Monday, December 11, 2017

Brief Guide to the CTE Brains in the News. Part 2: Fred McNeill

Chronic traumatic encephalopathy (CTE) is the neurodegenerative disease of the moment, made famous by the violent and untimely deaths of many retired professional athletes. Repeated blows to the head sustained in contact sports such as boxing and American football can result in abnormal accumulations of tau protein (usually many years later). The autopsied brains from two of these individuals are shown below.



Left: courtesy of Dr. Ann McKee in NYT.  Right: courtesy of Dr. Bennett Omalu in CNN. These are coronal sections1 from the autopsied brains of: (L) Aaron Hernandez, aged 27; and (R) Fred McNeill, aged 63.


Part 1 of this series looked at complicating factors in the life of Aaron Hernandez PCP abuse, death by asphyxiation that presumably had some impact on his brain beyond the effects of concussions in football.

Part 2 will discuss the tragic case of Fred McNeill, former star linebacker for the Minnesota Vikings. He died in 2015 from complications of Amyotrophic Lateral Sclerosis (ALS), suggesting that his was not a “pure” case of CTE, either.


Fred McNeill


McNeill in 1974 (Mike Zerby / Minneapolis Star Tribune).

Obituary: Standout of the 1970s and 1980s was suffering from dementia and died from complications from ALS, according to Matt Blair [close friend and former teammate]

ALS is a motor neuron disease that causes progressive wasting and death of neurons that control voluntary muscles of the limbs and ultimately the muscles that control breathing and swallowing. Around 30-50% of individuals with ALS show cognitive and behavioral impairments.

According to a recent review (Hobson and McDermott, 2016):
Overlap between ALS and other neurodegenerative diseases, in particular frontotemporal dementia (FTD) and parkinsonism, is increasingly recognized. ...

Approximately 10–15% of patients with ALS show signs of FTD ... typically behavioural variant of FTD. A further 50% experience mild cognitive or behavioural changes. Patients with executive dysfunction have a worse prognosis, and behavioural changes have a negative impact on carer quality of life.

This raises the issue that repetitive head trauma can result in multiple neurodegenerative diseases, not only CTE. In fact, this has been recognized by other researchers who studied 14 retired soccer players who were experts at heading the ball (Ling et al., 2017). Only four had pathologically confirmed CTE:
...concomitant pathologies included Alzheimer's disease (N = 6), TDP-43 (N = 6), cerebral amyloid angiopathy (N = 5), hippocampal sclerosis (N = 2), corticobasal degeneration (N = 1), dementia with Lewy bodies (N = 1), and vascular pathology (N = 1); and all would have contributed synergistically to the clinical manifestations. ...   Alzheimer's disease and TDP-43 pathologies are common concomitant findings in CTE, both of which are increasingly considered as part of the CTE pathological entity in older individuals.

So the blanket term of “CTE” can include build-up of not only tau, but other abnormal proteins typically seen in Alzheimer's disease (Aβ) and the ALS-FTD spectrum (TDP-43). This lowers the utility of an in vivo marker specific to tau in diagnosing CTE in living individuals, an important enterprise because definitive diagnosis is only obtained post-mortem.

This brings us to the problematic report on Mr. McNeill's brain and the news coverage surrounding it.


CTE confirmed for 1st time in live person, according to exam of ex-NFL player

The recent study by Omalu and colleagues (2017) performed a PET scan on Mr. Neill almost 4.5 years before he died. This was before any motor signs of ALS had appeared. Clearly, 4.5 years is a very long time in the course of progressive neurodegenerative diseases, so right off the bat a comparison of his PET scan and post-mortem pathology is highly problematic.


Former Vikings linebacker Fred McNeill identified as subject of breakthrough CTE study

Another reason this study was not the “breakthrough” of news headlines is because the type of pathology plainly visible on MRI, and the type of cognitive deficits shown on neuropsychological tests, were quite typical of Alzheimer's disease and perhaps also vascular dementia. The MRI scan taken at the time of PET “showed mild, global brain atrophy with enlarged ventricles, moderate bilateral hippocampal atrophy, and diffuse white matter hyperintensities.”

Among his worst cognitive deficits at the time of testing were memory and picture naming, which is characteristic of Alzheimer's disease (AD). Likewise, the behavioral deficits reported by his wife are typically seen in AD.




Two years after the PET scan, he developed motor symptoms of ALS. His wife noted he could no longer tie his shoes or button his shirts. He developed muscle twitching in his arms and showed decreased muscle mass in his arms and shoulders. He was diagnosed with ALS 17 months prior to death, which was in addition to his presumed diagnosis of CTE.




FDA says no to marketing FDDNP for CTE

Finally, the molecular imaging probe used to identify abnormal tau protein in the living brain, [18F]-FDDNP, is not specific for tau. It also binds to beta-amyloid and a variety of other misfolded proteins. Or maybe not!

As I've written before, the brain diagnostics company TauMark™ was admonished by the FDA for making false claims. Six authors on the current paper hold a financial interest in the company. Most other research groups use more specific tau imaging tracers such as [18F]T807 (aka [18F]AV-1451 or Flortaucipir).

I certainly acknowledge that theses types of pre- and post-mortem studies are very difficult to conduct, and although the n=1 is a known weakness, you have to start somewhere. Nonetheless, the stats relating FDDNP binding to tau pathology were very thin and not all that believable. The paragraph below presents the results in their entirety. Note that p=.0202 was considered “highly correlated” while p=.1066 was not significant.
Correlation analysis was performed to investigate whether the in vivo regional [F-18]FDDNP binding level agreed with the density of tau pathology based on autopsy findings. Spearman rank-order correlation coefficient (rs) was calculated for the regional [F-18]FDDNP DVRs (Figure 1) and the density of tau pathology, as well as for amyloid and TDP-43 substrates (Table 5). Our results showed that the tau regional findings and densities obtained from antemortem [F-18]FDDNP-PET imaging and postmortem autopsy were highly correlated (rs = 0.592, P = .0202). However, no statistical correlation was found with the presence of amyloid deposition (r s = -0.481; P = .0695) or of TDP-43 (rs = 0.433; P = .1066).

Also, FDDNP-PET showed that in cortical regions, the medial temporal lobes showed the highest distribution volume ratio (DVR), along with anterior and posterior cingulate cortices. Isn't this typical of the Aβ distribution in AD?

I'm not denying the existence of CTE as a complex clinical entity, or saying that multiple concussions don't harm your brain. Along with others (e.g., Iverson et al., 2018), I'm merely suggesting that the clinical, cognitive, behavioral, and pathological sequelae of repeated head trauma should be carefully studied, and not presented in a sensationalistic manner.


Footnotes

1 Illustration of the coronal plane of section.



2 Note that most cases of ALS and FTD are not caused by concussions.



Read Part 1 of the series:

Brief Guide to the CTE Brains in the News. Part 1: Aaron Hernandez


References

Hobson EV, McDermott CJ. (2016). Supportive and symptomatic management of amyotrophic lateral sclerosis. Nat Rev Neurol. 12(9):526-38.

Iverson GL, Keene CD, Perry G, Castellani RJ. (2018). The Need to Separate ChronicTraumatic Encephalopathy Neuropathology from Clinical Features. J Alzheimers Dis. 61(1):17-28.

Ling H, Morris HR, Neal JW, Lees AJ, Hardy J, Holton JL, Revesz T, Williams DD. (2017). Mixed pathologies including chronic traumatic encephalopathy account fordementia in retired association football (soccer) players. Acta Neuropathol. 133(3):337-352.

Omalu B, Small GW, Bailes J, Ercoli LM, Merrill DA, Wong KP, Huang SC, Satyamurthy N, Hammers JL, Lee J, Fitzsimmons RP. (2017). Postmortem Autopsy-Confirmation of Antemortem [F-18] FDDNP-PET Scans in a Football Player With Chronic Traumatic Encephalopathy. Neurosurgery. 2017 Nov 10.


Further Reading I've written about CTE a lot, you can read more below.

FDA says no to marketing FDDNP for CTE

Is CTE Detectable in Living NFL Players?

The Ethics of Public Diagnosis Using an Unvalidated Method

The Truth About Cognitive Impairment in Retired NFL Players

Lou Gehrig Probably Died of Lou Gehrig's Disease

Blast Wave Injury and Chronic Traumatic Encephalopathy: What's the Connection?

Little Evidence for a Direct Link between PTSD and Chronic Traumatic Encephalopathy

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Monday, December 04, 2017

Brief Guide to the CTE Brains in the News. Part 1: Aaron Hernandez

Chronic traumatic encephalopathy (CTE) is the neurodegenerative disease of the moment, made famous by the violent and untimely deaths of many retired professional athletes. Repeated blows to the head sustained in contact sports such as boxing and American football can result in abnormal accumulations of tau protein (usually many years later). The autopsied brains from two of these individuals are shown below.



Left: courtesy of Dr. Ann McKee in NYT.  Right: courtesy of Dr. Bennett Omalu in CNN. These are coronal sections1 from the autopsied brains of: (L) Aaron Hernandez, aged 27; and (R) Fred McNeill, aged 63.


Both men played professional football in the NFL. Both came upon some troubled times after leaving the game. And although the CTE pathology in their brains has been attributed directly to football — repeated concussive and sub-concussive events — other potential factors have been mostly ignored. Below I'll discuss these events and phenomena, and whether they could have contributed to the condition of the post-mortem brains.


Aaron Hernandez


Illustration by Sean McCabe for Rolling Stone


Talented ex-NFL football star, PCP addict, convicted murderer, and suicide by hanging. The Rolling Stone ran two riveting articles that detailed the life (and death) of Mr. Hernandez. Despite a difficult upbringing surrounded by violence and tragedy, he was a serious and stellar athlete at Bristol High School. The tragic death of his father from a medical accident led Aaron to hang out with a less savory crowd. He fortunately ended up at the University of Florida for college football. There he failed several drug tests, but the administration mostly looked the other way. He was on a national championship team, named an all-American, and involved in a shooting where he was not charged.

Most NFL teams took a pass because of his use of recreational drugs and reputation as a hot-head:
After seeing his pre-draft psychological report, where he received the lowest possible score, one out of 10, in the category of “social maturity” and which also noted that he enjoyed “living on the edge of acceptable behavior,” a handful of teams pulled him off their boards, and 25 others let him sink like a stone on draft day.

But he ended up signing with the New England Patriots in a $40 million deal. He smoked pot constantly and avoided hanging out with the other players. “Instead of teammates, Hernandez built a cohort of thugs, bringing stone-cold gangsters over to the house to play pool, smoke chronic and carouse.” Things spiraled downwards, in terms of thug life, use of PCP (angel dust), and ultimately the murder of a friend that ended in a life sentence without parole.

He was also tried and acquitted of a separate double homicide, but his days were numbered. Two days later he hanged himself with a bedsheet in his jail cell. He was rumored to have smoked K2 (nasty synthetic cannabis) just before his death, but this was ultimately unsubstantiated.

These complicating factors lengthy history of drug abuse, death by asphyxiation must have had some effect on his brain, I mused in another post.




Meanwhile, the New York Times had a splashy piece about how the pristine brain of Aaron Hernandez presented an opportunity to study a case of “pure” CTE:
What made the brain extraordinary, for the purpose of science, was not just the extent of the damage, but its singular cause. Most brains with that kind of damage have sustained a lifetime of other problems, too, from strokes to other diseases, like Alzheimer’s. Their samples are muddled, and not everything found can be connected to one particular disease.

This was a startling statement, as I said in my secondary blog:
I’ve been struggling to write a post that highlights the misleading nature of this claim. How much of that was [the writer's] own hyperbole? Or was he merely paraphrasing the famous neuropathologists who presented their results to the media, not to peer reviewers? Is it my job to find autopsied brains from PCP abusers and suicides by hanging? Searching for the latter, by the way, will turn up some very unsavory material in forensic journals and elsewhere. At any rate, I think much of this literature glosses over any complicating elements, and neglects to mention all of the cognitively intact former football players whose brains haven’t been autopsied.

In the next post, I'll discuss the case of Fred McNeill O'Neill.


Footnote

1 Illustration of the coronal plane of section.





Read Part 2 of the series:

Brief Guide to the CTE Brains in the News. Part 2: Fred McNeill



Further Reading  
I've written about CTE a lot, you can read more below.

FDA says no to marketing FDDNP for CTE

Is CTE Detectable in Living NFL Players?

The Ethics of Public Diagnosis Using an Unvalidated Method

The Truth About Cognitive Impairment in Retired NFL Players

Lou Gehrig Probably Died of Lou Gehrig's Disease

Blast Wave Injury and Chronic Traumatic Encephalopathy: What's the Connection?

Little Evidence for a Direct Link between PTSD and Chronic Traumatic Encephalopathy




New York Times: A neuropathologist and her associate examined slices of the brain of a 27-year-old man. Credit: Boston University.

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Thursday, November 02, 2017

Can a Computer Algorithm Identify Suicidal People from Brain Scans? The Answer Won't Surprise You



Death by suicide is a preventable tragedy if the suicidal individual is identified and receives appropriate treatment. Unfortunately, some suicidal individuals do not signal their intent, and others do not receive essential assistance. Youths with severe suicidal ideation are not taken seriously in many cases, and thus are not admitted to emergency rooms. A common scenario is that resources are scarce, the ER is backed up, and a cursory clinical assessment will determine who is admitted and who will be triaged. From a practical standpoint, using fMRI to determine suicide risk is a non-starter.

Yet here we are, with media coverage blaring that an Algorithm can identify suicidal people using brain scans and Brain Patterns May Predict People At Risk Of Suicide. These media pieces herald a new study claiming that fMRI can predict suicidal ideation with 91% accuracy (Just et al. 2017). The authors applied a complex algorithm (machine learning) to analyze brain scans obtained using a highly specialized protocol to examine semantic and emotional responses to life and death concepts.

Let me unpack that a bit. The scans of 17 young adults with suicidal ideation (thoughts about suicide) were compared to those from another 17 participants without suicidal ideation. A computer algorithm (Gaussian Naive Bayes) was trained on the neural responses to death-related and suicide-related words, and correctly classified 15 out of 17 suicidal ideators (88% sensitivity) and 16 out of 17 controls (94% specificity). Are these results too good to be true? Yes, probably. And yet they're not good enough, because two at-risk individuals were not picked up.




The computational methods used to classify the suicidal vs. control groups are suspect, according to many machine learning experts on social media. One problem is known as “overfitting using too many parameters taken from small populations that may not generalize to unique samples. The key metric is whether the algorithm will be able to classify individuals from independent, out-of-sample populations. And we don't know that for sure. Another problem is that the leave-one-out cross validation is problematic. I'm not an expert here, so the Twitter threads that start below (and here) are your best bet.


For the rest of this post, I'll raise other issues about this study that concerned me.


Why use an expensive technology in the first place?

The rationale for this included some questionable statements.
  • ...predictions by both clinicians and patients of future suicide risk have been shown to be relatively poor predictors of future suicide attempt2,3.
One of the papers cited as a poor predictor (Nock et al., 2010) was actually touted as a breakthrough when it was published: Implicit Cognition Predicts Suicidal Behavior. [n.b. Nock is an author on the Just et al. paper that trashes his earlier work]. Anyway, Nock et al. (2010) developed the death/suicide Implicit Association Test (IAT)1 which was able to identify ER patients at greatest risk for another suicide attempt in the future:
...the implicit association of death/suicide with self was associated with an approximately 6-fold increase in the odds of making a suicide attempt in the next 6 months, exceeding the predictive validity of known risk factors (e.g., depression, suicide-attempt history) and both patients’ and clinicians’ predictions.
But let's go ahead with an fMRI study that will be far more accurate than a short and easy-to-administer computerized test!

  • Nearly 80% of patients who die by suicide deny suicidal ideation in their last contact with a mental healthcare professional4.
This 2003 study was based on psychiatric inpatients who died by suicide while in hospital (5-6% of all suicides) or else shortly thereafter, and may not be representative of the entire at-risk population. Nonetheless, other research shows that current risk scales are indeed of limited use and may even waste valuable clinical resources. The scales “may be missing important aspects relevant to repeat suicidal behaviour (for example social, cultural, economic or psychological processes).” But a focus on brain scans would also miss social, cultural, and economic factors.


How do you measure the neural correlates of suicidal thoughts?

This is a tough one, but the authors propose to uncover the neural signatures of specific concepts, as well as the emotions they evoke:
...the neural signature of the test concepts was treated as a decomposable biomarker of thought processes that can be used to pinpoint particular components of the alteration [in participants with suicidal ideation]. This decomposition attempts to specify a particular component of the neural signature that is altered, namely, the emotional component...

How do you choose which concepts and emotions to measure?

The “concepts” were words from three different categories (although the designation of Suicide vs. Negative seems arbitrary for some of the stimuli). The set of 30 words was presented six times, with each word shown for three seconds followed by a four second blank screen. Subjects were “asked to actively think about the concepts ... while they were displayed, thinking about their main properties (and filling in details that come to mind) and attempting consistency across presentations.”




The “emotion signatures” were derived from a prior study (Kassam et al., 2013) that asked method actors to self-induce nine emotional states (anger, disgust, envy, fear, happiness, lust, pride, sadness, and shame). The emotional states selected for the present study were anger, pride, sadness, and shame (all chosen post hoc). Should we expect emotion signatures that are self-induced by actors to be the same as emotion signatures that are evoked by words? Should we expect a universal emotional response to Comfort or Evil or Apathy?

Six words (death, carefree, good, cruelty, praise, and trouble in descending order) and five brain regions (left superior medial frontal, medial frontal/anterior cingulate, right middle temporal, left inferior parietal, and left inferior frontal) from a whole-brain analysis (that excluded bilateral occipital lobes for some reason) provided the most accurate discrimination between the two groups. Why these specific words and voxels? Twenty-five voxels, specifically. It doesn't matter.
The neural representation of each concept, as used by the classifier, consisted of the mean activation level of the five most stable voxels in each of the five most discriminating locations.
...and...
All of these regions, especially the left superior medial frontal area and medial frontal/anterior cingulate, have repeatedly been strongly associated with self-referential thought...
...and...
...the concept of ‘death’ evoked more shame, whereas the concept of ‘trouble’ evoked more sadness in the suicidal ideator group. ‘Trouble’ also evoked less anger in the suicidal ideator group than in the control group. The positive concept ‘carefree’ evoked less pride in the suicidal ideator group. This pattern of differences in emotional response suggests that the altered perspective in suicidal ideation may reflect a resigned acceptance of a current or future negative state of affairs, manifested by listlessness, defeat and a degree of anhedonia (less pride evoked in the concept of ‘carefree’) [why not less pride to 'praise' or 'superior'? who knows...]

Not that this involves circularity or reverse inference or HARKing or anything...


How can a method that excludes data from 55% of the target participants be useful??

This one seems like a showstopper. A total of 38 suicidal participants were scanned, but those who did not show the desired semantic effects were excluded due to “poor data quality”:
The neurosemantic analyses ... are based on 34 participants, 17 participants per group whose fMRI data quality was sufficient for accurate (normalized rank accuracy > 0.6) identification of the 30 individual concepts from their fMRI signatures. The selection of participants included in the primary analyses was based only on the technical quality of the fMRI data. The data quality was assessed in terms of the ability of a classifier to identify which of the 30 individual concepts they were thinking about with a rank accuracy of at least 0.6, based on the neural signatures evoked by the concepts. The participants who met this criterion also showed less head motion (t(77) = 2.73, P < 0.01). The criterion was not based on group discriminability.

This logic seems circular to me, despite the claim that inclusion wasn't based on group classification accuracy. Seriously, if you throw out over half of your subjects, how can your method ever be useful? Nonetheless, the 21 “poor data quality” ideators with excessive head motion and bad semantic signatures were used in an out-of-sample analysis that also revealed relatively high classification accuracy (87%) compared to the data from the same 17 “good” controls (the data from 24 “bad” controls were excluded, apparently).
We attribute the suboptimal fMRI data quality (inaccurate concept identification from its neural signature) of the excluded participants to some combination of excessive head motion and an inability to sustain attention to the task of repeatedly thinking about each stimulus concept for 3 s over a 30-min testing period.

Furthermore, another classifier was even more accurate (94%) in discriminating between suicidal ideators who had made a suicide attempt (n=9) from those who had not (n=8), although the out-of-sample accuracy for the excluded 21 was only 61%. Perhaps I'm misunderstanding something here, but I'm puzzled...

I commend the authors for studying a neglected clinical group, but wish they were more rigorous, didn't overinterpret their results, and didn't overhype the miracle of machine learning.


Crisis Text Line [741741 in the US] uses machine learning to prioritize their call load based on word usage and emojis. There is a great variety of intersectional risk factors that may lead someone to death by suicide. At present, no method can capture the full scope of diversity of who will cross the line.

If you are feeling suicidal or know someone who might be, here is a link to a directory of online and mobile suicide help services.



Footnote

1 I won't discuss the problematic nature of the IAT here.


References

Just MA, Pan L, Cherkassky VL, McMakin DL, Cha c, Nock MK, & Brent D (2017). Machine learning of neural representations of suicide and emotion concepts identifies suicidal youth. Nature Human Behaviour. Published online: 30 October 2017

Kassam KS, Markey AR, Cherkassky VL, Loewenstein G, Just MA. (2013). Identifying Emotions on the Basis of Neural Activation. PLoS One. 8(6):e66032.

Nock MK, Park JM, Finn CT, Deliberto TL, Dour HJ, Banaji MR. (2010). Measuring the suicidal mind: implicit cognition predicts suicidal behavior. Psychol Sci. 21(4):511-7.

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Tuesday, October 31, 2017

The Devilish Side of Psychiatry




The devil always experienced malicious pleasure in imposing himself in neuropsychiatric nosology


Olry and Haines (2017) published a mischievous article in the Journal of the History of the Neurosciences:
Having an inquiring mind by nature, the Devil always managed to interfere in all spheres of human activity, including the sciences. ... Biologists use an enzyme called “luciferase” — Lucifer has been described as the “light-bearing” fallen angel, hence the bioluminescence — to spot certain proteins by chromogenous reactions (Lodish et al., 2005, p. 92). ...

But how did the Devil get a foot — of course cloven (!) — into the door of the neurosciences?

Demonic possession plays an important role, of course, even in modern day psychiatric nosology (see the debate over Possession Trance Disorder in DSM-5). Does it make any sense to use DSM-5 (or DSM-IV) criteria to diagnose spirit possession across cultures? Transcultural psychiatry takes a much more inclusive and sensitive approach to such phenomena, which are often precipitated by trauma.

Olry and Haines (2017) avoid this literature entirely and suggest that:
The concept of demonic possession has been mainly of theological (Omand, 1970; Balducci, 1975; Rodewyk, 1988; Amorth, 1999, 2002; Bamonte, 2006; Fortea, 2006, 2008) and/or historical concern (Villeneuve, 1975; Pigin, 1998; Kelly, 2010; Kiely & McKenna, 2007).  ...

Although conservative theologians might not question the reality of diabolical possession (see Haag, 1969; Cortès & Gatti, 1975, for the few exceptions), many psychiatrists and psychologists admit being interested in the concept though, of course, not declaring themselves in favor of a supernatural etiology...

But being diabolical sorts themselves, the authors namedrop and show off their autographed copy of The Exorcist.



Figure 1. Title page of William Peter Blatty’s The Exorcist, with signed dedication by the actress Linda Blair. Author’s (R.O.) copy.



They continue:
However, literature and the movie industry — let’s remember William Peter Blatty’s The Exorcist (Blatty, 1971) (see Fig. 1) and the sociological impact of William Friedkin’s screen adaptation two years later (Bozzuto, 1975) — not only generated impassioned movie critics ... but also brought back scientific discussions involving neurosciences and, more specifically, psychology, neurology, and psychiatry (Montgomery, 1976).



Häxan (1922)entire film available at archive.org


Deadly exorcisms have been reported recently in the medical literature, including several cases of Fatal Hypernatraemia from Excessive Salt Ingestion During Exorcism. One 20-year-old woman received a prescription for Prozac to treat her postpartum depression, but her family also advised her to undergo an exorcism. She reportedly drank six glasses of a mixture of 1 kg table salt in a liter of water.

The Church itself involved physicians many centuries ago in the differential diagnosis between possession and mental disease, as exemplified by the 1583 Rheims National Synod:

[Before he undertakes to exorcize, the priest has to inquire diligently about the life of the possessed [. . .], of his health [. . .], because melancholics, lunatics often need much more cures of the physician than the ministry of exorcists.] (Tonquédec, 1948, p. 330)

Physicians, and in actual fact, clinical neuroscientists, then had to name a phenomenon — nosology oblige — about which most did not believe.


The Devil's Influence Over Neuropsychiatry – “some lexicological compromises”
...neuropsychiatrists sometimes allow themselves the use of theological concepts (e.g., possession, diabolical, demonological), provided that an additional term — medical or not — grants them a little more scientific credibility. This addition may be “neurosis” (demonological neurosis: Hélot, 1898; Freud, 1923), “psychosis” (diabolical possession psychosis: Lhermitte, 1944), “delirium” (diabolical possession delirium: Gayral, 1944; Delay, 1945), “syndrome” (possession syndrome: Yap, 1960), “phenomenon” (phenomenon of possession: Bron, 1975), “state” (possession state: Wittkower, 1970), or “experience” (possession experience: Pattison, 1969, p. 323).

Or sometimes the patient may feel like they are literally in hell.



Self-Portrait in Hell, by Edvard Munch (1903)



Reference

Olry R, Haines DE. (2017). The devil always experienced malicious pleasure in imposing himself in neuropsychiatric nosology. J Hist Neurosci. 26(3):329-335.


Further Reading

Possession Trance Disorder in DSM-5

Spirit Possession as a Trauma-Related Disorder in Uganda

"The spirit came for me when I went to fetch firewood" - Personal Narrative of Spirit Possession in Uganda

Possession Trance Disorder Caused by Door-to-Door Sales

Fatal Hypernatraemia from Excessive Salt Ingestion During Exorcism

Diagnostic Criteria for Demonic Possession



The Wailing (aka 곡성, , Gokseong)


...and to make your Halloween nightmares complete...



Although it's certainly not for everybody, The Wailing is an amazing film.

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Tuesday, October 10, 2017

BROADEN Trial of DBS for Treatment-Resistant Depression No Better than Sham

Website for the BROADEN™ study, which was terminated by
the sponsor.


A multi-site, randomized, double-blind, placebo-controlled clinical trial of deep brain stimulation (DBS) for treatment-resistant depression has failed, according to a new article in Lancet Psychiatry. The targeted brain region was bilateral subcallosal cingulate white matter, which had been called the “Depression Switch” based on acute stimulation studies at Emory. These disappointing results were not surprising, since they were covered by Neurotech Business Report in December 2013 and then in depth by my posts here and here. The new paper followed the patients for a longer period of time, up to 24 months for some in the cohort.

The main portion of the trial was six months in length. All patients received implantation surgery. Two weeks later, they were randomized to either the treatment group (n=60), who received stimulation right away, or the “sham” control group (n=30), who did not. After six months, the blinding was uncovered and both sham and treatment groups were offered open label DBS for another six months.

In the figure below, Control (red line) and Stimulation (blue line) groups both showed slight improvements over time, with no significant difference in depression severity measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). This was the primary endpoint. We don't see a difference between groups at six months or any other time.


- click on image for a larger view -


Fig. 2. (Holtzheimer et al., 2017). At months 9 and 12, the control group was receiving active stimulation; therefore, for the control group, 9 months refers to 3 months of active stimulation, and 12 months refers to 6 months of active stimulation. Error bars indicate standard deviations.


Concerning the endpoint more specifically (Holtzheimer et al., 2017):
The primary efficacy endpoint for the study was defined as difference in proportion of patients achieving a response between the stimulation and control groups. Response was defined as a 40% or greater reduction in MADRS and no worsening in GAF from baseline (average of three baseline MADRS assessments) to the average scores at months 4, 5, and 6.


Table 3 (modified from Holtzheimer et al., 2017).


Here's the full scoop for the futility analysis that put an end to the trial (because of the low probability of success). I had erroneously stated in January 2014 that the trial was halted by the FDA. It wasn't. It was stopped by the sponsor, St. Jude Medical (Holtzheimer et al., 2017):
For the futility analysis, based on the first 6 months' data, the proportion of patients with response for the stimulation group was predicted to be 40%, and for the control group was predicted to be 18·5%. In the actual futility analysis, these figures were 20% for the stimulation group and 17% for the control group. It was concluded that the study had a 17% chance of success if continued. Although this did not meet the prespecified definition for futility (<10% chance of success), the sponsor chose to end study enrolment following the futility analysis.

Although “These findings are disappointing given the encouraging data from earlier open-label studies of subcallosal cingulate DBS,” all was not lost, according to the authors. They offered a number of possible explanations (which can be summarized as long duration of illness, suboptimal stimulation parameters, and lack of tractography):
  • “participants in this study had an average current episode duration of about 12 years, which is much longer than the average duration of current episode in previous studies of subcallosal cingulate DBS (approximately 5 years) and might have contributed to the low overall proportion of patients achieving a response.”
  • “possible that stimulation contacts and parameters were suboptimal during the first 12 months of this study, given the somewhat restrictive programming algorithm used. Greater improvement in depression occurred after the 12-month endpoint when more flexibility in stimulation contacts and parameters was allowed.”
  • “Neurosurgical placement of the DBS electrodes, based on this algorithm, was highly accurate and did not differ between eventual responders and non-responders.”
[NOTE: placement was verified by at least two of three experts: HSM, CH, PEH. Nonetheless, the authors argue that placement could improve with more detailed tractography, e.g. Riva-Posse et al. 2017. This refinement of protocol has been discussed for the last 10 years; see Johansen-Berg 2007 and ...But My Subgenual Cingulate Is Sad.]
  • “for maximal efficacy, the active electrode for subcallosal cingulate DBS must be placed such that it affects a crucial network of white matter tracts connecting key brain regions, including the forceps minor, cingulum bundle, and uncinate fasciculus. Therefore, it is possible that prospective targeting on the basis of individual diffusion tensor imaging tractography could optimise electrode placement in subcallosal cingulate DBS.”

In an earlier paper, a group of DBS investigators and ethics experts advised other researchers, industry mavens, and even bloggers on “Being open minded about neuromodulation trials: Finding success in our 'failures'.” (Finns et al., 2017)
“Similarly, another randomized double blind clinical trial comparing active versus sham stimulation for the treatment of severe depression targeting Brodmann Area 25 was also halted for futility prior to completion of the planned study (St Jude Medical sponsored BROADEN trial). While there are neither publications nor official industry statements, uninformed speculations as to causes of the failure are in the public domain [28, 29] to the detriment of the scientific process and progress.

In each of these instances, different combinations of variables can lead to disappointing results. For example, patient characteristics, surgical variability, stimulation algorithms, outcome metrics, and institutional variance, can all contribute to negative outcomes in complex trials that initially seem promising. Further, once a negative report is published, the work can become ‘toxic’, and there is little incentive to engage in small subset analyses that have a limited market.
Finally,
“We believe that investigators, industry, regulators and society need to fully understand what is casually described as success and failure in order to maximize return on investment, all the more so when opportunities for additional knowledge generation remain in place. To do otherwise, would be irresponsible.”

So to call the BROADEN trial a failure is “irresponsible”? Personally, I am aware that a multi-site trial using invasive new technology to treat intractable psychiatric patients with a terrible and (ultimately) ill-defined syndrome is a massive undertaking. And very, very, very expensive. I have no problem with the investigators trying to glean what they can from individual differences to move forward with better targets/parameters/etc. I wanted to see this procedure help a majority of patients.

The bottom line here is that the primary preregistered endpoint was as follows: 12/60 (20%) improved with stimulation, 5/30 (17%) improved with no stimulation, 8/60 (12%) patients with stimulation reported an increase in depressive symptoms (this was not defined or quantified), and 1/30 (3%) patients with no stimulation reported an increase in depressive symptoms.

Let's take a look at the registered clinical trial. Oh we can't.


Clinical Trial NCT00617162

[Trial of device that is not approved or cleared by the U.S. FDA]




However, we can look at other clinical trials using the same device (Libra Deep Brain Stimulation System) with the same sponsor (St. Jude Medical) in Europe and Canada. Oh by the way, an April 2016 news release announced: Abbott to Acquire St Jude Medical (DBS was not mentioned). In January 2017 Abbott Completes the Acquisition of St. Jude Medical (no DBS here, either). I won't speculate any further. I'm too tired.


I'd like to conclude with an upbeat tweet from a prominent neuroscientist who studies pain and the placebo effect.



References

Choi KS, Riva-Posse P, Gross RE, Mayberg HS. (2015). Mapping the "Depression Switch" During Intraoperative Testing of Subcallosal Cingulate Deep Brain Stimulation. JAMA Neurol. 72(11):1252-60.

Fins JJ, Kubu CS, Mayberg HS, Merkel R, Nuttin B, Schlaepfer TE. (2017). Being open minded about neuromodulation trials: Finding success in our "failures". Brain Stimul. 10(2):181-186. 

Holtzheimer PE, Husain MM, Lisanby SH, Taylor SF, Whitworth LA, McClintock S, Slavin KV, Berman J, McKhann GM, Patil PG, Rittberg BR. (2017). Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial. The Lancet Psychiatry. 2017 Oct 4.

Riva-Posse P, Choi KS, Holtzheimer PE, Crowell AL, Garlow SJ, Rajendra JK, McIntyre CC, Gross RE, Mayberg HS. (2017). A connectomic approach for subcallosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression. Mol Psychiatry. 2017 Apr 11. [Epub ahead of print].


Further Reading

BROADEN Trial of DBS for Treatment-Resistant Depression Halted by the FDA
 NOTE: the trial was actually halted by the sponsor, not the FDA

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

Deep Brain Stimulation for Bipolar Depression

Modern Tract-Tracing for Historical Psychosurgery

...But My Subgenual Cingulate Is Sad

The Sad Cingulate

Sad Cingulate on 60 Minutes and in Rats

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Tuesday, September 19, 2017

Neuroexistentialism: A Brain in Search of Meaning

[image from Huth et al., 2016]

No, not “meaning” in the semantic sense... 


“Neuroexistentialism” is the angst that some humans feel upon realizing that the mind and spirit have an entirely physical basis. At a personal level I don't understand all the hubbub, because I accepted that mind = brain when I entered graduate school to study neuroscience. But for others:
“Coming to terms with the neural basis of who we are can be very unnerving. It has been called “neuroexistentialism”, which really captures the essence of it. We’re not in the habit of thinking about ourselves that way” (Churchland, 2013). 

It's very 2013.




Neuroexistentialism is also the title of a forthcoming volume of essays edited by Caruso and Flanagan. In their introductory chapter, Flanagan and Caruso define this philosophical variant in the progression of existentialisms to the present third-wave:
“There are three kinds of existentialism that respond to three different kinds of grounding projects—grounding in God’s nature, in a shared vision of the collective good, or in science. The first-wave existentialism of Kierkegaard, Dostoevsky, and Nietzsche expressed anxiety about the idea that meaning and morals are made secure because of God’s omniscience and good will. The second-wave existentialism of Sartre, Camus, and de Beauvoir, was a post-holocaust response to the idea that some uplifting secular vision of the common good might serve as a foundation. Today, there is a third-wave existentialism, neuroexistentialism, which expresses the anxiety that even as science yields the truth about human nature it also disenchants. The theory of evolution together with advances in neuroscience remove the last vestiges of an immaterial soul or self that can know the nature of what is really true, good, and beautiful.”

But I don't understand why the neuroscientific view must be so disenchanting. (But then again I'm a neuroscientist.) I knew fellow students who went to church yet easily reconciled their cell culture day jobs with their religious beliefs.

Professor Patricia Churchland is the best at explaining the “Don't Worry, Be Happy” response to neuroexistential terror:
Q - Some might say the idea that you are just your brain makes life bleak, unforgiving and ultimately futile. How do you respond to that?
A - It’s not at all bleak. I don’t see how the existence of a god or a soul confers any meaning on my life. How does that work, exactly? Nobody has ever given an adequate answer. My life is meaningful because I have family, meaningful work, because I love to play, I have dogs, I love to dig in the garden. That’s what makes my life meaningful, and I think that’s true for most people.


Word cloud for the 18 chapter titles in Neuroexistentialism


The Scope of Neuroexistentialsim

In brief, it's about free will, morality, meaning, and purpose. And of course neuroscience.

Back to my puzzlement about who suffers from a modern-day ailment caused by science spoilers. I found the below sentence to be both condescending and hyperbolic (Flanagan and Caruso):
But for most ordinary folk and many members of the nonscientific academy, the idea that humans are animal and that the mind is the brain is destabilizing and disenchanting, quite possibly nauseating, a source of dread, fear and trembling, sickness unto death even.

Perhaps the authors overascribe the illness and exaggerate the depth of ennui experienced by “most ordinary folk” who are too busy to grapple with the scientific implications of social neuroscience.

Honestly, I don't mean to be overly snarky but right now I'm grappling with Survival and Grief, and with second-wave existential crises caused by crazed leaders with bad hair who wave around their phallic symbols of nuclear destruction, and with persisting racism that divides the country, and with the hypocrisy of anti-immigration Christians, and with a future of toxic air and coastal regions underwater. Maybe what I'm experiencing is actually fourth-wave existentialism...




Medicating Neuroexistential Angst

If neuroexistentialism is a narrow form of generalized anxiety or even panic, can't we use our scientific knowledge to sooth these troubled brains? Why not apply psychopharmacological principles (and/or psychotherapy) to calm the fearful and trembling mind? We have already presupposed that mind = brain (which brought us “sickness unto death even”), and that medications can alter brain function in psychiatric disorders.

But this is not the correct way forward (see Flanagan and Caruso).
“...Are there naturalistic resources that can quell the anxiety produced by the ascendancy of the scientific image generally, and specifically, the picture that comes from combining neo-Darwinism with neuroscience, which produces the new and nerve-wracking anxiety associated with neuroexistentialism?

One promising approach is to pursue a kind of descriptive-normative inquiry into the causes and conditions of flourishing for material beings living in a material world, whose self-understanding includes the idea that such a world is the only kind of world that there is and thus that the meaning and significance of their lives, if there is any, must be found in such a world. We can call such an inquiry eudaimonics (Flanagan 2007, 2009).”

So the solution to third-wave existentialism is positive psychology (as opposed to despair).1


Footnote

1 Despair:
What sets the existentialist notion of despair apart from the conventional definition is that existentialist despair is a state one is in even when he isn't overtly in despair. So long as a person's identity depends on qualities that can crumble, he is considered to be in perpetual despair. And as there is, in Sartrean terms, no human essence found in conventional reality on which to constitute the individual's sense of identity, despair is a universal human condition.


Further Reading



Existential Neuroscience: a field in search of meaning

Earlier in 2013, the field of Existential Neuroscience (distinct from Neuroexistentialism) took the journal SCAN by storm, with neuroimaging studies focused on terror management theory (which describes how we deal with the inevitability of death). At the time,
I asked:
But what is Existential Neuroscience, exactly? A group of French intellectuals discussing brain research in a cafe while smoking and sipping espresso? An authentic neuroscience of utter freedom that embraces a state of perpetual despair1 over the meaninglessness of existence? Or independent groups of German-speaking neuroscientists who scan subjects while they ponder death?

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Monday, September 04, 2017

Survival and Grief



There is no transcendent moment of growth or meaning in watching a childhood friend die of cancer. There is no learning experience that will somehow make me stronger. Only horror, helplessness, loss, and grief. I am deriving no spiritual uplift from this experience, only depression and despair. If someone wants to talk to me about post-traumatic growth, I will spray paint their car.

Others disagree with me, I'm sure of it. For religious reasons. And I will respect their beliefs. There is no point in being a skeptical asshole to a grieving family.

The most important point here is that dying patients should not have to suffer this much. I wrote about this and related issues seven years ago, as my father was dying of cancer.

Ketamine for Depression: Yay or Neigh?

Limbaugh/Palin "death panels" extend the lives of terminally ill patients

2009 Lie of the Year Redux: Palin's so-called Death Panels

Update on Ketamine in Palliative Care Settings


I had more of a voice back then. Today I feel hopeless about the state of the world and my ability to have any impact on it. But I will try to keep my happy memories alive.



I love you.
RIP.


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