Integrating across memory episodes: Developmental trends

Memory enables us to use information from our past experiences to guide new behaviours, calling for the need to integrate or form inference across multiple distinct episodic experiences. Here, we compared children (aged 9-10 years), adolescents (aged 12-13 years), and young adults (aged 19-25 years) on their ability to form integration across overlapping associations in memory. Participants first encoded a set of overlapping, direct AB- and BC-associations (object-face and face-object pairs) as well as non-overlapping, unique DE-associations. They were then tested on these associations and inferential AC-associations. The experiment consisted of four such encoding/retrieval cycles, each consisting of different stimuli set. For accuracy on both unique and inferential associations, young adults were found to outperform teenagers, who in turn outperformed children. However, children were particularly slower than teenagers and young adults in making judgements during inferential than during unique associations. This suggests that children may rely more on making inferences during retrieval, by first retrieving the direct associations, followed by making the inferential judgement. Furthermore, young adults showed a higher correlation between accuracy in direct (AB, BC) and inferential AC-associations than children. This suggests that, young adults relied closely on AB- and BC-associations for making AC decisions, potentially by forming integrated ABC-triplets during encoding or retrieval. Taken together, our findings suggest that there may be an age-related shift in how information is integrated across experienced episodes, namely from relying on making inferences at retrieval during middle childhood to forming integrated representations at different memory processing stages in adulthood

Disentangling Hippocampal and Amygdala Contribution to Human Anxiety-Like Behavior

Anxiety comprises a suite of behaviors to deal with potential threat and is often modeled in approach–avoidance conflict tasks. Collectively, these tests constitute a predominant preclinical model of anxiety disorder. A body of evidence suggests that both ventral hippocampus and amygdala lesions impair anxiety-like behavior, but the relative contribution of these two structures is unclear. A possible reason is that approach–avoidance conflict tasks involve a series of decisions and actions, which may be controlled by distinct neural mechanisms that are difficult to disentangle from behavioral readouts. Here, we capitalize on a human approach–avoidance conflict test, implemented as computer game, that separately measures several action components. We investigate three patients of both sexes with unspecific unilateral medial temporal lobe (MTL) damage, one male with selective bilateral hippocampal (HC), and one female with selective bilateral amygdala lesions, and compare them to matched controls. MTL and selective HC lesions, but not selective amygdala lesions, increased approach decision when possible loss was high. In contrast, MTL and selective amygdala lesions, but not selective HC lesions, increased return latency. Additionally, selective HC and selective amygdala lesions reduced approach latency. In a task targeted at revealing subjective assumptions about the structure of the computer game, MTL and selective HC lesions impacted on reaction time generation but not on the subjective task structure. We conclude that deciding to approach reward under threat relies on hippocampus but not amygdala, whereas vigor of returning to safety depends on amygdala but not on hippocampus

Decisional role of the dorsolateral prefrontal cortex in ocular motor behaviour

Three patients with a unilateral cortical lesion affecting the dorsolateral prefrontal cortex (DLPFC), i.e. Brodmann area 46, were tested using different paradigms of reflexive saccades (gap and overlap tasks), intentional saccades (antisaccades, memory‐guided and predictive saccades) and smooth pursuit movements. Visually guided saccades with gap and overlap, latency of correct antisaccades and memory‐guided saccades and the gain of smooth pursuit were normal, compared with controls. These results confirm our anatomical data showing that the adjacent frontal eye field (FEF) was unimpaired in these patients. The specific pattern of abnormalities after a unilateral DLPFC lesion, compared with that of the FEF lesions previously reported, consists mainly of: (i) a bilateral increase in the percentage of errors in the antisaccade task (misdirected reflexive saccades); (ii) a bilateral increase in the variable error in amplitude, without significant decrease in the gain, in the memory‐guided saccade task; and (iii) a bilateral decrease in the percentage of anticipatory saccades in the predictive task. Taken together, these results suggest that the DLPFC plays a crucial role in the decisional processes, preparing saccades by inhibiting unwanted reflexive saccades (inhibition), maintaining memorized information for ongoing intentional saccades (short‐term spatial memory) or facilitating anticipatory saccades (prediction), depending upon current external environmental and internal circumstance

Temporal–spectral signaling of sensory information and expectations in the cerebral processing of pain

The perception of pain is shaped by somatosensory information about threat. However, pain is also influenced by an individual's expectations. Such expectations can result in clinically relevant modulations and abnormalities of pain. In the brain, sensory information, expectations (predictions), and discrepancies thereof (prediction errors) are signaled by an extended network of brain areas which generate evoked potentials and oscillatory responses at different latencies and frequencies. However, a comprehensive picture of how evoked and oscillatory brain responses signal sensory information, predictions, and prediction errors in the processing of pain is lacking so far. Here, we therefore applied brief painful stimuli to 48 healthy human participants and independently modulated sensory information (stimulus intensity) and expectations of pain intensity while measuring brain activity using electroencephalography (EEG). Pain ratings confirmed that pain intensity was shaped by both sensory information and expectations. In contrast, Bayesian analyses revealed that stimulus-induced EEG responses at different latencies (the N1, N2, and P2 components) and frequencies (alpha, beta, and gamma oscillations) were shaped by sensory information but not by expectations. Expectations, however, shaped alpha and beta oscillations before the painful stimuli. These findings indicate that commonly analyzed EEG responses to painful stimuli are more involved in signaling sensory information than in signaling expectations or mismatches of sensory information and expectations. Moreover, they indicate that the effects of expectations on pain are served by brain mechanisms which differ from those conveying effects of sensory information on pain

Space-Time Distribution of G-Band and Ca II H-Line Intensity Oscillations in Hinode/SOT-FG Observations

We study the space-time distributions of intensity fluctuations in 2 - 3 hour sequences of multi-spectral, high-resolution, high-cadence broad-band filtergram images (BFI) made by the SOT-FG system aboard the Hinode spacecraft. In the frequency range 5.5 < f < 8.0 mHz both G-band and Ca II H-line oscillations are suppressed in the presence of magnetic fields, but the suppression disappears for f > 10 mHz. By looking at G-band frequencies above 10 mHz we find that the oscillatory power, both at these frequencies and at lower frequencies too, lies in a mesh pattern with cell scale 2 - 3 Mm, clearly larger than normal granulation, and with correlation times on the order of hours. The mesh pattern lies in the dark lanes between stable cells found in time-integrated G-band intensity images. It also underlies part of the bright pattern in time-integrated H-line emission. This discovery may reflect dynamical constraints on the sizes of rising granular convection cells together with the turbulence created in strong intercellular downflows.Comment: 24 pages, 15 figure

Risk stratification for venous thromboembolism in patients with testicular germ cell tumors

BACKGROUND:Patients with testicular germ cell tumors (TGCT) have an increased risk for venous thromboembolism (VTE). We identified risk factors for VTE in this patient cohort and developed a clinical risk model. METHODS:In this retrospective cohort study at the Medical University of Graz we included 657 consecutive TGCT patients across all clinical stages. A predictive model for VTE was developed and externally validated in 349 TGCT patients treated at the University Hospital Zurich. RESULTS:Venous thromboembolic events occurred in 34 (5.2%) patients in the Graz cohort. In univariable competing risk analysis, higher clinical stage (cS) and a retroperitoneal lymphadenopathy (RPLN) were the strongest predictors of VTE (p<0.0001). As the presence of a RPLN with more than 5cm in greatest dimension without coexisting visceral metastases is classified as cS IIC, we constructed an empirical VTE risk model with the following four categories (12-month-cumulative incidence): cS IA-B 8/463 patients (1.7%), cS IS-IIB 5/86 patients (5.9%), cS IIC 3/21 patients (14.3%) and cS IIIA-C 15/70 patients (21.4%). This risk model was externally validated in the Zurich cohort (12-month-cumulative incidence): cS IA-B (0.5%), cS IS-IIB (6.0%), cS IIC (11.1%) and cS IIIA-C (19.1%). Our model had a significantly higher discriminatory performance than a previously published classifier (RPLN-VTE-risk-classifier) which is based on the size of RPLN alone (AUC-ROC: 0.75 vs. 0.63, p = 0.007). CONCLUSIONS:According to our risk stratification, TGCT patients with cS IIC and cS III disease have a very high risk of VTE and may benefit from primary thromboprophylaxis for the duration of chemotherapy

Prefrontal gamma oscillations reflect ongoing pain intensity in chronic back pain patients

Chronic pain is a major health care issue characterized by ongoing pain and a variety of sensory, cognitive, and affective abnormalities. The neural basis of chronic pain is still not completely understood. Previous work has implicated prefrontal brain areas in chronic pain. Furthermore, prefrontal neuronal oscillations at gamma frequencies (60–90 Hz) have been shown to reflect the perceived intensity of longer lasting experimental pain in healthy human participants. In contrast, noxious stimulus intensity has been related to alpha (8–13 Hz) and beta (14–29 Hz) oscillations in sensorimotor areas. However, it is not fully understood how the intensity of ongoing pain as the key symptom of chronic pain is represented in the human brain. Here, we asked 31 chronic back pain patients to continuously rate their ongoing pain while simultaneously recording electroencephalography (EEG). Time–frequency analyses revealed a positive association between ongoing pain intensity and prefrontal beta and gamma oscillations. No association was found between pain and alpha or beta oscillations in sensorimotor areas. These findings indicate that ongoing pain as the key symptom of chronic pain is reflected by neuronal oscillations implicated in the subjective perception of longer lasting pain rather than by neuronal oscillations related to the processing of objective nociceptive input. The findings, thus, support a dissociation of pain intensity from nociceptive processing in chronic back pain patients. Furthermore, although possible confounds by muscle activity have to be taken into account, they might be useful for defining a neurophysiological marker of ongoing pain in the human brain

GX15-070 (obatoclax) overcomes glucocorticoid resistance in acute lymphoblastic leukemia through induction of apoptosis and autophagy

Glucocorticoids (GCs) are common components of many chemotherapeutic regimens for lymphoid malignancies including acute lymphoblastic leukemia (ALL). The BCL-2 family has an essential role in regulating GC-induced cell death. Here we show that downregulation of antiapoptotic BCL-2 family proteins, especially MCL-1, enhances GC-induced cell death. Thus we target MCL-1 by using GX15-070 (obatoclax) in ALL cells. Treatment with GX15-070 in both dexamethasone (Dex)-sensitive and -resistant ALL cells shows effective growth inhibition and cell death. GX15-070 induces caspase-3 cleavage and increases the Annexin V-positive population, which is indicative of apoptosis. Before the onset of apoptosis, GX15-070 induces LC3 conversion as well as p62 degradation, both of which are autophagic cell death markers. A pro-apoptotic molecule BAK is released from the BAK/MCL-1 complex following GX15-070 treatment. Consistently, downregulation of BAK reduces caspase-3 cleavage and cell death, but does not alter LC3 conversion. In contrast, downregulation of ATG5, an autophagy regulator, decreases LC3 conversion and cell death, but does not alter caspase-3 cleavage, suggesting that apoptosis and autophagy induced by GX15-070 are independently regulated. Downregulation of Beclin-1, which is capable of crosstalk between apoptosis and autophagy, affects GX15-070-induced cell death through apoptosis but not autophagy. Taken together, GX15-070 treatment in ALL could be an alternative regimen to overcome glucocorticoid resistance by inducing BAK-dependent apoptosis and ATG5-dependent autophagy