- Email: [email protected]
Social Cognition Analyzer Application (SCAN) - a new approach to analyse social cognition in schizophrenia
Abstracts of the ENCP Workshop for Junior Scientists in Europe, 2018 effect more pronounced when treated with 10mg/kg (po0.0161 and po0.0365, respectively). In addition, exposure to stress combined with Aβ1-40 infusion leads to a worst performance in Morris Water Maze task, that seems to be reverted upon chronic treatment with AMPAR (po0.0233). Also, the stress group or Aβ1-40 infused groups alone mimic the above phenotype, although in a minor extent, implicating that stress aggravates Aβ1-40-driven AD pathology. Moreover, no differences were found in any of the behavioral tasks between the control group and the control treated with 3 and 10mg/kg of AMPAR, indicating that this compound has no adverse effects when administer to healthy subjects. Our findings demonstrated that this compound is able to revert both recognition and spatial memory deficits in this AD animal model suggesting a beneficial effect of hippocampusand prefrontal-cortex-dependent function. On-going molecular analysis will provide the mechanistic evidence about the impact of AMPAR modulation on synaptic plasticity and its subsequent impact on the behavioral readout. These studies constitute the first in vivo screening of the potential beneficial effect of a novel compound targeting AMPA receptor and their signaling against AD.
References [1] Goedert, M., Spillantini, M., 2006. A Century of Alzheimer's Disease. Science, 314(5800), pp.777-781. [2] Folch, J., Petrov, D., Ettcheto, M., Abad, S., SánchezLópez, E., García, M., Olloquequi, J., Beas-Zarate, C., Auladell, C., Camins, A., 2016. Current Research Therapeutic Strategies for Alzheimer’s Disease Treatment. Neural Plasticity, 2016. [3] Sotiropoulos, I., Sousa, N., 2015. Tau as the Converging Protein between Chronic Stress and Alzheimer's Disease Synaptic Pathology. Neurodegenerative Diseases, 16(1-2), pp.22-25. [4] Giralt, A., Gómez-Climent, M., Alcalá, R., Bretin, S., Bertrand, D., María Delgado-García, J., Pérez-Navarro, E., Alberch, J., Gruart, A., 2017. The AMPA receptor positive allosteric modulator S 47445 rescues in vivo CA3-CA1 longterm potentiation and structural synaptic changes in old mice. Neuropharmacology, 123, pp.395-409. http://dx.doi.org/10.1016/j.euroneuro.2017.12.085
P.2.047 Validation of the canonical hemodynamic response function model used in fMRI studies
S55
available in fMRI analysis packages [3]. The most popular HRF model is the canonical HRF: sum of two fixed gamma curves. We compare some of the implemented HRF models in terms of sensitivity-specificity efficiency. Aims: We aim to identify an optimal HRF model for healthy subjects and to check if this model is flexible enough for unusual subject populations like impaired consciousness patients or the elderly. For such patient populations the hemodynamic response might differ and the canonical model might be too fixed to detect experimentally induced neural activation. Methods: We compare HRF models in the most popular fMRI analysis softwares: AFNI, FSL and SPM, regarding: (1) positive rates (at least one significant voxel in the entire brain) (2) spatial distribution of the significant voxels and (3) numbers of significant voxels. For our analyses we employ three different baselines: (1) simulated data, for which we developed an R package: https://github.com/ wiktorolszowy/HRF_simulation_for_fMRI_experiments, (2) resting state data with assumed dummy design and (3) task based data with assumed wrong design. Results: The following table shows mean numbers of significant voxels for 70 impaired consciousness subjects performing a visual task. The visual stimulus was presented for 16s after 16s of rest. This design was repeated 10 times. The results refer to different assumed experimental designs and different HRF models. Conclusions: The FIR model as implemented in FSL returned suspiciously high numbers of significant voxels which suggests that the degrees of freedom might be mis-specified. FIR behaved in a similar way when using simulated data and resting state data and for different subject populations (not shown in the above table). The effect of adding the first derivative to the gamma models was negligible. This suggests that the canonical HRF model is inflexible. Interestingly, significance was detected more often for assumed low experimental frequencies. This might suggest that the employed degrees of freedom do not model the correlations between periods when the stimulus was shown and the rest periods.
assumed design block block block block block
10s off + 10s on 12s off + 12s on 16s off + 16s on 30s off + 30s on 6s off + 2s on
FIR
gamma gamma2 gamma_D gamma2_D
1527 1376 1097 140 3204
36 112 576 286 1
33 107 570 272 5
40 130 618 319 1
38 125 613 302 5
W. Olszowyn,1, G. Williams1, C. Rua1, J. Aston2 1
University of Cambridge, Department of Clinical Neurosciences, Cambridge, United Kingdom 2 University of Cambridge, Department of Pure Mathematics and Mathematical Statistics, Cambridge, United Kingdom Introduction: There is need to validate the fMRI analysis methods using large-scale datasets [1]. It is known that the hemodynamic response function (HRF) varies across brain regions and subjects [2]. Different HRF models are currently
'FIR' = Finite Impulse Response HRF model with 12 bins of 2s each. 'gamma' = gamma HRF model. 'gamma2' = double gamma HRF model. 'gamma_D' = gamma HRF model combined with its first derivative. 'gamma2_D' = double gamma HRF model combined with its first derivative.
References [1] Eklund, A., Nichols, T.E., Knutsson, H., 2016. Cluster failure: why fMRI inferences for spatial extent have inflated
S56 false-positive rates. Proceedings of the National Academy of Sciences, 201602413. [2] Handwerker, D.A., Ollinger, J.M., D'Esposito, M., 2004. Variation of BOLD hemodynamic responses across subjects and brain regions and their effects on statistical analyses. NeuroImage, 21(4), 1639-1651. [3] Lindquist, M.A., Loh, J.M., Atlas, L.Y., Wager, T.D., 2009. Modeling the hemodynamic response function in fMRI: efficiency, bias and mis-modeling. NeuroImage, 45(1), S187-S198. http://dx.doi.org/10.1016/j.euroneuro.2017.12.086
P.2.048 On the synaptic tagging and capture hypothesis and the process of memory reconsolidation n
L. Cassini , J. Lee University of Birmingham, Psychology School, Birmingham, United Kingdom The Synaptic Tagging and Capture (STC) hypothesis proposes that a strong stimulation of a synaptic pathway leads to two dissociable events: (a) local tag setting and (b) the synthesis of diffusible plasticity-related proteins (PRPs) [1]. The PRPs are then “captured” by the tagged synapses allowing the sustenance of long-term potentiation (LTP). Recent behavioral studies suggest that long-term memory (LTM) may also require both synaptic tagging and PRP synthesis in order to persist [2,3]. The studies show that weak events, only able to induce short-term memory (STM), could lead to LTM when the training was associated with parallel stronger experience (i.e. capable of inducing the synthesis of PRPs). Here we investigate whether the process of labilization and reconsolidation of a memory could also involve a mechanism of Synaptic Tagging and Capture. More specifically, for the pilot study presented here (n = 5-8), we aimed to evaluate whether the amnesic effect of the NMDAr inhibitor, MK-801, upon the reactivation of a contextual fear memory (CFC), could be prevented by pairing the event with a strong experience (exposure to novel environment). For that, adult male long-evans rats (200–300g), co-housed in groups of 4 per cage, under a 12 h light/dark cycle and at temperature of 24 C, with water and food ad libitum were used, in accordance to local and national animal care guidelines. On day one, rats were placed in the CFC chamber for 3 min, received 2 foot shocks (0.7 mA 1.5 sec), separated by a 30-sec interval, and after 1 min, rats returned to their home cages. Two days later, animals on the experimental group were exposed to a novel arena (control animals remained on homecages) and one hour later were reexposed to the CFC context (5 min). MK-801 or Saline was injected intraperitoneally (1mg/kg) immediately after. On the next day, all animals were exposed once more to the CFC context (4 min) in order to assess memory expression. The aversive response (freezing) were recorded during all sessions and used as the memory index. Two-way ANOVA revealed marginal effect of drug (p = 0.08; Saline x MK-801), a significant effect of group (p = 0.02; Control x Novelty) and no interaction (p = 0.22; Drug x Group).
Further analysis with Tukey post-hoc revealed a significant difference between the animals not exposed to novelty and treated with MK-801, and those treated with MK-801 as well, but previously exposed to novelty (p = 0.03). The results are still preliminary, but indicate that the exposure to a novel experience (supposedly capable of inducing PRPs synthesis in Hippocampus) is able to prevent the effects associated to amnesic treatment after the reactivation of a contextual fear memory. This associative phenomenon could be the first step suggesting the involvement of a Synaptic Tagging and Capture mechanism in process of memory labilization and reconsolidation.
References [1] Redondo, R.L., Morris, R.G., 2011. Making memories last: the synaptic tagging and capture hypothesis. Nat Rev Neurosci 12, 17-30. [2] Moncada, D., Viola, H., 2007. Induction of long-term memory by exposure to novelty requires protein synthesis: Evidence for a behavioral tagging. J Neurosci 27, 7476-7481. [3] Cassini, L.F., Sierra, R.O., Haubrich, J., Crestani, A.P., Santana, F., de Oliveira Alvares, L., Quillfeldt, J.A., 2013. Memory reconsolidation allows the consolidation of a concomitant weak learning through a synaptic tagging and capture mechanism. Hippocampus 23, 931-941. http://dx.doi.org/10.1016/j.euroneuro.2017.12.087
P.2.049 Fronto-parietal connectivity and its relation to frontal glutamate in patients suffering from schizophrenia J. Kaminskin, T. Gleich, Y. Fukuda, T. Katthagen, L. Deserno, A. Heinz, F. Schlagenhauf Charité Universitätsmedizin Berlin Campus Charité Mitte, Department of Psychiatry and Psychotherapy, Berlin, Germany Cognitive deficits like working memory impairment in schizophrenia are of great importance for clinical outcome, but the underlying neurobiology is not fully understood. During working memory (WM) altered connectivity patterns in the fronto-parietal network are present in patients suffering from schizophrenia [1–3]. One candidate biochemical marker for the integrity of connectivity is glutamate [4]. Here we tested for group differences in fronto-parietal connectivity and it’s relation to possible glutamatergic influences. During a functional magnetic resonance imaging (fMRI) scan, a sample of 42 medicated patients (SZ) and 41 age and gender matched healthy controls (HC) were asked to perform a numeric n-back working memory task, which consisted of two conditions “2-back” and “0-back”. FMRI was conducted on a 3T Siemens Trio scanner with a 12 channel head coil using gradient-echo echo-planar imaging. Data were further preprocessed using the statistical parametric mapping (SPM 8; Welcome Department of Imaging Neuroscience, London, UK; htt://www.fil.ion.ucl.ac.uk/spm) in MATLAB 2009b. We performed dynamic causal modeling [5] (DCM) on a model
References [1] Goedert, M., Spillantini, M., 2006. A Century of Alzheimer's Disease. Science, 314(5800), pp.777-781. [2] Folch, J., Petrov, D., Ettcheto, M., Abad, S., SánchezLópez, E., García, M., Olloquequi, J., Beas-Zarate, C., Auladell, C., Camins, A., 2016. Current Research Therapeutic Strategies for Alzheimer’s Disease Treatment. Neural Plasticity, 2016. [3] Sotiropoulos, I., Sousa, N., 2015. Tau as the Converging Protein between Chronic Stress and Alzheimer's Disease Synaptic Pathology. Neurodegenerative Diseases, 16(1-2), pp.22-25. [4] Giralt, A., Gómez-Climent, M., Alcalá, R., Bretin, S., Bertrand, D., María Delgado-García, J., Pérez-Navarro, E., Alberch, J., Gruart, A., 2017. The AMPA receptor positive allosteric modulator S 47445 rescues in vivo CA3-CA1 longterm potentiation and structural synaptic changes in old mice. Neuropharmacology, 123, pp.395-409. http://dx.doi.org/10.1016/j.euroneuro.2017.12.085
P.2.047 Validation of the canonical hemodynamic response function model used in fMRI studies
S55
available in fMRI analysis packages [3]. The most popular HRF model is the canonical HRF: sum of two fixed gamma curves. We compare some of the implemented HRF models in terms of sensitivity-specificity efficiency. Aims: We aim to identify an optimal HRF model for healthy subjects and to check if this model is flexible enough for unusual subject populations like impaired consciousness patients or the elderly. For such patient populations the hemodynamic response might differ and the canonical model might be too fixed to detect experimentally induced neural activation. Methods: We compare HRF models in the most popular fMRI analysis softwares: AFNI, FSL and SPM, regarding: (1) positive rates (at least one significant voxel in the entire brain) (2) spatial distribution of the significant voxels and (3) numbers of significant voxels. For our analyses we employ three different baselines: (1) simulated data, for which we developed an R package: https://github.com/ wiktorolszowy/HRF_simulation_for_fMRI_experiments, (2) resting state data with assumed dummy design and (3) task based data with assumed wrong design. Results: The following table shows mean numbers of significant voxels for 70 impaired consciousness subjects performing a visual task. The visual stimulus was presented for 16s after 16s of rest. This design was repeated 10 times. The results refer to different assumed experimental designs and different HRF models. Conclusions: The FIR model as implemented in FSL returned suspiciously high numbers of significant voxels which suggests that the degrees of freedom might be mis-specified. FIR behaved in a similar way when using simulated data and resting state data and for different subject populations (not shown in the above table). The effect of adding the first derivative to the gamma models was negligible. This suggests that the canonical HRF model is inflexible. Interestingly, significance was detected more often for assumed low experimental frequencies. This might suggest that the employed degrees of freedom do not model the correlations between periods when the stimulus was shown and the rest periods.
assumed design block block block block block
10s off + 10s on 12s off + 12s on 16s off + 16s on 30s off + 30s on 6s off + 2s on
FIR
gamma gamma2 gamma_D gamma2_D
1527 1376 1097 140 3204
36 112 576 286 1
33 107 570 272 5
40 130 618 319 1
38 125 613 302 5
W. Olszowyn,1, G. Williams1, C. Rua1, J. Aston2 1
University of Cambridge, Department of Clinical Neurosciences, Cambridge, United Kingdom 2 University of Cambridge, Department of Pure Mathematics and Mathematical Statistics, Cambridge, United Kingdom Introduction: There is need to validate the fMRI analysis methods using large-scale datasets [1]. It is known that the hemodynamic response function (HRF) varies across brain regions and subjects [2]. Different HRF models are currently
'FIR' = Finite Impulse Response HRF model with 12 bins of 2s each. 'gamma' = gamma HRF model. 'gamma2' = double gamma HRF model. 'gamma_D' = gamma HRF model combined with its first derivative. 'gamma2_D' = double gamma HRF model combined with its first derivative.
References [1] Eklund, A., Nichols, T.E., Knutsson, H., 2016. Cluster failure: why fMRI inferences for spatial extent have inflated
S56 false-positive rates. Proceedings of the National Academy of Sciences, 201602413. [2] Handwerker, D.A., Ollinger, J.M., D'Esposito, M., 2004. Variation of BOLD hemodynamic responses across subjects and brain regions and their effects on statistical analyses. NeuroImage, 21(4), 1639-1651. [3] Lindquist, M.A., Loh, J.M., Atlas, L.Y., Wager, T.D., 2009. Modeling the hemodynamic response function in fMRI: efficiency, bias and mis-modeling. NeuroImage, 45(1), S187-S198. http://dx.doi.org/10.1016/j.euroneuro.2017.12.086
P.2.048 On the synaptic tagging and capture hypothesis and the process of memory reconsolidation n
L. Cassini , J. Lee University of Birmingham, Psychology School, Birmingham, United Kingdom The Synaptic Tagging and Capture (STC) hypothesis proposes that a strong stimulation of a synaptic pathway leads to two dissociable events: (a) local tag setting and (b) the synthesis of diffusible plasticity-related proteins (PRPs) [1]. The PRPs are then “captured” by the tagged synapses allowing the sustenance of long-term potentiation (LTP). Recent behavioral studies suggest that long-term memory (LTM) may also require both synaptic tagging and PRP synthesis in order to persist [2,3]. The studies show that weak events, only able to induce short-term memory (STM), could lead to LTM when the training was associated with parallel stronger experience (i.e. capable of inducing the synthesis of PRPs). Here we investigate whether the process of labilization and reconsolidation of a memory could also involve a mechanism of Synaptic Tagging and Capture. More specifically, for the pilot study presented here (n = 5-8), we aimed to evaluate whether the amnesic effect of the NMDAr inhibitor, MK-801, upon the reactivation of a contextual fear memory (CFC), could be prevented by pairing the event with a strong experience (exposure to novel environment). For that, adult male long-evans rats (200–300g), co-housed in groups of 4 per cage, under a 12 h light/dark cycle and at temperature of 24 C, with water and food ad libitum were used, in accordance to local and national animal care guidelines. On day one, rats were placed in the CFC chamber for 3 min, received 2 foot shocks (0.7 mA 1.5 sec), separated by a 30-sec interval, and after 1 min, rats returned to their home cages. Two days later, animals on the experimental group were exposed to a novel arena (control animals remained on homecages) and one hour later were reexposed to the CFC context (5 min). MK-801 or Saline was injected intraperitoneally (1mg/kg) immediately after. On the next day, all animals were exposed once more to the CFC context (4 min) in order to assess memory expression. The aversive response (freezing) were recorded during all sessions and used as the memory index. Two-way ANOVA revealed marginal effect of drug (p = 0.08; Saline x MK-801), a significant effect of group (p = 0.02; Control x Novelty) and no interaction (p = 0.22; Drug x Group).
Further analysis with Tukey post-hoc revealed a significant difference between the animals not exposed to novelty and treated with MK-801, and those treated with MK-801 as well, but previously exposed to novelty (p = 0.03). The results are still preliminary, but indicate that the exposure to a novel experience (supposedly capable of inducing PRPs synthesis in Hippocampus) is able to prevent the effects associated to amnesic treatment after the reactivation of a contextual fear memory. This associative phenomenon could be the first step suggesting the involvement of a Synaptic Tagging and Capture mechanism in process of memory labilization and reconsolidation.
References [1] Redondo, R.L., Morris, R.G., 2011. Making memories last: the synaptic tagging and capture hypothesis. Nat Rev Neurosci 12, 17-30. [2] Moncada, D., Viola, H., 2007. Induction of long-term memory by exposure to novelty requires protein synthesis: Evidence for a behavioral tagging. J Neurosci 27, 7476-7481. [3] Cassini, L.F., Sierra, R.O., Haubrich, J., Crestani, A.P., Santana, F., de Oliveira Alvares, L., Quillfeldt, J.A., 2013. Memory reconsolidation allows the consolidation of a concomitant weak learning through a synaptic tagging and capture mechanism. Hippocampus 23, 931-941. http://dx.doi.org/10.1016/j.euroneuro.2017.12.087
P.2.049 Fronto-parietal connectivity and its relation to frontal glutamate in patients suffering from schizophrenia J. Kaminskin, T. Gleich, Y. Fukuda, T. Katthagen, L. Deserno, A. Heinz, F. Schlagenhauf Charité Universitätsmedizin Berlin Campus Charité Mitte, Department of Psychiatry and Psychotherapy, Berlin, Germany Cognitive deficits like working memory impairment in schizophrenia are of great importance for clinical outcome, but the underlying neurobiology is not fully understood. During working memory (WM) altered connectivity patterns in the fronto-parietal network are present in patients suffering from schizophrenia [1–3]. One candidate biochemical marker for the integrity of connectivity is glutamate [4]. Here we tested for group differences in fronto-parietal connectivity and it’s relation to possible glutamatergic influences. During a functional magnetic resonance imaging (fMRI) scan, a sample of 42 medicated patients (SZ) and 41 age and gender matched healthy controls (HC) were asked to perform a numeric n-back working memory task, which consisted of two conditions “2-back” and “0-back”. FMRI was conducted on a 3T Siemens Trio scanner with a 12 channel head coil using gradient-echo echo-planar imaging. Data were further preprocessed using the statistical parametric mapping (SPM 8; Welcome Department of Imaging Neuroscience, London, UK; htt://www.fil.ion.ucl.ac.uk/spm) in MATLAB 2009b. We performed dynamic causal modeling [5] (DCM) on a model