Emotional Memory, PTSD, and Clinical Intervention Updates

Transcription

1 Emotional Memory, PTSD, and Clinical Intervention Updates Wen Cai, MD, Ph.D. Chief Medical Officer--La Frontera Arizona Clinical Associate Professor--Psychiatry and Psychology University of Arizona College of Medicine Tucson, AZ Chris Edwards, RN Nursing Administrator, La Frontera Center, Tucson, AZ

2 OKC National Memorial

3 OKC National Memorial

4 OKC National Memorial We come here to remember those who were killed, those who survived and those changed forever

5 OKC Data Psychiatric Disorders Among Survivors of the Oklahoma City Bombing Carol S. North et al., JAMA. 1999;282:

6 OKC Data

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8 Post-Traumatic Stress Disorder DSM-IV criteria 1. The person has been exposed to a traumatic event in which of the following present: The person experienced, witnessed, or was confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others. The person s response involved intense fear, helplessness, or horror.

9 Post-Traumatic Stress Disorder DSM-IV criteria The traumatic event is persistently re-experienced (nightmare or recurrent intrusive thoughts). 2. Persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness. 3. Persistent symptoms of increased arousal (difficulty falling asleep, hypervigilance, irritability, exaggerated startle response). 4. Duration is more than 1 month.

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11 Why some people develop PTSD while others do not?

12 Questions for Psychiatrists 1. Can we stop their PTSD relapse? 2. Can we selectively delete their traumatic memory? 3. Can we prevent the PTSD development?

13 Memory Formation Process Acquisition or Encoding Consolidation/Storage Retrieval Extinction

14 Memory Types Cognitive Memory Working Memory Spatial Memory Emotional Memory Others

15 Emotional Memory & Amgydala Amgydala magnifies emotional memory BasoLateral Nucleus (BLA), rather than Central Nucleus, is the key site for emotional memory Neurosteroids could modify the emotional memory formation

16 Glucocorticoid and PTSD Low cortisol levels in PTSD patients. (Yehuda R. et al Am J Psychiatry) High CSF CRH levels in PTSD patients. (Baker DG et al Am J Psychiatry)

17 Glucocorticoids and Memory Glucocorticoids enhances memory consolidation in inverted U curve fashion. Glucocorticoid effect on object recognition memory require training-associated emotional arousal. Okuda et al., 2004, PNAS

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19 Glucocorticoids and Memory Glucocorticoids impairs Spatial Memory Retrieval Process. de Quervain, D.J.-F. et al., Nature.

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21 Glucocorticoids and Fear Memory Lesion study indicates that Amygdala (BLA) is critical for fear memory formation. Roozendaal and McGaugh, 1996, Neurobiol. Learn. Mem. and 1997 PNAS.

22 Glucocorticoids and Fear Memory Amygdala (BLA) and Hippocampus (Dorsal CA1) are important sites for fear memory formation. Circuitry study is still incomplete, however, possible other sites include Cingulate, Prefrontal Lobe, and other cortical areas.

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25 Glucocorticoids and Memory 1. What is the function of glucocorticoids in fear memory retrieval? 2. What is the function of glucocorticoids in fear memory reconsolidation?

26 Fear Memory Research Give mice electric foot shock stimulus paired with auditory tone stimulus. 24 hours later, expose the shocked mice to the same environment (context) or different environment but provide the same tone stimulus (auditory cue-dependent). The freezing time is recorded as the index of fear memory.

27 Retrieval Study

28 Memory Retrieval Study Presentation of Information to CNS. Wait till the new memory has been consolidated (4 hours to 24 hours or longer). Intervention procedure is performed (pharmacological or surgical) prior to memory measurement.

29 70 Feeeze Time Percentage (%) ** ** 10 0 vehicle metyrapone (50mg/Kg) corticosterone(mg/kg) Retrieval-CONTEXT

30 50 Freeze time percentage (%) ** ** 10 0 vehicle metyrapone (50mg/Kg) corticosterone(mg/kg) Retrieval-CUE

31 Freezing Time Percentage (%) * Freezing Time Percentage (%) vehicle cort3.0 0 vehicle cort3.0 (no injection before test) Retrieval-Context (24 hours) Retrieval-Context (48 hours) 50 Freezing Time Percentage (%) vehicle cort3.0 (no injection before test) Retrieval-Cue (48 hours)

32 Retrieval Study Conclusion Glucocorticoids impairs contextual and cue-dependent fear memory retrieval. This impairing effect does not influence the fear memory stability,i.e. it only blocks the retrieval process itself.

33 Possible Confounding Factors General Anxiety Level Locomotor Activity Sensory Function Motor Coordination Function

34 Open Field Test

35 Open Field Test Total time spent in the central zone area. Frequency of central zone entry. Total distance the animal moved. Average speed of their movement.

36 12.5 Central Zone-Total Duration 12.5 Central Zone-Frequency Total Duration (sec) Frequency (times) vehical cort 3.0 mg/kg 0.0 vehicle cort 3.0 mg/kg Distance Moved (total) Velocity (mean) Distance (cm) 2000 Velocity (m/s) vehicle cort 3.0 mg/kg 0.0 vehicle cor t3.0 mg/kg

37 Elevated Plus Maze Test

38 Elevated Plus Maze Test Frequency of their entrance into closed and open arms. Time they spend in closed and open arms respectively.

39 20 Frequency (times) vehicle cort3.0 0 Close Arm Entrance Open Arm Entrance Elevated Plus Maze

40 200 Time (sec) vehicle cort Close Arm Time Open Arm Time Elevated Plus Maze

41 RotaRod Test

42 RotaRod Test Goal: Testing motor coordination Measurement: Time to Fall

43 1750 Time (msec) first time second time third time forth time fifth time vehicle metyapone (50 mg/kg) corticosterone (mg/kg) Rotarod

44 1250 Time (msec) vehicle metyrapone cort 0.3 cort 1.0 cort 3.0 cort vehicle metyrapon cort0.3 cort1.0 cort3.0 cort10.0 Rotarod

45 Pain Threshold Test

46 Pain Threshold Test Goal: Testing the Sensational Function Measurement: Level of electricity shock to cause different activities, including flinch, jumping and vocalization.

47 0.5 Footshock Strength (ma) vehicle metyrapone cort 0.3 cort 1.0 cort 3.0 cort flinch jump vocalization Pain Threshold

48 Control Study Conclusion Glucocorticoids Injection does not influence: General Anxiety Level Locomotor Activity Sensory Function Motor Coordination

49 Reconsolidation Study

50 Reconsolidation Study Goal: After the fear memory is consolidated, is there a way to modulate its stability? Method: Footshock Wait for different length of time (2 days and 14 days) Reactivate the context fear memory Provide Corticosterone Injection immediately after the reactivation Measure the contextual fear memory 24 hours later.

51 CONTEXT (24 hour) % Time Spent Freezing * ** *** 10 0 no injection vehicle metyrepone cort1.0 cort3.0 cort10.0 anisomycin (50mg/kg) corticosterone (mg/kg)

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53 REACTIVE (14 DAY) % Time Spent Freezing no injectionvehicle metyreponecort0.3 cort1.0 cort3.0 cort10.0 anisomycin

54 CONTEXT 15 DAY % Freezing Time * * no injection vehiclemetyrepone cort0.3cort1.0cort3.0cort10.0 anisomycin * no injection vehicle metyrepone cort0.3 cort1.0 cort3.0 cort10.0 anisomycin

55 Conclusion and Potential Clinical Significance (1) Glucocorticoids impair fear memory retrieval Potential Pharmacological treatment option for maintenance therapy.

56 Conclusion and Potential Clinical Significance (2) Glucocorticoids impair fear memory reconsolidation Potential capability to delete emotional traumatic memory permanently and cure the PTSD patients.

57 Other Potential Significance Ethical issues of selectively deleting human memory Misuse of this technique with its social consequence

58 The End

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60 Footshock Strength (ma) Flinch Jump Vocalization 0.0 vehicle metyrapon cort0.3 cort1.0 cort3.0 cort10.0 Pain Threshold

61 %Time Spent Freezing CONTEXT- 18 Day vehicle cort3.0 cort10.0 anisomycin vehicle cort3.0 cort10.0 anisomycin

62 Old group-reactive14day no injection vehiclemetyrepone cort0.3cort1.0cort3.0cort10.0 anisomycin no injection vehicle metyrepone cort0.3 cort1.0 cort3.0 cort10.0 anisomycin

63 VA PTSD Data Reduction of nightmares and other PTSD symptoms in combat veterans by prazosin: a placebo-controlled study. Raskind MA, et al., Am J Psychiatry Feb;160(2):371-3.

64 VA Data Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. Shin LM, et al., Arch Gen Psychiatry Feb;61(2):168-76

65 Acquisition Study

66 60 50 Freeze time percentage (%) ** ** 10 0 vehicle metyrapone (50mg/kg) corticosterone(mg per kg) Acquisition- CONTEXT

67 50 FREEZE TIME PERCENTAGE(%) * ** ** 0 Vehicle Metyrapon e(50mg/kg) corticosterone(mg per kg) Acquisition-CUE

68 Context (24hours) 50 Context (48hours) % Time Spent Freezing * % Time Spent Freezing v ehicle cort 3.0 mg/kg 0 v ehicle cort 3.0 mg/kg (injection before test 30 mins) (no injection before test) Cue (48hours) % Time Spent Freezing vehicle cort 3.0 mg/kg (no injection before test)