Primate Spatial Memory Cells Become Tuned Early and Lose Tuning at Cell-Specific Times.

Working memory, the ability to maintain and transform information, is critical for cognition. Spatial working memory is particularly well studied. The premier model for spatial memory is the continuous attractor network, which posits that cells maintain constant activity over memory periods. Alternative models propose complex dynamics that result in a variety of cell activity time courses. We recorded from neurons in the frontal eye fields and dorsolateral prefrontal cortex of 2 macaques during long (5-15 s) memory periods. We found that memory cells turn on early after stimulus presentation, sustain activity for distinct and fixed lengths of time, then turn off and stay off for the remainder of the memory period. These dynamics are more complex than the dynamics of a canonical bump attractor network model (either decaying or nondecaying) but more constrained than the dynamics of fully heterogeneous memory models. We speculate that memory may be supported by multiple attractor networks working in parallel, with each network having its own characteristic mean turn-off time such that mnemonic resources are gradually freed up over time.

Dissociation of LFP Power and Tuning in the Frontal Cortex during Memory.

Working memory, the ability to maintain and manipulate information in the brain, is critical for cognition. During the memory period of spatial memory tasks, neurons in the prefrontal cortex code for memorized locations via persistent, spatially tuned increases in activity. Local field potentials (LFPs) are understood to reflect summed synaptic activity of local neuron populations and may offer a window into network-level processing. We recorded LFPs from areas 8A and 9/46 while two male cynomolgus macaques (Macaca fascicularis) performed a long duration (5.1-15.6 s) memory-guided saccade task. Greater than ∼16 Hz, LFP power was contralaterally tuned throughout the memory period. Yet power for both contralateral and ipsilateral targets fell gradually after the first second of the memory period, dropping below baseline after a few seconds. Our results dissociate absolute LFP power from mnemonic tuning and are consistent with modeling work that suggests that decreasing synchronization within a network may improve the stability of memory coding.SIGNIFICANCE STATEMENT The frontal cortex is an important site for working memory. There, individual neurons reflect memorized information with selective increases in activity, but how collections of neurons work together to achieve memory is not well understood. In this work, we examined rhythmic electrical activity surrounding these neurons, which may reflect the operation of recurrent circuitry that could underlie memory. This rhythmic activity was spatially tuned with respect to memorized locations as long as memory was tested (∼7.5 s). Surprisingly, however, the overall magnitude of rhythmic activity decreased steadily over this period, dropping below baseline levels after a few seconds. These findings suggest that collections of neurons may actively desynchronize to promote stability in memory circuitry.

Ghosts in the Machine II: Neural Correlates of Memory Interference from the Previous Trial.

Previous memoranda interfere with working memory. For example, spatial memories are biased toward locations memorized on the previous trial. We predicted, based on attractor network models of memory, that activity in the frontal eye fields (FEFs) encoding a previous target location can persist into the subsequent trial and that this ghost will then bias the readout of the current target. Contrary to this prediction, we find that FEF memory representations appear biased away from (not toward) the previous target location. The behavioral and neural data can be reconciled by a model in which receptive fields of memory neurons converge toward remembered locations, much as receptive fields converge toward attended locations. Convergence increases the resources available to encode the relevant memoranda and decreases overall error in the network, but the residual convergence from the previous trial can give rise to an attractive behavioral bias on the next trial.

Ghosts in the machine: memory interference from the previous trial.

Previous memoranda can interfere with the memorization or storage of new information, a concept known as proactive interference. Studies of proactive interference typically use categorical memoranda and match-to-sample tasks with categorical measures such as the proportion of correct to incorrect responses. In this study we instead train five macaques in a spatial memory task with continuous memoranda and responses, allowing us to more finely probe working memory circuits. We first ask whether the memoranda from the previous trial result in proactive interference in an oculomotor delayed response task. We then characterize the spatial and temporal profile of this interference and ask whether this profile can be predicted by an attractor network model of working memory. We find that memory in the current trial shows a bias toward the location of the memorandum of the previous trial. The magnitude of this bias increases with the duration of the memory period within which it is measured. Our simulations using standard attractor network models of working memory show that these models easily replicate the spatial profile of the bias. However, unlike the behavioral findings, these attractor models show an increase in bias with the duration of the previous rather than the current memory period. To model a bias that increases with current trial duration we posit two separate memory stores, a rapidly decaying visual store that resists proactive interference effects and a sustained memory store that is susceptible to proactive interference.

Inflammation markers in essential hypertension.

Essential hypertension is a common health disorder with uncertain etiology and unclear pathophysiology. There is evidence that various systems interact in uncertain ways and mechanisms to cause hypertension. It is also well known that inflammation is a key feature in the initiation, progression and clinical implication of several cardiovascular diseases. Recently, it has become evident that the immune system and inflammatory response are also essential in the pathogenesis of hypertension. Many inflammation markers such as CRP, cytokines, and adhesion molecules have been found elevated in hypertensive patients supporting the role of inflammation in the pathogenesis of hypertension. Also, in normotensive individuals, these markers have been associated with the risk of developing hypertension, whereas in hypertensive patients they have been associated with target organ damage as well as with the risk for future cardiovascular events. Thus, understanding the role of inflammation in hypertension provides new insights for novel therapeutic approaches, targeting inflammation for the treatment of hypertension and its complications.

Association of virtual histology characteristics of the culprit plaque with post-fibrinolysis flow restoration in ST-elevation myocardial infarction.

OBJECTIVES: We sought to test the hypothesis that virtual histology characteristics of the culprit lesion in patients with ST-elevation myocardial infarction are associated with blood flow restoration after thrombolysis. METHODS: Consecutive patients referred for coronary angiography after successful thrombolysis were included in this correlational cross-sectional study. Evaluation with intravascular ultrasound (IVUS) and virtual histology of the culprit arterial segment was performed in all cases. RESULTS: Forty-eight patients (60.5 ± 10.7 years) were included. TIMI flow grade 3 was found in 24 (50%). Diabetes was strongly associated with lower TIMI flow 3 rate (26.7% vs 60.6%; p = 0.029) and there was a significant difference in the time to thrombolysis (2.0 ± 0.8 hours in those with TIMI flow 3 vs 3.0 ± 0.7 hours in TIMI flow grades 1-2; p < 0.001). Patients with TIMI flow grades 3 and 1-2 had similar absolute total plaque volume (152.8 ± 59.3mm(3) vs 147.5 ± 92.3mm(3); p = 0.817) and absolute necrotic core (NC) volume (31.2 ± 13.9 mm(3) vs 33.6 ± 23.2mm(3); p = 0.671). However, there were significant differences in the relative NC content, both in proportion to the whole plaque volume (26.3% vs 29.9%; p = 0.016) and as an area fraction at the largest NC site (31.5% vs 40.3%; p < 0.001). CONCLUSION: The NC content of atherosclerotic plaques is meaningful for flow restoration after the occurrence of a coronary event. This finding highlights the importance of plaque composition, as studied with virtual histology, not only for the sequence of processes leading to an acute plaque-related event, but also for thrombus formation and lysis, following the occurrence of such an event.

Anti-inflammatory treatment with colchicine in stable chronic heart failure: a prospective, randomized study.

OBJECTIVES: The purpose of this study was to test the efficacy of a 6-month course of anti-inflammatory treatment with colchicine in improving functional status of patients with stable chronic heart failure (CHF). BACKGROUND: CHF has been shown to be associated with inflammatory activation. Inflammation has been designated as a therapeutic target in CHF. METHODS: Patients with stable CHF were randomly assigned to colchicine (0.5 mg twice daily) or placebo for 6 months. The primary endpoint was the proportion of patients achieving at least one-grade improvement in New York Heart Association class. RESULTS: Two hundred sixty-seven patients were available for final evaluation of the primary endpoint: its rate was 11% in the control group and 14% in the colchicine group (odds ratio: 1.40; 95% confidence interval: 0.67 to 2.93; p = 0.365). The rate of the composite of death or hospital stay for heart failure was 9.4% in the control group, compared with 10.1% in the colchicine group (p = 0.839). The changes in treadmill exercise time with treatment were insignificant and similar in the 2 groups (p = 0.938). C-reactive protein and interleukin-6 were both significantly reduced in the colchicine group (-5.1 mg/l and -4.8 pg/ml, respectively; p < 0.001 for both, compared with the control group). CONCLUSIONS: According to this prospective, randomized study, anti-inflammatory treatment with colchicine in patients with stable CHF, although effective in reducing inflammation biomarker levels, did not affect in any significant way patient functional status (in terms of New York Heart Association class and objective treadmill exercise tolerance) or the likelihood of death or hospital stay for heart failure.

Interatrial conduction time and incident atrial fibrillation: a prospective cohort study.

BACKGROUND: Atrial electrical conduction properties have been implicated in atrial fibrillation (AF) pathogenesis. OBJECTIVE: The purpose of this study was to prospectively assess the potential association of interatrial conduction time (IACT) with incident AF. METHODS: The study included persons referred for invasive electrophysiologic study (EPS), aged ≥50 years, without AF history or valvular disease. IACT was defined as the interval between the high right atrium electrogram and the distal coronary sinus atrial electrogram. RESULTS: Six hundred twelve subjects were included (median follow-up 43 months, interquartile range 40-47). AF incidence was 21.7 cases per 1000 person-years. IACT was a significant predictor of AF with a c-statistic of 0.770 (95% confidence interval 0.702-0.838). In time-dependent analysis, IACT was a significant stratifier of AF risk (log-rank 28.0, P <.001). The corresponding incidences of AF in each tertile of IACT were 3, 17, and 46 per 1000 person-years, respectively (all differences between tertiles were significant). IACT remained significant in multivariable Cox regression analysis, after adjustment for age, sex, hypertension, and left atrial diameter, with each millisecond of prolonged IACT corresponding to 7% (95% confidence interval 2%-12%) higher adjusted risk of incident AF. CONCLUSION: IACT is independently associated with incident AF. The invasive nature of the measurement is a limitation for its use as a clinical risk stratifier (although it could be used in patients referred for EPS), but these results are of interest in themselves because they suggest a strong pathophysiologic connection between atrial conduction times and substrate alterations ultimately leading to AF.

Association of asymmetric dimethylarginine levels with treadmill-stress-test-derived prognosticators.

BACKGROUND: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide production. The purpose of this study was to assess the correlation between ADMA and treadmill stress test outcome parameters with known prognostic value, in patients with intermediate risk for coronary artery disease (CAD). METHODS: Study participants were referred for treadmill exercise stress test (EST) due to symptoms of suspected CAD. Participants with prior history of CAD, cerebrovascular events, peripheral artery disease, systemic inflammatory disease or use of anti-inflammatory agents were excluded. ADMA levels were measured before EST. RESULTS: The study prospectively enrolled 209 individuals (165 males, aged 58.1±10.9). A significant negative correlation was detected between ADMA and maximal exercise time (r=-0.556, p<0.001), metabolic equivalents (METs) (r=-0.555, p<0.001) and Duke treadmill score (DTS) (r=-0.347, p<0.001). Subjects who exercised to ≥10 METs (n=114) had lower ADMA levels than those who achieved <7 METs (n=30) (0.58±0.06 vs 0.87±0.08µmol/L, p<0.001), and those with DTS<5 (n=63) had higher ADMA (0.75±0.19 vs 0.64±0.15µmol/L, p<0.001) compared to those with DTS ≥5 (n=146). In multivariable analysis, ADMA remained an independent predictor of DTS (R(2)=0.210; beta=-10.5; 95% confidence interval -14.9 to -6.2; adjusted p<0.001) and METs (R(2)=0.500; beta -8.5; 95% confidence interval -9.7 to -6.0; adjusted p<0.001) after adjustment for age, BMI, gender, diabetes, smoking status, dyslipidemia, hypertension and family history of premature CAD. CONCLUSION: ADMA is correlated to EST parameters with proven prognostic value. This implies that ADMA itself might be a useful prognosticator in patients with suspected CAD.

Colchicine for prevention of atrial fibrillation recurrence after pulmonary vein isolation: mid-term efficacy and effect on quality of life.

BACKGROUND: Our group previously showed that colchicine treatment is associated with decreased early recurrence rate after ablation for atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to test the mid-term efficacy of colchicine in reducing AF recurrences after a single procedure of pulmonary vein isolation in patients with paroxysmal AF. Assessment of quality-of-life (QOL) changes was a secondary objective. METHODS: Patients with paroxysmal AF who were scheduled for ablation were randomized to a 3-month course of colchicine 0.5 mg twice daily or placebo and were followed for a median of 15 months (with a 3-month blanking period). QOL was assessed with a general-purpose health-related QOL tool (26-item World Health Organization QOL questionnaire) at baseline and after 3 and 12 months. RESULTS: Two hundred twenty-three randomized patients underwent ablation, and 206 patients were available for analysis (144 male, age 62.2 ± 5.8 years). AF recurrence rate in the colchicine group was 31.1% (32/103) vs 49.5% (51/103) in the control group (P = .010), translated in a relative risk reduction of 37% (odds ratio 0.46, 95% confidence interval 0.26-0.81). The number needed to treat was 6 (95% confidence interval 3.2-19.8). Physical domain QOL scores at 12 months were 63.6 ± 13.8 in the colchicine group and 52.5 ± 18.1 in controls, whereas psychological domain scores were 56.1 ± 13.7 vs 44.7 ± 17.3, respectively (P <.001, for both). CONCLUSION: Colchicine treatment after pulmonary vein isolation for paroxysmal AF is associated with lower AF recurrence rates after a single procedure. This reduction is accompanied by corresponding improvements in physical and psychological health-related QOL scores.

Using a compound gain field to compute a reach plan.

A gain field, the scaling of a tuned neuronal response by a postural signal, may help support neuronal computation. Here, we characterize eye and hand position gain fields in the parietal reach region (PRR). Eye and hand gain fields in individual PRR neurons are similar in magnitude but opposite in sign to one another. This systematic arrangement produces a compound gain field that is proportional to the distance between gaze location and initial hand position. As a result, the visual response to a target for an upcoming reach is scaled by the initial gaze-to-hand distance. Such a scaling is similar to what would be predicted in a neural network that mediates between eye- and hand-centered representations of target location. This systematic arrangement supports a role of PRR in visually guided reaching and provides strong evidence that gain fields are used for neural computations.