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 and cognitive diseases

Abstract

Computer modeling of interactions between and among cortico and subcortical areas of the human brain predicts the effect of drugs in psychiatric and cognitive diseases on one or more clinical scales. 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. The computer model preferably uses the biological state of interactions between and among cortico and subcortical areas of the human brain, 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, as well as certain mathematical relationships related to interactions among biological variables associated with the biological processes.

1 . A computer model of a generic receptor, comprising:
 a first plurality of biological processes related to a synapse combined to form a quantitative simulation of the functional concentration of a pharmacological agent in the synapse; and   a second plurality of biological processes related to neuronal activity combined to form a simulation of activity of a brain region.   
     
     
         2 . The computer model of  claim 1 , wherein said brain region 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 computer model of  claim 1  wherein the plurality of biological processes are related to a biological state of a normal or diseased state brain. 
     
     
         4 . The computer model 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 computer model of  claim 1 , further comprising:
 a therapeutic agent selected from a list of cerebro-active drugs,   the selected therapeutic agent is associated with at least one biological process from the plurality of biological processes.   
     
     
         6 . The computer model 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 computer model of  claim 1 , further comprising:
 a simulated biological attribute associated with a biological state of the synapse;   wherein the simulated biological attribute is substantially consistent with a biological attribute associated with a reference activity pattern of the synapse.   
     
     
         8 . The method of  claim 1 , further comprising:
 a simulated biological attribute associated with a biological state of the striatum and cortex;   wherein if the simulated biological attribute is substantially consistent with a biological attribute associated with a reference activity pattern of the striatum and cortex.   
     
     
         9 . The method of  claim 1 , further comprising
 a plurality of simulated biological attributes of the effect of a list of defined antipsychotics at a defined dose;   wherein the simulated biological attributes are substantially correlated with a reference list of clinical attributes.   
     
     
         10 - 20 . (canceled) 
     
     
         21 . A computer model of diseased interactions between and among cortical and sub-cortical brain areas, comprising:
 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,   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   wherein the simulated biological attribute is translated to an effect on a clinical scale with appropriate confidence and prediction intervals, based upon statistical analysis.   
     
     
         22 . The model 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 model 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 model of  claim 21 , further comprising:
 means for selecting the therapeutic agent from at least one of cerebro-active therapeutic agents and   means for associating the selected therapeutic agent with at least one biological process from the plurality of biological processes.   
     
     
         25 - 28 . (canceled) 
     
     
         29 . The model 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 . (canceled) 
     
     
         31 . The model 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 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 are determined using the information gathered in the regression equation. 
     
     
         32 . The model of  claim 31 , 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 model 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. 
     
     
         34 . (canceled) 
     
     
         35 . The model 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 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 . (canceled)