Method For Modifying The Therapeutic Effects Of Drugs Patent Application (2025)

U.S. patent application number 16/473256 was filed with the patent office on 2019-10-31 for method for modifying the therapeutic effects of drugs. This patent application is currently assigned to The Medical Research, Infrastructure and Health Services Fund of the Tel Aviv Medical Center. The applicant listed for this patent is The Medical Research, Infrastructure and Health Services Fund of the Tel Aviv Medical Center. Invention is credited to Talma HENDLER, Gal RAZ, Roy Itzhak SAR-EL.

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METHOD FOR MODIFYING THE THERAPEUTIC EFFECTS OF DRUGS

Abstract

A method for modifying the effect of a drug by application of anactivation protocol, comprising: administering a drug according toa treatment protocol; applying an activation protocol in a timedrelationship to the administering, for differentially activation ofat least one selected brain region; wherein the differentiallyactivation allows the drug to selectively interact with the atleast one selected brain region.

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Claims

1. A method for modifying the effect of a drug by application of anactivation protocol, comprising: administering a drug according toa treatment protocol; applying an activation protocol in a timedrelationship to said administering, for differentially activationof at least one selected brain region; wherein said differentiallyactivation allows said drug to selectively interact with said atleast one selected brain region.

2. (canceled)

3. The method of claim 1, wherein said applying further comprisesapplying an activation protocol before and/or after saidadministering.

4. (canceled)

5. The method of claim 1, further comprising determining a brainactivation profile prior to and/or following said applying.

6. The method of claim 5, further comprising modifying saidactivation protocol according to said determining.

7. The method of claim 6 wherein said modifying comprises modifyingsaid activation protocol to reach desired activation levels of atleast one specific region and/or desired connectivity measures ofat least one neural network by explicit or covertneurofeedback.

8. The method of claim 5, further comprising modifying said drugdosage according to said determining.

9. The method of claim 1, further comprising determining the effectof said drug by measuring at least one clinical parameter value,following said applying.

10. (canceled)

11. The method of claim 9, further comprising modifying saidactivation protocol if said effect of said drug is not a desiredeffect.

12. (canceled)

13. The method of claim 1, wherein said timed relationship isadjusted according to said effect and/or according to saiddrug.

14. (canceled)

15. The method of claim 9, wherein said effect comprises reducingat least one side effect of said drug.

16. The method of claim 1, wherein said drug is methylphenidate andwherein said treatment protocol is used to treat ADHD.

17-19. (canceled)

20. The method of claim 1, wherein said drug is Levodopa andwherein said treatment protocol is used to treat PD.

21-23. (canceled)

24. The method of claim 1, wherein said drug is Haloperidol andwherein said treatment protocol is used to treat Schizophrenia.

25-27. (canceled)

28. The method of claim 1, wherein said applying an activationprotocol comprises performing a neurofeedback protocol.

29. (canceled)

30. The method claim 1, wherein said applying an activationprotocol comprises performing at least one executive function taskand/or at least one control inhibition task and/or at least oneaction planning paradigm.

31-32. (canceled)

33. A method for treating a neurological disease, comprising:administering a drug according to a treatment protocol; applying anactivation protocol in a timed relationship to said administering,for differentially activation of at least one selected brainregion; wherein said differentially activation allows said drug toselectively interact with said at least one selected brainregion.

34. (canceled)

35. The method according to claim 33, wherein said applyingcomprises applying said activation protocol prior to and/or aftersaid administering.

36. The method of claim 33, further comprising determining a brainactivation profile prior to said applying.

37. (canceled)

38. The method of claim 36, further comprising modifying saidactivation protocol according to said determining.

39. The method of claim 36, further comprising modifying said drugdosage according to said determining.

40-80. (canceled)

Description

RELATED APPLICATION

[0001] This application claims the benefit of priority under 35 USC.sctn. 119(e) of U.S. Provisional Patent Application No. 62/439,041filed 25 Dec. 2016, the contents of which are incorporated hereinby reference in their entirety.

FIELD AND BACKGROUND OF THE INVENTION

[0002] The present invention, in some embodiments thereof, relatesto a method for modifying the effect of a drug and, moreparticularly, but not exclusively, to a method for modifying theeffect of psychotropic drugs.

SUMMARY OF THE INVENTION

[0003] Following are some examples of some embodiments of theinvention: [0004] Example 1. A method for modifying the effect of adrug by application of an activation protocol, comprising:

[0005] administering a drug according to a treatment protocol;

[0006] applying an activation protocol in a timed relationship tosaid administering, for selectively activation of at least oneselected brain region;

[0007] wherein said selectively activation allows said drug toselectively interact with said at least one selected brain region.[0008] Example 2. The method of example 1, wherein said applyingfurther comprises applying an activation protocol before saidadministering. [0009] Example 3. The method of example 1, whereinsaid applying further comprises applying an activation protocolafter said administering. [0010] Example 4. The method of any ofthe previous examples, further comprising determining a brainactivation profile prior to said applying. [0011] Example 5. Themethod of any of the previous examples, further comprisingdetermining a brain activation profile following said applying.[0012] Example 6. The method of examples 4 or 5, further comprisingmodifying said activation protocol according to said determining.[0013] Example 7. The method of any one of examples 4 to 6, furthercomprising modifying said drug dosage according to saiddetermining. [0014] Example 8. The method of any of the previousexamples, further comprising determining the effect of said drug bymeasuring at least one clinical parameter value, following saidapplying. [0015] Example 9. The method of example 8, wherein saidclinical parameter is selected from a group comprising skinconductance, heart rate, blood pressure or blood flow, pupildiameter. [0016] Example 10. The method of examples 8 or 9, furthercomprising modifying said activation protocol if said effect ofsaid drug is not a desired effect. [0017] Example 11. The method ofexample 1, wherein said timed relationship is adjusted according tosaid drug. [0018] Example 12. The method of example 5, wherein saidtimed relationship is adjusted according to said effect. [0019]Example 13. The method of example 1, wherein said timedrelationship is at least 5 minutes before or after said applying.[0020] Example 14. The method of example 8, wherein said effectcomprises reducing at least one side effect of said drug. [0021]Example 15. The method of any of the previous examples, whereinsaid drug is methylphenidate and wherein said treatment protocol isused to treat ADHD. [0022] Example 16. The method of example 15,wherein said methylphenidate dosage is in the range of 0.5-30 mg.[0023] Example 17. The method of examples 15 or 16, wherein saidactivation protocol increases the activation level of at least onebrain region selected from the list of: right/left dorsolateralprefrontal cortex ventrolateral prefrontal cortex, parietal lobule.[0024] Example 18. The method of any one of examples 15 to 17,wherein said activation protocol decreases the activation level ofat least one brain region, selected from the list of dorsolateralprefrontal cortex, ventrolateral prefrontal cortex, parietallobule. [0025] Example 19. The method of any one of examples 1 to14, wherein said drug is Levodopa and wherein said treatmentprotocol is used to treat PD. [0026] Example 20. The method ofexample 19, wherein said Levodopa dosage is in the range of 50-6000mg. [0027] Example 21. The method of examples 19 or 20, whereinsaid activation protocol increases the activation level of at leastone brain region, selected from the list of: substantia nigra,caudate nucleus, putamen. [0028] Example 22. The method of examples19 or 20, wherein said activation protocol decreases the activationlevel of at least one brain region, selected from the list of:substantia nigra, caudate nucleus, putamen. [0029] Example 23. Themethod of any one of examples 1 to 14, wherein said drug isHaloperidol and wherein said treatment protocol is used to treatSchizophrenia. [0030] Example 24. The method of example 23, whereinsaid Haloperidol dosage is in the range of 1-10 mg. [0031] Example25. The method of examples 23 or 24, wherein said activationprotocol increases the activation level of at least one brainregion, selected from the list of: dorsolateral prefrontal cortex,dorsomedial prefrontal cortex, ventrolateral prefrontal cortex.[0032] Example 26. The method of examples 23 or 24, wherein saidactivation protocol decreases the activation level of at least onebrain region, selected from the list of: dorsolateral prefrontalcortex, dorsomedial prefrontal cortex, ventrolateral prefrontalcortex. [0033] Example 27. A method for treating a neurologicaldisease, comprising:

[0034] administering a drug according to a treatment protocol;

[0035] applying an activation protocol in a timed relationship tosaid administering, for selectively activation of at least oneselected brain region;

[0036] wherein said selectively activation allows said drug toselectively interact with said at least one selected brain region.[0037] Example 28. The method of example 27, wherein said applyingcomprises applying said activation protocol prior to saidadministering. [0038] Example 29. The method according to example27, wherein said applying comprises applying said activationprotocol after said administering. [0039] Example 30. The method ofany one of examples 27 to 29, further comprising determining abrain activation profile prior to said applying. [0040] Example 31.The method of any one of examples 27 to 30, further comprisingdetermining a brain activation profile following said applying.[0041] Example 32. The method of examples 30 or 31, furthercomprising modifying said activation protocol according to saiddetermining. [0042] Example 33. The method of any one of examples30 to 32, further comprising modifying said drug dosage accordingto said determining. [0043] Example 34. The method of any one ofexamples 27 to 33, further comprising determining the effect ofsaid drug by measuring at least one clinical parameter value,following said applying. [0044] Example 35. The method of example34, wherein said clinical parameter is selected from a groupcomprising skin conductance, heart rate, blood pressure or bloodflow, pupil diameter. [0045] Example 36. The method of examples 34or 35, further comprising modifying said activation protocol ifsaid effect of said drug is not a desired effect. [0046] Example37. The method of any one of examples 27 to 36, wherein said timedrelationship is adjusted according to said drug. [0047] Example 38.The method of any one of examples 34 to 37, wherein said timedrelationship is adjusted according to said effect. [0048] Example39. The method of any one of examples 27 to 38, wherein said timedrelationship is at least 5 minutes before or after said applying.[0049] Example 40. The method of any one of examples 34 to 39,wherein said effect comprises reducing at least one side effect ofsaid drug. [0050] Example 41. The method of any one of example s 27to 40, wherein said drug is methylphenidate and wherein saidneurological disease is ADHD. [0051] Example 42. The method ofexample 41, wherein said methylphenidate dosage is in the range of0.5-30 mg. [0052] Example 43. The method of examples 41 or 42,wherein said activation protocol increases the activation level ofat least one brain region selected from the list of: right/leftdorsolateral prefrontal cortex ventrolateral prefrontal cortex,parietal lobule. [0053] Example 44. The method of examples 41 or42, wherein said activation protocol decreases the activation levelof at least one brain region, selected from the list ofdorsolateral prefrontal cortex, ventrolateral prefrontal cortex,parietal lobule. [0054] Example 45. The method of any one ofexamples 27 to 40, wherein said drug is Levodopa and wherein saidneurological disease is PD. [0055] Example 46. The method ofexample 45, wherein said Levodopa dosage is in the range of 50-6000mg. [0056] Example 47. The method of examples 45 or 46, whereinsaid activation protocol increases the activation level of at leastone brain region, selected from the list of: substantia nigra,caudate nucleus, putamen. [0057] Example 48. The method of examples45 or 46, wherein said activation protocol decreases the activationlevel of at least one brain region, selected from the list of:substantia nigra, caudate nucleus, putamen. [0058] Example 49. Themethod of any one of examples 27 to 40, wherein said drug isHaloperidol and wherein said neurological disease is Schizophrenia.[0059] Example 50. The method of example 49, wherein saidHaloperidol dosage is in the range of 1-10 mg. [0060] Example 51.The method of examples 49 or 50, wherein said activation protocolincreases the activation level of at least one brain region,selected from the list of: dorsolateral prefrontal cortex,dorsomedial prefrontal cortex, ventrolateral prefrontal cortex.[0061] Example 52. The method of examples 49 or 50, wherein saidactivation protocol decreases the activation level of at least onebrain region, selected from the list of: dorsolateral prefrontalcortex, dorsomedial prefrontal cortex, ventrolateral prefrontalcortex. [0062] Example 53. A drug in combination with an activationprotocol for the treatment of a neurological disease. [0063]Example 54. The drug according to example 53, wherein said drug ismethylphenidate and wherein said neurological disease is ADHD.[0064] Example 55. The drug according to example 54, wherein saidactivation protocol is applied at least 1 minute after or prior tothe administration of said methylphenidate. [0065] Example 56. Thedrug according to examples 54 or 55, wherein said activationprotocol duration is at least 2 minutes. [0066] Example 57. Thedrug according to any one of examples 54 to 56, wherein dosage ofsaid methylphenidate is in the range of 0.5-30 mg. [0067] Example58. The drug according to any one of examples 54 to 57, whereinsaid activation protocol increases the activation level of at leastone brain region selected from the list of: right/left dorsolateralprefrontal cortex ventrolateral prefrontal cortex, parietal lobule.[0068] Example 59. The drug according to any one of examples 54 to57, wherein said activation protocol decreases the activation levelof at least one brain region, selected from the list ofdorsolateral prefrontal cortex, ventrolateral prefrontal cortex,parietal lobule. [0069] Example 60. The drug according to example53, wherein said drug is Levodopa and wherein said neurologicaldisease is PD. [0070] Example 61. The drug according to example 60,wherein said activation protocol is applied at least 1 minute afteror prior to the administration of said Levodopa. [0071] Example 62.The drug according to examples 60 or 61, wherein said activationprotocol duration is at least 2 minutes. [0072] Example 63. Thedrug according to any one of examples 60 to 62, wherein saidLevodopa dosage is in the range of 50-6000 mg. [0073] Example 64.The drug according to any one of examples 60 to 63, wherein saidactivation protocol increases the activation level of at least onebrain region, selected from the list of: substantia nigra, caudatenucleus, putamen. [0074] Example 65. The drug according to any oneof examples 60 to 63, wherein said activation protocol decreasesthe activation level of at least one brain region, selected fromthe list of: substantia nigra, caudate nucleus, putamen. [0075]Example 66. The drug according to example 53, wherein said drug isHaloperidol and wherein said neurological disease is Schizophrenia.[0076] Example 67. The drug according to example 66, wherein saidactivation protocol is applied at least 1 minute after or prior tothe administration of said Haloperidol. [0077] Example 68. The drugaccording to examples 66 or 67, wherein said activation protocolduration is at least 2 minutes. [0078] Example 69. The drugaccording to any one of examples 66 to 68, wherein said Haloperidoldosage is in the range of 1-10 mg. [0079] Example 70. The drugaccording to any one of examples 66 to 69, wherein said activationprotocol increases the activation level of at least one brainregion, selected from the list of: dorsolateral prefrontal cortex,dorsomedial prefrontal cortex, ventrolateral prefrontal cortex.[0080] Example 71. The drug according to any one of examples 66 to69, wherein said activation protocol decreases the activation levelof at least one brain region, selected from the list of:dorsolateral prefrontal cortex, dorsomedial prefrontal cortex,ventrolateral prefrontal cortex. [0081] Example 72. The drugaccording to any one of examples 53 to 71, wherein said drug is apsychotropic drug. [0082] Example 73. A method for treating aneurological disease, comprising:

[0083] inhaling hyperbaric gas according to a hyperbaric treatmentprotocol;

[0084] applying an activation protocol in a timed relationship tosaid inhaling, for selectively activation of at least one selectedbrain region;

[0085] wherein said selectively activation allows said hyperbaricgas to selectively interact with said at least one selected brainregion. [0086] Example 74. The method of example 73, wherein saidapplying comprises applying said activation protocol during saidinhaling. [0087] Example 75. The method of examples 73 or 74,wherein said hyperbaric gas comprises oxygen or oxygen compounds.[0088] Example 76. The method of examples 73 or 74, wherein saidhyperbaric gas comprises nitrogen or nitrogen compounds. [0089]Example 77. The method according to anyone of examples 73 to 76,wherein said neurological disease comprises stroke or TBI, andwherein said activation protocol selectively activates at least onedamaged brain region. [0090] Example 78. The method of example 1,wherein said administering further comprises inhaling said drug.[0091] Example 79. The method of example 1, wherein saidadministering further comprises inhaling said drug.

[0092] Following are some additional examples of some embodimentsof the invention: [0093] Example 1. A method for modifying theeffect of a drug by application of an activation protocol,comprising:

[0094] administering a drug according to a treatment protocol;

[0095] applying an activation protocol in a timed relationship tosaid administering, for differentially activation of at least oneselected brain region;

[0096] wherein said differentially activation allows said drug toselectively interact with said at least one selected brain region.[0097] Example 2. The method of example 1, wherein said applyingfurther comprises applying an activation protocol before saidadministering. [0098] Example 3. The method of example 1, whereinsaid applying further comprises applying an activation protocolafter said administering. [0099] Example 4. The method of any ofthe previous examples, further comprising determining a brainactivation profile prior to said applying. [0100] Example 5. Themethod of any of the previous examples, further comprisingdetermining a brain activation profile following said applying.[0101] Example 6. The method of examples 4 or 5, further comprisingmodifying said activation protocol according to said determining.[0102] Example 7. The method of example 6 wherein said modifyingcomprises modifying said activation protocol to reach desiredactivation levels of at least one specific region and/or desiredconnectivity measures of at least one neural network by explicit orcovert neurofeedback. [0103] Example 8. The method of any one ofexamples 4 to 7, further comprising modifying said drug dosageaccording to said determining. [0104] Example 9. The method of anyof the previous examples, further comprising determining the effectof said drug by measuring at least one clinical parameter value,following said applying. [0105] Example 10. The method of example9, wherein said clinical parameter is selected from a groupcomprising skin conductance, heart rate, blood pressure or bloodflow, pupil diameter. [0106] Example 11. The method of examples 9or 10, further comprising modifying said activation protocol ifsaid effect of said drug is not a desired effect. [0107] Example12. The method of example 1, wherein said timed relationship isadjusted according to said drug. [0108] Example 13. The method ofexample 5, wherein said timed relationship is adjusted according tosaid effect. [0109] Example 14. The method of example 1, whereinsaid timed relationship is at least 5 minutes before or after saidapplying. [0110] Example 15. The method of example 9, wherein saideffect comprises reducing at least one side effect of said drug.[0111] Example 16. The method of any of the previous examples,wherein said drug is methylphenidate and wherein said treatmentprotocol is used to treat ADHD. [0112] Example 17. The method ofexample 16, wherein said methylphenidate dosage is in the range of0.5-30 mg. [0113] Example 18. The method of examples 16 or 17,wherein said activation protocol increases the activation level ofat least one brain region selected from the list of: right/leftdorsolateral prefrontal cortex ventrolateral prefrontal cortex,parietal lobule, striatum. [0114] Example 19. The method of any oneof examples 16 to 18, wherein said activation protocol decreasesthe activation level of at least one brain region, selected fromthe list of dorsolateral prefrontal cortex, ventrolateralprefrontal cortex, parietal lobule. [0115] Example 20. The methodof any one of examples 1 to 15, wherein said drug is Levodopa andwherein said treatment protocol is used to treat PD. [0116] Example21. The method of example 20, wherein said Levodopa dosage is inthe range of 50-6000 mg. [0117] Example 22. The method of examples20 or 21, wherein said activation protocol increases the activationlevel of at least one brain region, selected from the list of:substantia nigra, caudate nucleus, putamen. [0118] Example 23. Themethod of examples 20 or 21, wherein said activation protocoldecreases the activation level of at least one brain region,selected from the list of: substantia nigra, caudate nucleus,putamen. [0119] Example 24. The method of any one of examples 1 to15, wherein said drug is Haloperidol and wherein said treatmentprotocol is used to treat Schizophrenia. [0120] Example 25. Themethod of example 24, wherein said Haloperidol dosage is in therange of 1-10 mg. [0121] Example 26. The method of examples 24 or25, wherein said activation protocol increases the activation levelof at least one brain region, selected from the list of:dorsolateral prefrontal cortex, dorsomedial prefrontal cortex,ventrolateral prefrontal cortex, striatum. [0122] Example 27. Themethod of examples 24 or 25, wherein said activation protocoldecreases the activation level of at least one brain region,selected from the list of: dorsolateral prefrontal cortex,dorsomedial prefrontal cortex, ventrolateral prefrontal cortex,striatum. [0123] Example 28. The method of any one of the previousexamples, wherein said applying an activation protocol comprisesperforming a neurofeedback protocol. [0124] Example 29. The methodof any one of the previous examples, wherein said activationprotocol comprises a physical and/or a cognitive task. [0125]Example 30. The method of any one of the previous examples, whereinsaid applying an activation protocol comprises performing at leastone executive function task and/or at least one control inhibitiontask and/or at least one action planning paradigm. [0126] Example31. The method of any one of the previous examples, wherein saidapplying an activation protocol comprises performing at least onememory task and/or an interactive game. [0127] Example 32. Themethod of any one of the previous examples, wherein said applyingan activation protocol comprises applying said activation protocolusing virtual reality. [0128] Example 33. A method for treating aneurological disease, comprising:

[0129] administering a drug according to a treatment protocol;

[0130] applying an activation protocol in a timed relationship tosaid administering, for differentially activation of at least oneselected brain region;

[0131] wherein said differentially activation allows said drug toselectively interact with said at least one selected brain region.[0132] Example 34. The method of example 33, wherein said applyingcomprises applying said activation protocol prior to saidadministering. [0133] Example 35. The method according to example33, wherein said applying comprises applying said activationprotocol after said administering. [0134] Example 36. The method ofany one of examples 33 to 35, further comprising determining abrain activation profile prior to said applying. [0135] Example 37.The method of any one of examples 33 to 36, further comprisingdetermining a brain activation profile following said applying.[0136] Example 38. The method of examples 36 or 37, furthercomprising modifying said activation protocol according to saiddetermining. [0137] Example 39. The method of any one of examples36 to 38, further comprising modifying said drug dosage accordingto said determining. [0138] Example 40. The method of any one ofexamples 33 to 39, further comprising determining the effect ofsaid drug by measuring at least one clinical parameter value,following said applying. [0139] Example 41. The method of example40, wherein said clinical parameter is selected from a groupcomprising skin conductance, heart rate, blood pressure or bloodflow, pupil diameter. [0140] Example 42. The method of examples 40or 41, further comprising modifying said activation protocol ifsaid effect of said drug is not a desired effect. [0141] Example43. The method of any one of examples 33 to 42, wherein said timedrelationship is adjusted according to said drug. [0142] Example 44.The method of any one of examples 40 to 43, wherein said timedrelationship is adjusted according to said effect. [0143] Example45. The method of any one of examples 33 to 44, wherein said timedrelationship is at least 5 minutes before or after said applying.[0144] Example 46. The method of any one of examples 40 to 45,wherein said effect comprises reducing at least one side effect ofsaid drug. [0145] Example 47. The method of any one of examples 33to 46, wherein said drug is methylphenidate and wherein saidneurological disease is ADHD. [0146] Example 48. The method ofexample 47, wherein said methylphenidate dosage is in the range of0.5-30 mg. [0147] Example 49. The method of examples 47 or 48,wherein said activation protocol increases the activation level ofat least one brain region selected from the list of: right/leftdorsolateral prefrontal cortex ventrolateral prefrontal cortex,parietal lobule. [0148] Example 50. The method of examples 47 or48, wherein said activation protocol decreases the activation levelof at least one brain region, selected from the list ofdorsolateral prefrontal cortex, ventrolateral prefrontal cortex,parietal lobule. [0149] Example 51. The method of any one ofexamples 33 to 46, wherein said drug is Levodopa and wherein saidneurological disease is PD. [0150] Example 52. The method ofexample 51, wherein said Levodopa dosage is in the range of 50-6000mg. [0151] Example 53. The method of examples 51 or 52, whereinsaid activation protocol increases the activation level of at leastone brain region, selected from the list of: substantia nigra,caudate nucleus, putamen. [0152] Example 54. The method of examples51 or 52, wherein said activation protocol decreases the activationlevel of at least one brain region, selected from the list of:substantia nigra, caudate nucleus, putamen. [0153] Example 55. Themethod of any one of examples 33 to 46, wherein said drug isHaloperidol and wherein said neurological disease is Schizophrenia.[0154] Example 56. The method of example 55, wherein saidHaloperidol dosage is in the range of 1-10 mg. [0155] Example 57.The method of examples 55 or 56, wherein said activation protocolincreases the activation level of at least one brain region,selected from the list of: dorsolateral prefrontal cortex,dorsomedial prefrontal cortex, ventrolateral prefrontal cortex.[0156] Example 58. The method of examples 55 or 56, wherein saidactivation protocol decreases the activation level of at least onebrain region, selected from the list of: dorsolateral prefrontalcortex, dorsomedial prefrontal cortex, ventrolateral prefrontalcortex. [0157] Example 59. A drug for use in the treatment of aneurological disease, wherein said drug is administered in a timedrelationship to application of an activation protocol fordifferentially activation of at least one selected brain region.[0158] Example 60. The drug according to example 59, wherein saiddrug is Venlafaxine or Tiagabine and said neurological disease isADHD; or wherein said drug is Citalopram and said neurologicaldisease is PTSD; or wherein said drug is selected from a list ofClomipramine, Tiagabine, Bupropion and Methylphenidate and saidneurological disease is PTSD; or wherein said drug is selected froma list of Citalopram, Sertraline, Clomipramine and Venlafaxine andsaid neurological disease is OCD; or wherein said drug is selectedfrom a list of Fluoxetine, Trazodone, N-arachidonoylaminophenol,and Risperadal and said neurological disease is Schizophrenia; orwherein said drug is selected from a list of Bupropion,Methylphenidate, and Venlafaxine and said neurological disease isSocial anxiety; or wherein said drug is selected from a list ofMilnacipran, Cannabis, Nabilone and Bupropion and said neurologicaldisease is Chronic pain; or wherein said drug is selected from alist of Bupropion, Fluoxetine, Venlafaxine and Methylphenidate andsaid neurological disease is Addiction; or wherein said drug isAmphetamine and said neurological disease is Narcolepsy; or whereinsaid drug is Roboxetine and said neurological disease is Mildcognitive impairment; or wherein said drug is selected from a listof Methylphenidate, Ketamine, Bupropion, and Venlafaxine and saidneurological disease is Depression; or wherein said drug isApomorphine or Levodopa and said neurological disease is Movementdisturbances; or wherein said drug is Valproic acid or Ibuprofenand said neurological disease is Epilepsy. [0159] Example 61. Thedrug according to example 59, wherein said drug is methylphenidateand wherein said neurological disease is ADHD. [0160] Example 62.The drug according to example 61, wherein said activation protocolis applied at least 1 minute after or prior to the administrationof said methylphenidate. [0161] Example 63. The drug according toexamples 61 or 62, wherein said activation protocol duration is atleast 2 minutes. [0162] Example 64. The drug according to any oneof examples 61 to 63, wherein dosage of said methylphenidate is inthe range of 0.5-30 mg. [0163] Example 65. The drug according toany one of examples 61 to 64, wherein said activation protocolincreases the activation level of at least one brain regionselected from the list of: right/left dorsolateral prefrontalcortex ventrolateral prefrontal cortex, parietal lobule. [0164]Example 66. The drug according to any one of examples 61 to 64,wherein said activation protocol decreases the activation level ofat least one brain region, selected from the list of dorsolateralprefrontal cortex, ventrolateral prefrontal cortex, parietallobule. [0165] Example 67. The drug according to example 59,wherein said drug is Levodopa and wherein said neurological diseaseis PD. [0166] Example 68. The drug according to example 67, whereinsaid activation protocol is applied at least 1 minute after orprior to the administration of said Levodopa. [0167] Example 69.The drug according to examples 67 or 68, wherein said activationprotocol duration is at least 2 minutes. [0168] Example 70. Thedrug according to any one of examples 67 to 69, wherein saidLevodopa dosage is in the range of 50-6000 mg. [0169] Example 71.The drug according to any one of examples 67 to 70, wherein saidactivation protocol increases the activation level of at least onebrain region, selected from the list of: substantia nigra, caudatenucleus, putamen. [0170] Example 72. The drug according to any oneof examples 67 to 70, wherein said activation protocol decreasesthe activation level of at least one brain region, selected fromthe list of: substantia nigra, caudate nucleus, putamen. [0171]Example 73. The drug according to example 59, wherein said drug isHaloperidol and wherein said neurological disease is Schizophrenia.[0172] Example 74. The drug according to example 73, wherein saidactivation protocol is applied at least 1 minute after or prior tothe administration of said Haloperidol. [0173] Example 75. The drugaccording to examples 73 or 74, wherein said activation protocolduration is at least 2 minutes. [0174] Example 76. The drugaccording to any one of examples 73 to 75, wherein said Haloperidoldosage is in the range of 1-10 mg. [0175] Example 77. The drugaccording to any one of examples 73 to 76, wherein said activationprotocol increases the activation level of at least one brainregion, selected from the list of: dorsolateral prefrontal cortex,dorsomedial prefrontal cortex, ventrolateral prefrontal cortex.[0176] Example 78. The drug according to any one of examples 73 to76, wherein said activation protocol decreases the activation levelof at least one brain region, selected from the list of:dorsolateral prefrontal cortex, dorsomedial prefrontal cortex,ventrolateral prefrontal cortex. [0177] Example 79. The drugaccording to any one of examples 59 to 78, wherein said drug is apsychotropic drug. [0178] Example 80. A device for delivery of anactivation protocol, comprising:

[0179] a memory, wherein said memory stores indications related toat least one drug and at least one activation protocol;

[0180] an interface configured to deliver at least one humandetectable indication and said activation protocol;

[0181] a control circuitry, wherein said control circuitry signalssaid interface to deliver said at least one human detectableindication and said activation protocol based on said indicationsstored in said memory.

[0182] Unless otherwise defined, all technical and/or scientificterms used herein have the same meaning as commonly understood byone of ordinary skill in the art to which the invention pertains.Although methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing ofembodiments of the invention, exemplary methods and/or materialsare described below. In case of conflict, the patent specification,including definitions, will control. In addition, the materials,methods, and examples are illustrative only and are not intended tobe necessarily limiting.

[0183] As will be appreciated by one skilled in the art, someembodiments of the present invention may be embodied as a system,method or computer program product.

[0184] Accordingly, some embodiments of the present invention maytake the form of an entirely hardware embodiment, an entirelysoftware embodiment (including firmware, resident software,micro-code, etc.) or an embodiment combining software and hardwareaspects that may all generally be referred to herein as a"circuit," "module" or "system." Furthermore, some embodiments ofthe present invention may take the form of a computer programproduct embodied in one or more computer readable medium(s) havingcomputer readable program code embodied thereon. Implementation ofthe method and/or system of some embodiments of the invention caninvolve performing and/or completing selected tasks manually,automatically, or a combination thereof. Moreover, according toactual instrumentation and equipment of some embodiments of themethod and/or system of the invention, several selected tasks couldbe implemented by hardware, by software or by firmware and/or by acombination thereof, e.g., using an operating system.

[0185] For example, hardware for performing selected tasksaccording to some embodiments of the invention could be implementedas a chip or a circuit. As software, selected tasks according tosome embodiments of the invention could be implemented as aplurality of software instructions being executed by a computerusing any suitable operating system. In an exemplary embodiment ofthe invention, one or more tasks according to some exemplaryembodiments of method and/or system as described herein areperformed by a data processor, such as a computing platform forexecuting a plurality of instructions. Optionally, the dataprocessor includes a volatile memory for storing instructionsand/or data and/or a non-volatile storage, for example, a magnetichard-disk and/or removable media, for storing instructions and/ordata. Optionally, a network connection is provided as well. Adisplay and/or a user input device such as a keyboard or mouse areoptionally provided as well.

[0186] Any combination of one or more computer readable medium(s)may be utilized for some embodiments of the invention. The computerreadable medium may be a computer readable signal medium or acomputer readable storage medium. A computer readable storagemedium may be, for example, but not limited to, an electronic,magnetic, optical, electromagnetic, infrared, or semiconductorsystem, apparatus, or device, or any suitable combination of theforegoing. More specific examples (a non-exhaustive list) of thecomputer readable storage medium would include the following: anelectrical connection having one or more wires, a portable computerdiskette, a hard disk, a random access memory (RAM), a read-onlymemory (ROM), an erasable programmable read-only memory (EPROM orFlash memory), an optical fiber, a portable compact disc read-onlymemory (CD-ROM), an optical storage device, a magnetic storagedevice, or any suitable combination of the foregoing. In thecontext of this document, a computer readable storage medium may beany tangible medium that can contain, or store a program for use byor in connection with an instruction execution system, apparatus,or device.

[0187] A computer readable signal medium may include a propagateddata signal with computer readable program code embodied therein,for example, in baseband or as part of a carrier wave.

[0188] Such a propagated signal may take any of a variety of forms,including, but not limited to, electro-magnetic, optical, or anysuitable combination thereof. A computer readable signal medium maybe any computer readable medium that is not a computer readablestorage medium and that can communicate, propagate, or transport aprogram for use by or in connection with an instruction executionsystem, apparatus, or device.

[0189] Program code embodied on a computer readable medium and/ordata used thereby may be transmitted using any appropriate medium,including but not limited to wireless, wireline, optical fibercable, RF, etc., or any suitable combination of the foregoing.

[0190] Computer program code for carrying out operations for someembodiments of the present invention may be written in anycombination of one or more programming languages, including anobject oriented programming language such as Java, Smalltalk, C++or the like and conventional procedural programming languages, suchas the "C" programming language or similar programming languages.The program code may execute entirely on the user's computer,partly on the user's computer, as a stand-alone software package,partly on the user's computer and partly on a remote computer orentirely on the remote computer or server. In the latter scenario,the remote computer may be connected to the user's computer throughany type of network, including a local area network (LAN) or a widearea network (WAN), or the connection may be made to an externalcomputer (for example, through the Internet using an InternetService Provider).

[0191] Some embodiments of the present invention may be describedbelow with reference to flowchart illustrations and/or blockdiagrams of methods, apparatus (systems) and computer programproducts according to embodiments of the invention. It will beunderstood that each block of the flowchart illustrations and/orblock diagrams, and combinations of blocks in the flowchartillustrations and/or block diagrams, can be implemented by computerprogram instructions. These computer program instructions may beprovided to a processor of a general purpose computer, specialpurpose computer, or other programmable data processing apparatusto produce a machine, such that the instructions, which execute viathe processor of the computer or other programmable data processingapparatus, create means for implementing the functions/actsspecified in the flowchart and/or block diagram block orblocks.

[0192] These computer program instructions may also be stored in acomputer readable medium that can direct a computer, otherprogrammable data processing apparatus, or other devices tofunction in a particular manner, such that the instructions storedin the computer readable medium produce an article of manufactureincluding instructions which implement the function/act specifiedin the flowchart and/or block diagram block or blocks.

[0193] The computer program instructions may also be loaded onto acomputer, other programmable data processing apparatus, or otherdevices to cause a series of operational steps to be performed onthe computer, other programmable apparatus or other devices toproduce a computer implemented process such that the instructionswhich execute on the computer or other programmable apparatusprovide processes for implementing the functions/acts specified inthe flowchart and/or block diagram block or blocks.

[0194] Some of the methods described herein are generally designedonly for use by a computer, and may not be feasible or practicalfor performing purely manually, by a human expert. A human expertwho wanted to manually perform similar tasks, such as activation ofbrain regions, might be expected to use completely differentmethods, e.g., making use of expert knowledge and/or the patternrecognition capabilities of the human brain, which would be vastlymore efficient than manually going through the steps of the methodsdescribed herein.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0195] Some embodiments of the invention are herein described, byway of example only, with reference to the accompanying drawings.With specific reference now to the drawings in detail, it isstressed that the particulars shown are by way of example and forpurposes of illustrative discussion of embodiments of theinvention. In this regard, the description taken with the drawingsmakes apparent to those skilled in the art how embodiments of theinvention may be practiced.

[0196] In the drawings:

[0197] Table A is a table depicting examples of the conditions(clinical diagnosis), mental indications, candidate brain targets,drugs/compounds, pathological subclasses of the drugs/compounds,biochemical subclasses of the drugs/compounds, mechanism of eachdrug/compound, range of daily dosage for each drug/compound inmilligram, of the drug and mechanisms, according to someembodiments of the invention;

[0198] FIG. 1A is a block diagram depicting the main components ofa system for enhancement of drug effect, according to someembodiments of the invention;

[0199] FIG. 1B is a general flow chart depicting a process for drugeffect enhancement, according to some embodiments of theinvention;

[0200] FIG. 2 is a block diagram depicting the relation between adrug, an activation protocol and a brain activation profile,according to some embodiments of the invention;

[0201] FIG. 3A is a general flow chart depicting a process forusing a device for applying an activation protocol, according tosome embodiments of the invention;

[0202] FIGS. 3B-3G are graphs depicting the pharmacokinetics andpharmacodynamics of a drug following an activation protocol,according to some embodiments of the invention;

[0203] FIG. 3H is a flow chart depicting a process for applicationof an activation protocol using neurofeedback and/or virtualreality techniques, according to some embodiments of theinvention;

[0204] FIG. 4 is a flow chart depicting a process for matching anactivation treatment to a desired activation profile, according tosome embodiments of the invention;

[0205] FIGS. 5A-5C are flow charts depicting a detailed process forusing a device for application of an activation protocol, accordingto some embodiments of the invention;

[0206] FIGS. 5D-5E are block diagrams depicting the components of adevice for drug effect enhancement, according to some embodimentsof the invention;

[0207] FIG. 5F is an illustration depicting a system forenhancement of drug effect, according to some embodiments of theinvention;

[0208] FIGS. 6A-6D describe the design and the results of avalidation experiment when comparing the coupling of a cognitivetask with a drug or with a placebo, according to some embodimentsof the invention;

[0209] FIGS. 7A-7B describe the design and the results of avalidation experiment, comparing the coupling of a cognitive taskwith a varying dose of a drug, according to some embodiments of theinvention; and

[0210] FIGS. 8A-8H describe the results of a validation experimentfor measuring neurobehavioral effects of Methylphenidate and rightinferior frontal gyms neurofeedback activation combined treatmentfor ADHD, according to some embodiments of the invention.

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

[0211] The present invention, in some embodiments thereof, relatesto a method for modifying the effect of a drug and, moreparticularly, but not exclusively, to a method for modifying theeffect of psychotropic drugs.

[0212] An aspect of some embodiments relates to modifying theeffect of a drug by affecting at least one brain region. In someembodiments, the brain region is affected before and/or after theadministration of the drug, for example using an activationprotocol. In some embodiments, the activation protocol affectingthe at least one brain region increases the therapeutic effect ofthe drug, for example by modulating the availability of drugmolecules in the at least one brain region and/or in other brainregions. Alternatively, the activation protocol affecting the atleast one brain region decreases the therapeutic effect of thedrug, for example, by reducing the availability of drug moleculesin at least one brain region and/or in other brain regions.Optionally, the activation protocol activates at least one brainregion before or after the administration of a drug for example toreduce at least one side effect of the drug.

[0213] In some embodiments, an activation protocol is a physicaland/or a cognitive task, which is not chemically induced. In someembodiments, application of an activation protocol selectivelyaffects at least one selected brain region, optionally byincreasing or reducing the activity of neurons or other neural celltypes such as glia cells in that region. In some embodiments,increasing the activity of cells in a selected region leads to anincrease in blood flow to this region. In some embodiments, byincreasing the blood flow to a selected brain region, thebioavailability of a drug, for example a psychotropic drug, in thatselected brain region, is also increased. In some embodiments ofthe invention, the drug being used is a psychotropic drug which isa chemical compound that changes brain function and results inalterations in perception and/or mood and/or consciousness.Optionally, activation of a selected brain region reduces at leastone side-effect of the drug, for example by minimizing thebioavailability of the drug in undesirable regions of the brain. Insome embodiments, the activation protocol is determined accordingto a desired activation of at least one brain region or a neuronalnetwork. Alternatively or additionally, the activation protocol isdetermined according to at least one desired effect of the drug.Optionally, the activation protocol is determined according to thepharmacokinetic and/or pharmacodynamics properties of the drug.

[0214] In some embodiments, application of an activation protocolbefore and/or after the administration of the drug allows to, forexample to administer a lower dose of the drug in order to reach adesired effect. Optionally, lowering the drug dosage allows to forexample, to minimize undesired side effects of the drug.Alternatively or additionally, application of an activationprotocol before and/or after the administration of a drug reducesthe time needed to reach a desired effect of the drug.

[0215] In some embodiments, the drug belongs to at least one ofthree drug families, reuptake inhibitors drugs for exampleRitalin.RTM., agonist drugs for example Levodopa or antagonisticdrugs for example Haloperidol. In some embodiments, Ritalin.RTM. isused for treating attention deficit hyperactivity disorder (ADHD),for example by blocking dopamine and norepinephrine transporters.In some embodiments, Levodopa is used for treating Parkinson'sdisease (PD). In some embodiments, Levodopa is converted intoDopamine and replaces the endogenous dopamine molecules in thecentral nervous system (CNS). In some embodiments, Haloperidol isused for the treatment of Schizophrenia, for example, by blockingdopaminergic receptors.

[0216] A method for affecting one or more brain regions, forexample using an activation protocol, is based on an endogenousmechanism which may couple vascular changes withbehaviorally-induced neural responses. These responses maycorrespond to increased cerebral blood flow, and may thus enhancelocal availability of pharmacological agents. In some embodiments,the neurovascular coupling mechanism leads, for example, tofunctional hyperemia. Functional hyperemia may comprise increasingblood supply to regions with neuronal activation. Enhancing theefficacy of a drug is probably achieved by synchronizing thisneurovascular coupling process with the administration of a drugrelated to one of the abovementioned drug families.

[0217] In some embodiments, the method may enhance apharmacological therapeutic effect of a drug and/or diminishing anadverse side effect associated with the drug, for example, in asubject who has been treated with the drug or who is to beadministered with the drug. The method comprises, for example,structured protocols for psychological stimulation, which may betightly timed according to the drug's pharmacokinetic and/orpharmacodynamic characteristics. In some embodiments, the protocolsmay comprise neurofeedback protocols in which the subjectmodulates, for example, the activity level of brain regions ofinterest on the basis of a continuous feedback on the activation ofthe target region. In these cases, the neurofeedback is based, forexample, on functional Magnetic Resonance Imaging (fMRI) and/orfunctional Near-Infrared Spectroscopy (fNIRS), and/orelectroencephalography (EEG; especially scalp EEG fingerprint oflocal activity as measured with higher spatial resolution such asfMRI and intracranial recording). The monitoring of the targetbrain regions may cue drug administration so that the drug fractionin the target brain region will be highest when the blood supply tothe target region culminates.

[0218] The enhancement of a pharmacological therapeutic effect of adrug may refer to the enhancement of at least one measurable orobservable clinical therapeutic parameter (characteristic) of themental and/or physiological state (treated, prevented or enhanced)by the drug. The enhancement may be, for example, in the reductionor elimination or prevention of a disease, symptoms of the disease,and/or side effects of a disease in the subject who has beentreated with said drug or who is to be guided with saidprocedure.

[0219] Optionally or additionally, enhancement may be in apsychophysiological function of non-patients that is improved by acertain drug.

[0220] Without being necessarily bound by theory, the two majorfactors that play a key role in mediating thepharmacologic-functional effects are most probably the cerebralblood volume (CBV) and the cerebral blood flow (CBF). The totalcerebral blood volume (i.e., across the different types of bloodvessels) may be increased in about 20%, following neuralactivation. Additionally, animal, human, and simulation studiesestimated that capillary blood volume increases during functionalstimulation in about 10.5%-17% (e.g., Chen and Pike, 2009; Ciris etal., 2014; Krieger et al., 2012; Stefanovic et al., 2008).

[0221] Functional stimulation may also affect the cerebral bloodflow. The flow-volume power law relationship in humans is estimatedas .DELTA.CBV=.DELTA.CBF0.23 on average, and CBF is increased inabout 47%-60% following high intensity visual and sensorimotorstimulations in humans (Chen and Pike, 2009; Ciris et al.,2014).

[0222] An estimation of the Functional Pharmacological Coupling(FPC) on the momentary influx of the drug from the plasma to thebrain (K.sub.in) can be derived from the Renkin-Crone equation ofcapillary transport (Bickel, 2005; Crone, 1963; Renkin, 1959) undera few assumptions:

K in = F ( 1 - e - PS F ) ( 1 ) ##EQU00001##

[0223] where F is the cerebral blood flow (CBF) velocity, P is thepermeability constant, and S is the capillary surface area. In someembodiments, the influx gain following the FPC will depend onS.sub.o and F.sub.o (the surface area and flow rate beforestimulation) as follows:

.DELTA. K in = F c ( 1 - e - PS 0 F 0 V c F c ) 1 - e - PS 0 F 0 (2 ) ##EQU00002##

[0224] where V.sub.c and F.sub.c are factors of the capillary bloodvolume and blood flow change following functional stimulation,respectively. In some embodiments, with high permeabilityconstants, .DELTA.K.sub.in will approach F.sub.c; i.e., an FPCeffect of 47%-60%.

[0225] It should be noted that this estimation relies on a model,which does not take into account the efflux rate (i.e.,brain-to-plasma flow), tissue binding, local metabolism, andclearance by the interstitial fluid flow. Additional parametersthat may interact with the FPC effect comprise potential change inBBB permeability following activation, and the enhancement ofvesicle formation in the BBB following an increase in the ligandavailability to membrane receptors.

[0226] FPC may be particularly advantageous in cases in which anincrease in drug doses is not linearly translated into higher drugfraction in the target tissue due to "bottlenecks" such asmetabolic processing in the liver. Since the FPC effect takes placein situ (i.e., by redistributing the drug fraction that is alreadyin the brain), it may produce a linear effect in spite of themetabolic bottleneck.

[0227] FPC may decrease adverse effects, for example, by reducingthe local CBF in non-target regions. Therefore the functionalstimuli in the FPC protocol most probably will be designed tofacilitate not only the activation of the target regions, but alsothe deactivation of non-target regions.

[0228] Reference is now being made to Table A listing theconditions (clinical diagnosis), mental indications, candidatebrain targets, drugs/compounds, pathological subclasses of thedrugs/compounds, biochemical subclasses of the drugs/compounds,mechanism of each drug/compound, range of daily dosage for eachdrug/compound in milligram, of the drug and mechanisms, accordingto some embodiments of the invention. In addition, table A includesan example of an activation protocol task for each drug/compound inthe list. In some embodiments, application of the listed activationprotocol for each drug increases the bioavailability of the drug inthe corresponding candidate brain target, as described herein.

[0229] Table A abbreviations: ACC--anterior cingulate cortex,ADHD--Attention deficit hyperactivity disorder, DA--dopamine,dLPFC--dorsolateral prefrontal cortex, dmPFC--dorsomedialprefrontal cortex, IFG--inferior frontal gyrus, NaCC--nucleusaccumbens, OCD--obsessive compulsive disorder, OFC--orbitofrontalcortex, PFC--prefrontal cortex, PTSD--posttraumatic stressdisorder, RAS--reticular activating system, sg--subgenual,SMA--Supplementary motor area, a--anterior, d--dorsal, r--right,m--medial, v--ventral. IR: immediate-release, SR:sustained-release, ER: extended-release, PO: per os.

[0230] According to some embodiments and without being bound bytheory, attention deficit hyperactivity disorder (ADHD) is acondition in which an individual chronically manifests one of thefollowing behaviors: not being able to focus (inattentiveness),being overactive (hyperactivity), or not being able controlbehavior (impulsivity).

[0231] According to some embodiments and without being bound bytheory, post-traumatic stress disorder (PTSD) is a type of anxietydisorder following an extreme emotional and/or physical trauma thatusually involves threat. PTSD symptoms include highly emotional andnegatively episodes during which an individual of relives thetraumatic event, avoidance from elements that are associated withthe traumatic event, hypervigilance, and negative thoughts and moodor feelings.

[0232] According to some embodiments and without being bound bytheory, social anxiety disorder is a condition in which anindividual is persistently afraid and tends to avoid socialsituations in which he or she may be judged by other individuals sothat his or her social functioning is considerably impaired.

[0233] According to some embodiments and without being bound bytheory, obsessive-compulsive disorder (OCD) is a condition ofrepeated feelings, sensations, and thoughts, (obsessions), and anurge to perform repeatedly a behavior regardless of its effect andin a non-adaptive manner (compulsions).

[0234] According to some embodiments and without being bound bytheory, schizophrenia is a condition of impaired distinctionbetween reality and non-reality. Its symptoms includehallucinations, delusions, and intrusive thoughts (positivesymptoms), blunting of affect, apathy, and anhedonia (negativesymptoms).

[0235] According to some embodiments and without being bound bytheory, chronic pain is often defined as any pain lasting more thanthree months. It may follow a physical injury, but in other casesit may have no clear organic source. Chronic pain may beaccompanied with other adverse conditions including sleepdisturbance and chronic fatigue, and mood changes, and decreasedappetite.

[0236] According to some embodiments and without being bound bytheory, addiction is a chronic compulsive need for a substanceaccompanied with a substantial psychological and physiologicaldifficulty to abstain this substance. It is characterized by anincreased tolerance to the substance and physiological symptomsupon withdrawal.

[0237] According to some embodiments and without being bound bytheory, narcolepsy is a neurological disorder characterized byextreme sleepiness and attacks of daytime sleep.

[0238] According to some embodiments and without being bound bytheory, mild cognitive impairment (MCI) involves minor deficits incognitive abilities that do not significantly impact dailyfunctioning. MCI patients may have impairments in memory, language,thinking and executive functions that are higher than normalage-related changes.

[0239] According to some embodiments and without being bound bytheory, depression (major depressive disorder) is a common mooddisorder that may involve a continuous loss of interest in humanactivities, a prolonged sense of sadness, worthless, hopelessnessand emptiness, anhedonia, fatigue or lack of energy,self-isolation, thoughts of death and suicide attempts, aches, andsudden change in appetite.

[0240] According to some embodiments and without being bound bytheory, movement disturbances involve impaired control overmovement that is caused by neural disorder. Movement disturbancesinclude tremor, dystonia (sustained or repetitive musclecontractions), Chorea (rapid, involuntary movement), hypokinesia(reduced amplitude of movements), and rigidity.

[0241] According to some embodiments and without being bound bytheory, epilepsy is a condition of recurrent epileptic seizures,unprovoked by any immediate identified cause. Epileptic seizuresare caused by a sudden abnormal excessive and synchronous neuronaldischarge in the central nervous system. They are accompanied bytransient changes in motor behavior, autonomic function, andconsciousness.

[0242] According to some embodiments, the activation protocol, forexample one or more of the activation protocols described in tableA and/or in other parts of the application, is applied in a timedrelationship, for example before, during and/or after theadministration of a drug, for example one of the drugs listed inTable A. In some embodiments, the activation protocol applicationis initiated at least 1 minute after the administration of a drug,for example 1 minute, 2 minute, 5 minute, 10 minute or anyintermediate, shorter or longer time after the administration of adrug. In some embodiments, the activation protocol application isinitiated up to 1 hour after the administration of a drug, forexample 60 minutes, 50 minutes, 30 minutes after the administrationof the drug or any intermediate, shorter or longer period.

[0243] According to some embodiments, the activation protocol isapplied according to a pharmacokinetic profile and/or apharmacodynamics profile of the drug. In some embodiments, theactivation protocol is applied in a timed relationship to apharmacokinetic profile and/or a pharmacodynamics profile of thedrug. In some embodiments, the application of the activationprotocol initiates or ends when at least 10% of the drug entersinto the brain, for example 10%, 20%, 30%, 40%, 50% or anyintermediate, smaller or larger percentage. Alternatively oradditionally, the application of the activation protocol initiatesor ends at least 5 minutes prior to reaching the maximal effect ofthe drug in a selected brain region, for example the brain regionbeing activated by the activation protocol. In some embodiments,the duration of the application protocol is in a range of 10seconds to 40 minutes, for example, 10 seconds, 30 seconds, 1minute, 5 minute, 10 minute, 20 minute or any intermediate, smalleror larger value.

[0244] According to some embodiments, the activation protocol isapplied for differentially activation of at least one selectedbrain region. In some embodiments, differential activation of atleast one selected brain region refers to a relative increase inthe firing of a population of neurons in the selected brain regioncompared to other brain regions. Alternatively or additionally,differential activation of at least one selected brain regionrefers to an increase of up to 100% in local cerebral blood flow inthe at least one selected brain region compared to other brainregions, for example an increase of 80%, an increase of 70%, anincrease of 60%, an increase of 50% or any intermediate, smaller orlarger increase in cerebral blood flow. Alternatively oradditionally, differential activation of at least one selectedbrain region refers to up to 60% increase in the local blood volumein the selected brain region compared to other brain regions, forexample an increase of 50%, an increase of 40%, an increase of 30%,an increase of 20% or any intermediate, smaller or larger increasein the local blood volume.

[0245] An aspect of some embodiments relates to applying anactivation protocol together with a hyperbaric gas, for example toaffect the uptake of the gas by a brain tissue. In someembodiments, the activation protocol is applied before, during orafter the inhalation of the hyperbaric gas. In some embodiments,the activation protocol is applied before, during or after ahyperbaric medicine treatment session.

[0246] In some embodiments, the application of the activationprotocol increases and/or decreases the uptake of the gas with atleast one brain region. In some embodiments, the hyperbaric gascomprises hyperbaric atmospheric gas, or hyperbaric atmospheric gascompounds.

[0247] In some embodiments, the hyperbaric gas comprises hyperbaricoxygen gas or hyperbaric oxygen gas compounds. In some embodiments,the hyperbaric gas comprises hyperbaric nitrogen gas or hyperbaricnitrogen gas compounds.

[0248] Without being bound by theory, application of activationprotocol to affect at least one brain region increase the flow ofthe gas into at least one brain region or tissue type. Additionallyor alternatively, application of activation protocol directs anangiogenic effect of the hyperbaric gas to the activated brainregion.

[0249] Before explaining at least one embodiment of the inventionin detail, it is to be understood that the invention is notnecessarily limited in its application to the details ofconstruction and the arrangement of the components and/or methodsset forth in the following description and/or illustrated in thedrawings and/or the Examples. The invention is capable of otherembodiments or of being practiced or carried out in variousways.

Exemplary System for Enhancing the Effect of a PsychotropicDrug

[0250] Reference is now made to FIG. 1A depicting the maincomponents of a system for modifying the effect of a psychotropicdrug, according to some embodiments of the invention.

[0251] According to some exemplary embodiments, drug 100, forexample a psychotropic drug acts on specific regions of the brain104 and/or on at least one neuronal network. In some embodiments,drug 100, for example Ritalin.RTM., enhances working memory byoptionally acting on the dorsolateral prefrontal cortex and/or theposterior parietal cortex. Alternatively, drug 100, for exampleLevodopa, acts on the nigrostriatal pathway. In some embodiments,Levodopa is administered in a dosage range of 50-6000 mg.Optionally, drug 100, for example haloperidol, acts on at least oneof the frontal cortical regions of the brain. In some embodiments,Haloperidol is administered in a dosage range of 1-10 mg.Alternatively, drug 100 affects specific sub-populations ofneurons, for example dopaminergic neurons and/or neural cells, forexample glia cells.

[0252] In some embodiments, drug 100 is a reuptake inhibitor (RI)drug, for example Ritalin.RTM. (Methylphenidate) which is used fortreating ADHD. In some embodiments RI drugs act by counteract atarget neurotransmitter by directly competing with it on thebinding to a membrane transporter and blocking. Alternatively, RIdrugs indirectly counteract a target neurotransmitter by binding toallosteric sites. In some embodiments, when using RI drugs, theremoval of the neurotransmitter from the extracellular space isreduced, its availability to the synaptic receptors increases andso is the neurotransmission.

[0253] In some embodiments, drug 100 is an agonist drug, forexample Levodopa which is used for treating Parkinson's disease(PD). In some embodiments, agonist drugs compete with an endogenousligand on binding and activating a receptor for example, Levodopais converted to dopamine in the body and competes with endogenousdopamine on binding and activating dopaminergic receptors.

[0254] In some embodiments, drug 100 is an antagonistic drug, forexample Haloperidol which is used for treating schizophrenia. Insome embodiments, antagonistic drugs block the binding of anendogenous agonist to a receptor, which dampens theagonist-mediated response.

[0255] According to some exemplary embodiments, an activationprotocol 102, for example a neurofeedback treatment increases theactivation of at least one brain region in the brain and/ordecreases the activation of at least one other brain region.Alternatively, activation protocol 102 increases the activation ofat least one sub-population of neurons for example, dopaminergicneurons and/or decreases the activation of at least onesub-population of cells. Optionally, activation protocol 102increases the activity of a selected neural network and/ordecreases the activity of at least one neuronal network.

[0256] According to some exemplary embodiments, drug 100 isdistributed throughout the body, and enters brain 104 through theblood flow. In some embodiments, drug 100 distribution in brain 104is based on the blood supply to different regions of brain 104.

[0257] In some embodiments, controlling the blood supply todifferent brain regions allows, for example, to control thedistribution of drug 100 throughout brain 104. In some embodiments,activation protocol 102 increases the blood supply to the activatedbrain regions and/or neuronal networks. Alternatively oradditionally, activation protocol 102 increases the blood supply toactivated neuronal cells. In some embodiments, increasing the bloodsupply to selective brain regions, leads for example, to anincrease in the concentration of drug 100 in these selective brainregions.

[0258] Optionally, increasing the blood supply to selective brainregions, leads for example, to a decrease in drug 100concentrations in less active brain regions.

[0259] Reference is now made to FIG. 1B, depicting a process forapplication of an activation protocol after administration of adrug, according to some embodiments of the invention.

[0260] According to some exemplary embodiments, a psychotropicdrug, for example drug 100 is administered to treat a neurologicalcondition. In some embodiments, drug 100 enters the brain and isdistributed throughout different brain regions. In someembodiments, drug 100 induces drug effect 101 when drug 100 affectsselected brain regions related to the neurological condition.Additionally, drug 100 is distributed in brain regions that are notrelated to the neurological condition, which may lead for example,to unwanted side effects.

[0261] According to some exemplary embodiments, an activationprotocol 102, for example a cognitive task or a TMS treatment, or atranscranial direct current stimulation (tDCS), or a transcranialalternating current stimulation (tACS) or a direct stimulation isapplied after the administration of drug 100. Alternatively,activation protocol 102 is applied before and/or during theadministration of drug 100. In some embodiments, activationprotocol 102 leads to selective brain activation 105 of at leastone selected brain region. In some embodiments, the selected brainregion is related to the neurological condition. In someembodiments, selective brain activation 105 leads to an increase inblood supply to the activated brain region. In some embodiments,the increase in blood supply to at least one brain region that isrelated to the neurological condition, increase the concentrationof drug 100 in the activated brain region, which leads for example,to an enhanced drug effect 106.

[0262] In some embodiments, selective brain activation 105comprises selective activation of at least one selected brainregion. In some embodiments, selective activation of at least oneselected brain region is determined by blood flow measurements inthis selected region or by neuronal activation measurements, forexample using EEG or functional MRI measurements. In someembodiments, when using EEG to measure neuronal activation in atleast one brain region, the neuronal activation pattern and/or thesynchronization level of neurons in that region is determined.

[0263] In some embodiments, activation protocol 102 is applied toactivate at least one brain region that is not related to theneurological condition, for example to decrease the effect of drug100 in brain regions related to the neurological condition.

[0264] According to some exemplary embodiments, application ofactivation protocol 102 before and/or during and/or afteradministration of drug 100, allows for example, to control theeffect of drug 100 by affecting the distribution of drug 100throughout selective brain regions. In some embodiments,application of activation protocol 102, allows to, for example toreduce the dosage of drug 100 that is required to reach a desireddrug effect.

[0265] According to some exemplary embodiments, the drug 100 is MPHand the activation protocol 102 is selected to increase and/ordecrease the activation of at least one brain region selected froma list of right/left dorsolateral prefrontal cortex ventrolateralprefrontal cortex, parietal lobule, and/or striatum.

[0266] According to some exemplary embodiments, the drug 100 isHaloperidol and the activation protocol 102 is selected to increaseand/or decrease at least one brain region selected from a list ofdorsolateral prefrontal cortex, dorsomedial prefrontal cortex,ventrolateral prefrontal cortex, striatum.

Exemplary Activation Protocols

[0267] According to some exemplary embodiments, activation protocol102 is selected to match drug 100, for example Ritalin.RTM. orLevodopa. Alternatively or additionally, the activation protocol102 is selected according to drug 100 dosage. Optionally, theactivation protocol is selected according to pharmacokineticsand/or pharmacodynamics of drug 100, for example according to thepenetration rate of the drug through the BBB and/or according tothe clearance rate of the drug from the blood.

[0268] In some embodiments, activation protocol 102 is selectedaccording to the activation mechanism of drug 100 and/or accordingto the distribution of drug 100 in neural tissue. Alternatively oradditionally, activation protocol 102 is selected according to theadministration regime of the drug.

[0269] According to some embodiments, the activation protocolcomprises application of at least one cognitive task, for example,viewing of dynamic emotional content (e.g., movies, music, andvirtual reality) to optionally direct drugs to the amygdala.

[0270] Alternatively or additionally, the activation protocolcomprises performing at least one executive function and/or controlinhibition tasks (e.g., go-no go, N-back), for example to directthe drug to dorsolateral and/or ventrolateral prefrontal regions.In some embodiments, the activation protocol comprises performingat least one action planning paradigm, for example to direct drugsto the dorsal anterior cingulate cortex.

[0271] Alternatively or additionally, the activation protocolcomprises performing at least one interactive game optionally withrisk and/or punishment and/or reward, for example to direct thedrug to the nucleus accumbens. In some embodiments, the activationprotocol comprises performing at least one memory task, for exampleto direct the drug to the hippocampus.

[0272] According to some exemplary embodiments, the activationprotocol comprises application of at least one physical task forexample game-like scenario in virtual reality using treadmills orhaptic devices, and motion capturing equipment to enhance thedelivery of drugs such as Levodopa (L-DOPA) optionally across thenigrostriatal stream. In some embodiments, the cognitive and/orphysical task is performed only once before or after theadministration of the drug. Alternatively, the cognitive task isrepeated at least 2 times before or after the administration of thedrug.

[0273] According to some embodiments, when drug 100 comprisesRitalin.RTM., activation protocol 102 includes visualizing at leastone directed movement scenario, for example in a virtual-realityenvironment and/or using a handheld device. In some embodiments, inthis scenario, the subject will is prompted to perform at least onemotoric activity. In some embodiments, the activation protocol 102for Levodopa lasts for 1-60 minutes, and optionally is be applied1-30 minutes or 30-60 minutes after the administration of Levodopa.In some embodiments, the abovementioned activation protocol directsLevodopa to striatal locations in the brain, for example thecaudate nucleus.

[0274] According to some embodiments, when drug 100 comprisesRitalin.RTM., activation protocol 102 includes performing at leastone task related to sustained attention and/or working memoryand/or at least one arithmetic challenge, for example using ahandheld device. In some embodiments, these tasks comprise N-backtasks, visual puzzles, and span tasks. In some embodiments, theactivation protocol 102 for Ritalin.RTM. lasts for 1-60 minutes,for example 30-45 minutes. In some embodiments, the activationprotocol is applied 1-80 minutes, for example 5-30 minutes or 30-60minutes after administration of Ritalin.RTM.. Alternatively, theactivation protocol is applied 1-10 minutes before Ritalin.RTM.administration. In some embodiments, application of activationprotocol 102 directs Ritalin.RTM. to the inferior frontal gyrusand/or the dorsolateral prefrontal cortex and/or the parietallobule.

[0275] According to some exemplary embodiments, the activationprotocol is applied before or after administration of 0.5-30 mg ofRitalin.RTM..

[0276] According to some embodiments, when drug 100 comprisesHaloperidol, activation protocol 102 includes performing at leastone task related to working memory, arithmetic challenges forexample N-back tasks, visual puzzles and/or span tasks. Optionally,the activation protocol 102 comprises visualizing self-relatedand/or empathy-eliciting content, for example using a handhelddevice. In some embodiments, the activation protocol 102 forHaloperidol lasts for 1-60 minutes, for example 30-45 minutes. Insome embodiments, the activation protocol is applied 1-80 minutes,for example 5-30 minutes or 30-60 minutes after administration ofHaloperidol. In some embodiments, application of activationprotocol 102 directs Haloperidol to at least one prefrontal regionof the brain.

Exemplary Activation Profile of a Drug

[0277] According to some exemplary embodiments, a drug isadministered for a treatment of a neurological condition. In someembodiments, a desired activation profile of the drug includesactivation of at least one selected brain region and/or a sub-classof neuronal cells located in the selected brain region. In someembodiments, the selected brain region and/or the sub-class ofneuronal cells are related to the neurological condition.Optionally, the selected brain region and/or the sub-class ofneuronal cells are related to at least one symptom of theneurological condition. In some embodiments, a desired activationprofile of the drug includes reducing the effect of the drug in atleast one selected brain region and/or in at least onesub-population of neuronal cells located in this brain region.

[0278] Reference is now made to FIG. 2 depicting an activationprofile of a drug based on activation of at least one selectivebrain region, according to some embodiments of the invention.

[0279] According to some exemplary embodiments, an activationprotocol 206 is applied after the administration of drug 200. Insome embodiments, application of activation protocol 206 leads to,for example an increased activation of brain regions 216 and 218.Optionally, application of activation protocol 206 leads to, forexample, a decreased activation of brain regions 220 and 222. Insome embodiments, the blood supply to brain regions 216 and 218 isincreased following the activation. In some embodiments, the bloodsupply to brain regions 220 and 222 is decreased following theactivation

[0280] In some embodiments, drug molecules 219 travel in the bloodstream and concentrate in or at the vicinity of activated brainregions, for example brain regions 216 and 218. In someembodiments, the concentration of drug molecules 219 is reduced inor at the vicinity of regions where blood supply is decreased, forexample brain regions 220 and 222.

[0281] In some embodiments, the brain regions that are affectedfrom the activation protocol are selected from a list ofventrolateral prefrontal cortex, parietal lobule, substantia nigra,caudate nucleus, putamen, dorsomedial prefrontal cortex,dorsolateral prefrontal cortex,

[0282] According to some exemplary embodiments, each drug, forexample psychotropic drug, has its own desired activation profile.In some embodiments, the desired activation profile of a drug isdetermined by its composition, and/or dosage and/or structureand/or pharmacokinetic properties. In some embodiments, a desiredactivation profile of a drug is based, for example, on at least onedesired brain target for the drug. In some embodiments, anactivation protocol is selected and/or adjusted for each drugand/or to induce, for example, a desired activation profile of thedrug.

Exemplary Process for Application of an Activation Protocol

[0283] Reference is now being made to FIG. 3A depicting a processfor application of an activation protocol, according to someembodiments of the invention.

[0284] According to some exemplary embodiments, a patient receivesan indication for a treatment at 300. In some embodiments, theindication comprises the time schedule for the treatment, forexample the timing parameters for drug administration and/or forthe application of an activation protocol.

[0285] According to some exemplary embodiments, the drug isadministered at 302. In some embodiments, the patient receivesinstructions regarding the activation protocol, for example, afterthe drug is administered. Alternatively, the patient receives theinstructions before administering the drug. In some embodiments,the instructions and/or indications are delivered to the patientusing a computer or a handheld device. In some embodiments, theinstructions and/or indications are delivered by an application ora program installed on the computer or on the handheld device. Insome embodiments, the instructions comprise the desired timeinterval between the drug administration and the activationprotocol application. In some embodiments, the instructionscomprise at least one desired position for placing an electrode ora device configured to deliver the activation treatment.Additionally or optionally, the instructions comprise at least onedesired position and/or instructions for placing at least onesensor, for example to monitor at least one clinical parameterrelated to the treatment.

[0286] According to some exemplary embodiments, the drug is abreathable drug. In some embodiments, the drug is administered byinhalation.

[0287] According to some exemplary embodiments, the activationprotocol is applied at 306. In some embodiments, the activationprotocol is applied using a program and or an application stored ina computer or a handheld device. In some embodiments, the patientreceives an indication for starting the activation protocol and/oran indication for ending the activation protocol.

[0288] Optionally, the effect of the treatment is determined at308. In some embodiments, the effect of the treatment isdetermined, for example, by measuring EEG parameters. Alternativelyor additionally, the effect of the treatment is determined bymeasuring at least one clinical parameter. In some embodiments, theeffect of the treatment is determined by receiving a feedback fromthe patient, for example, the feeling of the patient after thetreatment session. In some embodiments, the at least one clinicalparameter and/or the EEG parameters are measured at least 10minutes following the treatment, for example 60 minutes followingthe treatment. In some embodiments, the effect is tested via atleast one psychometric and/or physical test. In some embodiments,if the effect of the drug is not a desired effect, then anindication is delivered to the patient and/or to an expert, forexample a physician. In some embodiments, a modified activationtreatment is delivered to the patient by the expert in response tothe indication. Alternatively, an application or a program selectsa modified activation protocol or a modified treatment protocol, inresponse to the indication.

[0289] According to some embodiments, at least one additionalactivation protocol is applied after the application of the firstactivation protocol at 306. In some embodiments, the additionalactivation protocol is applied, for example to prolong the effectof the first activation protocol. In some embodiments, the timedifference between the application of the first activation protocoland the additional activation protocol is determined based, forexample, on the pharmacokinetics and/or the pharmacodynamics of thedrug.

Exemplary Treatment Pharmacokinetics and Pharmacodynamics

[0290] Reference is now made to FIG. 3B depicting the change indrug concentration in specific brain regions over time, when anactivation protocol is applied after administration of a drug,according to some embodiments of the invention. According to someexemplary embodiments, a drug is administered at to and anactivation protocol is applied at t.sub.activ., for example 1minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes,or 30 minutes after drug administration. Alternatively, anactivation protocol is applied before drug administration, forexample 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25minutes, or 30 minutes after drug administration.

[0291] According to some exemplary embodiments, when an activationprotocol is applied after drug administration, for example asdescribed by curve 312, the drug concentration in the brain reachesa higher value over time, for example Conc.activ(concentrationactivation), compared to Conc.norm (Concentration normal) where anactivation protocol is not applied, for example as described bycurve 310. Alternatively, or additionally the drug remains for alonger period of time in the brain when an activation protocol isapplied, for example as demonstrated by the value of t.sub.2 ofcurve 312 which is larger compared to t.sub.1 value of curve310.

[0292] In some embodiments, when an activation protocol is appliedat t.sub.activ, the maximal concentration of the drug in at leastone brain region is reached after a shorter period of time,compared to a treatment protocol where an activation protocol isnot applied.

[0293] According to some exemplary embodiments, the amount of drugpresent in the brain, after the application of an activationprotocol at is t.sub.activ, higher compared to a treatment protocolwhere an activation protocol is not applied. In some embodiments,the amount of drug in the brain can be calculated, for example, bymeasuring the area under curve 312 to the area under curve 310.

[0294] According to some exemplary embodiments, application of anactivation protocol increases the activity of selected brainregions, which leads to an increase in blood flow carrying drugmolecules into the brain. In some embodiments, more drug moleculesenter the brain following the activation protocol. In someembodiments, activation of selected brain regions, followingadministration of a drug, for example a psychotropic drug, leads toa reduced clearance rate of drug molecules from the brain.

[0295] Optionally, application of an activation protocol increasesthe drug's effect, for example by changing the reactivity ofmembrane receptors and/or transporters in the neuron. In someembodiments, application of an activation protocol increases thedrug's effect, for example by changing association parametersbetween the drug molecules and active transporters molecules.Optionally, application of an activation protocol increases theassociation rate between the transporter molecules and the drugmolecules.

[0296] Alternatively or additionally, the activation protocolincreases the availability of transporter molecules in activatedbrain regions. In some embodiments, application of an activationprotocol increases the penetration rate of transporter moleculesand/or the penetration rate of drug-transporter complexes throughthe BBB and into the brain.

[0297] Reference is now made to FIG. 3C depicting the change in thedrug effect over time, when an activation protocol is applied afteradministration of a drug, according to some embodiments of theinvention.

[0298] According to some exemplary embodiments, a drug isadministered at to, and an activation protocol is applied att.sub.activ, for example as previously described. In someembodiments, when an activation protocol is applied after drugadministration at t.sub.activ, for example, as depicted by curve324, the maximal effect of the drug (Effect max) is reached earliercompared to a treatment protocol where an activation protocol isnot applied, for example, as depicted by curve 322. In someembodiments, activation of selected brain regions, leads toaccumulation of drug molecules in the activated brain regions. Insome embodiments, the accumulation of the drug molecules leads, forexample, to a faster response of the neural tissue to the drug.

[0299] Alternatively or additionally, the effect of the drug isprolonged when an activation protocol is applied. Optionally oradditionally, the overall effect of the drug after application ofan activation protocol is larger compared to the overall effect ofthe drug when an activation protocol is not applied, asdemonstrated, for example, by the area under curve 324 which islarger compared to the area under curve 322.

[0300] Optionally or additionally, the maximal effect of the drug,when an activation protocol is applied is higher compared to atreatment protocol where the drug is administered but an activationprotocol is not applied.

[0301] Reference is now made to FIG. 3D depicting the change inblood drug concentration over time when an activation protocol isapplied after administration of a drug, according to someembodiments of the invention.

[0302] According to some exemplary embodiments, a drug isadministered at t.sub.0, followed by application of an activationprotocol at t.sub.activ, for example, as previously described. Insome embodiments, when an activation protocol is applied after drugadministration at t.sub.activ, for example, as depicted by curve328, the maximal blood drug concentration is achieved at an earliertime point compared to a treatment protocol where an activationprotocol is not applied, for example, as depicted by curve 326.This effect is caused, in some embodiments, by the increase of drugdelivery into the brain following the activation protocol.

[0303] According to some exemplary embodiments, the clearance ofthe drug from the blood is slower when an activation protocol isapplied, compared to a treatment protocol when an activationprotocol is not applied, for example as depicted by the largervalue of t.sub.2 compared to the value of t.sub.1. Optionally,application of an activation protocol affects the clearance rate ofunwanted compounds from the tissue.

[0304] Reference is now made to FIG. 3E depicting the change in thedrug effect over time when applying an activation protocolfollowing administration of a lower drug dosage, according to someembodiments of the invention.

[0305] According to some exemplary embodiments, when a drug, forexample Ritalin.RTM. or Levodopa is administered at to, as depictedby graph 330 a desired effect is reached. In some embodiments, whenadministering a lower dosage of the drug, for example 50% of thedosage, a reduced drug effect is reached, as depicted by graph 332.In some embodiments, a reduced dosage of the drug is administered,for example to lower at least one side effect of the drug. In someembodiments, a lower drug dosage is administered at to, followed byapplication of an activation protocol at t.sub.activ, as depictedby graph 334. Alternatively, an activation protocol is appliedbefore the administration of a lower dosage of the drug. In someembodiments when an activation protocol is applied before or afterthe administration of a lower drug dose, the effect of the drug ishigher compared to administration of the drug without applicationof the activation protocol. Optionally, the effect of a lower drugdose, for example 50% of the drug dose when an activation protocolis applied, is similar to the effect when administering 100% of thedrug without activation protocol application.

[0306] Reference is now made to FIG. 3F depicting the change in thedrug concentration in specific brain regions over time after anactivation protocol is applied following the administration of alower drug dosage, according to some embodiments of theinvention.

[0307] According to some exemplary embodiments, when a drug forexample Ritalin.RTM. or Levodopa is administered, it penetratesthrough the blood brain barrier (BBB), and enters the neuraltissue, as depicted by graph 336. In some embodiments, when anactivation protocol is applied after the drug administration, thereis an increase in drug concentration in the neural tissue. In someembodiments, more drug molecules penetrate through the BBB and intothe neural tissue following the activation protocol.

[0308] Optionally, there is an increase in drug concentration in atleast one neural tissue region and/or reduction in drugconcentration in other one or more neural tissue regions.

[0309] Reference is now made to FIG. 3G depicting the change indrug levels over time in the blood compartment of the brainfollowing application of an activation protocol, according to someembodiments of the invention.

[0310] According to some exemplary embodiments, when a drug, forexample Ritalin.RTM. or Levodopa or Haloperidol is administered, itis delivered through the blood flow into the blood compartment ofthe brain, before it penetrates through the BBB into the neuraltissue as depicted by graph 340. In some embodiments, applicationof an activation protocol leads to an increase in blood flow andblood-borne drug molecules into the blood compartment of the brain,for example, as depicted by graph 342. Optionally, application ofan activation protocol before or after drug administration leads toan increase in blood flow and in blood-borne drug molecules levelsin at least one selected blood compartment region, for example, ablood compartment region near at least one activated brain region.Alternatively or additionally, application of an activationprotocol before or after drug administration leads to a decrease inblood flow to at least one selected blood compartment region, forexample blood compartment region near at least one brain regionswith reduced activation levels. In some embodiments, the bloodcompartment of the brain comprises blood vessels that interact withneural tissue in the brain.

Exemplary Process for Application of an Activation Protocol UsingNeurofeedback and/or Virtual Reality Techniques

[0311] Reference is now being made to FIG. 3H depicting a processfor application of an activation protocol using virtual realitytechniques, according to some embodiments of the invention.

[0312] According to some exemplary embodiments, a patient receivesan indication for a treatment at 300, for example as previouslyshown in FIG. 3A. In some embodiments, a drug is administered at302, for example as previously shown in FIG. 3A.

[0313] According to some exemplary embodiments, a neurofeedbackprotocol is applied at 350 optionally combined with a virtualreality protocol, for example to activate at least one brainregion. In some embodiments, a virtual reality protocol is appliedwithout a neurofeedback protocol. In some embodiments, the virtualreality protocol comprises recorded and/or presented scenarios,optionally in three-dimensions (3D). In some embodiments, theneurofeedback protocol and/or the virtual realityprotocol/scenarios are delivered to a subject or a patient via amobile device, for example a cellular device or a mobile computer,for example handheld device 536 shown in FIG. 5F.

[0314] In some embodiments, when treating a patient suffering froma type of phobia, for example fear of height and/or agoraphobiaand/or snakes, an SSRI or an anxiolytic drug is administered, forexample at 302. In some embodiments, a neurofeedback protocol isapplied before, during or after the administration of the drug, forexample to down-regulate the activity of the amygdala and/or to upregulate the activity of the IFG. In some embodiments, theneurofeedback protocol is applied while interfacing with at leastone virtual reality scenario, for example at least one virtualreality scenario which corresponds to the phobic object orenvironment.

[0315] In some embodiments, when treating a patient suffering fromPTSD, for example suffering from arousal and/or re-experience, ananxiolytic or an anticonvulsant drug is administered, for exampleat 302 In some embodiments, a neurofeedback protocol is appliedbefore, during or after the administration of the drug, for exampleto regulate the activity of the amygdala and/or hippocampus and/orlocus ceruleus. In some embodiments, the neurofeedback protocol isapplied while interfacing with at least one virtual realityscenario, for example at least one virtual reality scenario relatedto a traumatic story. In some embodiments, which corresponds to thephobic object or environment.

[0316] In some embodiments, when treating a patient suffering fromPTSD, for example suffering from avoidance, a Bupropion drug isadministered, for example at 302. In some embodiments, In someembodiments, a neurofeedback protocol is applied before, during orafter the administration of the drug, for example to up-regulatethe activity of the dorsal ACCC/preSMA. In some embodiments, theneurofeedback protocol is applied while interfacing with at leastone virtual reality scenario, for example at least one virtualreality scenario demonstrating goal-directed situations that demandmotivation decision making.

[0317] In some embodiments, when treating a patient suffering fromADHD symptoms, for example suffering from attention deficits and/orimpulsivity, Ritalin .RTM. drug is administered, for example at302. In some embodiments, a neurofeedback protocol is appliedbefore, during or after the administration of the drug, for exampleto up-regulate the activity of the right-IFG. In some embodiments,the neurofeedback protocol is applied while interfacing with atleast one virtual reality scenario, for example at least onevirtual reality scenario where the patient is required to perform(or not to perform) actions according to cues appearing in high orlow probabilities. In some embodiments, the virtual realityscenarios are applied without neurofeedback.

[0318] In some embodiments, when treating a patient suffering fromchronic pain, at least one analgesic drug is administered, forexample at 302. In some embodiments, a neurofeedback protocol isapplied before, during or after the administration of the drug, forexample to up-regulate the activity of the viscero-somatic system(including insula cortex, somatosensory cortex and cingulatecortex. In some embodiments, the neurofeedback protocol is appliedwhile interfacing with at least one virtual reality scenario, forexample at least one virtual reality scenario optionallydemonstrating the presence near or in a room in-fire, includingvarious levels of heat sensations.

[0319] In some embodiments, when treating a patient suffering fromsocial anxiety, an SSRI drug is administered, for example at 302.In some embodiments, a neurofeedback protocol is applied before,during or after the administration of the drug, for example toup-regulate the activity of at least one brain region related toself-referential, for example the vmPFC region. In someembodiments, the neurofeedback protocol is applied whileinterfacing with at least one virtual reality scenario, for exampleat least one virtual reality scenario demonstrating at least oneperson socially interacting with the patient, for example speakingwith the patient from varying distances.

[0320] In some embodiments, when treating a patient suffering fromdepressive mood symptoms, an SSRI drug is administered, for exampleat 302. In some embodiments, a neurofeedback protocol is appliedbefore, during or after the administration of the drug, for exampleto up-regulate the activity of at least one brain region related tothe reward system, for example the nucleaus accumbens and/or vmPFCbrain regions. In some embodiments, the neurofeedback protocol isapplied while interfacing with at least one virtual realityscenario, for example at least one virtual reality scenariodemonstrating a rewarding cue, for example a highly desiredrewarding cue in a context of a game, for example the hidden moneygame.

Exemplary Process for Selection of an Activation Treatment

[0321] Reference is now made to FIG. 4 depicting a process forselecting an activation treatment, according to some embodiments ofthe invention.

[0322] According to some exemplary embodiments, a patient, forexample a patient suffering from at least one neurological and/orpsychiatric symptom is diagnosed using cognitive assays.Optionally, the patient is diagnosed using at least one imagingtechnique, for example CT, MRI, fMRI, or ultrasound.

[0323] According to some exemplary embodiments, at least one drugis selected at 402 for the treatment of the at least oneneurological and/or psychiatric symptom of the patient. In someembodiments, the drug is selected to treat the clinical conditionof the patient.

[0324] According to some exemplary embodiments, the desiredactivation profile of the selected drug is determined at 404. Insome embodiments, the activation profile comprises at least onedesired brain region and/or neuronal network to be affected by theselected drug. Optionally, the activation profile of the selecteddrug comprises at least one undesired brain region and/or neuronalnetwork to be affected by the selected drug.

[0325] According to some exemplary embodiments, an activationtreatment, for example a cognitive exercise, a neurofeedbacktreatment or a TMS treatment, is selected at 406, for example tomatch the desired activation profile of the drug. In someembodiments, the activation treatment is selected from a pluralityof activation treatments that selectively match, for example, adesired activation profile and/or a drug.

[0326] In some embodiments, at least one treatment protocolparameter is adjusted to match a desired activation profile, forexample as determined at 404.

[0327] According to some exemplary embodiments, the activationprotocol is applied at 408. In some embodiments, the activationprofile of at least one brain region and/or at least one neuronalnetwork is determined at 412, for example by measuring EEGparameters or by monitoring at least one clinical parameter.Optionally, the activation profile is determined using, an imagingtechnique, for example fMRI.

[0328] In some embodiments, the activation profile is determinedduring the application of the activation protocol. Alternatively oradditionally, the activation profile is determined at least 10minutes following the activation treatment, for example 10 minutes,15 minutes, 20 minutes, 30 minutes or 1 hour. In some embodiments,the time period required for determination of the applicationprofile depends on pharmacodynamics and/or pharmacokineticsproperties of the drug.

[0329] In some embodiments, the activation protocol or activationprotocols are modified according to the measured activationprofile. Optionally, the activation protocol intensity and/orduration and/or type of cognitive and/or physical task are modifiedaccording to the measured activation profile.

[0330] Alternatively or additionally, the drug dosage is modifiedaccording to the measured activation profile. In some embodiments,if the measured activation profile is not the desired activationprofile then the drug dosage is increased and/or the dugadministration protocol is modified. In some embodiments, if themeasured activation profile is the desired activation protocol thenthe drug dosage is lowered, for example during a calibrationprocess of the combined drug-activation protocol treatment.

[0331] In some embodiments, if the desired activation profile isreached then an indication is delivered to the patient. In someembodiments, if the desired activation profile is not reached, thenthe activation protocol is modified or replaced at 414. In someembodiments, if the desired activation profile is not reached atleast one parameter of the activation protocol is modified, forexample the duration of the treatment.

[0332] According to some embodiments, the activation protocol ismodified or replaced to reach desired activation levels of at leastone specific brain region and/or to reach desired connectivitymeasures of at least one neuronal network. Optionally, the desiredactivation levels and/or the desired connectivity measures aredetermined optionally in a clinic by an expert, for example aneurologist. In some embodments, the desired activation levelsand/or the desired connectivity are determined using EEG, MRI,functional MRI, EMG or any other method suitable for monitoringbrain activity and/or the effect of brain activity on other partsof the body, for example the muscles.

[0333] According to some embodiments, the application protocol ismodified using explicit neurofeedback or covert neurofeedbackmethods. Covert neurofeedback refers to a neurofeedback protocol inwhich the subject is not asked to modulate her brain signalsvolitionally. In covert neurofeedback, the subject's brainreactions to specific external stimuli are probed and these stimuliare modified to elicit desired brain states without the subject'sawareness. In some embodiments, for example, when presenting a setof stimuli to the subject in order to trigger local brainactivation, the most effective stimulus may be selected and reusedto optimize the activation protocol. Alternatively or additionally,in a different scenario, spontaneous activation of a specificregion may be reinforced by rewarding cues, while the subject isunaware of the cause of the reward.

[0334] According to some exemplary embodiments, the new or themodified activation protocol is delivered to the patient, forexample, to a handheld device of the patient. In some embodiments,the new or modified activation protocol is applied at 308 and theactivation profile is determined as previously described.

Exemplary Process for Application of an Activation Protocol

[0335] Reference is now made to FIGS. 5A-5C, depicting a processfor application of an activation treatment, according to someembodiments of the invention.

[0336] According to some exemplary embodiments, after an indicationfor a treatment is delivered at 300, the brain activation profileis measured at 502. In some embodiments, the brain activationprofile is measured by at least two electrodes connected to thehead of the patient. Alternatively, the brain activation profile isdetermined using a cognitive task.

[0337] In some embodiments, the activation profile of the brain ismeasured before the administration of a drug or an application ofan activation protocol to determine, for example, whether theactivation profile of the brain is a desired activation profile andtherefore there is no need to apply the activation protocol.Additionally, if the application profile is a desired applicationprofile then, optionally, the drug dosage can be modified.

[0338] According to some exemplary embodiments, the activationprofile is determined at 504. In some embodiments, the determinedactivation profile is compared to a desired activation profile at506. In some embodiments, if the measured activation profile is nota desired activation profile then an indication is delivered to thepatient and/or to an expert for example a physician. Additionally,a drug is administered at 302. In some embodiments, the indicationis provided to the user as part of a game-like activationprotocol.

[0339] According to some exemplary embodiments, if the measuredactivation profile is a desired activation profile then anactivation protocol is not applied. Optionally, the drug dosage ismodified based on the activation profile parameters, for examplethe drug dosage is reduced by 10%, 25% or 50%.

[0340] According to some exemplary embodiments, a drug isadministered at 302 and the treatment effect is determined, forexample as previously described.

[0341] According to some exemplary embodiments, as described inFIG. 5B, after the administration of a drug at 302, brainactivation is measured at 502, and the activation profile isdetermined at 504 as previously described.

[0342] In some embodiments, the measured activation profile iscompared to a desired application profile at 506. In someembodiments, if the measured activation is a desired activationprofile then an activation protocol is not applied, and thetreatment effect is determined at 308, for example as preciouslydescribed.

[0343] Alternatively, if the measured activation profile is not adesired activation profile, then an activation profile is appliedat 304, for example as described in FIG. 5A.

[0344] According to some exemplary embodiments, as described inFIG. 5C, after the application of an activation protocol at 306,brain activation is measured at 502 and an activation profile isdetermined, for example as previously described. In someembodiments, the measured activation profile is compared to adesired activation profile at 506, to decide whether the measuredactivation profile is a desired application profile. In someembodiments, if the measured activation profile is a desiredactivation profile, then the treatment effect is determined at 308,as previously described.

[0345] In some embodiments, if the measured activation profile isnot a desired activation profile, then at least one parameter ofthe activation protocol is modified at 508. Alternatively, adifferent activation protocol is selected at 510. Optionally, anindication is delivered to the patient, and to an expert, forexample a physician if the measured activation profile is not adesired activation profile.

[0346] In some embodiments, the different activation protocol orthe modified activation protocol is applied at 306, for example, asdescribed at FIG. 3A.

Exemplary Device for Application of a Brain Activation Protocol

[0347] Reference is now made to FIGS. 5D-5E, depicting a device forapplication of a brain activation protocol, according to someembodiments of the invention.

[0348] According to some exemplary embodiments, device 512comprises a memory 516 for storing at least one treatment protocoland/or at least one activation protocol. In some embodiments,memory 516 stores log files of device 512.

[0349] In some embodiments, a control circuitry 514 deliversinstructions and/or at least one indication to a patient and/or anexpert via an interface circuitry 518. In some embodiments, controlcircuitry 514 reads and/or writes log files and/or at least onetreatment protocol to memory 516. Additionally, control circuitry514 reads and/or writes at least one activation protocol to memory516.

[0350] In some embodiments, device 512 comprises a battery 520,connected to control circuitry 514. In some embodiments, battery520 is a rechargeable battery, for example a lithium-ion battery.In some embodiments, if battery 520 is at least 50% discharged, forexample 75%, 85%, 90%, 95% then control circuitry 514 delivers anindication, for example an alert signal to the patient viainterface circuitry 518. In some embodiments, a patient and/or anexpert and/or a caregiver delivers feedback parameters viainterface circuitry 518.

[0351] In some embodiments, device comprises a casing 522. In someembodiments, casing 522 comprises at least one attachment anddetachment member configured to attach device 512 to the body or tothe clothes of the patient.

[0352] According to some exemplary embodiments, device 512comprises at least one electrode connected to the body of thepatient. In some embodiments, the at least one electrode measuresat least one clinical parameter of the body, for example EEGparameters. In some embodiments, electrode 528 delivers themeasured parameters to control circuitry 514 through wire 530.

[0353] According to some exemplary embodiments, device 512comprises at least one sensor 532 for measuring at least oneclinical parameter, for example skin conductance, heart rate, bloodpressure, blood flow parameters or pupil diameter. In someembodiments, sensor 532 and/or electrode 528 measures at least oneclinical parameter before and/or after the administration of adrug, for example to determine the activation profile of the brain.Optionally or additionally, sensor 532 and/or electrode 528 measureat least one clinical parameter, for example to determine thetreatment effect on the patient. In some embodiments, theparameters measured by sensor 532 and/or electrode 528 are storedin memory 532.

[0354] According to some exemplary embodiments, in response to themeasured clinical parameter and/or to the received feedback,control circuitry 514 modifies the treatment protocol and/or theactivation protocol. Optionally, in response to the measuredclinical parameter and/or to the received feedback, controlcircuitry 514 stops the treatment protocol and/or the activationprotocol. In some embodiments, in response to the measured clinicalparameter and/or to the received feedback, control circuitry 514changes the dosage of the drug and/or the administration procedure,for example administration time schedule.

[0355] According to some exemplary embodiments, device 512 deliversan indication to a remote computer and/or a handheld device viatransmitter 524, for example when the measured activity profile isnot a desired profile or when the determined treatment effect isnot a desired treatment effect. In some embodiments, theinformation transferred via transmitter 524 includes parametersstored in memory 516, for example feedback parameters received fromthe patient via interface circuitry 518.

[0356] According to some exemplary embodiments, device 512 receivesinformation from a remote computer and/or a handheld device viareceiver 526. In some embodiments, the information deliveredthrough receiver 526 comprises instructions to the patient, and/ormodifications of an activation protocol and/or a new activationprotocol. In some embodiments, the information received by receiver526 is stored in memory 526.

Exemplary System for Application of an Activation Protocol

[0357] Reference is now made to FIG. 5F depicting a system forapplication of an activation protocol, according to someembodiments of the invention.

[0358] According to some exemplary embodiments, system 550comprises a handheld device 526 for example, for delivering atleast one indication to patient 534. In some embodiments, handhelddevice 536 delivers instructions regarding the treatment protocoland/or regarding the activation protocol to patient 534 before,during or after the administration of drug 538.

[0359] According to some exemplary embodiments, system 550comprises at least one sensor, for example sensor 542 or electrodefor measuring at least one clinical parameter of patient 534, forexample EEG parameters, heart rate parameters, blood pressureparameters, skin conductance parameters, blood flow parameters orpupil diameter. In some embodiments, sensor 542 and/or electrode540 delivers the measured parameter to handheld device 536 via awireless signal. Optionally, the signal is delivered from sensor542 or electrode 540 via a wire. In some embodiments, sensor 542and/or electrode 540 measures the at least one clinical parameterbefore, during, or after the administration of drug 538.

[0360] According to some exemplary embodiments, a remote computer544 delivers instructions and/or at least one treatment protocoland/or at least one activation protocol to handheld device 536. Insome embodiments, handheld device 536 delivers an indication toremote computer 544, for example when the measured clinicalparameter is not in a desired range of parameters. Optionally,patient 534 delivers feedback to handheld device 536. In someembodiments, handheld device 536 transmits the feedback to remotecomputer 544.

Exemplary Application of an Activation Protocol Using a HandheldDevice

[0361] According to some exemplary embodiments, a patient, forexample patient 534 receives a human detectable indication from ahandheld device, for example handheld device 536 before theadministration of drug 538. In some embodiments, the indication isdelivered according to a treatment protocol stored in the memory ofhandheld device 536.

[0362] In some embodiments, after the administration of drug 538,patient 534 receives instructions for application of an activationprotocol, by a user interface of handheld device 536. In someembodiments, the instructions comprise instructions for applicationof at least one cognitive task and/or at least one physical task.Additionally or optionally, the instructions comprise the durationof each task and/or the number of repetitions for each task and thetime interval between drug administration and application of anactivation protocol. In some embodiments, the instructions comprisethe time interval between each task and the following task.

[0363] In some embodiments, when the activation protocol is applieda human detectable indication is delivered by the handheld deviceto the patient. In some embodiments, the indication comprise thetime to the next drug administration and/or to the next applicationof an activation protocol.

[0364] In some embodiments, the handheld device measures at leastone cognitive and/or clinical parameter before and/or after theapplication of an activation protocol.

[0365] Alternatively or additionally, the handheld device measuresat least one cognitive and/or clinical parameter before and/orafter the administration of the drug. In some embodiments, the atleast one cognitive and/or clinical parameter is measured by atleast one sensor or electrode connected to the body of the patient,for example to the head and/or to the hand and/or to the chest ofthe patient. In some embodiments, the at least one sensor transmitsthe at least one cognitive and/or clinical parameter to thehandheld device by a wireless signal. Alternatively, the at leastone sensor or electrode transmits the at least one cognitive and/orclinical parameter via a wire connected to the handheld device.

[0366] In some embodiments, a program on the handheld devicedetermines whether the measured cognitive and/or clinical parametervalue is a desired clinical and/or cognitive value. In someembodiments, if the measured cognitive and/or clinical parametervalue is a desired value, then handheld device 536 delivers anindication to patient 534, for example a treatment complianceindication. Alternatively, if the measured parameter value is not adesired value, then handheld device 536 modifies the treatmentprotocol which comprises the drug administration and activationprotocol application, for example the handheld device modifies drugdosage and/or the interval between drug administration andapplication of an activation protocol. Optionally, the handhelddevice modifies at least one parameter of the activation protocol,for example the duration of the activation protocol, the type ofthe cognitive and/or the physical task, the number of repetitionsof the task.

Exemplary Activation Mechanism of an Activation Protocol

[0367] According to some embodiments, a patient, for examplepatient 534, is administered with a Norepinephrine ReuptakeInhibitor, for example Venlafaxine.

[0368] Optionally, Venlafaxine is administered to treat Anxietyand/or at least one symptom related to Anxiety. In someembodiments, an activation protocol is applied 5-90 minutes afterVenlafaxine administration, for example 5-40 minutes, 30-60 minutesor 50-90 minutes. In some embodiments, the activation protocol willbe applied for 5-60 minutes, for example 10-30 minutes, 25-50minutes or 30-45 minutes. In some embodiments, the activationprotocol directs Venlafaxine at least partially to theAmygdala.

[0369] In some embodiments, the activation protocol comprisesviewing of dynamic emotional content, for example movies,optionally by using virtual reality or augmented reality means.Alternatively or additionally, the activation protocol compriseslistening to music. In some embodiments, the activation protocolwill be applied using a handheld device, for example handhelddevice 536.

[0370] According to some embodiments, a patient, for examplepatient 534, is administered with MPH, for example to treatattention deficits and/or at least one symptom associated withattention deficits. In some embodiments, an activation protocol isapplied 5-90 minutes after MPH administration, for example 5-40minutes, 30-60 minutes or 50-90 minutes. In some embodiments, theactivation protocol will be applied for 5-60 minutes, for example10-30 minutes, 25-50 minutes or 30-45 minutes. In some embodiments,the activation protocol directs MPH, at least partially todorsolateral and/or ventrolateral prefrontal brain regions.

[0371] In some embodiments, the activation protocol comprises atleast one task related to executive function and/or controlinhibition, for example go-no go and/or N-back tasks. In someembodiments, the activation protocol will be applied using ahandheld device, for example handheld device 536.

[0372] According to some embodiments, a patient, for examplepatient 534, is administered with Bupropion, for example to treatpost-traumatic stress disorder (PTSD) and/or at least one symptomassociated with PTSD. In some embodiments, an activation protocolis applied 5-90 minutes after Bupropion administration, for example5-40 minutes, 20-60 minutes or 50-90 minutes. In some embodiments,the activation protocol will be applied for 5-60 minutes, forexample 10-30 minutes, 25-50 minutes or 30-45 minutes. In someembodiments, the activation protocol directs Bupropion at leastpartially to the dorsal anterior cingulate cortex brain region.

[0373] In some embodiments, the activation protocol comprises atleast one Action planning related task for example, an objectmanipulation task, a grid sailing task which includes the moving ofa cursor with at least one finger to a selected target position,and/or a finger tapping task which include instructed andnon-instructed finger tapping sequences. In some embodiments, theactivation protocol is applied using a handheld device, for examplehandheld device 536.

[0374] According to some embodiments, a patient, for examplepatient 534, is administered with Reboxetine, for example to treatMCI and/or at least one symptom associated with MCI. In someembodiments, an activation protocol is applied 5-90 minutes afterReboxetine administration, for example 5-40 minutes, 30-60 minutesor 50-90 minutes. In some embodiments, the activation protocol isapplied for 5-60 minutes, for example 10-30 minutes, 25-50 minutesor 30-45 minutes. In some embodiments, the activation protocoldirects the drug at least partially to the hippocampus.

[0375] In some embodiments, the activation protocol comprises atleast one task related to memory, for example a paired associationtask which relates to verbal declarative memory, an N-back task ora Digital Span Test which relate to working memory, and/or a verbalgeneration task which relate to episodic memory. In someembodiments, the activation protocol is applied using a handhelddevice, for example handheld device 536.

[0376] According to some embodiments, a patient, for examplepatient 534, is administered with Levodopa, for example to treatParkinson's disease. In some embodiments, an activation protocol isapplied 5-90 minutes after Levodopa administration, for example5-40 minutes, 30-60 minutes or 50-90 minutes. In some embodiments,the activation protocol will be applied for 5-60 minutes, forexample 10-30 minutes, 25-50 minutes or 30-45 minutes. In someembodiments, the activation protocol directs Levodopa at leastpartially to the caudate nucleus brain region.

[0377] Optionally, the applied activation protocol directs Levodopaat least partially away from mesocortical brain regions.

[0378] In some embodiments, the activation protocol comprises atleast one task related to motor actions, for example game-likescenarios. In some embodiments, the activation protocol is appliedusing a handheld device, for example handheld device 536.

[0379] Optionally, the motor action related task is applied usingvirtual reality or augmented reality means.

Exemplary Application of an Activation Protocol Combined withInhalation of Hyperbaric Gas

[0380] According to some exemplary embodiments, an activationprotocol is applied together with a hyperbaric gas, for exampleduring a hyperbaric medicine treatment. In some embodiments, theactivation protocol is applied before, during or after theinhalation of the hyperbaric gas. In some embodiments, unlikepsychotropic drugs that are directed mostly to affect the brain ortissues of the nervous system, the hyperbaric gas acts systemicallyon the entire body and is not directed to the brain under normalconditions. Therefore, and without being bound by theory,application of an activation protocol increases the probability ofthe hyperbaric gas to enter the brain and to enable a more specificeffect, optionally a more robust effect compared to normalconditions, on the activated brain regions.

[0381] In some embodiments, a treatment session combiningapplication of an activation protocol in combination withinhalation of a hyperbaric gas lasts between 15-120 minutes, forexample 30 minutes, 45 minutes, or 60 minutes. In some embodimentsa treatment is repeated at least twice a week, for example 3 times,4 times, 5 times or 6 times in a week. Alternatively, the treatmentsession is applied only once, for example as a treatment to anacute disease or condition. In some embodiments, the maximalpressure of the gas during the hyperbaric treatment is in the rangeof 1.5 bar to 8 bar. In some embodiments, the average concentrationof the hyperbaric gas in the breathable air is between 25-100%, forexample 25-60%, 50-75% or 70-100%.

[0382] In some embodiments, the combination of an activationprotocol with a hyperbaric treatment is used to treat stroke,traumatic brain ischemia (TBI), fibromyalgia, Asperger syndrome andautism.

[0383] In some embodiments, for treating stroke and/or TBI anapplication protocol is applied to activate damaged brain regions.Alternatively, the application protocol is applied to increase theactivation of undamaged brain regions, for example to compensatefor the loss of the damaged regions.

[0384] In some embodiments, an application protocol is applied toactivate at least one brain region related to autism including thesuperior temporal sulcus, the temporoparietal junction, the insulaand the premotor cortex during hyperbaric treatment to induceneurogenesis in the target regions.

Exemplary Validation Experiments

[0385] Reference is now made to FIGS. 6A-6D depicting a validationexperiment comparing the coupling of an activation protocol withadministration of Methylphenidate (MPH, Ritalin.RTM.) to couplingthe activation protocol with placebo administration, according tosome embodiments of the invention.

[0386] According to some exemplary embodiments, an N-back task isperformed together with fMRI analysis at 602 before the applicationof an activation treatment and drug administration. In someembodiments, the N-back task measures the working memory. In someembodiments, performing fMRI while performing the N-back taskallows, for example, to identify which brain region is involvedwhen working memory is used.

[0387] According to some exemplary embodiments, during treatment604, a cognitive challenge 606 was coupled with MPH administration610 and compared to a motivational task 608 and administration ofplacebo (PLAC) 612, in a 2.times.2 factorial design. In someembodiments, the cognitive challenge 606 and the motivational task608 are performed after the MPH 610 and the PLAC 612administration. In some embodiments, group 614 received MPH 610 andperformed cognitive challenge 606. In some embodiments, group 616received PLAC 612 and performed cognitive challenge 606. In someembodiments, group 618 received MPH and performed a motivationaltask 608. In some embodiments, a motivational task comprises a taskthat involves expectation for reward and/or punishment. In someembodiments, group 620 received PLAC and performed a motivationaltask 608. In some embodiments, cognitive challenge was performedusing the NeuroTrax computerized cognitive testing (NeuroTraxCorp., Bellaire, Tex.). In some embodiments, the NeuroTraxcomputerized cognitive testing is designed for assessingADHD-related measures such as attention and visual-spatialperformance (Auriel et al., 2006). In some embodiments, theNeuroTrax computerized cognitive testing comprises a battery of aGoNoGo, Stroop interference, and non-verbal memory tasks.

[0388] In some embodiments, groups 614, 616, 618 and 620 performedthe N-back task 60-90 minutes after treatment 604, while performingfMRI, at 622.

[0389] According to some exemplary embodiments, when using fMRIanalysis while performing the N-back task, a whole brain activationmap is generated at 624. In some embodiments, the brain activationmap demonstrates the activation of brain regions related toexecutive functional network, for example frontal, parietal, andparahippocampal regions. In some embodiments, the rightdorsolateral prefrontal cortex (rDLPFC) 626 is activated.

[0390] According to some exemplary embodiments, the activation ofthe rDLPFC is examined using fMRI when performing a 0-back task(control), a 2-back task and a 3-back task before and aftertreatment 604. In some embodiments the rDLPFC region was shown tomediate N-back performance (Owen et al., 2005). In someembodiments, an increased activity of the rDLPFC is demonstratedwhen performing 2-back task and 3-back task compared to 0-backtask, at 628.

[0391] According to some exemplary embodiments, the link betweenpost-pre rDLPFC activity change and the corresponding change inN-back performance is examined in 630. In some embodiments, in theMPH/cognitive condition 632, the change in the post-pre dLPFC betaweights difference negatively correlated with the post-pre changein reaction time (R=-0.75, p=0.003). In some embodiments, thisindicates that a greater increase in 3-back-related rDLPFCactivation following MPH/cognitive induction corresponded to largerdecreases in reaction time during scanning. Additionally, thiseffect was not found for the other induction conditions(MPH/motivation 636: R=0.15; p=0.61, PLAC/cognitive 634: R=0.3;p=0.3, PLAC/motivation 638: R=-0.19; p=0.52). In some embodiments,a Steiger's Z-test indicated a significant difference between thecorrelations and a unique dLPFC beta-RT association only when theMPH administration coincided with cognitive tasks (Steiger'sZ=-2.934, p<0.05, bonferroni-corrected for multiplecomparisons).

[0392] According to some exemplary embodiments, subjects who weremore successful in recruiting their attention during the cognitiveinduction state benefited more from the functional-pharmacologicalcoupling. In some embodiments, NeuroTrax attention scoresnegatively correlated with 3-back (maximal cognitive load) RTpost-pre difference in the MPH 640 (R=-0.76, p<0.01).Additionally, no significant correlation was found in the placebocondition 642 (R=0.03, ns). In some embodiments, the lack of asignificant correlation in the placebo condition 642 indicates, forexample, that the improvement is not explained by generalcapabilities of specific participants, but is rather specific tothe performance during the induction condition.

[0393] According to some exemplary embodiments, fMRI data that werecollected during the performance of the N-back task indicate thatthe FPC is mediated by the activation of the right dorsolateralprefrontal cortex, which has a key role in cognitive functions ingeneral and in the enhancement of working memory following MPHtreatment in specific (Gamo et al., 2010; Marquand et al., 2012).In some embodiments, the causal relations between the observedchange in the rDLPFC activation and the behavioral improvement (interms of 3-back RT), was assessed by a mediation analysis with theattention index scores of the cognitive induction state as amediator (Preacher & Hayes 2008). In some embodiments, asignificant indirect path from rDLPFC activity to 3-backreaction-times improvement through the attention scores--an indexfor the performance during the cognitive induction state (indirecteffect=-357.6, CI (95%)=-766.1 to -10.7) is observed, for examplein FIG. 6D. In some embodiments, this effect was not found for thecontrol conditions: placebo/cognitive, placebo/motivation, andMPH/motivation.

[0394] In some embodiments, the experimental results described inFIGS. 6A-6D suggest that successful performance of the task thatactivates target brain regions enhances the MPH effect via thefacilitation of a stronger activation of that region. While themechanistic characteristics of this process are yet to be detailed,this study provides a preliminary proof of concept for the benefitof FPC involving reuptake inhibitors.

[0395] Reference is now made to FIGS. 7A-7B, depicting validationexperiments for testing whether FPC improves attention functions ofsubjects medicated with MPH, according to some embodiments of theinvention. In some embodiments, the experiment includes threesessions. In some embodiments, in the first session 702, thesubjects performed a conjunctive continuous performance task (CPT,Shalev et al., 2011). In some embodiments, this test yieldsmeasures of sustained attention, which are generalized acrossdifferent sensory modalities.

[0396] According to some embodiments, in the second and the thirdsessions 706, the subjects took half of their prescribed drug 708dose by per os (PO) administration. In some embodiments, in thefirst epoch they went through either a cognitive inductioncondition 714 during which they performed the NeuroTrax tasks or acontrol condition 712 during which they listened to a piece oftheir favorite music. In some embodiments, these 30 min conditionswere followed by a 20-minutes rest epoch 716, for example to allowfor the testing of an enduring effect of the FPC. In someembodiments, an additional CPT session 704 was conducted, forexample, to assess the difference between the subjects' performanceafter the intervention. Optionally, the order of the conditions wascounterbalanced across subjects (it should be noted that CPT is notimproved with experience).

[0397] According to some exemplary embodiments, FPC effect wasmeasured for the sustained attention measures of average 722 andstandard deviation 724 response time, which show high reliabilityand validity (Shalev et al., 2011). In some embodiments, the rawscores were converted into standard deviations computed for anindependent CPT data set. In some embodiments, the sustainedattention measures of average 722 and standard deviation 724response time were improved in two subjects 718 and 720 (males;ages 28, 40) with the administration of half dose MPH. In someembodiments, the improvement was higher when the drugadministration was coupled with the cognitive induction task 728relative to the control task 730 (music).

[0398] In some embodiments, the findings presented in FIGS. 7A and7B indicate, for example, that FPC allows for the enhancement ofthe advantageous pharmacological effects with reduced drugdoses.

[0399] Reference is now made to FIGS. 8A-8H depicting the resultsof a validation experiment for measuring neurobehavioral effects ofMethylphenidate and right inferior frontal gyrus neurofeedbackactivation combined treatment for ADHD, according to someembodiments of the invention.

[0400] Without being bound to theory, and as previously describedit is plausible to assume that one could improve apsycho-pharmacological treatment by administering a drug, whileinducing an advantageous physiological state in brain regions thatinteract with the drug's active ingredients (by selectivelymanipulating pharmacokinetic\dynamic properties of a drug), andthat the induction of such state could be achieved with a certainkind of a behavioral task. The concept of coupling drugadministration with a specific task that activates therapeuticallyrelevant brain regions, was coined "Functional Pharmacology".

[0401] According to some exemplary embodiments, 24 ADHD patientsparticipated in a three session within-subject experimental design.In some embodiments, following administration of a weight-adjusteddose (0.1-0.2 mg/kg) of Ritalin IRTM (activeingredient--Methylphenidate (MPH)), they either "Up" (experimentalcondition) or "Down" (control condition) regulated their right-IFG(an area that mediates executive functions, and one of MPH's sitesof action) BOLD activity via real-time fMRI Neurofeedback task. Insome embodiments, fMRI BOLD activity is the physiological index ofneuronal activity, measuring Cerebral Blood Flow and magneticproperties of the blood (Chen & Ogawa, 1996), hence, it offersan exploitable "window" to pharmacoketic manipulation.

[0402] In some embodiments, taking the known pharmacokineticproperties of MPH into account, the neurofeedback paradigm wasscheduled to begin towards the estimated peak concentration of MPHin brain blood plasma (45 min), and last for 40 minutes, well intothe drug's plateau of concentration phase, thus assuming a maximumeffect of drug delivery and absorption to the rIFG and relatedbrain regions. Additionally, cognitive performance was evaluatedbefore administration and following the NF task via threebehavioral tasks (CPTi, CPT and Strooplike, measuring responseinhibition, sustained attention and executive attention,respectively; Shalev-Mevorach et al. 2005; 2011).

[0403] According to some embodiments, two out of three measuredcognitive functions (sustained attention (CPT task) and responseinhibition (CPTi task)) showed substantially larger effectsfollowing the up regulation condition, for example as shown inFIGS. 8A-8D. In some embodiments, although the manipulation of thephysiological contrast created in the rIFG between up and downconditions was not absolute, but gradually increased along thesessions and peaked toward its end, for example as shown in FIGS.8E-8F, we found a significant positive correlation between rIFGBOLD activity during the neurofeedback task and improvement insustained attention, for example as shown in FIG. 8G. In someembodiments, response inhibition was not significantly correlatedto the rIFG BOLD activity, but did exhibit a strong significantpositive correlation to the drug's administered dose only in the Upregulation condition, suggesting perhaps a more complex connectionbetween response inhibition improvement and rIFG up regulationphysiological outcomes, for example as shown in FIG. 8H.

[0404] It is expected that during the life of a patent maturingfrom this application many relevant brain activation protocols willbe developed; the scope of the term activation protocol is intendedto include all such new technologies a priori.

[0405] As used herein with reference to quantity or value, the term"about" means "within .+-.10% of".

[0406] The terms "comprises", "comprising", "includes","including", "has", "having" and their conjugates mean "includingbut not limited to".

[0407] The term "consisting of" means "including and limitedto".

[0408] The term "consisting essentially of" means that thecomposition, method or structure may include additionalingredients, steps and/or parts, but only if the additionalingredients, steps and/or parts do not materially alter the basicand novel characteristics of the claimed composition, method orstructure.

[0409] As used herein, the singular forms "a", "an" and "the"include plural references unless the context clearly dictatesotherwise. For example, the term "a compound" or "at least onecompound" may include a plurality of compounds, including mixturesthereof.

[0410] Throughout this application, embodiments of this inventionmay be presented with reference to a range format. It should beunderstood that the description in range format is merely forconvenience and brevity and should not be construed as aninflexible limitation on the scope of the invention. Accordingly,the descr