Older adults benefit from more widespread brain network integration during working memory.

Neuroimaging evidence suggests that the aging brain relies on a more distributed set of cortical regions than younger adults in order to maintain successful levels of performance during demanding cognitive tasks. However, it remains unclear how task demands give rise to this age-related expansion in cortical networks. To investigate this issue, functional magnetic resonance imaging was used to measure univariate activity, network connectivity, and cognitive performance in younger and older adults during a working memory (WM) task. Here, individuals performed a WM task in which they held letters online while reordering them alphabetically. WM load was titrated to obtain four individualized difficulty levels with different set sizes. Network integration-defined as the ratio of within-versus between-network connectivity-was linked to individual differences in WM capacity. The study yielded three main findings. First, as task difficulty increased, network integration decreased in younger adults, whereas it increased in older adults. Second, age-related increases in network integration were driven by increases in right hemisphere connectivity to both left and right cortical regions, a finding that helps to reconcile existing theories of compensatory recruitment in aging. Lastly, older adults with higher WM capacity demonstrated higher levels of network integration in the most difficult task condition. These results shed light on the mechanisms of age-related network reorganization by demonstrating that changes in network connectivity may act as an adaptive form of compensation, with older adults recruiting a more distributed cortical network as task demands increase.

Cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric cancer: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

BACKGROUND: Cetuximab enhances the efficacy of chemotherapy in several cancer types. This trial assessed the activity of cetuximab and chemotherapy in advanced gastric cancer. METHODS: Patients with previously untreated, metastatic, gastric cancer received cetuximab 400 mg m(-2) at first infusion followed by weekly infusions of 250 mg m(-2) combined with FUFOX (oxaliplatin 50 mg m(-2), 5-FU 2000 mg m(-2), and DL-folinic acid 200 mg m(-2) d1, 8, 15 and 22 qd36). The primary endpoint was tumour response. RESULTS: Overall, 52 patients were enrolled. The most common grade 3/4 toxicities were diarrhoea (33%), and skin toxicity (24%). Efficacy was evaluable in 46 patients who showed a response rate of 65% (CI 95%: 50-79%) including four complete responses. Time to progression (TTP) was 7.6 months (CI 95%: 5.0-10.1 months) and overall survival (OS) was 9.5 months (CI 95%: 7.9-11.1 months). Epidermal growth factor receptor (EGFR) was detectable in 60% of tumours but showed no correlation with treatment outcome. A KRAS mutation was found in only 1 of 32 (3%) tumour samples analysed. CONCLUSION: Cetuximab plus FUFOX showed an interesting high response rate in metastatic gastric cancer. Cetuximab plus platinum-fluoropyrimidine chemotherapy is at present being investigated in a phase III randomised controlled trial.

Remediation of sleep-deprivation-induced working memory impairment with fMRI-guided transcranial magnetic stimulation.

Repetitive transcranial magnetic stimulation (rTMS) was applied to test the role of selected cortical regions in remediating sleep-deprivation-induced deficits in visual working memory (WM) performance. Three rTMS targets were chosen using a functional magnetic resonance imaging (fMRI)-identified network associated with sleep-deprivation-induced WM performance impairment: 2 regions from the network (upper left middle occipital gyrus and midline parietal cortex) and 1 nonnetwork region (lower left middle occipital gyrus). Fifteen participants underwent total sleep deprivation for 48 h. rTMS was applied at 5 Hz during a WM task in a within-subject sham-controlled design. The rTMS to the upper-middle occipital site resulted in a reduction of the sleep-induced reaction time deficit without a corresponding decrease in accuracy, whereas stimulation at the other sites did not. Each subject had undergone fMRI scanning while performing the task both pre- and postsleep deprivation, and the degree to which each individual activated the fMRI network was measured. The degree of performance enhancement with upper-middle occipital rTMS correlated with the degree to which each individual failed to sustain network activation. No effects were found in a subset of participants who performed the same rTMS procedure after recovering from sleep deprivation, suggesting that the performance enhancements seen following sleep deprivation were state dependent.

Online repetitive transcranial magnetic stimulation during working memory in younger and older adults: A randomized within-subject comparison.

Working memory is the ability to perform mental operations on information that is stored in a flexible, limited capacity buffer. The ability to manipulate information in working memory is central to many aspects of human cognition, but also declines with healthy aging. Given the profound importance of such working memory manipulation abilities, there is a concerted effort towards developing approaches to improve them. The current study tested the capacity to enhance working memory manipulation with online repetitive transcranial magnetic stimulation in healthy young and older adults. Online high frequency (5Hz) repetitive transcranial magnetic stimulation was applied over the left dorsolateral prefrontal cortex to test the hypothesis that active repetitive transcranial magnetic stimulation would lead to significant improvements in memory recall accuracy compared to sham stimulation, and that these effects would be most pronounced in working memory manipulation conditions with the highest cognitive demand in both young and older adults. Repetitive transcranial magnetic stimulation was applied while participants were performing a delayed response alphabetization task with three individually-titrated levels of difficulty. The left dorsolateral prefrontal cortex was identified by combining electric field modeling to individualized functional magnetic resonance imaging activation maps and was targeted during the experiment using stereotactic neuronavigation with real-time robotic guidance, allowing optimal coil placement during the stimulation. As no accuracy differences were found between young and older adults, the results from both groups were collapsed. Subsequent analyses revealed that active stimulation significantly increased accuracy relative to sham stimulation, but only for the hardest condition. These results point towards further investigation of repetitive transcranial magnetic stimulation for memory enhancement focusing on high difficulty conditions as those most likely to exhibit benefits.

Prognostic value of protein tyrosine kinase 6 (PTK6) for long-term survival of breast cancer patients.

The cytoplasmic tyrosine kinase PTK6 (BRK) shows elevated expression in approximately two-thirds of primary breast tumours, and is implicated in EGF receptor-dependent signalling and epithelial tumorigenesis. Using immunohistochemistry, we performed a retrospective study on 426 archival breast cancer samples from patients with long-term follow-up and compared the protein expression levels of PTK6, the HER receptors, Sam68 (a substrate of PTK6), and signalling proteins including MAP kinase (MAPK), phosphorylated MAPK (P-MAPK), and PTEN. We show that PTK6 expression is of significant prognostic value in the outcome of breast carcinomas. In multivariate analysis, the disease-free survival of patients of >or=240 months was directly associated with the protein expression level of PTK6 (P

Complementary topology of maintenance and manipulation brain networks in working memory.

Working memory (WM) is assumed to consist of a process that sustains memory representations in an active state (maintenance) and a process that operates on these activated representations (manipulation). We examined evidence for two distinct, concurrent cognitive functions supporting maintenance and manipulation abilities by testing brain activity as participants performed a WM alphabetization task. Maintenance was investigated by varying the number of letters held in WM and manipulation by varying the number of moves required to sort the list alphabetically. We found that both maintenance and manipulation demand had significant effects on behavior that were associated with different cortical regions: maintenance was associated with bilateral prefrontal and left parietal cortex, and manipulation with right parietal activity, a link that is consistent with the role of parietal cortex in symbolic computations. Both structural and functional architecture of these systems suggested that these cognitive functions are supported by two dissociable brain networks. Critically, maintenance and manipulation functional networks became increasingly segregated with increasing demand, an effect that was positively associated with individual WM ability. These results provide evidence that network segregation may act as a protective mechanism to enable successful performance under increasing WM demand.

Facilitation of performance in a working memory task with rTMS stimulation of the precuneus: frequency- and time-dependent effects.

Although improvements in performance due to TMS have been demonstrated with some cognitive tasks, performance improvement has not previously been demonstrated with working memory tasks. In the present study, a delayed match-to-sample task was used in which repetitive TMS (rTMS) at 1, 5, or 20 Hz was applied to either left dorsolateral prefrontal or midline parietal cortex during the retention (delay) phase of the task. Only 5 Hz stimulation to the parietal site resulted in a significant decrease in reaction time (RT) without a corresponding decrease in accuracy. This finding was replicated in a second experiment, in which 5 Hz rTMS at the parietal site was applied during the retention phase or during presentation of the recognition probe. Significant speeding of RT occurred in the retention phase but not the probe phase. This finding suggests that TMS may improve working memory performance, in a manner that is specific to the timing of stimulation relative to performance of the task, and to stimulation frequency.

The influence of prednisone on the efficacy of docetaxel in men with metastatic castration-resistant prostate cancer.

BACKGROUND: Prednisone and other corticosteroids can provide palliation and tumor responses in patients with prostate cancer. The combination of docetaxel and prednisone was the first treatment shown to prolong survival in men with metastatic castration-resistant prostate cancer (mCRPC). Since the approval of docetaxel in 2004, additional treatments are available, including abiraterone, which is also administered with prednisone. Therefore, patients are increasingly likely to have prednisone therapy several times throughout their disease course, and the contribution of prednisone to the efficacy of docetaxel is unknown. METHODS: We conducted a retrospective study of patients with mCPRC treated with docetaxel at our institution between 2004 and 2014. Patients were divided into two cohorts based upon whether prednisone was co-administered with docetaxel. Cohorts were further stratified based upon prior prednisone (with abiraterone) or hydrocortisone (with ketoconazole) use. The primary end point was clinical/radiographic progression-free survival (PFS). The secondary end points were >50% PSA response rate and PSA progression-free survival (PSA PFS). A multivariable Cox regression model was constructed to determine whether prednisone use was independently predictive of PFS. RESULTS: We identified 200 consecutive patients for inclusion in the study: 131 men received docetaxel with prednisone and 69 received docetaxel alone. The docetaxel-prednisone cohort had superior PFS compared with the docetaxel-alone cohort (median PFS: 7.8 vs. 6.2 months, HR 0.68 (95% confidence interval (CI) 0.48-0.97), P=0.03). Prednisone use was associated with a reduced risk of progression on docetaxel in the propensity score-weighted multivariable Cox model (P=0.002). Among abiraterone- or ketoconazole-pretreated patients, no difference in PFS was observed between prednisone-containing and non-prednisone-containing docetaxel regimens (median PFS: 7.1 vs. 6.3 months, HR 0.96 (95% CI 0.59-1.57), P=0.87). CONCLUSIONS: The incorporation of prednisone potentially augments the efficacy of docetaxel in patients with mCRPC. We hypothesize that this advantage is limited to patients who have not previously received corticosteroids. Prospective confirmation is needed.

The proapoptotic effect of hepatitis B virus HBx protein correlates with its transactivation activity in stably transfected cell lines.

The role of hepatitis B virus HBx protein in the carcinogenesis associated with chronic viral infection remains ill-defined. Indeed, pleiotropic effects have been ascribed to HBx: in addition to its well-documented ability to indirectly stimulate transcription, the protein has been reported to affect cell growth, signal transduction, DNA repair and apoptosis. In this work, we generated Chang (CCL-13)-derived cell lines constitutively expressing wild type or mutant HBx, as a model of HBx-host cell interaction closer to the chronic infection setting, than the classically used transient expression systems. We document the potentiation by HBx of the apoptotic cell death pathway in the recipient cells. This effect is unlikely to rely on p53 activity since the protein is functionally inactivated in CCL-13. In addition, antioxidants and cyclosporin A failed to reduce the apoptotic response back to the normal level, suggesting that production of reactive oxygen species and calcineurin activation are not directly involved in the proapoptotic effect of HBx. In contrast, our data show that transactivation and stimulation of apoptosis are tightly linked HBx activities. Finally, expression of transactivation-active protein did not result in detectable change in the pattern of MAP kinases phosphorylation nor did it affect the ability of the host cell to repair in vitro irradiated plasmid DNA.

Hepatoma-derived integrated HBV DNA causes multi-stage transformation in vitro.

The hepatoma-derived hepatitis B virus (HBV) DNA insert HU-a has recently been shown to contain two viral transactivator genes, X and preS2 /S. We report here that HU-a induces malignant transformation after stable transfection of the fetal mouse hepatocyte line FMH202, as indicated by soft agar growth and nude mouse tumorigenicity. Transfections with HU-a subclones, containing the X gene of the preS2 /S gene alone or sequences without transactivator gene, respectively, suggested that the X gene is essential for transformation. Sequential stages of transformation and tumor progression were analysed by injection of the stably transfected FMH202 lines into nude mice, explanation of the resulting tumors and re-establishment of cell lines from the tumors. Comparison of two HU-a-transformed cell lines by HBV mRNA hybridization, Southern analysis and chromosomal in situ hybridization revealed that integrated HBV DNAs were involved in major chromosomal rearrangements in both cases. Interestingly, recombination of the HBV Dna insert during the nude mouse passage had completely abolished HBV-specific transcription in one case, indicating that expression of integrated HBV genes, while presumably involved in early transformation, is dispensable at later stages of tumor progression. The sequential transformation observed in this experimental system suggests that expression of the X gene by integrated viral DNA and subsequent hepatocyte genome mutations might both contribute to HBV-associated liver carcinogenesis.

Tumour-associated E-cadherin mutations alter cellular morphology, decrease cellular adhesion and increase cellular motility.

A major function of the cell-to-cell adhesion molecule E-cadherin is the maintenance of cell adhesion and tissue integrity. E-cadherin deficiency in tumours leads to changes in cell morphology and motility, so that E-cadherin is considered to be a suppressor of invasion. In this study we investigated the functional consequences of three tumour-associated gene mutations that affect the extracellular portion of E-cadherin: in-frame deletions of exons 8 or 9 and a point mutation in exon 8, as they were found in human gastric carcinomas. Human MDA-MB-435S breast carcinoma cells and mouse L fibroblasts were stably transfected with the wild-type and mutant cDNAs, and the resulting changes in localization of E-cadherin, cell morphology, strength of calcium-dependent aggregation as well as cell motility and actin cytoskeleton organization were studied. We found that cells transfected with wild-type E-cadherin showed an epitheloid morphology, while all cell lines expressing mutant E-cadherin exhibited more irregular cell shapes. Cells expressing E-cadherin mutated in exon 8 showed the most scattered appearance, whereas cells with deletion of exon 9 had an intermediate state. Mutant E-cadherins were localized to the lateral regions of cell-to-cell contact sites. Additionally, both exon 8-mutated E-cadherins showed apical and perinuclear localization, and actin filaments were drastically reduced. MDA-MB-435S cells with initial calcium-dependent cell aggregation exhibited decreased aggregation and, remarkably, increased cell motility, when mutant E-cadherin was expressed. Therefore, we conclude that these E-cadherin mutations may not simply affect cell adhesion but may act in a trans-dominant-active manner, i.e. lead to increased cell motility. Our study suggests that E-cadherin mutations affecting exons 8 or 9 are the cause of multiple morphological and functional disorders and could induce the scattered morphology and the invasive behaviour of diffuse type-gastric carcinomas.

Single amino acid substitutions in conserved extracellular domains of E-cadherin differ in their functional consequences.

The calcium-dependent homophilic cell adhesion molecule E-cadherin typically connects epithelial cells. The extracellular portion of the mature transmembrane protein consists of five homologous domains. The four sequences linking these domains contain the structural amino acid motif DXXD that is thought to be involved in direct calcium binding. In gastric cancer patients mutations affecting this motif between the second and third domain are frequently seen. In order to determine the functional significance of similar sequence alterations with regard to their location, we analyzed single amino acid substitutions changing the DXXD motif to DXXA in each linker region according to a mutation found in gastric cancer (D370A). The cDNA sequences coding for DQND, DVLD and DVND were changed (D257A, D479A, D590A, respectively) and stably expressed in E-cadherin negative MDA-MB-435S mammary carcinoma cells. We found that the D257A and D370A mutations result in abnormal protein localization, changes in the actin cytoskeleton, markedly reduced homophilic cell adhesion, and altered cell morphology. Unexpectedly, the tumor-associated D370A mutation but not the D257A mutation induced increased cell motility. The D479A mutation only had slight functional consequences whereas cells expressing the D590A mutant did not differ from cells expressing the wild-type molecule. Although the putative calcium binding motif DXXD is located at repetitive positions in the extracellular portion of E-cadherin, our results indicate that it has different functions depending on the location. Remarkably, tumor cells select for mutations in the most critical domains resulting both in loss of function (decreased cell adhesion) and in gain of function (increased cell motility). Since multiple DXXD motifs are typically seen in other cadherins, our structure-function study is relevant for this gene family in general.

The effects of electroconvulsive therapy on quantitative electroencephalograms. Relationship to clinical outcome.

BACKGROUND: The efficacy of electroconvulsive therapy (ECT) is determined by stimulus electrical intensity and electrode placement. Three theories offer different accounts for why increasing the stimulus dosage of right unilateral ECT enhances antidepressant effects. This study examined the effects of ECT on interictal quantitative electroencephalograms (EEGs), contrasting these theories in their predictions regarding global, lateralized, and topographic changes in ECT-induced slow-wave activity. The time course of EEG changes and associations with efficacy were also determined. METHODS: Sixty-two inpatients with major depressive disorder were randomized to ECT conditions that differed in stimulus intensity (low vs high dosage) and electrode placement (right unilateral vs bilateral). Resting, eyes closed, 19-lead EEG recordings were obtained at pretreatment, following a single treatment, following an average of 7 treatments, during the week following the ECT course, and after a 2-month follow-up period. RESULTS: Electroconvulsive therapy produced a marked short-term increase in delta and theta power. At a 2-month follow-up, there were no significant alterations in any frequency band. The ECT treatment conditions differed markedly in efficacy. Global and lateralized EEG effects did not distinguish effective and ineffective forms of treatment. Effective forms of ECT resulted in increased delta power in prefrontal regions, and this change was associated with the magnitude of symptomatic improvement. CONCLUSION: The induction of slow-wave activity in prefrontal cortex is linked to the efficacy of ECT.

EEG manifestations during ECT: effects of electrode placement and stimulus intensity.

This study examined the ictal electroencephalographic (EEG) characteristics of four forms of electroconvulsive therapy (ECT) known to differ in efficacy. Previously, we demonstrated that titrated, low-dose right unilateral ECT reliably produces generalized seizures of adequate duration, but is remarkably weak in antidepressant effects. Using a new rating scale, we found that specific features of the ictal and immediate postictal EEG varied significantly with ECT stimulus intensity and electrode placement. The low-dose right unilateral condition differed from more effective forms of ECT in having the longest polyspike phase duration, averaging twice that of the other conditions; it was also the condition least likely to manifest bioelectric suppression immediately following seizure termination. In contrast, high-dose bilateral ECT--a treatment with particularly rapid antidepressant effects--resulted in the greatest peak slow-wave amplitude in both hemispheres. Total seizure duration did not differ among the four treatment conditions. These findings indicate that seizure duration is not a useful marker of therapeutic efficacy, and instead provide preliminary evidence that other features of the EEG may be more useful markers of treatment adequacy.

Sham TMS: intracerebral measurement of the induced electrical field and the induction of motor-evoked potentials.

Testing the therapeutic potential of transcranial magnetic stimulation (TMS) in controlled trials requires a valid sham condition. Sham TMS is typically administered by tilting the coil 45--90 degrees off the scalp, with one or two wings of the coil touching the scalp. Lack of cortical effects has not been verified. We compared sham manipulations in their thresholds for eliciting motor-evoked potentials (MEPs) in human volunteers and in intracerebral measurements of voltage induced in the prefrontal cortex of a rhesus monkey. Three types of sham (one-wing 45 degrees and 90 degrees and two-wing 90 degrees tilt) induced much lower voltage in the brain than active TMS (67--73% reductions). However, the two-wing 45 degrees sham induced values just 24% below active TMS. This sham was about half as potent in inducing MEPs over the motor cortex as active TMS. Some sham TMS conditions produce substantial cortical stimulation, making it critical to carefully select the sham manipulation for clinical trials.

Amphetamine disrupts P50 suppression in normal subjects.

BACKGROUND: P50 suppression is viewed as an operational measure of sensory "gating" that is reduced in patients with schizophrenia and their family members. Previous reports have demonstrated that neural gating is regulated by monoaminergic tone in rodent models of P50 suppression. METHODS: In this study, 11 healthy subjects participated in P50 event-related potential recordings at baseline and after either oral administration of dextroamphetamine (.3 mg/kg) or placebo, to determine if the administration of a monoaminergic agonist produces P50 suppression deficits similar to those observed in patients with schizophrenia. RESULTS: As hypothesized, amphetamine disrupted the suppression of the P50 event-related potential. There was a statistically significant decrement in P50 suppression during the amphetamine challenge condition (t10 = 3.15, p < .01, mean difference = -44.1%, d = -2.5) relative to the baseline P50 condition. A comparison of P50 suppression in the placebo and amphetamine conditions (both after a baseline recording session) revealed a significant amphetamine-induced disruption of P50 suppression (t6 = 3.71, p < .01, mean difference = -54.4%, d = -3.14). CONCLUSIONS: The biochemical alterations associated with an amphetamine-induced disruption of P50 suppression in this study may be related to the pathophysiology of P50 suppression deficits in schizophrenia. The findings are consistent with several careful examinations of suppression deficits in rodent models that have identified the monoaminergic regulation of P50 suppression. These data indicate that amphetamine induces a disruption of P50 suppression in normal subjects.

Different brain networks mediate task performance in normal aging and AD: defining compensation.

OBJECTIVE: To determine whether the pathologic mechanisms of AD alter the brain networks subserving performance of a verbal recognition task. BACKGROUND: Functional imaging studies comparing task-related activation in AD patients and controls generally have not used network analysis and have not controlled for task difficulty. METHODS: H2 15O PET was used to measure regional cerebral blood flow in 14 patients and 11 healthy elders during the performance of a serial verbal recognition task under two conditions: low demand, with study list size (SLS) equal to one; and titrated demand, with SLS adjusted so that each subject recognized words at 75% accuracy. The Scaled Subprofile Model was used to identify networks of regionally covarying activity across these task conditions. RESULTS: In the elders, higher SLS was associated with the recruitment of a network of brain areas involving left anterior cingulate and anterior insula (R2 = 0.94; p < 0.0001). Three patients also expressed this network. In the remaining patients, higher SLS was associated with the recruitment of an alternate network consisting of left posterior temporal cortex, calcarine cortex, posterior cingulate, and the vermis (R2 = 0.81, p < 0.001). Expression of this network was unrelated to SLS in the elders and more intact AD patients. CONCLUSIONS: The patients' use of the alternate network may indicate compensation for processing deficits. The transition from the normal to the alternate network may indicate a point where brain disease has irreversibly altered brain function and thus may have important implications for therapeutic intervention.

The fate of training cases.

The authors regard the treatment of analytic patients as a crucial, formative and ultimately integrative experience in a candidate's development that has received remarkably little direct attention as an aspect of analytic education. From 1983 to 1992 a questionnaire was sent to all graduates of the Columbia University Psychoanalytic Center for Training and Research asking for information on training cases, both those terminated before graduation and those still ongoing at the time of graduation. The authors report data on pre-graduation candidate case experience, treatment duration of training cases, the impact of graduation on the course of analysis and on a global assessment of the outcome. 70 per cent of the 71 who graduated between 1983 and 1992 returned the questionnaire. The survey showed that before graduation the average candidate had a cumulative nine-year experience of treating training cases. 35 per cent of cases terminated before graduation and were invariably considered to have an unsuccessful outcome. Thus the 'failed case' was a common event and should be anticipated as part of a candidate's education. There was no evidence of precipitous termination of cases after graduation; in fact the data suggest that graduation has no discernible effect on the timing of termination. The vast majority of candidates at Columbia continue to be supervised after graduation, which suggests that graduation is only a marker in the training of an analyst, rather than the point of completion. With respect to outcome, 23 per cent of the 151 terminated cases were rated successful. Though this finding is consistent with previous reports, the methodological limitations of this study limit the confidence in this result. One of the important issues raised by these results is the impact of training requirements on the candidate's education and the Fate of Training Cases.

Classical conditioned learning using transcranial magnetic stimulation.

This study examined whether brain responses to transcranial magnetic stimulation (TMS) would be amenable to classical conditioning. Motor cortex in human participants was stimulated with TMS pulses, which elicited a peripheral motor response in the form of a motor evoked potential (MEP). The TMS pulses were paired with audio-visual cues that served as conditioned stimuli. Over the course of training, MEPs following the conditioned stimuli decreased in amplitude. Two experiments demonstrated that the attenuated response only occurred when the TMS was preceded by the conditioned stimulus. Unsignaled TMS and TMS preceded by a cue that was not previously paired did not attenuate the response. The experiments demonstrate that the modulation of the motor response depended on the prior pairings of the conditioned stimuli and TMS and that the effects were stimulus specific. Thus we demonstrate here, for the first time, that TMS can serve as the unconditioned stimulus in Pavlovian conditioning.