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BACKGROUND: Computational research had determined that adults with obsessive-compulsive disorder (OCD) display heightened action updating in response to noise in the environment and neglect metacognitive information (such as confidence) when making decisions. These features are proposed to underlie patients' compulsions despite the knowledge they are irrational. Nonetheless, it is unclear whether this extends to adolescents with OCD as research in this population is lacking. Thus, this study aimed to investigate the interplay between action and confidence in adolescents with OCD. METHODS: Twenty-seven adolescents with OCD and 46 controls completed a predictive-inference task, designed to probe how subjects' actions and confidence ratings fluctuate in response to unexpected outcomes. We investigated how subjects update actions in response to prediction errors (indexing mismatches between expectations and outcomes) and used parameters from a Bayesian model to predict how confidence and action evolve over time. Confidence-action association strength was assessed using a regression model. We also investigated the effects of serotonergic medication. RESULTS: Adolescents with OCD showed significantly increased learning rates, particularly following small prediction errors. Results were driven primarily by unmedicated patients. Confidence ratings appeared equivalent between groups, although model-based analysis revealed that patients' confidence was less affected by prediction errors compared to controls. Patients and controls did not differ in the extent to which they updated actions and confidence in tandem. CONCLUSIONS: Adolescents with OCD showed enhanced action adjustments, especially in the face of small prediction errors, consistent with previous research establishing 'just-right' compulsions, enhanced error-related negativity, and greater decision uncertainty in paediatric-OCD. These tendencies were ameliorated in patients receiving serotonergic medication, emphasising the importance of early intervention in preventing disorder-related cognitive deficits. Confidence ratings were equivalent between young patients and controls, mirroring findings in adult OCD research.

The symptoms of obsessive–compulsive disorder (OCD) are suggestive of cognitive rigidity, and previous work identified impaired flexible responding on set-shifting tasks in such patients. The basal ganglia are central to habit learning and are thought to be abnormal in OCD, contributing to inflexible, rigid habitual patterns of behaviour. Here, we demonstrate that increased cognitive inflexibility, indexed by poor performance on the set-shifting task, correlated with putamen morphology, and that patients and their asymptomatic relatives had common curvature abnormalities within this same structure. The association between the structure of the putamen and the extradimensional errors was found to be significantly familial in OCD proband–relative pairs. The data implicate changes in basal ganglia structure linked to cognitive inflexibility as a familial marker of OCD. This may reflect a predisposing heightened propensity toward habitual response patterns and deficits in goal-directed planning.

Significance How does the human brain change during adolescence? We found 2 distinct modes of change in functional connectivity between brain regions, “conservative” and “disruptive,” measured using functional MRI (fMRI) in healthy young people (14 to 26 y old). Conservative regions, often specialized for basic sensory and motor functions, were strongly connected at age 14 before strengthening more by age 26, whereas disruptive regions that were activated by complex tasks comprised both connections that were weak at age 14 but strengthened by age 26 and connections that were strong at age 14 but weakened by age 26. Disruptive maturation of fMRI connectivity between cortex and subcortex could represent metabolically costly remodeling that underpins development of adult faculties., Adolescent changes in human brain function are not entirely understood. Here, we used multiecho functional MRI (fMRI) to measure developmental change in functional connectivity (FC) of resting-state oscillations between pairs of 330 cortical regions and 16 subcortical regions in 298 healthy adolescents scanned 520 times. Participants were aged 14 to 26 y and were scanned on 1 to 3 occasions at least 6 mo apart. We found 2 distinct modes of age-related change in FC: “conservative” and “disruptive.” Conservative development was characteristic of primary cortex, which was strongly connected at 14 y and became even more connected in the period from 14 to 26 y. Disruptive development was characteristic of association cortex and subcortical regions, where connectivity was remodeled: connections that were weak at 14 y became stronger during adolescence, and connections that were strong at 14 y became weaker. These modes of development were quantified using the maturational index (MI), estimated as Spearman’s correlation between edgewise baseline FC (at 14 y, FC14) and adolescent change in FC (ΔFC14−26), at each region. Disruptive systems (with negative MI) were activated by social cognition and autobiographical memory tasks in prior fMRI data and significantly colocated with prior maps of aerobic glycolysis (AG), AG-related gene expression, postnatal cortical surface expansion, and adolescent shrinkage of cortical thickness. The presence of these 2 modes of development was robust to numerous sensitivity analyses. We conclude that human brain organization is disrupted during adolescence by remodeling of FC between association cortical and subcortical areas.

Disruptions of self-regulation are a hallmark of numerous psychiatric disorders. Here, we examine the relationship between transdiagnostic dimensions of psychopathology and changes in self-regulation in the early phase of the COVID-19 pandemic. We used a data-driven approach on a large number of cognitive tasks and self-reported surveys in training datasets. Then, we derived measures of self-regulation and psychiatric functioning in an independent population sample (N = 102) tested both before and after the onset of the COVID-19 pandemic, when the restrictions in place represented a threat to mental health and forced people to flexibly adjust to modifications of daily routines. We found independent relationships between transdiagnostic dimensions of psychopathology and longitudinal alterations in specific domains of self-regulation defined using a diffusion decision model. Compared to the period preceding the onset of the pandemic, a symptom dimension related to anxiety and depression was characterized by a more cautious behavior, indexed by the need to accumulate more evidence before making a decision. Instead, social withdrawal related to faster non-decision processes. Self-reported measures of self-regulation predicted variance in psychiatric symptoms both concurrently and prospectively, revealing the psychological dimensions relevant for separate transdiagnostic dimensions of psychiatry, but tasks did not. Taken together, our results are suggestive of potential cognitive vulnerabilities in the domain of self-regulation in people with underlying psychiatric difficulties in face of real-life stressors. More generally, they also suggest that the study of cognition needs to take into account the dynamic nature of real-world events as well as within-subject variability over time.

BackgroundGoal-directed control guides optimal decision-making and it is an important cognitive faculty that protects against developing habits. Previous studies have found some evidence of goal-directed deficits when healthy individuals are stressed, and in psychiatric conditions characterised by compulsive behaviours and anxiety. Here, we tested if goal-directed control is affected by state anxiety, which might explain the former results.MethodsWe carried out a causal test of this hypothesis in two experiments (between-subject N = 88; within-subject N = 50) that used the inhalation of hypercapnic gas (7.5% CO2) to induce an acute state of anxiety in healthy volunteers. In a third experiment (N = 1413), we used a correlational design to test if real-life anxiety-provoking events (panic attacks, stressful events) are associated with impaired goal-directed control.ResultsIn the former two causal experiments, we induced a profoundly anxious state, both physiologically and psychologically, but this did not affect goal-directed performance. In the third, correlational, study, we found no evidence for an association between goal-directed control, panic attacks or stressful life eventsover and above variance accounted for by trait differences in compulsivity.ConclusionsIn sum, three complementary experiments found no evidence that anxiety impairs goal-directed control in human subjects.

Background The balance between goal-directed behavior and habits has been hypothesized to be biased toward the latter in individuals with cocaine use disorder (CUD), suggesting possible neurochemical changes in the putamen, which may contribute to their compulsive behavior. Methods We assessed habitual behavior in 48 patients with CUD and 42 healthy control participants using a contingency degradation paradigm and the Creature of Habit Scale. In a subgroup of this sample (CUD: n = 21; control participants: n = 22), we also measured glutamate and glutamine concentrations in the left putamen using ultra-high-field (7T) magnetic resonance spectroscopy. We hypothesized that increased habitual tendencies in patients with CUD would be associated with abnormal glutamatergic metabolites in the putamen. Results Compared with their non–drug-using peers, patients with CUD exhibited greater habitual tendencies during contingency degradation, which correlated with increased levels of self-reported daily habits. We further identified a significant reduction in glutamate concentration and glutamate turnover (glutamate-to-glutamine ratio) in the putamen in patients with CUD, which was significantly related to the level of self-reported daily habits. Conclusions Patients with CUD exhibit enhanced habitual behavior, as assessed both by questionnaire and by a laboratory paradigm of contingency degradation. This automatic habitual tendency is related to a reduced glutamate turnover in the putamen, suggesting a dysregulation of habits caused by chronic cocaine use.

BACKGROUND: In obsessive-compulsive disorder (OCD), actions persist despite being inappropriate to the situation and without relationship to the overall goal. Dysfunctional beliefs have traditionally been postulated to underlie this condition. More recently, OCD has been characterized in terms of an imbalance between the goal-directed and the habit systems. To test these competing hypotheses, we used a novel experimental task designed to test subjective action-outcome knowledge of the effectiveness of actions (i.e., instrumental contingency), together with the balance between goal-directed and habitual responding. METHODS: Twenty-seven patients with OCD and 27 healthy control subjects were tested on a novel task involving the degradation of an action-outcome contingency. Sensitivity to instrumental contingency and the extent to which explicitly reported action-outcome knowledge guided behavior were probed by measuring response rate and subjectively reported judgments. RESULTS: Patients with OCD responded more than healthy control subjects in situations in which an action was less causally related to obtaining an outcome. However, patients showed intact explicit action-outcome knowledge, as assessed by self-report. In patients, the relationship between causality judgment and responding was altered; therefore, their actions were dissociated from explicit action-outcome knowledge. CONCLUSIONS: These findings indicate reduced sensitivity to instrumental contingency in OCD, reinforcing the notion of a deficient goal-directed system in this disorder. By showing a dissociation between subjectively reported action-outcome knowledge and behavior, the data provide experimental evidence for the ego-dystonic nature of OCD.

In this chapter, I address the concept of endophenotypes for obsessive-compulsive disorder (OCD). Endophenotypes are objective and heritable quantitative traits hypothesized to be more biologically tractable than distal clinical phenotypes. This approach has been adopted to gain a better understanding of psychiatric conditions in general. It is theorized that endophenotypes will particularly assist in clarifying both the diagnostic status and aetiological origins of complex neuropsychiatric conditions such as OCD. At the cognitive level, separable constructs of relevance for OCD have been identified. The prevailing model for OCD assumes the development of abnormalities within fronto-striatal neural circuits leading to impairment of executive functions and their neuropsychological subcomponents. Here, I address whether this model can guide towards the identification of endophenotypes for this condition and discuss possible implications.

Cognitive inflexibility is suggested by the hallmark symptoms of obsessive-compulsive disorder (OCD), namely the occurrence of repetitive thoughts and/or behaviours that persist despite being functionally impairing and egodystonic to the individual. As well as being implied by the top-level symptoms, cognitive inflexibility in OCD, and some related conditions, has also been objectively quantified in case-control studies using computerised cognitive tasks. This chapter begins by considering the objective measurement of different aspects of cognitive flexibility using neuropsychological paradigms, with a focus on neural and neurochemical substrates. It moves on to conduct a systematic review and meta-analysis of findings from a widely deployed flexibility task: the Intra-Dimensional/Extra-Dimensional Set-Shift Task (IDED). By pooling data from 11 studies (335 OCD patients and 311 controls), we show that Extra-Dimensional (ED) shift deficits are a robust and reproducible finding (effect size medium-large) in OCD across the literature, and that this deficit is not attributable to group differences in age or IQ. The OCD ED deficit is then discussed in terms of dysfunction of fronto-striatal pathways (as exemplified, for example, by functional connectivity data), and the putative role of different neurotransmitters. We consider evidence that impaired ED shifting constitutes a candidate vulnerability marker (or 'endophenotype') for OCD. The available literature is then surveyed as to ED findings in other obsessive-compulsive (OC) related disorders (e.g. hoarding, body-dysmorphic disorder, and trichotillomania), as well as in non-OC disorders (schizophrenia and anxiety symptoms in general). Lastly, we consider more recent, emerging developments in the quantification of compulsivity using cognitive tasks and questionnaires, as well as key directions for future research, including the need to refine compulsivity and its composite cognitive processes.

In this chapter, I address the concept of endophenotypes for obsessive-compulsive disorder (OCD). Endophenotypes are objective and heritable quantitative traits hypothesized to be more biologically tractable than distal clinical phenotypes. This approach has been adopted to gain a better understanding of psychiatric conditions in general. It is theorized that endophenotypes will particularly assist in clarifying both the diagnostic status and aetiological origins of complex neuropsychiatric conditions such as OCD. At the cognitive level, separable constructs of relevance for OCD have been identified. The prevailing model for OCD assumes the development of abnormalities within fronto-striatal neural circuits leading to impairment of executive functions and their neuropsychological subcomponents. Here, I address whether this model can guide towards the identification of endophenotypes for this condition and discuss possible implications.

Cognitive inflexibility is suggested by the hallmark symptoms of obsessive-compulsive disorder (OCD), namely the occurrence of repetitive thoughts and/or behaviours that persist despite being functionally impairing and egodystonic to the individual. As well as being implied by the top-level symptoms, cognitive inflexibility in OCD, and some related conditions, has also been objectively quantified in case–control studies using computerised cognitive tasks. This chapter begins by considering the objective measurement of different aspects of cognitive flexibility using neuropsychological paradigms, with a focus on neural and neurochemical substrates. It moves on to conduct a systematic review and meta-analysis of findings from a widely deployed flexibility task: the Intra-Dimensional/Extra-Dimensional Set-Shift Task (IDED). By pooling data from 11 studies (335 OCD patients and 311 controls), we show that Extra-Dimensional (ED) shift deficits are a robust and reproducible finding (effect size medium–large) in OCD across the literature, and that this deficit is not attributable to group differences in age or IQ. The OCD ED deficit is then discussed in terms of dysfunction of fronto-striatal pathways (as exemplified, for example, by functional connectivity data), and the putative role of different neurotransmitters. We consider evidence that impaired ED shifting constitutes a candidate vulnerability marker (or ‘endophenotype’) for OCD. The available literature is then surveyed as to ED findings in other obsessive-compulsive (OC) related disorders (e.g. hoarding, body-dysmorphic disorder, and trichotillomania), as well as in non-OC disorders (schizophrenia and anxiety symptoms in general). Lastly, we consider more recent, emerging developments in the quantification of compulsivity using cognitive tasks and questionnaires, as well as key directions for future research, including the need to refine compulsivity and its composite cognitive processes.

Significance Goal-directed behavior is impaired in disorders of compulsivity. Here, we characterize the developmental trajectory of model-based control and show a progressive strengthening from adolescence to early adulthood. We found that the presence of compulsivity traits impacts on this trajectory as well as on the degree of remodeling in functional connectivity within frontostriatal circuits. These findings have implications for understanding the interplay between compulsivity, the developmental trajectory of model-based planning, and functional connectivity in frontostriatal circuits., A characteristic of adaptive behavior is its goal-directed nature. An ability to act in a goal-directed manner is progressively refined during development, but this refinement can be impacted by the emergence of psychiatric disorders. Disorders of compulsivity have been framed computationally as a deficit in model-based control, and have been linked also to abnormal frontostriatal connectivity. However, the developmental trajectory of model-based control, including an interplay between its maturation and an emergence of compulsivity, has not been characterized. Availing of a large sample of healthy adolescents (n = 569) aged 14 to 24 y, we show behaviorally that over the course of adolescence there is a within-person increase in model-based control, and this is more pronounced in younger participants. Using a bivariate latent change score model, we provide evidence that the presence of higher compulsivity traits is associated with an atypical profile of this developmental maturation in model-based control. Resting-state fMRI data from a subset of the behaviorally assessed subjects (n = 230) revealed that compulsivity is associated with a less pronounced change of within-subject developmental remodeling of functional connectivity, specifically between the striatum and a frontoparietal network. Thus, in an otherwise clinically healthy population sample, in early development, individual differences in compulsivity are linked to the developmental trajectory of model-based control and a remodeling of frontostriatal connectivity.

Obsessive-compulsive disorder is a severe and disabling psychiatric disorder that presents several challenges for neuroscience. Recent advances in its genetic and developmental causation, as well as its neuropsychological basis, are reviewed. Hypotheses concerning an imbalance between goal-directed and habitual behavior together with neural correlates in cortico-striatal circuitry are evaluated and contrasted with metacognitive theories. Treatments for obsessive-compulsive disorder (OCD) tend to be of mixed efficacy but include psychological, pharmacological, and surgical approaches, the underlying mechanisms of which are still under debate. Overall, the prospects for new animal models and an integrated understanding of the pathophysiology of OCD are considered in the context of dimensional psychiatry.

Adolescent changes in human brain function are not entirely understood. Here we used multi-echo functional magnetic resonance imaging (fMRI) to measure developmental change in functional connectivity (FC) of resting-state oscillations between pairs of 330 cortical regions and 16 subcortical regions in N=298 healthy adolescents. Participants were aged 14-26 years and were scanned on two or more occasions at least 6 months apart. We found two distinct modes of age-related change in FC: “conservative” and “disruptive”. Conservative development was characteristic of primary cortex, which was strongly connected at 14 years and became even more connected in the period 14-26 years. Disruptive development was characteristic of association cortex, hippocampus and amygdala, which were not strongly connected at 14 years but became more strongly connected during adolescence. We defined the maturational index (MI) as the signed coefficient of the linear relationship between baseline FC (at 14 years,FC14) and adolescent change in FC (∆FC14−26). Disruptive systems (with negative MI) were functionally specialised for social cognition and autobiographical memory and were significantly co-located with prior maps of aerobic glycolysis (AG), AG-related gene expression, post-natal expansion of cortical surface area, and adolescent shrinkage of cortical depth. We conclude that human brain organization is disrupted during adolescence by the emergence of strong functional connectivity of subcortical nuclei and association cortical areas, representing metabolically expensive re-modelling of synaptic connectivity between brain regions that were not strongly connected in childhood. We suggest that this re-modelling process may support emergence of social skills and self-awareness during healthy human adolescence.

Compulsions are repetitive, stereotyped thoughts and behaviors designed to reduce harm. Growing evidence suggests that the neurocognitive mechanisms mediating behavioral inhibition (motor inhibition, cognitive inflexibility) reversal learning and habit formation (shift from goal-directed to habitual responding) contribute toward compulsive activity in a broad range of disorders. In obsessive compulsive disorder, distributed network perturbation appears focused around the prefrontal cortex, caudate, putamen, and associated neuro-circuitry. Obsessive compulsive disorder-related attentional set-shifting deficits correlated with reduced resting state functional connectivity between the dorsal caudate and the ventrolateral prefrontal cortex on neuroimaging. In contrast, experimental provocation of obsessive compulsive disorder symptoms reduced neural activation in brain regions implicated in goal-directed behavioral control (ventromedial prefrontal cortex, caudate) with concordant increased activation in regions implicated in habit learning (presupplementary motor area,putamen). The ventromedial prefrontal cortex plays a multifaceted role, integrating affective evaluative processes, flexible behavior, and fear learning. Findings from a neuroimaging study of Pavlovian fear reversal, in which obsessive compulsive disorder patients failed to flexibly update fear responses despite normal initial fear conditioning, suggest there is an absence of ventromedial prefrontal cortex safety signaling in obsessive compulsive disorder, which potentially undermines explicit Compulsions are repetitive, stereotyped thoughts and behaviors designed to reduce harm. Growing evidence suggests that the neurocognitive mechanisms mediating behavioral inhibition (motor inhibition, cognitive inflexibility) reversal learning and habit formation (shift from goal-directed to habitual responding) contribute toward compulsive activity in a broad range of disorders. In obsessive compulsive disorder, distributed network perturbation appears focused around the prefrontal cortex, caudate, putamen, and associated neuro-circuitry. Obsessive compulsive disorder-related attentional set-shifting deficits correlated with reduced resting state functional connectivity between the dorsal caudate and the ventrolateral prefrontal cortex on neuroimaging. In contrast, experimental provocation of obsessive compulsive disorder symptoms reduced neural activation in brain regions implicated in goal-directed behavioral control (ventromedial prefrontal cortex, caudate) with concordant increased activation in regions implicated in habit learning (presupplementary motor area, putamen). The ventromedial prefrontal cortex plays a multifaceted role, integrating affective evaluative processes, flexible behavior, and fear learning. Findings from a neuroimaging study of Pavlovian fear reversal, in which obsessive compulsive disorder patients failed to flexibly update fear responses despite normal initial fear conditioning, suggest there is an absence of ventromedial prefrontal cortex safety signaling in obsessive compulsive disorder, which potentially undermines explicit contingency knowledge and may help to explain the link between cognitive inflexibility, fear, and anxiety processing in compulsive disorders such as obsessive compulsive disorder.

We rarely use abstract and concrete concepts in isolation but rather embedded within a linguistic context. To examine the modulatory impact of the linguistic context on conceptual processing, we isolated the case of sentential negation polarity, in which an interaction occurs between the syntactic operator not and conceptual information in the negation's scope. Previous studies suggested that sentential negation of concrete action-related concepts modulates activation in the fronto-parieto-temporal action representation network. In this functional magnetic resonance imaging study, we examined the influence of negation on a wider spectrum of meanings, by factorially manipulating sentence polarity (affirmative, negative) and fine-grained abstract (mental state, emotion, mathematics) and concrete (related to mouth, hand, leg actions) conceptual categories. We adopted a multivariate pattern analysis approach, and tested the accuracy of a machine learning classifier in discriminating brain activation patterns associated to the factorial manipulation. Searchlight analysis was used to localize the discriminating patterns. Overall, the neural processing of affirmative and negative sentences with either an abstract or concrete content could be accurately predicted by means of multivariate classification. We suggest that sentential negation polarity modulates brain activation in distributed representational semantic networks, through the functional mediation of syntactic and cognitive control systems. This article is part of the theme issue ‘Varieties of abstract concepts: development, use and representation in the brain’.

The neurobiological basis of Obsessive Compulsive Disorder (OCD) has been probed using functional magnetic resonance in hundreds of studies over three decades. This complex literature can be syntheized using a theory-informed approach. At a theoretical level, separable, independent, constructs of relevance to OCD have been identified. At the experimental level, extensive translational evidence has provided an account that relates specific brain systems to these neuropsychological constructs. Parallels between neural substrates implicated in OCD and functional specialization of different brain regions suggest that abnormalities within fronto-striatal circuitry impinge on executive functions, and their subcomponents, and on goal-directed learning and habit formation. In OCD, this is reflected at a functional level in patterns of abnormal activations in particular brain regions during specific cognitive tasks. However, many issues still need to be addressed. The authors suggest that the experimental context might represent a pivotal variable that should be taken into account.

An Intention Processing Network (IPN), involving the medial prefrontal cortex, precuneus, bilateral posterior superior temporal sulcus, and temporoparietal junctions, plays a fundamental role in comprehending intentions underlying action goals. In a previous fMRI study, we showed that, depending on the linguistic or extralinguistic (gestural) modality used to convey the intention, the IPN is complemented by activation of additional brain areas, reflecting distinct modality-specific input gateways to the IPN. These areas involve, for the linguistic modality, the left inferior frontal gyrus (LIFG), and for the extralinguistic modality, the right inferior frontal gyrus (RIFG). Here, we tested the modality-specific gateway hypothesis, by using DCM to measure inter-regional functional integration dynamics between the IPN and LIFG/RIFG gateways. We found strong evidence of a well-defined effective connectivity architecture mediating the functional integration between the IPN and the inferior frontal cortices. The connectivity dynamics indicate a modality-specific propagation of stimulus information from LIFG to IPN for the linguistic modality, and from RIFG to IPN for the extralinguistic modality. Thus, we suggest a functional model in which the modality-specific gateways mediate the structural and semantic decoding of the stimuli, and allow for the modality-specific communicative information to be integrated in Theory of Mind inferences elaborated through the IPN.

Background The symptoms of obsessive-compulsive disorder (OCD) have been postulated to result from impaired executive functioning and excessive habit formation at the expense of goal-directed control and have been objectively demonstrated using neuropsychological tests in such patients. This study tested whether there is functional hypoactivation as well as dysconnectivity of discrete frontostriatal pathways during goal-directed planning in patients with OCD and in their unaffected first-degree relatives. Methods In total, 21 comorbidity-free patients with OCD, 19 clinically asymptomatic first-degree relatives of these patients, and 20 control participants were tested on a functional magnetic resonance optimized version of the Tower of London task. Group differences in brain activation during goal-directed planning were measured together with associated frontostriatal functional connectivity. Results Patients with OCD and their clinically asymptomatic relatives manifested hypoactivation of the right dorsolateral prefrontal cortex during goal-directed planning coupled with reduced functional connectivity between this cortical region and the basal ganglia (putamen). Conclusions Hypoactivation of cortical regions associated with goal-directed planning and associated frontostriatal dysconnectivity represent a candidate endophenotype for OCD. These findings accord with abnormalities in neural networks supporting the balance between goal-directed and habitual behavior, with implications for recent neuropsychological theories of OCD and the major neurobiological model for this disorder.

Background A recent hypothesis has suggested that core deficits in goal-directed behavior in obsessive-compulsive disorder (OCD) are caused by impaired frontostriatal function. We tested this hypothesis in OCD patients and control subjects by relating measures of goal-directed planning and cognitive flexibility to underlying resting-state functional connectivity. Methods Multiecho resting-state acquisition, combined with micromovement correction by blood oxygen level–dependent sensitive independent component analysis, was used to obtain in vivo measures of functional connectivity in 44 OCD patients and 43 healthy comparison subjects. We measured cognitive flexibility (attentional set-shifting) and goal-directed performance (planning of sequential response sequences) by means of well-validated, standardized behavioral cognitive paradigms. Functional connectivity strength of striatal seed regions was related to cognitive flexibility and goal-directed performance. To gain insights into fundamental network alterations, graph theoretical models of brain networks were derived. Results Reduced functional connectivity between the caudate and the ventrolateral prefrontal cortex was selectively associated with reduced cognitive flexibility. In contrast, goal-directed performance was selectively related to reduced functional connectivity between the putamen and the dorsolateral prefrontal cortex in OCD patients, as well as to symptom severity. Whole-brain data-driven graph theoretical analysis disclosed that striatal regions constitute a cohesive module of the community structure of the functional connectome in OCD patients as nodes within the basal ganglia and cerebellum were more strongly connected to one another than in healthy control subjects. Conclusions These data extend major neuropsychological models of OCD by providing a direct link between intrinsically abnormal functional connectivity within dissociable frontostriatal circuits and those cognitive processes underlying OCD symptoms.

Neuroscientific research on conceptual knowledge based on the grounded cognition framework has shed light on the organization of concrete concepts into semantic categories that rely on different types of experiential information. Abstract concepts have traditionally been investigated as an undifferentiated whole, and have only recently been addressed in a grounded cognition perspective. The present fMRI study investigated the involvement of brain systems coding for experiential information in the conceptual processing of fine-grained semantic categories along the abstract-concrete continuum. These categories consisted of mental state-, emotion-, mathematics-, mouth action-, hand action-, and leg action-related meanings. Thirty-five sentences for each category were used as stimuli in a 1-back task performed by 36 healthy participants. A univariate analysis failed to reveal category-specific activations. Multivariate pattern analyses, in turn, revealed that fMRI data contained sufficient information to disentangle all six fine-grained semantic categories across participants. However, the category-specific activity patterns showed no overlap with the regions coding for experiential information. These findings demonstrate the possibility of detecting specific patterns of neural representation associated with the processing of fine-grained conceptual categories, crucially including abstract ones, though bearing no anatomical correspondence with regions coding for experiential information as predicted by the grounded cognition hypothesis.

OBJECTIVE: Biomarkers are defined as anatomical, biochemical or physiological traits that are specific to certain disorders or syndromes. The objective of this paper is to summarise the current knowledge of biomarkers for anxiety disorders, obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD).METHODS: Findings in biomarker research were reviewed by a task force of international experts in the field, consisting of members of the World Federation of Societies for Biological Psychiatry Task Force on Biological Markers and of the European College of Neuropsychopharmacology Anxiety Disorders Research Network.RESULTS: The present article (Part II) summarises findings on potential biomarkers in neurochemistry (neurotransmitters such as serotonin, norepinephrine, dopamine or GABA, neuropeptides such as cholecystokinin, neurokinins, atrial natriuretic peptide, or oxytocin, the HPA axis, neurotrophic factors such as NGF and BDNF, immunology and CO2 hypersensitivity), neurophysiology (EEG, heart rate variability) and neurocognition. The accompanying paper (Part I) focuses on neuroimaging and genetics.CONCLUSIONS: Although at present, none of the putative biomarkers is sufficient and specific as a diagnostic tool, an abundance of high quality research has accumulated that should improve our understanding of the neurobiological causes of anxiety disorders, OCD and PTSD.

Biomarkers are defined as anatomical, biochemical or physiological traits that are specific to certain disorders or syndromes. The objective of this paper is to summarise the current knowledge of biomarkers for anxiety disorders, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD).Findings in biomarker research were reviewed by a task force of international experts in the field, consisting of members of the World Federation of Societies for Biological Psychiatry Task Force on Biological Markers and of the European College of Neuropsychopharmacology Anxiety Disorders Research Network.The present article (Part I) summarises findings on potential biomarkers in neuroimaging studies, including structural brain morphology, functional magnetic resonance imaging and techniques for measuring metabolic changes, including positron emission tomography and others. Furthermore, this review reports on the clinical and molecular genetic findings of family, twin, linkage, association and genome-wide association studies. Part II of the review focuses on neurochemistry, neurophysiology and neurocognition.Although at present, none of the putative biomarkers is sufficient and specific as a diagnostic tool, an abundance of high-quality research has accumulated that will improve our understanding of the neurobiological causes of anxiety disorders, OCD and PTSD.

Congenital vascular bone syndrome (CVBS) is an abnormal enhancement or reduction of growth in long bones due to pathologic circulation during childhood. Several authors have described these clinical pictures with limb lengthening; well known are Klippel and Trenaunay and Parkes-Weber. Later, Servelle and Martorell also described cases of limb length difference, but with shortening of the pathologic limb. The mechanism of limb overgrowth is probably due to the effect of A-V shunts, while shortening occurs due to mechanical compression on bones by dysplastic vessels or flow reduction. Some molecules, like vascular endothelial growth factor and others, probably affect bone growth through a poorly understood mechanism. Diagnostically, one should try to demonstrate A-V shunts around or inside the bone or low flow vascular mass. Correction of length differences can occur spontaneously if the cause of CVBS is treated in childhood. In adults, limb length differences may be corrected by orthopaedic techniques.

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Venose Gefasmalformationen sind die am haufigsten vorkommende Gruppe der Gefasmissbildungen. Sie werden nach der Hamburger Klassifikation in trunkulare und extratrunkulare Formen eingeteilt. Die moderne Chirurgie verfugt uber verschiedene Behandlungsmoglichkeiten, abhangig von der Art des Defekts. Bei trunkularen Formen mit dysplastischer Erweiterung der oberflachlichen Venen werden spezifische Resektionen zur Entfernung der nichtfunktionellen abnormen Venen durchgefuhrt. Kongenitale, venose Aneurysmen, u. a. bei der V. poplitea, werden mit einer tangentialen Resektion behandelt. Die persistierende Marginalvene wird nach einer genauen Studie der Anatomie und Hamodynamik reseziert oder skelettisiert. Extratrunkulare Formen sind manchmal schwer zu behandeln. Vor jeder Behandlung ist eine genaue diagnostische Untersuchung extrem wichtig. Verschiedene spezifische Techniken stehen zur Verfugung, je nach Art und Lokalisation des Defekts. Die Behandlung ist in fast jedem Fall moglich, auch mit anderen Methoden, die mit den chirurgischen kombiniert werden konnen.

Objectives: Duplex ultrasonography was assessed for its advanced role as a contemporary guide for the safer management of venous malformation (VM) at the lower extremities through a comparison study with matching magnetic resonance imaging (MRI) and/or ascending phlebography findings. Methods: A retrospective review of 50 patients with a VM in the lower extremities was performed using the duplex scan findings on the initial diagnosis and the subsequent follow-up assessment of the treatment response. The screening findings of deep vein thrombosis (DVT) development following ethanol sclerotherapy on 40 patients were also included. A marginal vein (lateral embryonal) compression test was also performed on 10 patients, who were candidates for a resection preoperatively, in order to assess its value in predicting the response to the subsequent resection. The duplex scan findings were compared with the available ascending phlebography results in 38 patients, and also with the MRI findings available for all 50 patients. Results: The duplex scan on the 50 patients confirmed the existence of a normal deep vein system in the lower extremities in 43 patients as the true-positive test findings. One false-negative test finding was subsequently confirmed by an angiographic evaluation. The duplex scan also confirmed the absence of a normal deep vein system in four patients as a true-negative test. MRI subsequently confirmed two false-positive findings in one patient, and angiography confirmed two false-positive findings in another (sensitivity − 97.8%, specificity − 66.7%, positive predictive value − 95.6%, and negative predictive value − 80%). Among a total of 40 patients who received ethanol sclerotherapy, the duplex scan identified DVT in three patients, and also screened out properly in 37 patients through a total of 185 ethanol sclerotherapy sessions. The compression test predicted the surgical outcome successfully in the majority (7/8). The duplex scan appears to have comparable reliability to MRI and/or angiography for diagnosing and managing VM. Conclusions: The duplex scan can provide the critical haemodynamic information of both the deep venous system and VM lesions quite effectively with the cost-effectiveness of a non-invasive test. In particular, the duplex scan is an excellent test for the safe management of VM of the lower extremity, including the early detection of DVT through multi-session ethanol sclerotherapy.

Venous malformations (VMs) are the most common vascular developmental anomalies (birth defects). These defects are caused by developmental arrest of the venous system during various stages of embryogenesis. VMs remain a difficult diagnostic and therapeutic challenge due to the wide range of clinical presentations, unpredictable clinical course, erratic response to the treatment with high recurrence/persistence rates, high morbidity following nonspecific conventional treatment, and confusing terminology. The Consensus Panel reviewed the recent scientific literature up to the year 2013 to update a previous IUP Consensus (2009) on the same subject. ISSVA Classification with special merits for the differentiation between the congenital vascular malformation (CVM) and vascular tumors was reinforced with an additional review on syndrome-based classification. A "modified" Hamburg classification was adopted to emphasize the importance of extratruncular vs. truncular subtypes of VMs. This incorporated the embryological origin, morphological differences, unique characteristics, prognosis and recurrence rates of VMs based on this embryological classification. The definition and classification of VMs were strengthened with the addition of angiographic data that determines the hemodynamic characteristics, the anatomical pattern of draining veins and hence the risk of complication following sclerotherapy. The hemolymphatic malformations, a combined condition incorporating LMs and other CVMs, were illustratedas a separate topic to differentiate from isolated VMs and to rectify the existing confusion with namebased eponyms such as Klippel-Trenaunay syndrome. Contemporary concepts on VMs were updated with new data including genetic findings linked to the etiology of CVMs and chronic cerebrospinal venous insufficiency. Besides, newly established information on coagulopathy including the role of D-Dimer was thoroughly reviewed to provide guidelines on investigations and anticoagulation therapy in the management of VMs. Congenital vascular bone syndrome resulting in angio-osteo-hyper/hypotrophy and (lateral) marginal vein was separately reviewed. Background data on arterio-venous malformations was included to differentiate this anomaly from syndrome-based VMs. For the treatment, a new section on laser therapy and also a practical guideline for follow up assessment were added to strengthen the management principle of the multidisciplinary approach. All other therapeutic modalities were thoroughly updated to accommodate a changing concept through the years.

Cancer-related deficiency in circulating dendritic cells (DC), whose important anticancer role is well established, has been proven to be associated with lymphocytopenia. This study was performed to evaluate which lymphocyte subset is most markedly related to the failure of the DC system. The study included 30 patients with gastrointestinal tract cancer, 10 of whom had distant organ metastases. Immature and mature DCs were measured by FACS and monoclonal antibodies against CD123 and CD11c antigens, respectively. Low levels of immature and mature DCs were observed in 63% and 43% of patients, respectively. Patients with low levels of circulating mature DCs had significantly lower values of T lymphocytes, T helper lymphocytes and NK cells than those with normal mature DC levels. In contrast, no significant difference was seen between patients with normal or abnormally low values of immature DCs. Conversely, patients with a decreased number of T lymphocytes, T helper lymphocytes and NK cells showed significantly lower values of circulating mature DCs than those with lymphocyte subsets within the normal range, whereas no difference was seen in immature DC amounts. This study suggests that only mature DC deficiency may be associated with important lymphocyte subset alterations in cancer patients, whereas deficiency in immature DCs does not seem to be related to other immune cell disorders.

Evidence suggests that neurohormones such as GH and IGF-I are involved in the neuroreparative processes in multiple sclerosis (MS). GH and IGF-I blood levels in naïve MS patients with different disease courses were investigated in this study. Serum GH and IGF-I in untreated MS patients (n=64), healthy controls (HC,n=62), and patients affected by other neurological diseases (OND,n=46) were evaluated with a solid-phase-enzyme-labeled-chemiluminescent-immunometric assay. No differences were detected in GH across MS, OND, and HC (MS=0.87±1.32 ng/mL;OND=1.66±3.7; andHC=1.69±3.35;P=0.858) when considering gender, disease duration, and disease course. However, GH was lower (P=0.007) in patients with more severe disease (expanded disability scale score,EDSS≥4.0) compared with milder forms (EDSS<4). IGF-I l did not differ across the 3 groups (P=0.160), as far as concern disease course, disability, and gender were. Lower IGF-I levels were detected in subjects older than 50 years compared to younger ones for all 3 groups. Lower GH was detected in patients with more severe MS, and age was confirmed as the main factor driving IGF-I levels in all subjects. These findings, relying on the natural course of the disease, could help in shedding lights on the mechanisms involved in autoreparative failure associated with poorer prognosis in MS.

Background Multiple Sclerosis (MS) is a multi-factorial disease, where a single biomarker unlikely can provide comprehensive information. Moreover, due to the non-linearity of biomarkers, traditional statistic is both unsuitable and underpowered to dissect their relationship. Patients affected with primary (PP=14), secondary (SP=33), benign (BB=26), relapsing-remitting (RR=30) MS, and 42 sex and age matched healthy controls were studied. We performed a depth immune-phenotypic and functional analysis of peripheral blood mononuclear cell (PBMCs) by flow-cytometry. Semantic connectivity maps (AutoCM) were applied to find the natural associations among immunological markers. AutoCM is a special kind of Artificial Neural Network able to find consistent trends and associations among variables. The matrix of connections, visualized through minimum spanning tree, keeps non linear associations among variables and captures connection schemes among clusters. Results Complex immunological relationships were shown to be related to different disease courses. Low CD4IL25+ cells level was strongly related (link strength, ls=0.81) to SP MS. This phenotype was also associated to high CD4ROR+ cells levels (ls=0.56). BB MS was related to high CD4+IL13 cell levels (ls=0.90), as well as to high CD14+IL6 cells percentage (ls=0.80). RR MS was strongly (ls=0.87) related to CD4+IL25 high cell levels, as well indirectly to high percentages of CD4+IL13 cells. In this latter strong (ls=0.92) association could be confirmed the induction activity of the former cells (CD4+IL25) on the latter (CD4+IL13). Another interesting topographic data was the isolation of Th9 cells (CD4IL9) from the main part of the immunological network related to MS, suggesting a possible secondary role of this new described cell phenotype in MS disease. Conclusions This novel application of non-linear mathematical techniques suggests peculiar immunological signatures for different MS phenotypes. Notably, the immune-network displayed by this new method, rather than a single marker, might be viewed as the right target of immunotherapy. Furthermore, this new statistical technique could be also employed to increase the knowledge of other age-related multifactorial disease in which complex immunological networks play a substantial role.

A consolidated approach to the study of the mental representation of word meanings has consisted in contrasting different domains of knowledge, broadly reflecting the abstract-concrete dichotomy. More fine-grained semantic distinctions have emerged in neuropsychological and cognitive neuroscience work, reflecting semantic category specificity, but almost exclusively within the concrete domain. Theoretical advances, particularly within the area of embodied cognition, have more recently put forward the idea that distributed neural representations tied to the kinds of experience maintained with the concepts' referents might distinguish conceptual meanings with a high degree of specificity, including those within the abstract domain. Here we report the results of two psycholinguistic rating studies incorporating such theoretical advances with two main objectives: first, to provide empirical evidence of fine-grained distinctions within both the abstract and the concrete semantic domains with respect to relevant psycholinguistic dimensions; second, to develop a carefully controlled linguistic stimulus set that may be used for auditory as well as visual neuroimaging studies focusing on the parametrization of the semantic space beyond the abstract-concrete dichotomy. Ninety-six participants rated a set of 210 sentences across pre-selected concrete (mouth, hand, or leg action-related) and abstract (mental state-, emotion-, mathematics-related) categories, with respect either to different semantic domain-related scales (rating study 1), or to concreteness, familiarity, and context availability (rating study 2). Inferential statistics and correspondence analyses highlighted distinguishing semantic and psycholinguistic traits for each of the pre-selected categories, indicating that a simple abstract-concrete dichotomy is not sufficient to account for the entire semantic variability within either domains.

Percutaneous dilatational tracheostomy (PDT) is one of the most commonly performed procedures in critically ill patients receiving mechanical ventilation. Although many papers have compared different PDT techniques, few records on the outcome of tracheostomized patients after intensive care unit (ICU) discharge are available.Prospective observational study to evaluate efficacy, safety and long-term consequences of PDT performed over a 6-year period (January 2002-December 2007) in a combined medical/surgical ICU in Rho, Milan, Italy. A total of 181 patients were subjected to PDT, 26.5% with the Ciaglia technique and 73.5% with the Percu-twist technique.The main endpoints that were examined were complications related to PDT and the final outcome of tracheostomized patients. Early complications included minor bleeding in 4 patients, stomal infection in 8 patients, and the occurrence of hypoxic/desaturation events during the procedure in 3 cases. Late complications included: tracheal stenosis in a single case, recurrent stomal granuloma in 2 cases, and tracheal mucosa injury caused by the endotracheal tube cuff in 3 patients. All patients who were decannulated late underwent bronchoscopic follow-up at 3, 6 and 12 months. Hospital discharge: of the 137 patients alive at the time of discharge from the hospital, 115 were decannulated (40 early decannulation, 75 late decannulation). In total, 22 patients were never decannulated (14 breathed spontaneously whereas 8 needed ventilator support). In the group of patients that were decannulated late, the mortality rate at 1 year was 20.6%.PDT-related early complications without clinical consequences were observed. Conversely, late complications were infrequent but had significant clinical implications. Although late decannulation is the major risk for complications, in 83.9% of cases tracheostomy is only a temporary measure.

The evaluation of the immune status of cancer patients is not routinely included in clinical oncological practice mainly because of the great number of candidate immune parameters that could potentially be the best index of the status of anticancer immunity. Until recently, the T-helper/T-suppressor lymphocyte ratio (CD4/CD8) was considered to be an index of immunosuppression in cancer patients. Successive studies documented the existence of several subtypes of CD4+ lymphocytes, as well as showing that CD8+ cells were not in fact suppressive, but cytotoxic lymphocytes. More recently, the existence of a subtype of T-helper lymphocytes has been demonstrated provided by an evident suppressive activity on anticancer immunity. These are the so-called T-regulator (T-reg) lymphocytes, which may be detected as CD4+CD25+ cells.A study was carried out to evaluate CD4+/CD4+CD25+ ratio, corresponding to the T-helper/T-reg cell ratio (TH/TR), in a group of 50 cancer patients in relation to their disease extension and in 20 healthy controls.The mean TH/TR ratio observed in patients with metasytases was significantly lower with respect to that found in both patients without metastases and controls. On the contrary, the absolute mean number of T-reg cells was higher in patients with metastases than in those without, but the difference was not statistically significant.The evaluation of T-reg cells in terms of their proportion with respect to T-helper cell total number seems to be more appropriate than the simple measurement of their absolute count, in order to quantify cancer-related immunosuppression. Thus, the TH/TR ratio could represent a useful biological marker to explore the immune status of cancer patients.

The marginal vein, an abnormal superficial vein of the lateral lower limb, is a remnant of primitive embryonic vessels that have failed to regress. According to the extent, topography and sites of connection with the deep veins, five types have been distinguished by Weber. The marginal vein is valveless and may create venous stasis. Limb–length discrepancy and nevus may coexist. Diagnosis is made by duplex scan examination and phlebography; angio computerized tomography or magnetic resonance effectively demonstrates the vein but yield less haemodynamic data. The best treatment is complete surgical resection of the vein. Resection should be avoided in the rare cases when aplasia of the deep veins exists. A careful skeletonization can be performed if arterio-venous fistulas converge into the vein.

Corticosteroids, antidopaminergig agents and 5-HT3 antagonists are the most commonly used drugs in the treatment of chemotherapy-induced vomiting. Acupuncture and acupressure have also appeared to exert antiemetic effects. The aim of this study was to evaluate the efficacy of acupressure in the treatment of chemotherapy-induced vomiting resistant to the standard antiemetic therapies.The study included 40 consecutive advanced cancer patients with untreatable chemotherapy-induced vomiting. Colorectal cancer, lung cancer and breast cancer were the neoplasm most frequent in our patients. According to tumour histotype, patients received chemotherapeutic regimens containing the main emetic cytotoxic agents, including cisplatin and athracyclines. Acupressure was made by PC6 point stimulation for at least 6 h/day at the onset of chemotherapy.The therapeutic approach was well accepted by the overall patients. An evident improvement in the emetic symptomatology was achieved in 28/40 (70%) patients, without significant differences in relation to neither tumor histotype, nor type of chemotherapeutic agent.This preliminary study seems to suggest that a bioenergetic approach by acupressure on PC6 point may be effective in the treatment of chemotherapy-induced vomiting resistant to the conventional pharmacological strategies, as previously demonstrated for vomiting occurring during pregnancy.

Recent experimental observations, showing the potential role of prolactin (PRL) as a tumor growth factor for prostate cancer and the unfavourable prognostic significance of enhanced chromogranin-A-secreting neuroendocrine cell proliferation, could contribute to a better understanding of the mechanisms responsible for the occurrence of hormone-resistance in the prostate cancer. Moreover, it has been shown that tamoxifen, which consistently exerts estrogenic activity in males, may inhibit prostate cancer cell proliferation in experimental studies. At present, there are no clinical data in humans. This preliminary phase II study was planned in an attempt to evaluate the therapeutic efficacy of tamoxifen in hormone-refractory metastatic prostate cancer. The study included 14 consecutive metastatic prostate cancer patients, who had progressed under the classical endocrine therapy with LHRH-analogs and/or anti-androgens. Patients received the same treatment plus tamoxifen at 20 mg/day orally. A decline greater than 50% in prostate-specific antigen (PSA) levels occurred in 4/14 (29%) patients within the first 2 months of therapy, with a median duration of 5 months. Mean pre-treatment levels of PRL were significantly higher in responder patients than in those who progressed. Moreover, abnormally high pre-treatment levels of PRL were found in 5/14 (36%) patients. The percent of clinical responses observed in patients with pre-treatment hyperprolactinemia was significantly higher than that found in patients with normal pre-treatment PRL concentrations. Finally, a significant decline in mean PRL levels upon tamoxifen therapy occurred only in the responder patients. This preliminary study seems to justify further clinical research to confirm the potential efficacy of tamoxifen in the treatment of hormone-refractory prostate cancer and to identify possible parameters, which may predict the response to treatment.

The biochemical modulation of 5-fluorouracil (5-FU) by means of methotrexate (MTX) and 6-S leucovorin (LV) seems mainly directed at two different intracellular targets, supporting the hypothesis of possible non-cross resistance between these two methods of 5-FU potentia-tion. Thirty-one patients, all previously treated with 5-FU and LV for advanced colorectal cancer (ACC), were treated with MTX=200 mg/m2 iv day 1 and 5-FU 600 mg/m2 day 2 with 6-S LV 10 mg/m2 po q 6 h X 6 starting 24 h after MTX, repeated every 2 weeks. Of 30 eva-luable patients, 2 Partial Remissions (PR) were achieved (Response Rate=6.6%; 95% Confidence Interval 0%-14%). Eight patients had disease stabilization (SD). The overall median survival was 5 months (range 1-11). No WHO grade III-IV toxicities were reported. Despite the good tolerability, this combination of MTX, 5-FU and LV rescue has minimal activity in ACC after the failure of 5FU+LV-based chemotherapy.

The evidence of lymphocytopenia has been demonstrated to predict a poor prognosis in terms of survival in advanced cancer patients. This finding is not surprising because of the fundamental role of lymphocytes in mediating tumor cell destruction. Despite the importance of lymphocytes in the pathogenesis of cancer, there are only few data about the profile and the function of lymphocytes during the various antitumor therapies, and in particular the relation between lymphocyte pretreatment number and response to chemotherapy remains to be established. The present study was performed to evaluate whether the evidence of lymphocytopenia before the onset of treatment may influence the efficacy of chemotherapy in metastatic cancer patients affected by the most frequent tumor types. The study included 183 patients (lung cancer: 89; colorectal cancer: 63; breast cancer: 31), 95 of whom had been previously treated with chemotherapy. The chemotherapeutic regimens consisted of oxaliplatin plus 5-fluorouracil and folates in untreated colorectal cancer, weekly irinotecan in pretreated colorectal cancer, cisplatin plus gemcitabine or etoposide in untreated lung cancer, weekly vinorelbine in pretreated lung cancer, and taxotere in breast cancer patients who had been previously treated with anthracyclines. Lymphocyte count was considered to be abnormally low for values below 1500/mm3. Lymphocytopenia was found in 79/183 (43%) patients, without any significant differences in relation to tumor histology. A complete response (CR) was achieved in 6/104 patients with a normal lymphocyte count and in none of the 79 lymphocytopenic patients. A partial response (PR) was obtained in 39 patients with a normal lymphocyte count and in only eight patients with a low lymphocyte count prior to therapy. Therefore, irrespective of the type of chemotherapy, the objective tumor response rate (CR + PR) in lymphocytopenic patients was significantly lower than in patients with normal pretreatment lymphocyte counts (8/79 vs 45/104; p

In addition to the occurrence of pain, the evidence of a diminished capacity to feel pleasure is one of the most common cancer-related symptoms. Recent advances in psychoneuroendocrinological knowledge has shown that the perception of pleasure is mainly mediated by the dopaminergic pathways in the brain. Moreover, it has also been demonstrated that the brain dopaminergic sensitivity may be clinically explored by evaluating the endocrine response to the administration of dopaminergic agents, such as apomorphine, which consists of a decline in PRL concentrations and an increase in GH and cortisol levels. The present study was performed to evaluate dopaminergic sensitivity by the administration of apomorphine in cancer patients in an attempt to document possible cancer-related neuroendocrine anomalies, which could explain the psychological status of the patients. The study included 24 cancer patients (breast cancer: 12; colorectal cancer: 7; non-small cell lung cancer: 5), 12 of whom showed distant organ metastases. Apomorphine was given orally at 0.01 mg/kg b.w., by collecting venous blood samples before and after 20 and 60 minutes. A normal decline in PRL levels was seen in both non-metastatic and metastatic cancer patients. No cortisol increase in response to apomorphine was achieved and the lack of cortisol response was particularly evident in metastatic patients. No GH rise occurred in either metastatic or non-metastatic cancer patients. Finally, no significant difference in the endocrine response to apomorphine was seen in relation to the histotype of tumor. The results of this study show that the neoplastic disease is characterized by neurochemical alterations involving pleasure-related dopaminergic pathways, which are more evident in the metastatic disease, without particular differences in relation to tumor histotype. Therefore, the psychological condition of cancer patients would not depend only on psychological factors, but it could be due at least in part to cancer-related neuroendocrine alterations involving the dopaminergic system.

Recent advances in immunobiological knowledge have suggested the possibility of enhancing the therapeutic activity of various chemotherapeutic agents by a concomitant administration of anti-oxidant drugs and/or immunomodulating neurohormones. In particular, the pineal neurohormone melatonin (MLT), which is able to exert both antioxidant and immunomodulating effects, has been proven to enhance the efficacy of various chemotherapeutic drugs, namely cisplatin, anthracyclines and 5-fluorouracil, whereas at present there are no data about its possible influence on cytotoxic drugs effective in the treatment of colon cancer other than 5-fluorouracil, such as irinotecan (CPT-11). The present study was performed to evaluate the influence of a concomitant administration of MLT on CPT-11 therapeutic activity in metastatic colorectal cancer. The study included 30 metastatic colorectal cancer patients progressing after at least one previous chemotherapeutic line containing 5-fluorouracil, who were randomized to be treated with CPT-11 alone or CPT-11 plus MLT. According to a weekly low-dose schedule, CPT-11 was given i.v. at 125 mg/m2/week for 9 consecutive weeks. MLT was administered orally at 20 mg/day during the dark period of the day. No complete response was observed. A partial response (PR) was achieved in 2 out of 16 patients treated with CPT-11 alone and in 5 out of 14 patients concomitantly treated with MLT. Moreover, a stable disease (SD) was obtained in 5 out of 16 patients treated with CPT-11 alone and in 7 out of 14 patients treated with CPT-11 plus MLT. Therefore, the percent of disease-control achieved in patients concomitantly treated with MLT was significantly higher than that observed in those treated with chemotherapy alone (12 out of 14 vs 7 out of 16, p0.05). The only important toxicity was diarrhoea grade 3-4, which occurred in 6 out of 16 patients treated with CPT-11 alone and in 4 out of 14 patients treated with CPT-11 plus MLT, which required a 50% dose reduction. However, taken together, patients treated with CPT-11 at 50% of the planned dose showed a percent of disease control comparable to that achieved in patients who had no dose reduction (6 out of 10 vs 13 out of 20). This preliminary study shows that the efficacy of weekly low-dose CPT-11 in pretreated metastatic colorectal cancer patients may be enhanced by a concomitant daily administration of the pineal hormone MLT, according to the results previously reported for other chemotherapeutic agents. Moreover, since the dose reduction of CPT-11 does not influence its efficacy, the dose of CPT-11 for successive studies might be not greater than 70 mg/m2.

Despite the well-demonstrated stimulatory role of prolactin (PRL) on breast cancer cell growth and the possible existence of a PRL-dependency in estrogen-independent mammary tumors, the therapeutic role of the antiprolactinemic drugs in the treatment of human breast cancer has still to be investigated and defined. Previous preliminary studies have already shown that the concomitant administration of antiprolactinemic agents may enhance the efficacy of cancer chemotherapy for breast carcinoma, whereas their impact on the efficacy of the endocrine therapy is still unknown. At present, the classic endocrine therapy for breast cancer consists of anti-estrogens plus LHRH-analogue. The concomitant administration of antiprolactinemic drugs could enhance the efficacy of treatment by blocking not only the action of estrogens, but also that of another growth factor for breast cancer, such as PRL. The present phase II study was performed to evaluate the efficacy and tolerability of a polyneuroendocrine approach for breast cancer, consisting of LHRH-analogue plus the anti-estrogen tamoxifen plus a long-acting antiprolactinemic agent, cabergoline. The study included 14 consecutive metastatic breast cancer women, heavily pretreated with the standard anticancer therapies and for whom no other conventional treatment was available. The LHRH-analogue, triptorelin, was given intramuscularly at a dose of 3.75 mg every 28 days, tamoxifen was given orally at 20 mg/day and cabergoline was given orally at 0.5 mg once/week. The clinical response consisted of partial response (PR) in 4 out of 14 (29%) patients, including one who had progressed on a previous treatment with triptorelin plus tamoxifen alone. A stable disease (SD) was achieved in another 5 patients, whereas the other 5 patients had a progressive disease (PD). Mean serum levels of PRL significantly decreased on treatment within the first month of therapy, and its decline was significantly more evident in patients with PR or SD than in those with PD. The treatment was well-tolerated in all patients, and in particular no cabergoline-related toxicity occurred. This preliminary study would suggest that the association of the long-acting antiprolactinemic drug cabergoline may further enhance the efficacy of the classical endocrine therapy for advanced breast cancer with anti-estrogens plus LHRH-analogues.

Prolactin (PRL) constitutes a growth factor for breast cancer cell proliferation and abnormally elevated blood concentrations of PRL are associated with poor prognosis and reduced efficacy of antitumor therapies in metastatic breast carcinoma. It has already been demonstrated that low-dose bromocriptine, an antiprolactinemic long-acting dopaminergic drug, normalizes PRL blood concentrations in metastatic breast cancer patients with abnormally elevated PRL levels. In addition, previous clinical studies have already demonstrated a lower efficacy of chemotherapy with taxotere in metastatic breast cancer, with persistent hyperprolactinemia. We planned a controlled clinical study to evaluate the influence of a concomitant administration of the antiprolactinemic drug bromocriptine on the efficacy of chemotherapy with taxotere, in metastatic breast cancer patients progressing after chemotherapeutic combinations containing anthracyclines. The study included 30 randomized consecutive patients treated with taxotere alone or taxotere plus bromocriptine. Taxotere was given I.V. at 100 mg/m2 every 21 days for 3 cycles. Bromocriptine was given orally at 2.5 mg/day every day until the end of the chemotherapeutic treatment. Bromocriptine therapy induced a significant decline in PRL mean blood concentrations compared to patients treated by chemotherapy alone. No complete response was obtained. A partial response (PR) occurred in 5 out of 14 (36%) patients treated with taxotere plus bromocriptine and in only 2 out of 16 (13%) patients treated with taxotere alone. Moreover, a stable disease (SD) was obtained in 5 out of 16 patients treated with taxotere alone and in 7 out of 14 patients concomitantly treated with bromocriptine. Therefore, the percent of non-progressive disease (PR + SD) achieved in patients treated with taxotere plus bromocriptine was significantly higher with respect to that found in patients treated with taxotere alone (12 out of 14 vs 7 out of 16, p0.025). This preliminary clinical study would suggest that the inhibition of PRL secretion by antiprolactinemic drugs such as bromocriptine may enhance the efficacy of chemotherapy for metastatic breast cancer.

The recent availability of adequate methods for cytokine measurement could contribute to better understanding the immunophysiopathology of neoplastic disease. Unfortunately, very little data is available about cytokine secretion in cancer patients. At present, IL-2, IL-12 and IL-15 represent the major antitumor cytokines in humans. Preliminary clinical studies have shown a progressive decline in IL-2 levels with cancer progression, whereas IL-12 seems to increase in the advanced disease. IL-18 is the latest cytokine discovered by potential anticancer and anti-angiogenetic activity, and it has effects similar to those of IL-12. This preliminary study was carried out to analyze IL-18 secretion in early or advanced cancer patients. The study included 40 cancer patients (lung cancer, 21; gastrointestinal tumors, 19), 17 of whom had metastatic disease, and 50 healthy controls. Serum levels of IL-18 were measured by ELISA. No significant difference in IL-18 mean levels was seen between controls and non-metastatic patients. In contrast, metastatic patients showed significantly higher IL-18 mean values with respect to both healthy controls and non-metastatic patients. This preliminary study seems to suggest that metastatic disease may be characterized by enhanced IL-18 secretion the biological and prognostic significance to be established by successive clinical investigation.