Saturday, August 01, 2015

The Idiosyncratic Side of Diagnosis by Brain Scan and Machine Learning


R2D3 recently had a fantastic Visual Introduction to Machine Learning, using the classification of homes in San Francisco vs. New York as their example. As they explain quite simply:
In machine learning, computers apply statistical learning techniques to automatically identify patterns in data. These techniques can be used to make highly accurate predictions.
You should really head over there right now to view it, because it's very impressive.


Computational neuroscience types are using machine learning algorithms to classify all sorts of brain states, and diagnose brain disorders, in humans. How accurate are these classifications? Do the studies all use separate training sets and test sets, as shown in the example above?

Let's say your fMRI measure is able to differentiate individuals with panic disorder (n=33) from those with panic disorder + depression (n=26) with 79% accuracy.1 Or with structural MRI scans you can distinguish 20 participants with treatment-refractory depression from 21 never-depressed individuals with 85% accuracy.2 Besides the issues outlined in the footnotes, the reality check is that the model must be able to predict group membership for a new (untrained) data set. And most studies don't seem to do this.

I was originally drawn to the topic by a 3 page article entitled, Machine learning algorithm accurately detects fMRI signature of vulnerability to major depression (Sato et al., 2015). Wow! Really? How accurate? Which fMRI signature? Let's take a look.
  • machine learning algorithm = Maximum Entropy Linear Discriminant Analysis (MLDA)
  • accurately predicts = 78.3% (72.0% sensitivity and 85.7% specificity)
  • fMRI signature = guilt-selective anterior temporal functional connectivity changes (seems a bit overly specific and esoteric, no?)
  • vulnerability to major depression = 25 participants with remitted depression vs. 21 never-depressed participants
The authors used a standard leave-one-subject-out procedure in which the classification is cross-validated iteratively by using a model based on the sample after excluding one subject to independently predict group membership but they did not test their fMRI signature in completely independent groups of participants.

Nor did they try to compare individuals who are currently depressed to those who are currently remitted. That didn't matter, apparently, because the authors suggest the fMRI signature is a trait marker of vulnerability, not a state marker of current mood. But the classifier missed 28% of the remitted group who did not have the guilt-selective anterior temporal functional connectivity changes.”

What is that, you ask? This is a set of mini-regions (i.e., not too many voxels in each) functionally connected to a right superior anterior temporal lobe seed region of interest during a contrast of guilt vs. anger feelings (selected from a number of other possible emotions) for self or best friend, based on written imaginary scenarios like “Angela [self] does act stingily towards Rachel [friend]” and “Rachel does act stingily towards Angela” conducted outside the scanner (after the fMRI session is over). Got that?

You really need to read a bunch of other articles to understand what that means, because the current paper is less than 3 pages long. Did I say that already?


modified from Fig 1B (Sato et al., 2015). Weight vector maps highlighting voxels among the 1% most discriminative for remitted major depression vs. controls, including the subgenual cingulate cortex, both hippocampi, the right thalamus and the anterior insulae.


The patients were previously diagnosed according to DSM-IV-TR (which was current at the time), and in remission for at least 12 months. The study was conducted by investigators from Brazil and the UK, so they didn't have to worry about RDoC, i.e. “new ways of classifying mental disorders based on behavioral dimensions and neurobiological measures” (instead of DSM-5 criteria). A “guilt-proneness” behavioral construct, along with the “guilt-selective” network of idiosyncratic brain regions, might be more in line with RDoC than past major depression diagnosis.

Could these results possibly generalize to other populations of remitted and never-depressed individuals? Well, the fMRI signature seems a bit specialized (and convoluted). And overfitting is another likely problem here...

In their next post, R2D3 will discuss overfitting:
Ideally, the [decision] tree should perform similarly on both known and unknown data.

So this one is less than ideal. [NOTE: the one that's 90% in the top figure]

These errors are due to overfitting. Our model has learned to treat every detail in the training data as important, even details that turned out to be irrelevant.

In my next post, I'll present an unsystematic review of machine learning as applied to the classification of major depression. It's notable that Sato et al. (2015) used the word “classification” instead of “diagnosis.”3


ADDENDUM (Aug 3 2015): In the comments, I've presented more specific critiques of: (1) the leave-one-out procedure and (2) how the biomarker is temporally disconnected from when the participants identify their feeling as 'guilt' or 'anger' or etc. (and why shame is more closely related to depression than guilt).


Footnotes

1 The sensitivity (true positive rate) was 73% and the specificity (true negative rate) was 85%. After correcting for confounding variables, these numbers were 77% and 70%, respectively.

2 The abstract concludes this is a “high degree of accuracy.” Not to pick on these particular authors (this is a typical study), but Dr. Dorothy Bishop explains why this is not very helpful for screening or diagnostic purposes. And what you'd really want to do here is to discriminate between treatment-resistant vs. treatment-responsive depression. If an individual does not respond to standard treatments, it would be highly beneficial to avoid a long futile period of medication trials.

3 In case you're wondering, the title of this post was based on The Dark Side of Diagnosis by Brain Scan, which is about Dr  Daniel Amen. The work of the investigators discussed here is in no way, shape, or form related to any of the issues discussed in that post.


Reference

Sato, J., Moll, J., Green, S., Deakin, J., Thomaz, C., & Zahn, R. (2015). Machine learning algorithm accurately detects fMRI signature of vulnerability to major depression Psychiatry Research: Neuroimaging DOI: 10.1016/j.pscychresns.2015.07.001

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Sunday, July 19, 2015

Scary Brains and the Garden of Earthly Deep Dreams


In case you've been living under a rock the past few weeks, Google's foray into artificial neural networks has yielded hundreds of thousands of phantasmagoric images. The company has an obvious interest in image classification, and here's how they explain the DeepDream process in their Research Blog:
Inceptionism: Going Deeper into Neural Networks

. . .
We train an artificial neural network by showing it millions of training examples [of dogs and eyes and pagodas, let's say] and gradually adjusting the network parameters until it gives the classifications we want. The network typically consists of 10-30 stacked layers of artificial neurons. Each image is fed into the input layer, which then talks to the next layer, until eventually the “output” layer is reached. The network’s “answer” comes from this final output layer.

. . .
One way to visualize what goes on is to turn the network upside down and ask it to enhance an input image in such a way as to elicit a particular interpretation. Say you want to know what sort of image would result in “Banana.” Start with an image full of random noise, then gradually tweak the image towards what the neural net considers a banana... By itself, that doesn’t work very well, but it does if we impose a prior constraint that the image should have similar statistics to natural images, such as neighboring pixels needing to be correlated.

After Google released the deepdream code on GitHub, Psychic VR Lab set up a Deep Dream web interface, which currently has over 300,000 groovy and scary images.

I've taken an interest in the hallucinogenic and distorted brain images, including the one above. I can't properly credit the human input interface (which wasn't me), but I found it after a submitting a file of my own in the early stages of http://psychic-vr-lab.com/deepdream/.  I can't find the url hosting my image, but I came across the frightening brain here, along with the original.





I've included a few more for your viewing pleasure. Brain Decoder posted a dreamy mouse hippocampus Brainbow.




Here's one by HofmannsBicycle.



And a fun fave courtesy of @rogierK and @katestorrs. This one is cartoonish instead of menacing.



Rogier said: "According to #deepdream the homunculus in our brains is a terrifying bird-dog hybrid."

Aw, I thought it was kind of cute. More small birds, fewer staring judgmental eyeballs.


And the grand finale isn't a brain at all. But who doesn't want to see the dreamified version of The Garden of Earthly Delights, by Hieronymus Bosch? Here it is, via @aut0mata. Click on image for a larger view.
 




When nothing's right, just close your eyes
Close your eyes and you're gone

-Beck, Dreams




ADDENDUM (July 21 2015): It's worth reading Deepdream: Avoiding Kitsch by Josh Nimoy, which confirms the training set was filled with dogs, birds, and pagodas. Nimoy also shows deepdream images done with neural networks trained on other datasets.

For example, the image below was generated by a neural network trained to do gender classification.

Read more »

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Tuesday, July 14, 2015

Can Tetris Reduce Intrusive Memories of a Trauma Film?



For some inexplicable reason, you watched the torture gore horror film Hostel over the weekend. On Monday, you're having trouble concentrating at work. Images of severed limbs and bludgeoned heads keep intruding on your attempts to code or write a paper. So you decide to read about the making of Hostel.You end up seeing pictures of the most horrifying scenes from the movie. It's all way too way much to simply shake off so then you decide to play Tetris.

But a funny thing happens. The unwelcome images start to become less frequent. By Friday, the gory mental snapshots are no longer forcing their way into your mind's eye. The ugly flashbacks are gone.

Meanwhile, your parnter in crime is having similar images of eye gouging pop into his head. Except he didn't review the tortuous highlights on Monday, and he didn't play Tetris. He continues to have involuntary intrusions of Hostel images once or twice a day for the rest of the week.

This is basically the premise (and outcome) of a new paper in Psychological Science by Ella James and colleagues at Cambridge and Oxford. It builds on earlier work suggesting that healthy participants who play Tetris shortly after watching a “trauma” film will have fewer intrusive memories (Holmes et al, 2009, 2010). This is based on the idea that involuntary “flashbacks” in real post-traumatic stress disorder (PTSD) are visual in nature, and require visuospatial processing resources to generate and maintain. Playing Tetris will interfere with consolidation and subsequent intrusion of the images, at least in an experimental setting (Holmes et al, 2009):
...Trauma flashbacks are sensory-perceptual, visuospatial mental images. Visuospatial cognitive tasks selectively compete for resources required to generate mental images. Thus, a visuospatial computer game (e.g. "Tetris") will interfere with flashbacks. Visuospatial tasks post-trauma, performed within the time window for memory consolidation [6 hrs], will reduce subsequent flashbacks. We predicted that playing "Tetris" half an hour after viewing trauma would reduce flashback frequency over 1-week.

The timing is key here. In the earlier experiments, Tetris play commenced 30 min after the trauma film experience, during the 6 hour window when memories for the event are stabilized and consolidated. Newly formed memories are thought to be malleable during this time.

However, if one wants to extrapolate directly to clinical application in cases of real life trauma exposure (and this is problematic, as we'll see later), it's pretty impractical to play Tetris right after an earthquake, auto accident, mortar attack, or sexual assault. So the new paper relies on the process of reconsolidation, when an act of remembering will place the memory in a labile state once again, so it can be modified (James et al., 2015).




The procedure was as follows: 52 participants came into the lab on Day 0 and completed questionnaires about depression, anxiety, and previous trauma exposure. Then they watched a 12 min trauma film that included 11 scenes of actual death (or threatened death) or serious injury (James et al., 2015):
...the film functioned as an experimental analogue of viewing a traumatic event in real life. Scenes contained different types of context; examples include a young girl hit by a car with blood dripping out of her ear, a man drowning in the sea, and a van hitting a teenage boy while he was using his mobile phone crossing the road. This film footage has been used in previous studies to evoke intrusive memories...

After the film, they rated “how sad, hopeless, depressed, fearful, horrified, and anxious they felt right at this very moment” and “how distressing did you find the film you just watched?” They were instructed to keep a diary of intrusive images and come back to the lab 24 hours later.

On Day 1, participants were randomized to either the experimental group (memory reactivation + Tetris) or the control group (neither manipulation). The experimental group viewed 11 still images from the film that served as reminder cues to initiate reconsolidation. This was followed by a 10 min filler task and then 12 min of playing Tetris (the Marathon mode shown above). The game instructions aimed to maximize the amount of mental rotation the subjects would use. The controls did the filler task and then sat quietly for 12 min.

Both groups kept a diary of intrusions for the next week, and then returned on Day 7. All participants performed the Intrusion Provocation Task (IPT). Eleven blurred pictures from the film were shown, and subjects indicated when any intrusive mental images were provoked. Finally, the participants completed a few more questionnaires, as well as a recognition task that tested their verbal (T/F written statements) and visual (Y/N for scenes) memories of the film.1

The results indicated that the Reactivation + Tetris manipulation was successful in decreasing the number of visual memory intrusions in both the 7-day diary and the IPT (as shown below).


modified from Fig. 1 (James et al., 2015). Asterisks indicate a significant difference between groups (**p < .001). Error bars represent +1 SEM.


Cool little snowman plots (actually frequency scatter plots) illustrate the time course of intrusive memories in the two groups.


modified from Fig. 2 (James et al., 2015). Frequency scatter plots showing the time course of intrusive memories reported in the diary daily from Day 0 (prior to intervention) to Day 7. The intervention was on Day 1, and the red arrow is 24 hrs later (when the intervention starts working). The solid lines are the results of a generalized additive model. The size of the bubbles represents the number of participants who reported the indicated number of intrusive memories on that particular day.


But now, you might be asking yourself if the critical element was Tetris or the reconsolidation update procedure (or both), since the control group did neither. Not to worry. Experiment 2 tried to disentangle this by recruiting four groups of participants (n=18 in each) the original two groups plus two new ones: Reactivation only and Tetris only.

And the results from Exp. 2 demonstrated that both were needed.


modified from Fig. 4 (James et al., 2015). Asterisks indicate that results for the Reactivation + Tetris group were significantly different from results for the other three groups (*p < .01). Error bars represent +1 SEM. The No-Task Control and Tetris Only groups did not differ for diary intrusions (n.s.).


The authors' interpretation:
Overall, the results of the present experiments indicate that the frequency of intrusive memories induced by experimental trauma can be reduced by disrupting reconsolidation via a competing cognitive-task procedure, even for established memories (here, events viewed 24 hours previously). ... Critically, neither playing Tetris alone (a nonreactivation control condition) nor the control of memory reactivation alone was sufficient to reduce intrusions... Rather, their combination is required, which supports a reconsolidation-theory account. We suggest that intrusive-memory reduction is due to engaging in a visuospatial task within the window of memory reconsolidation, which interferes with intrusive image reconsolidation (via competition for shared resources).

Surprisingly (perhaps), I don't have anything negative to say about the study. It was carefully conducted and interpreted with restraint. They don't overextrapolate to PTSD. They don't use the word “flashback” to describe the memory phenomenon. And they repeatedly point out that it's “experimental trauma.” I actually considered reviving The Neurocomplimenter for this post, but that would be going too far...

Compare this flattering post with one I wrote in 2010, about a related study by the same authors (Holmes et al.. 2010). That paper certainly had a modest title: Key Steps in Developing a Cognitive Vaccine against Traumatic Flashbacks: Visuospatial Tetris versus Verbal Pub Quiz.

Cognitive vaccine. Traumatic. Flashbacks. Twelve mentions of PTSD. This led to ridiculous headlines like Doctors Prescribing 'Tetris Therapy'.

Here, let me fix that for you:

Tetris Helps Prevent Unpleasant Memories of Gory Film in Happy People

My problem wasn't with the actual study, but with the way the authors hyped the results and exaggerated their clinical significance. So I'm pleased to see a more restrained approach here.


The media coverage for the new paper was generally more accurate too:

Can playing Tetris reduce intrusive memories? (Medical News Today)

Moving tiles as an unintrusive way to handle flashbacks (Medical Express)

Intrusiveness of Old Emotional Memories Can Be Reduced by Computer Game Play Procedure (APS)

But we can always count on the Daily Mail for a good time: Could playing TETRIS banish bad memories? Retro Nintendo game 'reduces the risk of post-traumatic stress disorder' 2

Gizmodo is a bit hyperbolic as well: Tetris Blocks Flashbacks of Traumatic Events Lodged in the Brain [“lodged in the brain” for all of 24 hrs]


Questions for Now and the Future

Is there really nothing wrong with this study?? Being The Neurocritic, I always have to find something to criticize... and here I had to dig through the Supplemental Material to find issues that may affect the translational potential of Tetris-based interventions.

  • The Intrusion subscale of the Impact of Event Scale (IES-R) was used as an exploratory measure, and subject ratings were between 0 and 1.
The Intrusion subscale consists of 8 questions like “I found myself acting or feeling like I was back at that time” and “I had dreams about it” that are rated from 0 (not at all) to 4 (extremely). The IES-R is given to people after distressing, traumatic life events. These individuals may have actual PTSD symptoms like flashbacks and nightmares.

In Exp. 1, the Reactivation + Tetris group (M = .68) had significantly lower scores (p = .016) on Day 7 than the control group (M = 1.01). BUT this is not terribly meaningful, due to a floor effect. And in Exp. 2 there was no difference between the four groups, with scores ranging from 0.61 to 0.81.3

As an overall comment, watching a film of a girl getting hit by a car is not the same as witnessing it in person (obviously). But this real-life scenario may be the most amenable to Tetris, because the witness was not in the accident themselves and did not know the girl (both of which would heighten the emotional intensity and vividness of the trauma, elements that transcend visual imagery).

It's true that in PTSD, the involuntary intrusion of trauma memories (i.e., flashbacks) have a distinctly sensory quality to them (Ehlers et al. 2004). Visual images are most common, but bodily sensations, sounds, and smells can be incorporated into a multimodal flashback. Or could occur on their own.

  • The effectiveness of the Tetris intervention was related to game score and self-rated task difficulty.
This means that people who were better at playing Tetris showed a greater decrease in intrusive memories. This result wasn't covered in the main paper, but it makes you wonder about cause and effect. Is it because the game was more enjoyable for them? Or could it be that their superior visual-spatial abilities (or greater game experience) resulted in greater interference, perhaps by using up more processing resources? That's always a dicey argument, as you could also predict that better, more efficient game play uses fewer visual-spatial resources.

An interesting recent paper found that individuals with PTSD (who presumably experience intrusive visual memories) have worse allocentric spatial processing abilities than controls (Smith et al., 2015). This means they have problems representing the locations of environmental features relative to each other (instead of relative to the self). So are weak spatial processing and spatial memory abilities caused by the trauma, or are weak spatial abilities a vulnerability factor for developing PTSD?

  • As noted by the authors, the modality-specificity of the intervention needs to be assessed.
Their previous paper showed that the effect was indeed specific to Tetris. A verbally based video game (Pub Quiz) actually increased the frequency of intrusive images (Holmes et al., 2010).

It would be interesting to disentangle the interfering elements of Tetris even further. Would any old mental rotation task do the trick? How about passive viewing of Tetris blocks, or is active game play necessary? Would a visuospatial n-back working memory task work? It wouldn't be as fun, but it obviously uses up visual working memory processing resources. What about Asteroids or Pac-Man or...? 4

This body of work raises a number of interesting questions about the nature of intrusive visual memories, traumatic and non-traumatic alike. Do avid players of action video games (or Tetris) have fewer intrusive memories of past trauma or trauma-analogues in everyday life? I'm not sure this is likely, but you could find out pretty quickly on Amazon Mechanical Turk or one of its alternatives.

There are also many hurdles to surmount before Doctors Prescribe 'Tetris Therapy'. For instance, what does it mean to have the number of weekly Hostel intrusions drop from five to two? How would that scale to an actual trauma flashback, which may involve a fear or panic response?

The authors conclude the paper by briefly addressing these points:
A critical next step is to  investigate  whether  findings  extend  to  reducing  the psychological impact of real-world emotional events and media. Conversely, could computer gaming be affecting intrusions of everyday events?

A number of different research avenues await these investigators (and other interested parties). And — wait for it — a clinical trial of Tetris for flashback reduction has already been completed by the investigators at Oxford and Cambridge!

A Simple Cognitive Task to Reduce the Build-Up of Flashbacks After a Road Traffic Accident (SCARTA)

Holmes and colleagues took the consolidation window very seriously: participants played Tetris in the emergency room within 6 hours of experiencing or witnessing an accident. I'll be very curious to see how this turns out...


Footnotes

1 Interestingly, voluntary retrieval of visual and verbal memories was not affected by the manipulation, highlighting the uniqueness of flashback-like phenomena.

2 It does no such thing. But they did embed a video of Dr. Tom Stafford explaining why Tetris is so compelling...

3 The maximum total score on the IES-R is 32. The mean total score in a group of car accident survivors was 17; in Croatian war veterans it was 25. At first I assumed the authors reported the total score out of 32, rather than the mean score per item. I could be very wrong, however. By way of comparison, the mean item score in female survivors of intimate partner violence was 2.26. Either way, the impact of the trauma film was pretty low in this study, as you might expect.

4 OK, now I'm getting ridiculous. I'm also leaving aside modern first-person shooter games as potentially too traumatic and triggering.


References

Ehlers A, Hackmann A, Michael T. (2004). Intrusive re-experiencing in post-traumaticstress disorder: phenomenology, theory, and therapy. Memory 12(4):403-15.

Holmes EA, James EL, Coode-Bate T, Deeprose C. (2009). Can playing the computer game "Tetris" reduce the build-up of flashbacks for trauma? A proposal from cognitive science. PLoS One 4(1):e4153.

Holmes, E., James, E., Kilford, E., & Deeprose, C. (2010). Key Steps in Developing a Cognitive Vaccine against Traumatic Flashbacks: Visuospatial Tetris versus Verbal Pub Quiz. PLoS ONE, 5 (11) DOI: 10.1371/journal.pone.0013706

James, E., Bonsall, M., Hoppitt, L., Tunbridge, E., Geddes, J., Milton, A., & Holmes, E. (2015). Computer Game Play Reduces Intrusive Memories of Experimental Trauma via Reconsolidation-Update Mechanisms. Psychological Science DOI: 10.1177/0956797615583071

Smith KV, Burgess N, Brewin CR, King JA. (2015). Impaired allocentric spatialprocessing in posttraumatic stress disorder. Neurobiol Learn Mem. 119:69-76.

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Saturday, June 27, 2015

Who Will Pay for All the New DBS Implants?



Recently, Science and Nature had news features on big BRAIN funding for the development of deep brain stimulation technologies. The ultimate aim of this research is to treat and correct malfunctioning neural circuits in psychiatric and neurological disorders. Both pieces raised ethical issues, focused on device manufacturers and potential military applications, respectively.

A different ethical concern, not mentioned in either article, is who will have access to these new devices, and who is going to pay the medical costs once they hit the market. DBS for movement disorders is a test case, because Medicare (U.S.) approved coverage for Parkinson's disease (PD) and essential tremor in 2003. Which is good, given that unilateral surgery costs about $50,000.

Willis et al. (2014) examined Medicare records for 657,000 PD patients and found striking racial disparities. The odds of receiving DBS in white PD patients were five times higher than for African Americans, and 1.8 times higher than for Asians. And living in a neighborhood with high socioeconomic status was associated with 1.4-fold higher odds of receiving DBS. Out-of-pocket costs for Medicare patients receiving DBS are over $2,000 per year, which is quite a lot of money for low-income senior citizens.

Aaron Saenz raised a similar issue regarding the cost of the DEKA prosthetic arm (aka "Luke"):
But if you're not a veteran, neither DARPA project may really help you much. The Luke Arm is slated to cost $100,000+.... That's well beyond the means of most amputees if they do not have the insurance coverage provided by the Veteran's Administration. ... As most amputees are not veterans, I think that the Luke Arm has a good chance of being priced out of a large market share.

The availability of qualified neurosurgeons, even in affluent areas, will be another problem once future indications are FDA-approved (or even trialed).

The situation in one Canadian province (British Columbia, with a population of 4.6 million) is instructive. An article in the Vancouver Sun noted that in March 2013, only one neurosurgeon was qualified to perform DBS surgeries for Parkinson's disease (or for dystonia). This resulted in a three year waiting list. Imagine, all these eligible patients with Parkinson's have to endure their current condition (and worse) for years longer, instead of having a vastly improved quality of life.
Funding, doctors needed if brain stimulation surgery to expand in B.C.:

... “But here’s the problem: We already have a waiting list of almost three years, from the time family doctors first put in the referral to the DBS clinic. And I’m the only one in B.C. doing this. So we really aren’t able to do more than 40 cases a year,” [Dr. Christopher Honey] said.
. . .
...The health authority allocates funding of $1.1 million annually, which includes the cost of the $20,000 devices, and $14,000 for each battery replacement. On average, batteries need to be replaced every three years.
. . .
To reduce wait times, the budget would have to increase and a Honey clone would have to be trained and hired.

Back in the U.S., Rossi et al. (2014) called out Medicare for curbing medical progress:
Devices for DBS have been approved by the FDA for use in treating Parkinson disease, essential tremor, obsessive-compulsive disorder, and dystonia,2 but expanding DBS use to include new indications has proven difficult—specifically because of the high cost of DBS devices and generally because of disincentives for device manufacturers to sponsor studies when disease populations are small and the potential for a return on investment is not clear. In many of these cases, Medicare coverage will determine whether a study will proceed. ... Ultimately, uncertain Medicare coverage coupled with the lack of economic incentives for industry sponsorship could limit investigators’ freedom of inquiry and ability to conduct clinical trials for new uses of DBS therapy.

But the question remains, where is all this health care money supposed to come from?

The device manufacturers aren't off the hook, either, but BRAIN is trying to reel them in. NIH recently sponsored a two-day workshop, BRAIN Initiative Program for Industry Partnerships to Facilitate Early Access Neuromodulation and Recording Devices for Human Clinical Studies [agenda PDF]. The purpose was to:
  • Bring together stakeholders and interested parties to disseminate information on opportunities for research using latest-generation devices for CNS neuromodulation and interfacing with the brain in humans.
  • Describe the proposed NIH framework for facilitating and lowering the cost of new studies using these devices.
  • Discuss regulatory and intellectual property considerations.
  • Solicit recommendations for data coordination and access.

The Program Goals [PDF]:
...we hope to spur human research bridging the “valley of death” that has been a barrier to translating pre-clinical research into therapeutic outcomes. We expect the new framework will allow academic researchers to test innovative ideas for new therapies, or to address scientific unknowns regarding mechanisms of disease or device action, which will facilitate the creation of solid business cases by industry and venture capital for the larger clinical trials required to take these ideas to market.

To advance these goals, NIH is pursuing general agreements (Memoranda of Understanding, MOUs) with device manufacturers to set up a framework for this funding program. In the MOUs, we expect each company to specify the capabilities of their devices, along with information, support and any other concessions they are willing to provide to researchers.

In other words, it's a public/private partnership to advance the goal of having all depressed Americans implanted with the CyberNeuroTron WritBit device by 2035 (just kidding!!).

But seriously... before touting the impending clinical relevance of a study in rodents, basic scientists and bureaucrats alike should listen to patients with the current generation of DBS devices. Participants in the halted BROADEN Trial for refractory depression reported outcomes ranging from “...the side effects caused by the device were, at times, worse than the depression itself” to “I feel like I have a second chance at life.”

What do you do with a medical device that causes great physical harm to one person but is a godsend for another? What are the factors involved? Sloppy patient selection criteria? Surgeon ineptitude? Anatomical variation? All of the above and more are likely to contribute to the wildly divergent outcomes.

One anonymous commenter on a previous post recently said that the study sponsor had abandoned them:
The BROADEN study isn't continuing the 4 year follow-up study. I'm in it and just got a phone call. They'll put in a rechargeable device for those of us enrolled and will not follow up with us. The FDA approved it just for us who had the surgery. It looks like St. Judes isn't going foe FDA approval anymore. I have no public reference for this but it was what I was just told over the phone. It has helped me and I don't know what I'm going to do about follow-up care except with my psychiatrist who doesn't have DBS experience. Scary.

Why isn't the manufacturer providing medical care for the study participants? Because they don't have to! In her Science piece, Emily Underwood reported:
Recent failures of several large clinical trials of deep brain stimulation for depression loomed large over the meeting. In the United States, companies or institutions sponsoring research are rarely, if ever, required to pay medical costs that trial subjects incur as a result of their participation, [Hank] Greely points out. “Many people who work in research ethics, including me, think this is wrong,” he says. 

Hopefully the workshop attendees considered not only how to lower the cost of new DBS studies, but also how to provide equitable circuit-based health care in the future.


Further Reading (and viewing)

Watch the NIH videocast: Day 1 and Day 2.

BROADEN Trial of DBS for Treatment-Resistant Depression

Update on the BROADEN Trial of DBS for Treatment-Resistant Depression


References

Rossi, P., Machado, A., & Okun, M. (2014). Medicare Coverage of Investigational Devices. JAMA Neurology, 71 (5) DOI: 10.1001/jamaneurol.2013.6042

Willis, A., Schootman, M., Kung, N., Wang, X., Perlmutter, J., & Racette, B. (2014). Disparities in deep brain stimulation surgery among insured elders with Parkinson disease. Neurology, 82 (2), 163-171 DOI: 10.1212/WNL.0000000000000017

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Sunday, June 21, 2015

The Future of Depression Treatment



2014

Jessica is depressed again. After six straight weeks of overtime, her boss blandly praised her teamwork at the product launch party. And the following week she was passed over for a promotion in favor of Jason, her junior co-worker. "It's always that way, I'll never get ahead..."

She arrives at her therapist's office late, looking stressed, disheveled, and dejected. The same old feelings of worthlessness and despair prompted her to resume her medication and CBT routine.

"You deserve to be recognized for your work," said Dr. Harrison. "The things you're telling yourself right now are cognitive distortions: the black and white thinking, the overgeneralization, the self-blame, jumping to conclusions... " 

"I guess so," muttered Jessica, looking down.

"And you need a vacation!"
. . .


A brilliant suggestion, Dr. Harrison. As we all know, taking time off to relax and recharge after a stressful time will do wonders for our mental health. And building up a reserve of happy memories to draw upon during darker times is a cornerstone of positive psychology.

Jessica and her husband Michael take a week-long vacation in Hawaii, creating new episodic memories that involve snorkling, parasailing, luaus, and mai tais on the beach. Jessica ultimately decides to quit her job and sell jewelry on Etsy.


2015

Michael is depressed after losing his job. His self-esteem has plummeted, and he feels useless. But he's too proud to ask for help. "Depression is something that happens to other people (like my wife), but not to me." He grows increasingly angry and starts drinking too much.

Jessica finally convinces him to see Dr. Harrison's colleague. Dr. Roberts is a psychiatrist with a Ph.D. in neuroscience. She's adopted a translational approach and tries to incorporate the latest preclinical research into her practice. She's intrigued by the latest finding from Tonegawa's lab, which suggests that the reactivation of a happy memory is more effective in alleviating depression than experiencing a similar event in the present.

Recalling happier memories can reverse depression, said the MIT press release. 

So instead of telling Michael to take time off and travel and practice mindfulness and live in the present, she tells him to recall his fondest memory from last year's vacation in Hawaii.  

It doesn't work.

Michael goes to see Dr. Harrison, who prescribes bupropion and venlafaxine. Four weeks later, he feels much better, and starts a popular website that repudiates positive psychology. Seligman and Zimbardo are secretly chagrined. 

. . .


Happy Hippocampus
photo credit: S. Ramirez


Artificially reactivating positive [sexual] memories [in male mice] could offer an alternative to traditional antidepressants makes them struggle more when you hold them by the tail after 10 days of confinement.1

Not as upbeat as the press release, eh?
The findings ... offer a possible explanation for the success of psychotherapies in which depression patients are encouraged to recall pleasant experiences. They also suggest new ways to treat depression by manipulating the brain cells where memories are stored...

“Once you identify specific sites in the memory circuit which are not functioning well, or whose boosting will bring a beneficial consequence, there is a possibility of inventing new medical technology where the improvement will be targeted to the specific part of the circuit, rather than administering a drug and letting that drug function everywhere in the brain,” says Susumu Tonegawa, ... senior author of the paper.

Although this type of intervention is not yet possible in humans, “This type of analysis gives information as to where to target specific disorders,” Tonegawa adds.

Before considering what the mice might actually experience when their happy memory cells are activated with light, let's all marvel at what was accomplished here.

Ramirez et al. (2015) studied mice that were genetically engineered to allow blue light to activate a specific set of granule cells in the dentate gyrus subfield of the hippocampus. These neurons are critical for the formation of new memories and are considered “engram cells” that undergo physical changes and store discrete memories (Liu et al., 2014). When a cue reactivates the same set of neurons, the episodic memory is retrieved. In this study, the engram cells were part of a larger circuit that included the amygdala and the nucleus accumbens, regions important for processing emotion, motivation, and reward.

Ramiriez, Liu, Tonegawa and colleagues have repeatedly demonstrated their masterful manipulation of mouse memories: activating fear memories, implanting false memories, and changing the valence of memories. These experiments are technically challenging and far outside my areas of expertise (greater detail in the Appendix below). In brief, the authors were able to label discrete sets of dentate gyrus cells while they were naturally activated during an interval of positive, neutral, or negative treatment. Then some groups of  animals were stressed for 10 days, and others remained in their home cages.


The stressed mice exhibited signs of “depression-like” and “anxiety-like” behaviors.2  I'll spare you the long digression about whether the tail suspension test successfully models the anguished human experience of abject states, but you can read my earlier musings on the topic.


The most astounding part of the experiment is that optical stimulation of positive-memory engram cells in stressed mice induced a reversal of “depressive” behaviors (but not “anxious” behaviors; see Appendix). Curiously, re-exposing the stressed male mice to an actual female did not have this positive benefit. So mediated experience artificial reactivation of the engram is even better than the real thing.

The first author, graduate student Steve Ramirez, offered a post hoc explanation:
“People who suffer from depression have those positive experiences in the brain, but the brain pieces necessary to recall them are broken. What we’re doing, in mice, is bypassing that circuitry and forcing it to be jump-started,” Ramirez says. “We’re harnessing the brain’s power from within itself and forcing the activation of that positive memory, whereas if you give a natural positive memory to the person or the animal, the depression that they have prevents them from finding that experience rewarding.”

In other words, “We'll force you to be happy [i.e., possibly remember a positive experience], whether you like it or not.” And since the authors discussed therapeutic implications in the paper, they have to deal with the problem of phenomenology, whether they like it or not. What do the mice actually remember? Generic sexual experiences, a feeling of reward? An episodic-like memory, e.g. a specific act and all its spatiotemporal contextual information? Even if we allow mice to have “episodic-like” memories, the latter seems unlikely given the highly artificial and non-physiological method of neural stimulation that bypasses the precisely timed patterns of activity thought to “represent” past experience. These memory manipulation studies seem very futuristic and scary but Inception they are not.

Our memories are plastic and malleable, and their physical instantiation changes each time we recall them. Which version of the Hawaii trip shall we target? What other memories show the greatest overlap with the happy one? Has the problem of hippocampal pattern separation been solved already?? Garden-variety deep brain stimulation seems easy in comparison (and we know how well that's gone in humans, so far). But: “In rodents, optogenetic stimulation of mPFC neurons, mPFC to raphe projections, and ventral tegmental dopaminergic neurons achieved a rapid reversal of stress-induced maladaptive behaviours” (Ramirez et al., 2015).

Why can't we just appreciate the basic knowledge gained from these experiments? But no. There has to be a human application right around the corner.
That link between the neural circuit manipulations in mice and therapies now used in humans makes the findings particularly exciting, says Tom Insel, director of the National Institute of Mental Health.

“This is a big step toward helping to understand not only the underlying circuits for a really serious illness like depression, but also the circuits that underlie treatment,” says Insel...

Was that actually an endorsement of mediated experience? If we go down that road, we must acknowledge that an artificially created reality, albeit one that originates within a being's own brain, is superior to real life. This is the most profound implication of activating positive memory engrams.


When Mediated Experience Replaces a Medicated Existence
Mediated experiences increasingly dominate our lives. Movies and television already confuse the real and the mediated. New technology is blurring the line further. Video games and virtual reality are becoming increasingly realistic. “Augmented reality” technology is on its way to the public. Wearable computers will allow people to enter a news story and see and feel the events the way the journalist who was there did and no doubt eventually we’ll be able to experience the events live. As the line between real and mediated gets harder to see, presence increases. An important and overlooked consequence of this trend is an increasing confusion from the other direction, in which “real life” seems to be mediated. People will have more and more trouble distinguishing reality, and some may not even appreciate that there is a difference. It will get harder for people to trust their own senses and judgment and it will be more difficult to impress people with non-mediated experiences.

Reeves Timmins & Lombard (2005)When “Real” Seems Mediated: Inverse Presence.

Heavy social media users already accept a reality filtered through Instagram and Facebook. As the interest in personal biometrics and the Quantified Self movement rises, so too will tolerance of increasingly invasive performance enhancing and “lifestyle” brain stimulation methods (see DIY tDCS). No one has said that optogenetic-type treatments are (or will be) possible in humans (OK, almost no one; see Albert, 2014). Others are more modest, and see the translational potential in non-invasive transcranial magnetic stimulation (Deisseroth et al., 2015).

. . .


2035

DARPA has mandated that all depressed Americans must be implanted with its CyberNeuroTron WritBit device, which cost $100 billion to develop. CNTWB is a closed-loop DBS system that automatically adjusts the stimulation parameters at 12 different customized target locations. It uses state-of-the-art syringe-injectable mesh electronics, incorporating silicon nanowires and microvoltammetry. Electrical and chemical signals are continuously recorded and uploaded to a centralized data center, where machine learning algorithms determine with high accuracy whether a given pattern of activity signals a significant change in mood.

The data are compiled, analyzed, and stored by the global search engine conglomerate BlueBook, which in 2032 swallowed up Google, Facebook, Apple, and every other internet data mining company.



. . .


2055

Sophia, the daughter of Jessica and Michael, is depressed again. The Ramirez et al. (2050) protocol for Positive Memory Engram Activation is in widespread use. Sophia searches for her dentate gyrus recordings from a vacation in Hawaii five months earlier. Then she selects the specific memory she wants to be artificially reactivated: watching the sunset on the beach with her partner, drinking mai tais and eating taro chips.



"We had a great time on that trip, didn't we Lucas?" 

Lucas the intelligent AI nods in agreement. "It's true," he thought. "Humans can no longer distinguish between virtual reality and the real thing."

This has been especially useful for the Ramirez protocol, since most Pacific Island nations have been underwater since 2047.



Footnotes

1 As an aside, I wonder what the female mice think of all this. What would be an equivalently positive experience? Is sex as rewarding for them? Will there be a new animal model of shopping at Nordstrom? Fortunately, this work was funded by RIKEN Brain Science Institute and Howard Hughes Medical Institute, so the authors don't have to follow the pesky impending NIH guidelines to include females in animal research.

2 “Depression-related” behaviors were assessed using the Tail Suspension Test (TST) and the Sucrose Preference Test (SPT), which are supposed to mimic giving up hope and loss of pleasure, respectively. Different tests were used to measure “anxiety-related” behaviors. Interestingly, none of the happy engram manipulations improved anxiety-like behavior in the mice. Not a very good model of anxious depression, then.


References

Albert PR. (2014). Light up your life: optogenetics for depression? J Psychiatry Neurosci. 39(1):3-5.

Deisseroth K, Etkin A, Malenka RC. (2015). Optogenetics and the circuit dynamics ofpsychiatric disease. JAMA 313(20):2019-20.

Liu, X., Ramirez, S., Redondo, R., & Tonegawa, S. (2014). Identification and Manipulation of Memory Engram Cells Cold Spring Harbor Symposia on Quantitative Biology, 79, 59-65. DOI: 10.1101/sqb.2014.79.024901

Ramirez, S., Liu, X., MacDonald, C., Moffa, A., Zhou, J., Redondo, R., & Tonegawa, S. (2015). Activating positive memory engrams suppresses depression-like behaviour. Nature, 522 (7556), 335-339. DOI: 10.1038/nature14514

Timmins, L., & Lombard, M. (2005). When “Real” Seems Mediated: Inverse Presence. Presence: Teleoperators and Virtual Environments, 14 (4), 492-500. DOI: 10.1162/105474605774785307


Appendix

These experiments are indeed difficult, but if you successfully execute them, a publication is Nature nearly guaranteed. A review by Liu et al. (2014) explained their general protocol in an easier-to-understand fashion:
...we combined activity-dependent, drug-regulatable expression system with optogenetics (Liu et al. 2012). We used a transgenic mouse model where the artificial tetracycline transactivator (tTA), which can be blocked by doxycycline (Dox), is driven by the promoter of immediate early gene (IEG) c-fos (Reijmers et al. 2007). The activity dependency of c-fos promoter poses a natural spatial constrain on the identities of the neurons that can be labeled, reflecting the normal biological selection process of the brain during memory formation, whereas the Dox-dependency of the system poses an artificial temporal constrain as to when these neurons can be labeled, which can be controlled by the experimenters. With these two constraints, the down-stream effector of tTA can express selectively in neurons that are active during a particular behavior episode, only if the animals are off Dox diet. Using this system, we expressed channelrhodopsin-2 (ChR2) delivered by a viral vector AAV-TRE-ChR2-EYFP targeting the dentate gyrus (DG) of the hippocampus and implanted optical fibers right above the infected areas. 

One of the major treatment protocols is shown below (adapted from Fig. 1A).



There were a number of control conditions too. Reactivation of neutral or negative engram neurons didn't change depression-like behaviors on the TST and SPT.  Reactivation of positive engram neurons in non-stressed mice didn't alter behavior, either.



A very impressive body of work, with a special dedication by the authors: "We dedicate this study to the memory of Xu Liu, who made major contributions to memory engram research."

Xu Liu in memoriam.

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Sunday, June 14, 2015

8 1/2 Reward Prediction Errors: #MovieDirectorNeuroscientistMashup

Fellini/Schultz: 8½ Reward Prediction Errors



On Twitter, movie/brain buff My Cousin Amygdala issued the #MovieDirectorNeuroscientistMashup challenge using the following selections:


I made a few movie posters to go along with my suggestions...


Kurosawa/Tonegawa: Rashomon and the Memory Engram



David Lynch/Eric Kandel: Blue Velvet Aplysia


Write-in nominations were allowed, too.



How about Scorsese / Lynch / Maguire: Mulholland Taxi Driver's Hippocampus  {that one was a bit too involved for a poster}


Finally, I'll write in one by David Cronenberg and....


Cronenberg/Friston: Statistical Parametric Mapping to the Stars


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Sunday, June 07, 2015

Use of Anti-Inflammatories Associated with Threefold Increase in Homicides

Scene from Elephant, a fictional film by Gus Van Sant


Regular use of over-the-counter pain relievers like aspirin, ibuprofen, naproxen, and acetaminophen was associated with three times the risk of committing a homicide in a new Finnish study (Tiihonen et al., 2015). The association between NSAID use and murderous acts was far greater than the risk posed by antidepressants.

Clearly, drug companies are pushing dangerous, toxic chemicals and we should ban the substances that are causing school massacres Advil and Alleve and Tylenol are evil!!

Wait..... what?


Tiihonen and colleagues wanted to test the hypothesis that antidepressant treatment is associated with an increased risk of committing a homicide. Because, you know, the Scientology-backed Citizens Commission on Human Rights of Colorado thinks so (and their blog is cited in the paper!!):
After a high-profile homicide case, there is often discussion in the media on whether or not the killing was caused or facilitated by a psychotropic medication. Antidepressants have especially been blamed by non-scientific organizations for a large number of senseless acts of violence, e.g., 13 school shootings in the last decade in the U.S. and Finland [1].

The authors reviewed a database of all homicides investigated by the police in Finland between 2003 and 2011. A total of 959 offenders were included in the analysis. Each offender was matched to 10 controls selected from the Population Information System. Then the authors checked purchases in the Finnish Prescription Register. A participant was considered a "user" if they had a current purchase in the system.1

The main drug classes examined were antidepressants, benzodiazepines, and antipsychotics. The primary outcome measure was risk of offending for current use vs. no use of those drugs (with significance set to p<0.016 to correct for multiple comparisons). Seven other drug classes were examined as secondary outcome measures (with α adjusted to .005): opioid analgesics, non-opioid analgesics (e.g., NSAIDs), antiepileptics, lithium, stimulants, meds for addictive disorders, and non-benzo anxiolytics.

Lo and behold, current use of antidepressants in the adult offender population was associated with a 31% greater risk of committing a homicide, but this did not reach significance (p=0.022). On the other hand, benzodiazepine use was associated with a 45% greater risk (p<.001), while antipsychotics were not associated with greater risk of offending (p=0.54).

Most dangerous of all were pain relievers. Current use of opioid analgesics (like Oxycontin and Vicodin) was associated with 92% greater risk. Non-opioid analgesics were even worse: individuals taking these meds were at 206% greater risk of offending that's a threefold increase. 2  Taken in the context of this surprising result, the anti-psych-med faction doth complain too much about antidepressants.

Furthermore, analysis of young offenders (25 yrs or less) revealed that none of the medications were associated with greater risk of committing a homicide (benzos and opioids were p=.07 and .04 respectively). To repeat: In Finland at least, there was no association between antidepressant use and the risk of becoming a school shooter.

What are we to make of the provocative NSAIDs? More study is needed:
The surprisingly high risk associated with opioid and non-opioid analgesics deserves further attention in the treatment of pain among individuals with criminal history.

Drug-related murders in oxycodone abusers don't come as a great surprise, but aspirin-related violence is hard to explain...3


Footnotes

1 Having a purchase doesn't mean the individual was actually taking the drug before/during the time of the offense, however.

2 RR = 3.06; 95% CI: 1.78-5.24, p<0.001 for Advil, Tylenol, and the like. And the population-adjusted odds ratios (OR) weren't substantially different, although this wasn't reported for NSAIDs:
The analysis based on case-control design showed an adjusted OR of 1.30 (95% CI: 0.97-1.75) as the risk of homicide for the current use of an antidepressant, 2.52 (95% CI: 1.90-3.35) for benzodiazepines, 0.62 (95% CI: 0.41-0.93) for antipsychotics, and 2.16 (95% CI: 1.41-3.30) for opioid analgesics.

3 P.S. Just to be clear here, correlation ≠ causation. Disregarding the anomalous nature of the finding in the first place, it could be that murderers have more headaches and muscle pain, so they take more anti-inflammatories (rather than ibuprofen "causing" violence). But if the anti-med faction uses these results to argue that "antidepressants cause school shootings" then explain how ibuprofen raises the risk threefold...


Reference

Tiihonen, J., Lehti, M., Aaltonen, M., Kivivuori, J., Kautiainen, H., J. Virta, L., Hoti, F., Tanskanen, A., & Korhonen, P. (2015). Psychotropic drugs and homicide: A prospective cohort study from Finland. World Psychiatry, 14 (2), 245-247. DOI: 10.1002/wps.20220

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