Depletion of the Transcriptional Coactivator Amplified in Breast Cancer 1 (AIB1) Uncovers Functionally Distinct Subpopulations in Triple-Negative Breast Cancer.

The transcriptional coactivator Amplified in Breast Cancer 1 (AIB1) plays a major role in the progression of hormone and HER2-dependent breast cancers but its role in triple negative breast cancer (TNBC) is undefined. Here, we report that established TNBC cell lines, as well as cells from a TNBC patient-derived xenograft (PDX) that survive chemotherapy treatment in vitro express lower levels of AIB1 protein. The surviving cell population has an impaired tube-formation phenotype when cultured onto basement membrane, a property shared with TNBC cells that survive shRNA-mediated depletion of AIB1 (AIB1LOW cells). DNA analysis by exome sequencing revealed that AIB1LOW cells represent a distinct subpopulation. Consistent with their in vitro phenotype AIB1LOW cells implanted orthotopically generated slower growing tumors with less capacity for pulmonary metastases. Gene expression analysis of cultured cells and tumors revealed that AIB1LOW cells display a distinct expression signature of genes in pro-inflammatory pathways, cell adhesion, proteolysis and tissue remodeling. Interestingly, the presence of this AIB1LOW expression signature in breast cancer specimens is associated with shorter disease free survival of chemotherapy treated patients. We concluded that TNBC cell lines contain heterogeneous populations with differential dependence on AIB1 and that the gene expression pattern of AIB1LOW cells may represent a signature indicative of poor response to chemotherapy in TNBC patients.

Child attention to pain and pain tolerance are dependent upon anxiety and attention control: An eye-tracking study.

BACKGROUND: Pain is common and can be debilitating in childhood. Theoretical models propose that attention to pain plays a key role in pain outcomes, however, very little research has investigated this in youth. This study examined how anxiety-related variables and attention control interacted to predict children's attention to pain cues using eye-tracking methodology, and their pain tolerance on the cold pressor test (CPT). METHODS: Children aged 8-17 years had their eye-gaze tracked whilst they viewed photographs of other children displaying painful facial expressions during the CPT, before completing the CPT themselves. Children also completed self-report measures of anxiety and attention control. RESULTS: Findings indicated that anxiety and attention control did not impact children's initial fixations on pain or neutral faces, but did impact how long they dwelled on pain versus neutral faces. For children reporting low levels of attention control, higher anxiety was associated with less dwell time on pain faces as opposed to neutral faces, and the opposite pattern was observed for children with high attention control. Anxiety and attention control also interacted to predict pain outcomes. For children with low attention control, increasing anxiety was associated with anticipating more pain and tolerating pain for less time. CONCLUSIONS: This is the first study to examine children's attention to pain cues using eye-tracking technology in the context of a salient painful experience. Data suggest that attention control is an important moderator of anxiety on multiple outcomes relevant to young people's pain experiences. SIGNIFICANCE: This study uses eye tracking to study attention to pain cues in children. Attention control is an important moderator of anxiety on attention bias to pain and tolerance of cold pressor pain in youth.

Reactivation of mutant p53 by a dietary-related compound phenethyl isothiocyanate inhibits tumor growth.

Mutations in the p53 tumor-suppressor gene are prevalent in human cancers. The majority of p53 mutations are missense, which can be classified into contact mutations (that directly disrupts the DNA-binding activity of p53) and structural mutations (that disrupts the conformation of p53). Both of the mutations can disable the normal wild-type (WT) p53 activities. Nevertheless, it has been amply documented that small molecules can rescue activity from mutant p53 by restoring WT tumor-suppressive functions. These compounds hold promise for cancer therapy and have now entered clinical trials. In this study, we show that cruciferous-vegetable-derived phenethyl isothiocyanate (PEITC) can reactivate p53 mutant under in vitro and in vivo conditions, revealing a new mechanism of action for a dietary-related compound. PEITC exhibits growth-inhibitory activity in cells expressing p53 mutants with preferential activity toward p53(R175), one of the most frequent 'hotspot' mutations within the p53 sequence. Mechanistic studies revealed that PEITC induces apoptosis in a p53(R175) mutant-dependent manner by restoring p53 WT conformation and transactivation functions. Accordingly, in PEITC-treated cells the reactivated p53(R175) mutant induces apoptosis by activating canonical WT p53 targets, inducing a delay in S and G2/M phase, and by phosphorylating ATM/CHK2. Interestingly, the growth-inhibitory effects of PEITC depend on the redox state of the cell. Further, PEITC treatments render the p53(R175) mutant sensitive to degradation by the proteasome and autophagy in a concentration-dependent manner. PEITC-induced reactivation of p53(R175) and its subsequent sensitivity to the degradation pathways likely contribute to its anticancer activities. We further show that dietary supplementation of PEITC is able to reactivate WT activity in vivo as well, inhibiting tumor growth in xenograft mouse model. These findings provide the first example of mutant p53 reactivation by a dietary compound and have important implications for cancer prevention and therapy.

The contribution of the androgen receptor (AR) in human spatial learning and memory: A study in women with complete androgen insensitivity syndrome (CAIS).

Few studies have examined the impact of androgen insensitivity on human spatial learning and memory. In the present study, we tested 11 women with complete androgen insensitivity syndrome (CAIS), a rare genetic disorder characterized by complete absence of AR activity, and compared their performance against 20 comparison males and 19 comparison females on a virtual analog of the Morris Water Maze task. The results replicated a main sex effect showing that men relative to women were faster in finding the hidden platform and had reduced heading error. Furthermore, findings indicated that mean performance of women with CAIS was between control women and control men, though the differences were not statistically significant. Effect size estimates (and corresponding confidence intervals) of spatial learning trials showed little difference between women with CAIS and control women but CAIS women differed from men, but not women, on two variables, latency to find the platform and first-move latency. No differences between groups were present during visible platform trials or the probe trial, a measure of spatial memory. Moreover, groups also did not differ on estimates of IQ and variability of performance. The findings are discussed in relation to androgen insensitivity in human spatial learning and memory.

The effect of parental loss on cognitive and affective interference in adolescent boys from a post-conflict region.

Little is known about the impact of early-life stressors such as parental loss on cognitive-affective processing during adolescence, especially in regions chronically affected by war and armed conflict. Here, we tested 72 male adolescents living in Northern Uganda (ages 14-19), 52 of whom still had both of their parents and 20 participants who had experienced parental loss. Participants completed a classic color-naming Stroop task as well as an affective interference task, the opposite emotions test (OET). Adolescents with parental loss showed a decrease in performance over time, especially on the Stroop task. Critically, this decrement in performance was positively associated with reported symptoms of trauma, but only in the parental loss group. The current data suggest a difficulty in maintaining cognitive control performance in youths with experience of parental loss. The findings are discussed in relation to traumatic stress and mental health in post-conflict regions.

Assessing gonadal hormone contributions to affective psychopathologies across humans and animal models.

Despite increasing acknowledgement of hormonal contributions to mood and anxiety disorders, the underlying mechanisms by which gonadal hormones influence psychopathology-related behaviours remain unknown. This review focuses on recent research that examines the influence of gonadal steroid hormones, including androgens, oestrogens, and progesterone, on mood and anxiety-related behaviours in human health and disease. To this aim, the literature was surveyed for studies that assess conditions with suspected underlying hormonal imbalances in otherwise healthy participants (e.g., premenstrual dysphoric disorder, postmenopausal depression) as well as conditions linked to congenital endocrine abnormalities (e.g., Turner Syndrome, Klinefelter Syndrome, polycystic ovary syndrome, congenital adrenal hyperplasia, familial male precocious puberty, androgen insensitivity syndrome). Furthermore, to better inform clinical work and to create a translational bridge, a second goal was to set human psychopathologies and animal models of these conditions side-by-side. In the second part of the review, based on consistencies revealed in the existing literature across conditions, a new model for the impact of gonadal hormones on anxious and depressed behavioural states is proposed. Finally, we conclude by proposing directions for future research, including the development of specific tasks suitable for cross-species comparisons to increase our knowledge of the role of gonadal hormones in mood and anxiety.

Combination of C-TRUS with multiparametric MRI: potential for improving detection of prostate cancer.

PURPOSE: To improve the detection of prostate cancer, especially in pre-biopsied patients, a guided biopsy based on radiologic findings is an option. We addressed the question, whether the combination of multiparametric MRI and computerized transrectal ultrasound (C-TRUS) improves the detection of prostate cancer. METHODS: Twenty patients suspicious of having prostate cancer were included. Seventeen patients were pre-biopsied once or more. Each patient was examined by multiparametric MRI and C-TRUS, followed by a guided transrectal prostate biopsy series. Patients were stratified in a "low-risk" and "high-risk" group. The results were analyzed using descriptive statistics. RESULTS: In 58 % (11 pat.) of patients, prostate cancer was found. In the "high-risk" group, biopsy in 73 % (8 pat.) of patients was positive for prostate cancer. All prostate cancer patients were found by C-TRUS-guided biopsies, whereas MRI did not reveal cancer in 27 %. 72 % (8 pat.) of patients had undergone radical prostatectomy. 65 % (6 pat.) had higher tumor stages after prostatectomy and 62.5 % (5 pat.) had higher Gleason-score. CONCLUSIONS: Combination of multiparametric MRI and C-TRUS seems to improve detection of prostate cancer, especially in high-risk patients. Detection rates of C-TRUS in this study could confirm those of the primary C-TRUS studies. The benefit of MRI is the additional visualization of the tumor extension. The technique is an option for pre-biopsied patients. Both imaging methods often fail to predict correct tumor stage, but further studies are necessary.

The nuclear coactivator amplified in breast cancer 1 maintains tumor-initiating cells during development of ductal carcinoma in situ.

The key molecular events required for the formation of ductal carcinoma in situ (DCIS) and its progression to invasive breast carcinoma have not been defined. Here, we show that the nuclear receptor coactivator amplified in breast cancer 1 (AIB1) is expressed at low levels in normal breast but is highly expressed in DCIS lesions. This is of significance since reduction of AIB1 in human MCFDCIS cells restored a more normal three-dimensional mammary acinar structure. Reduction of AIB1 in MCFDCIS cells, both before DCIS development or in existing MCFDCIS lesions in vivo, inhibited tumor growth and led to smaller, necrotic lesions. AIB1 reduction in MCFDCIS cells was correlated with significant reduction in the CD24-/CD44+ breast cancer-initiating cell (BCIC) population, and a decrease in myoepithelial progenitor cells in the DCIS lesions in vitro and in vivo. The loss of AIB1 in MCFDCIS cells was also accompanied by a loss of expression of NOTCH 2, 3 and 4, JAG2, HES1, GATA3, human epidermal growth factor receptor 2 (HER2) and HER3 in vivo. These signaling molecules have been associated with differentiation of breast epithelial progenitor cells. These data indicate that AIB1 has a central role in the initiation and maintenance of DCIS and that reduction of AIB1 causes loss of BCIC, loss of components of the NOTCH, HER2 and HER3 signaling pathways and fewer DCIS myoepithelial progenitor cells in vivo. We propose that increased expression of AIB1, through the maintenance of BCIC, facilitates formation of DCIS, a necessary step before development of invasive disease.

Magnetic resonance imaging in paediatric psychoneuroendocrinology: a new frontier for understanding the impact of hormones on emotion and cognition.

Mounting magnetic resonance imaging (MRI) research is characterising the neurobiological trajectories of healthy human brain development. In parallel, studies increasingly acknowledge the relevance of perturbations of these trajectories for adolescent and adult psychopathology. Although an influence of steroid hormones on mood and anxiety disorders has been demonstrated in adults, very little is known about how steroid hormones alter human brain development and contribute to adolescent psychopathology. This review focuses on recent evidence obtained from structural and functional MRI in children and adolescents with genetic endocrine disorders and with characteristic fluctuations in androgen or oestrogen levels (familial male precocious puberty, congenital adrenal hyperplasia, Klinefelter syndrome and Turner syndrome). It aims to highlight how neurobiological findings from these paediatric endocrine disorders can provide insight into the contribution of sex steroids with respect to the development of neurocircuitry involved in affective processing (amygdala, hippocampus) and cognitive control (prefrontal cortex, inferior frontal gyrus, striatum). In addition, findings from these populations may also provide important information on aberrant psychological processes relevant for the clinical care and management of these populations. Finally, the findings are discussed within the context of current frameworks in animal models, such as the organisational-activational hypothesis or the aromatisation hypothesis. The review ends with a discussion of open questions for future enquiry with the goal of integrating translational models with current knowledge of endocrine disorders and developmental studies in healthy populations.

Comparison of transrectal prostate biopsy results with histology of transurethral resection of the prostate in men undergoing high-intensity focused ultrasound.

INTRODUCTION: The aim of our study was to evaluate the significance of transurethral resection of the prostate (TURP) to detect prostate cancer (PCa). A comparison was performed of the TURP specimens of patients undergoing high-intensity focused ultrasound (HIFU) with the core biopsies. MATERIALS AND METHODS: TURP before undergoing HIFU therapy was performed in 106 patients without neoadjuvant treatment. The resected tissue was subjected to histopathological evaluation and compared to the histological results of transrectal prostate biopsy. RESULTS: Cancer was detected in the resected tissue of 69 patients (65%). A positive correlation of the amount of resected tissue and detection of PCa could be demonstrated in a multivariate analysis. CONCLUSIONS: With a rate of 65% PCa detected by TURP, our data provide evidence that TURP might be suitable to detect PCa in a small group of selected patients with continuously rising PSA levels and several negative biopsies. On the other hand, these data underline/reinforce the necessity to treat the whole gland using modern treatment modalities such as HIFU and cryotherapy.

Grey matter volume correlates with virtual water maze task performance in boys with androgen excess.

Major questions remain about the specific role of testosterone in human spatial navigation. We tested 10 boys (mean age 11.65 years) with an extremely rare disorder of androgen excess (Familial Male Precocious Puberty, FMPP) and 40 healthy boys (mean age 12.81 years) on a virtual version of the Morris Water Maze task. In addition, anatomical magnetic resonance images were collected for all patients and a subsample of the controls (n=21) after task completion. Behaviourally, no significant differences were found between both groups. However, in the MRI analyses, grey matter volume (GMV) was correlated with performance using voxel-based morphometry (VBM). Group differences in correlations of performance with GMV were apparent in medial regions of the prefrontal cortex as well as the middle occipital gyrus and the cuneus. By comparison, similar correlations for both groups were found in the inferior parietal lobule. These data provide novel insight into the relation between testosterone and brain development and suggest that morphological differences in a spatial navigation network covary with performance in spatial ability.

[Education of medical students in urology in Germany: present status]. / Ausbildung von Medizinstudenten auf dem Gebiet der Urologie in Deutschland : Aktuelle Situation.

BACKGROUND: There is a growing demand for doctors in Germany and diseases of the genitourinary tract have become more prevalent in recent years. Politicians plan to increase the number of students in an already heavily overloaded system but data on quality and structure of medical education in Urology are lacking. The purpose of this study was to investigate the extent and quality of undergraduate medical education in urology. MATERIAL AND METHODS: Departments of Urology at German University Hospitals were surveyed using a questionnaire. Questions covered four different fields of medical education and answers were analyzed by descriptive statistics. RESULTS: Of the teachers involved in medical education 97% are physicians and 4% of these have special didactic qualifications. On average 1 teacher is responsible for 13 students and 44% of departments also have to carry out medical duties during teaching lessons. More than half of the departments offer modern learning forms, such as e-learning, problem-oriented learning or skills laboratory training. CONCLUSIONS: Urology departments at German University Hospitals spend much time on medical education. Nearly all physicians are involved in medical education, whether they are experienced or not and in many cases teaching is carried out in parallel to patient care. In more than half of the cases modern education tools were employed which implies a good standard of quality but there are no data on outcome.

Antiproliferative and apoptosis inducing effects of indirubin-3'-monoxime in renal cell cancer cells.

OBJECTIVES: Indirubin-3'-monoxime, which is a selective and potent inhibitor of cyclin-dependent kinases (CDKs) has shown preclinical activity in several human cancer cells. This study investigated if indirubin-3'-monoxime can induce apoptosis and tumor cell death in 3 human (A498, CAKI-1, CAKI-2) and 1 murine renal cell cancer (RENCA) cell line. METHODS: The growth inhibitory and apoptosis induction properties were evaluated by EZ4U, a cytotoxic assay and by flow cytometry of annexin-V/PI staining during treatment with doses ranging from 5.0 to 15.0 µM indirubin-3'-monoxime over 72 hours. To further establish the underlying molecular targets of indirubin-3'-monoxime, survivin, a major anti-apoptotic protein was additionally determined by intracellular flow cytometry. RESULTS: Our results show that indirubin-3'-monoxime induces growth arrest and apoptosis in all renal cell cancer (RCC) cell lines. All RCC lines expressed survivin. However, a clear correlation between apoptosis induction and expression of survivin was not found. CONCLUSIONS: As treatment of metastatic renal cell cancer (mRCC) remains a challenge, and the need for continuing assessment of novel agents in the treatment of this disease is mandatory. Indirubin-3'-monoxime seems to be a candidate for further evaluation.

c-Src differentially regulates the functions of microtentacles and invadopodia.

During metastasis, invading cells produce various actin-based membrane protrusions that promote directional migration and proteolysis of extracellular matrix (ECM). Observations of actin staining within thin, tubulin-based microtentacle (McTN) protrusions in suspended MDA-MB-231 tumor cells, prompted an investigation of whether McTNs are structural or functional analogs of invadopodia. We show here that MDA-MB-231 cells are capable of producing invadopodia and McTNs, both of which contain F-actin. Invadopodium formation was enhanced by the expression of a constitutively active c-Src kinase, and repressed by the expression of dominant-negative, catalytically inactive form of c-Src. In contrast, expression of inactive c-Src significantly increased McTN formation. Direct inhibition of c-Src with the SU6656 inhibitor compound also significantly enhanced McTN formation, but suppressed invadopodia, including the appearance of F-actin cores and phospho-cortactin foci, as well as completely blocking focal degradation of ECM. In addition, silencing of Tks5 in Src-transformed fibroblasts blocked invadopodia without affecting McTNs. Genetic modification of c-Src activity that promoted McTN formation augmented capillary retention of circulating tumor cells in vivo and rapid re-attachment of suspended cells in vitro, even though invadopodia were strongly suppressed. These results indicate that McTNs are capable of enhancing tumor cell reattachment, even in the absence of Tks5 and active Src, and define separate cytoskeletal mechanisms and functions for McTNs and invadopodia.

ERP indices of persisting and current inhibitory control: a study of saccadic task switching.

Previous studies have found that inhibition of a biologically dominant prepotent response tendency is required during the execution of a less familiar, non-prepotent response. However, the lasting impact of this inhibition and the cognitive mechanisms to flexibly switch between prepotent and non-prepotent responses are poorly understood. We examined the neurophysiological (ERP) correlates of switching between prosaccade and antisaccade responses in 22 healthy volunteers. The behavioural data showed significant switch costs in terms of response latency for the prosaccade task only. These costs occurred exclusively in trials when preparation for the switch was limited to 300 ms, suggesting that inhibition of the prepotent prosaccade task either passively dissipated or was actively overcome during the longer 1000 ms preparation interval. In the neurophysiological data, a late frontal negativity (LFN) was visible during preparation for a switch to the prosaccade task that was absent when switching to the antisaccade task, which may reflect the overcoming of persisting inhibition. During task implementation both saccade types were associated with a late parietal positivity (LPP) for switch relative to repetition trials, possibly indicating attentional reorienting to the switched-to task, and visible only with short preparation intervals. When the prosaccade and antisaccade task were contrasted directly during task implementation, the antisaccade task exhibited increased stimulus-locked N2 and decreased P3 amplitudes indicative of active inhibition. The present findings indicate that neurophysiological markers of persisting and current inhibition can be revealed using a prosaccade/antisaccade-switching task.

Early androgen exposure modulates spatial cognition in congenital adrenal hyperplasia (CAH).

Major questions remain about the exact role of hormones in cognition. Furthermore, the extent to which early perturbation in steroid function affects human brain development continues to be a wide open area of research. Congenital adrenal hyperplasia (CAH), a genetic disorder of steroid dysfunction characterized in part by in utero over-production of testosterone, was used as a natural model for addressing this question. Here, CAH (n=54, mean age=17.53, 31 female) patients were compared to healthy age- and sex-matched individuals (n=55, mean age=19.02, 22 female) on a virtual equivalent of the Morris Water Maze task [Morris, R., 1984. Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Methods 11, 47-60], an established measure of sex differences in spatial cognition in rodents. Findings revealed that females with CAH with the most severe form of the disease and expected highest level of in utero exposure to androgens were found to perform similarly to both healthy males and CAH males, whereas strong sex differences were apparent in milder forms of the disorder and in controls. Moreover, advanced bone age, an indicator of long-term childhood exposure to testosterone was correlated with improved performance. The results indicate that individuals exposed to both excess androgens prenatally and prolonged exposure during childhood may manifest long-lasting changes in cognitive function. Such finding suggests a pivotal role of hormonal function on brain development in humans, mirroring results from the animal literature.

Pharmacokinetics of oral mycophenolate mofetil in combination with CsA in dogs after nonmyeloablative allogeneic hematopoietic stem cell transplantation.

Mycophenolate mofetil (MMF) has been used successfully in solid organ transplantation (SOT) and more recently in nonmyeloablative hematopoietic stem cell transplantation (HSCT) for prophylaxis of graft rejection and acute graft-versus-host disease. However, the pharmacokinetics of MMF seem to differ when applied in HSCT compared to SOT. Here, we analyzed pharmacokinetics of mycophenolic acid (MPA), the active metabolite of MMF, in a nonmyeloablative canine HSCT model. Dogs received nonmyeloablative TBI for conditioning followed by leukocyte antigen-identical littermate HSCT and immunosuppression containing cyclosporin A (CsA) and different doses of MMF. Pharmacokinetics were performed on days 2, 14 and 27. Dose escalation of MMF from 10 to 30 mg/kg tended to increase area under the curve (AUC) and the apparent oral clearance by 45 and 110%, respectively. Doses applied had no linear association with MPA concentration or blood trough level. No significant drug accumulation occurred over time. Using a twice daily MMF regimen, we conclude that an AUC of 30-60 mug/ml h as recommended for SOT cannot be reached in HSCT. Toxicities did not permit single doses higher than 30 mg/kg. Thus, if larger AUCs are desired in order to assure sufficient immunosuppression in HSCT, MMF might have to be administered at least three times daily.

Clearance of levofloxacin by an in vitro model of continuous venovenous hemodialysis (CVVHD).

Information about the elimination and the adequate dosing of levofloxacin during renal replacement therapy is scarce. The aim of this study was to characterize in vitro the elimination of levofloxacin during continuous venovenous hemodialysis (CVVHD) and to investigate whether the CVVHD clearances of creatinine and urea are correlated with the levofloxacin clearance in order to facilitate dosage adjustments. An in vitro model of CVVHD was established using five dialyzer membranes at varying dialysate flow rates applied in the clinical setting (8, 16, 25, 33 and 41 ml/min). Plasma and dialysate samples were drawn for determination of levofloxacin, creatinine and urea concentrations to evaluate clearances by CVVHD. During CVVHD, the clearance of levofloxacin varied between 9.02 and 33.30 ml/min, depending on the chosen setup. Positive correlations (p<0.001) were received for: dialysate flow rate (QD) and creatinine/ urea clearances (R(2)>0.93); QD and levofloxacin clearance (R(2) 0.59-0.71); levofloxacin and creatinine clearance (R(2) 0.69-0.75); and levofloxacin and urea clearance (R(2) 0.56-0.75) as well. When dosing critically ill patients, therefore, extracorporeal as well as total clearance of levofloxacin should be considered.

Enhanced cognitive control in Tourette Syndrome during task uncertainty.

Tourette Syndrome (TS) is a developmental neurological condition that is characterised by the presence of multiple motor and one or more vocal tics. Tics are highly stereotyped repetitive behaviours that fluctuate in type, complexity and severity. TS has been linked to impaired cognitive control processes, however, a recent study (Mueller et al. in Curr Biol 16:570-573, 2006) demonstrated that young people with TS, although exhibiting chronic motor and vocal tics, nevertheless performed significantly better than a group of age-matched controls on a task that required extremely high levels of cognitive control (i.e., predictably shifting between executing pro-saccade and anti-saccade responses to a visual stimulus). As predictable task sequences allow task-related cognitive processes to commence prior to the presentation of target stimuli we examined whether the superior performance of the TS group could be replicated when task sequences were varied unpredictably. Our results confirmed that both the TS group and an age-matched control group benefited, by the same extent, when the saccade task (pro-saccade vs. anti-saccade) was pre-cued. In contrast, while the control group showed a significant decrease in performance on task switch trials relative to task repetition trials-the TS group exhibited no significant 'costs' of switching task. While task performance was modulated by response and target location shifts in the control group, these factors had less impact on the TS group's performance on task switch trials. These results confirm and extend the previous demonstration that individuals with TS exhibit paradoxically greater levels of cognitive control than healthy controls.

Behavioural and neurophysiological correlates of bivalent and univalent responses during task switching.

A hallmark of human behaviour is its flexibility. In any given circumstance there is typically a range of possible responses that could be selected. In the current study participants were presented with stimulus displays that afforded two simple cognitive tasks and were required to switch predictably between them. The judgements for each task were either uniquely mapped onto separate effectors (univalent conditions) or else mapped onto shared effectors (bivalent condition). The results demonstrated that whilst behavioural switch costs were similar across the mapping conditions, these conditions differed in the patterns of brain activity observed during task preparation and early visual processing of the target. Specifically, a cue-locked switch-related late frontal negativity was present over frontal sensors for the bivalent condition only, and a target-locked N1 over occipital sensors was larger in the bivalent condition than the univalent conditions. In contrast, a switch-related target-locked P3b component was common to all mapping conditions. These findings are discussed with respect to differences in processing demands for switching between tasks with bivalent versus univalent responses.