Hippocampal representation of threat features and behavior in a human approach-avoidance conflict anxiety task

Decisions under threat are crucial to survival and require integration of distinct situational features such as threat probability and magnitude. Recent evidence from human lesion and neuroimaging studies implicated anterior hippocampus (aHC) and amygdala in approach/avoidance decisions under threat, and linked their integrity to cautious behavior. Here we sought to elucidate how threat dimensions and behavior are represented in these structures. Twenty human participants (11 female) completed an approach-avoidance conflict task during high-resolution functional MRI. Participants could gather tokens under threat of capture by a virtual predator, which would lead to token loss. Threat probability (predator wake-up rate) and magnitude (amount of token loss) varied on each trial. To disentangle effects of threat features, and ensuing behavior, we performed a multifold parametric analysis. We found that high threat probability and magnitude related to BOLD signal in left anterior hippocampus/entorhinal cortex. However BOLD signal in this region was better explained by avoidance behavior than by these threat features. A priori region-of-interest analysis confirmed the relation of anterior hippocampus BOLD response with avoidance. Exploratory subfield analysis revealed that this relation was specific to anterior CA2/3 but not CA1. Left lateral amygdala responded to low and high, but not intermediate threat probability. Our results suggest that anterior hippocampus BOLD signal is better explained by avoidance behavior than by threat features in approach-avoidance conflict. Rather than representing threat features in a monotonic manner, it appears that anterior hippocampus may compute approach/avoidance decisions based on integration of situational threat features represented in other neural structures

Modeling startle eyeblink electromyogram to assess fear learning

Pavlovian fear conditioning is widely used as a laboratory model of associative learning in human and nonhuman species. In this model, an organism is trained to predict an aversive unconditioned stimulus from initially neutral events (conditioned stimuli, CS). In humans, fear memory is typically measured via conditioned autonomic responses or fear-potentiated startle. For the latter, various analysis approaches have been developed, but a systematic comparison of competing methodologies is lacking. Here, we investigate the suitability of a model-based approach to startle eyeblink analysis for assessment of fear memory, and compare this to extant analysis strategies. First, we build a psychophysiological model (PsPM) on a generic startle response. Then, we optimize and validate this PsPM on three independent fear-conditioning data sets. We demonstrate that our model can robustly distinguish aversive (CS+) from nonaversive stimuli (CS-, i.e., has high predictive validity). Importantly, our model-based approach captures fear-potentiated startle during fear retention as well as fear acquisition. Our results establish a PsPM-based approach to assessment of fear-potentiated startle, and qualify previous peak-scoring methods. Our proposed model represents a generic startle response and can potentially be used beyond fear conditioning, for example, to quantify affective startle modulation or prepulse inhibition of the acoustic startle response

Minimally invasive medial patellofemoral ligament reconstruction for patellar instability using an artificial ligament: A two year follow-up

Introduction: Recurrence of acute patellar dislocation affects approximately 30% of individuals, and up to 75% of those with grade IV instability. The medial patellofemoral ligament (MPFL) is considered to be critical for patella stabilisation. MPFL reconstruction with allografts has been proposed to reduce risk of recurrence, but there is limited evidence about the safety and effectiveness of techniques using synthetic allografts. Method: We present a retrospective case series of 29 individuals who underwent a MPFL reconstruction between 2009 and 2012, using an artificial ligament for patellar instability by a single surgeon. Clinical, radiological and functional outcomes were measured at a minimum of 24 months. Results: 31 knees (29 individuals) were followed up for a median of 43 (range: 24 – 68) months. Using the Crosby and Insall grading system, 21 (68%) were graded as excellent, 9 (29%) were good, 1 (3%) as fair and none as worse at 24 months. The mean improvement in Lysholm knee score for knee instability was 68 points (standard deviation 10). Ligamentous laxity was seen in 17 (55 %) of individuals. In this subset, 12 were graded as excellent, 4 as good and 1 as fair. The mean improvement in patellar height was 11 % at 3 months follow-up. All knees had a stable graft fixation with one re-dislocation following trauma. Conclusions: We propose a minimally invasive technique to reconstruct the MPFL using an artificial ligament allowing early mobilization without bracing. This study indicates the procedure is safe, with a low risk of re-dislocation in all grades of instability

Mathematical modeling of the dynamics of the bladder cancer and the immune response applied to a patient: Evolution and short-term prediction

[EN] Bladder cancer is one of the most common malignant diseases in the urinary system and a highly aggressive neoplasm. The prognosis is not favorable usually, and its evolution for particular patients is very difficult to find out. In this paper, we propose a dynamic mathematical model that describes the bladder tumor growth and the immune response evolution. This model is customized for a single patient, determining appropriate model parameter values via model calibration. Due to the uncertainty of the tumor evolution, using the calibrated model parameters, we predict the tumor size and the immune response evolution over the next few months assuming three different scenarios: favorable, neutral, and unfavorable. In the former, it is not expected any trace of the cancer in the middle of September 2018 (after 16 mo). In the neutral scenario, at the same date, a 7- to 8-mm tumor is expected. In the worst case, a 40-mm tumor is expected. The patient was cited on 10 September 2018 to check the tumor size, and according to the doctors, there was no sign of recurrence. It seems that we are in the favorable scenario. The patient will be called again for follow-up in mid-2019.This work has been supported by the Ministerio de Economía, Industria y Competitividad grant MTM2017-89664-P.Burgos-Simon, C.; García-Medina, N.; Martínez-Rodríguez, D.; Villanueva Micó, RJ. (2019). Mathematical modeling of the dynamics of the bladder cancer and the immune response applied to a patient: Evolution and short-term prediction. Mathematical Methods in the Applied Sciences. 42(17):5746-5757. https://doi.org/10.1002/mma.5536S574657574217Official Site for Spanish Medic Oncology Society.https://www.seom.org. Accessed: 25/09/2018.Greenlee, R. T., Hill-Harmon, M. B., Murray, T., & Thun, M. (2001). Cancer Statistics, 2001. CA: A Cancer Journal for Clinicians, 51(1), 15-36. doi:10.3322/canjclin.51.1.15Holmang, S., Hedelin, H., Anderstrom, C., & Johansson, S. L. (1995). The Relationship Among Multiple Recurrences, Progression and Prognosis of Patients with Stages TA and T1 Transitional Cell Cancer of the Bladder Followed for at least 20 years. Journal of Urology, 153(6), 1823-1827. doi:10.1016/s0022-5347(01)67321-xRedelman-Sidi, G., Glickman, M. S., & Bochner, B. H. (2014). The mechanism of action of BCG therapy for bladder cancer—a current perspective. Nature Reviews Urology, 11(3), 153-162. doi:10.1038/nrurol.2014.15Bladder Cancer Treatment (PDQ)‐Health Professional Version.https://www.cancer.gov/types/bladder/hp/bladder-treatment-pdq. Accessed: 25/09/2018.Bladder Cancer Treatment (PDQ)‐Patient Version.https://www.cancer.gov/types/bladder/patient/bladder-treatment-pdq. Accessed: 25/09/2018.Official Site for Hospital Universitari i Politècnic La Fe Valencia Spain.http://www.hospital-lafe.com. Accessed: 25/09/2018.Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of Cancer: The Next Generation. Cell, 144(5), 646-674. doi:10.1016/j.cell.2011.02.013Dong, H., Strome, S. E., Salomao, D. R., Tamura, H., Hirano, F., Flies, D. B., … Chen, L. (2002). Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nature Medicine, 8(8), 793-800. doi:10.1038/nm730Fernandez, N. C., Lozier, A., Flament, C., Ricciardi-Castagnoli, P., Bellet, D., Suter, M., … Zitvogel, L. (1999). Dendritic cells directly trigger NK cell functions: Cross-talk relevant in innate anti-tumor immune responses in vivo. Nature Medicine, 5(4), 405-411. doi:10.1038/7403Factsheet of OncoTICE 2 − 8 × 108UFC powder for suspension intravesical (in Spanish).https://www.aemps.gob.es/cima/pdfs/es/ft/61377/61377_ft.pdf. Accessed: 25/09/2018

Orthostatic headache and bilateral abducens palsy secondary to spontaneous intracranial hypotension

Spontaneous intracranial hypotension (SIH) is a well-documented syndrome characterized typically by a benign, self-limited course. Patients typically present with postural or exertional headaches that can be temporarily relieved by lying in a supine or recumbent position. A 35-year-old Caucasian male suffered orthostatic headache that developed to a bilateral abducens palsy. We ordered relative rest and the patient improved and completely recovered after 3 months. Although SIH is considered as a benign and self limited process it could also be associated with disabling complications. We should be aware of the possible complications and inform our patients. SIH can present with headache and bilateral abducens palsy even when the headache is improving

Blocking human fear memory with the matrix metalloproteinase inhibitor doxycycline

Learning to predict threat is a fundamental ability of many biological organisms, and a laboratory model for anxiety disorders. Interfering with such memories in humans would be of high clinical relevance. On the basis of studies in cell cultures and slice preparations, it is hypothesised that synaptic remodelling required for threat learning involves the extracellular enzyme matrix metalloproteinase (MMP) 9. However, in vivo evidence for this proposal is lacking. Here we investigate human Pavlovian fear conditioning under the blood-brain barrier crossing MMP inhibitor doxycyline in a pre-registered, randomised, double-blind, placebo-controlled trial. We find that recall of threat memory, measured with fear-potentiated startle 7 days after acquisition, is attenuated by ~60% in individuals who were under doxycycline during acquisition. This threat memory impairment is also reflected in increased behavioural surprise signals to the conditioned stimulus during subsequent re-learning, and already late during initial acquisition. Our findings support an emerging view that extracellular signalling pathways are crucially required for threat memory formation. Furthermore, they suggest novel pharmacological methods for primary prevention and treatment of posttraumatic stress disorder.Molecular Psychiatry advance online publication, 4 April 2017; doi:10.1038/mp.2017.65