Neurofeedback for PTSD

A Virtual World/Neuro-feedback Real-time Functional MRI Approach to PTSD Treatment

Despite availability of treatment, posttraumatic stress disorder (PTSD) remains a major
problem in Veterans, with tremendous impact on patients, their families, and the VHA system.
A major therapeutic approach used for Veterans with PTSD is exposure therapy, which has
beneficial effects in many patients. However, improvements on current therapies are needed as
many Veterans improve less than the investigators would like.

The overarching hypotheses of this proposal are two-fold. First, that brain activity measured
with functional MRI (fMRI) can be used to discern the different brain states of a PTSD
patient during a threatening experience vs. during a calm moment, and that patients, aided by
neuro-feedback derived from real-time fMRI during a virtual reality experience, can learn to
reduce their response by willfully modifying their brain state. Secondly, that the continuous
measurement of physical activity, heart rate, and sleep patterns using wearable devices can
help in the study of PTSD treatment trajectories.

The investigators will combine virtual worlds, machine learning, real-time fMRI, and
neuro-feedback to provide a novel PTSD treatment that the investigators hope will be more
effective than current alternatives, at least in certain challenging cases. Importantly, the
investigators will construct a computational model that is specific for patient+stimulus
combination. This is critical as PTSD patients are very heterogeneous.

Aim 1. Use of Virtual World/Neurofeedback with Real-Time fMRI as therapy for PTSD Fifteen
PTSD patients recruited at MEDVAMC will be exposed to Virtual Iraq, a virtual world platform
in which they will be exposed to war-like scenarios, and to calm scenes where no threat will
be present. Brain activity will be collected using fMRI and analyzed with machine learning to
discern between both extreme brain states (STRESS vs. CALM). These two states will be used
during neurofeedback training: In the following weeks, participants will be exposed to 7
fMRI/Virtual World sessions in which they will be instructed to try to move a gauge to the
CALM side by using individual mental strategies (active like concentrating on a particular
memory, or passive as it has been shown that neurofeedback does not necessarily need willful
effort to work). The stressfulness of the Virtual World will be manipulated by the gauge:
when the patient is able to move the bar toward CALM (by bringing the brain toward that
state) the stressfulness of the Virtual World will decrease.

Hypothesis 1: PTSD symptoms will decrease as training progresses and patients learn mental
strategies to "bring the world" to a CALM state.

Aim 2. Study of wearable technology to assess treatment success in PTSD While there are PTSD
measuring tools and the investigators will use them before, during, and after training, in
general self-reports are not as robust and reliable as one would like. Thus, it would be
beneficial to have more physiological measures of treatment progression for PTSD, and for
psychiatry in general. The investigators will use a wearable device similar to a wristwatch
that the participant will continuously wear throughout the training, and will allow the
investigators to measure physical activity, heart rate, and sleep quality.

Hypothesis 2: Data from the wearable device will correlate with self reports and with
increased ability to willfully bring the Virtual World to the CALM state during training.

In conclusion, the investigators propose that neurofeedback will give PTSD patients the
possibility of discovering personal mental strategies to become calmer during stressful
situations. However, the learning process does not need to be the result of willful effort,
as it has been shown that real time fMRI-related learning can occur without conscious effort
or awareness. In addition, the investigators postulate that wearable devices will capture
physiological data linked to the trajectories during PTSD treatment.

The investigators understand that unfortunately the approach may be too expensive to be
routinely used (a careful post-study cost-benefit study may prove otherwise, though).
However, the investigators hypothesize that if this pilot is successful, it will be possible
to use this data to develop less expensive hybrid alternatives to add to exposure therapy,
such as using fMRI in combination with EEG to discern between brain states (only one MRI
visit needed), and then using only EEG during training.

Preliminary Studies The research in this proposal will build upon the investigators' 4-year
research project at UT Austin funded by the Army Research Office. That work greatly extended
the utility of 3D Virtual Worlds for use as stimuli for fMRI-based research, and laid the
groundwork for individualized therapies and training. It will play a central role in
providing neuro-feedback by analyzing brain activity of patients in response to virtual
worlds designed to elicit PTSD responses, such as those provided by BRAVEMIND.

fMRI data acquisition samples a volume of brain activity every 2-3 seconds for several
minutes as needed. Each sample is a 3D array of voxels that measure the aggregate brain
activity for a few million neurons. Conventional fMRI data analysis treats the values from
each voxel as separate time series, and performs a linear statistical analysis that relates
the stimulus to the measured activity. To deal with the increased complexity of using
real-time virtual worlds as a stimulus, the investigators instead used machine learning for
analysis. Machine learning based methods can extract complex correlations over many voxels
rather than a single voxel. The method involves "training" by feeding example input/output
pairs into the algorithm. In the investigators' case, the input is an fMRI time sample and
the output, reflecting the stimulus, is a category in which the investigators are interested.
The investigators refer to each category as a "brain state", which is the brain activation
pattern specified by labeling each time slice with a particular stimulus category.

The investigators were able to achieve accurate performance for detecting brain states in two
different experiments. Both used virtual worlds suggestive of Iraqi towns and virtual
characters of U.S. Army and native hostile combatants. In the first experiment, the
investigators used a passive viewing paradigm in which 1-6 combatants were presented at
different locations in a virtual town. Performance averaged across subjects was quite good
and far above chance in terms of determining how many combatants (1-6) was the participant
seeing at each time. The second experiment used a similar but more complex stimulus that
included a specific visual task requiring user reaction. Subjects were asked to rapidly
respond via a button press to a weapon being pulled out suddenly by a single hostile
combatant within a crowd of 20 characters, half of which were friendly forces. Task
difficulty was varied randomly over encounters that lasted 30 sec each. The investigators'
machine-learning methods could recognize this brain state dimension with 70%-90% accuracy.

Research Design and Methods Aim 1. Use of Virtual World/Neurofeedback with Real-Time fMRI as
therapy for PTSD The investigators will combine virtual worlds, real-time fMRI, machine
learning, and neuro-feedback, to provide a novel PTSD treatment that the investigators hope
will be more effective than current alternatives. The investigators also anticipate that by
examining the brain maps like those above the investigators will gain insight into how PTSD
manifests in the brains of different subjects. The stereo audio/visual stimulus will be
provided by the BRAVEMIND system. Prior to scanning, each subject will participate in a
side-lab therapy session attended by a trained therapist. The investigators will adjust
stimulus parameters to provide an appropriately therapeutic range of responses between CALM
and STRESSED. Various scenes/scenarios will be available. This range of parameter settings
will be captured for subsequent scanning sessions. In the scanner, the virtual-reality
stimuli will be delivered using an MR-compatible 3D display. Subjects will provide
self-report their level of "STRESSED" anxiety using a five-button MR-compatible response
device. This response data and the MRI data from the first two sessions will be used by
machine-learning algorithms to build classifiers that can discriminate the subject's
responses between CALM - STRESSED at every 1.5 sec time sample. In the following 6 sessions,
the subject will be presented with similar but not identical stimuli while receiving feedback
from the machine learning. This will enable them to gradually learn how to self-modulate
their own brain response toward a calmer reaction. Such self-induced changes will be detected
by the fMRI system and will be used to modulate the virtual world to directly reduce the
degree of perceived threat; thus, providing the real-time neuro-feedback required by
extinction therapy (a "thermometer" will be displayed).

Whole-brain FMRI data will be collected using a 3T Siemens Prisma scanner using SMS
acceleration to obtain 2-mm voxel size and TR = 1.5 sec (SMS x3, G = 2, TE = 30 ms, FA = 72
). Scanning sessions will last ~1 hour, and begin with the collection of localizers and a
high-resolution anatomy (MP-RAGE), 1-mm cubic voxels, followed by the collection of fMRI data
during virtual-reality stimulus presentation. Each fMRI run will last ~6 min, and 6-8 runs
will be collected.

Pitfalls and alternative strategies. The investigators have demonstrated the ability to
classify an internal brain dimension with 89% accuracy, but it may not be possible to obtain
similar accuracy for the "PTSD" dimension. It may be possible to improve results by including
the observed pulse and respiration data as input into the machine learning. Moreover, even if
the feedback is unsuccessful, the investigators will still gain insights into the physiology
of PTSD from the sensitivity maps that are generated by the machine learning.

Aim 2. Study of wearable technology to assess treatment success in PTSD Physical activity,
heart rate, and sleep patterns all play important roles in PTSD. Wearable technology has
recently evolved such that the investigators can now constantly measure these three
parameters in a non-invasive manner throughout the course of a study. The investigators
propose to study self-reported symptoms in conjunction with physical activity, sleep
patterns, and heart rate date over 9 weeks. The investigators will use linear regression to
study whether CAPS5, PCL, and diary symptoms correlate with activity, sleep, and heart rate
patterns during treatment. The investigators hypothesize that in patients in which the
treatment is most successful, a) Average HR will decrease more, b) Bouts of high HR during
day and night will be less common, c) Average physical activity will increase, d) Physical
activity will regularize to more activity during the day and less activity during the night,
e) Average time asleep will increase, and f) Sleep patterns will regularize with less awake
epochs during the night.

Pitfalls and alternative strategies. It is possible that the data from wearable devices will
not correlate with symptom improvement. A likely explanation would be that the error rate of
current devices does not allow for correlations to be significant. If that is the case, this
approach should be tested again in the future. Another less likely explanation would be that
physical activity, heart rate, and sleep quality are not as strongly correlated with PTSD
symptoms as the available data suggests. Since this is a small pilot study, data suggesting a
trend would point into possible directions to study in the future.

General conclusion

The main idea of the study is that the VR will change to a less stressful environment as the
brain approaches the state previously defined as CALM. The investigators postulate that over
time, patients will learn to consciously bring their brain to CALM state, which will provide
them with individualized mental strategies to calm down when a trauma/stress trigger is
present.

Inclusion Criteria:

- Meet CAPS5 PTSD criteria

- OEF/OIF/OND & PGW Veterans

- Seeking treatment for PTSD

Exclusion Criteria:

- DSM-5 criteria for drug or alcohol abuse or dependence in past 30 days

- History of moderate to severe traumatic brain injury

- Presence of contraindications to MRI

- Current neurological or general medical conditions known to impact cognitive and/or
emotional functioning (epilepsy, Parkinson's, etc.)

- Acute psychological instability, schizophrenia, etc.