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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Sunday, May 31, 2015

Capgras for Cats and Canaries



Capgras syndrome is the delusion that a familiar person has been replaced by a nearly identical duplicate. The imposter is usually a loved one or a person otherwise close to the patient.

Originally thought to be a manifestation of schizophrenia and other psychotic illnesses, the syndrome is most often seen in individuals with dementia (Josephs, 2007). It can also result from acquired damage to a secondary (dorsal) face recognition system important for connecting the received images with an affective tone (Ellis & Young, 1990).1 Because of this, the delusion crosses the border between psychiatry and neurology.

The porous etiology of Capgras syndrome raises the question of how phenomenologically similar delusional belief systems can be constructed from such different underlying neural malfunctions. This is not a problem for Freudian types, who promote psychodynamic explanations (e.g., psychic conflict, regression, etc.). For example, Koritar and Steiner (1988) maintain that “Capgras' Syndrome represents a nonspecific symptom of regression to an early developmental stage characterized by archaic modes of thought, resulting from a relative activation of primitive brain centres.”

The psychodynamic view was nicely dismissed by de Pauw (1994), who states:
While often ill-founded and convoluted, these formulations have, until recently, dominated many theoretical approaches to the phenomenon. Generally post hoc and teleological in nature, they postulate motives that are not introspectable and defence mechanisms that cannot be observed, measured or refuted. While psychosocial factors can and often do play a part in the development, content and course of the Capgras delusion in individual patients it remains to be proven that such factors are necessary and sufficient to account for delusional misidentification in general and the Capgras delusion in particular.

Canary Capgras

Although psychodynamic explanations were sometimes applied 2 to cases of Capgras syndrome for animals,3 other clinicians report that the delusional misindentification of pets can be ameliorated by pharmacological treatment of the underlying psychotic disorder. Rösler et al. (2001) presented the case of “a socially isolated woman who felt her canary was replaced by a duplicate”:
Mrs. G., a 67-year-old woman, was admitted for the first time to a psychiatric hospital for late paraphrenia. ... She had been a widow for 11 years, had no children, and lived on her own with very few social contacts. Furthermore, she suffered from concerns that her canary was alone at home. She was delighted with the suggestion that the bird be transferred to the ward. However, during the first two days she repeatedly asserted that the canary in the cage was not her canary and reported that the bird looked exactly like her canary, but was in fact a duplicate. There were otherwise no misidentifications of persons or objects.

Earlier, Somerfield (1999) had reported a case of parrot Capgras, also in an elderly woman with a late-onset delusional disorder:
I would like to report an unusual case of a 91-year-old woman with a 10-year history of late paraphrenia (LP) and episodes of Capgras syndrome involving her parrot. She was a widow of 22 years, nulliparous, with profound deafness and a fiercely independent character.  The psychotic symptoms were usually well controlled by haloperidol 0.5 mg orally. However, she was periodically non-compliant with medication, resulting in deterioration of her mental state, refusal of food and her barricading herself in her room to stop her parrot being stolen. At times she accused others of “swapping” the parrot and said the bird was an identical imposter. There was no misidentifcation of people or objects. Her symptoms would attenuate rapidly with reinstatement of haloperidol.

Both of these patients believed their beloved pet birds had been replaced by impostors, but neither of them misidentified any human beings. Clearly, this form of Capgras syndrome is different from what can happen after acquired damage to the affective face identification system (Ellis & Young, 1990). Is there an isolated case of sudden onset Capgras for animals that does not encompass person identification as well? I couldn't find one.


A Common Explanation?

Despite these differences, Ellis and Lewis (2001) suggested that “It seems parsimonious to seek a common explanation for the delusion, regardless of its aetiology.” I'm not so sure. If that's true, then haloperidol should effectively treat all instances of Capgras syndrome, including those that arise after a stroke. And there's evidence suggesting that antipsychotics would be ineffective in such patients.

Are there systematic differences in the symptoms shown by Capgras patients with varying etiologies? Josephs (2007) reviewed 47 patient records and found no major differences between the delusions in patients with neurodegenerative vs. non-neurodegenerative disorders. In all 47 cases, the delusion involved a spouse, child, or other relative. {There were no cases involving animals or objects.}



The factors that did differ were age of onset (older in dementia patients) and other reported symptoms (e.g., visual hallucinations 4 in all patients with Lewy body dementia, LBD). In this series, 81% of patients had a neurodegenerative disease, and only 4% had schizophrenia [perhaps the Capgras delusion was under-reported in the context of wide-ranging delusions?]. Other cases were due to methamphetamine abuse (4%) or sudden onset brain injury, e.g. hemorrhage (11%).

Interestingly, Josephs puts forth dopamine dysfunction as a unifying theme, in line with Ellis and Lewis's general suggestion of a common explanation. The pathology in dementia with Lewy bodies includes degeneration of neurons containing dopamine and acetylcholine. The cognitive/behavioral symptoms of LBD overlap with those seen in Parkinson's dementia, which also involves degeneration of dopaminergic neurons. But dopamine-blocking antipsychotics like haloperidol should not be used in treating LBD. So from a circuit perspective, using “dopamine dysregulation” as a parsimonious explanation isn't really an explanation. And this conception doesn't fit with the neuropsychological model (shown at the bottom of the page).

I'm not a fan of parsimony in matters of brain function and dysfunction. We don't know why one person thinks her canary has been replaced by an impostor, another thinks her husband has been replaced by a woman, while a third is convinced there are six copies of his wife floating around.5 I don't expect there to be a unifying explanation. The BRAIN Initiative and the Human Brain Project will teach us absolutely nothing about the content of delusions. Ultimately, the study of Capgras and other delusional misidentification syndromes present a challenging puzzle for those of us seeking neural explanations of thought and behavior.


Footnotes

1 From Ellis and Young (1990). Also see figure below.
Bauer (1984, 1986) advanced the view that there are two routes to facial recognition. The main route runs from visual cortex to temporal lobes via the inferior longitudinal fasciculus....the 'vental route' corresponds to the system responsible for overt or conscious recognition, and it is the route which typically is damaged in cases of prosopagnosia. The other, described as the 'dorsal route', runs between the visual cortex and the limbic system, via the inferior parietal lobule, and is sometimes intact in prosopagnosic patients. It is this latter route which ... gives the face its emotional significance and hence, when the ventral route is selectively damaged, can give rise to covert recognition (i.e. recognition at an unconscious level).

2 Canine Capgras:
Reports 2 separate cases (a 76-yr-old woman and a 57-yr-old woman) in which the S believed that her pet dog had been replaced by an identical double. The psychodynamic issues that these cases raise are discussed. [NOTE: I don't have access to this article, sorry I can't say more.] In the Capgras delusion the double is usually a key figure in the life of the patient.

3 Capgras for animals was dubbed zoocentric Capgras syndrome by Ehrt (1999). He presented the “case of a 23-year old women who had the delusional belief that her cat had been replaced by the cat of her former boy-friend.”

4 There are a number of interesting hypotheses on why visual hallucinations are so common in Lewy body dementias.

5 Unless he's a character in Orphan Black... But really, why six copies instead of three? What I mean here is an explanation beyond the trivial: one person lives alone with a canary, while the other two live with a spouse.


References

de Pauw KW. (1994). Psychodynamic approaches to the Capgras delusion: a critical historical review. Psychopathology 27(3-5):154-60.

Ellis HD, Lewis MB. (2001). Capgras delusion: a window on face recognition. Trends Cogn Sci. 5(4):149-156.

Ellis, H., & Young, A. (1990). Accounting for delusional misidentifications. The British Journal of Psychiatry, 157 (2), 239-248 DOI: 10.1192/bjp.157.2.239

Josephs, K. (2007). Capgras Syndrome and Its Relationship to Neurodegenerative Disease. Archives of Neurology, 64 (12) DOI: 10.1001/archneur.64.12.1762

Koritar E, Steiner W. (1988). Capgras' syndrome: a synthesis of various viewpoints. Can J Psychiatry 33(1):62-6.

Rösler, A., Holder, G., & Seifritz, E. (2001). Canary Capgras. The Journal of Neuropsychiatry and Clinical Neurosciences, 13 (3), 429-429 DOI: 10.1176/jnp.13.3.429

Somerfield D. (1999). Capgras syndrome and animals. Int J Geriatr Psychiatry 14(10):893-4.



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Saturday, May 16, 2015

Shooting the Phantom Head (perceptual delusional bicephaly)



I have two heads
Where's the man, he's late

--Throwing Muses, Devil's Roof


Medical journals are enlivened by case reports of bizarre and unusual syndromes. Although somatic delusions are relatively common in schizophrenia, reports of hallucinations and delusions of bicephaly are rare. For a patient to attempt to remove a perceived second head by shooting and to survive the experience for more than two years may well be unique, and merits presentation.

--David Ames, British Journal of Psychiatry (1984)

In 1984, Dr. David Ames of Royal Melbourne Hospital published a truly bizarre case report about a 39 year old man hospitalized with a self-inflicted gunshot wound through the left frontal lobe (Ames, 1984). The man was driven to this desperate act by the delusion of having a second head on his shoulder. The interloping head belonged to his wife's gynecologist.




In an even more macabre twist, his wife had died in a car accident two years earlier..... and the poor man had been driving at the time!

Surprisingly, the man survived a bullet through his skull (in true Phineas Gage fashion). After waking from surgery to remove the bullet fragments, the patient was interviewed:
He described a second head on his shoulder. He believed that the head belonged to his wife's gynaecologist, and described previously having felt that his wife was having an affair with this gynaecologist, prior to her death. He described being able to see the second head when he went to bed at night, and stated that it had been trying to dominate his normal head. He also stated that he was hearing voices, including the voice of his wife's gynaecologist from the second head, as well as the voices of Jesus and Abraham around him, conversing with each other. All the voices were confirming that he had two heads...

I'm two headed one free one sticky
--Throwing Muses, Devil's Roof

The other head kept trying to dominate my normal head, and I would not let it. It kept trying to say to me I would lose, and I said bull-shit ... and decided to shoot my other head off.”

A gun was not his first choice, however... he originally wanted to use an ax.




He stated that he fired six shots, the first at the second head, which he then decided was hanging by a thread, and then another one through the roof of his mouth. He then fired four more shots, one of which appeared to have gone through the roof of his mouth and three of which missed. He said that he felt good at that stage, and that the other head was not felt any more. Then he passed out. Prior to shooting himself, he had considered using an axe to remove the phantom head.

Not surprisingly, the patient was diagnosed with schizophrenia and given antipsychotics.
He was seen regularly in psychiatric out-patients following this operation and by March, stated that the second head was dead, that he was taking his chlorpromazine regularly, and that he had no worries.  [This was Australia, after all.]

Unfortunately, the man died two years later from a Streptococcus pneumoniae infection in his brain.  Ames (1984) concluded his lively and bizarre case report by naming the singular syndromeperceptual delusional bicephaly”:
This case illustrates an interesting phenomenon of perceptual delusional bicephaly; the delusion caused the patient to attempt to remove the second head by shooting. It is notable that following his head injury and treatment with chlorpromazine, the initial symptoms resolved, although he was left with the problems of social disinhibition and poor volition, typical of patients with frontal lobe injuries.

As far as I know, this specific delusion has not yet been depicted in a horror film (or in an episode of Perception or Black Box).


Reference

Ames, D. (1984). Self shooting of a phantom head The British Journal of Psychiatry, 145 (2), 193-194 DOI: 10.1192/bjp.145.2.193




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Tuesday, May 05, 2015

Tylenol Doesn't Really Blunt Your Emotions



A new study has found that the pain reliever TYLENOL® (acetaminophen) not only dampens negative emotions, it blunts positive emotions too. Or does it?

Durso and colleagues (2015) reckoned that if acetaminophen can lessen the sting of psychological pain (Dewall et al., 2010; Randles et al., 2013) — which is doubtful in my view then it might also lessen reactivity to positive stimuli. Evidence in favor of their hypothesis would support differential susceptibility, the notion that the same factors govern reactivity to positive and negative experiences.1 This outcome would also contradict the framework of acetaminophen as an all-purpose treatment for physical and psychological pain.

The Neurocritic is not keen on TYLENOL® as a remedy for existential dread or social rejection. In high doses acetaminophen isn't great for your liver, either. And a recent meta-analysis even showed that it's ineffective in treating lower back pain (Machado et al., 2015)...

But I'll try to be less negative than usual. The evidence presented in the main manuscript supported the authors' hypothesis. Participants who took acetaminophen rated positive and negative IAPS pictures as less emotionally arousing compared to a separate group of participants on placebo. The drug group also rated the unpleasant pictures less negatively and the pleasant pictures less positively. “In all, rather than being labeled as merely a pain reliever, acetaminophen might be better described as an all-purpose emotion reliever,” they concluded (Durso et al., 2015).

Appearing in the prestigious Journal of Psychological Acetaminophen Studies, the paper described two experiments on healthy undergraduates, both of which yielded a raft of null results.

Wait a minute..... what? How can that be?

The main manuscript reported the results collapsed across the two studies, and the Supplemental Material presented the results from each experiment separately. Why does this matter?
Eighty-two participants in Study 1 and 85 participants in Study 2 were recruited to participate in an experiment on “Tylenol and social cognition” in exchange for course credit. Our stopping rule of at least 80 participants per study was based on previously published research on acetaminophen (DeWall et al., 2010; Randles et al., 2013), in which 30 to 50 participants were recruited per condition (i.e., acetaminophen vs. a placebo).  ... The analyses reported here for the combined studies are reported for each study separately in the Supplemental Material available online.

What this means is that the authors violated their stopping rule, and recruited twice the number of participants as originally planned. Like the other JPAS articles, this was a between-subjects design (unfortunately), and there were over 80 participants in each condition (instead of 30 to 50).

After running Experiment 1, the authors were faced with results like these:
As expected, however, a main effect of treatment (though not significantly significant in this study) was obtained, F(1,72) = 2.15, p = .147, ηp2 = .029, as was the predicted interaction (although it was not statistically significant in this study), F(3.3, 240.3) = 1.15, p = .330, ηp2 = .016. Contrast analyses indicated that participants taking acetaminophen were marginally significantly less emotionally aroused by extremely pleasant stimuli (M = 5.01, SD = 1.75) than were participants taking placebo (M = 5.65, SD = 1.55), t(72) = 1.67, p = .099. Similarly, participants receiving acetaminophen were less emotionally aroused by extremely unpleasant stimuli (M = 6.88, SD = 1.25) than were participants assigned the placebo condition (M = 7.23, SD = 1.84), although this difference was not statistically significant in this study, t(72) = 0.96, p = .341. Furthermore, participants taking acetaminophen tended to be less emotionally aroused by moderately pleasant stimuli (M = 2.91, SD = 1.64) than participants taking placebo (M = 3.49, SD = 1.89), t(72) = 1.44, p = .155, and participants taking acetaminophen also tended to be less emotionally aroused by moderated unpleasant stimuli (M = 4.68, SD = 1.42) than participants taking placebo (M = 5.25, SD = 2.02), t(72) = 1.42, p = .161, although these differences were not statistically significant in this study. 

Wow, what a disappointment to get these results. Nothing looks statistically significant!

Let's look at Experiment 2:
...Contrast analyses revealed that participants taking acetaminophen tended to rate extremely unpleasant stimuli (M = -3.39, SD = 1.14) less negatively than participants receiving placebo (M = -3.74, SD = 0.74), t(77) = 1.60, p = .115, though this contrast was not itself statistically significant within this study. Participants taking acetaminophen also rated extremely pleasant stimuli (M = +2.51, SD = 1.07) significantly less positively than participants receiving placebo (M = +3.19, SD = 0.88), t(77) = 3.06, p = .003.

Participants taking acetaminophen also tended to evaluate moderately pleasant stimuli (M = +1.15, SD = 0.91) less positively than participants receiving placebo (M = +1.42, SD = 0.89), t(77) = 1.30, p = .198, although this difference was not statistically significant in this study. Finally, participants taking acetaminophen tended to rate moderately unpleasant stimuli less negatively (M = -1.84, SD = 0.99) than participants taking placebo (M = -1.93, SD = 0.95), although this difference was not significant in this study, t(77) = 0.42, p = .678. [NOTE: "tended"? really?] Evaluations of neutral stimuli surprisingly differed as a function of treatment, t(77) = 2.94, p = .004, such that participants taking acetaminophen evaluated these stimuli significantly less positively (M = -0.05, SD = 0.42) than did participants taking placebo (M = +0.22, SD = 0.38).

One of the arguments that acetaminophen affects ratings of emotional stimuli specifically (both positive and negative) is that it does not affect ratings for neutral stimuli. Yet it did here. So in the paragraphs above, extremely pleasant stimuli and neutral stimuli were both rated as less positive by the drug group, but ratings for extremely unpleasant, moderately pleasant, and moderately unpleasant pictures did not differ between drug and placebo groups.

The subjective emotional arousal ratings fared better than the picture ratings in Experiment 2, but there were still some unexpected and non-significant results. Overall, support for the “acetaminophen as an all-purpose emotion reliever” was underwhelming when the studies are examined singly (which is how they were run). 2

[Right about now you're saying, “Hey! I thought you said you'd be less negative here!”]

Let's accept that the combined results reported in the main manuscript present a challenge to the “acetaminophen as a psychological pain reliever” view, and support the differential susceptibility hypothesis. To convince those of us outside the field of social psychology, it would be beneficial to: (1) design within-subjects experiments, and (2) seriously consider possible mechanisms of action, beyond speculations about serotonin and (gasp!) 5-HTTLPR. For instance, why choose acetaminophen (which may act via the spinal cord) and not aspirin or ibuprofen? 3

At the risk of sounding overbearing and pedantic, I hereby issue the following friendly suggestions to all TYLENOL® psychology researchers...


The Proper Pharmacological Study Design Challenge

(1) Please consider using a double-blind, randomized crossover design, like studies that have examined IAPS picture ratings after acute administration of SSRI antidepressants or placebo in healthy participants (Kemp et al., 2004; van der Veen et al., 2012; Outhred et al., 2014).

Speaking of SSRIs, did you know that citalopram did not alter IAPS valence or arousal ratings relative to placebo (Kemp et al., 2004)? Or that paroxetine produced only minor effects on valence and arousal ratings for two of the eight conditions (van der Veen et al., 2012)? 4 What are the implications of these findings for your theoretical framework, that an OTC pain reliever supposedly has a greater impact on emotional processing than a prescription antidepressant? And that before the recent JPAS papers, no one has ever suspected that TYLENOL® affects reactions to emotionally evocative stimuli or David Lynch films?

(2) Please consider that acetaminophen may act via COX-1, COX-2, COX-3, peroxidase, nitric oxide synthase, cannabinoid receptors, and/or descending serotoninergic projections to the spinal cord (Toussaint et al., 2010) before mentioning the anterior cingulate cortex or the serotonin transporter gene. Just another friendly suggestion.

I usually give all my ideas away for free, but if you're interested in hiring me as a consultant, please leave a comment.


ADDENDUM (May 6 2015): A comment by Dr. R (who developed the Replication-Index) said there was nothing wrong with combining the two studies. Study 1 was non-significant but Study 2 was significant, and combined the results were statistically credible (although I'm not exactly sure which of the many tests he checked). Perhaps one source of trouble was that Durso et al.'s estimated number of participants was based on inflated effect sizes in the earlier papers...


Footnotes

1 Turns out differential susceptibility is more or less The Orchid and the Dandelion, or as author David Dobbs puts it, “some of the genes and traits generating our greatest maladies and misdeeds — depression, anxiety, hyper-aggression, a failure to focus — also underlie many of our greatest satisfactions and success." I don't really see how this acetaminophen study informs the differential susceptibility hypothesis, which is based on individual differences (beyond a metaphorical kinship, perhaps).

2 But then I missed the memo from Psych Sci on “recently recommended approaches to presenting the results of multiple studies through combined analyses.”  [paging @mc_hankins...]

3 I know the original social rejection study used Tylenol, but why does everyone persist in doing so?? I was pleased to see that in the press release, first author Geoffrey Durso said they're branching out to test ibuprofen and aspirin.  [There, something positive.]

4 To be precise, participants gave lower arousal ratings to high arousal, low valence pictures and slightly lower valence ratings to high arousal, high valence pictures. The other six cells in the arousal/pleasure ratings of high/low arousal, high/low pleasure were no different on drug vs. placebo.


References

Dewall CN, Macdonald G, Webster GD, Masten CL, Baumeister RF, Powell C, Combs D, Schurtz DR, Stillman TF, Tice DM, Eisenberger NI. (2010). Acetaminophen reduces social pain: behavioral and neural evidence. Psychol Sci. 21:931-7.

Durso, G., Luttrell, A., & Way, B. (2015). Over-the-Counter Relief From Pains and Pleasures Alike: Acetaminophen Blunts Evaluation Sensitivity to Both Negative and Positive Stimuli. Psychological Science DOI: 10.1177/0956797615570366

Kemp AH, Gray MA, Silberstein RB, Armstrong SM, Nathan PJ. (2004). Augmentation of serotonin enhances pleasant and suppresses unpleasant cortical electrophysiological responses to visual emotional stimuli in humans. Neuroimage 22:1084-96.

Machado GC, Maher CG, Ferreira PH, Pinheiro MB, Lin CW, Day RO, McLachlan AJ, Ferreira ML. (2015). Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ. 350:h1225.

Outhred T, Das P, Felmingham KL, Bryant RA, Nathan PJ, Malhi GS, Kemp AH. (2014). Impact of acute administration of escitalopram on the processing of emotional and neutral images: a randomized crossover fMRI study of healthy women. J Psychiatry Neurosci. 39:267-75.

Randles D, Heine SJ, Santos N. (2015). The common pain of surrealism and death: acetaminophen reduces compensatory affirmation following meaning threats. Psychol Sci. 24:966-73.

van der Veen FM, Jorritsma J, Krijger C, Vingerhoets AJ. (2012). Paroxetine reduces crying in young women watching emotional movies. Psychopharmacology 220:303-8.


Better get this woman a damn fine cup of coffee and 1000 mg of TYLENOL®



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