A theory of brain-computer interface learning via low-dimensional control.

A remarkable demonstration of the flexibility of mammalian motor systems is primates' ability to learn to control brain-computer interfaces (BCIs). This constitutes a completely novel motor behavior, yet primates are capable of learning to control BCIs under a wide range of conditions. BCIs with carefully calibrated decoders, for example, can be learned with only minutes to hours of practice. With a few weeks of practice, even BCIs with randomly constructed decoders can be learned. What are the biological substrates of this learning process? Here, we develop a theory based on a re-aiming strategy, whereby learning operates within a low-dimensional subspace of task-relevant inputs driving the local population of recorded neurons. Through comprehensive numerical and formal analysis, we demonstrate that this theory can provide a unifying explanation for disparate phenomena previously reported in three different BCI learning tasks, and we derive a novel experimental prediction that we verify with previously published data. By explicitly modeling the underlying neural circuitry, the theory reveals an interpretation of these phenomena in terms of biological constraints on neural activity.

Naltrexone and cognitive behavioral therapy for the treatment of alcohol dependence: do sex differences exist?

BACKGROUND: Sex differences in regards to pharmacotherapy for alcoholism is a topic of concern following publications suggesting naltrexone, one of the longest approved treatments of alcoholism, is not as effective in women as in men. This study was conducted by combining 2 randomized placebo controlled clinical trials utilizing similar methodologies and personnel in which the data was amalgamated to evaluate sex effects in a reasonable sized sample. METHODS: A total of 211 alcoholics (57 female and 154 male) were randomized to the naltrexone/cognitive behavorial thearpy (CBT) or placebo/CBT arm of the 2 clinical trials analyzed. Baseline variables were examined for differences between sex and treatment groups via ANOVA for continuous variable or chi-squared test for categorical variables. All initial outcome analysis was conducted under an intent-to-treat analysis plan. Effect sizes for naltrexone over placebo were determined by Cohen's D (d). RESULTS: The effect size of naltrexone over placebo for the following outcome variables was similar in men and women [% days abstinent (PDA) d = 0.36, % heavy drinking days (PHDD) d = 0.36, and total standard drinks (TSD) d = 0.36]. Only for men were the differences significant secondary to the larger sample size (PDA p = 0.03; PHDD p = 0.03; TSD p = 0.04). There were a few variables (GGT at week-12 change from baseline to week-12: men d = 0.36, p = 0.05; women d = 0.20, p = 0.45 and drinks per drinking day: men d = 0.36, p = 0.05; women d = 0.28, p = 0.34) where the naltrexone effect size for men was greater than women. In women, naltrexone tended to increase continuous abstinent days before a first drink (women d = 0.46, p = 0.09 and men d = 0.00, p = 0.44). CONCLUSIONS: The effect size of naltrexone over placebo appeared similar in women and men in our hands suggesting the findings of sex differences in naltrexone response might have to do with sample size and/or endpoint drinking variables rather than any inherent pharmacological or biological differences in response.

Alcohol consumption, %CDT, GGT and blood pressure change during alcohol treatment.

AIMS: Blood pressure (BP) changes in alcohol-dependent individuals during a 12-week alcohol relapse prevention study were examined in light of drinking status and biomarkers of alcohol consumption [carbohydrate-deficient transferrin (%CDT) and gamma-glutamyl transpeptidase (GGT)]. METHODS: Of 160 randomized alcoholic individuals, 120 who had hypertension and in whom daily drinking data was available, at 6 and 12 weeks of treatment were included. The impact of alcohol consumption on change in systolic BP (SBP) and diastolic BP (DBP) was examined. Further analysis determined the relationship between BP and alcohol-use biomarkers. RESULTS: A significant effect of complete abstinence on both SBP (-10 mmHg; P = 0.003) and DBP (-7 mmHg; P = 0.001) when compared to any drinking (SBP and DBP = -1 mmHg) was observed. At week 12, participants with a positive %CDT (> or =2.6) had 7 mmHg greater SBP (P = 0.01) and DBP (P < 0.001) than those with negative %CDT. Participants with positive GGT (> or =50 IU) had 10 mmHg greater SBP (P = 0.12) and 9 mmHg greater DBP (P = 0.03) than those with negative GGT. The percent change in SBP was correlated with percent change in %CDT (P = 0.003) but not GGT (P = ns). The percent change in DBP was correlated with both percent change in %CDT (P < 0.0001) and GGT (P = 0.03). CONCLUSIONS: Abstinence from alcohol significantly decreased the BP and a positive relationship between BP and both alcohol-use biomarkers was illustrated. Since %CDT is more specific than GGT for heavy alcohol consumption, clinicians may monitor the role of alcohol in hypertension using %CDT as a supplemental aid, providing an objective assessment of drinking to influence BP treatment decisions.

Probabilistic population codes and the exponential family of distributions.

Many experiments have shown that human behavior is nearly Bayes optimal in a variety of tasks. This implies that neural activity is capable of representing both the value and uncertainty of a stimulus, if not an entire probability distribution, and can also combine such representations in an optimal manner. Moreover, this computation can be performed optimally despite the fact that observed neural activity is highly variable (noisy) on a trial-by-trial basis. Here, we argue that this observed variability is actually expected in a neural system which represents uncertainty. Specifically, we note that Bayes' rule implies that a variable pattern of activity provides a natural representation of a probability distribution, and that the specific form of neural variability can be structured so that optimal inference can be executed using simple operations available to neural circuits.

Pulmonary tuberculosis and extreme prematurity.

A mother, newly found to be positive for HIV, delivered her first baby at 25 weeks gestation. The infant initially did well in spite of a symptomatic patent duct and a severe intraventricular haemorrhage, but became severely unwell needing further respiratory support on day 18. Acid fast bacilli were found in endotracheal secretions. After the baby's death, the bacilli were confirmed to be Mycobacterium tuberculosis, and the same organism was grown from the mother's urine. The case raised challenging issues in relatively uncharted territory in terms of treatment of the infant, public health issues, ethical decision making, and media management.

Corrosion of cemented titanium femoral stems.

Cemented titanium stems in hip arthroplasty are associated with proximal cement-stem ebonding and early failure. This was well publicised with the 3M Capital hip. However, corrosion in this setting has been reported with only one stem design and is less widely accepted. We present a series of 12 cemented titanium Furlong Straight Stems which required revision at a mean of 78 months for thigh pain. At revision the stems were severely corroded in a pattern which was typical of crevice corrosion. Symptoms were eliminated after revision to an all-stainless steel femoral prosthesis of the same design. We discuss the likely causes for the corrosion. The combination of a titanium stem and cement appears to facilitate crevice corrosion.

Response of old-growth conifers to reduction in stand density in western Oregon forests.

The positive growth response of healthy young trees to density reduction is well known. In contrast, large old trees are usually thought to be intrinsically limited in their ability to respond to increased growing space; therefore, density reduction is seldom used in stands of old-growth trees. We tested the null hypothesis that old-growth trees are incapable of responding with increased growth following density reduction. The diameter growth response of 271 Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco), ponderosa pine (Pinus ponderosa Dougl. ex Laws) and sugar pine (Pinus lambertiana Dougl.) trees ranging in age from 158 to 650 years was examined 20 to 50 years after density reduction. Density reduction involved either light thinning with removal of less vigorous trees, or shelterwood treatments in which overstory trees were not removed. Ratios of basal area growth after treatment to basal area growth before treatment, and several other measures of growth, all indicated that the old trees sometimes benefited and were not harmed by density reduction. Growth increased by 10% or more for 68% of the trees in treated stands, and nearly 30% of trees increased growth by over 50%. This growth response persisted for at least 20 years. During this 20-year period, only three trees in treated stands (1.5%) exhibited a rapid decrease in growth, whereas growth decreased in 64% of trees in untreated stands. The length of time before a growth response to density reduction occurred varied from 5 to 25 years, with the greatest growth response often occurring 20 to 25 years after treatment. These results have important implications both for the basic biology of aging in woody plants as well as for silvicultural practices in forests with old-growth trees.

The rat approximates an ideal detector of changes in rates of reward: implications for the law of effect.

Rats responded on 2 levers delivering brain stimulation reward on concurrent variable interval schedules. Following many successive sessions with unchanging relative rates of reward, subjects adjusted to an eventual change slowly and showed spontaneous reversions at the beginning of subsequent sessions. When changes in rates of reward occurred between and within every session, subjects adjusted to them about as rapidly as they could in principle do so, as shown by comparison to a Bayesian model of an ideal detector. This and other features of the adjustments to frequent changes imply that the behavioral effect of reinforcement depends on the subject's perception of incomes and changes in incomes rather than on the strengthening and weakening of behaviors in accord with their past effects or expected results. Models for the process by which perceived incomes determine stay durations and for the process that detects changes in rates are developed.

Aprotinin but not epsilon-aminocaproic acid decreases interleukin-10 after cardiac surgery with extracorporeal circulation: randomized, double-blind, placebo-controlled study in patients receiving aprotinin and epsilon-aminocaproic acid.

BACKGROUND: Extracorporeal circulation induces a systemic inflammatory response, which may adversely affect organ function. One manifestation of this response is increased fibrinolysis. Antifibrinolytic drugs such as aprotinin and epsilon-aminocaproic acid have been effective in reducing fibrinolysis and blood loss after extracorporeal circulation; however, the effects of antifibrinolytic drugs on proinflammatory and anti-inflammatory mediators are not known. This study examined the effects of aprotinin and epsilon-aminocaproic acid on plasma levels of proinflammatory [interleukin-6 (IL-6)] and anti-inflammatory [interleukin-10 (IL-10)] cytokines during and after extracorporeal circulation. METHODS AND RESULTS: Seventy-two patients undergoing coronary artery bypass grafting with extracorporeal circulation were randomly assigned in a double-blind study to receive high-dose aprotinin, epsilon-aminocaproic acid, or saline placebo. Plasma levels of IL-6 and IL-10 were measured at 5 time points before, during, and after extracorporeal circulation. In all 3 groups, both IL-6 and IL-10 rose significantly after institution of extracorporeal circulation and remained elevated through the first postoperative day. Compared with saline, aprotinin significantly reduced IL-10 (P=0.02) and peak IL-6 (P=0.02) after extracorporeal circulation. In contrast, none of the reductions in IL-6 and IL-10 by epsilon-aminocaproic acid achieved statistical significance. Both aprotinin and epsilon-aminocaproic acid decreased blood loss compared with saline, but there was no significant difference in the number of patients receiving blood products among the treatment groups. CONCLUSIONS: These data suggest that aprotinin and epsilon-aminocaproic acid differ in their effects on the inflammatory response to extracorporeal circulation. Aprotinin but not epsilon-aminocaproic acid appears to attenuate the rise in the proinflammatory and anti-inflammatory cytokines IL-6 and IL-10. Further studies will be required to determine if these cytokine alterations translate to changes in clinical outcomes.

Efficient computation and cue integration with noisy population codes.

The brain represents sensory and motor variables through the activity of large populations of neurons. It is not understood how the nervous system computes with these population codes, given that individual neurons are noisy and thus unreliable. We focus here on two general types of computation, function approximation and cue integration, as these are powerful enough to handle a range of tasks, including sensorimotor transformations, feature extraction in sensory systems and multisensory integration. We demonstrate that a particular class of neural networks, basis function networks with multidimensional attractors, can perform both types of computation optimally with noisy neurons. Moreover, neurons in the intermediate layers of our model show response properties similar to those observed in several multimodal cortical areas. Thus, basis function networks with multidimensional attractors may be used by the brain to compute efficiently with population codes.

Effects of cellular redox balance on induction of apoptosis by eicosapentaenoic acid in HT29 colorectal adenocarcinoma cells and rat colon in vivo.

BACKGROUND AND AIMS: Epidemiological evidence suggests n-3 polyunsaturated lipids may protect against colorectal neoplasia. Consumption of fish oil modulates crypt cytokinetics in humans, and crypt apoptosis in animal models. To explore these effects, we investigated involvement of caspase enzymes and cellular redox balance in the induction of apoptosis by eicosapentaenoic acid (EPA) in HT29 cells, and in rat colon in vivo. METHODS: Survival of HT29 cells grown with EPA in the presence of caspase inhibitors, antioxidants, or buthionine sulphoximine, an inhibitor of glutathione neosynthesis, was determined. The effects of EPA enriched fish oil and glutathione depletion on apoptosis in rat colon were assessed using microdissected crypts. RESULTS: Treatment of HT29 cells with EPA reduced viable cell number and activated caspase 3, prior to cell detachment. Antioxidants and caspase inhibitors blocked HT29 cell death whereas glutathione depletion increased it. Rats fed fish oil had higher crypt cell apoptosis than those fed corn oil, and glutathione depletion enhanced this effect. CONCLUSIONS: Incorporation of EPA into colonic epithelial cell lipids increases apoptosis. The results of this study, using both an animal and cell line model, support the hypothesis that this effect is mediated via cellular redox tone, and is sensitive to glutathione metabolism. The data suggest a mechanism whereby polyunsaturated fatty acids may influence the susceptibility of colorectal crypt cells to induction or progression of neoplasia.

Retinal ganglion cells act largely as independent encoders.

Correlated firing among neurons is widespread in the visual system. Neighbouring neurons, in areas from retina to cortex, tend to fire together more often than would be expected by chance. The importance of this correlated firing for encoding visual information is unclear and controversial. Here we examine its importance in the retina. We present the retina with natural stimuli and record the responses of its output cells, the ganglion cells. We then use information theoretic techniques to measure the amount of information about the stimuli that can be obtained from the cells under two conditions: when their correlated firing is taken into account, and when their correlated firing is ignored. We find that more than 90% of the information about the stimuli can be obtained from the cells when their correlated firing is ignored. This indicates that ganglion cells act largely independently to encode information, which greatly simplifies the problem of decoding their activity.

Transcriptional repression and developmental functions of the atypical vertebrate GATA protein TRPS1.

Known vertebrate GATA proteins contain two zinc fingers and are required in development, whereas invertebrates express a class of essential proteins containing one GATA-type zinc finger. We isolated the gene encoding TRPS1, a vertebrate protein with a single GATA-type zinc finger. TRPS1 is highly conserved between Xenopus and mammals, and the human gene is implicated in dominantly inherited tricho-rhino-phalangeal (TRP) syndromes. TRPS1 is a nuclear protein that binds GATA sequences but fails to transactivate a GATA-dependent reporter. Instead, TRPS1 potently and specifically represses transcriptional activation mediated by other GATA factors. Repression does not occur from competition for DNA binding and depends on a C-terminal region related to repressive domains found in Ikaros proteins. During mouse development, TRPS1 expression is prominent in sites showing pathology in TRP syndromes, which are thought to result from TRPS1 haploinsufficiency. We show instead that truncating mutations identified in patients encode dominant inhibitors of wild-type TRPS1 function, suggesting an alternative mechanism for the disease. TRPS1 is the first example of a GATA protein with intrinsic transcriptional repression activity and possibly a negative regulator of GATA-dependent processes in vertebrate development.

Complications of thoracoscopy.

Thoracoscopy is a minimally invasive thoracic surgical technique that is gaining widespread use for several surgical procedures. Although the complication rate is relatively low, there are definable risks associated with the technique. Careful attention to patient selection and an understanding of the complications associated with one-lung ventilation and video-assisted surgical techniques can help one to anticipate and prevent complications.

Posttreatment results of combining naltrexone with cognitive-behavior therapy for the treatment of alcoholism.

Naltrexone, an opiate antagonist medication, has been reported to be efficacious in the treatment of alcohol dependence when added to psychosocial treatments. Although the within-treatment efficacy of naltrexone has received primary attention, there has been little published on the outcome of individuals once the medication is discontinued. Animal studies have led to concern regarding a quick rebound to heavy drinking. This report extends the data previously reported by evaluating the outcome in alcoholic subjects during the 14 weeks after a 12-week treatment with naltrexone or placebo in conjunction with cognitive behavioral therapy. Of the 131 subjects evaluated during the treatment phase, 124 (95%) had up to 14 weeks of posttreatment drinking data available for analysis. Measures of craving and blood markers of heavy drinking were also evaluated. By the end of treatment, naltrexone demonstrated significantly greater efficacy than placebo. However, once the medication was discontinued, there was a gradual increase in relapse rates, heavy drinking days, and drinks per drinking day, and fewer days of abstinence were reported. By the end of the 14-week follow-up period, although naltrexone-treated subjects were, on average, still doing better than control subjects, the effectiveness of naltrexone was no longer statistically significant. There was no evidence that naltrexone subjects had an immediate return to heavy alcohol use as suggested in animals. These data suggest that, for a number of alcoholic subjects, continued treatment with naltrexone, or perhaps psychosocial intervention, for longer than 3 months is indicated. Future research should identify which alcohol-dependent individuals may need prolonged treatment to improve treatment success in the long term.

Neuropsychological performance deficits in adults with attention deficit/hyperactivity disorder.

Neuropsychological deficits in children diagnosed with attention deficit/hyperactivity disorder (ADHD) have been well documented utilizing various neuropsychological tests. Only recently has research begun to examine if similar deficits are present in adults with ADHD. A neuropsychological testing battery was constructed that assessed verbal learning and memory, psychomotor speed, and sustained attention--all demonstrated to be deficient in individuals with ADHD. Fifty-six self-referred nonmedicated adults with a DSM-IV diagnosis of ADHD and 38 normal comparison adults participated. ADHD adults demonstrated verbal and nonverbal memory deficits and decreased psychomotor speed compared to normal controls. Differences between ADHD and normal adults were not documented on traditional measures of executive functioning. A pattern of results emerged whereby ADHD adults' performance, particularly with regard to psychomotor speed, became more impaired as task complexity increased. This study's results largely corroborate similar neuropsychological testing results in ADHD children and recent ADHD adult findings, and support a frontal lobe dysfunction hypothesis of ADHD.

Esophageal Doppler monitor determinations of cardiac output and preload during cardiac operations.

BACKGROUND: Perioperative management of cardiac surgical patients frequently mandates measurements of cardiac output and left ventricular filling. This study compared cardiac output and left ventricular filling measured by pulmonary artery (PA) catheter and esophageal Doppler monitor (EDM). METHODS: Thirty-four patients undergoing coronary artery bypass grafting were prepared by implanting a PA catheter, an EDM, and a transit-time ultrasonic flow probe around the ascending aorta. In 20 patients, left ventricular end-diastolic short-axis area (EDA) was measured by transesophageal echocardiography. At five time points, cardiac output was measured from the flow probe, the EDM, and the PA catheter (by thermodilution), and left ventricular filling was assessed from the PA catheter (as PA diastolic pressure), the EDM (corrected flow time), and the EDA. For cardiac output, concordance correlations relating EDM to flow probe and PA catheter to flow probe were calculated, transformed (Fisher's z transformation), and compared by Student's t test. For left ventricular filling, regression coefficients were created between corrected flow time and EDA and between PA diastolic pressure and EDA. Spearman correlations were compared by Wilcoxon rank sum test. RESULTS: The EDM and the PA catheter exhibited similar relationships to the flow probe (concordance correlations, 0.55 +/- 0.35 [mean +/- standard deviation] and 0.49 +/- 0.34, respectively; p = 0.088). The correlation between corrected flow time and EDA was better than the correlation between PA diastolic pressure and EDA (concordance correlations, 0.49 +/- 0.55 versus 0.10 +/- 0.43, respectively; p < 0.01). CONCLUSIONS: These data suggest that the EDM may offer a less invasive technique for evaluating cardiac output and a more accurate estimate for preload compared with the PA catheter.

Fast-track cardiac anesthesia: use of remifentanil combined with intrathecal morphine as an alternative to sufentanil during desflurane anesthesia.

UNLABELLED: The purpose of this cardiac fast-track study was to evaluate the use of remifentanil (R) combined with intrathecal (IT) morphine as an alternative to sufentanil (S) during desflurane anesthesia with respect to postoperative pain control. Prior to entering the operating room, patients in the R group (n = 20) received morphine, 8 microg/kg IT. Anesthesia was induced using a standardized anesthetic technique in all patients. In the R group, anesthesia was maintained with R, 0.1 microg. kg(-1). min(-1) in combination with desflurane 3-10%. In the S group (n = 20), patients received S 0.3 microg. kg(-1). h(-1) and desflurane 3-10%. There were no differences between the two groups with respect to time from arrival in the intensive care unit to tracheal extubation (5.1 +/- 4.3 h vs 5.8 +/- 6.7 h for R and S groups, respectively). After extubation, patients in the R group had significantly lower visual analog pain scores, reduced patient-controlled analgesic requirements, and greater satisfaction with their perioperative pain management, compared with patients in the S group. We conclude that R combined with IT morphine provided superior pain control after cardiac surgery compared with a S-based general anesthetic technique. IMPLICATIONS: As part of a cardiac fast-tracking program involving desflurane anesthesia, the use of intrathecal morphine in combination with a remifentanil infusion provided improved postoperative pain control, compared with IV sufentanil alone.

Intrinsic dynamics in neuronal networks. I. Theory.

Many networks in the mammalian nervous system remain active in the absence of stimuli. This activity falls into two main patterns: steady firing at low rates and rhythmic bursting. How are these firing patterns generated? Specifically, how do dynamic interactions between excitatory and inhibitory neurons produce these firing patterns, and how do networks switch from one firing pattern to the other? We investigated these questions theoretically by examining the intrinsic dynamics of large networks of neurons. Using both a semianalytic model based on mean firing rate dynamics and simulations with large neuronal networks, we found that the dynamics, and thus the firing patterns, are controlled largely by one parameter, the fraction of endogenously active cells. When no endogenously active cells are present, networks are either silent or fire at a high rate; as the number of endogenously active cells increases, there is a transition to bursting; and, with a further increase, there is a second transition to steady firing at a low rate. A secondary role is played by network connectivity, which determines whether activity occurs at a constant mean firing rate or oscillates around that mean. These conclusions require only conventional assumptions: excitatory input to a neuron increases its firing rate, inhibitory input decreases it, and neurons exhibit spike-frequency adaptation. These conclusions also lead to two experimentally testable predictions: 1) isolated networks that fire at low rates must contain endogenously active cells and 2) a reduction in the fraction of endogenously active cells in such networks must lead to bursting.

Intrinsic dynamics in neuronal networks. II. experiment.

Neurons in many regions of the mammalian CNS remain active in the absence of stimuli. This activity falls into two main patterns: steady firing at low rates and rhythmic bursting. How these firing patterns are maintained in the presence of powerful recurrent excitation, and how networks switch between them, is not well understood. In the previous paper, we addressed these issues theoretically; in this paper we address them experimentally. We found in both studies that a key parameter in controlling firing patterns is the fraction of endogenously active cells. The theoretical analysis indicated that steady firing rates are possible only when the fraction of endogenously active cells is above some threshold, that there is a transition to bursting when it falls below that threshold, and that networks becomes silent when the fraction drops to zero. Experimentally, we found that all steadily firing cultures contain endogenously active cells, and that reducing the fraction of such cells in steadily firing cultures causes a transition to bursting. The latter finding implies indirectly that the elimination of endogenously active cells would cause a permanent drop to zero firing rate. The experiments described here thus corroborate the theoretical analysis.