Modern life is a daily mental balancing act of performing tasks while being distracted. You write an email. The phone rings and you answer it. After the call, you try to remember what exactly you wanted to write in your email. Fortunately, staring at the screen brings back the last ideas before the call. These cognitive operations with information―distraction of attention, intermediate storage, redirecting attention, recall―are made possible by “working memory.” Impairment of working memory function results in loss of information immediately after it was learned, insufficient action planning and control, and a reduced ability to make decisions. A cup of coffee, elevating the dopamine level in the brain, might help you remember. But if you are under stress or drank too much coffee, you simply cannot concentrate. Dopamine plays a key role in these operations, and either too little or too much of it derails them.

Dysfunctions of working memory are particularly severe in many schizophrenic patients who persistently produce too much dopamine. They may be in the shadows of better-known symptoms like hallucinations, delusions, and withdrawal from the social life but can without a doubt be just as devastating.


Understanding the neural circuitry

The neural circuitry underlying working memory is localized in the prefrontal cortex. It consists of a circular connection between excitatory glutamate cells in the prefrontal cortex that allows persistent activation. Dopamine projections from the brain stem can up- or down-regulate this activity, for instance, by modulating the level of activation of inhibitory GABA neurons that are connected with this circuit. But while the frontal cortex plays a central role, the entire brain is involved in this balancing act. Moreover, lifestyle, drug use, genetic predisposition, and a host of environmental and epigenetic factors or events may contribute to the dysfunction of working memory. The effect of dopamine even depends on the level of motivation to perform a cognitive task.

Explaining these neuronal mechanisms of the illness to schizophrenic patients and their relatives is a formidable challenge for the physician. Confronted with this task in thousands of psychiatric cases in a clinical setting, one of us conceived the conceptual model of a dynamic set of balances among neurotransmitters1. This empirical model was based on uncounted observations associated with drug-induced alterations of consciousness and the effects of psychopharmaceuticals in schizophrenia, depression, addiction, and other mental disorders. The model also tried to make sense of the four common, yet distinct, hypotheses regarding the causes of improper neurotransmission in schizophrenia2, namely

  • increased function of (sub-cortical) dopamine
  • reduced function of (prefrontal) glutamate
  • reduced function of (cortical) gamma-aminobutyric acid (GABA)
  • increased function of serotonin

Over two millennia ago, Hippocrates interpreted diseases with the metaphor of imbalances among the body’s “humors” or “juices.” Would it be possible to explain at least some aspects of mental disorders with the metaphor of a “chemical mobile” among neurotransmitters?

In a modern-day view, the imbalances among neurotransmitters constitute a nonlinear system that dynamically changes during day and night in response to numerous stimuli. At first glance, these changes may not show many distinctive patterns and one could even think that they might be chaotic. However, semi-quantitative observations made regarding drug psychoses and the effects of psychopharmaceuticals have taught us quite a bit about systemic neurotransmitter interactions. For instance, we have learned that norepinephrine (NE) and acetylcholine (ACh) exert opposing functions on several organs, thereby supporting the basic circadian rhythm. Serotonin (HT) and dopamine (DA) synergistically affect NE, while GABA and glutamate (GLU) seem to affect ACh in a synergistic manner. Antagonistic actions between these neurotransmitter modules exhibit asymmetries that explain a number of clinical symptoms in several psychiatric disorders.


Building a schizophrenia simulator

With the metaphor of balances in mind, our team of a psychiatrist, two neuroscientists, a computational engineer, and a systems biologist collected and integrated research data from a large domain of anatomy, physiology, biochemistry, and pharmacology with the aim of formalizing these observations in a heuristic, yet rigorous manner. The result is a mathematical model consisting of two modules3,4.

Wiring diagram of 6 neurotransmitter systems 600 x 457

The first captures and quantifies the various interactions among neurotransmitters quasi as a systemic wiring diagram (Figure 1). It permits simulation experiments of mild or strong disturbances in any or all of the neurotransmitters, as well as explorations of different drug treatments. The second module transforms the complex output dynamics of the first module into specific constellations of a mobile which, metaphorically, visualizes the results with a dynamic tilting of its rods (Figure 2).

Neurochemical mobile 484 x 447Tilted rods are intuitive reminders that some chemicals are “out of balance,” whereas a successful treatment is rewarded with regaining balance. Perturbations and treatments—real, experimental, or speculative—are easily explored and visualized. For instance, it can be demonstrated that one of the most effective antipsychotic drugs, clozapine, has a broad spectrum of interference in the different neurochemical transmission systems, and it is possible to explore the efficacy and immediate side effects of “new” atypical antipsychotics like quetiapine.

Intriguingly, the heuristic model naturally unifies the established, but apparently contradictory to the neurotransmitter hypotheses regarding the causes of schizophrenia, as outlined before. It offers an exploratory tool that will become available more widely, once the simulator is equipped with a user-friendly graphical user interface, which is currently under construction.

The simulator is a paradigm of the newly emerging fields of systems biology and systems medicine5. It is the result of reaching beyond traditional disciplinary boundaries, learning to understand each other’s language, injecting, interpreting, and merging complementary expertise, and breaking down the walls and comforts of traditional academic silos.

Here’s a video on the schizophrenia simulator by Georgia Tech:

1. Bender, W., Albus, M., Moller, H.J., and Tretter, F. Towards systemic theories in biological psychiatry. Pharmacopsychiatry, 39 Suppl 1 (2006) S4-9.
2. Qi, Z., Miller, G.W., and Voit, E.O. Mathematical Models in Schizophrenia. Chapter 14 in Volume I of M.S. Ritsner (Ed.): Textbook of Schizophrenia Spectrum Disorders. Springer Verlag, New York, 2011.
3. Qi, Z., Tretter, F., and Voit, E.O. A Heuristic Model of Alcohol Dependence. PLoS One, 9(3): e92221, 2014.
4. Qi, Z., Yu, G., Tretter, F., Pogarell, O., Grace, A.A., and Voit, E.O. A Heuristic Model for Working Memory Deficit in Schizophrenia. Bioch. Biophys. Acta – Systems Genetics 1860, 2696-2705, 2016.
5. Tretter, F., Winterer, G., Gebicke-Haerter, P.J., Mendoza, E.R. (Eds) Systems Biology in Psychiatric Research: From High-Throughput Data to Mathematical Modeling. Wiley, Weinheim 2010.

Eberhard O. Voit, MS, Ph.D, Zhen Qi, MS, Ph.D, and Felix Tretter, Dr. phil, Dr. rer. pol, Dr. med
Eberhard O. Voit (L) received Master’s degrees in biology and mathematics and a Ph.D in developmental and theoretical biology from Cologne University, Germany. He is presently a Professor and Georgia Research Alliance Eminent Scholar in the Department of Biomedical Engineering at Georgia Tech and Emory and holds the David D. Flanagan Chair in Biological Systems. Voit’s research interests are in the area of complex biomedical systems. His newest book on systems biology entitled, The Inner Workings of Life, addresses the educated lay population. Zhen Qi (M) received a BS in physics, MS in geographic information systems, and Ph.D. in bioinformatics. He is currently a research engineer in the department of biomedical engineering at Georgia Institute of Technology, USA. His interests are in the development of computational and statistical methods for inferring information from large-scale biomedical data. A specific focus during the past decade has been a computer-aided systemic understanding of neurological diseases, including Parkinson’s, schizophrenia, and drug addiction. Felix Tretter (R) received doctorate degrees in statistics and psychology (Dr. phil.), sociology, economics, and management (Dr. rer. pol.) and medicine (Dr. med.). He subsequently received specialized training as a neurologist, psychiatrist, and psychotherapist. He held the position of senior physician in the Department for Addiction of a large mental hospital in Munich, Germany, and is presently a Research Fellow at the Bertalanffy Center for the Study of Systems Science in Vienna, Austria. His research interests are in experimental neurobiology and systems psychiatry.


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