Enhanced Hippocampal Neuroplasticity for Surfacing of Inaccessible Traumatic Memories in Veterans With PTSD

Study Overview
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Brief Summary
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Hyperbaric oxygen therapy (HBOT) includes the inhalation of 100% oxygen at pressures exceeding one atmosphere absolute. HBOT has been applied worldwide, mostly for chronic non-healing wounds. Our team demonstrated that HBOT induced hippocampal neuroplasticity in veterans with long-standing treatment-resistant PTSD; this led to enhanced memory recovery and significant improvement in PTSD symptoms. Both physical activity, such as aerobic exercise, and cognitive training were shown to support neurogenesis in the hippocampus. Therefore, the current study aims to evaluate whether hippocampal training, induced by physical and cognitive training, will augment the hippocampal neuroplasticity effect of HBOT and further enhance recovery of inaccessible memories in veterans with PTSD. The protocol will include forty male veterans aged 25 to 60 years, with combat-associated PTSD and peritraumatic amnesia, who will receive either HBOT alone or HBOT and hippocampal training. The HBOT protocol will consist of 60 daily sessions, 90-minutes each, five days a week. Hippocampal training will combine physical and cognitive training 3 times per week, prior to HBOT sessions. Detailed psychological evaluation, anatomic and functional MRI, electroencephalogram and autonomic nervous system data will be obtained at baseline, and during and after treatment. The proposed study offers a new approach of biological treatment for memory manipulations. The findings will help elucidate the mechanism of PTSD-related memory impairment and is expected to contribute to the development of biological memory manipulations for treating PTSD and other memory-related conditions.

Detailed Description
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Our memory constructs a sense of coherence and defines the way we perceive the world. Effective encoding of memories in an adequate context, and their deliberate retrieval at a later time, are crucial for maintaining biographic continuity, and are both heavily dependent on hippocampal function. Post-traumatic stress disorder (PTSD) can be considered a prototype disorder in which a stressogenic event leads to hippocampal malfunction and mal-encoding of a traumatic memory. Persistent hippocampal dysfunction contributes to the unremitting nature of PTSD years after the acute event. The upshot is not only amnesia, but also difficulty in memory integration in the context of time and location, and the feeling that the traumatic event is present all the time and everywhere. Improved hippocampal function may contribute to better access to memories of a traumatic event and to memory contextualization and neutralization. Memory processing is essential for PTSD recovery. Hyperbaric oxygen therapy (HBOT) includes the inhalation of 100% oxygen at pressures exceeding one atmosphere absolute. HBOT has been applied worldwide, mostly for chronic non-healing wounds. Our team demonstrated that HBOT induced hippocampal neuroplasticity in veterans with long-standing treatment-resistant PTSD; this led to enhanced memory recovery and significant improvement in PTSD symptoms. The investigators also demonstrated effects of HBOT on memory recovery among women with fibromyalgia due to childhood sexual abuse. Both physical activity, such as aerobic exercise, and cognitive training were shown to support neurogenesis in the hippocampus. Therefore, the current study aims to evaluate whether hippocampal training, induced by physical and cognitive training, will augment the hippocampal neuroplasticity effect of HBOT and further enhance recovery of inaccessible memories in veterans with PTSD. The protocol will include forty male veterans aged 25 to 60 years, with combat-associated PTSD and peritraumatic amnesia, who will receive either HBOT alone or HBOT and hippocampal training. The HBOT protocol will consist of 60 daily sessions, 90-minutes each, five days a week. Hippocampal training will combine physical and cognitive training 3 times per week, prior to HBOT sessions. Detailed psychological evaluation, anatomic and functional MRI, electroencephalogram and autonomic nervous system data will be obtained at baseline, and during and after treatment. The proposed study offers a new approach of biological treatment for memory manipulations. The findings will help elucidate the mechanism of PTSD-related memory impairment, and is expected to contribute to the development of biological memory manipulations for treating PTSD and other memory-related conditions.

Official Title
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Enhanced Hippocampal Neuroplasticity for Surfacing of Inaccessible Traumatic Memories in Veterans With PTSD

Conditions
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PTSD, Peritraumatic Amnesia

Intervention / Treatment
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* Other: HBOT
* Other: Hippocampal training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of PTSD A history of trauma of at least one course of trauma-focused psychotherapy The presence of peri-traumatic amnesia Exclusion Criteria: A history of traumatic brain injury or any other known brain pathology except PTSD Active smoking Drugs or alcohol abuse other than prescribed cannabis Active asthma, lung pathology, epilepsy or otolaryngological disease incompatible with HBOT The presence of shards or another contraindication for MRI

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be recruited from veterans' clinics and veterans' organizations. After screening, eligible participants will undergo baseline evaluation. Enrolled participants will be 1:1 randomly assigned to the HBOT or HBOT + hippocampal training, according to a computer-generated randomization list. Assessors will be blinded to the participants' allocation. During the study period, all the participants will continue their psychological and pharmacological treatment as prior to their inclusion in the study. Any changes in the frequency of psychologic treatment or pharmacotherapy dose will be reported and documented. The study is designed as a per protocol trial, and thus, participants will only be included in the analysis if they completed the treatment protocol and attained study analysis.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: HBOT<br>Participants will be treated in a multiplace chamber (HAUX-Life-Support GmbH) for a total of 60 daily sessions, five days a week. Each session will consist of 90 minutes exposure to 100% oxygen at 2 ATA (atmospheres), with five-minute air brakes every 20 minutes. | Other: HBOT<br>* Participants will be treated in a multiplace chamber (HAUX-Life-Support GmbH) for a total of 60 daily sessions, five days a week. Each session will consist of 90 minutes exposure to 100% oxygen at 2 ATA, with five-minute air breaks every 20 minutes.<br>|
| Active Comparator: HBOT + hippocampal training<br>Participants will be treated in a multiplace chamber (HAUX-Life-Support GmbH) for a total of 60 daily sessions, five days a week. Each session will consist of 90 minutes exposure to 100% oxygen at 2 ATA, with five-minute air breaks every 20 minutes. Hippocampal training: This will combine physical and cognitive training. Training will be given 3 times per week, prior to the next HBOT, and more than 20 hours after the last HBOT session. | Other: HBOT<br>* Participants will be treated in a multiplace chamber (HAUX-Life-Support GmbH) for a total of 60 daily sessions, five days a week. Each session will consist of 90 minutes exposure to 100% oxygen at 2 ATA, with five-minute air breaks every 20 minutes.<br>Other: Hippocampal training<br>* Hippocampal training: This will combine physical and cognitive training. Training will be given 3 times per week, prior to the next HBOT, and more than 20 hours after the last HBOT session.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in memory gaps (as assessed by the traumatic scene form) | traumatic scene form will be used to assess memory gaps. The intensity of each part sensation will be scored between 0 and 10 (higher score reflects stronger memory). A time line of the event will be drown, and amnestic parts of the memory will be marked (the presumed amnestic time will be evaluated in minutes) | through study completion, an average of 4 months | 
| Time to inaccessible memory surfacing | Daily questionnaire will be used to assess surfacing of new memories. The time of memory surfacing will be defined (session number) | through study completion, an average of 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in brain activity as assessed by fMRI (functional magnetic resonance imaging) | Three different fMRI paradigms will be used to assess hippocampal function, prefrontal cortex activity and the response to the traumatic memory | through study completion, an average of 4 months | 
| cognitive performance as assessed using Neurotrax | Global Score is calculated based on the scores given for Memory performance, Attention, Information Processing speed, Executive Function and Motor skills. The score ranges between 0 and 100, and higher score reflects better performance. | through study completion, an average of 4 months | 
| RAVLT memory test | The test is designed as a list-learning paradigm in which the patient hears a list of 15 nouns and is asked to recall as many words from the list as possible. After five repetitions of free-recall, a second interference list (List B) is presented in the same manner, and the participant is asked to recall as many words from List B as possible. After the interference trial, the participant is immediately asked to recall the words from List A, which she or he heard five times previously. After a 20 min delay, the participant is asked to again recall the words from List A. After this delayed recall task, a list of 50 words is presented containing all of the words from Lists A and B, in addition to 20 phonemically and/or semantically similar words. The multiple memory processes assessed as a global score, called Total Learning The score ranges between 0 and 100, and higher score reflects better performance. | through study completion, an average of 4 months | 
| ROCFT memory test | Copy Z Immediate recall Raw Delayed recall Z will be used to evaluate memory performance, higher scores reflects better performance. | through study completion, an average of 4 months | 
| Verbal Pairs memory test | Recall Total Score First Recall Total Score Learning Slope Delayed List Recall Score Percent retention Recognition Score will be used to evaluate memory performance, higher scores reflects better performance. | through study completion, an average of 4 months |