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

Fig. 2 (Omalu et al., 2011). Photomicrographs of tau-immunostained section of the frontal cortex.

Nicholas Kristof wrote an op-ed piece in the New York Times the other day about an Iraq War veteran with post-traumatic stress disorder (PTSD) and alcohol use problems who ultimately took his own life.

Veterans and Brain Disease

By NICHOLAS D. KRISTOF
Published: April 25, 2012

He was a 27-year-old former Marine, struggling to adjust to civilian life after two tours in Iraq. Once an A student, he now found himself unable to remember conversations, dates and routine bits of daily life. He became irritable, snapped at his children and withdrew from his family. He and his wife began divorce proceedings.

This young man took to alcohol, and a drunken car crash cost him his driver’s license. The Department of Veterans Affairs diagnosed him with post-traumatic stress disorder, or P.T.S.D. When his parents hadn’t heard from him in two days, they asked the police to check on him. The officers found his body; he had hanged himself with a belt.

This tragic but all-too-common story had an unusual ending. An autopsy of the veteran's brain revealed signs of chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease seen most often in athletes with repeated concussions from contact sports such as professional football and boxing. CTE results in cognitive and behavioral changes including memory impairments, poor impulse control, alterations in mood, suicidal behavior, disorientation, and ultimately dementia (Lakhan & Kirchgessner, 2012).

Diagnosis of CTE is usually post-mortem, because the brain tissue has to be stained for characteristic protein abnormalities which cannot be visualized in a living human. A defining pathological feature is tauopathy - abnormal accumulations of the tau protein seen in other dementias (e.g., Alzheimer's disease). In particular, aggregations of hyperphosphorylated tau into neurofibrillary tangles and accumulations of neuronal TAR DNA-binding protein-43 (TDP-43) are seen, as in frontotemporal lobar degeneration and amyotrophic lateral sclerosis (Lakhan & Kirchgessner, 2012).

There have been a string of high profile media reports about CTE pathology found at the autopsy of several American football players: Mike Webster, Terry Long, Chris Henry, Tom McHale, Owen Thomas, and others. Dr. Bennett Omalu and his colleagues at the Brain Injury Research Institute have conducted some of these autopsies (e.g., Omalu, Bailes et al., 2011).¹

Now, Omalu and colleagues have put forth the speculative idea that PTSD is on a continuum with CTE (Omalu, Hammers et al., 2011). Why? PTSD needn't be associated with concussions or traumatic brain injury (TBI) at all. The traumatic event exposure for PTSD (from DSM-IV-TR) "...must have involved both (a) loss of 'physical integrity', or risk of serious injury or death, to self or others, and (b) a response to the event that involved intense fear, horror, or helplessness (or in children, the response must involve disorganized or agitated behavior)." Head injury isn't part of the definition.

Omalu's target population is soldiers and veterans with TBI from the war (not, for instance, survivors of the 2011 earthquake and tsunami in Japan):

Following our elucidation of CTE in athletes, we hypothesized that PTSD in war veterans may belong to the CTE spectrum given that active military personnel are high-risk cohorts for repeated subconcussive and concussive traumatic brain injuries; for example, bomb blasts can cause traumatic brain injuries from primary pressure wave and acceleration-deceleration injury mechanisms. We expanded our CTE surveillance and brain tissue analyses to include deceased military veterans who were diagnosed with PTSD.

OK, that sounds reasonable -- if there's well-documented evidence of subconcussive and concussive brain injuries. Which brings us back to Kristof's article:

That Marine was the first Iraq veteran found to have C.T.E., but experts have since autopsied a dozen or more other veterans’ brains and have repeatedly found C.T.E. [NOTE: none of these cases has been published.] The findings raise a critical question: Could blasts from bombs or grenades have a catastrophic impact similar to those of repeated concussions in sports, and could the rash of suicides among young veterans be a result?

“P.T.S.D. in a high-risk cohort like war veterans could actually be a physical disease from permanent brain damage, not a psychological disease,” said Bennet Omalu, the neuropathologist who examined the veteran.

Oh no! Here we have an unfortunate example of mind-body dualism. PTSD is a physical brain disease, and this is independent of exposure to bomb blasts. There is ample evidence that exposure to traumatic events can physically change the brain (Sapolsky, 1996, 2001). Stress increases the levels of glucocorticoids, which in turn damage the hippocampus. This is visible on MRI scans (Bremner, 2006). The amygdala, a subcortical area involved in processing fear and other emotions, is overactive in those with PTSD while frontal lobe regions controlling the amygdala are underactive (Koenigs & Grafman, 2009).

However, it needn't result in permanent brain damage! In his 2006 review, Bremner notes that effective PTSD treatments can improve memory and restore hippocampal volume.

With this background in mind, let's return to the case report of the 27 yr old Marine. I believe there could be causes of CTE pathology that are unrelated to his military service in Iraq. I'll introduce these items as bullet points and then go into detail about each.

• Committed suicide by hanging.
• After deployment, played football in a league on base.
• One hit from the side caused him to fall to the ground; after this, he was confused and showed signs of a concussion [in my view].
  
• He continued to play football and hockey but was not diagnosed with a concussion (although he suffered his “bell rung”).
• Motor vehicle accident under the influence of alcohol, flipped his car, woke up later hanging upside down in the car.

Any or all of these incidents might have injured his brain in a way that could result in (or at least exacerbate) CTE, yet the authors either dismissed them as insignificant or minimized their impact. I am not a neuropathologist so I won't address the actual autopsy findings at this point. However, I do believe there are legitimate questions about the cause(s) of CTE in this Marine, as outlined below.

• Suicide by hanging - this causes anoxia, or a lack of oxygen to the brain. Anoxia causes permanent damage and shrinkage of certain brain regions. It also produces astrogliosis, which was reported in the present case study. But can it cause any of the other microscopic neuropathological findings? Perhaps not, but a few relevant papers are listed in the Appendix.

• Football - this is a classic cause of CTE. The Marine suffered at least one concussion after his service in Iraq (described below) and had his "bell rung" a number of times (possible subconcussive events):

After his deployments he was stationed at a base and played football in a base league. During a football game in 2009, approximately 9 months after his second deployment, he reported being hit from the side causing him to fall to the ground. He stood up, stumbled, fell again, and then continued the game. Other players noticed that he was confused and kept asking the count and details of the next play and he had to be removed from the game. The events of the following week were unclear and he reported residual headaches and memory problems.

There were no significant findings on a conventional CT scan, but this is standard (as the authors themselves have noted).

• The Marine also had a remote injury that resulted in a nasal bone fracture and other possible blows to the head before and after deployment. Yet the authors speculate:

It is our belief that his eventual CTE risk outcome occurred as a result of his lifetime and cumulative exposure to repeated subconcussive and concussive traumatic brain injuries, with his military exposures being the primary injuries that precipitated CTE.

Very little information is provided about his history of blast exposures in Iraq so it seems highly speculative to attribute CTE to those events primarily.

• Motor vehicle accident

He woke up later hanging upside down in the car. It was not clear whether he lost consciousness from a head injury or from stuporous alcohol intoxication. He noted the following morning that he suffered from headaches and vomited; however, it was not also clear whether these symptoms were alcohol-related or head injury–related. He lost his driver's license after this crash for driving under the influence and refusing a blood-alcohol test.

But the loss of consciousness, headaches, and vomiting could very well be due to a TBI or concussion he suffered in the car accident!


Military Service:

• Reported exposures to mortar blasts and IED blasts less than 50 m away (but was never diagnosed with TBI)
• During the second deployment he was court marshaled twice for acting out, insubordination, fighting, hazing, and assault, and was dropped 1 rank.

• "Described only a few incidents during his deployment that he found bothersome":

There was an incident during the 3rd week of his first deployment when he witnessed a vehicle in his patrol blown up, and marines killed and wounded. In another incident, approximately 2 weeks later, while hooking up their disabled vehicle to tow, 2 marines in his section were shot and he helped to patch them up. In yet another incident, he witnessed a school bus full of Iraqi citizens, many of whom were children, blown up by an IED.

• Diagnoses: PTSD with hyperarousal (irritability and insomnia) and numbing. Also alcohol abuse... In a clinic visit 2 months prior to his suicide, he reported persistent PTSD symptoms.

He visited a Veteran Affairs Medical Center the day before he committed suicide and reported having a new job as a football coach with his old high school, and was currently attending a community college. His driving under the influence charges had been dismissed.

This is certainly a very tragic case study, and I'm in favor of autopsies to consider possible causes of suicides in military veterans. But to speculate that PTSD is a permanent degenerative brain disease on the basis of one published case,² without adequate explanation and appropriate caveats, is irresponsible and damaging.


Let's return to Kristof's opinion piece:

The discovery of C.T.E. in veterans could be stunningly important. Sadly, it could also suggest that the worst is yet to come, for C.T.E. typically develops in midlife, decades after exposure. If we are seeing C.T.E. now in war veterans, we may see much more in the coming years.

So far, just this one case of a veteran with C.T.E. has been published in a peer-reviewed medical journal. But at least three groups of scientists are now conducting brain autopsies on veterans, and they have found C.T.E. again and again, experts tell me. Publication of this research is in the works.

The finding of C.T.E. may help answer a puzzle. Returning Vietnam veterans did not have sharply elevated suicide rates as Iraq and Afghan veterans do today. One obvious difference is that Afghan and Iraq veterans are much more likely to have been exposed to blasts, whose shock waves send the brain crashing into the skull.

Kristof must not have read Omalu et al. very closely, because in that paper they described an earlier autopsy conducted on a Vietnam veteran who died of natural causes.

In 2010 we encountered CTE changes in the brain of a 61-year-old deceased Vietnam war veteran, who died suddenly as a result of coronary atherosclerotic disease. This case was reported in the Stars and Stripes news magazine of the Department of Defense. The case was not published because we did not have comprehensive access to the medical records and family and social histories.

Yes, that study was presented in Stars and Stripes, a military newspaper:

“This is a sentinel case,” Omalu said. “The brain findings in this deceased Army veteran are similar to the brain findings in the retired contact-sport athletes. Now, we need to look at more brains.”

The case suggests that some veterans diagnosed with post-traumatic stress disorder, a psychological disorder, may actually have brain disease caused by concussions, he said.

...and why don't we go ahead and speculate about TBI even though there are no records of such:

Though he cannot prove the veteran suffered head trauma from blasts in combat, Omalu said it’s possible, because the former soldier had never shown any signs of psychotic behavior or drug use prior to going to Vietnam, according to family members and medical records.

It's also possible that the veteran was traumatized by events in Vietnam and started using stimulant drugs, which can cause psychotic behavior. Returning to case published in Neurosurgical Focus:

The authors report this case as a sentinel case of CTE in an Iraqi war veteran diagnosed with PTSD to possibly stimulate new lines of thought and research in the possible pathoetiology and pathogenesis of PTSD in military veterans as part of the CTE spectrum of diseases, and as chronic sequelae and outcomes of repetitive traumatic brain injuries.

Now that's a study for Medical Hypotheses, isn't it?

But seriously, I'm not denying CTE "as chronic sequelae and outcomes of repetitive traumatic brain injuries." And I mean absolutely no disrespect to the veterans and families who are affected by PTSD, concussions, and perhaps CTE in some cases.

Kristof again:

Frankly, I was hesitant to write this column. Some veterans and their families are at wit’s end. If the problem in some cases is a degenerative physical ailment, currently incurable and fated to get worse, do they want to know?

I called Cheryl DeBow, a mother I wrote about recently. She sent two strong, healthy sons to Iraq. One committed suicide, and the other is struggling. DeBow said that it would actually be comforting to know that there might be an underlying physical ailment, even if it is progressive.

“You’re dealing with a ghost when it’s P.T.S.D.,” she told me a couple of days ago. “Everything changes when it’s something physical. People are more understanding. It’s a relief to the veterans and to the family. And, anyway, we want to know.”

What would I tell Ms. DeBow? That PTSD is indeed a physical brain disease. It's not a ghost. And it isn't necessarily permanent.

Yes, it's easier to understand a brain injury that is caused by a physical force outside the head, instead of by a state of turmoil, sadness, and grief inside the head. But PTSD is a physically real injury nonetheless.


Footnotes

¹ The other major CTE research group is the Center for the Study of Traumatic Encephalopathy at Boston University (e.g., McKee et al., 2009).

² Yes, Kristof keeps mentioning other unpublished cases. Perhaps I'll amend this post or do a follow-up once they're published. Or even if I find them online in abstract form.

UPDATE (May 17, 2012): A new paper by Goldstein et al., 2012 reports on 4 new cases of CTE in military veterans, linking the pathology to blast exposure. However, 3 of the 4 also had concussions from other events. See Blast Wave Injury and Chronic Traumatic Encephalopathy: What's the Connection?


References

Bremner JD. (2006). Traumatic stress: effects on the brain. Dialogues Clin Neurosci. 8:445-61.

Koenigs M, Grafman J. (2009). Posttraumatic stress disorder: the role of medial prefrontal cortex and amygdala. Neuroscientist 15:540-8.

Lakhan SE, Kirchgessner A (2012). Chronic traumatic encephalopathy: the dangers of getting "dinged". SpringerPlus 1:2 doi:10.1186/2193-1801-1-2.

McKee AC, Cantu RC, Nowinski CJ, Hedley-Whyte ET, Gavett BE, Budson AE, Santini VE, Lee HS, Kubilus CA, Stern RA. (2009). Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol. 68:709-35.

Omalu B, Bailes J, Hamilton RL, Kamboh MI, Hammers J, Case M, Fitzsimmons R. (2011). Emerging histomorphologic phenotypes of chronic traumatic encephalopathy in American athletes. Neurosurgery 69:173-83; discussion 183.

Omalu B, Hammers JL, Bailes J, Hamilton RL, Kamboh MI, Webster G, & Fitzsimmons RP (2011). Chronic traumatic encephalopathy in an Iraqi war veteran with posttraumatic stress disorder who committed suicide. Neurosurgical focus, 31 (5) PMID: 22044102

Sapolsky RM. (1996). Why stress is bad for your brain. Science 273:749-50.

Sapolsky RM. (2001). Atrophy of the hippocampus in posttraumatic stress disorder: how and when? Hippocampus 11:90-1.

Appendix

Anoxia/hypoxia:

Acute hypoxia promote[s] the phosphorylation of tau via ERK pathway - hyperphosphorylated tau is a hallmark of CTE, but it did not appear to result in neurofibrillary tangles in this case.

Morphological analysis of astrocytes in the hippocampus in mechanical asphyxiation

Pathological role of hypoxia in Alzheimer's disease - mostly about amyloid beta, not tau.

TDP-43 immunoreactivity in anoxic, ischemic and neoplastic lesions of the central nervous system - did not exhibit TDP-43 inclusions, however.

[NOTE: It could have been that the cause of death was entirely irrelevant, but a statement to that effect would be reassuring.]

New York Times Opinion Page or Medical Hypotheses?

Medical Hypotheses is an Elsevier journal that publishes highly speculative oddball ideas. The previous editor, Bruce G. Charlton, published pretty much anything he wanted without sending it out for peer review. This got him into a great deal of trouble with legitimate scientists (and ultimately, the publisher) when the dangerous HIV denialism of Peter Duesberg was accepted for publication (only to be later WITHDRAWN). Although savvy researchers know Medical Hypotheses is an outlet for cranks, its articles do appear in PubMed, lending it an air of legitimacy in the eyes of the unsuspecting public.

The journal is now edited by Mehar Manku and its mandate is:

...to give novel, radical new ideas and speculations in medicine open-minded consideration, opening the field to radical hypotheses which would be rejected by most conventional journals. Papers in Medical Hypotheses take a standard scientific form in terms of style, structure and referencing. The journal therefore constitutes a bridge between cutting-edge theory and the mainstream of medical and scientific communication, which ideas must eventually enter if they are to be critiqued and tested against observations.

Submitted manuscripts are now reviewed by both the Editor and external reviewers. But why publish your highly speculative scientific [or pseudoscientific] ideas in a relatively esoteric forum, when you can reach millions and millions of readers with NO PEER REVIEW whatsoever? What sort of journal is this, you ask?

It's not a scientific journal at all, it's..... the Opinion Pages of the venerable New York Times!!




NYT Opinion Page or Medical Hypotheses? The Game!

The rules of NYTOPORMHTG are simple: guess which of the two outlets published the propositions and recommendations listed below.

(1) Meat is brain food

(2) Take magnesium if you're depressed

(3) Masturbate if you're congested

(4) Masturbate if you have restless legs syndrome

(5) Micron strokes cause Alzheimer's disease

(6) Joblessness causes suicide in U.S. military veterans

(7) Chronic traumatic encephalopathy causes suicide in veterans

(8) A noxious factor released into the third ventricle causes depression

(9) Enhanced activity in the anterior insula proves we love our iPhones

(10) Enhanced activity in the anterior insula proves disgust with John Edwards

(11) If you're about to have a panic attack, watch a scary movie

(12) Yoga is good for everything

(13) Stimulants cause PTSD

(14) PTSD causes chronic traumatic encephalopathy

(15) High heels cause schizophrenia



ANSWERS BELOW





NYT - 1, 6, 7, 9, 10, 12, 13, 14

MH - 2, 3, 5, 8, 11, 12, 15

Sleep Medicine (trick question!) - 4


Of the recent opinion pieces in the NYT, I found item #14 by Nicholas Kristof to be particularly egregious, inaccurate, and irresponsible. He cites one terrible (albeit published) case study claiming that chronic traumatic encephalopathy can be caused by post-traumatic stress disorder and considers no alternate explanations. I will address the issues he raised in a future post.

Item #13 by Dr. Richard A. Friedman was speculative and bothersome but ultimately less objectionable. He suggested there's a causal relationship between higher rates of stimulant prescriptions in the US military and rising rates of PTSD. I was very skeptical (because there's no evidence for that) and critical because the article leads the lay reader to believe that Ritalin and other stimulants cause PTSD. Ultimately, he put a "correlation does not equal causation" caveat at the very end, but by then the rhetorical damage was already done.


References

(1) Meat Is Brain Food - NYT

(2) Magnesium for treatment-resistant depression: A review and hypothesis - MH

(3) Ejaculation as a potential treatment of nasal congestion in mature males - MH

(4) Sexual intercourse and masturbation: Potential relief factors for restless legs syndrome? - SM

[also see Orgasm for Relief of Restless Legs Syndrome: A Case Study]

(5) The Micron Stroke Hypothesis of Alzheimer’s Disease and Dementia - MH

(6) The Best Medicine Just Might Be a Job - NYT

(7) Veterans and Brain Disease - NYT

(8) Depression as an evolutionary adaptation: Anatomical organisation around the third ventricle - MH

(9) You Love Your iPhone. Literally. - NYT

[see also NYT Editorial + fMRI = complete crap and the New York Times blows it big time on brain imaging and Neuromarketing means never having to say you're peer reviewed (but here's your NYT op-ed space)]

(10) This Is Your Brain on Politics - NYT -- prompted a letter to the editor from 17 neuroscientists, Politics and the Brain

[also see This Is Your Brain on Bad fMRI Studies and This Is Your Brain on Additional Critiques]

(11) Aborting panic attacks using false misattribution: a new treatment option - MH

(12) Effects of yoga on the autonomic nervous system, gamma-aminobutyric-acid, and allostasis in epilepsy, depression, and post-traumatic stress disorder - MH and Why Are We Discussing This? - NYT

(13) Why Are We Drugging Our Soldiers? - NYT

(14) Veterans and Brain Disease - NYT

(15) Is there an association between the use of heeled footwear and schizophrenia? - MH


Appendix: The Neurocritic on Medical Hypotheses

The pseudonymous ‘quant bloggers’- Figureheads, ghost-writers and pseudonymous quant bloggers: The recent evolution of authorship in science publishing.

Noxious mystery substance released into the third ventricle is the cause of depression! - Depression as an evolutionary adaptation: Anatomical organisation around the third ventricle.

JFK Neurotoxin Conspiracy Theory Published in Medical Hypotheses - President Kennedy's death: a poison arrow-assisted homicide.

Mirror Neuron Dance Party for Autism Spectrum Disorders - Synchronized dance therapy to stimulate mirror neurons in autism.

The Journal of Truly, Truly Outrageous Medical Hypotheses - Two for one! The classic, Is there an association between the use of heeled footwear and schizophrenia? and Two manic-depressives, two tyrants, two world wars.

More Truly, Truly Outrageous Medical Hypotheses - Ejaculation as a potential treatment of nasal congestion in mature males.

Magic Buttons, Silver Linings, and Two-Edged Swords

The Subjective Ups and Downs of Mood Disorders

The last post, Suffering for art is still suffering, took a critical look at studies claiming that individuals with bipolar disorder are more creative.¹ And instead of romanticizing the tortured bipolar artist, it considered the toll the disorder can take on those who live with it (and the people around them).

Some readers might have objected to the overly pessimistic tone of that post, prompting them to say things like, "It was a very negative post and clearly you are down on bipolar disorder, if not people who have it." That was not my intent.



So why don't we take a look at the sunnier side of serious mental illness!


The 'Magic Button Question'

“If you could live your life again, would you press the ‘magic button’ to experience life without a mood disorder?”

That's the question Parker et al. (2012) asked 885 patients attending an affective disorders clinic.² Of that number, 335 patients (38%) returned the questionnaires: 111 with bipolar disorder and 224 with unipolar depression. The authors wanted to assess whether the respondents perceived any advantages to their disorders.

Such positives are rarely volunteered, more commonly emerging only when the individual contemplates whether, if they were to live their life again, they would choose to have their mood disorder. A variant of this question was evident in Stephen Fry's BBC documentary (Wilson, 2006) where he explored his and others' experiences of a bipolar disorder. He asked several people to imagine there was “a button” that, if pressed, “…would take away every aspect of your bipolarity and cyclothymia”, and questioned whether they would press that button.

The results of Parker et al.'s study are based on a biased sample of patients who returned the survey: 83% of the bipolar population was diagnosed with Bipolar II (n=92), compared to only 17% with Bipolar I (n=19). In New Zealand,³ the lifetime prevalence of Bipolar I is 1.0%, compared to 0.7% for Bipolar II (Merikangas et al., 2011; see their Table 2). In the US, the figures are 1.0% and 1.1%, respectively. So we know right away the sample is highly self-selected.

Individuals with Bipolar II were three times more likely to endorse advantages to their disorder than those with Bipolar I.⁴ Because of the small number of individuals with Bipolar I, the authors collapsed across subtypes [which doesn't make sense] and found that 62% of bipolar people claimed some positive elements to their illness, compared to only 22% of the unipolar depressed group. "Thematic analyses" suggested that the four most common benefits named by bipolar individuals were:

• increased empathy (18%) ⁵
• increased creativity (14%)
  
• increased self-awareness (12%)
• increased productivity (8%)
  

Not to belabor the obvious, but this means that 86% did not identify creativity as a benefit, and 92% did not see productivity as an advantage of being bipolar. Hmm. Hardly a ringing endorsement for the bipolar advantage.

In the unipolar depressed group, 14% listed increased empathy as a positive aspect of depression; 9% mentioned self-awareness, 1% creativity and 0% productivity.

Wait, what about the 'magic button' question? The questionnaires didn't ask directly. Despite the title of the paper and four other references to buttons, Parker et al. never did get their answer.


Clouds and Silver Linings

An older paper by Dr. Kay Redfield Jamison and colleagues didn't ask the 'magic button' question either, but it left a sunnier impression of bipolar's positive side. In 1980, Jamison et al. wrote:

Although the psychiatric literature is replete with case reports, symptom checklists, and rating forms designed to assess changes during different mood states, to our knowledge there has been no systematic study of short-term, or state-dependent, positive experiences of affective, behavioral, and perceptual changes perceived by the patients themselves. Nor have patients been asked what long-term benefits they feel they derive from their mood disorders. For these reasons we did a preliminary, admittedly subjective investigation of such experiences in patients with primary affective disorders. We were interested in which changes during hypomania were evaluated as the most important and enjoyable. ... Although the usual caveats about retrospective and self-report data apply, the purpose of our study necessarily makes them less applicable than for other types of research.

Their sample consisted of 61 patients attending an outpatient clinic: 35 were diagnosed as bipolar and 26 as unipolar. The format of the questionnaire was more constrained than that of Parker et al. (2012). While euthymic (asymptomatic) or only mildly depressed, the patients were asked:

“Do you feel that your mood swings have resulted in overall personality characteristics that make you different from most people in the following ways?” for each of the several attributes: overall psychological sensitivity, sexual enjoyment, productivity, creativity, and social outgoingness and ease. Response choices were 1) yes, definitely, 2) probably, 3) probably not, and 4) definitely not.

The bipolar individuals were queried further about specific changes they perceived during episodes of mania or hypomania. Of particular interest was whether the phenomenology of hypomania differed between men and women. The authors readily admit that the phrasing of their questions might have elicited a positive response bias, and that the participants' answers were based on perceptions (and not necessarily reality). Perhaps this can account for the much higher percentage of very positive or somewhat positive ratings for productivity and creativity (relative to the study of Parker et al., 2012), as shown below.



Women in general endorsed "very much increased" positive attributes more often than men, but when collapsed across "very much" and "somewhat" increased, only productivity reached statistical significance. The authors noted that...

...it is interesting that manic-depressive illness -- which ostensibly carries with it more negative social, financial, and interpersonal sequelae and results in more frequent episodes of dysfunction and mood swings (which might also account for its perceived greater influence) than unipolar illness -- is assessed by most patients as making positive contributions to their lives in one or more important ways.

One issue of note for clinicians is the possibility of medication non-compliance. If manic or hypomanic episodes are very enjoyable, a bipolar individual may be inclined to go off medication so as not to blunt or eliminate such experiences.


Two-Edged Swords

Finally, a recent paper in the Journal of Affective Disorders (Lobban et al., 2012) appeared to be the most positive of all, but also the most biased [at least to me] and therefore limited in its generalizability. It presented the opinions of 10 bipolar people in the UK using qualitative methodology:

Interpretative Phenomenological Analysis (IPA) was used to understand the data. This approach is grounded in interpretive epistemology and emphasises the perceptions and experiences of individual participants from their point of view. It attempts to understand how participants make sense of their world and, in this instance, the positive aspects of their bipolar experiences. IPA recognises the active role of the interviewer and analysts and, therefore, prior to the interviews the authors documented their expectations about what the study would find and made explicit
their underlying assumptions where possible. The interviewer also informed all participants of her own diagnosis of BD at the outset of the interview.

While the experiences of these 10 people are certainly valid, it was odd for me to see them represented in a peer-reviewed medical journal. In brief:

Positive aspects were numerous, highly valued and participants welcomed the opportunity to discuss them. Three important themes emerged: 1) Direct positive impact of bipolar experiences on everyday life including amplification of internal states, enhanced abilities and more intense human connectedness; 2) Lucky to be bipolar – the sense of having been given a special gift; 3) Relationship between the self and bipolar experiences.

The participants were all recruited from outside a formal mental health setting and were (perhaps) more likely to see the bright side of their diagnoses. In the words of one participant:

Alan: “It's almost as if it opens up something in the brain that isn't otherwise there, and er I see colour much more vividly than I used to. .....So I think that my access to music and art are something for which I'm grateful to bipolar for enhancing. It's almost as it's a magnifying glass that sits between that and myself.”

Footnotes

¹ Based on Rothenberg's 2001 critique of the work of Andreasen and Jamison.

² The Black Dog Institute Depression Clinic, based in Sydney, Australia.

Patients are requested to complete a detailed series of questionnaires prior to attending the clinic, with salient questions asking them to describe the “best” and “worst” aspects of having a mood disorder, to agree or disagree with the statement that “having a mood disorder can have advantages” and, if the latter is affirmed, to describe any such advantages they had experienced. Questionnaire data were collected from patients referred to the clinic over the 2008–2011 period.

³ Sorry, Australia, you weren't included in that study.

⁴ The numbers given in the paper to support this statement make absolutely no sense, so I won't reproduce them here.

⁵ However, some studies have reported a decrease in cognitive empathy.


References

Jamison KR, Gerner RH, Hammen C, & Padesky C (1980). Clouds and silver linings: positive experiences associated with primary affective disorders. The American journal of psychiatry, 137 (2), 198-202 PMID: 7352574

Lobban, F., Taylor, K., Murray, C., & Jones, S. (2012). Bipolar Disorder is a two-edged sword: a qualitative study to understand the positive edge. Journal of Affective Disorders DOI: 10.1016/j.jad.2012.03.001

Merikangas KR, Jin R, He JP, Kessler RC, Lee S, Sampson NA, Viana MC, Andrade LH, Hu C, Karam EG, Ladea M, Medina-Mora ME, Ono Y, Posada-Villa J, Sagar R, Wells JE, Zarkov Z. (2011). Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry 68:241-51.

Parker, G., Paterson, A., Fletcher, K., Blanch, B., & Graham, R. (2012). The ‘magic button question’ for those with a mood disorder — Would they wish to re-live their condition? Journal of Affective Disorders, 136 (3), 419-424 DOI: 10.1016/j.jad.2011.11.008

Wilson, R., (Director). 2006. Stephen Fry: The secret life of a manic depressive [Motion Picture - YouTube]. BBC: Scotland.

Suffering for art is still suffering

Edvard Munch, Self-Portrait in Hell (1903)

"I inherited two of mankind's most frightful enemies — the inheritance of consumption and insanity — disease and madness and death were the black angels that stood at my cradle." ¹

-Edvard Munch

Many contemporary observers believe that Edvard Munch, the brilliant Norwegian artist best known for The Scream, had bipolar disorder. According to Rothenberg (2001):

A diagnosis of bipolar disorder with psychosis is based on his own diary descriptions of visual and auditory hallucinations, a multiply documented instance of his travelling throughout Europe manifesting manic disrupted behavior that culminated in his shooting two joints off the ring finger of his left hand, and his psychiatric hospitalization in 1908 for an intensification of auditory hallucinations, depression, and suicidal urges. He also suffered from bouts of alcoholism.

In the same article, the abstract expressionist painter Jackson Pollock was raised as another example of the innovative, tortured, bipolar artist. This might be taken as support for the view that creative individuals are more likely be bipolar than those in the general population. Clinical psychologist Kay Redfield Jamison, herself a prolific and talented person with bipolar disorder, has written extensively on this topic (Jamison, 1989, 1993). However, Rothenberg is actually critical of this general notion:

...it has been alleged that the illness makes creative persons more sensitive because of depressive diatheses and more productive while undergoing manic episodes. These allegations represent a romantic notion about creativity—the saga of the suffering artist—with little evidence to support them. Only comedians such as Jackie Gleason and Dick Van Dyke have seemed to derive direct benefit in their work from manic and hypomanic tendencies. Artistic products containing depressive or manic flight of ideas content have, only at particular times in history, been of social and aesthetic interest.

He continues with specific critiques of the methods used by Andreasen (1987) and Jamison (1989). In her sample, Andreasen found that 43% of writers attending the prestigious University of Iowa Creative Writing Program were bipolar, but only 10% of the controls (who included “hospital administrators, businessmen, social workers, lawyers, medical and computer science students”). The groups were not matched for socioeconomic status, peer recognition, intelligence, or success. Finally, Rothenberg notes that "the Iowa Program has long served as a retreat for writers at times of career shifts or setbacks" -- when they might be more likely to be depressed or otherwise affected by a mental illness.

He's even more scathing about Jamison's study of 47 prizewinning British artists and writers:

Stating that the design of the study could not allow for systematic diagnostic inquiry regarding mania and hypomania, Jamison reported that 38% of the sample had been treated for an “affective” illness. No controls, however, were used in the study. Investigator interviews here also were not “blind” and no attempt at differential diagnosis was made. Subjects were asked only “whether or not they had received treatment, and the nature of that treatment, for a mood disorder” (p. 126), and no further diagnostic assessment was reported. This problem was compounded by the fact that subjects were self-selected which, in the absence of controls, introduces the possibility of an overrepresentation of psychiatric illness in the group.

In the last few days, author and blogger David Dobbs (whom I respect and admire) has written about mental illness and creativity. In Jonah Lehrer Meets Stephen Fry – The Paradoxes of Bipolar and Creativity, he discussed Andreasen's work and the third chapter of Lehrer’s new book Imagine:

...[Andreasen] adds that the ideas one comes up with during such phases tend to be quite original, as the manic person, in a set of long-distance synaptic leaps that Lehrer explains earlier, draws associations that lie beyond the reach of more ordinary modes of thought. (NB: Not everyone with bipolar gets these manic “highs.”)* ² The ideas they come up with, in short, can be a bit crazy. If they spit them out then and published them, they’d likely be of little worth. But, as Lehrer explains,

then the mania ebbs. The extravagant high descends into a profound low. While this volatility is horribly painful, it can also enable creativity, since the exuberant ideas of the manic period are refined during the depression.

In other words, the emotional extremes of the illness reflect the extremes of the creative process: there is the ecstatic generation phase, full of divergent thoughts, and the attentive editing phase, in which all those ideas are made to converge. This doesn’t take away, of course, from the agony of the mental illness, and it doesn’t mean that people can create only when they’re horribly sad or manic. But it does begin to explain the significant correlations that have been repeatedly observed between depressive syndromes and artistic achievement.

A new idea is borne during mania, refined when it subsides. If you read only that, you can mistakenly think bipolar disorder is a good thing to have, to let run amok. Lehrer is quick to note that but fairly quickly to move on — he’s writing a book about creativity, not depression.

These ideas sparked a discussion and a follow-up post at Neuron Culture, Madness Ain’t All It’s Cracked Up to Be: A Corrective.³ David graciously included an update, saying that "These links between madness and creativity don’t make the more severe manifestations of depression or bipolar disorder any less destructive or painful." Then he quoted me:

Sometimes I think those who talk about bipolar and creativity haven’t been around many severely manic individuals. There’s overspending, lying, cheating, alienating friends, paranoia, psychosis, taking off and abandoning family, etc. I don’t think there’s anything especially creative about that.

Here’s another idea about bipolar and creativity: the percentage of manic people who engage in creative pursuits exceeds that in the general population. However, much of the output is incoherent. Some small percentage might be brilliant (either during or in between episodes), but then how many people are Kay Redfield Jamison or Stephen Fry (collapsing across bipolar subtypes)?

At any rate, bipolar can be a very destructive illness, and I hope those that romanticize it (or are viewed as romanticizing it) truly understand that. End of rant.

Kay Redfield Jamison is an extremely impressive woman, and a wonderful writer and speaker. I don't mean to detract from all she's done in her professional and personal lives to advance understanding of manic-depressive illness. But how many others (with or without bipolar) are as accomplished? You might as well ask, how many of us will win an Oscar or a Nobel Prize? Not many. Expecting that severe mental illness should confer special creativity is a mistake.

In An Unquiet Mind, Jamison said: “I have often asked myself whether given the choice, I would choose to have manic depressive illness…..strangely enough I think I would” (pp 217–218).

Not everyone feels this way, and the title of this post is taken from the quote below (from an anonymous person with Bipolar I disorder):

"...I've read a fair bit about bipolar disorders and creativity, some interesting theories, and have analyzed my own cycles.

But, this disorder destroyed my life and whatever moments of brilliance I may have had during episodes were not at all worth it. Suffering for art is still suffering.

A few people have found good outlets and moods enhance their work. Good for them. Kay Redfield Jamison is an example. Various famous people. Hemingway. Kurt Cobain. Wonder what they'd say about the mad pride movement?"

Footnotes

¹ Translations are by Bente Torjusen, Words and Images of Edvard Munch.

² David kindly added some of my cranky suggestions:

*Added 4/10/12, 6:13 a.m. EDT. Thanks to a friend for a prod on this. Fry addresses it in the film, but I forgot to include that definitional wrinkle in my post the first time through.

³ NOTE: I found the Rothenberg critique after our exchange, while writing the present post. One thing we did discuss was the difference between Stephen Fry's cyclothymia (Fry has called it "bipolar lite") and the full-blown mania of Bipolar I reflected in my quote.


References

Andreasen NC. (1987). Creativity and mental illness: Prevalence rates in writers and their first degree relatives. American Journal of Psychiatry 144:1288–1292.

Jamison KR. (1989). Mood disorders and patterns of creativity in British writers and artists. Psychiatry 52:125-34.

Jamison KR (1993). Touched With Fire: Manic-Depressive Illness and the Artistic Temperament. New York: Free Press (Macmillan).

Jamison KR (1996). An Unquiet Mind. Crown Publishing Group/Random House, New York, NY.

Rothenberg, A. (2001). Bipolar Illness, Creativity, and Treatment. Psychiatric Quarterly, 72 (2), 131-147 DOI: 10.1023/A:1010367525951

Edvard Munch, Self-Portrait with Skeleton Arm (1895)

What is art -
Art grows from joy and
sorrow - but mostly
from sorrow -
It grows from man's life -
Is art a description of
this life this movement -
Shall one depict the different
pleasures - the different
misfortunes - or shall one
only see the flower - whose
nature substance and vibration
are determined by
the joy and the pain -

I do not believe in an art which
has not forced its way out through
man's need to open his heart -
All art literature as well as
music must be brought out
with one's heart blood -

-E.M., Words and Images of Edvard Munch

Morbidly Curious Blog

Chicago Cultural Center
78 E. Washington Street
Chicago, IL 60602

Skull Table

While I was in Chicago for the CNS Meeting, I saw the Morbid Curiosity exhibit:

The exhibition explores the ways in which artists and cultures use skulls, bones and skeletons to explore human experiences and perceptions of mortality. Our awareness of death while we are still alive gives shape and meaning to our existence. Mortality is a universal theme in all arts, found repeatedly throughout time and across many cultures. The human body in skeleton form is a rich source of inspiration for contemporary artists as it was for our ancestors, from ancient civilization to the present.

As it is experienced here, the human skeleton represent more than the death. It reveals our shared identity as a species, our most profound common denominator. Signs of race, gender, status and identity melt away. Comntemporary artists use this aspect of the skeleton as an image to represent the ways in which human beings physically interact with the worlds..

Ancient trephined Skull
Pre-Columbian / 16th century human skull with brown patina

The exhibition also includes an extensive Dia de los Muertos (Day of the Dead) section, a small Rembrandt, Albrech Durer's Four Horsemen of the Apocalypse (1518 woodcut), the humorous My Portrait in 1960 (James Ensor, 1888), Death and the Woman by Käthe Kollwitz [who may have had Alice in Wonderland syndrome], and a very memorable mixed media piece by Steve Dilworth:

Hanging Figure [close-up]
1979 / Human skeleton, heart, liver, meat, horsehair, seagrass

Even more gruesome, however, was this sculpture made entirely of wax (and other artificial materials):

Are You Still Mad at Me? By John Isaacs
2001 / steel, wax, artificial blood, mixed media

John Isaacs is interested in the physical functioning of the human body, and this figure is shocking in its realism. Isaacs studied biology and once created a replica of his own body in the style of a wax anatomical model. This modern reinterpretation of the vanitas theme emphasizes the fragility of the human body.

Check out the great blog for Morbid Curiosity: The Richard Harris Collection to see more morbid images!

tDCS Symposium Stimulates Giant Brain in Chicago

The 2012 Cognitive Neuroscience Society Meeting was held in Chicago from March 31 to April 3. The schedule was packed with three and a half days of symposia, slide sessions, and posters. One well-attended event was Symposium Session 2, on non-invasive brain stimulation.

Using Non-Invasive Brain Stimulation to Enhance Cognitive and Motor Abilities in the Typical, Atypical, and Aging Brain

Chair: Roi Cohen Kadosh, University of Oxford
Speakers: Roi Cohen Kadosh, Jenny Crinion, Paulo S. Boggio, Leonardo G. Cohen


The talk by Dr Jenny Crinion, a speech and language therapist who has gone over to the "dark side" of research (as she put it), drew a lot of attention and media coverage. It's no wonder, given her clinically relevant results.

Jolt to brain aids language recovery

Stroke patients improve on picture-naming task after stimulation treatment

By Laura Sanders
Web edition : Monday, April 2nd, 2012

CHICAGO — A brain zapping technique helps people recover language after a stroke, new research shows. The results may point to a better way for people to relearn how to talk after a brain injury.

The "brain zapping" technique is transcranial direct current stimulation. According to a 2010 review by George and Aston-Jones, it is a very old method undergoing a recent revival:

Transcranial direct current stimulation (tDCS) is perhaps one of the simplest ways of focally stimulating the brain. Similar techniques were practiced almost immediately after electricity was 'discovered' in the late 1880s. Passing a direct current through muscle, or the brain, was in vogue in Europe. For example, one of Charcot's residents, Georges Duchenne de Boulogne, traveled around Paris with a small battery and passed electricity through patients' muscles, examining the effects on numerous disorders and using it to better understand muscle–nerve innervations, particularly in the muscular dystrophies (George, 1994).

How does it work?

Quite simply, tDCS involves passing a weak (usually ≤ 1 mA) direct current through the brain between two electrodes. The current enters the brain from the anode, travels through the tissue, and exits out the cathode. Some researchers refer to this as either cathodal tDCS or anodal tDCS depending on which electrode is placed over the region that is being modified (Figure 5).

Figure 5 (George & Aston-Jones, 2010). A tDCS device uses an anode and cathode connected to a direct current source much like a 9 V battery (a). The direct current passes through the intervening tissue, with some shunting through the skull but much of it passes through the brain and changes resting electrical charge, particularly under the cathode (b).


Crinion started her talk by saying she originally wanted to use transcranial magnetic stimulation (TMS) -- another non-invasive brain stimulation technique -- but this would be too painful if applied over the left inferior frontal cortex (Broca's area). She lamented the NHS limit of 12 hours of speech therapy for stroke patients with aphasia. These individuals would benefit from more intensive therapy (e.g., phonemic cueing) for a longer period of time. From a practical standpoint, then, would tDCS maximize the results obtained during a truncated retraining period?¹ What sort of behavioral and neural effects might be expected with such a regimen?

She continued by describing a study in control participants that combined behavioral priming for overt picture naming, true and sham tDCS, and fMRI (Holland et al., 2011). Anodal tDCS² was applied over the left IFC.³

What are the effects of tDCS on echo planar imaging (EPI)? Any potential for artifacts, you ask? No problem! Supposedly there's signal dropout at the scalp/skull but not the brain. See?



This is what I first saw on the slide. "EPI is not affected," apparently, but the images looked mighty odd to me. What the &^$% kind of brain is that??

It's not a brain, it's a watermelon! Oh...

Figure S1. Effects of A-tDCS on Echo-Planar Images (EPI). Field distortions from control (watermelon) and one participant.
(A) Multi-slice coronal view of watermelon field distortion with indices for each slice. Blue bar indicates the location of anodal electrode... Perturbations were localized to the surface layer only of the watermelon.

Here's more, from Holland et al. (2011).

Figure S1. (D) Consistent with the control data, perturbations in the participants’ data were also localized to the scalp surface only. Here we illustrate in one participant’s coronal sections the effect of the anode electrode on B0 field map data.

All right, so what were the effects of tDCS on picture naming times?



My god, what a giant effect! Oh wait... It's more like a 25 msec improvement (see below), which is still statistically significant.⁴


Figure 1 (modified from Holland et al., 2011). Behavioral Effects of Anodal Transcranial Direct Current Stimulation. Main effects of order, i.e., position of run during scanning session (P1 versus P2; A) ... and stimulation (sham vs. A-tDCS; C), on naming reaction times (n = 10). ... Error bars indicate standard error of the mean (SEM). ^∗∗∗p < 0.001, ^∗∗p < 0.05.

How about the effects of tDCS on the BOLD response? Briefly, stimulation decreased naming-related activity in two localized regions: left inferior frontal sulcus and left ventral premotor cortex (suggestive of neural facilitation):

A-tDCS—by depolarizing neurons nearer to threshold—can reduce the amount of excitatory input required to produce a naming response. Thus, we can have a situation in which there is increased excitability (manifest as a faster response time to a given input) accompanied by reduced BOLD (less synaptic input for a given output, in this case naming).

Finally, the preliminary results of a clinical study were presented. Thirteen participants with aphasia received 60 hours of behavioral training with specific pictures. Patients receiving tDCS over intact left IFC (n=6) or sham stimulation (n=7) were compared. Picture naming accuracy for the trained items improved by 56% in the sham group and by 92% in those getting real stimulation. There was no improvement on the untrained items in either group.

These results are very impressive. However, a quick PubMed search of tDCS, aphasia revealed 20 published articles already⁵ [which was surprising to me, as it wasn't mentioned in the talk. Or else I forgot about it. Or didn't hear it]. Turns out some of these were reviewed in Holland and Crinion (2011). Nevertheless, none of this detracts from the current findings:

This gap persisted after the initial testing, though it diminished in size. Three months out, volunteers who received the stimulation performed 82 percent better than they had performed before treatment, while those receiving sham treatment held steady with a 55 percent improvement. “These are huge effects,” Crinion said. “It’s really encouraging.”

The 3 month followup is longer than previous studies (e.g., Baker et al., 2010; Fridriksson et al, 2011; Marangolo et al., 2011). Crinion and colleagues also plan on publishing the brain imaging results from their ongoing trial.

Where do things go from here? DIY treatment kits? Perhaps (Holland & Crinion, 2011)...

Due to its appeal as a potential treatment tool, some manufacturers (NeuroConn, Germany, personal communication) are exploring mini-tDCS kits for patient's self-administration at home with stimulation dosages pre-programmed by their clinician. Some additional precautions should be considered for safe use of tDCS: (i) patients should have no metallic implants near the electrodes, and (ii) personnel conducting tDCS should be appropriately trained before applying the technique, as experience with the method is still limited and the risk profile of stimulation is not yet completely known.

Further Reading:

Give your brain an electric shock, learn stuff faster

How To Electrify Your Brain To Be Smarter With a 9-Volt Battery -- Kids! Don't try this at home!

DARPA Study Uses Video Game to Research tDCS, Finds More Amps Mean More Frags

Australian Researchers Create “Thinking Cap”, Scheme to Breed Army of Nobel Laureates and Mad Scientists

Neurostimulation - The Genius Machine? -- covers the latest from Richard Chi and Allan "thinking cap" Snyder.


Footnotes

¹ Surprisingly, the NHS website mentions both tDCS and TMS as treatment modalities for aphasia, although no coverage is provided.

It has been suggested that both tDCS and TMS may help to stimulate parts of the language centre that have been damaged and encourage a certain degree of recovery and repair. For example, initial research has found that these types of treatment may help people to improve their ability to remember the names of certain objects, people and places.

As transcranial stimulation is a new method of treatment, access is currently limited to people who are willing to take part in a clinical trial.

² Anodal tDCS (A-tDCS) is thought to increase cortical excitability.

³ MNI coordinates were -48 20 19. More about location and parameters:

A-tDCS stimulation was generated by a specially designed MRI-compatible neuroConn stimulator system and delivered at 2 mA continuously for 20 min via a pair of identical MRI-compatible leads and rectangular rubber MRI-compatible electrodes (5 × 7 cm), allowing for a current density of 0.057 mA/cm². For all participants, the anode was placed over the left IFC (equivalent to electrode position FC5 in a 10-10 EEG nomenclature), with the cathode placed over the contralateral frontopolar cortex.

⁴ More fine print...

Participants were selected based on previous behavioral performance during a speech-priming fMRI task. The main criterion for selection was a word versus control cue priming effect of greater than 85 ms.

...and:

Participants reported no adverse sensations during A-tDCS and sham. They could detect a difference between the two conditions (p = 0.07), but they were unable to reliably distinguish which was A-tDCS.

⁵ Not all of these were double-blind treatment studies, though.


References

Baker JM, Rorden C, Fridriksson J. (2010). Using transcranial direct-current stimulation to treat stroke patients with aphasia. Stroke 41:1229-36.

Fridriksson J, Richardson JD, Baker JM, Rorden C. (2011). Transcranial direct current stimulation improves naming reaction time in fluent aphasia: a double-blind, sham-controlled study. Stroke 42:819-21.

George, M., & Aston-Jones, G. (2009). Noninvasive techniques for probing neurocircuitry and treating illness: vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). Neuropsychopharmacology, 35 (1), 301-316. DOI: 10.1038/npp.2009.87

Holland, R., & Crinion, J. (2011). Can tDCS enhance treatment of aphasia after stroke? Aphasiology, 1-23. DOI: 10.1080/02687038.2011.616925

Holland, R., Leff, A., Josephs, O., Galea, J., Desikan, M., Price, C., Rothwell, J., & Crinion, J. (2011). Speech Facilitation by Left Inferior Frontal Cortex Stimulation. Current Biology, 21 (16), 1403-1407. DOI: 10.1016/j.cub.2011.07.021

Marangolo P, Marinelli CV, Bonifazi S, Fiori V, Ceravolo MG, Provinciali L, Tomaiuolo F. (2011). Electrical stimulation over the left inferior frontal gyrus (IFG) determines long-term effects in the recovery of speech apraxia in three chronic aphasics. Behav Brain Res. 225:498-504.