tuomomm

• Assis, Denis Reis de; Pentz, Atle Bråthen; Osete, Jordi Requena; Ievglevskyi, Oleksandr; Vandenberghe, Matthieu & Akkouh, Ibrahim Ahmed [Show all 12 contributors for this article] (2026). Investigating neural impairments in psychotic disorders using electroencephalography and cortical spheroids. Translational Psychiatry. 16(1). doi: 10.1038/s41398-026-03863-4. Full text in Research Archive Show summary

  Synaptic dysfunction is a candidate mechanism in psychotic disorders, yet the precise underlying substrates remain elusive. We investigated how combining in vivo electroencephalography (EEG) and in vitro human cortical spheroid (hCS)-based methods can further our understanding of psychosis pathophysiology during fetal stages of neurodevelopment. Ten individuals with schizophrenia (SZ) or bipolar disorder (BD; 5 males and 5 females) and five controls (CTRL; 3 males and 2 females) underwent EEG assessments, including long-term potentiation (LTP)-like cortical plasticity and mismatch negativity (MMN). hCS were generated from induced pluripotent stem cells of all participants, and immunohistochemistry, Seahorse bioenergetics and patch-clamp recordings were performed. EEG-based LTP-like plasticity was reduced in individuals with SZ and BD. Basal respiration was decreased in BD hCS and VGLUT1 levels were reduced in both SZ and BD hCS. There was a positive association between EEG-based LTP-like plasticity and hCS basal respiration which survived correction. Our data provide further support for roles of mitochondrial and glutamatergic impairments in the synaptic dysfunction of psychosis and demonstrate the potential of combining EEG- and hCS-based methods for early development mechanistic studies of brain disorders.

• Eissa, Ahmed; Fredrik Kismul, Jan; Pentz, Atle Bråthen; Elvsåshagen, Torbjørn; Metzner, Christoph & Akkouh, Ibrahim Ahmed [Show all 12 contributors for this article] (2026). Computational Modelling of Novelty Detection in the Mismatch Negativity Protocols and Its Impairments in Schizophrenia. European Journal of Neuroscience. ISSN 0953-816X. 63(6). doi: 10.1111/ejn.70453. Full text in Research Archive
• Mäki-Marttunen, Tuomo; Kismul, Jan Fredrik; Pajo, Kadri; Schulz, Jan Michael; Manninen, Tiina & Einevoll, Gaute Tomas [Show all 9 contributors for this article] (2025). Pre- and Post-synaptic Mechanisms of Neuronal Inhibition Assessed Through Biochemically Detailed Modeling of GABAB Receptor Signaling. Journal of Neuroscience. ISSN 0270-6474. 45(36). doi: 10.1523/JNEUROSCI.0544-25.2025. Full text in Research Archive
• Mäki-Marttunen, Tuomo; Blackwell, Kim T.; Akkouh, Ibrahim Ahmed; Shadrin, Alexey; Valstad, Mathias & Elvsåshagen, Torbjørn [Show all 10 contributors for this article] (2024). Genetic mechanisms for impaired synaptic plasticity in schizophrenia revealed by computational modeling. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 121(34). doi: 10.1073/pnas.2312511121. Full text in Research Archive Show summary

  Schizophrenia phenotypes are suggestive of impaired cortical plasticity in the disease, but the mechanisms of these deficits are unknown. Genomic association studies have implicated a large number of genes that regulate neuromodulation and plasticity, indicating that the plasticity deficits have a genetic origin. Here, we used biochemically detailed computational modeling of postsynaptic plasticity to investigate how schizophrenia-associated genes regulate long-term potentiation (LTP) and depression (LTD). We combined our model with data from postmortem RNA expression studies (CommonMind gene-expression datasets) to assess the consequences of altered expression of plasticity-regulating genes for the amplitude of LTP and LTD. Our results show that the expression alterations observed post mortem, especially those in the anterior cingulate cortex, lead to impaired protein kinase A (PKA)-pathway-mediated LTP in synapses containing GluR1 receptors. We validated these findings using a genotyped electroencephalogram (EEG) dataset where polygenic risk scores for synaptic and ion channel-encoding genes as well as modulation of visual evoked potentials were determined for 286 healthy controls. Our results provide a possible genetic mechanism for plasticity impairments in schizophrenia, which can lead to improved understanding and, ultimately, treatment of the disorder.

• Mäki-Marttunen, Tuomo & Mäki-Marttunen, Verónica (2022). Excitatory and inhibitory effects of HCN channel modulation on excitability of layer V pyramidal cells. PLoS Computational Biology. ISSN 1553-734X. 18(9). doi: 10.1371/journal.pcbi.1010506. Full text in Research Archive Show summary

  Dendrites of cortical pyramidal cells are densely populated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, a.k.a. I h channels. I h channels are targeted by multiple neuromodulatory pathways, and thus are one of the key ion-channel populations regulating the pyramidal cell activity. Previous observations and theories attribute opposing effects of the I h channels on neuronal excitability due to their mildly hyperpolarized reversal potential. These effects are difficult to measure experimentally due to the fine spatiotemporal landscape of the I h activity in the dendrites, but computational models provide an efficient tool for studying this question in a reduced but generalizable setting. In this work, we build upon existing biophysically detailed models of thick-tufted layer V pyramidal cells and model the effects of over- and under-expression of I h channels as well as their neuromodulation. We show that I h channels facilitate the action potentials of layer V pyramidal cells in response to proximal dendritic stimulus while they hinder the action potentials in response to distal dendritic stimulus at the apical dendrite. We also show that the inhibitory action of the I h channels in layer V pyramidal cells is due to the interactions between I h channels and a hot zone of low voltage-activated Ca 2+ channels at the apical dendrite. Our simulations suggest that a combination of I h -enhancing neuromodulation at the proximal part of the apical dendrite and I h -inhibiting modulation at the distal part of the apical dendrite can increase the layer V pyramidal excitability more than either of the two alone. Our analyses uncover the effects of I h -channel neuromodulation of layer V pyramidal cells at a single-cell level and shed light on how these neurons integrate information and enable higher-order functions of the brain.

• Valstad, Mathias; Roelfs, Daniel; Slapø, Nora Berz; Timpe, Clara Marie Fides; Rai, Ahsan & Matziorinis, Anna Maria [Show all 24 contributors for this article] (2021). Evidence for Reduced Long-Term Potentiation-Like Visual Cortical Plasticity in Schizophrenia and Bipolar Disorder. Schizophrenia Bulletin. ISSN 0586-7614. 47(6), p. 1751–1760. doi: 10.1093/schbul/sbab049. Full text in Research Archive Show summary

  Several lines of research suggest that impairments in long-term potentiation (LTP)-like synaptic plasticity might be a key pathophysiological mechanism in schizophrenia (SZ) and bipolar disorder type I (BDI) and II (BDII). Using modulations of visually evoked potentials (VEP) of the electroencephalogram, impaired LTP-like visual cortical plasticity has been implicated in patients with BDII, while there has been conflicting evidence in SZ, a lack of research in BDI, and mixed results regarding associations with symptom severity, mood states, and medication. We measured the VEP of patients with SZ spectrum disorders (n = 31), BDI (n = 34), BDII (n = 33), and other BD spectrum disorders (n = 2), and age-matched healthy control (HC) participants (n = 200) before and after prolonged visual stimulation. Compared to HCs, modulation of VEP component N1b, but not C1 or P1, was impaired both in patients within the SZ spectrum (χ 2 = 35.1, P = 3.1 × 10−9) and BD spectrum (χ 2 = 7.0, P = 8.2 × 10−3), including BDI (χ 2 = 6.4, P = .012), but not BDII (χ 2 = 2.2, P = .14). N1b modulation was also more severely impaired in SZ spectrum than BD spectrum patients (χ 2 = 14.2, P = 1.7 × 10−4). N1b modulation was not significantly associated with Positive and Negative Syndrome Scale (PANSS) negative or positive symptoms scores, number of psychotic episodes, Montgomery and Åsberg Depression Rating Scale (MADRS) scores, or Young Mania Rating Scale (YMRS) scores after multiple comparison correction, although a nominal association was observed between N1b modulation and PANSS negative symptoms scores among SZ spectrum patients. These results suggest that LTP-like plasticity is impaired in SZ and BD. Adding to previous genetic, pharmacological, and electrophysiological evidence, these results implicate aberrant synaptic plasticity as a mechanism underlying SZ and BD.

• Valstad, Mathias; Moberget, Torgeir; Roelfs, Daniël Thomas Heimen; Slapø, Nora Berz; Timpe, Clara Marie Fides & Beck, Dani [Show all 18 contributors for this article] (2020). Experience-dependent modulation of the visual evoked potential: Testing effect sizes, retention over time, and associations with age in 415 healthy individuals. NeuroImage. ISSN 1053-8119. doi: 10.1016/j.neuroimage.2020.117302. Full text in Research Archive Show summary

  Experience-dependent modulation of the visual evoked potential (VEP) is a promising proxy measure of synaptic plasticity in the cerebral cortex. However, existing studies are limited by small to moderate sample sizes as well as by considerable variability in how VEP modulation is quantified. In the present study, we used a large sample (n = 415) of healthy volunteers to compare different quantifications of VEP modulation with regards to effect sizes and retention of the modulation effect over time. We observed significant modulation for VEP components C1 (Cohen's d = 0.53), P1 (d = 0.66), N1 (d=-0.27), N1b (d=-0.66), but not P2 (d = 0.08), and in three clusters of total power modulation, 2–4 min after 2 Hz prolonged visual stimulation. For components N1 (d=-0.21) and N1b (d=-0.38), as well for the total power clusters, this effect was retained after 54–56 min, by which time also the P2 component had gained modulation (d = 0.54). Moderate to high correlations (0.39≤ρ≤0.69) between modulation at different postintervention blocks revealed a relatively high temporal stability in the modulation effect for each VEP component. However, different VEP components also showed markedly different temporal retention patterns. Finally, participant age correlated negatively with C1 (χ2=30.4), and positively with P1 modulation (χ2=13.4), whereas P2 modulation was larger for female participants (χ2=15.4). There were no effects of either age or sex on N1 and N1b potentiation. These results provide strong support for VEP modulation, and especially N1b modulation, as a robust measure of synaptic plasticity, but underscore the need to differentiate between components, and to control for demographic confounders.

• Mäki-Marttunen, Tuomo; Iannella, Nicolangelo Libero; Edwards, Andrew; Einevoll, Gaute & Blackwell, Kim T. (2020). A unified computational model for cortical post-synaptic plasticity. eLIFE. 9, p. 1–37. doi: 10.7554/eLife.55714. Full text in Research Archive Show summary

  Signalling pathways leading to post-synaptic plasticity have been examined in many types of experimental studies, but a unified picture on how multiple biochemical pathways collectively shape neocortical plasticity is missing. We built a biochemically detailed model of post-synaptic plasticity describing CaMKII, PKA, and PKC pathways and their contribution to synaptic potentiation or depression. We developed a statistical AMPA-receptor-tetramer model, which permits the estimation of the AMPA-receptor-mediated maximal synaptic conductance based on numbers of GluR1s and GluR2s predicted by the biochemical signalling model. We show that our model reproduces neuromodulator-gated spike-timing-dependent plasticity as observed in the visual cortex and can be fit to data from many cortical areas, uncovering the biochemical contributions of the pathways pinpointed by the underlying experimental studies. Our model explains the dependence of different forms of plasticity on the availability of different proteins and can be used for the study of mental disorder-associated impairments of cortical plasticity.

• Mäki-Marttunen, Tuomo; Kaufmann, Tobias; Elvs\aashagen, Torbjørn; Devor, Anna; Djurovic, Srdjan & Westlye, Lars [Show all 17 contributors for this article] (2019). Biophysical Psychiatry—How Computational Neuroscience Can Help to Understand the Complex Mechanisms of Mental Disorders. Frontiers in Psychiatry. 10. Full text in Research Archive
• Mäki-Marttunen, Tuomo; Kaufmann, Tobias; Elvsåshagen, Torbjørn; Devor, Anna; Djurovic, Srdjan & Westlye, Lars Tjelta [Show all 23 contributors for this article] (2019). Biophysical Psychiatry—How Computational Neuroscience Can Help to Understand the Complex Mechanisms of Mental Disorders. Frontiers in Psychiatry. 10. doi: 10.3389/fpsyt.2019.00534. Full text in Research Archive Show summary

  The brain is the most complex of human organs, and the pathophysiology underlying abnormal brain function in psychiatric disorders is largely unknown. Despite the rapid development of diagnostic tools and treatments in most areas of medicine, our understanding of mental disorders and their treatment has made limited progress during the last decades. While recent advances in genetics and neuroscience have a large potential, the complexity and multidimensionality of the brain processes hinder the discovery of disease mechanisms that would link genetic findings to clinical symptoms and behavior. This applies also to schizophrenia, for which genome-wide association studies have identified a large number of genetic risk loci, spanning hundreds of genes with diverse functionalities. Importantly, the multitude of the associated variants and their prevalence in the healthy population limit the potential of a reductionist functional genetics approach as a stand-alone solution to discover the disease pathology. In this review, we outline the key concepts of a “biophysical psychiatry,” an approach that employs large-scale mechanistic, biophysics-founded computational modelling to increase transdisciplinary understanding of the pathophysiology and strive toward robust predictions. We discuss recent scientific advances that allow a synthesis of previously disparate fields of psychiatry, neurophysiology, functional genomics, and computational modelling to tackle open questions regarding the pathophysiology of heritable mental disorders. We argue that the complexity of the increasing amount of genetic data exceeds the capabilities of classical experimental assays and requires computational approaches. Biophysical psychiatry, based on modelling diseased brain networks using existing and future knowledge of basic genetic, biochemical, and functional properties on a single neuron to a microcircuit level, may allow a leap forward in deriving interpretable biomarkers and move the field toward novel treatment options.

• Mäki-Marttunen, Tuomo; Krull, Florian; Bettella, Francesco; Hagen, Espen; Næss, Solveig & Ness, Torbjørn V [Show all 16 contributors for this article] (2019). Alterations in schizophrenia-associated genes can lead to increased power in delta oscillations. Cerebral Cortex. ISSN 1047-3211. 29(2), p. 875–891. doi: 10.1093/cercor/bhy291. Full text in Research Archive Show summary

  Genome-wide association studies have implicated many ion channels in schizophrenia pathophysiology. Although the functions of these channels are relatively well characterized by single-cell studies, the contributions of common variation in these channels to neurophysiological biomarkers and symptoms of schizophrenia remain elusive. Here, using computational modeling, we show that a common biomarker of schizophrenia, namely, an increase in delta-oscillation power, may be a direct consequence of altered expression or kinetics of voltage-gated ion channels or calcium transporters. Our model of a circuit of layer V pyramidal cells highlights multiple types of schizophrenia-related variants that contribute to altered dynamics in the delta-frequency band. Moreover, our model predicts that the same membrane mechanisms that increase the layer V pyramidal cell network gain and response to delta-frequency oscillations may also cause a deficit in a single-cell correlate of the prepulse inhibition, which is a behavioral biomarker highly associated with schizophrenia.

• Mäki-Marttunen, Tuomo; Devor, Anna; Phillips, William A; Dale, Anders M.; Andreassen, Ole Andreas & Einevoll, Gaute (2019). Computational Modeling of Genetic Contributions to Excitability and Neural Coding in Layer V Pyramidal Cells: Applications to Schizophrenia Pathology. Frontiers in Computational Neuroscience. 13. doi: 10.3389/fncom.2019.00066. Full text in Research Archive Show summary

  Pyramidal cells in layer V of the neocortex are one of the most widely studied neuron types in the mammalian brain. Due to their role as integrators of feedforward and cortical feedback inputs, they are well-positioned to contribute to the symptoms and pathology in mental disorders—such as schizophrenia—that are characterized by a mismatch between the internal perception and external inputs. In this modeling study, we analyze the input/output properties of layer V pyramidal cells and their sensitivity to modeled genetic variants in schizophrenia-associated genes. We show that the excitability of layer V pyramidal cells and the way they integrate inputs in space and time are altered by many types of variants in ion-channel and Ca2+ transporter-encoding genes that have been identified as risk genes by recent genome-wide association studies. We also show that the variability in the output patterns of spiking and Ca2+ transients in layer V pyramidal cells is altered by these model variants. Importantly, we show that many of the predicted effects are robust to noise and qualitatively similar across different computational models of layer V pyramidal cells. Our modeling framework reveals several aspects of single-neuron excitability that can be linked to known schizophrenia-related phenotypes and existing hypotheses on disease mechanisms. In particular, our models predict that single-cell steady-state firing rate is positively correlated with the coding capacity of the neuron and negatively correlated with the amplitude of a prepulse-mediated adaptation and sensitivity to coincidence of stimuli in the apical dendrite and the perisomatic region of a layer V pyramidal cell. These results help to uncover the voltage-gated ion-channel and Ca2+ transporter-associated genetic underpinnings of schizophrenia phenotypes and biomarkers.

• Mäki-Marttunen, Tuomo; Krull, Florian; Bettella, Francesco; Hagen, Espen; Næss, Solveig & Ness, Torbjørn [Show all 15 contributors for this article] (2018). Alterations in Schizophrenia-Associated Genes Can Lead to Increased Power in Delta Oscillations. Cerebral Cortex. ISSN 1047-3211. 29. Full text in Research Archive
• Li, Wen; Fan, Chun Chieh; Mäki-Marttunen, Tuomo; Thompson, Wesley Kurt; Schork, Andrew J. & Bettella, Francesco [Show all 10 contributors for this article] (2018). A molecule-based genetic association approach implicates a range of voltage-gated calcium channels associated with schizophrenia. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. ISSN 1552-4841. 177(4), p. 454–467. doi: 10.1002/ajmg.b.32634. Full text in Research Archive
• Medan, Violeta; Mäki-Marttunen, Tuomo; Sztarker, Julieta & Preuss, Thomas (2018). Differential processing in modality-specific Mauthner cell dendrites. Journal of Physiology. ISSN 0022-3751. 596(4), p. 667–689. doi: 10.1113/JP274861. Full text in Research Archive
• Mäki-Marttunen, Tuomo; Halnes, Geir; Devor, Anna; Metzner, Christoph; Dale, Anders M. & Andreassen, Ole Andreas [Show all 7 contributors for this article] (2018). A stepwise neuron model fitting procedure designed for recordings with high spatial resolution: Application to layer 5 pyramidal cells. Journal of Neuroscience Methods. ISSN 0165-0270. 293, p. 264–283. doi: 10.1016/j.jneumeth.2017.10.007. Full text in Research Archive Show summary

  Background Recent progress in electrophysiological and optical methods for neuronal recordings provides vast amounts of high-resolution data. In parallel, the development of computer technology has allowed simulation of ever-larger neuronal circuits. A challenge in taking advantage of these developments is the construction of single-cell and network models in a way that faithfully reproduces neuronal biophysics with subcellular level of details while keeping the simulation costs at an acceptable level. New method In this work, we develop and apply an automated, stepwise method for fitting a neuron model to data with fine spatial resolution, such as that achievable with voltage sensitive dyes (VSDs) and Ca2+ imaging. Result We apply our method to simulated data from layer 5 pyramidal cells (L5PCs) and construct a model with reduced neuronal morphology. We connect the reduced-morphology neurons into a network and validate against simulated data from a high-resolution L5PC network model. Comparison with existing methods Our approach combines features from several previously applied model-fitting strategies. The reduced-morphology neuron model obtained using our approach reliably reproduces the membrane-potential dynamics across the dendrites as predicted by the full-morphology model. Conclusions The network models produced using our method are cost-efficient and predict that interconnected L5PCs are able to amplify delta-range oscillatory inputs across a large range of network sizes and topologies, largely due to the medium after hyperpolarization mediated by the Ca2+-activated SK current.

• Tveito, Aslak; Jæger, Karoline Horgmo; Lines, Glenn Terje; Paszkowski, Lukasz; Sundnes, Joakim & Edwards, Andrew [Show all 9 contributors for this article] (2017). An evaluation of the accuracy of classical models for computing the membrane potential and extracellular potential for neurons. Frontiers in Computational Neuroscience. 11. doi: 10.3389/fncom.2017.00027. Full text in Research Archive Show summary

  Two mathematical models are part of the foundation of Computational neurophysiology; (a) the Cable equation is used to compute the membrane potential of neurons, and, (b) volume-conductor theory describes the extracellular potential around neurons. In the standard procedure for computing extracellular potentials, the transmembrane currents are computed by means of (a) and the extracellular potentials are computed using an explicit sum over analytical point-current source solutions as prescribed by volume conductor theory. Both models are extremely useful as they allow huge simplifications of the computational efforts involved in computing extracellular potentials. However, there are more accurate, though computationally very expensive, models available where the potentials inside and outside the neurons are computed simultaneously in a self-consistent scheme. In the present work we explore the accuracy of the classical models (a) and (b) by comparing them to these more accurate schemes. The main assumption of (a) is that the ephaptic current can be ignored in the derivation of the Cable equation. We find, however, for our examples with stylized neurons, that the ephaptic current is comparable in magnitude to other currents involved in the computations, suggesting that it may be significant—at least in parts of the simulation. The magnitude of the error introduced in the membrane potential is several millivolts, and this error also translates into errors in the predicted extracellular potentials. While the error becomes negligible if we assume the extracellular conductivity to be very large, this assumption is, unfortunately, not easy to justify a priori for all situations of interest.

• Devor, Anna; Andreassen, Ole Andreas; Wang, Yunpeng; Mäki-Marttunen, Tuomo; Smeland, Olav Bjerkehagen & Fan, Chun Chieh [Show all 18 contributors for this article] (2017). Genetic evidence for role of integration of fast and slow neurotransmission in schizophrenia. Molecular Psychiatry. ISSN 1359-4184. 22(6), p. 792–801. doi: 10.1038/mp.2017.33. Full text in Research Archive Show summary

  The most recent genome-wide association studies (GWAS) of schizophrenia (SCZ) identified hundreds of risk variants potentially implicated in the disease. Further, novel statistical methodology designed for polygenic architecture revealed more potential risk variants. This can provide a link between individual genetic factors and the mechanistic underpinnings of SCZ. Intriguingly, a large number of genes coding for ionotropic and metabotropic receptors for various neurotransmitters—glutamate, γ-aminobutyric acid (GABA), dopamine, serotonin, acetylcholine and opioids—and numerous ion channels were associated with SCZ. Here, we review these findings from the standpoint of classical neurobiological knowledge of neuronal synaptic transmission and regulation of electrical excitability. We show that a substantial proportion of the identified genes are involved in intracellular cascades known to integrate ‘slow’ (G-protein-coupled receptors) and ‘fast’ (ionotropic receptors) neurotransmission converging on the protein DARPP-32. Inspection of the Human Brain Transcriptome Project database confirms that that these genes are indeed expressed in the brain, with the expression profile following specific developmental trajectories, underscoring their relevance to brain organization and function. These findings extend the existing pathophysiology hypothesis by suggesting a unifying role of dysregulation in neuronal excitability and synaptic integration in SCZ. This emergent model supports the concept of SCZ as an ‘associative’ disorder—a breakdown in the communication across different slow and fast neurotransmitter systems through intracellular signaling pathways—and may unify a number of currently competing hypotheses of SCZ pathophysiology.

• Mäki-Marttunen, Tuomo (2017). An Algorithm for Motif-Based Network Design. IEEE/ACM Transactions on Computational Biology & Bioinformatics. ISSN 1545-5963. 14(5), p. 1181–1186. doi: 10.1109/TCBB.2016.2576442. Full text in Research Archive
• Mäki-Marttunen, Tuomo; Lines, Glenn Terje; Edwards, Andrew G; Tveito, Aslak; Dale, Anders M. & Einevoll, Gaute [Show all 7 contributors for this article] (2017). Pleiotropic effects of schizophrenia-associated genetic variants in neuron firing and cardiac pacemaking revealed by computational modeling. Translational Psychiatry. 7(5). doi: 10.1038/s41398-017-0007-4. Full text in Research Archive Show summary

  Schizophrenia patients have an increased risk of cardiac dysfunction. A possible factor underlying this comorbidity are the common variants in the large set of genes that have recently been discovered in genome-wide association studies (GWASs) as risk genes of schizophrenia. Many of these genes control the cell electrogenesis and calcium homeostasis. We applied biophysically detailed models of layer V pyramidal cells and sinoatrial node cells to study the contribution of schizophrenia-associated genes on cellular excitability. By including data from functional genomics literature to simulate the effects of common variants of these genes, we showed that variants of voltage-gated Na+ channel or hyperpolarization-activated cation channel-encoding genes cause qualitatively similar effects on layer V pyramidal cell and sinoatrial node cell excitability. By contrast, variants of Ca2+ channel or transporter-encoding genes mostly have opposite effects on cellular excitability in the two cell types. We also show that the variants may crucially affect the propagation of the cardiac action potential in the sinus node. These results may help explain some of the cardiac comorbidity in schizophrenia, and may facilitate generation of effective antipsychotic medications without cardiac side-effects such as arrhythmia.

• Halnes, Geir; Mäki-Marttunen, Tuomo; Pettersen, Klas; Andreassen, Ole Andreas & Einevoll, Gaute (2017). Ion diffusion may introduce spurious current sources in current-source density (CSD) analysis. Journal of Neurophysiology. ISSN 0022-3077. 118(1), p. 114–120. doi: 10.1152/jn.00976.2016. Full text in Research Archive Show summary

  Current-source density (CSD) analysis is a well-established method for analyzing recorded local field potentials (LFPs), that is, the low-frequency part of extracellular potentials. Standard CSD theory is based on the assumption that all extracellular currents are purely ohmic, and thus neglects the possible impact from ionic diffusion on recorded potentials. However, it has previously been shown that in physiological conditions with large ion-concentration gradients, diffusive currents can evoke slow shifts in extracellular potentials. Using computer simulations, we here show that diffusion-evoked potential shifts can introduce errors in standard CSD analysis, and can lead to prediction of spurious current sources. Further, we here show that the diffusion-evoked prediction errors can be removed by using an improved CSD estimator which accounts for concentration-dependent effects.

• Halnes, Geir; Mäki-Marttunen, Tuomo; Keller, Daniel; Pettersen, Klas; Andreassen, Ole Andreas & Einevoll, Gaute (2016). Effect of Ionic Diffusion on Extracellular Potentials in Neural Tissue. PLoS Computational Biology. ISSN 1553-734X. 12(11). doi: 10.1371/journal.pcbi.1005193. Full text in Research Archive Show summary

  Recorded potentials in the extracellular space (ECS) of the brain is a standard measure of population activity in neural tissue. Computational models that simulate the relationship between the ECS potential and its underlying neurophysiological processes are commonly used in the interpretation of such measurements. Standard methods, such as volume-conductor theory and current-source density theory, assume that diffusion has a negligible effect on the ECS potential, at least in the range of frequencies picked up by most recording systems. This assumption remains to be verified. We here present a hybrid simulation framework that accounts for diffusive effects on the ECS potential. The framework uses (1) the NEURON simulator to compute the activity and ionic output currents from multicompartmental neuron models, and (2) the electrodiffusive Kirchhoff-Nernst-Planck framework to simulate the resulting dynamics of the potential and ion concentrations in the ECS, accounting for the effect of electrical migration as well as diffusion. Using this framework, we explore the effect that ECS diffusion has on the electrical potential surrounding a small population of 10 pyramidal neurons. The neural model was tuned so that simulations over ∼100 seconds of biological time led to shifts in ECS concentrations by a few millimolars, similar to what has been seen in experiments. By comparing simulations where ECS diffusion was absent with simulations where ECS diffusion was included, we made the following key findings: (i) ECS diffusion shifted the local potential by up to ∼0.2 mV. (ii) The power spectral density (PSD) of the diffusion-evoked potential shifts followed a 1/f2 power law. (iii) Diffusion effects dominated the PSD of the ECS potential for frequencies up to several hertz. In scenarios with large, but physiologically realistic ECS concentration gradients, diffusion was thus found to affect the ECS potential well within the frequency range picked up in experimental recordings.

• Mäki-Marttunen, Tuomo; Halnes, Geir; Devor, Anna; Witoelar, Aree; Bettella, Francesco & Djurovic, Srdjan [Show all 10 contributors for this article] (2016). Functional effects of schizophrenia-linked genetic variants on intrinsic single-neuron excitability: a modeling study. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. ISSN 2451-9022. 1(1), p. 49–59. doi: 10.1016/j.bpsc.2015.09.002. Full text in Research Archive Show summary

  BACKGROUND: Recent genome-wide association studies have identified a large number of genetic risk factors for schizophrenia (SCZ) featuring ion channels and calcium transporters. For some of these risk factors, independent prior investigations have examined the effects of genetic alterations on the cellular electrical excitability and calcium homeostasis. In the present proof-of-concept study, we harnessed these experimental results for modeling of computational properties on layer V cortical pyramidal cells and identified possible common alterations in behavior across SCZ-related genes. METHODS: We applied a biophysically detailed multicompartmental model to study the excitability of a layer V pyramidal cell. We reviewed the literature on functional genomics for variants of genes associated with SCZ and used changes in neuron model parameters to represent the effects of these variants. RESULTS: We present and apply a framework for examining the effects of subtle single nucleotide polymorphisms in ion channel and calcium transporter-encoding genes on neuron excitability. Our analysis indicates that most of the considered SCZ-related genetic variants affect the spiking behavior and intracellular calcium dynamics resulting from summation of inputs across the dendritic tree. CONCLUSIONS: Our results suggest that alteration in the ability of a single neuron to integrate the inputs and scale its excitability may constitute a fundamental mechanistic contributor to mental disease, alongside the previously proposed deficits in synaptic communication and network behavior. Keywords: Biophysical modeling, Functional genomics, Genome-wide association studies, Layer V pyramidal cell, Neuron excitability, Schizophrenia

• Aćimović, Jugoslava; Mäki-Marttunen, Tuomo Mikael & Linne, Marja-Leena (2015). The effects of neuron morphology on graph theoretic measures of network connectivity: The analysis of a two-level statistical model. Frontiers in Neuroanatomy. 9:76(June). doi: 10.3389/fnana.2015.00076. Full text in Research Archive

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• Kismul, Jan Fredrik; Ness, Torbjørn V; Einevoll, Gaute; Linne, Marja Leena & Mäki-Marttunen, Tuomo (2024). Modeling the effects of schizophrenia related ion-channel encoding genes on P50 suppression. Full text in Research Archive
• Banono, Nancy Saana; Gawel, Kinga Aurelia; Mäki-Marttunen, Tuomo; Ent, Wietske van der; Kukula-Koch, Wirginia & Fyhn, Marianne [Show all 10 contributors for this article] (2023). Novel zebrafish model for studying neurodevelopment in Timothy syndrome. Full text in Research Archive
• Banono, Nancy Saana; Ent, Wietske van der; Gawel, Kinga Aurelia; Mäki-Marttunen, Tuomo; Kukula-Koch, Wirginia & Einevoll, Gaute [Show all 9 contributors for this article] (2021). Functional characterisation of cacna1c mutations in zebrafish larvae. Full text in Research Archive
• Mäki-Marttunen, Tuomo; Edwards, Andrew G; Einevoll, Gaute & Blackwell, Kim T (2020). Biochemically detailed single compartmental model for neocortical postsynaptic long term plasticity. Full text in Research Archive
• Iannella, Nicolangelo Libero & Mäki-Marttunen, Tuomo (2019). Modelling intracellular cascades and neural plasticity. Full text in Research Archive
• Mäki-Marttunen, Tuomo; Einevoll, Gaute; Devor, Anna; Phillips, Wiliam; Dale, Anders M. & Andreassen, Ole Andreas (2019). A computational model of the spontaneous activity of gonadotropin-releasing cells in the teleos fish medaka. Full text in Research Archive
• Mäki-Marttunen, Tuomo; Blackwell, Kim T & Edwards, Andrew G (2018). Unified biochemical model for long-term synaptic plasticity in the cortex – what are the essential pathways? Full text in Research Archive
• Mäki-Marttunen, Tuomo; Edwards, Andrew G & Blackwell, Kim T (2018). Construction of a biochemically detailed single-compartment model for post-synaptic long-term potentiation: application to cortical plasticity. Full text in Research Archive
• Mäki-Marttunen, Tuomo (2018). Lecture series on modelling of neuronal electrophysiology. Full text in Research Archive
• Halnes, Geir; Solbrå, Andreas Våvang; Mäki-Marttunen, Tuomo; Pettersen, Klas; Andreassen, Ole Andreas & Malthe-Sørensen, Anders [Show all 7 contributors for this article] (2017). Modelling electrical and chemical dynamics in brain tissue. Full text in Research Archive
• Halnes, Geir; Mäki-Marttunen, Tuomo; Pettersen, Klas; Andreassen, Ole Andreas & Einevoll, Gaute T. (2017). Extracellular diffusion can introduce errors in current source density estimates. Full text in Research Archive
• Mäki-Marttunen, Tuomo; Krull, Florian; Bettella, Francesco; Moberget, Torgeir; Elvsåshagen, Torbjørn & Metzner, Christoph [Show all 11 contributors for this article] (2017). Delta oscillations in schizophrenia: Insights from biophysically detailed modeling of networks of layer V pyramidal cells. Full text in Research Archive
• Mäki-Marttunen, Tuomo; Krull, Florian; Bettella, Francesco; Metzner, Christoph; Devor, Anna & Djurovic, Srdjan [Show all 9 contributors for this article] (2017). Layer V pyramidal cells as mediators of delta oscillations: Insights from biophysically detailed modeling and connections with schizophrenia genetics. Full text in Research Archive
• Halnes, Geir; Mäki-Marttunen, Tuomo; Pettersen, Klas; Keller, Daniel; Andreassen, Ole Andreas & Einevoll, Gaute (2016). Effects of ionic diffusion on power spectra of local field potentials (LFP). Full text in Research Archive
• Mäki-Marttunen, Tuomo; Einevoll, Gaute & Andreassen, Ole Andreas (2015). Neural modeling for schizophrenia research. META : Magazine. 02. Full text in Research Archive
• Mäki-Marttunen, Tuomo; Halnes, Geir; Devor, Anna; Witoelar, Aree; Bettella, Francesco & Djurovic, Srdjan [Show all 10 contributors for this article] (2015). Towards biophysical psychiatry: A modeling approach for studying effects of schizophrenia-linked gens on single-neuron excitability. Full text in Research Archive
• Halnes, Geir; Mäki-Marttunen, Tuomo; Pettersen, Klas Henning; Keller, Daniel; Andreassen, Ole Andreas & Einevoll, Gaute (2015). Can ionic diffusion have an effect on extracellular potentials? Full text in Research Archive
• Mäki-Marttunen, Tuomo; Halnes, Geir; Devor, Anna; Witoelar, Aree; Bettella, Francesco & Djurovic, Srdjan [Show all 10 contributors for this article] (2015). Towards biophysical psychiatry: A modeling approach for studying effects of schizophrenia-linked genes on single-neuron excitability. Full text in Research Archive

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