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Article ; Online: An in Silico, Biomarker-Based Method for the Evaluation of Virtual Neuropsychiatric Drug Effects.

Siekmeier, Peter J

2017 Volume 29, Issue 4, Page(s) 1021–1052

Abstract: The recent explosion in neuroscience research has markedly increased our understanding of the neurobiological correlates of many psychiatric illnesses, but this has unfortunately not translated into more effective pharmacologic treatments for these ... ...

Abstract	The recent explosion in neuroscience research has markedly increased our understanding of the neurobiological correlates of many psychiatric illnesses, but this has unfortunately not translated into more effective pharmacologic treatments for these conditions. At the same time, researchers have increasingly sought out biological markers, or biomarkers, as a way to categorize psychiatric illness, as these are felt to be closer to underlying genetic and neurobiological vulnerabilities. While biomarker-based drug discovery approaches have tended to employ in vivo (e.g., rodent) or in vitro test systems, relatively little attention has been paid to the potential of computational, or in silico, methodologies. Here we describe such a methodology, using as an example a biophysically detailed computational model of hippocampus that is made to generate putative schizophrenia biomarkers by the inclusion of a number of neuropathological changes that have been associated with the illness (NMDA system deficit, decreased neural connectivity, hyperdopaminergia). We use the specific inability to attune to gamma band (40 Hz) auditory stimulus as our illness biomarker. We expose this system to a large number of virtual medications, defined by systematic variation of model parameters corresponding to five cellular-level effects. The potential efficacy of virtual medications is determined by a wellness metric (WM) that we have developed. We identify a number of virtual agents that consist of combinations of mechanisms, which are not simply reversals of the causative lesions. The manner in which this methodology could be extended to other neuropsychiatric conditions, such as Alzheimer's disease, autism, and fragile X syndrome, is discussed.
MeSH term(s)	Acoustic Stimulation ; Antipsychotic Agents/therapeutic use ; Biomarkers/metabolism ; Brain Waves/drug effects ; Computer Simulation ; Hippocampus/drug effects ; Hippocampus/pathology ; Humans ; Neurons/drug effects ; Schizophrenia/drug therapy ; Schizophrenia/pathology ; Schizophrenia/physiopathology
Chemical Substances	Antipsychotic Agents ; Biomarkers
Language	English
Publishing date	2017-02-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1025692-1
ISSN	1530-888X ; 0899-7667
ISSN (online)	1530-888X
ISSN	0899-7667
DOI	10.1162/NECO_a_00944
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Article ; Online: Computational modeling of psychiatric illnesses via well-defined neurophysiological and neurocognitive biomarkers.

Siekmeier, Peter J

Neuroscience and biobehavioral reviews

2015 Volume 57, Page(s) 365–380

Abstract: A good deal of recent research has centered on the identification of biomarkers and endophenotypic measures of psychiatric illnesses using in vivo and in vitro studies. This is understandable, as these measures-as opposed to complex clinical phenotypes- ... ...

Abstract	A good deal of recent research has centered on the identification of biomarkers and endophenotypic measures of psychiatric illnesses using in vivo and in vitro studies. This is understandable, as these measures-as opposed to complex clinical phenotypes-may be more closely related to neurobiological and genetic vulnerabilities. However, instantiation of such biomarkers using computational models-in silico studies-has received less attention. This approach could become increasingly important, given the wealth of detailed information produced by recent basic neuroscience research, and increasing availability of high capacity computing platforms. The purpose of this review is to survey the current state of the art of research in this area. We discuss computational approaches to schizophrenia, bipolar disorder, Alzheimer's disease, fragile X syndrome and autism, and argue that it represents a promising and underappreciated research modality. In conclusion, we outline specific avenues for future research; also, potential uses of in silico models to conduct "virtual experiments" and to generate novel hypotheses, and as an aid in neuropsychiatric drug development are discussed.
MeSH term(s)	Animals ; Biomarkers ; Computer Simulation ; Humans ; Mental Disorders ; Models, Theoretical
Chemical Substances	Biomarkers
Language	English
Publishing date	2015-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	282464-4
ISSN	1873-7528 ; 0149-7634
ISSN (online)	1873-7528
ISSN	0149-7634
DOI	10.1016/j.neubiorev.2015.09.014
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Article ; Online: Evidence of multistability in a realistic computer simulation of hippocampus subfield CA1.

Siekmeier, Peter J

Behavioural brain research

2009 Volume 200, Issue 1, Page(s) 220–231

Abstract: ... CA3 pyramidal neurone. J Physiol (Lond) 1994;481:79-95] and interneuron [Traub RD, Miles R ... cell. J Comput Neurosci 1995;2:291-8] models, incorporating patterns of synaptic connectivity based ... T, Matsuki N, Ikegaya Y. Metastability of active CA3 networks. J Neurosci 2007;27:517-28 ...

Abstract	The manner in which hippocampus processes neural signals is thought to be central to the memory encoding process. A theoretically oriented literature has suggested that this is carried out via "attractors" or distinctive spatio-temporal patterns of activity. However, these ideas have not been thoroughly investigated using computational models featuring both realistic single-cell physiology and detailed cell-to-cell connectivity. Here we present a 452 cell simulation based on Traub et al.'s pyramidal cell [Traub RD, Jefferys JG, Miles R, Whittington MA, Toth K. A branching dendritic model of a rodent CA3 pyramidal neurone. J Physiol (Lond) 1994;481:79-95] and interneuron [Traub RD, Miles R, Pyramidal cell-to-inhibitory cell spike transduction explicable by active dendritic conductances in inhibitory cell. J Comput Neurosci 1995;2:291-8] models, incorporating patterns of synaptic connectivity based on an extensive review of the neuroanatomic literature. When stimulated with a one second physiologically realistic input, our simulated tissue shows the ability to hold activity on-line for several seconds; furthermore, its spiking activity, as measured by frequency and interspike interval (ISI) distributions, resembles that of in vivo hippocampus. An interesting emergent property of the system is its tendency to transition from stable state to stable state, a behavior consistent with recent experimental findings [Sasaki T, Matsuki N, Ikegaya Y. Metastability of active CA3 networks. J Neurosci 2007;27:517-28]. Inspection of spike trains and simulated blockade of K(AHP) channels suggest that this is mediated by spike frequency adaptation. This finding, in conjunction with studies showing that apamin, a K(AHP) channel blocker, enhances the memory consolidation process in laboratory animals, suggests the formation of stable attractor states is central to the process by which memories are encoded. Ways that this methodology could shed light on the etiology of mental illness, such as schizophrenia, are discussed.
MeSH term(s)	Action Potentials/physiology ; Animals ; Axons/metabolism ; Axons/physiology ; Calcium-Binding Proteins/metabolism ; Computer Simulation ; Hippocampus/cytology ; Models, Neurological ; Nerve Net/physiology ; Neural Networks, Computer ; Neural Pathways ; Neurons/classification ; Neurons/cytology ; Neurons/physiology ; Synapses/physiology
Chemical Substances	Calcium-Binding Proteins
Language	English
Publishing date	2009-04-18
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	449927-x
ISSN	1872-7549 ; 0166-4328
ISSN (online)	1872-7549
ISSN	0166-4328
DOI	10.1016/j.bbr.2009.01.021
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Zs.A 1599: Show issues

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Article ; Online: Dopaminergic contributions to hippocampal pathophysiology in schizophrenia: a computational study.

Siekmeier, Peter J / vanMaanen, David P

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2014 Volume 39, Issue 7, Page(s) 1713–1721

Abstract: Since the original formulation of the dopamine hypothesis, a number of other cellular-level abnormalities--eg, NMDA receptor hypofunction, GABA system dysfunction, neural connectivity disturbances--have been identified in schizophrenia, but the manner in ...

Abstract	Since the original formulation of the dopamine hypothesis, a number of other cellular-level abnormalities--eg, NMDA receptor hypofunction, GABA system dysfunction, neural connectivity disturbances--have been identified in schizophrenia, but the manner in which these potentially interact with hyperdopaminergia to lead to schizophrenic symptomatology remains uncertain. Previously, we created a neuroanatomically detailed, biophysically realistic computational model of hippocampus in the control (unaffected) and schizophrenic conditions, implemented on a 72-processor supercomputer platform. In the current study, we apply the effects of dopamine (DA), dose-dependently, to both models on the basis of an exhaustive review of the neurophysiologic literature on DA's ion channel and synaptic level effects. To index schizophrenic behavior, we use the specific inability of the model to attune to the 40 Hz (gamma band) frequency, a finding that has been well replicated in the clinical electroencephalography (EEG) and magnetoencephalography literature. In trials using 20 'simulated patients', we find that DA applied to the control model produces modest increases in 40 Hz activity, similar to experimental studies. However, in the schizophrenic model, increasing DA induces a decrement in 40 Hz resonance. This modeling work is significant in that it suggests that DA's effects may vary based on the neural substrate on which it acts, and--via simulated EEG recordings-points to the neurophysiologic mechanisms by which this may occur. We also feel that it makes a methodological contribution, as it exhibits a process by which a large amount of neurobiological data can be integrated to run pharmacologically relevant in silico experiments, using a systems biology approach.
MeSH term(s)	Acoustic Stimulation ; Animals ; Brain Waves/drug effects ; Brain Waves/physiology ; Computer Simulation ; Dopamine/metabolism ; Electroencephalography ; Hippocampus/physiopathology ; Humans ; Models, Neurological ; Schizophrenia/pathology ; Schizophrenia/physiopathology
Chemical Substances	Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2014-01-28
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	639471-1
ISSN	1740-634X ; 0893-133X
ISSN (online)	1740-634X
ISSN	0893-133X
DOI	10.1038/npp.2014.19
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Zs.A 2379: Show issues

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Article ; Online: Patterns of spontaneous magnetoencephalographic activity in patients with schizophrenia.

Siekmeier, Peter J / Stufflebeam, Steven M

Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society

2010 Volume 27, Issue 3, Page(s) 179–190

Abstract: Magnetoencephalography noninvasively measures the magnetic fields produced by the brain. Pertinent research articles from 1993 to 2009 that measured spontaneous, whole-head magnetoencephalography activity in patients with schizophrenia were reviewed. ... ...

Abstract	Magnetoencephalography noninvasively measures the magnetic fields produced by the brain. Pertinent research articles from 1993 to 2009 that measured spontaneous, whole-head magnetoencephalography activity in patients with schizophrenia were reviewed. Data on localization of oscillatory activity and correlation of these findings with psychotic symptoms are summarized. Although the variety of measures used by different research groups makes a quantitative meta-analysis difficult, it appears that magnetoencephalography activity in patients may exhibit identifiable patterns, defined by topographic organization and frequency band. Specifically, 11 of the 12 studies showed increased theta (4-8 Hz) and delta (1-4 Hz) band oscillations in the temporal lobes of patients; of the 10 studies that examined the relationship between oscillatory activity and symptomatology, 8 found a positive correlation between temporal lobe theta activity and positive schizophrenic symptoms. Abnormally high frontal delta activity was not seen. These findings are analyzed in comparison with the electroencephalogram literature on schizophrenics, and possible confounds (e.g., medication effects) are discussed. In the future, magnetoencephalography might be used to assist in diagnosis or might be fruitfully used in conjunction with new neuroscience research approaches such as computational modeling, which may be able to link oscillatory activity and cellular-level pathology.
MeSH term(s)	Brain/physiopathology ; Brain Mapping ; Electroencephalography/methods ; Humans ; Magnetoencephalography/drug effects ; Schizophrenia/drug therapy ; Schizophrenia/pathology ; Schizophrenia/physiopathology
Language	English
Publishing date	2010-05-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	605640-4
ISSN	1537-1603 ; 0736-0258
ISSN (online)	1537-1603
ISSN	0736-0258
DOI	10.1097/WNP.0b013e3181e0b20a
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Zs.A 1921: Show issues

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Article ; Online: Development of antipsychotic medications with novel mechanisms of action based on computational modeling of hippocampal neuropathology.

Siekmeier, Peter J / vanMaanen, David P

PloS one

2013 Volume 8, Issue 3, Page(s) e58607

Abstract: A large number of cellular level abnormalities have been identified in the hippocampus of schizophrenic subjects. Nonetheless, it remains uncertain how these pathologies interact at a system level to create clinical symptoms, and this has hindered the ... ...

Abstract	A large number of cellular level abnormalities have been identified in the hippocampus of schizophrenic subjects. Nonetheless, it remains uncertain how these pathologies interact at a system level to create clinical symptoms, and this has hindered the development of more effective antipsychotic medications. Using a 72-processor supercomputer, we created a tissue level hippocampal simulation, featuring multicompartmental neuron models with multiple ion channel subtypes and synaptic channels with realistic temporal dynamics. As an index of the schizophrenic phenotype, we used the specific inability of the model to attune to 40 Hz (gamma band) stimulation, a well-characterized abnormality in schizophrenia. We examined several possible combinations of putatively schizophrenogenic cellular lesions by systematically varying model parameters representing NMDA channel function, dendritic spine density, and GABA system integrity, conducting 910 trials in total. Two discrete "clusters" of neuropathological changes were identified. The most robust was characterized by co-occurring modest reductions in NMDA system function (-30%) and dendritic spine density (-30%). Another set of lesions had greater NMDA hypofunction along with low level GABA system dysregulation. To the schizophrenic model, we applied the effects of 1,500 virtual medications, which were implemented by varying five model parameters, independently, in a graded manner; the effects of known drugs were also applied. The simulation accurately distinguished agents that are known to lack clinical efficacy, and identified novel mechanisms (e.g., decrease in AMPA conductance decay time constant, increase in projection strength of calretinin-positive interneurons) and combinations of mechanisms that could re-equilibrate model behavior. These findings shed light on the mechanistic links between schizophrenic neuropathology and the gamma band oscillatory abnormalities observed in the illness. As such, they generate specific falsifiable hypotheses, which can guide postmortem and other laboratory research. Significantly, this work also suggests specific non-obvious targets for potential pharmacologic agents.
MeSH term(s)	Antipsychotic Agents/pharmacology ; Computer Simulation ; Drug Discovery/methods ; Hippocampus/drug effects ; Hippocampus/pathology ; Hippocampus/physiopathology ; Humans ; Models, Neurological ; N-Methylaspartate/physiology ; Neural Networks, Computer ; Schizophrenia/drug therapy ; Schizophrenia/pathology ; Schizophrenia/physiopathology ; User-Computer Interface ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism ; gamma-Aminobutyric Acid/physiology
Chemical Substances	Antipsychotic Agents ; gamma-Aminobutyric Acid (56-12-2) ; N-Methylaspartate (6384-92-5) ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (77521-29-0)
Language	English
Publishing date	2013-03-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0058607
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Article ; Online: Development of antipsychotic medications with novel mechanisms of action based on computational modeling of hippocampal neuropathology.

Peter J Siekmeier / David P vanMaanen

PLoS ONE, Vol 8, Iss 3, p e

2013 Volume 58607

Abstract	A large number of cellular level abnormalities have been identified in the hippocampus of schizophrenic subjects. Nonetheless, it remains uncertain how these pathologies interact at a system level to create clinical symptoms, and this has hindered the development of more effective antipsychotic medications. Using a 72-processor supercomputer, we created a tissue level hippocampal simulation, featuring multicompartmental neuron models with multiple ion channel subtypes and synaptic channels with realistic temporal dynamics. As an index of the schizophrenic phenotype, we used the specific inability of the model to attune to 40 Hz (gamma band) stimulation, a well-characterized abnormality in schizophrenia. We examined several possible combinations of putatively schizophrenogenic cellular lesions by systematically varying model parameters representing NMDA channel function, dendritic spine density, and GABA system integrity, conducting 910 trials in total. Two discrete "clusters" of neuropathological changes were identified. The most robust was characterized by co-occurring modest reductions in NMDA system function (-30%) and dendritic spine density (-30%). Another set of lesions had greater NMDA hypofunction along with low level GABA system dysregulation. To the schizophrenic model, we applied the effects of 1,500 virtual medications, which were implemented by varying five model parameters, independently, in a graded manner; the effects of known drugs were also applied. The simulation accurately distinguished agents that are known to lack clinical efficacy, and identified novel mechanisms (e.g., decrease in AMPA conductance decay time constant, increase in projection strength of calretinin-positive interneurons) and combinations of mechanisms that could re-equilibrate model behavior. These findings shed light on the mechanistic links between schizophrenic neuropathology and the gamma band oscillatory abnormalities observed in the illness. As such, they generate specific falsifiable hypotheses, which can guide ...
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Enhanced semantic priming in schizophrenia: a computer model based on excessive pruning of local connections in association cortex.

Siekmeier, Peter J / Hoffman, Ralph E

The British journal of psychiatry : the journal of mental science

1999 Volume 180, Page(s) 345–350

Abstract: Background: Many studies have found that people with schizophrenia exhibit abnormally high levels of semantic priming. Post-mortem and neuroimaging studies of schizophrenia suggest a reduction of neuritic processes (dendrites and synapses).: Aims: To ...

Abstract	Background: Many studies have found that people with schizophrenia exhibit abnormally high levels of semantic priming. Post-mortem and neuroimaging studies of schizophrenia suggest a reduction of neuritic processes (dendrites and synapses). Aims: To demonstrate that reductions in neuritic processes can produce excessive priming in patients with schizophrenia. Method: Associative memory was simulated using a computer-based neural network system consisting of two interactive neural groups, one coding for individual memories and the other for the category to which each memory belonged. Results: Variation of a single parameter determining the density of local connections within the two neuronal groups gave a close approximation to levels of memory access and semantic priming previously reported in normal subjects and in patients with schizophrenia. Conclusions: This study suggests that schizophrenia arises from excessive pruning of local connections in association cortex. Its findings shed light on the mechanisms underlying cognitive priming more generally, and how it might emerge developmentally.
MeSH term(s)	Adolescent ; Brain Diseases/pathology ; Cerebral Cortex ; Cognition Disorders/etiology ; Cognition Disorders/pathology ; Computer Simulation ; Humans ; Memory/physiology ; Models, Neurological ; Nerve Net ; Neural Pathways ; Schizophrenia/pathology ; Schizophrenia/physiopathology ; Schizophrenic Psychology ; Semantics ; Thinking/physiology ; Verbal Behavior
Language	English
Publishing date	1999-08-11
Publishing country	England
Document type	Journal Article
ZDB-ID	218103-4
ISSN	1472-1465 ; 0007-1250
ISSN (online)	1472-1465
ISSN	0007-1250
DOI	10.1192/bjp.180.4.345
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Article: Modeling of context-dependent retrieval in hippocampal region CA1: implications for cognitive function in schizophrenia.

Siekmeier, Peter J / Hasselmo, Michael E / Howard, Marc W / Coyle, Joseph

Schizophrenia research

2007 Volume 89, Issue 1-3, Page(s) 177–190

Abstract: The symptoms of schizophrenia may be associated with reductions in NMDA receptor (NMDAR) function. This is suggested by the psychotomimetic effects of NMDA antagonists, the ameliorative effects of NMDAR indirect agonists, elevated levels of the NMDA ... ...

Abstract	The symptoms of schizophrenia may be associated with reductions in NMDA receptor (NMDAR) function. This is suggested by the psychotomimetic effects of NMDA antagonists, the ameliorative effects of NMDAR indirect agonists, elevated levels of the NMDA antagonist N-acetyl-aspartyl-glutamate (NAAG) in schizophrenic brain, and findings from recent genetic studies. However, the link between reduced NMDAR function and the behavioral features of schizophrenics has not been made explicit. Here we present a network simulation of hippocampal function, focused on retrieval of verbal stimuli in human memory tasks. Specifically, we trained a computational model of the hippocampal complex to perform a context-dependent paired associate task, a free recall task with category clustering, and the transitive inference (TI) task. In this network, direct perforant pathway input from entorhinal cortex to region CA1 provides the basis for semantic context cueing during initial encoding and retrieval, allowing selective retrieval on the basis of category cues. Alterations in the magnitude of this direct perforant pathway input to region CA1 causes impairments in use of organizational strategies for memory, accounting for specific features of memory dysfunction in schizophrenics and in normals treated with ketamine. This model provides a theoretical link between cellular physiological changes and specific cognitive symptoms. As such, it can shed light on the etiology of schizophrenia in a fundamental way, and also holds the promise of pointing the way to more effective treatments.
MeSH term(s)	Brain Mapping ; Cognition Disorders/diagnosis ; Cognition Disorders/physiopathology ; Entorhinal Cortex/physiopathology ; Hippocampus/physiopathology ; Humans ; Mental Recall/physiology ; Neural Networks (Computer) ; Paired-Associate Learning/physiology ; Perforant Pathway/physiopathology ; Receptors, N-Methyl-D-Aspartate/physiology ; Schizophrenia/diagnosis ; Schizophrenia/physiopathology ; Semantics
Chemical Substances	Receptors, N-Methyl-D-Aspartate
Language	English
Publishing date	2007-01
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	639422-x
ISSN	1573-2509 ; 0920-9964
ISSN (online)	1573-2509
ISSN	0920-9964
DOI	10.1016/j.schres.2006.08.007
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Article: Clinical perspectives on pulmonary systemic and macromolecular delivery.

Scheuch, Gerhard / Kohlhaeufl, Martin J / Brand, Peter / Siekmeier, Ruediger

Advanced drug delivery reviews

2006 Volume 58, Issue 9-10, Page(s) 996–1008

Abstract: The large epithelial surface area, the high organ vascularization, the thin nature of the alveolar epithelium and the immense capacity for solute exchange are factors that led the lung to serve as an ideal administration route for the application of ... ...

Abstract	The large epithelial surface area, the high organ vascularization, the thin nature of the alveolar epithelium and the immense capacity for solute exchange are factors that led the lung to serve as an ideal administration route for the application of drugs for treatment of systemic disorders. However, the deposition behaviour of aerosol particles in the respiratory tract depends on a number of physical (e.g. properties of the particle), chemical (e.g. properties of the drug) and physiological (e.g. breathing pattern, pulmonary diseases) factors. If these are not considered, it will not be possible to deposit a reproducible and sufficient amount of drug in a predefined lung region by means of aerosol inhalation. The lack of consideration of such issues led to many problems in inhalation drug therapy for many years mainly because physiological background of aerosol inhalation was not fully understood. However, over the last 20 years, there has been considerable progress in aerosol research and in the understanding of the underlying mechanisms of particle inhalation and pulmonary particle deposition. As a consequence, an increasing number of studies have been performed for the lung administration of drugs using a variety of different inhalation techniques. This review describes the physical and in part some of the physiological requirements that need to be considered for the optimization of pulmonary drug delivery to target certain lung regions.
MeSH term(s)	Administration, Inhalation ; Aerosols ; Biological Transport ; Drug Delivery Systems/methods ; Humans ; Lung/metabolism ; Lung/physiology ; Particle Size ; Pharmaceutical Preparations/administration & dosage
Chemical Substances	Aerosols ; Pharmaceutical Preparations
Language	English
Publishing date	2006-10-31
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	639113-8
ISSN	1872-8294 ; 0169-409X
ISSN (online)	1872-8294
ISSN	0169-409X
DOI	10.1016/j.addr.2006.07.009
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