Method and apparatus for computer modeling of the interaction between and among cortical and subcortical areas in the human brain for the purpose of predicting the effect of drugs in psychiatric & cognitive diseases

• US 20070106479A1
• Filed: 11/10/2006
• Published: 05/10/2007
• Est. Priority Date: 11/10/2005
• Status: Active Grant

• Current Assignee: Certara, L.P. (Certara, Inc.)
• Original Assignee: In-Silico Sciences Incorporated
• Inventors: Geerts, Hugo, Spiros, Athan
• Granted Patent: US 8,150,629 B2
• Time in Patent Office: Days
• US Class Current: 702/19
• CPC Class Codes: G09B 23/28 for medicine
• CPC Class Codes: G16H 50/50 for simulation or modelling of medical disorders

Abstract

Computer modeling of interactions between and among cortico and subcortical areas of the human brain, for example in a normal and a pathological state resembling schizophrenia which pathological state has inputs representing the effects of a drug(s), for the purpose of using the outputs to predict the effect of drugs in psychiatric and cognitive diseases. A method is provided for developing a computer model of interactions between and among cortico and subcortical areas of the human brain which comprises the steps of identifying data relating to a biological state of a generic synapse model, the striatum, Locus Coeruleus, Dorsal raphe, hippocampus, amygdala and cortex; identifying biological processes related to the data, these identified biological processes defining at least one portion of the biological state of the generic synapse model, the striatum, Locus Coeruleus, Dorsal raphe, hippocampus, amygdala, and cortex; and combining the biological processes to form a simulation of the biological state of interactions between and among cortico and subcortical areas of the human brain. Diseases that can be modeled include psychiatric disorders, such as schizophrenia, bipolar disorder, major depression, ADHD, autism, obsessive-compulsive disorder, substance abuse and cognitive deficits therein and neurological disorders such as Alzheimer'"'"'s disease, Mild Cognitive impairment, Parkinson'"'"'s disease, stroke, vascular dementia, Huntington'"'"'s disease, epilepsy and Down syndrome. A resulting computer model is of the biological state of interactions between and among cortico and subcortical areas of the human brain, comprising code to define the biological processes related to the biological state of the generic synapse model, the striatum, Locus Coeruleus, Dorsal raphe, hippocampus, amygdala and cortex, and code to define the mathematical relationships related to interactions among biological variables associated with the biological processes. At least two of the biological processes are associated with the mathematical relationships. A combination of the code to define the biological processes and the code to define the mathematical relationships define a simulation of the biological state of the interactions between and among cortico and subcortical areas of the human brain. Computer executable software code is provided comprised of code to define biological processes related to a biological state of interactions between and among cortico and subcortical areas of the human brain including code to define mathematical relations associated with the biological processes. A computer model of interactions between and among cortico and subcortical areas of the human brain is provided, comprising a computer-readable memory storing codes and a processor coupled to the computer-readable memory, the processor configured to execute the codes. The memory comprises code to define biological processes related to the biological state of interactions between and among cortico and subcortical areas of the human brain, and code to define mathematical relationships related to interactions among biological variables associated with the biological processes.

Claims

1. A method for developing a computer model of a generic receptor, comprising:

(a)(i) identifying a plurality of biological processes related to a synapse; and

(a)(ii)combining the plurality of biological processes to form a quantitative simulation of the functional concentration of a pharmacological agent in the synapse;

or

(b)(i) identifying a plurality of biological processes related to a region within a brain, the plurality of biological processes including at least one biological process related to neuronal activity; and

(b)(ii) combining the plurality of biological processes to form a simulation of activity of the region.

2. A method for developing a computer model of claim 1, wherein said region of in (b)(i) is selected from the group consisting of striatum;

cortex; and

Locus Coeruleus and Dorsal Raphe; and

Hippocampus and Amygdala or any combination thereof.

3. The method of claim 1 wherein the plurality of biological processes are related to a biological state of a normal or diseased state brain.

4. The method of claim 1, wherein at least one biological process from the plurality of biological processes is associated with a biological variable that is a therapeutic agent.

5. The method of claim 1, further comprising:

selecting a therapeutic agent from a list of cerebro-active drugs, and

associating the selected therapeutic agent with at least one biological process from the plurality of biological processes.

6. The method of claim 3, wherein the diseased state brain is associated with at least one of the conditions including schizophrenia, bipolar disorder, major depression, ADHD, autism obsessive-compulsive disorder, substance abuse, Alzheimer'"'"'s disease, Mild Cognitive impairment, Parkinson'"'"'s disease, stroke, vascular dementia, Huntington'"'"'s disease, epilepsy and Down syndrome.

7. The method of claim 1, further comprising:

producing a simulated biological attribute associated with a biological state of the synapse;

comparing the simulated biological attribute with a corresponding biological attribute associated with a reference activity pattern of the synapse; and

identifying a computer model as a valid computer model of the synapse if the simulated biological attribute is substantially consistent with the biological attribute associated with the reference activity pattern of the synapse.

8. The method of claim 1, further comprising:

producing a simulated biological attribute associated with a biological state of the striatum and cortex;

comparing the simulated biological attribute with a corresponding biological attribute associated with a reference activity pattern of the brain; and

identifying a computer model as a valid computer model of the striatum and cortex if the simulated biological attribute is substantially consistent with the biological attribute associated with the reference activity pattern of the striatum and cortex.

9. The method of claim 1, further comprising

producing a simulated biological attribute of the effect of a list of defined antipsychotics at a defined dose;

comparing the simulated biological attribute with the corresponding clinical attribute associated with the same list of defined antipsychotics at a defined dose; and

identifying a computer model as a valid computer model of the synapse if the simulated biological attributes are substantially correlated with the clinical attributes.

10. A processor-readable medium comprising code representing instructions to cause a processor to:

define a plurality of biological processes related to a biological state of an animal or human striatum, Locus Coeruleus, Dorsal Raphe, Hippocampus, Amygdala and cortex, the plurality of biological processes including at least one of a first set of biological processes related to neurotransmitter dynamics and a second set of biological processes related to neuronal activation; and

define a plurality of mathematical relationships related to interactions among biological variables associated with the plurality of biological processes;

at least two biological processes from the plurality of biological processes being associated with the plurality of mathematical relationships, a combination of the plurality of biological processes and the plurality of mathematical relationships defining a simulation of the biological state of the animal or human striatum, Locus Coeruleus, Dorsal Raphe, Hippocampus, Amygdala or cortex.

11. The processor-readable medium of claim 10, wherein the first set of biological processes includes at least one biological process related to neurotransmitter dynamics.

12. The processor-readable medium of claim 10, wherein at least one biological process from the plurality of biological processes is associated with a biological variable that is a therapeutic agent.

13. The processor-readable medium of claim 10, further comprising code representing instructions to cause the processor to:

select a therapeutic agent from at least one group of cerebro-active drugs; and

associate the selected therapeutic agent with at least one biological process from the plurality of biological processes.

14. The processor-readable medium of claim 10, further comprising code representing instructions to cause the processor to:

define a first compartment, the first compartment including the interactions contained within the animal or human striatum, and

define a second compartment, the second compartment including interactions contained in the animal or human cortex.

define a third compartment, the third compartment including interactions contained in the animal or human Locus Coeruleus and/or Dorsal Raphe, or Hippocampus and/or Amygdala

15. The processor-readable medium of claim 10, further comprising code representing instructions to cause the processor to:

define a fourth set of biological processes related to the interaction of the first compartment with the second and third compartment.

16. The processor-readable medium of claim 10, wherein the biological state is the state of a diseased brain.

17. The processor-readable medium of claim 10, wherein the biological state is the state is the state of a diseased brain afflicted with at least one of the psychiatric diseases including schizophrenia, bipolar disorder, major depression, ADHD, autism, obsessive-compulsive disorder, substance abuse and cognitive deficits therein.

18. The processor-readable medium of claim 10, wherein the biological state is the state is the state of a diseased brain afflicted with at least one of the neurological diseases including Alzheimer'"'"'s disease, Mild Cognitive impairment, Parkinson'"'"'s disease, stroke, vascular dementia, Huntington'"'"'s disease, epilepsy and Down syndrome.

19. The processor-readable medium of claim 10, further comprising code representing instructions to cause the processor to:

define a first set of mathematical relations associated with the first set of biological processes and associated with interactions among biological variables associated with the first set of biological processes;

define a set of mathematical relations associated with the second set of biological processes and associated with interactions among biological variables associated with the second set of biological processes; and

define a set of mathematical relations associated with the third set of biological processes and associated with interactions among biological variables associated with the third set of biological processes.

20. The processor-readable medium of claim 10, further comprising code representing instructions to cause the processor to:

define a fourth set of biological processes related to the interaction of the first compartment with the second and third compartment.

21. A method for developing a computer model of diseased interactions between and among cortical and sub-cortical brain areas, comprising:

receiving a plurality of user-selected therapeutic interventions to modulate a plurality of biological processes, each biological process from the plurality of biological processes being based on data that relates changes in biological states to biological attributes of the diseased cortico-subcortical pathways,

producing a simulated biological attribute associated with at least one biological attribute of the diseased interactions between and among cortical and sub-cortical brain areas based on the combined plurality of biology processes and a user-defined input, and

translating the simulated biological attribute to an effect on a clinical scale with appropriate confidence and prediction intervals, based upon statistical analysis.

22. The method of claim 21, wherein the diseased cortico-subcortical pathway is afflicted with at least one of the psychiatric diseases including schizophrenia, bipolar disorder, major depression, ADHD, autism, obsessive-compulsive disorder, substance abuse and cognitive deficits therein.

23. The method of claim 21, wherein the diseased interactions between and among cortical and sub-cortical brain areas is afflicted with at least one of the neurological diseases including Alzheimer'"'"'s disease, Mild Cognitive impairment, Parkinson'"'"'s disease, stroke, vascular dementia, Huntington'"'"'s disease, epilepsy and Down syndrome.

24. The method of claim 21, further comprising:

providing code to select the therapeutic agent from at least one of cerebro-active therapeutic agents and

providing code to associate the selected therapeutic agent with at least one biological process from the plurality of biological processes.

25. The method of claim 21, wherein the plurality of biological processes include a first set of biological processes related to striatal interaction, a second set of biological processes related to cortical interaction and a third set of biological processes related to the interaction between Locus Coeruleus and/or Dorsal Raphe, Hippocampus and/or Amygdala the computer model further comprising:

providing code to define a first compartment, the first compartment including the first set of biological processes;

providing code to define a second compartment, the second compartment including the second set of biological processes; and

providing code to define a third compartment, the third compartment including the third set of biological processes.

26. The method of claim 21, further comprising:

providing code to define a third set of biological processes related to the interaction of the first compartment with the second and third compartment.

27. The method of claim 21, wherein the biological state is the state of diseased cortico-subcortical pathways, afflicted with at least one of the psychiatric diseases including schizophrenia, bipolar disorder, major depression, ADHD, autism, obsessive-compulsive disorder, substance abuse and cognitive deficits therein.

28. The method of claim 21, wherein the biological state is the state of diseased cortico-subcortical pathways, afflicted with at least one of the neurological diseases including Alzheimer'"'"'s disease, Mild Cognitive impairment, Parkinson'"'"'s disease, stroke, vascular dementia, Huntington'"'"'s disease, epilepsy and Down syndrome.

29. The method of claim 21, wherein upon execution of the computer model for a number of pharmaceutical agents with a specific dose, a simulated biological attribute for the biological state of the diseased interactions between and among cortical and sub-cortical brain areas is produced, the simulated biological attribute being substantially consistent with the effect of that number of pharmaceutical agents at that specific dose in at least one clinical scale currently used for assessing the clinical benefits in that disease, the degree of correlation quantified using regression analysis with the production of a regression equation.

30. The method of claim 21, wherein upon execution of the computer model for a novel pharmaceutical agent with a specific dose, a simulated attribute for the biological state of the diseased interactions between and among cortical and sub-cortical brain areas is produced, and that attribute is to be correlated with a clinical outcome on one of the clinical scales using the regression equation.

31. The method of claim 21, wherein upon execution of the computer model for a novel pharmaceutical agent with a specific dose, a simulated attribute for the biological state of the diseased interactions between and among cortical and sub-cortical brain areas is produced, and that attribute is to be correlated with a clinical outcome on one of the clinical scales using the regression equation and that confidence intervals for that clinical outcome on one of the clinical scales can be determined using the information gathered in the regression equation.

32. The method of claim 21, wherein upon systematic execution of the computer model for a novel pharmaceutical agent in the parameter space of possible pharmacological attributes, an ‘

ideal’

pharmacological attribute is identified, leading to a simulated attribute for the biological state of the diseased interactions between and among cortical and sub-cortical brain areas pathway, and that attribute is to be correlated with the best clinical outcome on one or several of the clinical scales using the regression equations and that confidence intervals for that clinical outcome on one or several of the clinical scales can be determined using the information gathered in the regression equation.

33. The method of claim 21, wherein upon execution of the computer model for a combination of pharmaceutical agents a simulated attribute for the biological state of the diseased cortico-subcortical pathway is produced, and that attribute is to be correlated with the clinical outcome on one or several of the clinical scales using the regression equations and that confidence intervals for that clinical outcome on one or several of the clinical scales can be determined using the information gathered in the regression equation.

34. The method of claim 21, wherein upon execution of the computer model for a combination of pharmaceutical agents or a single pharmaceutical agent, in combination with known circadian profiles of physiological parameters, a simulated attribute for the biological state of the diseased cortico-subcortical pathway over the course of a 24 hr day is produced, and that attribute is to be correlated with the clinical outcome on one or several of the clinical scales using the regression equations and that confidence intervals for that clinical outcome on one or several of the clinical scales can be determined using the information gathered in the regression equation.

35. The method of claim 21, wherein upon execution of the computer model for a combination of pharmaceutical agents or a single pharmaceutical agent, in combination with know functional consequences of certain genotypes, a simulated attribute for the biological state of the diseased interactions between and among cortical and sub-cortical brain areas is produced for a particular genotype, and that attribute is to be correlated with the clinical outcome on one or several of the clinical scales using the regression equations and that confidence intervals for that clinical outcome on one or several of the clinical scales can be determined using the information gathered in the regression equation.

36. The method of claim 21, wherein upon execution of the computer model for a combination of pharmaceutical agents or a single pharmaceutical agent, in combination with sampling from a known probability of physiological parameters and the known plasma variability of the agent(s) under study, a simulated attribute for the biological state of the diseasedinteractions between and among cortical and sub-cortical brain areas for each sample is produced, and that attribute is to be correlated with the clinical outcome on one or several of the clinical scales using the regression equations and that confidence intervals for that clinical outcome on one or several of the clinical scales can be determined using the information gathered in the regression equation.