The hippocampus and spatial constraints on mental imagery

We review a model of imagery and memory retrieval based on allocentric spatial representation by place cells and boundary vector cells (BVCs) in the medial temporal lobe, and their translation into egocentric images in retrosplenial and parietal areas. In this model, the activity of place cells constrain the contents of imagery and retrieval to be coherent and consistent with the subject occupying a single location, while the activity of head-direction cells along Papez's circuit determine the viewpoint direction for which the egocentric image is generated. An extension of this model is discussed in which a role for grid cells in dynamic updating of representations (mental navigation) is included. We also discuss the extension of this model to implement a version of the dual representation theory of post-traumatic stress disorder (PTSD) in which PTSD arises from an imbalance between weak allocentric hippocampal-mediated contextual representations and strong affective/sensory representations. The implications of these models for behavioral, neuropsychological, and neuroimaging data in humans are explored

Time-resolved nanosecond fluorescence lifetime imaging and picosecond infrared spectroscopy of combretastatin A-4 in solution and in cellular systems

Fluorescence lifetime images of intrinsic fluorescence obtained with two-photon excitation at 630 nm are shown following uptake of a series of E-combretastatins into live cells, including human umbilical vein endothelial cells (HUVECs) that are the target for the anticancer activity of combretastatins. Images show distribution of the compounds within the cell cytoplasm and in structures identified as lipid droplets by comparison with images obtained following Nile red staining of the same cells. The intracellular fluorescent lifetimes are generally longer than in fluid solution as a consequence of the high viscosity of the cellular environment. Following incubation the intracellular concentrations of a fluorinated derivative of E combretastatin A4 in HUVECs are up to between 2 and 3 orders of magnitude higher than the concentration in the surrounding medium. Evidence is presented to indicate that at moderate laser powers (up to 6 mW) it is possible to isomerize up to 25% of the combretastatin within the femtolitre focal volume of the femtosecond laser beam. This suggests that it may be possible to activate the E-combretastatin (with low cellular toxicity) to the Z-isomer with high anticancer drug activity using two-photon irradiation. The isomerization of Z- and E-combretastatins by 266 nm irradiation has been probed by ultrafast time-resolved infrared spectroscopy. Results for the E-isomer show a rapid loss of excess vibrational energy in the excited state with a lifetime of 7 ps, followed by a slower process with a lifetime of 500 ps corresponding to the return to the ground state as also determined from the fluorescence lifetime. In contrast the Z-isomer, whilst also appearing to undergo a rapid cooling of the initial excited state, has a much shorter overall excited state lifetime of 14 ps

Anticancer phototherapy using activation of E-combretastatins by two-photon–induced isomerization

The photoisomerization of relatively nontoxic E-combretastatins to clinically active Z-isomers is shown to occur in solution through both one- and two-photon excitations at 340 and 625 nm, respectively. The photoisomerization is also demonstrated to induce mammalian cell death by a two-photon absorption process at 625 nm. Unlike conventional photodynamic therapy (PDT), the mechanism of photoisomerization is oxygen- independent and active in hypoxic environments such as in tumors. The use of red or near-infrared (NIR) light for two-photon excitation allows greater tissue penetration than conventional UV one-photon excitation. The results provide a baseline for the development of a novel phototherapy that overcomes nondiscriminative systemic toxicity of Z-combretastatins and the limitations of PDT drugs that require the presence of oxygen to promote their activity, with the added benefits of two-photon red or NIR excitation for deeper tissue penetration

Repetitive negative thinking in the perinatal period and its relationship with anxiety and depression

Background: Rumination and worry represent two types of repetitive negative thinking (RNT), and their predictive and maintaining roles are well-established in depression and anxiety, respectively. Furthermore, there is an emerging literature on the link between RNT and psychological wellbeing in the perinatal period. Methods: We conducted a scoping review of studies that have investigated the relationship between RNT and perinatal depression and anxiety. We identified 87 papers eligible for inclusion in the review; they included cross-sectional and longitudinal studies, as well as treatment evaluations (pilot trials and randomised controlled trials). Results: Cross-sectional studies provided evidence of an association between RNT (i.e., rumination and worry) and depression and anxiety, in both pregnancy and postpartum. Longitudinal findings were mixed. Whilst antenatal worry consistently predicted subsequent depression and anxiety (both later in pregnancy and postpartum), rumination did not consistently predict depression. However, there was some evidence that RNT interacted with other processes to predict later psychopathology. Three randomised controlled trials evaluated whether psychological treatments reduce RNT in the perinatal period, only one of which included a clinical sample. Limitations: No experimental investigations were eligible for inclusion in the review. Conclusions: Further studies are needed to further our understanding of the nature and role of RNT in pregnancy and postpartum, and its consequences for maternal mental health. These include (but are not limited to) experimental investigations, studies with large clinical samples, and RCTs evaluating the effectiveness of psychological interventions targeting RNT to prevent and treat perinatal depression and anxiety

Location-dependent threat and associated neural abnormalities in clinical anxiety

Anxiety disorders are characterized by maladaptive defensive responses to distal or uncertain threats. Elucidating neural mechanisms of anxiety is essential to understand the development and maintenance of anxiety disorders. In fMRI, patients with pathological anxiety (ANX, n = 23) and healthy controls (HC, n = 28) completed a contextual threat learning paradigm in which they picked flowers in a virtual environment comprising a danger zone in which flowers were paired with shock and a safe zone (no shock). ANX compared with HC showed 1) decreased ventromedial prefrontal cortex and anterior hippocampus activation during the task, particularly in the safe zone, 2) increased insula and dorsomedial prefrontal cortex activation during the task, particularly in the danger zone, and 3) increased amygdala and midbrain/periaqueductal gray activation in the danger zone prior to potential shock delivery. Findings suggest that ANX engage brain areas differently to modulate context-appropriate emotional responses when learning to discriminate cues within an environment

Auto-extinction of engineered timber

Engineered timber products are becoming increasingly popular in the construction industry due to their attractive aesthetic and sustainability credentials. Cross-laminated timber (CLT) is one such engineered timber product, formed of multiple layers of timber planks glued together with adjacent layers perpendicular to each other. Unlike traditional building materials such as steel and concrete, the timber structural elements can ignite and burn when exposed to fire, and thus this risk must be explicitly addressed during design. Current design guidance focusses on the structural response of engineered timber, with the flammability risk typically addressed by encapsulation of any structural timber elements with the intention of preventing their involvement in a fire. Exposed structural timber elements may act as an additional fuel load, and this risk must be adequately quantified to satisfy the intent of the building regulations in that the structure does not continue burning. This can be achieved through timber’s natural capacity to auto-extinguish when the external heat source is removed or sufficiently reduced. To address these issues, a fundamental understanding of auto-extinction and the conditions necessary to achieve it in real fire scenarios is needed. Bench-scale flammability studies were undertaken in the Fire Propagation Apparatus to explore the conditions under which auto-extinction will occur. Critical conditions were determined experimentally as a mass loss rate of 3.48 ± 0.31 g/m2s, or an incident heat flux of ~30 kW/m2. Mass loss rate was identified as the better criterion, as critical heat flux was shown by comparison with literature data to be heavily dependent on apparatus. Subsequently, full-scale compartment fire experiments with exposed timber surfaces were performed to determine if auto-extinction could be achieved in real fire scenarios. It was demonstrated that auto-extinction could be achieved in a compartment fire scenario, but only if significant delamination of the engineered timber product could be prevented. A full-scale compartment fire experiment with an exposed back wall and ceiling achieved auto-extinction after around 21 minutes, at which point no significant delamination of the first lamella had been observed. Experiments with an exposed back and side wall, and experiments with an exposed back wall, side wall, and ceiling underwent sustained burning due to repeated delamination, and an increased quantity of exposed timber respectively. Firepoint theory was used to predict the mass loss rate as a function of external heat flux and heat losses, and was successfully applied to the bench-scale experiments. This approach was then extended to the full-scale compartment fire experiment which achieved auto-extinction. A simplified approach based on experimentally obtained internal temperature fields was able to predict auto-extinction if delamination had not occurred – predicting an extinction time of 20-21 minutes. This demonstrates that the critical mass loss rate of 3.48 ± 0.31 g/m2s determined from bench-scale experiments was valid for application to full-scale compartment fire experiments. This was further explored through a series of reduced-scale compartment fire experiments, demonstrating that auto-extinction can only reliably be achieved if burnout of the compartment fuel load is achieved before significant delamination of the outer lamella takes place. The quantification of the auto-extinction phenomena and their applicability to full-scale compartment fires explored herein thus allows greater understanding of the effects of exposed timber surfaces on compartment fire dynamics

Value-based decision-making of cigarette and nondrug rewards in dependent and occasional cigarette smokers:An FMRI study

Little is known about the neural functioning that underpins drug valuation and choice in addiction, including nicotine dependence. Following ad libitum smoking, 19 dependent smokers (smoked≥10/day) and 19 occasional smokers (smoked 0.5‐5/week) completed a decision‐making task. First, participants stated how much they were willing‐to‐pay for various amounts of cigarettes and shop vouchers. Second, during functional magnetic resonance imaging, participants decided if they wanted to buy these cigarettes and vouchers for a set amount of money. We examined decision‐making behaviour and brain activity when faced with cigarette and voucher decisions, purchasing (vs not purchasing) cigarettes and vouchers, and “value signals” where brain activity correlated with cigarette and voucher value. Dependent smokers had a higher willingness‐to‐pay for cigarettes and greater activity in the bilateral middle temporal gyrus when faced with cigarette decisions than occasional smokers. Across both groups, the decision to buy cigarettes was associated with activity in the left paracingulate gyrus, right nucleus accumbens, and left amygdala. The decision to buy vouchers was associated with activity in the left superior frontal gyrus, but dependent smokers showed weaker activity in the left posterior cingulate gyrus than occasional smokers. Across both groups, cigarette value signals were observed in the left striatum and ventromedial prefrontal cortex. To summarise, nicotine dependence was associated with greater behavioural valuation of cigarettes and brain activity during cigarette decisions. When purchasing cigarettes and vouchers, reward and decision‐related brain regions were activated in both groups. For the first time, we identified value signals for cigarettes in the brain

Cannabis dampens the effects of music in brain regions sensitive to reward and emotion

Background: Despite the current shift towards permissive cannabis policies, few studies have investigated the pleasurable effects users seek. Here we investigate the effects of cannabis on listening to music - a rewarding activity that frequently occurs in the context of recreational cannabis use. We additionally tested how these effects are influenced by cannabidiol (CBD), which may offset cannabis-related harms. Methods: Across three sessions, sixteen cannabis users inhaled cannabis with CBD, cannabis without CBD, and placebo. We compared their response to music relative to control excerpts of scrambled sound during functional Magnetic Resonance Imaging (fMRI) within regions identified in a meta-analysis of music-evoked reward and emotion. All results were False Discovery Rate corrected (p<0.05). Results: Compared to placebo, cannabis without CBD dampened response to music in bilateral auditory cortex (right: p=0.005, left: p=0.008), right hippocampus/parahippocampal gyrus (p=0.025), right amygdala (p=0.025) and right ventral striatum (p=0.033). Across all sessions, the effects of music in this ventral striatal region correlated with pleasure ratings (p=0.002) and increased functional connectivity with auditory cortex (right: p=0.000, left: p=0.000), supporting its involvement in music reward. Functional connectivity between right ventral striatum and auditory cortex was increased by CBD (right: p=0.003, left: p=0.030), and cannabis with CBD did not differ from placebo on any fMRI measures. Both types of cannabis increased ratings of wanting to listen to music (p<0.002) and enhanced sound perception (p<0.001). Conclusions: Cannabis dampens the effects of music in brain regions sensitive to reward and emotion. These effects were offset by a key cannabis constituent, cannabidol