Computational models of neural networks can be based on a variety of different parameters. These parameters include, for example, the 3d shape of neuron layers, the neurons' spatial projection patterns, spiking dynamics and neurotransmitter systems. While many well-developed approaches are available to model, for example, the spiking dynamics, there is a lack of approaches for modeling the anatomical layout of neurons and their projections. We present a new method, called Parametric Anatomical Modeling (PAM), to fill this gap. PAM can be used to derive network connectivities and conduction delays from anatomical data, such as the position and shape of the neuronal layers and the dendritic and axonal projection patterns. Within the PAM framework, several mapping techniques between layers can account for a large variety of connection properties between pre- and post-synaptic neuron layers. PAM is implemented as a Python tool and integrated in the 3d modeling software Blender. We demonstrate on a 3d model of the hippocampal formation how PAM can help reveal complex properties of the synaptic connectivity and conduction delays, properties that might be relevant to uncover the function of the hippocampus. Based on these analyses, two experimentally testable predictions arose: (i) the number of neurons and the spread of connections is heterogeneously distributed across the main anatomical axes, (ii) the distribution of connection lengths in CA3-CA1 differ qualitatively from those between DG-CA3 and CA3-CA3. Models created by PAM can also serve as an educational tool to visualize the 3d connectivity of brain regions. The low-dimensional, but yet biologically plausible, parameter space renders PAM suitable to analyse allometric and evolutionary factors in networks and to model the complexity of real networks with comparatively little effort.
The basic structure of the cortico-hippocampal system is highly conserved across mammalian species. Comparatively few hippocampal neurons can represent and address a multitude of cortical patterns, establish associations between cortical patterns and consolidate these associations in the cortex. In this study, we investigate how elementary anatomical properties in the cortex-hippocampus loop along with synaptic plasticity contribute to these functions. Specifically, we focus on the high degree of connectivity between cortex and hippocampus leading to converging and diverging forward and backward projections and heterogenous synaptic transmission delays that result from the detached location of the hippocampus and its multiple loops. We found that in a model incorporating these concepts, each cortical pattern can evoke a unique spatio-temporal spiking pattern in hippocampal neurons. This hippocampal response facilitates a reliable disambiguation of learned associations and a bridging of a time interval larger than the time window of spike-timing dependent plasticity in the cortex. Moreover, we found that repeated retrieval of a stored association leads to a compression of the interval between cue presentation and retrieval of the associated pattern from the cortex. Neither a high degree of connectivity nor heterogenous synaptic delays alone is sufficient for this behavior. We conclude that basic anatomical properties between cortex and hippocampus implement mechanisms for representing and consolidating temporal information. Since our model reveals the observed functions for a range of parameters, we suggest that these functions are robust to evolutionary changes consistent with the preserved function of the hippocampal loop across different species.
Social cognition and the corresponding functionality of involved brain networks are essential for effortless social interaction. Patients with schizophrenia exhibit impaired social functioning. In this study, we focused on the neural networks involved in the automatic perception of cooperative behavior and their alterations in schizophrenia. We performed a functional magnetic resonance imaging study of 19 schizophrenia patients and 19 healthy matched controls. Participants watched a set of short videos with two actors manipulating objects, either with (C+) or without cooperation (C-). Additionally, we assessed delusional symptoms in patients using the Scales for the Assessment of Positive Symptoms and psychosis proneness in healthy controls using the brief schizotypal personality questionnaire. The observed group-by-condition interaction revealed a contrasting activation pattern for patients versus healthy controls in the medial and lateral prefrontal cortex, the middle cingulate cortex, and the left angular gyrus. Furthermore, increased activation of the middle prefrontal areas, left angular gyrus, and the posterior sulcus temporalis superior in response to the noncooperative condition (C-) was positively correlated with delusional symptoms in patients. Our findings suggest an overactivated "theory of mind" network in patients for the processing of noncooperative behavior. Thus, "overmentalizing" might be based on delusions and altered processing of cooperative behavior in patients with schizophrenia.
The Behavioral Inhibition System (BIS) as defined within the Reinforcement Sensitivity Theory (RST) modulates reactions to stimuli indicating aversive events. Grays trait Anxiety determines the extent to which stimuli activate the BIS. While studies have identified the amygdala-septo-hippocampal circuit as the key-neural substrate of this system in recent years and measures of resting-state dynamics such as randomness and local synchronization of spontaneous BOLD fluctuations have recently been linked to personality traits, the relation between resting-state dynamics and the BIS remains unexplored. In the present study, we thus examined the local synchronization of spontaneous fMRI BOLD fluctuations as measured by Regional Homogeneity (ReHo) in the hippocampus and the amygdala in twenty-seven healthy subjects. Correlation analyses showed that Grays trait Anxiety was significantly associated with mean ReHo in both the amygdala and the hippocampus. Specifically, Grays trait Anxiety explained 23% and 17% of resting-state ReHo variance in the left amygdala and the left hippocampus, respectively. In summary, we found individual differences in Grays trait Anxiety to be associated with ReHo in areas previously associated with BIS functioning. Specifically, higher ReHo in resting-state neural dynamics corresponded to lower sensitivity to punishment scores both in the amygdala and the hippocampus. These findings corroborate and extend recent findings relating resting-state dynamics and personality while providing first evidence linking properties of resting-state fluctuations to Grays BIS.
Attributions are constantly assigned in everyday life. A well-known phenomenon is the self-serving bias: that is, peoples tendency to attribute positive events to internal causes (themselves) and negative events to external causes (other persons/circumstances). Here, we investigated the neural correlates of the cognitive processes implicated in self-serving attributions using social situations that differed in their emotional saliences. We administered an attributional bias task during fMRI scanning in a large sample of healthy subjects (n = 71). Eighty sentences describing positive or negative social situations were presented, and subjects decided via buttonpress whether the situation had been caused by themselves or by the other person involved. Comparing positive with negative sentences revealed activations of the bilateral posterior cingulate cortex (PCC). Self-attribution correlated with activation of the posterior portion of the precuneus. However, self-attributed positive versus negative sentences showed activation of the anterior portion of the precuneus, and self-attributed negative versus positive sentences demonstrated activation of the bilateral insular cortex. All significant activations were reported with a statistical threshold of p ? .001, uncorrected. In addition, a comparison of our fMRI task with data from the Internal, Personal and Situational Attributions Questionnaire, Revised German Version, demonstrated convergent validity. Our findings suggest that the precuneus and the PCC are involved in the evaluation of social events with particular regional specificities: The PCC is activated during emotional evaluation, the posterior precuneus during attributional evaluation, and the anterior precuneus during self-serving processes. Furthermore, we assume that insula activation is a correlate of awareness of personal agency in negative situations.
Functional magnetic resonance imaging (fMRI) can be combined with genotype assessment to identify brain systems that mediate genetic vulnerability to mental disorders ("imaging genetics"). A data analysis approach that is widely applied is "functional connectivity". In this approach, the temporal correlation between the fMRI signal from a pre-defined brain region (the so-called "seed point") and other brain voxels is determined. In this technical note, we show how the choice of freely selectable data analysis parameters strongly influences the assessment of the genetic modulation of connectivity features. In our data analysis we exemplarily focus on three methodological parameters: (i) seed voxel selection, (ii) noise reduction algorithms, and (iii) use of additional second level covariates. Our results show that even small variations in the implementation of a functional connectivity analysis can have an impact on the connectivity pattern that is as strong as the potential modulation by genetic allele variants. Some effects of genetic variation can only be found for one specific implementation of the connectivity analysis. A reoccurring difficulty in the field of psychiatric genetics is the non-replication of initially promising findings, partly caused by the small effects of single genes. The replication of imaging genetic results is therefore crucial for the long-term assessment of genetic effects on neural connectivity parameters. For a meaningful comparison of imaging genetics studies however, it is therefore necessary to provide more details on specific methodological parameters (e.g., seed voxel distribution) and to give information how robust effects are across the choice of methodological parameters.
Maturation inhibitors such as Bevirimat are a new class of antiretroviral drugs that hamper the cleavage of HIV-1 proteins into their functional active forms. They bind to these preproteins and inhibit their cleavage by the HIV-1 protease, resulting in non-functional virus particles. Nevertheless, there exist mutations in this region leading to resistance against Bevirimat. Highly specific and accurate tools to predict resistance to maturation inhibitors can help to identify patients, who might benefit from the usage of these new drugs.
It has been shown that astrocyte-derived extracellular matrix (ECM) is important for formation and maintenance of CNS synapses. In order to study the effects of glial-derived ECM on synaptogenesis, E18 rat hippocampal neurons and primary astrocytes were co-cultivated using a cell-insert system. Under these conditions, neurons differentiated under low density conditions (3500 cells/cm(2) ) in defined, serum-free medium and in the absence of direct, membrane-mediated neuron-astrocyte interactions. Astrocytes promoted the formation of structurally intact synapses, as documented by the co-localisation of bassoon- and ProSAP1/Shank2-positive puncta, markers of the pre- and postsynapse, respectively. The development of synapses was paralleled by the emergence of perineuronal net (PNN)-like structures that contained various ECM components such as hyaluronic acid, brevican and neurocan. In order to assess potential functions for synaptogenesis, the ECM was removed by treatment with hyaluronidase or chondroitinase ABC. Both enzymes significantly enhanced the number of synaptic puncta. Whole-cell voltage-clamp recordings of control and enzyme-treated hippocampal neurons revealed that chondroitinase ABC treatment led to a significant decrease in amplitude and a reduced charge of miniature excitatory postsynaptic currents, whereas inhibitory postsynaptic currents were not affected. When the response to the application of glutamate was measured, a reduced sensitivity could be detected and resulted in decreased currents in response to the excitatory neurotransmitter. These findings are consistent with the interpretation that the ECM partakes in the regulation of the density of glutamate receptors in subsynaptic sites.
Genome-wide association studies identified the single nucleotide polymorphism rs1344706 in ZNF804A as a common risk-variant for schizophrenia and bipolar disorder. Whereas the molecular function of ZNF804A is yet unclear, recent imaging genetics studies have started to characterize the neural systems architecture linking rs1344706 genotype to psychosis. Carring rs1344706 risk-alleles was associated with a decrease in functional connectivity within the dorsolateral prefrontal cortices (DLPFCs) as well as an increase in connectivity between the DLPFC and the hippocampal formation (HF) in the context of a working memory task. The present study aimed at replicating these findings in an independent sample of 94 healthy subjects. Subjects were genotyped for rs1344706 and performed a working memory task during functional magnetic resonance imaging. Results indicate no support for a decrease of functional coupling between the bilateral DLPFCs at higher ZNF804A risk status. However, the current data show the previously described alteration in functional coupling between the right DLPFC and the HFs, albeit with weaker effects. Decoupled by default, the functional connectivity between the right DLPFC and anterior HFs increased with the number of rs1344706 risk alleles. The present data support fronto-hippocampal dysconnectivity as intermediate phenotype linking rs1344706 genotype to psychosis. We discuss the issues in replicating the interhemispheric DLPFC coupling in light of the effect sizes rs1344706 genotype has on brain function, concluding that further independent replication studies are fundamentally needed to ascertain the role of rs1344706 in the functional integration of neural systems.
Randomness of functional Magnetic Resonance Imaging (fMRI) resting-state time-series has recently been used as a biomarker for numerous disorders including Alzheimers and Parkinsons disease as well as autism. To date, however, it remains unknown whether and to what degree personality traits are associated with the randomness of resting-state temporal dynamics. To investigate this question, we estimated the Hurst exponent - a measure of the randomness of a time-series - during resting-state fMRI in brain areas previously associated with trait Impulsivity as defined in Grays Reinforcement Sensitivity Theory of Personality in 15 healthy individuals. The Hurst exponent in the ventral striatum as well as in the orbitofrontal cortex (OFC) was significantly associated with the measure of Grays trait Impulsivity. Specifically, more random resting-state neural dynamics corresponded to higher Impulsivity scores both in the ventral striatum (r(15)=-.71; p=.003) and the OFC (r(15)=-.81; p<.001). In summary, we provide evidence for an association between individual differences in Grays Impulsivity and randomness in key areas of the reward system which have previously been associated with this personality trait. Based on evidence from fMRI and electroencephalographical studies, we suggest that this association might arise from resting-state fluctuations constraining task-related neural responsiveness. Thereby, we outline a potential mechanism linking randomness of resting-state dynamics and personality.
The concept of the tripartite synapse proposes that in addition to the presynapse and the postsynaptic membrane closely apposed processes of astrocytes constitute an integral part of the synapse. Accordingly, astrocytes may influence synaptic activity by various ways. Thus glia- and neuron-derived neurotrophins, cytokines and metabolites influence neuronal survival, synaptic activity and plasticity. Beyond these facts, the past years have shown that astrocytes are required for synaptogenesis, the structural maintenance and proper functioning of synapses. In particular, astrocytes seem to play a key role in the organization of the brains extracellular matrix (ECM) - most prominently the so-called perineuronal nets (PNNs), complex macromolecular assemblies of ECM components. Due to progress in cellular and molecular neurosciences, it has been possible to decipher the composition of ECM structures and to obtain insight into their function(s) and underlying mechanisms. It appears that PNN-related structures are involved in regulating the sprouting and pruning of synapses, which represents an important morphological correlate of synaptic plasticity in the adult nervous system. Perturbation assays and gene elimination by recombinant techniques have provided clear indications that astrocyte-derived ECM components, e.g. the tenascins and chondroitinsulfate proteoglycans (CSPGs) of the lectican family participate in these biological functions. The present review will discuss the glia-derived glycoproteins and CSPGs of the perisynaptic ECM, their neuronal and glial receptors, and in vitro assays to test their physiological functions in the framework of the synapse, the pivotal element of communication in the central nervous system.
Neuropsychological abnormalities in transsexual patients have been reported in comparison with subjects without gender identity disorder (GID), suggesting differences in underlying neurobiological processes. However, these results have not consistently been confirmed. Furthermore, studies on cognitive effects of cross-sex hormone therapy also yield heterogeneous results.
A functional polymorphism in the serotonin transporter gene (5-HTTLPR) has been reported to modulate amygdala responsiveness to negative environmental cues. However, it remains unclear whether 5-HTTLPR modulates amygdala responses specifically to negative stimuli or rather to emotionally salient stimuli in general. In 44 healthy subjects, amygdala responses to subliminally presented happy and sad facial expressions were assessed by means of fMRI at 3 Tesla. All subjects were genotyped for 5-HTTLPR and the recently discovered 5-HTT rs25531. We observed a robust emotion by genotype group interaction in the right amygdala. Risk allele carriers (S or L(G)) showed similar amygdala responses to happy faces compared to homozygous L(A)L(A) carriers but increased amygdala responses to sad faces. The right amygdala was the only anatomical region across the whole brain demonstrating this interaction at a reasonable threshold. It appears that whereas 5-HTT gene variation modulates automatic amygdala responsiveness to sad faces, no such association was found for happy faces. We conclude that 5-HTTLPR genotype predominantly impacts the central processing predominantly of negative environmental cues but not of emotionally salient stimuli in general.
The default-mode network (DMN) is a functional network with increasing relevance for psychiatric research, characterized by increased activation at rest and decreased activation during task performance. The degree of DMN deactivation during a cognitively demanding task depends on its difficulty. However, the relation of hemodynamic responses in the resting phase after a preceding cognitive challenge remains relatively unexplored. We test the hypothesis that the degree of activation of the DMN following cognitive challenge is influenced by the cognitive load of a preceding working-memory task.
DNA watermarks can be applied to identify the unauthorized use of genetically modified organisms. It has been shown that coding regions can be used to encrypt information into living organisms by using the DNA-Crypt algorithm. Yet, if the sequence of interest presents a non-coding DNA sequence, either the function of a resulting functional RNA molecule or a regulatory sequence, such as a promoter, could be affected. For our studies we used the small cytoplasmic RNA 1 in yeast and the lac promoter region of Escherichia coli.
Learning by conditioning is a key ability of animals and humans for acquiring novel behavior necessary for survival in a changing environment. Aberrant conditioning has been considered a crucial factor in the etiology and maintenance of panic disorder with agoraphobia (PD/A). Cognitive-behavioral therapy (CBT) is an effective treatment for PD/A. However, the neural mechanisms underlying the effects of CBT on conditioning processes in PD/A are unknown.
The neurobiological basis of non-organic movement impairments is still unknown. As conversion disorder and hypnotic states share many characteristics, we applied an experimental design established in conversion disorder to investigate hypnotic paralysis.
The conceptual notion of the so-called resting state of the brain has been recently challenged by studies indicating a continuing effect of cognitive processes on subsequent rest. In particular, activity in posterior parietal and medial prefrontal areas has been found to be modulated by preceding experimental conditions. In this study, we investigated which brain areas show working memory dependent patterns in subsequent baseline periods and how specific they are for the preceding experimental condition. During functional magnetic resonance imaging, 94 subjects performed a letter-version of the n-back task with the conditions 0-back and 2-back followed by a low-level baseline in which subjects had to passively observe the letters appearing. In a univariate analysis, 2-back served as control condition while 0-back, baseline after 0-back and baseline after 2-back were modeled as regressors to test for activity changes between both baseline conditions. Additionally, we tested, using Gaussian process classifiers, the recognition of task condition from functional images acquired during baseline. Besides the expected activity changes in the precuneus and medial prefrontal cortex, we found differential activity in the thalamus, putamen, and postcentral gyrus that were affected by the preceding task. The multivariate analysis revealed that images of the subsequent baseline block contain task related patterns that yield a recognition rate of 70%. The results suggest that the influence of a cognitive task on subsequent baseline is strong and specific for some areas but not restricted to areas of the so-called default mode network.
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