Sunday, January 31, 2016

Was I Wrong?

In honor of The Neurocritic's 10th anniversary, I'd like to announce a new occasional feature:

Was I Wrong?

In science, as in life, we learn from our mistakes. We can't move forward if we don't admit we were wrong and revise our entrenched theory (or tentative hypothesis) when faced with contradictory evidence. Likewise, it's possible that some of the critiques in this blog are no longer valid because additional evidence shows that the authors were correct. And vindicated. At least for now...

I've been collecting possible instances of this phenomenon for months, and I'll preview two of these today.

(1) In November 2015, I said that Obesity Is Not Like Being "Addicted to Food". Drugs of abuse are consistently associated with decreases in D2 dopamine receptors, but D2 receptor binding in obese women is not different from that in lean participants (Karlsson et al., 2015). Conversely, μ-opioid receptor (MOR) binding is reduced, which supports lowered hedonic processing. After the women had bariatric surgery, MOR returned to control values, while the unaltered D2 receptors stayed the same.

However, a recent study in mice “points to a causal link between striatal dopamine signaling and the outcomes of bariatric interventions” (Han et al., 2016). How relevant is this new finding for clinical studies in humans?

(2) In another post, I poo-pooed the notion that there is One Brain Network for All Mental Illness. However, a subsequent paper in Molecular Psychiatry claimed that common psychiatric disorders share the same genetic origin (Pettersson et al., 2015). If so, could this result in common brain abnormalities alterations across disorders?

In the future, I'll take a closer look at these and other examples to see if I should revise my opinions.

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Wednesday, January 27, 2016

How do you celebrate 10 years of an anonymous blog?

Today, The Neurocritic celebrates ten years as a blog. Given the ongoing use of a pseudonym, how should I commemorate the occasion?

1. Should I finally update my blog template? (“Hey, 2004 wants their Blogger template back”).

2. Should I throw a party? Popular London-based blogs Mind Hacks and BPS Research Digest held big public bashes in November 2014 and December 2015, respectively. My audience is only a fraction of theirs, however.  I doubt a local gathering of fans would fill more than a broom closet.

3. How about a Happy Hour, where I privately invite social media folks who live nearby? I know where many of you live, but not vice versa.

4. Or I could publicly announce the location of an informal gathering or night on the town with an open invitation to readers. In either of those scenarios, you'd get to meet me in person. Other pseudonymous bloggers appear in public all the time, why shouldn't I?

5. Another idea was inspired by the cooking competition show Top Chef, which is celebrating its 10th Anniversary this season. In the most recent elimination challenge, the contestants were asked to recall what they were like 10 years ago. The goal was to prepare a dish that represents themselves, professionally and emotionally, at that stage of their lives.
Top Chef 13: The chefs must create a dish that tells the story of who they were 10 years ago.
This was not a pleasant experience for some of the contestants. Chef Isaac, from New Orleans, had to remember the devastation after Hurricane Katrina. He prepared duck gumbo with roasted jalapeno andouille sausage, crispy rice cake and duck cracklings the type of a dish he made for large numbers of displaced people 10 years ago.

Front runner Chef Kwame was quite upset by recalling his estranged relationship with his father. He made jerk broccoli with corn bread pudding and smokey blue cheese as an homage to his Jamaican father. This wasn't a wise decision, however. He ended up at the bottom.

I thought about how I might write a post based on a similar theme: to tell the story of who I was 10 years ago and why I started to blog. I remembered some of the major things in my life at the time, and decided it would be too personal. For 10 years, I've avoided revealing anything about myself.

“I tried my best to stay under the radar and hoped that no one would think of me as a real person,” I said two years ago.

Why did I decide to start a neuroscience blog?

It was out of sheer frustration. I was facing some rejection of my own work, and felt I didn't have much of a voice in the neuroscience community. I was annoyed by flawed journal articles and overblown press coverage, and decided that blogging would be a cathartic outlet for my complaints. I didn't expect that many people would actually read it, but at least writing might make me feel a bit better.

6. I could do a retrospective of my most popular and commented-on posts, but that would be boring. Nobody cares, no one would read it.

7. Perhaps a look back at how the science blogosphere has evolved would have broader appeal? Or not. I wrote an opinion piece in 2013 during a time of #scicomm upheaval, that was enough. Although lifestyle pieces on the rise of social media and the decline of blogs are ever-popular...

8. Should I write a personal reflection on the greatest advances in Human Brain Imaging, Cognitive Neuroscience, and Psychopharmacology since 2006? Such a piece would be time consuming, and needs no special ties to a 10 year blogiversary celebration. Any specific requests for this type of post?

9. Or I could mention other neuro/psych blogs that have been around for 8-10 years, like Neurophilosophy (Mo Costandi soon celebrates his 10th), BPS Research Digest, SciCurious, Neuroskeptic, Neuron Culture (now here), Providentia (now nine), Addiction Inbox, Talking Brains, NeuroDojo (established in 2002), BrainBlog, Deric's MindBlog, and of course Shrink Rap. I could also recognize some influential legacy blogs of the era, including Neurofuture, Developing Intelligence, Mixing Memory, Cognitive Daily, and Omni Brain. Finally, I could credit major influences like Bad Neuro-Journalism (which dates back to 1998) and Mind Hacks.

10. Finally, I may announce a new occasional feature in the coming days or weeks.

Thank you for reading!

More Navel Gazing

Eight Years of Neurocriticism

The Decline of Neurocriticism

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Friday, January 22, 2016

This Neuroimaging Method Has 100% Diagnostic Accuracy (or your money back)


Did you know that SPECT imaging can diagnose PTSD with 100% accuracy (Amen et al., 2015)? Not only that, out of a sample of 397 patients from the Amen Clinic in Newport Beach, SPECT was able to distinguish between four different groups with 100% accuracy! That's right, the scans of (1) healthy participants, and patients with (2) classic post-traumatic stress disorder (PTSD), (3) classic traumatic brain injury (TBI), and (4) both disorders..... were all classified with 100% accuracy!

TRACK-TBI investigators, your 3T structural and functional MRI outcome measures are obsolete.

NIMH, the hard work of developing biomarkers for mental illness is done, you can shut down now. Except none of this research was funded by you...

The finding was #19 in a list of the top 100 stories by Discover Magazine.

How could the Amen Clinics, a for-profit commercial enterprise, accomplish what an army of investigators with billions in federal funding could not?

The authors1 relied on a large database of scans collected from multiple sites over a 20 year period. The total sample included 20,746 individuals who visited one of nine Amen Clinics from 1995-2014 for psychiatric and/or neurological evaluation (Amen et al., 2015). The first analysis included a smaller, highly selected sample matched on a number of dimensions, including psychiatric comorbidities (Group 1).

- click on image for larger view -

You'll notice the percentage of patients with ADHD was remarkably high (58%, matched across the three patient groups). Perhaps that's because...

I did not know that.
 Featuring Johnny Cash ADD.

SPECT uses a radioactive tracer injected 30 minutes before a scan that will assess either the “resting state” or an “on-task” condition (a continuous performance task, in this study). Clearly, SPECT is not the go-to method if you're looking for decent temporal resolution to compare two conditions of an active attention task. The authors used a region of interest (ROI) analysis to measure tracer activity (counts) in specific brain regions.

I wondered about the circularity of the clinical diagnosis (i.e., were the SPECT scans used to aid diagnosis), particularly since “Diagnoses were made by board certified or eligible psychiatrists, using all of the data available to them, including detailed clinical history, mental status examination and DSM-IV or V criteria...” But we were assured that wasn't the case: “These quantitative ROI metrics were in no way used to aid in the clinical diagnosis of PTSD or TBI.” The rest of the methods (see Footnote 2) were opaque to me, as I know nothing about SPECT.

A second analysis relied on visual readings (VR) of about 30 cortical and subcortical ROIs. “Raters did not have access to detailed clinical information, but did know age, gender, medications, and primary presenting symptoms (ex. depressive symptoms, apathy, etc.).”  Hmm...

But the quantitative ROI analysis gave superior results to the clinician VR. So superior, in fact, that the sensitivity/specificity in distinguishing one group from another was 100% (indicated by red boxes below). The VR distinguished patients from controls with 100% accuracy, but was not as good for classifying the different patient groups during the resting state scan only a measly 86% sensitivity, 81% specificity for TBI vs. PTSD, which is still much better than other studies. However, results from the massively sized Group 2 were completely unimpressive. 3

- click on image for larger view, you'll want to see this -

Why is this so important? PTSD and TBI can show overlapping symptoms in war veterans and civilians alike, and the disorders can co-occur in the same individual. More accurate diagnosis can lead to better treatments. This active area of research is nicely reviewed in the paper, but no major breakthroughs have been reported yet. So the claims of Amen et al. are remarkable. Stunning if true. But they're not. They can't be. The accuracy of the classifier exceeds the precision of the measurements, so this can't be possible. What is the test-retest reliability of SPECT? What is the concordance across sites? Was there no change in imaging protocol, no improvements or upgrades to the equipment over 20 years? SPECT is sensitive to motion artifact, so how was that handled, especially in patients who purportedly have ADHD?

SPECT has been noted for its poor spatial resolution compared to other functional neuroimaging techniques like PET and fMRI. A panel of 16 experts did not include SPECT among the recommended imaging modalities for the detection of TBI. Dr. Amen and his Clinics in particular have been criticized in journals (Farah, 2009; Adinoff & Devous, 2010a, 2010b; Chancellor &, Chatterjee, 2011) and blogs (Science-Based Medicine, The Neurocritic, and Neurobollocks) for making unsubstantiated claims about the diagnostic accuracy and usefulness of SPECT.

Are his latest results too good to be true? You can check for yourself! The paper was published in PLOS ONE, which has an open data policy:
PLOS journals require authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception.

When submitting a manuscript online, authors must provide a Data Availability Statement describing compliance with PLOS's policy. If the article is accepted for publication, the data availability statement will be published as part of the final article.

Before you get too excited, here's the Data Availability Statement:
Data Availability: All relevant data are within the paper.

But this is not true. NONE of the data are available within the paper. There's no way to reproduce the authors' analyses, or to conduct your own. This is a problem, because...
Refusal to share data and related metadata and methods in accordance with this policy will be grounds for rejection. PLOS journal editors encourage researchers to contact them if they encounter difficulties in obtaining data from articles published in PLOS journals. If restrictions on access to data come to light after publication, we reserve the right to post a correction, to contact the authors' institutions and funders, or in extreme cases to retract the publication.

So all you “research parasites” out there4 you can request the data. I thought this modest proposal would create a brouhaha until I saw a 2014 press release announcing the World's Largest Database of Functional Brain Scans Produces New Insights to Help Better Diagnose and Treat Mental Health Issues:
With a generous grant from the Seeds Foundation [a Christian philanthropic organization] in Hong Kong, Dr. Amen and his research team led by neuroscientist Kristen Willeumier, PhD, have turned the de-identified scans and clinical information into a searchable database that is shared with other researchers around the world.

In the last two years, Amen and colleagues have presented 20 posters at the National Academy of Neuropsychology. The PR continues:
The magnitude and clinical significance of the Amen Clinics database – being the world's largest SPECT imaging database having such volume and breadth of data from patients 9 months old to 101 years of age – makes it a treasure trove for researchers to help advance and revolutionize the practice of psychiatry.

Does this mean that Dr. Amen will grant you access to the PLOS ONE dataset (or to the entire Amen Clinics database) if you ask nicely? If anyone tries to do this, please leave a comment.


1 The other authors included Dr. Andrew “Glossolalia” Newberg and Dr. Theodore “Neuro-Luminance Synaptic Space” Henderson.

2 Methods:
To account for outliers, T-score derived ROI count measurements were derived using trimmed means [91] that are calculated using all scores within the 98% confidence interval (-2.58 < Z < -2.58). The ROI mean for each subject and the trimmed mean for the sample are used to calculate T with the following formula: T = 10*((subject ROI_mean - trimmed regional_avg)/trimmed regional_stdev)+50.
3 Results from the less pristine Group 2 were not impressive at all, I must say. Group 2 had TBI (n=7,505), PTSD (n=1,077), or both (n=1,017) compared to n=11,147 patients without either (these were not clean controls as in Group 1). Given the massive number of subjects, the results were clinically useless, for the most part (see Table 6).

4 A brand new editorial in NEJM by Longo and Drazen (who decry “research parasites”) is causing a twitterstorm with the hashtags #researchparasites and #IAmAResearchParasite.


Adinoff B, Devous M. (2010a). Scientifically unfounded claims in diagnosing and treating patients. Am J Psychiatry 167(5):598.

Adinoff B, Devous M. (2010b). Response to Amen letter. Am J Psychiatry 167(9):1125-1126.

Amen, D., Raji, C., Willeumier, K., Taylor, D., Tarzwell, R., Newberg, A., & Henderson, T. (2015). Functional Neuroimaging Distinguishes Posttraumatic Stress Disorder from Traumatic Brain Injury in Focused and Large Community Datasets PLOS ONE, 10 (7) DOI: 10.1371/journal.pone.0129659

Chancellor B, Chatterjee A. (2011). Brain branding: When neuroscience and commerce collide. AJOB Neuroscience 2(4): 18-27.

Farah MJ. (2009). A picture is worth a thousand dollars. J Cogn Neurosci. 21(4):623-4.

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Friday, January 08, 2016

Opioid Drugs for Mental Anguish: Basic Research and Clinical Trials

The prescription opioid crisis of overdosing and overprescribing has reached epic proportions, according to the North American media. Just last week, we learned that 91% of patients who survive opioid overdose are prescribed more opioids! The CDC calls it an epidemic, and notes there's been “a 200% increase in the rate of overdose deaths involving opioid pain relievers and heroin.” A recent paper in the Annual Review of Public Health labels it a “public health crisis” and proposes “interventions to address the epidemic of opioid addiction” (Kolodny et al., 2015).

In the midst of this public and professional outcry, why on earth would anyone recommend opioid drugs as a treatment for severe depression and suicidal ideation??

Let's revisit the questions posed in my previous post:

  1.  Does the pain of mental anguish rely on the same neural machinery as physical pain?
  3.  Can we treat these dreaded ailments with the same medications?

The opioid-for-depression proponents would answer both of those questions in the affirmative,1 with some qualifications. First off, the actual medication in question (and its dose) is different from the typically abused opiate / opioid drug. As far as I can tell, no one is clamoring for narcotic analgesics like OxyContin and Vicodin to be used as antidepressants.

In his 2008 paper on the Psychotherapeutic Benefits of Opioid Agonist Therapy, Dr. Peter L. Tenore reviewred the history of the Opium Cure and declared, “Opioids have been used for centuries to treat a variety of psychiatric conditions with much success.” However, these drugs can be highly addictive (obviously) so he issued this caveat at the end of the paper:
It should be noted that opioids do not have FDA approval for the treatment of psychiatric disorders. The intent of this paper was not to suggest that practitioners should prescribe opioids in a manner not approved by the FDA, but rather it was to explore the mechanisms and develop hypotheses that might explain the observation that opioid-dependent psychiatric patients in appropriately certified opioid replacement therapy programs (i.e., methadone treatment programs) stabilize on higher opioid dosages than those without psychiatric diagnoses.

Methadone and especially low-dose buprenorphine are the drugs being tested for their antidepressant efficacy, even in those who have no opioid abuse issues. Buprenorphine is a mixed partial μ/κ agonist with complex actions, including:
  • Antagonist (blocker) of κ-opioid receptors (KORs) that bind dynorphins (endogenous opioids associated with anxiety and dysphoria)
  • Partial agonist at μ-opioid receptors (MORs), producing analgesic effects but with less euphoria and less respiratory depression than full agonists
Basic research in rodents suggests that KORs may be a promising target for potential psychiatric treatments in humans, based on improvements shown in standard behavioral assays such as the forced swim test and the elevated maze test (Crowley & Kash, 2015).2 But there's still a long way to go. In addition to the difficulty of modeling mental anguish in animals, the complexity of the dynorphin/KOR system which can exhibit paradoxical and “convoluted” effects on behavior3 presents a barrier to clinical translation.

In contrast, a very different approach uses affect modeling in an effort to accelerate drug development in neuropsychiatry (Panksepp & Yovell, 2014). In this view, current models of depression have hindered new breakthroughs because of their focus on animal behaviors, instead of animal emotions. Panksepp maintains that separation distress and infant versions of psychic pain, excessive sadness, and grief are mediated by the PANIC system, which is soothed by opioids. Chicks, kittens, puppies, and other infant animals emit distress vocalizations when separated from their mothers. Rat pups emit ultrasonic vocalizations and baby monkeys “coo”. These innate, reflexive, and adaptive behaviors are reduced with low doses of morphine.4

Panksepp and colleagues have inferred that very strong and human-like emotions are associated with distress vocalizations.

By way of example, here is my adult cat. He's very affectionate and chatty. He requires a lot of attention and doesn't like to be alone. Does he meow and miss me when I'm on vacation? I imagine he does. Do I think he feels psychic pain and grief while I'm gone? No.

Watt and Panskepp (2009) argue that depression is an evolutionarily conserved mechanism to terminate separation distress, drawing on psychoanalytic concepts like object relations theory as well as the literature on neuropeptides and neuromodulators implicated in major depression.

Nopan Treatment of Acute Suicidality

The research on separation distress in animals helped motivate a clinical trial that was recently published in the American Journal of Psychiatry (Yovell et al., 2015). The initial daily dose of Nopan (0.1 or 0.2 mg sublingual buprenorphine hydrochloride) was relatively low, reaching a maximum dose of 0.8 mg daily by the end of the four week trial (mean = 0.44 mg). By way of comparison, the maintenance dose for opioid dependence is 4 to 24 mg/day.5 Analgesic effects are obtained at 0.1– 8 mg (according to Heit, 2010), although Yovell et al. said their doses were subanalgesic.

Eighty-eight severely suicidal patients were enrolled in the double-blind, placebo-controlled trial, about 2/3 of whom had made at least one suicide attempt. Over half met criteria for borderline personality disorder (BPD), which includes symptoms like affective instability, self-harm, high rates of substance abuse, and fear of abandonment (i.e., heightened separation distress). Although 50 patients had BPD, the other 48 did not. If separation distress is a major motivating construct for the trial, it seems problematic to have a heterogeneous population on that dimension. Nevertheless...
Almost all were clinically unstable, and their ability to cooperate with the study team was compromised, as reflected in a high dropout rate (29.5%) during the first week of treatment.

This sort of study is very difficult to conduct, so it's not surprising that the completion rate was low (57%):  33 patients on buprenorphine, 17 on placebo (the original randomization was deliberately 2:1).

- click on image for a larger view -

Modified from Fig. S2 (Yovell et al., 2015). A portion of the flow diagram (starting from those who were enrolled).

Importantly, participants with a lifetime history of opioid abuse were excluded. Buprenorphine is a Schedule III controlled substance in the US (same as ketamine), with a lower potential for abuse than heroin (Schedule I) and morphine, methadone, OxyContin, etc. (Schedule II).6 As we know, individuals with BPD have high rates of substance abuse. In one study, 44% of patients seeking buprenorphine treatment for opioid addiction were diagnosed with BPD. Therefore, the investigators had to screen the participants very closely, in partnership with their regular clinical providers. Other exclusionary criteria were schizophrenia, current psychosis, and ECT within the past month. Finally, there could be no substance or alcohol abuse or benzodiazepine dependence within the past 2 years.

Regarding patient demographics, 70% were female, 43% had major depression, 25% were currently hospitalized, 49% had experienced major stressors in the last year (but separation during past month in only 24%), 70% on antidepressants, 49% on benzos, and about 20% on mood stabilizers and antipsychotics.
A week’s supply of medication (<5.6 mg, usually <2.8 mg) was not considered to present a high risk for suicide by overdose. Outpatients received the study medication for the following week during their weekly visits, and took it independently at home.

Another difficulty is that opioids have notable side effects, and this was true with the “ultra-low-dose” used here (Yovell et al., 2015) which isn't really all that low.
One or more adverse events were reported in 77.2% of participants in the buprenorphine group and 54.8% of those in the placebo group (p=0.03). Among participants in the buprenorphine group, there were more reports of fatigue (49.1% compared with 22.6% in the placebo group), nausea (36.8% compared with 12.9%), dry mouth (29.8% compared with 9.7%), and constipation (26.3% compared with 9.7%).

The primary outcome measure was change in suicidal ideation after four weeks of treatment. To make up for high dropout, the Last Observation Carried Forward (LOCF) was used. In this way, data from all participants who received at least one dose of drug and one suicidal ideation score were included. However, LOCF is a flawed procedure that can overestimate effect sizes.7

The buprenorphine group had lower suicidal ideation than the placebo group at weeks 2 and 4, but an analysis restricted to patients who completed the study was not reported. Furthermore, the suicidal ideation scores were highly variable, and improvements in many secondary outcome measures (e.g., depression severity) didn't reach statistical significance (Fig. S3 below).

The authors acknowledged seven critical limitations, summarized below (the most egregious in red):
  1. Outcome measures based on self-report. Clinician ratings of suicidality, depression, and overall functioning should be part of any future trial. 
  3. Participants were unstable and severely suicidal; many had BPD; high dropout rates. Are the findings applicable to more stable, less severely suicidal patients?
  5. Flexible and gradual dosing limits inferences about the optimal dosage of buprenorphine to treat suicidal ideation.
  7. Heterogeneity of the study population [e.g., why were both BPD and non-BPD included?] and its modest size limited ability to stratify results by dose, gender, and diagnosis.
  9. Study did not assess nonsuicidal self-injury, which is associated with BPD, mental pain, and abnormalities in the endogenous opioid system.
    •     I'll add that a case series on buprenorphine for NSSI was not cited.
  10. Trial did not include an extended follow-up period to allow assessment of possible long-term effects, including the possibility of developing drug craving or rebound suicidality.
  12. Despite its favorable safety profile, buprenorphine is potentially addictive and possibly lethal. 

The authors end by stating the “results do not support the widespread, long-term, or nonexperimental use of buprenorphine for suicidality.” In other words, don't open buprenorphine clinics to treat severe depression and suicidal ideation! [ketamine infusion clinics, I'm looking at you].

People suffering from suicidal thoughts and actions deserve the best possible care, yet many researchers and clinicians shy away from conducting clinical trials.  Ketamine seems to be the exception, where 24 studies are listed in While the present study has a long list of admitted flaws that make me wonder why it was published in AJP, the authors are in the admirable position of trying to help an extremely vulnerable population.

Read Part 1, Social Pain Revisited: Opioids for Severe Suicidal Ideation.


1 But not surprisingly, many others don't agree with this strategy e.g., Opioids in Depression: Not Quite There Yet (Xin et al. 2015), Psychiatry is the missing P in chronic pain care (Howe & Sullivan, 2014), and my previous post.

2 These tests measure “depression-like” and “anxiety-like” behaviors, respectively. We could certainly debate whether these are adequate models of depression and anxiety, and this was in fact the topic of an interesting discussion on Twitter. The problem of anthromorphism is greatly magnified with concepts like the “psychic pain” of separation distress (the PANIC system of Panksepp and colleagues). For now, I'll refer you to my old post, Of Mice and Women: Animal Models of Desire, Dread, and Despair.

3 The world of dynorphin and KORs has gotten even more complicated since the discovery that subpopulations of dynorphin neurons in the nucleus accumbens have opposing effects (aversion vs. reward). Crowley and Kash (2015) suggest that translation to humans may be..... uh difficult, to say the least:
 “Important studies using modern genetic approaches have highlighted the multiple ways that KORs effect behavior, and paradoxical effects have emerged when manipulating the dynorphin system.”  
“In addition, circuit and site-specific manipulations...provide some clarity as to the convoluted effect seen with systemic administration of KOR agonists. This provides key important information as to how KOR modulation can be used to shift anxiety-related behaviors: both low doses of KOR agonists, as well as KOR antagonists, may prove to be effective.”
“Despite of an abundance of literature showing KORs to be a promising therapeutic target for the treatment of drug addiction ... few drugs impacting the KOR system have been taken to the level of human clinical trials.”
4 I haven't heard that morphine or buprenorphine is recommended for human babies who cry persistently and excessively.

5  @debe: in addiction it's 2 to 32 mg (pure bup) or to 24 (bup+nalox). 0.2 mg cps are for pain.

6 The clinical trial was conducted in Israel, where buprenorphine is used to treat opioid dependence (as in many other countries) Litigiousness might be one possible reason such a study hasn't been conducted in the US?

7 Caution is needed when interpreting results using Last Observation Carried Forward (LOCF) analyses filling in missing values based on existing data because of the problematic nature of this method for handling missing data. See Appendix below.


Crowley NA, Kash TL. (2015). Kappa opioid receptor signaling in the brain: Circuitry and implications for treatment. Prog Neuropsychopharmacol Biol Psychiatry 62:51-60.

Howe CQ, Sullivan MD. (2014). The missing 'P' in pain management: how the current opioid epidemic highlights the need for psychiatric services in chronic pain care. Gen Hosp Psychiatry 36(1):99-104.

Kolodny A, Courtwright DT, Hwang CS, Kreiner P, Eadie JL, Clark TW, Alexander GC. (2015). The prescription opioid and heroin crisis: a public health approach to anepidemic of addiction. Annu Rev Public Health 36:559-74.

Panksepp, J., & Yovell, Y. (2014). Preclinical Modeling of Primal Emotional Affects (SEEKING, PANIC and PLAY): Gateways to the Development of New Treatments for Depression. Psychopathology, 47 (6), 383-393. DOI: 10.1159/000366208

Tenore, P. (2008). Psychotherapeutic Benefits of Opioid Agonist Therapy. Journal of Addictive Diseases, 27 (3), 49-65. DOI: 10.1080/10550880802122646

Watt, D., & Panksepp, J. (2009). Depression: An Evolutionarily Conserved Mechanism to Terminate Separation Distress? A Review of Aminergic, Peptidergic, and Neural Network Perspectives Neuropsychoanalysis, 11 (1), 7-51 DOI: 10.1080/15294145.2009.10773593

Yovell, Y., Bar, G., Mashiah, M., Baruch, Y., Briskman, I., Asherov, J., Lotan, A., Rigbi, A., & Panksepp, J. (2015). Ultra-Low-Dose Buprenorphine as a Time-Limited Treatment for Severe Suicidal Ideation: A Randomized Controlled Trial. American Journal of Psychiatry DOI: 10.1176/appi.ajp.2015.15040535

Yin X, Guven N, Dietis N. (2015). Opioids in Depression: Not Quite There Yet. UK Journal of Pharmaceutical and Biosciences 3(1):12-7.


Reasons to avoid Last Observation Carried Forward (LOCF):

Streiner 2014: “...LOCF has serious and, in some cases, fatal problems.”

Olsen et al. 2012: “Although these methods are simple to implement, they are deeply flawed in that they may introduce bias and underestimate uncertainty, leading to erroneous conclusions.” “For full longitudinal data analyses this is clearly disastrous: means and covariance structure are seriously distorted. For single time point analyses the means are still likely to be distorted, measures of precision are wrong and hence inferences are wrong. Note this is true even if the mechanism that causes the data to be missing is completely random.”

Molnar et al. 2008: “If there were a prize for the most inappropriate analytical technique in dementia research, 'last observation carried forward' would be the runaway winner.”

Molnar et al. 2009: “The published results of some randomized controlled trials of dementia drugs may be inaccurate (i.e., drug effectiveness may be exaggerated) or invalid (i.e., there may be false-positive results) because of bias introduced through the inappropriate use of LOCF analyses.”

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Tuesday, December 29, 2015

Social Pain Revisited: Opioids for Severe Suicidal Ideation

Does the pain of mental anguish rely on the same neural machinery as physical pain? Can we treat these dreaded ailments with the same medications? These issues have come to the fore in the field of social/cognitive/affective neuroscience.

As many readers know, Lieberman and Eisenberger (2015) recently published a controversial paper claiming that a brain region called the dorsal anterior cingulate cortex (dACC, shown above) is “selective” for pain.1 This finding fits with their long-time narrative that rejection literally “hurts” social pain is analogous to physical pain, and both are supported by activity in same regions of dACC (Eisenberger et al., 2003). Their argument is based on work by Dr. Jaak Panksepp and colleagues, who study separation distress and other affective responses in animals (Panksepp & Yovell, 2014).

Panksepp wrote The Book on Affective Neuroscience in 1998, and coined the term even earlier (Panksepp, 1992). He also wrote a Perspective piece in Science to accompany Eisenberger et al.'s 2003 paper:

We often speak about the loss of a loved one in terms of painful feelings, but it is still not clear to what extent such metaphors reflect what is actually happening in the human brain? Enter Eisenberger and colleagues ... with a bold neuroimaging experiment that seeks to discover whether the metaphor for the psychological pain of social loss is reflected in the neural circuitry of the human brain. Using functional magnetic resonance imaging (fMRI), they show that certain human brain areas that “light up” during physical pain are also activated during emotional pain induced by social exclusion [i.e., exclusion from playing a video game].

But as I've argued for years, Social Pain and Physical Pain Are Not Interchangeable. Whenever I read an article proclaiming that “the brain bases of social pain are similar to those of physical pain”, I am reminded of how phenomenologically DIFFERENT they are.

And subsequent work has demonstrated that physical pain and actual social rejection (a recent romantic break-up) do not activate the same regions of dACC (Woo et al., 2014). Furthermore, multivariate activation patterns across the entire brain can discriminate pain and rejection with high accuracy.2 

Modified from Fig. 3 (Woo et al., 2014). Differences between fMRI pattern-based classifiers for pain and rejection.

Feelings of rejection were elicited by showing the participants pictures of their ex-partners (vs. pictures of close friends), and physical pain was elicited by applying painful heat to the forearm (vs. warm heat).

Does this mean there is no overlap between brain systems that can dampen physical and emotional pain (e.g., endogenous opioids)? Of course not; otherwise those suffering from utter despair, unspeakable loneliness, and other forms of psychic turmoil would not self-medicate with mind-altering substances.

Separation Distress: Of Mice and Psychoanalysis

Although Panksepp has worked primarily with rodents and other animals throughout his career, he maintains a keen interest in neuropsychoanalysis, an attempt to merge Freudian psychoanalysis with contemporary neuroscience. Neuropsychoanalysis “seeks to understand the human mind, especially as it relates to first-person experience.” If you think that's a misguided (and impossible) quest, you might be surprised by some of the prominent neuroscientists who have signed on to this agenda (see these posts).

Prof. Panksepp is currently collaborating with Prof. Yoram Yovell, a Psychoanalyst and Neuroscientist at the Institute for the Study of Affective Neuroscience (ISAN) in Haifa. A recent review paper addresses their approach of affective modeling in animals as a way to accelerate drug development in neuropsychiatry (Panksepp & Yovell, 2014). Their view is that current models of depression, which focus on animal behaviors instead of animal emotions, have hindered new breakthroughs in treatments for depression. It’s actually a fascinating and ambitious research program:
We admit that our conceptual position may be only an empirical/ontological approximation, especially when contrasted to affective qualia in humans … but it is at least a workable empirical approach that remains much underutilized. Here we advance the view that such affective modeling can yield new medical treatments more rapidly than simply focusing on behavioral processes in animals. In sum, we propose that the neglect of affect in preclinical psychiatric modeling may be a major reason why no truly new psychiatric medicinal treatments have arisen from behavior-only preclinical modeling so far.

They propose that three key primal emotional systems3 may be critical for understanding depression: SEEKING (enthusiasm-exuberance), PANIC (psychic pain), and PLAY (joyful exuberance). If these constructs sound highly anthropormorphic when applied to rats, it's because they are!! Perhaps you'd rather “reaffirm classical behaviorist dogma (Panksepp & Yovell, 2014) and stick with more traditional notions like brain reward systems, separation distress, and 50-kHz ultrasonic vocalizations (e.g., during tickling, mating, and play) when studying rodents.

Of interest today is the PANIC system (Panksepp & Yovell, 2014), which mediates the psychic pain of separation distress (i.e. excessive sadness and grief), which can be counteracted by minimizing PANIC arousals (as with low-dose opioids).” Since low-dose opioids alleviate separation distress in animals (based on reductions in distress vocalizations), why not give them to suicidal humans suffering from psychic pain?

Well... because making strong inferences about the contents of animal minds is deeply problematic (Barrett et al., 2007). I've written about some of the problems with animal models of dread and despair. One might also question whether it's wise to give opioid drugs (even in very low doses) to severely ill people.

Low-Dose Buprenorphine for Suicidal Ideation
Recently investigators are increasingly entertaining the possibility of using ‘safe opioids’ for the treatment of depression, as well as the chronic ‘psychological pain’ that often promotes suicidal ideation. To be a ‘safe opioid’, the analgesic effects and the lethal (respiratory depression) effects of a particular opioid ligand need to be dissociated. Buprenorphine, a partial agonist at μ-opioid receptors (i.e. stimulating opioid receptors at low doses, but blocking them at high doses), is just such a drug.

Panksepp and Lovell's ideas led to a clinical trial (A Study of Nopan Treatment of Acute Suicidality) and a new paper in the American Journal of Psychiatry (Yovell et al., 2015). Nopan is sublingual buprenorphine hydrochloride 0.2 mg. At higher doses, buprenorphine is used as a treatment for opioid addiction, much like methadone.

Research on suicidal behavior is an important and tragically neglected topic, and many clinicians, organizations, and industry sponsors are reluctant to engage. So it's notable that the current study was funded by the Neuropsychoanalysis Foundation (which awards grants and sponsors the journal Neuropsychoanalysis), the Hope for Depression Research Foundation (whose Board is filled with some Heavy Hitters of Neuroscience e.g., Akil, Mayberg, McEwen, Nestler, Hen), and ISAN.

It's interesting to track some of the changes in the study protocol and description over time. The initial entry (dated 2010_01_11) dropped its psychoanalytic language on 2011_05_23:
The acutely suicidal patient presents a complex and dangerous clinical dilemma. Many suicidal patients receive antidepressant medications, but the onset of action of these medications is at least three weeks, and despite their established antidepressant effect, they have not shown a clear anti-suicidal benefit. Psychoanalysts hypothesized that depression (often leading to suicidality) shares important characteristics with the psychological sequelae of object loss and separation distress. Endogenous opioids (endorphins) have been implicated in mediating social bonding and separation distress in mammals. 

On the same date, the Secondary Outcome Measure (Reduction in psychache as measured by the Holden Psychache Scale) was replaced by a more standard and non-psychoanalytic instrument, the Beck Depression Inventory (Reduction in depression as measured by the BDI). Dr. Beck conceptualized depression in a cognitive framework.

On the other hand, “psychache” (coined by suicidologist Dr. Edwin Shneidman) means “unbearable psychological pain—hurt, anguish, soreness, and aching. ... Psychache stems from thwarted or distorted psychological needs . . . every suicidal act reflects some specific unfulfilled psychological need.”  Many of these views are at odds with neuropsychiatry (Schneidman, 1993):
Depression seems to have physiological, biochemical, and probably genetic components. The use of medications in treatment is on target. [so far so good] ... Suicide, on the other hand, is a phenomenological event... It is responsive to talk therapy and to changes in the environment. Suicide is not a psychiatric disorder. Suicide is a nervous dysfunction, not a mental disease.

But 90% of suicides are in people with clinically diagnosable psychiatric disorders; anxiety, depression, impulsivity, and alcohol abuse are major risk factors. While cases of psychache would certainly benefit from talk therapy and a change in environment, pharmacological (and/or brain stimulation) treatments seem to be essential. Which is the clearly the intention of Yovell et al. (2015), or else they wouldn't have conducted a drug study.

In short, I found it curious that the focus of their clinical trial changed so much mid-stream, and that the mental anguish of the original formulation is so completely and utterly human (given its genesis from the animal literature).

In the next post, I'll cover the actual study and the background on why anyone would think low-dose opioids are a good idea in cases of treatment-resistant depression and suicidality.

Read Part 2, Opioid Drugs for Mental Anguish: Basic Research and Clinical Trials.

Further Reading

Vicodin for Social Exclusion

Suffering from the pain of social rejection? Feel better with TYLENOL®

Existential Dread of Absurd Social Psychology Studies

Does Tylenol Exert its Analgesic Effects via the Spinal Cord?

The Mental Health of Lonely Marijuana Users

Tylenol Doesn't Really Blunt Your Emotions

Of Mice and Women: Animal Models of Desire, Dread, and Despair


1 In contrast, based on years of detailed neuroanatomical and neurophysiological experiments, most neuroscientists think the dACC is a functionally heterogeneous region (e.g., Vogt et al., 1992). Shortly after the Lieberman & Eisenberger (2015) paper was published, a number of researchers expressed their vehement disagreement in blog posts: Yarkoni-1, Lieberman reply, Yarkoni-2, Shackman, Wager.

2 In contrast to these results, an earlier study by this group claimed that social rejection shares somatosensory representations with physical pain. It's always nice to see examples where scientists update their own theories based on new evidence.

3 In Panksepp's scheme, there are seven basic or primal emotions that are subcortically based and evolutionarily conserved: SEEKING, RAGE, FEAR, LUST, CARE, PANIC/GRIEF, and PLAY. Needless to say, this model has not gone unchallenged (Barrett et al., 2007; LeDoux, 2015). Barrett and colleagues have argued that emotions are not natural kinds, but rather emergent psychological events constructed from core affect (positive or negative states) and a human conceptual system for emotion.


Barrett LF, Lindquist KA, Bliss-Moreau E, Duncan S, Gendron M, Mize J, Brennan L. (2007). Of Mice and Men: Natural Kinds of Emotions in the Mammalian Brain? A Response to Panksepp and Izard. Perspect Psychol Sci. 2(3):297-312.

Eisenberger NI, Lieberman MD, Williams KD. (2003). Does rejection hurt? An FMRI study of social exclusion. Science 302:290-2.

Panksepp, J., & Yovell, Y. (2014). Preclinical Modeling of Primal Emotional Affects (SEEKING, PANIC and PLAY): Gateways to the Development of New Treatments for Depression. Psychopathology, 47 (6), 383-393. DOI: 10.1159/000366208

Shneidman ES. (1993). Suicide as psychache. J Nerv Ment Dis. 181(3):145-7.

Woo CW, Koban L, Kross E, Lindquist MA, Banich MT, Ruzic L, Andrews-Hanna JR, & Wager TD (2014). Separate neural representations for physical pain and social rejection. Nature communications, 5. PMID: 25400102

Yovell, Y., Bar, G., Mashiah, M., Baruch, Y., Briskman, I., Asherov, J., Lotan, A., Rigbi, A., & Panksepp, J. (2015). Ultra-Low-Dose Buprenorphine as a Time-Limited Treatment for Severe Suicidal Ideation: A Randomized Controlled Trial. American Journal of Psychiatry DOI: 10.1176/appi.ajp.2015.15040535

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Sunday, December 13, 2015

This Week in Neuroblunders: fMRI Edition

My entire body of work has been called into question!

And what a fine week for technical neurogaffes it is. First was the threat that many trendy and important studies of neural circuits may need to be replicated using old-fashioned lesion methods, because of “off-target” effects:
Where do we go from here? Most acute manipulation studies that use optogenetics confirm, and so add valuable support to, existing hypotheses that were established in earlier studies. But for those studies that have proposed new circuit functions, it may be advisable to re-evaluate the conclusions using independent approaches.1

Up next we have....

fMRI Neuroblunders in Brief
The most notable one of late is a new paper by Eklund et al. (2015), which demonstrated that common statistical tests used to analyze fMRI data can give wildly inflated false positive rates of up to 60%, as illustrated in the top figure.

What they found is shocking”!
While voxel-wise error rates were valid, nearly all cluster-based parametric methods (except for FSL’s FLAME 1) have greatly inflated familywise Type I error rates. This inflation was worst for analyses using lower cluster-forming thresholds (e.g. p=0.01) compared to higher thresholds, but even with higher thresholds there was serious inflation. This should be a sobering wake-up call for fMRI researchers, as it suggests that the methods used in a large number of previous publications suffer from exceedingly high false positive rates (sometimes greater than 50%).

The problems (and recommended solutions) were expertly discussed already by Russ Poldrack, who is quoted above (see Big problems for common fMRI thresholding methods), and by Neuroskeptic (False Positive fMRI Revisited). I needn't belabor the issues any further.

Next question:

Is the ubiquitously activated dorsal anterior cingulate cortex (dACC) selective for pain (as opposed to conflict or cognitive control or salience)? That was the contention of a new paper by Lieberman and Eisenberger (2015) that made use of the Neurosynth meta-analytic framework developed by Tal Yarkoni.

It Depends on What “Selective” Means 2

A 15,000 word debate between Yarkoni (No, the dorsal anterior cingulate is not selective for pain) and Lieberman (Comparing Pain, Cognitive, and Salience Accounts of dACC) ensued, with no end in sight.

It Also Depends on What “Pain” Means

Social Pain and Physical Pain Are Not Interchangeable. This may sound obvious to you, but Eisenberger and Lieberman have argued otherwise, with their neural alarm view of dACC function. Neurosynth uses text mining and machine learning to build maps based on terms that appear in published papers, along with activation coordinates. So the map above doesn't distinguish between different types of experimentally-induced physical pain (heat, cold, pressure, etc.) vs. emotional pain or social exclusion in a video game.

This might be one of L&E's major points, but pain researchers aren't on board; many don't even think the dorsal posterior insula is a pain-specific region.


1 If anyone can parse the bold red sentence that appears in the Nature commentary (immediately after the first quoted passage in the post), please let me know.
In the future, it might be helpful always to correlate acute and chronic manipulations of specific neurons. If results from acute and chronic manipulations are discrepant, analyses of circuits that act in parallel to the manipulated circuit, or of similar neurons that are activated by different stimuli, might be more likely to provide an explanation for the discrepancy than examination of chains of hierarchically connected neurons, because off-target effects probably propagate throughout neural circuits by spilling over into adjacent, connected circuits.

2 Sam Schwarzkopf addressed this in his post, What is selectivity?

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Saturday, December 12, 2015

This Week in Neuroblunders: Optogenetics Edition

Recent technological developments in neuroscience have enabled rapid advances in our knowledge of how neural circuits function in awake behaving animals. Highly targeted and reversible manipulations using light (optogenetics) or drugs have allowed scientists to demonstrate that activating a tiny population of neurons can evoke specific memories or induce insatiable feeding.

But this week we learned these popular and precise brain stimulation and inactivation methods may produce spurious links to behavior!! And that “controlling neurons with light or drugs may affect the brain in more ways than expected”! Who knew that rapid and reversible manipulations of a specific cell population might actually affect (gasp) more than the targeted circuit, suggesting that neural circuits do not operate in isolation??

Apparently, a lot of people already knew this.

Here's the dire Nature News report:
...stimulating one part of the brain to induce certain behaviours might cause other, unrelated parts to fire simultaneously, and so make it seem as if these circuits are also involved in the behaviour.

According to Ölveczky, the experiments suggest that although techniques such as optogenetics may show that a circuit can perform a function, they do not necessarily show that it normally performs that function. “I don’t want to say other studies have been wrong, but there is a danger to overinterpreting,” he says.

But the paper in question (Otchy et al., 2015) was not primarily about that problem. The major theme is shown in the figure above the difference between acute manipulations using a drug (muscimol) to transiently inactivate a circuit versus the chronic effects of permanent damage (which show remarkable recovery).1 In the songbird example, acute inactivation of the nucleus interface (Nif) vocal control area (and its “off-target” attachments) warped singing, but the “chronic” lesion did not.2

In an accompanying commentary, Dr. Thomas C. Südhof asked:
How should we interpret these experiments? Two opposing hypotheses come to mind. First, that acute manipulations are unreliable and should be discarded in favour of chronic manipulations. Second, that acute manipulations elicit results that truly reflect normal circuit functions, and the lack of changes after chronic manipulations is caused by compensatory plasticity. 

But not so fast! said Südhof (2015), who then stated the obvious. “Many chronic manipulations of neural circuits (both permanent genetic changes and physical lesions) do actually produce major behavioural changes.” [as if no one had ever heard of H.M. or Phineas Gage or Leborgne before now.]

The acute/chronic conundrum is nothing new in the world of human neurology. But centuries of crudely observing accidents of nature, with no control over which brain regions are damaged, and no delineation of precise neural mechanisms for behavior, don't count for much in our store of knowledge about acute vs. chronic manipulations of neural circuits.

Let's take a look at a few examples anyway.

In his 1876 Lecture on the Prognosis of Cerebral Hæmorrhage, Dr. Julius Althaus discussed recovery of function:
Do patients ever completely recover from an attack of cerebral hæmorrhage?
This question used formerly to be unhesitatingly answered in the affirmative.
. . .

The extent to which recovery of function may take place depends—

1. Upon the quantity of blood which has been effused.  ...

2. Upon the portion of the brain into which the effusion has taken place. Sensation is more easily re-established than motion; and hæmorrhage into the thalamus opticus seems to give better prospects of recovery than when the blood tears up the corpus striatum.  ...


In his 1913 textbook of neurology (Organic and Functional Nervous Diseases), Dr. Moses Allen Starr discussed aspects of paralysis from cortical disease, and the uniqueness of motor representations across individuals: “Every artisan, every musician, every dancer, has a peculiar individual store of motor memories. Some individuals possess a greater variety of them than others. Hence the motor zone on the cortex is of different extent in different persons, each newly acquired set of movements increasing its area.”

In 1983, we could read about Behavioral abnormalities after right hemisphere stroke and then Recovery of behavioral abnormalities after right hemisphere stroke.

More recently, there's been an emphasis on connectome-based approaches for quantifying the effects of focal brain injuries on large-scale network interactions, and how this might predict neuropsychological outcomes. So the trend in human neuroscience is to acknowledge the impact of chronic lesions on distant brain regions, rather than the current contention [in animals, of course] that “acute manipulations are probably more susceptible to off-target effects than are chronic lesions.”

But I digress...

Based on two Nature commentaries about the Otchy et al. paper, I was expecting “ah ha, gotcha, optogenetics is a fatally flawed technique.” This Hold Your Horses narrative fits nicely into a recap of neurogaffes in high places. One of the experiments did indeed use an optogenetic manipulation, but the issue wasn't specific to that method.

Ultimately, the neuroblunder for me wasn't the Experimental mismatch in neural circuits (or a failure of optogenetics per se), it was the mismatch between the-problem-as-hyped and a lack of historical context for said problem.


1 Here's a figure from the other experiment, which involved acute vs. chronic inactivation of motor cortex in rats. Basically, the tiny injection of muscimol impaired lever-pressing behavior (acutely), but the large lesion did not (chronically). Panel H shows a similar deleterious effect using optogenetic stimulation.

Modified from Fig. 1 (Otchy et al., 2015).

I can't stress this point enough a human with a comparably sized lesion in primary motor cortex would not [likely] show that much spontaneous recovery of function in 5-10 days. Yes, of course there's plasticity in the central nervous system of adult humans, but I think Otchy et al. (2015) overstate the case here:
As in our experimental animals, patients with lesions to motor-related brain areas have motor deficits that resolve in the days and weeks following the injury. Aspects of this recovery are thought to be independent of rehabilitation, suggesting spontaneous processes at work.

2 It isn't exactly true that the lesions had no effect on song: “A fraction of the initial post-lesion vocalizations were severely degraded and did not resemble pre-lesion song.”


Althaus J (1876). A Lecture on the Prognosis of Cerebral Haemorrhage. British medical journal, 2 (812), 101-4. PMID: 20748269

Otchy, T., Wolff, S., Rhee, J., Pehlevan, C., Kawai, R., Kempf, A., Gobes, S., & Ölveczky, B. (2015). Acute off-target effects of neural circuit manipulations. Nature DOI: 10.1038/nature16442

Reardon, S. (2015). Brain-manipulation studies may produce spurious links to behaviour. Nature DOI: 10.1038/nature.2015.19003

Südhof, T. (2015). Reproducibility: Experimental mismatch in neural circuits. Nature DOI: 10.1038/nature16323

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