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.

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.

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.

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.

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.

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

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.

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.

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.

Transcranial magnetic stimulation differentially affects speed and direction judgments.

This study was conducted to determine whether humans' judgments about the speed and direction of moving stimuli was differentially affected by transcranial magnetic stimulation (TMS). Subjects viewed two successively presented moving stimuli that differed from each other both in speed and direction of motion. Single-pulse TMS was applied either medially (approximately 2 cm above the inion) or laterally (approximately 5 cm lateral to and 4 cm above the inion), while subjects judged the speed and direction differences. The physical stimulation (visual and TMS) was identical on the two tasks, as was discriminability (d') when TMS was not applied. We found significant criterion (beta) shifts on the speed discrimination task at both stimulation sites. Specifically, on TMS trials the proportion of "slower" judgments increased significantly, consistent with subjective reports that stimuli often appeared to slow when TMS was applied. The subjective reports indicated no corresponding change in perceived direction. We also found that speed discriminability was impaired significantly more than direction discriminability, but only when TMS was applied medially. Indeed, after controlling for TMS-related changes in reaction time, speed discriminability was impaired significantly, while direction discriminability remained largely intact. This dissociation suggests that the sensory response constraining speed discrimination is at least partially independent from the sensory response constraining direction discrimination. Combined with previous psychophysical data, the present data suggest a double dissociation between speed and direction discrimination in humans.

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.

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.

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.

Quantitative EEG during seizures induced by electroconvulsive therapy: relations to treatment modality and clinical features. I. Global analyses.

This study examined the effects of electroconvulsive therapy (ECT) treatment conditions, patient individual difference factors, and clinical outcome on global electroencephalogram (EEG) power during and immediately following ECT-induced seizures. Sixty-two patients were randomized to ECT conditions differing in electrode placement (right unilateral versus bilateral) and stimulus dosage (just above seizure threshold versus 2.5 times seizure threshold). At the second and penultimate treatments, global total power (1.5-28.5 Hz) and global power in specific frequency bands were quantified in 19-lead EEG recordings of the generalized seizure and the immediate postictal period. Seizures induced with high dosage, and to lesser extent, with bilateral electrode placement, resulted in greater global power. Patient age, initial seizure threshold, and baseline depression severity were inversely related to global power during seizures. While superior clinical outcome following ECT was associated with greater global power during seizures, this effect was small. The factors associated with more robust seizure expression also resulted in greater postictal bioelectric suppression. Associations with treatment parameters and patient variables were stronger at the second than penultimate treatment. We conclude that manipulations of ECT technique strongly determine the magnitude of seizure expression, but relations with clinical outcome are weak. The findings raise doubt about the clinical utility of algorithms based on analysis of EEG features to guide ECT parameter selection.

Quantitative EEG during seizures induced by electroconvulsive therapy: relations to treatment modality and clinical features. II. Topographic analyses.

This study tested three alternative theories of the mechanisms of therapeutic action of electroconvulsive therapy (ECT). The theories differed in predictions about the global and topographic effects of effective and ineffective forms of ECT on electroencephalogram (EEG) seizure expression. At the second treatment, 19-lead EEG recordings were obtained in 57 depressed patients randomized to conditions that differed in ECT electrode placement and stimulus dosage. Power in the delta frequency band was quantified during the seizure and analyzed with traditional multivariate methods and the Scaled Subprofile Model. Electrical dosage of the ECT stimulus had a powerful effect on ictal global delta power and, more so, than electrode placement. Greater ictal global delta power was associated with superior therapeutic outcome, but the magnitude of this effect was small. Effective forms of ECT resulted in a topography where delta power was accentuated in prefrontal EEG sites. High dosage right unilateral ECT also resulted in stronger asymmetry in prefrontal regions than the ineffective, low dosage right unilateral ECT. Greater bilateral generalization of seizure expression does not appear to be a prerequisite for therapeutic effects. Instead, more intense seizure expression in prefrontal regions may be critical for efficacy.

Tumor-derived mutated E-cadherin influences beta-catenin localization and increases susceptibility to actin cytoskeletal changes induced by pervanadate.

E-cadherin participates in homophilic cell-to-cell adhesion and is localized to intercellular junctions of the adherens type. In the present study, we investigated the localization of adherens junction components in cells expressing mutant E-cadherin derivatives which had been previously cloned from diffuse-type gastric carcinoma. The mutations are in frame deletions of exons 8 or 9 and a point mutation in exon 8 and affect the extracellular domain of E-cadherin. Our findings indicate that E-cadherin mutated in exon 8 causes beta-catenin staining at lateral cell-to-cell contact sites and, in addition, abnormally located beta-catenin in the perinuclear region. Moreover, the various mutant E-cadherin derivatives increased the steady-state levels of alpha- and beta-catenin and were found in association with these catenins even after induction of tyrosine phosphorylation by pervanadate. Sustained pervanadate treatment led, however, to rounding-up of cells and induction of filopodia, changes which were first detectable in cells expressing E-cadherin mutated in exon 8. The deterioration of the cell contact was not accompanied with disassembly of the E-cadherin-catenin complex. Based on these observations, we propose a model whereby in the presence of mutant E-cadherin tyrosine phoshorylation of components of the cell adhesion complex triggers loss of cell-to-cell contact and actin cytoskeletal changes which are not caused by the disruption of the E-cadherin-catenin complex per se, but instead might be due to phosphorylation of other signaling molecules or activation of proteins involved in the regulation of the actin cytoskeleton.

Electrophysiological correlates of the adverse cognitive effects of electroconvulsive therapy.

Resting state, eyes closed, 19-lead EEG recordings were obtained at pre-ECT baseline and just prior to penultimate treatment and during the week following the ECT course in 59 patients with major depression. Patients had been randomized to ECT conditions that varied in electrode placement and stimulus intensity. The EEG data were submitted to power spectral analysis, and global and topographic effects were characterized for the delta and theta frequency bands. Relations between the EEG changes and scores on three cognitive measures were examined. The period of disorientation immediately following RUL ECT was associated with an accentuation of delta power in anterior frontal and temporal regions. Across the electrode placements, increased theta activity in left frontotemporal regions was associated with longer recovery of orientation. Post-ECT decrements in global cognitive status, as assessed by the modified Mini-Mental State exam, were associated with a greater increase in delta relative to theta power, globally across the cortex. The magnitude of retrograde amnesia for autobiographical events correlated with increased theta activity in left frontotemporal regions. The findings suggest that distinct neurophysiological changes subserve the therapeutic and adverse cognitive effects of ECT. Postictal disorientation and post-ECT retrograde amnesia appear to share a common physiological substrate.

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.

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.