conditions characterized by decreased motivation and anhedonia and could also account for the experience of emotional blunting described by some patients during SSRI treatment.