The Neurocritic

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Born in West Virginia in 1980, The Neurocritic embarked upon a roadtrip across America at the age of thirteen with his mother. She abandoned him when they reached San Francisco and The Neurocritic descended into a spiral of drug abuse and prostitution. At fifteen, The Neurocritic's psychiatrist encouraged him to start writing as a form of therapy.

The Neurocritic
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  • October 12, 2013
  • 05:38 AM

Existential Neuroscience: a field in search of meaning

by The Neurocritic in The Neurocritic

What separates prior from subsequent is exactly nothing. This nothing is absolutely impassable, just because it is nothing...–Jean-Paul Sartre, Being and Nothingness (p. 28).If you read the journal Social Cognitive and Affective Neuroscience (SCAN), you might think that Existential Neuroscience is a hot new field, since three recent papers on the topic have been published there. Can it provide profound new insights into the human condition? From what I can tell, these references to a formal discipline of “Existential Neuroscience” are based entirely on terror management theory, which was developed by Greenberg and colleagues in the 1980s (Greenberg et al., 1986; Rosenblatt et al., 1989). How does this relate to existentialism?“Existence precedes essence” (Sartre, 1946). But first, what is Existentialism? The Stanford Encyclopedia of Philosophy is reluctant to admit that it's an actual philosophy, rather than a literary or artistic trend:By the mid 1970s the cultural image of existentialism had become a cliché, parodized in countless books and films by Woody Allen. It is sometimes suggested, therefore, that existentialism just is this bygone cultural movement rather than an identifiable philosophical position; or, alternatively, that the term should be restricted to Sartre's philosophy alone. Stanford Encyclopedia eventually tells us that the most distinctive aspect of existentialism is that standard notions of identity are wrong:The fundamental contribution of existential thought lies in the idea that one's identity is constituted neither by nature nor by culture, since to “exist” is precisely to constitute such an identity. It is in light of this idea that key existential notions such as facticity, transcendence (project), alienation, and authenticity must be understood.The first known account of “Existential Neuroscience” (EN) was written by mirror neuron researcher Dr. Marco Iacoboni in 2006 (PDF).1 It was published as a book chapter in Social Neuroscience: Integrating Biological and Psychological Explanations of Social Behavior (Harmon-Jones & Winkielman, 2007). Thus, EN appears to be a branch of Social Neuroscience.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 despair2 over the meaninglessness of existence? Or independent groups of German-speaking neuroscientists who scan subjects while they ponder death?Sartre and FriendsIf you guessed the latter, you'd be correct.  More precisely, EN thus far consists of neuroimaging studies of mortality salience, as you might expect by its reliance on terror management theory (TMT).3  Therefore, EN should be called “Fear of Death” Neuroscience. TMT holds that when people are confronted with their own mortality, they respond in ways to boost their self-esteem, reinforce their own values, and punish outsiders.In an ironic twist for the existentialist neuroscientists, however, Existentialism rejects science as means of understanding what it is to be human. Here's Sartre on the futility of science:From the outset physiology is condemned to understand nothing of life since it conceives life simply as a particular modality of death, since it sees the infinite divisibility of the corpse as primary, and since it does not know the synthetic unity of the "surpassing towards" for which infinite divisibility is the pure and simple past. Even the study of life in the living person, even vivisection, even the study of the life of protoplasm, even embryology or the study of the egg can not rediscover life; the organ which is observed is living, but it is not established in the synthetic unity of a particular life; it is understood in terms of anatomy—i.e., in terms of death. -Jean Paul Sartre, Being and Nothingness (p. 348).Even if one is a firm believer in the potential of neuroscience to lead to better treatments for mental illness, it's hard to envision what brain research can tell us about a philosophical system opposed to science (or most other philosophies, for that matter). Can we imagine what a Taoist Neuroscience or an Epicurean Neuroscience would be like? Not to mention the prospect of a Nihilist Neuroscience or a Post-Structural Neuroscience...By necessity, a true Existential Neuroscience must deal with human beings as the focus of study, since the withdrawal reflex of Aplysia might not be a valid model of existential angst. It's unlikely we'll see circuit models and optogenetic studies of the alienated self any time soon. As currently formulated, EN has more concrete goal: to study one specific element of existentialist thought that might be more closely related to Heidegger's views (see Quirin et al., 2012).This leads us to the most recent of the EN studies in SCAN (Silveira et al., 2013), which I'll discuss in some detail. This study is based on a different reaction to mortality salience, one that is derived from evolutionary psychology: the drive to reproduce. The heterosexual participants in the study viewed attractive opposite-sex faces and made decisions about whether they would like to meet them (a proxy for sexual desire) after being primed by death-related words (or not). Already, this seems like a bridge too far, but let us go on.Sixteen female and 16 male subjects participated in this fMRI experiment. They viewed a series of attractive faces (as judged by an independent group of participants) and decided, in separate blocks, if the faces were attractive or not (explicit evaluation) or whether they'd like to meet the person or not ("implicit" evaluation). The task was cued at the beginning of a block by the words Meet? or Attractive? Participants make their choice when the ? appears on the monitor. Below is an example of the implicit no-prime condition shown to the male subjects.... Read more »

  • September 30, 2013
  • 04:42 AM

A Neural Circuit for Voracious Overeating in Mice: Translation to Humans

by The Neurocritic in The Neurocritic

Optogenetic activation of inhibitory GABA neurons projecting from the limbic forebrain to the lateral hypothalamus causes this mouse to binge on cheese. The rapid onset and offset of the intense feeding behavior is striking. Credit: Jennings et al. (2013).The hypothalamus is a collection of discrete nuclei in the vertebrate diencephalon that control a variety of metabolic, neuroendocrine, and circadian functions. Since the 1940s, the ventromedial nucleus (VM) has been known for its important role in satiety — lesions of this nucleus cause rats to become obese, while electrical stimulation of this structure curtails feeding. On the other hand, the lateral hypothalamus (LH) controls hunger. In 1953, Delgado and Anand implanted multilead electrodes into the brains of cats and found that electrical stimulation of the LH caused an increase of food intake to 500-1,000% of control levels.Sixty years later, Jennings and colleagues (2013) set out to delineate the precise circuitry and neuronal population responsible for these effects using modern optogenetic techniques. They targeted a projection pathway from the bed nucleus of the stria terminalis (BNST), a part of the "extended amygdala" in the limbic forebrain, to the LH. These inhibitory GABAergic neurons synapse onto excitatory glutamatergic neurons in the LH. This specific cell type was targeted by using a genetically modified mouse line. The mice express a recombination enzyme only in neurons that express the vesicular GABA transporter (vGAT-ires-cre mouse).  A viral construct was used to insert a gene that codes for Channelrhodopsin-2, a light-sensitive protein that was fused to yellow fluorescent protein, directly into the BNST via microinjection. The BNST projections are stimulated by exposing them to blue light using specially implanted optical fibers. Since these neurons are GABAeric, they inhibit the postsynaptic LH neurons. This is shown schematically in the figure below. Fig. 1 (modified from Jennings et al., 2013). VgatBNST→LH circuit activation induces feeding in well-fed mice. (A) Schematic showing VgatBNST→LH circuit targeting.A different circuit was targeted in control mice, the projection from BNST to the ventral tegmental area (VTA). Activation of the VgatBNST→VTA projection did not induce voracious feeding behavior. But the mice did find it rewarding, which isn't a surprise... the VTA contains the dopaminergic cell bodies of the mesocortical dopamine system.This is very impressive work in tune with the priorities of the BRAIN Initiative. Unaffiliated expert commenters have noted:“This is a really important missing piece of the puzzle,” says neuroscientist Seth Blackshaw of Johns Hopkins University in Baltimore. “These are cell types that weren’t even predicted to exist.” A deeper understanding of how the brain orchestrates eating behavior could lead to better treatments for disorders such as anorexia and obesity, he says. And this:Cynthia Bulik, Distinguished Professor of Eating Disorders at UNC School of Medicine and the Gillings School of Global Public Health, says, “Stuber’s work drills down to the precise biological mechanisms that drive binge eating and will lead us away from stigmatizing explanations that invoke blame and a lack of willpower.”Finally, we have one minor skeptic:Previous studies from other groups had shown the opposite of what Stuber's team found: when other researchers activated the LH by exposing it to the neurotransmitter glutamate or by electrically stimulating the neurons, animals would start eating. However, B. Glenn Stanley, a professor at UC Riverside who studies the brain mechanisms of eating behavior, said Stuber's team’s results are not necessarily in conflict with earlier findings. “To see an inconsistency would be an oversimplification,” said Stanley.Stanley noted that Stuber's group focused on a subset of neurons in the LH, those interacting with neurons from the BNST.  ...It's possible that some areas of the LH stimulate feeding when they're activated, and others when they are inhibited, Berthoud added. “The lateral hypothalamus is really a big area,” he said, adding that the authors didn't describe precisely where those neurons turned off by the BNST reside.Two weeks ago, the BRAIN Working Group issued its Interim Report (PDF). High priority areas for 2014 include a focus on cell types and circuit manipulation:#1. Generate a Census of Cell Types. It is within reach to characterize all cell types in the nervous system, and to develop tools to record, mark, and manipulate these precisely defined neurons in vivo. We envision an integrated, systematic census of neuronal and glial cell types, and new genetic and non-genetic tools to deliver genes, proteins, and chemicals to cells of interest. Priority should be given to methods that can be applied to many animal species and even to humans. #4. Develop A Suite of Tools for Circuit Manipulation. By directly activating and inhibiting populations of neurons, neuroscience is progressing from observation to causation, and much more is possible. To enable the immense potential of circuit manipulation, a new generation of tools for optogenetics, pharmacogenetics, and biochemical and electromagnetic modulation should be developed for use in animals and eventually in human patients. Emphasis should be placed on achieving modulation of circuits in patterns that mimic natural activity.Translation to Treatments for Human Obesity and Binge Eating DisordersHow close are we to applying this knowledge to treat people with severe intractable obesity? Not very. Optogenetics is a very invasive method. That's why development of new technologies is another high priority area of BRAIN (i.e., "advancing innovative neurotechnologies"). Nevertheless, it's a key component that will advance basic knowledge of neurocircuit functioning.Has the potential for breakthrough treatments been overblown? Or is it all part of generating enthusiasm and public support (and hen... Read more »

  • September 27, 2013
  • 03:44 AM

Now we know the brain is "neuroplastic"... in the 19th century

by The Neurocritic in The Neurocritic

Until recently, scientists believed our brains were fixed, their circuits formed and finalised in childhood, or "hardwired". Now we know the brain is "neuroplastic", and not only can it change, but that it works by changing its structure in response to repeated mental experience.-Norman Doidge, M.D. (2013). Brain scans of porn addicts: what's wrong with this picture? Wow! I never knew that! You mean the brain can actually learn? And it changes with experience? Really?? Thank you, Norman Doidge, for that brilliant insight, and for many other gems in your wonderful Comment is Free piece on porn addiction in the Guardian.Let's see what physicians and psychologists of yesteryear have to say about these newly discovered "neuroplastic" brains. Here it may be asked whether the organs [of the brain] increase by exercise? This may certainly happen in the brain as well as in the muscles; nay, it seems more than probable, because the blood is carried in greater abundance to the parts which are excited, and nutrition is performed by the blood. In order however, to be able to answer this question positively, we ought to observe the same persons when exercised and when not exercised; or at least observe many persons who are, and many others who are not, exercised during all periods of life.-J.G. Spurzheim (1815). The physiognomical system of Drs. Gall and Spurzheim; founded on an anatomical and physiological examination of the nervous system in general, and of the brain in particular; and indicating the dispositions and manifestations of the mind. The question is not whether neural events change the status of the tissue in which they occur. The only question which may still be debated is: whether such changes as do undoubtedly occur have the permanence and those other properties which we must attribute to memory-traces. According to our present knowledge the primary effect which nerve impulses produce in ganglionic layers is chemical activity. . .-Wolfgang Köhler (1938), The Place Of Value In A World Of Facts.These quotes were taken from a 1964 review paper by Edward L. Bennett, Marian C. Diamond, David Krech, and Mark R. Rosenzweig. The title? Chemical and Anatomical Plasticity of Brain. Changes in brain through experience, demanded by learning theories, are found in experiments with rats.Fig. 1 (Bennett et al., 1964). Animals in Environmental Complexity and Training Cage.The authors compared the brains of rats exposed to complex, enriched environments to those housed in isolated cages. They found increases in cortical thickness, increases in cortical tissue weight (not related to overall brain or body size), and in increases acetylcholinesterase activity in rats who had lived in the fun and social cages. The project was launched 60 years ago, in 1953... so it's a bit disingenuous for Dr. Doidge to call neuroplasticity a "recent" discovery. Furthermore, Doidge's Freudian interpretation of porn would be rather quaint, if it weren't so disturbing:Porn sites are also filled with the complexes Freud described: "Milf" ("mothers I'd like to fuck") sites show us the Oedipus complex is alive; spanking sites sexualise a childhood trauma; and many other oral and anal fixations. All these features indicate that porn's dirty little secret is that what distinguishes "adult sites" is how "infantile," they are, in terms how much power they derive from our infantile complexes and forms of sexuality and aggression. Porn doesn't "cause" these complexes, but it can strengthen them, by wiring them into the reward system. And of course, reward = dopamine. And we all know that "dopamine is the ultimate feminist chemical in the female brain."  Oh wait...Guess Doidge hasn't watched any feminist porn.Further ReadingFeminist Dopamine, Conscious Vaginas, and the Goddess ArrayIs There Any Evidence for the "Porn-Addicted Brain"?Neuroplasticity is a dirty wordNeuroplasticity is not a new discoveryReferenceBENNETT EL, DIAMOND MC, KRECH D, & ROSENZWEIG MR (1964). CHEMICAL AND ANATOMICAL PLASTICITY of BRAIN. Science, 146 (3644), 610-9 PMID: 14191699My Love Affair With the Brain:The Life and Science of Marian Diamond
... Read more »


  • September 22, 2013
  • 06:56 AM

Neurological Art History

by The Neurocritic in The Neurocritic

“Wound man” woodcut by Johannes de Ketham, originally appearing in Fasciculus medicinae (1491). This image is from Fasiculo de medicina (1494), a translation into Italian by Sebastiano Manilio.We rationalize, we dissimilate, we pretend: we pretend that modern medicine is a rational science, all facts, no nonsense, and just what it seems. But we have only to tap its glossy veneer for it to split wide open, and reveal to us its roots and foundations, its old dark heart of metaphysics, mysticism, magic and myth. Medicine is the oldest of the arts, and the oldest of the sciences: would one not expect it to spring from the deepest knowledge and feelings we have?-Oliver Sacks, AwakeningsIs medicine an art or a science? Now you don't have to decide! Volume 203 of Progress in Brain Research examines the historical relationship between art and neurology.The Fine Arts, Neurology, and Neuroscience: Neuro-Historical Dimensions begins with the Renaissance anatomists, including the prolific Andreas Vesalius, author of the seven-volume De humani corporis fabrica (On the fabric of the human body). Illustrated anatomy textbooks were a still novelty at this time, and Vesalius was controversial for overturning some of Galen's tenets from the 2nd century AD, including the theory of animal spirits. The realistic woodcut illustrations in De humani were based on careful dissection of human cadavers (Russell, 2013). Andreas Vesalius (1543). De Humani Corporis Fabrica, Plate 49. Brain with seven cranial nerves. Woodcut.The talented artist is often assumed to be Jan Steven van Calcar from the studio of Titian, but the actual identity of this person(s) is unclear (Russell, 2013):But who were the artists? Who created such compelling images? Vesalius neither identifies nor acknowledges his exceptional artist(s) or his woodblock cutters. The absence of their identity has remained a subject of debate. Proto-Bloggers or Plagiarists?Vesalius tried valiantly to preserve his intellectual property from unlawful reproduction, to no avail. This is a bit ironic, since he never gave credit to the artists, and even seemed a bit annoyed with them (Lanska & Lanska, 2013):In 1546, 3 years after publication of the first edition of the Fabrica, Vesalii expressed frustration at the plurality of artists he had supervised: “[No longer] shall I have to put up with the bad temper of artists and sculptors [wood-block cutters] who made me more miserable than did the bodies I was dissecting” (translation in O’Malley, 1964, p. 124). Regardless of Vesalii’s frustrations with the artists, the beauty, accuracy, and utility of these woodcuts led to frequent plagiarism, despite Vesalii’s attempts to protect his work with the various privileges that were listed at the foot of the title page.Piracy and plagiarism of images vs. "fair use" for educational [or entertainment] purposes isn't a new problem that began with commercialization of the internet in 1995, nor with the rise in the popularity of Tumblr about four or five years ago.1Lanska and Lanska (2013) raised the issue of how the printing press made image theft easier in their chapter on Medieval and Renaissance anatomists: The printing and unauthorized copying of illustrations, and the dissemination of ideas:With the advent of the printing press and moveable type at this time, printed books began to supersede hand-copied medieval manuscripts, and labor-intensive techniques were soon developed to integrate text and illustrations on the printed page. The same technology was used to pirate the illustrations of prior authors with varying fidelity. Specific medieval and Renaissance anatomical illustrations can often be traced from their inceptions through different stages of development to the final printed images, and then through subsequent pirated versions in various abridgements or other compendia. The most important milestone in the development of anatomy and anatomical illustration was the publication in 1543 by Andreas Vesalii of De humani corporis fabrica... With this work, Vesalii succeeded in coordinating a publication production team (author, artists, block cutters, publisher, and typesetters) to achieve an unprecedented integration of scientific discourse, medical illustration, and typography. However, despite Vesalii’s valiant efforts to prevent unauthorized duplication, the illustrations from the Fabrica were extensively plagiarized. Although Vesalii found such piracy frustrating and annoying, the long-term effect was to make Vesalii’s ideas known to a wider readership and to help solidify his own revolutionary contributions to anatomy.Vesalius was angry because of the amount of work he put into the dissections, but the benefit was greater exposure of his ideas and an increase in stature.  Kind of like high profile (non-critical) science blogging?? 2  Except unauthorized reproduction was more laborious in the 16th century... e.g. copying woodcuts prints in a close but approximate form by freehand engraving onto copper plates (Lanska & Lanska, 2013b).  But at least one imitator did give him credit and even corrected his mistakes:Vesalius bitterly complained about Valverde's unauthorized abridgement of his work: “Valverde who never put his hand to a dissection and is ignorant of medicine as well as of the primary disciplines, undertook to expound our art in the Spanish language only for the sake of shameful profit.” (O'... Read more »

  • September 16, 2013
  • 01:23 AM

Everything's Unscented

by The Neurocritic in The Neurocritic

If you were forced to sacrifice one of your five senses, which would it be? Most people wouldn't consider losing their vision or hearing. It would be really dangerous to completely lose your sense of touch, so that won't be an option in our hypothetical scenario. So we're left with the chemical senses of smell and taste. I think most of us would choose one of these two.But what about someone who can't smell?  How can they miss something they've never known?“If I had to lose one of my senses, it would probably be smell... even though it's gone. I mean, if I had to choose between them, because it's the least hindering...”-Deven James Langston in his short video, Anosmia (embedded below).A World Without SmellCongenital anosmia is a rare condition where individuals are born without the ability to smell. This condition might not seem so bad to the osmic population (especially when cleaning up after your pet), but lack of smell can affect safety (e.g., can't detect a gas leak or burning toast), body weight, hygiene, and mate selection (Karstensen & Tommerup, 2011). But if you've never had the experience of odors, whether they're from cinnamon buns or rotting fish, this is a completely normal state of affairs (Tafalla, 2013).Isolated congenital anosmia unrelated to another condition (such as Kallmann syndrome) has been linked to genetic locus 18p11.23-q12.2 in two different families (Ghadami et al., 2004). However, no disease-causing mutations were found by sequencing eight candidate genes in this region. Studies in other families have suggested that the genetic basis of this trait is heterogeneous. Therefore, the specific genetic causes of isolated congenital anosmia remain elusive (Karstensen & Tommerup, 2011).Smells Like WordsRebecca Steinitz has congenital anosmia. She reached adulthood without knowing that other people actually do possess a sense of smell, as opposed to just pretending that they do. In an essay she describes what it's like to live in a world without smell.I don’t know what a rose smells like, though when I hold my nose to a full-blown bloom and inhale deeply, I sense a vague sweetness.I don’t know what my husband’s shirt smells like. If he died, I wouldn’t think to sleep in it so I could feel that he was with me.I don’t know what a baby’s head smells like – not my babies, not anyone else’s babies. I couldn’t pick my babies out of a crowd with my eyes closed, and I don’t miss that baby smell when I hug my growing children.I don’t know the smell of feet, chalk, lilacs, gardenias, sour milk, rain, new cars, Chanel No. 5, Old Spice, greasepaint, or napalm.I don’t know what old books smell like. I don’t know what new books smell like either.Ex Libris Anima Perfume Oil - 5 ml.“The bottled essence of an old, rare book - antique paper, old leather bindings, parchement, dust, and the faint scent of a wooden lecturn.”“I learned smells from books, which made me think they were fictional. When real people said That stinks, or I can smell the sea from here, I thought they were faking, that they were willing to pretend those smells existed beyond the page. I only discovered the word for people like me a few years ago. We are anosmic; we have anosmia: lack of the sense of smell.”-Rebecca Steinitz, Smells Like WordsSmells Like Teen SpiritSteinitz noted that she can't smell her husband's shirt or her baby's head. These types of scents bind us to people and cement our relationships. Odors have a way of linking us to times and places of the past, evoking remembrances in a sterotypically literary way, eliciting endless soliloquies of youthful memories. -graffiti by Kathleen Hanna (before the song was written) 1Do smells have a uniquely intimate connection to memory? Olfactory information reaches the piriform cortex after only two synapses. A chemical odorant activates receptors on sensory neurons in the nasal epithelium, which synapse onto mitral cells in the olfactory bulb. These mitral cells synapse onto neurons in the piriform (olfactory) cortex located in the temporal lobe, near the hippocampus and amygdala. What is it like to be a smeller?Anosmic philosopher Marta Tafalla, in a nod to the famous paper by Thomas Nagel, compares the foreignness of olfactory qualia to the exotic system of echolocation in bats (Tafalla, 2013).Neither do I have the sensation that I lack a sense, a window onto reality, that something in my body or my brain does not function properly. And because of all that, it would have been impossible for me to come up with the improbable idea that everyone else can perceive another dimension of reality, which consists of volatile chemical particles that are perceived in the mere act of breathing. It sounds as strange to me as the echolocation system of bats or some birds' capacity to align their flight with the earth's magnetic field.In this meditative and philosophical piece, Tafalla tells the story of when she first realized she was different from other people. At the age of eight, she spent some time at a summer boarding school. One of the teachers tactfully remarked on her smelly feet. Tafalla didn't understand, and didn't connect body odor to a lack of hygienic rituals. In response, she put cologne on her feet and in her shoes. Her teacher and her mother both found this odd, so she started wondering if something was wrong. A year or two later, ... Read more »

Karstensen HG, & Tommerup N. (2012) Isolated and syndromic forms of congenital anosmia. Clinical genetics, 81(3), 210-5. PMID: 21895637  

Tafalla M. (2013) A world without the olfactory dimension. Anatomical record (Hoboken, N.J. : 2007), 296(9), 1287-96. PMID: 23907763  

  • September 8, 2013
  • 03:47 AM

Update on Ketamine in Palliative Care Settings

by The Neurocritic in The Neurocritic

Many recent headlines have heralded a new use for the old veterinary anesthetic ketamine, which can provide rapid-onset (albeit short-lived) relief for some patients with treatment-resistant depression (aan het Rot et al., 2012). This finding has been inflated into “arguably the most important discovery in half a century” by Duman and Aghajanian (2012). While finding a cure for refractory depression is undoubtedly an important research priority, might ketamine be useful for other conditions that cause profound human misery? The care of terminally ill patients suffering from unbearable pain is not a sexy topic, and hospice and palliative medicine is not a glamorous subspecialty. You probably haven't seen the studies examining whether ketamine is effective as an add-on agent to opioid analgesics for cancer pain (Hardy et al., 2012), or as a treatment for depression and anxiety in patients receiving hospice care (Irwin et al., 2013).Three years ago, my father died of cancer. He had been released from the palliative care unit to a hospice, suffering with uncontrolled cancer pain. It was unbearable to watch, and beyond excruciating for him. During this time, I was writing a post for the Nature Blog Focus on hallucinogenic drugs in medicine and mental health. It included a section on drugs that might alleviate pain and anxiety in cancer patients. I told him about this, and he said to “get the word out.”As a tribute to my father, I wanted to present a brief overview of new developments in the field.Efficacy and Toxicity of Ketamine in the Management of Cancer PainIn 2008, BMJ published a set of clinical practice guidelines on pain control in adults with cancer. They called for further research to investigate the role of ketamine as an adjuvant analgesic – a drug with a primary indication other than pain that might have analgesic properties in some conditions.A recent Cochrane review evaluated the state of the literature on ketamine to alleviate cancer pain (Bell et al., 2012). Three new randomized controlled trials (RCTs) were identified since 2003, and all were excluded from further analysis. Among the older studies, the adverse effects of ketamine included hallucinations (as expected, since the drug is a dissociative anesthetic used at raves), drowsiness, nausea and vomiting, dry mouth, and confusion. The authors concluded that “Current evidence is insufficient to assess the benefits and harms of ketamine as an adjuvant to opioids for the relief of cancer pain. More RCTs are needed.” They also noted that clinical trials were ongoing, and that data by Hardy and colleagues were awaiting assessment. Unfortunately, the outcome of the trial conducted by Hardy et al. (2012) was not positive.  In this large RCT, 185 cancer patients with refractory chronic pain were randomized to receive either ketamine or placebo as an adjunct to their regular doses of opioids and other analgesics. Ketamine was administered subcutaneously in a dose-escalating regimen over 5 days. The response rate was 31% (29 of 93) in the treatment group compared to 27% (25 of 92) for placebo, which was not significantly different (p=.55). In addition, ketamine was associated with twice the number of adverse events relative to placebo. The authors concluded that ketamine did not have a net clinical benefit when used along with standard medications to treat cancer pain.However, Jackson and colleagues (2013) objected to this “sweeping conclusion” in a letter to the Journal of Clinical Oncology titled “Ketamine and Cancer Pain: The Reports of My Death Have Been Greatly Exaggerated”. Their major arguments were that ketamine has been used in this fashion for the last decade, and previous open-label studies were more successful. They also suggested that Hardy et al. were too quick to call ketamine a treatment failure, and too late in administering drugs to counteract any hallucinogenic side effects.1  Hardy et al. (2013) replied to the first set of objections by stating the obvious about the value of RCTs: “Open-label studies do not meet the specific scientific definition of control.” They stood by their “sweeping conclusions” that ketamine was not beneficial in this population. On the other hand, I can see why clinicians would be desperate to help their patients. The 27% placebo response in Hardy's study is quite high. So if you're a patient in terrible pain and grape Kool-Aid improves your condition, why argue with that?Ketamine for the Treatment of Depression and Anxiety in Hospice Patients Speaking of open-label studies, a 2010 study in two hospice patients, each with a prognosis of only weeks or months to live, showed beneficial effects of ketamine in the treatment of anxiety and depression (Irwin & Iglewicz, 2010). A single oral dose produced rapid improvement of symptoms and improved end of life quality. To disentangle the pain relieving and antidepressant effects of ketamine, the authors emphasized the importance of conducting clinical trials for this particular indication.2 A more recent open-label study by Irwin et al. (2013) enrolled 14 hospice patients with depression or depression + anxiety to receive oral ketamine for 28 days. Only 8 patients completed the study, but all showed a 30% or greater improvement in their depression or anxiety scores. Four withdrew from the study at day 14 because of no response to the drug, one dropped out earlier due to unrelated rapid decline, and one withdrew at day 21 because of a change in mental status (apparently unrelated to ketamine). “Few adverse events” were noted, the most common being diarrhea, trouble sleeping, and trouble sitting still (which to me sound problematic in an extremely ill population). It seems that dissociative symptoms, hallucinations, etc. were not evaluated. The authors again call for further studies using RCT designs to evaluate whether ketamine can improve the quality of the end-of-life experience.Although they were not entirely successful, these studies have aimed to achieve an important goal of any civil, caring society: to provide a manner of death that minimizes fear, pain, and suffering.Further ReadingThe entire Pallimed Blog"Do you have something stronger than this dilaudid?" The case for opioid rotationLimbaugh/Palin "death panels" extend the lives of terminally ill patientsKetamine for Depression: Yay or Neigh?Footnotes1 Jackson et al. reported using low doses of haloperidol (an antipsychotic) or midazolam (a benzodiazapine) prophy... Read more »

  • August 25, 2013
  • 05:27 PM

The Art of Resurrection

by The Neurocritic in The Neurocritic

Resurrection, Raffaellino del Garbo (1510)In the world outside of Christianity, horror, and science fiction, the dead cannot be brought back to life. Or can they? A feature in the The Observer from earlier this year profiled Dr. Sam Parnia, critical care physician and author of Erasing Death: The Science That Is Rewriting the Boundaries Between Life and Death (called The Lazarus Effect in the UK). The article begins in a dramatic fashion:Sam Parnia – the man who could bring you back from the deadSam Parnia MD has a highly sought after medical speciality: resurrection. His patients can be dead for several hours before they are restored to their former selves, with decades of life ahead of them.That's a pretty outrageous claim! Clinically dead for several hours? No brain activity the entire time? Even if anyone could emerge alive and conscious from such a state (unless it's a state of suspended animation, perhaps), they'd have severe brain damage (as we'll see below). There'd be no way they could have encoded their near-death experiences (NDEs), much less remembered any light at the end of a tunnel or a soothing presence drawing them home.There may be a semantic problem here: the definition of “death.” I haven't read the book, but the issue is described in a one-star review at Amazon:The core of this linguistic mess is his inconsistent use of the word "death". At times he uses this term properly, as defined by the Uniform Determination of Death Act (UDDA, 1981): "An individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions, or (2) irreversible cessation of all functions of the entire brain, including the brain stem is dead." This definition was developed in cooperation with the American Medical Association ... [etc.] and has been adopted by most states. It is the standard definition of death. [NOTE: I thought brain death is THE standard definition of death.] 1Unfortunately, he also refers to "death" as cardiac arrest (e.g. pages 1, 2, 23, 42, 43, 128, 131, 139, 140, and many more). This definition of death is inconsistent with the UDDA because cardiac arrest is reversible in some cases. In fact, much of this book includes accounts of individuals who have suffered cardiac arrest and been resuscitated... Dr. Parnia was quoted in my previous post about the “End of Life Gamma Waves” study in rats. He was skeptical that EEG during the 30 second interval after the heart stopped beating was anything more than a massive influx of calcium into the dying neurons. It wasn't a state of heightened consciousness that can explain the NDEs reported by 10-20% of his cardiac arrest patients. Instead, Parnia is a mind-body dualist, believing that the soul (or self) can persist separately from the body for several hours at a time:"It seems that when consciousness shuts down in death, psyche, or soul – by which I don't mean ghosts, I mean your individual self – persists for a least those hours before you are resuscitated. From which we might justifiably begin to conclude that the brain is acting as an intermediary to manifest your idea of soul or self but it may not be the source or originator of it… I think that the evidence is beginning to suggest that we should keep open our minds to the possibility that memory, while obviously a scientific entity of some kind – I'm not saying it is magic or anything like that – is not neuronal."Memory is not neuronal! And Death can be cured. Who knew. But how?? [NOTE: according to Parnia and The Observer, at least.]Extracorporeal membrane oxygenation (ECMO) is a temporary method of life support that introduces and circulates oxygen into the bloodstream of patients with acute respiratory failure or cardiac failure. It involves placing one or more large catheters into the patient's vessels (cannulation) and relies on an external pump to circulate and oxygenate blood and remove carbon dioxide (PDF). Primarily used in critically ill infants, its application to adults is risky and controversial, and the benefits are unclear.A meta-analysis of ECMO in adult patients found a mortality rate of 54% at 30 day follow-up, with almost half the fatalities occurring during ECMO (Zangrillo et al., 2013). On the other hand, the procedure is a last-ditch life saving effort in critically ill patients, so a 46% survival rate seems like an improvement over probable death. However, one review stated that "Credible evidence for mortality benefit of ECMO is lacking" in cases of acute respiratory distress (Hirshberg et al, 2013). Another study concluded that ECMO is even less successful in cases of acute heart failure, with the worst survival rate for those who experience cardiac arrest (Tsuneyoshi & Rao, 2012).Complications can be severe (Zangrillo et al., 2013) and include renal failure (occurring in 52%), bacterial pneumonia (33%), bleeding (33%), oxygenator dysfunction requiring replacement (29%), sepsis (26%), and liver dysfunction (16%).The rest of the post will focus on the possible neurological complications of ECMO (Mateen et al., 2011).Neurological Injury Associated with Heroic ResuscitationI do not want to detract in any way from the dedication of practioners who do heroic things every day to save people's lives, or from advances in medicine. What I would like to point out, however, is that sometimes one may resuscitate the heart but lose the brain (to paraphrase Horstman et al., 2010).Modified from Fig. 4 (Mateen et al., 2011). Brain scans of adult patients who received extracorporeal membrane oxygenation (ECMO). (A) parafalcine subarachnoid hemorrhage and hydrocephalus on axial-view head CT, (B) diffuse subarachnoid hemorrhage on T1-weighted MRI, and (C) septic cerebral emboli on axial-view MRI.Neurological events occurred in at least 50% (n=42) of patients treated with ECMO at one medical center over an 8 year period (... Read more »

Mateen FJ, Muralidharan R, Shinohara RT, Parisi JE, Schears GJ, & Wijdicks EF. (2011) Neurological injury in adults treated with extracorporeal membrane oxygenation. Archives of neurology, 68(12), 1543-9. PMID: 21825216  

  • August 18, 2013
  • 03:43 AM

Remembering the Work of Dr. Patricia Goldman-Rakic

by The Neurocritic in The Neurocritic

A touching and comprehensive review article in Cerebral Cortex commemorates the life and work of Dr. Patricia Goldman-Rakic on the ten year anniversary of her death (Arnsten, 2013). The author of over 600 publications, Goldman-Rakic worked at NIMH from 1965-1979 and was a professor at Yale from 1979-2003. She served as President of the Society for Neuroscience in 1989-90 and was elected to the National Academy of Sciences in 1990. The review was written by one of her former post-docs, Dr. Amy F.T. Arnsten, herself a professor at Yale.Keeping a Life "in mind" Dr. Goldman-Rakic is best known for her research on working memory and the prefrontal cortex (PFC). Working memory is a transient form of memory that actively maintains and manipulates information for brief periods of time (Goldman-Rakic, 1995):Working memory in its most elementary form, the ability to keep events "in mind" for short periods of time, has been studied in nonhuman primates by delayed-response paradigms. Whereas in humans, facts and events accessed from long-term memory stores can be instigated by verbal instructions, in experiments with animals, the information to be processed has to be provided by the experimenter.Building on the work of Fuster and colleagues, her studies demonstrated that neurons in the dorsolateral portion of the PFC fire more rapidly when a spatial location cue is removed from the visual field and must be remembered over a brief delay. The sample neuron in the figure below codes for targets located at 270 degrees and not for targets at other locations. Note that the neurons's response is specifically enhanced over the delay period (D).Fig 1 (modified from Goldman-Rakic, 1995). Neuron during the Many Trials over Which a Monkey Performed an Oculomotor Delayed-Response Working Memory Task. The neuron's response for all trials at the preferred target location is shown as a histogram of the average response per unit time for that location. The activity is also shown in relation to task events (C, cue; D, delay; R, response) on a trial-by-trial basis. These neurons are located in the dorsal bank of the principal sulcus in monkey dorsolateral PFC, equivalent to Brodmann area 46 in humans. Goldman-Rakic and colleagues conducted extensive neuroanatomical tracing studies in the 1980's to map out the connections of this region and the posterior parietal cortex, major hubs in the brain's larger scheme of visuospatial processing.Fig. 2 (Arnsten, 2013). The cortical circuitry for spatial cognition, based on the work of Goldman-Rakic and Selemon. Note that both the dlPFC (area 46) and parietal cortex have many shared connections to subcortical structures that are not shown in this illustration, as well as “nonshared” connections that are not included in this diagram {from L. Selemon}.Goldman-Rakic's work was enormously influential, as shown in the figure below.Fig. 1 (Arnsten, 2013). Timeline of the discoveries of the PFC role in working memory (WM) and the key contributions of Goldman-Rakic. The graph shows the number of papers cited on PubMed using the search term “prefrontal cortex” for each decade ending in the year noted. Key publications by Goldman-Rakic and other early pioneers are indicated. Other major areas of research reviewed by Arnsten (2013) include the Key Role of Dopamine and Neuromodulation (e.g., D1 vs. D2 Receptor Actions, the D1 Receptor “inverted-U” Dose–Response), the Neurobiological Foundations of Schizophrenia (e.g., Insults to dlPFC Microcircuitry), and the dlPFC Microcircuits that Generate Mental Representations. The tribute article is open access and can be read freely by all.A Life of the Mind, Shaped by Working Memory The significance of working memory for higher cortical function is not necessarily self-evident. Perhaps even the quality of its transient nature misleads us into thinking it is somehow less important than the more permanent archival nature of long-term memory. However, the brain’s working memory function, i.e., the ability to bring to mind events in the absence of direct stimulation, may be its inherently most flexible mechanism and its evolutionarily most significant achievement. Thus, working memory confers the ability to guide behavior by representations of the outside world rather than by immediate stimulation, and thus to base behavior on ideas and thoughts.- Pat Goldman-Rakic (1991)ReferencesArnsten AF (2013). The Neurobiology of Thought: The Groundbreaking Discoveries of Patricia Goldman-Rakic 1937-2003. Cerebral Cortex PMID: 23926115Goldman-Rakic PS (1995). Cellular basis of working memory. Neuron, 14 (3), 477-85 PMID: 7695894... Read more »

  • August 15, 2013
  • 11:16 PM

End of Life Gamma Waves: Altered State of Consciousness or Artifactual Brain Activity?

by The Neurocritic in The Neurocritic

"I had been in labor for my daughter for 16 hours. The labor was difficult and the Dr. approached me and told me it may come down to a choice between the child or myself.  ...  The labor dragged on and on and finally they came in and broke my water. I was rushed into delivery and within minutes my heart had stopped. I remember seeing a beautiful being of light enter the room. She told me I had to return as it was not my time yet. I was sucked back into my body as they restarted my breathing. My daughter began crying the moment I opened my eyes."-Description of a near-death experience1Are you afraid to die? We all are. Fear of pain and suffering, fear of the unknown, fear of eternal damnation (for the religious), fear of nothingness (for the atheist). Fear of the end. The finality of it all.The existential fear of death is part of the human condition. For a neuroscientist, studying what happens to conscious thought during the brain's own demise is one of the most profound of all questions. Short of conducting ill-advised scifi experiments on your med school classmates, how does one go about studying such a phenomenon? By using an animal model of cardiac arrest.thanks to Chris Chambers for the video ideaSurge of neurophysiological coherence and connectivity in the dying brainA popular new study by Borjigin et al. (2013) recorded EEG activity directly from the brains of nine dying rats. This paper was widely reported in mainstream media outlets, and has been nicely covered by bloggers Ed Yong, Mark Stokes, Chris Chambers, and Shelly Fan. What I would like to do here is to more closely examine the conditions surrounding the clinical death of these rats. Fig. 1A (modified from Borjigin et al., 2013). The time scale is in seconds.The y-axis is in microvolts.The figure above shows brain waves recorded from six electrodes implanted on the cerebral cortex, along with electrical activity from the muscles (EMG) and heart (EKG). The time period is 80 minutes before and 20 minutes after cardiac arrest (at time zero), which was induced by injection of potassium chloride into the heart. On its own, potassium chloride would cause a very painful death. Along with anesthetic and paralytic agents, potassium chloride is part of the drug sequence used for lethal injection in some U.S. states. In the present study, the animals were deeply anesthetized using ketamine (a dissociative anesthetic) and xylazine (veterinary sedative/analgesic which affects alpha-2 adrenergic receptors), a commonly used method of anesthesia in rodents. Fig. 1A shows that the animals were anesthetized for 30 min before cardiac arrest. The EEG exhibits fairly constant large amplitude activity during this time, shown spread out for a small interval of time in Fig. 1B below.Fig. 1B (modified from Borjigin et al., 2013). The time scale is in seconds. CAS =  cardiac arrest state. CAS3 (from 12 sec to 30 sec after cardiac arrest) is the critical time of increased EEG activity.To briefly summarize, the rats' brains were surprisingly active during the CAS3 period, showing highly coherent neural oscillations in the low gamma frequency band for a 20 sec interval after the heart and lungs stopped working. Fig. 1C below expands the vertical gray bars in Fig. 1B to show greater detail. Of note is the high amplitude rhythmic oscillations during CAS3. This low gamma activity (35-55 Hz) was strongly coupled to EEG activity in other frequency bands (theta and alpha) -- to an even greater extent than during active waking. The authors viewed this as a state of heightened consciousness, but such speculation is premature.- click on image for a larger view - Fig. 1C (modified from Borjigin et al., 2013). CAS = cardiac arrest state.Why would the authors maintain that a dying brain can generate the neural correlates of heightened conscious processing? Gamma (aka 40 Hz activity) has been viewed as a possible solution to the "binding problem" of how consciousness arises since the late 80s. In the visual system, synchronous gamma might be how the brain combines distributed activity conveying separate aspects of a stimulus (e.g., its color, shape, and form) into a unified percept. Furthermore, gamma might account for phenomenal awareness and consciousness, according to some. However, more recent evidence suggests that gamma band responses do not reflect conscious experience.In addition, it is not at all clear how highly synchronized low gamma can index "heightened conscious processing" in deeply anesthetized dying rats. Do the rats transition from ketamine/xylazine anesthesia (associated with altered thalamocortical connectivity) to a hyperaware internal state of....?  Of what?  The CAS3 activity is so abnormal that it might be artifactual or epiphenomenal, "a tale told by an idiot, full of sound and fury, signifying nothing" (Shakespeare, 1606). Near-death experience (NDE) researcher Sam Parnia believes the low gamma activity could be caused by a massive influx of calcium, as he stated in Ed Yong's ... Read more »

Borjigin J, Lee U, Liu T, Pal D, Huff S, Klarr D, Sloboda J, Hernandez J, Wang MM, & Mashour GA. (2013) Surge of neurophysiological coherence and connectivity in the dying brain. Proceedings of the National Academy of Sciences of the United States of America. PMID: 23940340  

  • August 11, 2013
  • 12:54 AM

Save Us From Misleading Press Releases

by The Neurocritic in The Neurocritic

Exposure to subliminal cues can help us choose the apple instead of the cake. Or can it...  Let's take a look.Our Brains Can (Unconsciously) Save Us from Temptation Aug. 8, 2013 — Inhibitory self control -- not picking up a cigarette, not having a second drink, not spending when we should be saving -- can operate without our awareness or intention. That was the finding by scientists at the University of Pennsylvania's Annenberg School for Communication and the University of Illinois at Urbana-Champaign. They demonstrated through neuroscience research that inaction-related words in our environment can unconsciously influence our self-control. Although we may mindlessly eat cookies at a party, stopping ourselves from over-indulging may seem impossible without a deliberate, conscious effort. However, it turns out that overhearing someone -- even in a completely unrelated conversation -- say something as simple as "calm down" might trigger us to stop our cookie eating frenzy without realizing it.The press release states that overhearing a message of restraint in a background conversation might prevent us from reaching for a second piece of cake at the holiday party. What's the evidence for this?A study by Hepler and Albarracin (2013) recorded EEG activity (brain waves) while 20 participants performed a "go/no-go" task that tests their inhibitory control abilities. The subjects responded every time they saw an "X" on the screen but refrained from responding when they saw a "Y". These target letters were preceded by a visual masking stimulus (&&&&&&) for 16.7 msec, a subliminal prime word for 33.4 msec, and then another masking stimulus (&&&&&&) for 50.1 msec. The idea here is to show the prime word very briefly and to "mask" conscious perception of the word.The prime words were general action words (go, run, move, hit, start), general inaction words (still, sit, rest, calm, stop), and control stimuli (scrambled action and inaction prime words – e.g., rnu). One obvious hypothesis would be that exposure to the masked inaction words would make you better at inhibiting a response to "Y". The authors didn't exactly say that, instead predicting that the amplitude of the P3 component extracted from averaged EEG on no-go trials would reflect the engagement of unconscious inhibitory processes.However, if behavior is unaffected by the masked inaction words, it ultimately doesn't matter what happens to the P3 component. There is nothing you can say about "resisting temptation" -- behavioral change is not the same thing as a change in the size of the P3 component. The latter may indicate that a subject's brain registered sit, rest, calm, or stop implicitly, but this neural activity wasn't enough to improve stopping ability.And in fact, this is exactly what the study demonstrated. The masked primes had a modest effect on the size of the P3 wave to the subsequent no-go stimulus, which reached its peak at around 400 msec post-stimulus (i.e., less than half a second after the "Y"). The inaction primes were significantly different from the action primes, but neither one differed from the neutral condition.1Fig. 1. (Hepler & Albarracin, 2013). Grand average waveforms at electrode Cz to correct no-go trials in Experiment 1. The authors interpreted this effect to indicate that inhibition processes were "engaged" by the subliminal primes.However, the primes had absolutely no impact on how well participants could resist responding to the no-go stimuli [F(2, 38) = .00, p = .99]. Accuracy in the inaction prime condition was exactly the same as in the action prime condition. In other words, the study showed that Our Brains Cannot (Unconsciously) Save Us from Temptation.Or as succinctly stated by Justin Kiggins on Twitter:I did not intend to nitpick about the details of this particular study or to single out the authors. But the press release provided by the University of Pennsylvania Annenberg School for Communication is completely misleading (and poorly communicated).Footnote1 This is somewhat problematic, because you'd rather see each of the experimental conditions differ from the control condition.ReferenceHepler J, & Albarracin D (2013). Complete unconscious control: Using (in)action primes to demonstrate completely unconscious activation of inhibitory control mechanisms. Cognition, 128 (3), 271-9 PMID: 23747649

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  • August 8, 2013
  • 03:37 PM

Possession Trance Disorder Caused by Door-to-Door Sales

by The Neurocritic in The Neurocritic

Some companies and organizations that employ door-to-door sales tactics are known for their cult-like practices (e.g., Amway, traveling magazine sales, and Jehovah's Witnesses). An unusual psychiatric report included this religious brainwashing element in presenting the case of a 47 year old Japanese housewife who felt possessed by God after a visit by a door-to-door salesman (Saitoh et al., 1996):In Japan, psychiatry has generally regarded the possessive state as symptomatic of religion- related mental disorders. ... Recently, there has been a proliferation of direct sales enterprises that incite anxiety in prospective customers in order to sell their products. Due to the prevalence of door-to-door peddling of items such as amulets and talismans to ward off curses and misfortune, the term ‘door-to-door sales’ has come to have a religious connotation.Recently, we treated a case of possessive state accompanied with suicidal tendencies which are thought to have developed in connection with door-to-door sales. Religious factors and elements of brainwashing were seen both in the conditions that promoted the possessive state and in the state itself.The patient grew up on a family farm in the Tokyo area. She was described as laconic, withdrawn, quiet, unsocial and nervous.When the patient was 47 years old, a male she described as a ‘salesperson type’ came to her home in May. He read her palm and asked for her husband’s family name and birth date. When she gave him this information he predicted that some misfortune would befall her husband. The patient’s husband had fallen in an accident a few days earlier, and she became extremely anxious. The man then said, ‘I have a talisman, a lucky name chop (family seal) which will protect your husband from misfortune’. Although she was hesitant at first, she finally agreed... When she paid for the chop the man recommended that she go to a certain room in a hotel in Saitama prefecture for a more in-depth palm reading ... where she was one of 20 women who received a lecture on subjects such as lineage, marriage, health and happiness.Approximately 1 week later, again at the salesman’s advice, she went to a rented room in a building in Tokyo where she received a scroll called a prayer book. At the same time she was urged to buy a sculpture which was called a ‘Fortune Tree’. Two days later she went to her bank with the salesman and a woman whom she did not know and paid the ¥5,400 000. The patient went to this room twice a month during June, July and August. The room was divided by a partition and she was shown biblical videotapes. In September, she complained of an inability to sleep, and stated, ‘I can hear God’s voice. He possesses me and is controlling my bodily movements’. Thereafter, she episodically gave orders to her family in an uninflected monotone, making unrealistic assertions such as, ‘Don’t eat that or you will die’ and ‘Don’t go out or you won’t come back’. In mid-September, she filed a complaint that she had been deceived into buying the ‘Fortune Tree’ at an exorbitant price. Shortly thereafter, she was taken to a private mental hospital and treated with the antipsychotic drug haloperidol. Two weeks later, she was able to recount her ordeal:... ‘I felt like God had taken over my body. I was ordered by Him to do this or do that. Even if I wasn’t talking, my mouth just moved on its own. I didn’t go so far as to be One with God, but it was almost like that. That’s why I gave orders to my husband and child as though I were God’. The patient showed no subsequent objective signs of abnormality, and was released 2 months after admission.The authors discussed her case in terms of the DSM-IV diagnosis, Dissociative Disorder Not Otherwise Specified, along with depressive symptoms and somatic complaints. Her attendance at the video lectures was described as a form of brainwashing. More specifically, her condition would fall under the category of Dissociative Trance Disorder (possession trance), a disturbance in consciousness or identity with a culturally specific element:Dissociative trance involves narrowing of awareness of immediate surroundings or stereotyped behaviors or movements that are experienced as being beyond one's control. Possession trance involves replacement of the customary sense of personal identity by a new identity, attributed to the influence of a spirit, power, deity, or other person and associated with stereotyped involuntary movements or amnesia...This case is rare not only because of its association with a business practice, but also because possession is usually seen in more isolated communities with traditional belief systems, quite unlike contemporary Tokyo. Further ReadingPossession Trance Disorder in DSM-5ReferenceSatoh S, Obata S, Seno E, Okada T, Morita N, Saito T, Yoshikawa M, & Yamagami A (1996). A case of possessive state with onset influenced by 'door-to-door' sales. Psychiatry and clinical neurosciences, 50 (6), 313-6. PMID: 9014228

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Satoh S, Obata S, Seno E, Okada T, Morita N, Saito T, Yoshikawa M, & Yamagami A. (1996) A case of possessive state with onset influenced by 'door-to-door' sales. Psychiatry and clinical neurosciences, 50(6), 313-6. PMID: 9014228  

  • August 2, 2013
  • 05:38 AM

Breakthroughs in Bipolar Treatment

by The Neurocritic in The Neurocritic

"We should continue to repurpose treatments and to recognise the role of serendipity" (Geddes & Miklowitz, 2013).That quote was from a recent review article in The Lancet, which did not hint at any impending pharmacological breakthroughs in the treatment of bipolar disorder. In other words, the future of bipolar treatment doesn't look much different from the present (at least in the immediate term). Bipolar disorder, an illness defined by the existence of manic or hypomanic highs, alternating with depressive lows, can be especially difficult to treat. And the mood episode known as a mixed state, where irritability, expansive mood, anxiety, and/or agitation occur simultaneously with depressive symptoms, is an under-recognized, moving-target diagnosis (Koukopoulos et al., 2013). Mood stabilizers such as lithium and divalproex have long been the first line pharmacological choices. But these don't always work, and polypharmacy seems to be the rule, rather than the exception.The spinning molecule above is haloperidol, a first generation antipsychotic drug developed in 1958 and approved by the FDA in 1967 as a treatment for schizophrenia. It's a dopamine blocker known for having untoward extrapyramidal side effects, or movement disorders such as tremors and tardive dyskinesia. Nonetheless, haloperidol (Haldol®) is still the most effective drug for the acute treatment of mania, and fairly well tolerated (see HAL in the figure below). The second generation (atypical) antipsychotics risperidone (RIS) and olanzapine (OLZ) also turn out pretty well in the antimanic sweepstakes. But these drugs can also have untoward side effects, notably substantial weight gain that can lead to high cholesterol, diabetes, and metabolic syndrome. Figure (Geddes & Miklowitz, 2013). Ranking of antimanic drugs according to primary outcomes derived from multiple treatment meta-analysis. Efficacy is shown as a continuous outcome against the dropout rate. Treatments toward the red section combine the worst efficacy and tolerability profiles and treatments towards the green[ish] section combine the best profiles.1 Clearly, effective medications with fewer side effects are needed. Unfortunately, there doesn't seem to be anything new on the horizon, according to Geddes and Miklowitz:Overall, advances in drug treatment remain quite modest. Antipsychotic drugs are effective in the acute treatment of mania; their efficacy in the treatment of depression is variable with the clearest evidence for quetiapine. Despite their widespread use, considerable uncertainty and controversy remains about the use of antidepressant drugs in the management of depressive episodes. Lithium has the strongest evidence for long-term relapse prevention; the evidence for anticonvulsants such as divalproex and lamotrigine is less robust and there is much uncertainty about the longer term benefits of antipsychotics.The article is actually more bullish on combining existing drugs with various psychosocial interventions (e.g., family-focused approaches, strict regulation of social and circadian schedules, etc.), which are touched on below in the Appendix (Table 1 of Geddes & Miklowitz, 2013). That table also mentions some of the usual drug suspects.To find out what else might be in the works, I looked through for open interventional drug studies in adults. There were a few surprises... foremost among those was Methylphenidate for the Treatment of Acute Mania. It seems bizarre to me that methylphenidate (the stimulant drug Ritalin) would be proposed as a treatment for mania, since 40% of patients prescribed stimulants for bipolar depression (or comorbid ADHD) experienced stimulant-induced mania/hypomania (Wingo & Ghaemi, 2008).The Ritalin trial was submitted to in Feb. 2012, but the study is not yet open for patient recruitment 1.5 years later. The investigators recently published the study protocol in BMC Psychiatry, however (Kluge et al., 2013). They proposed the ‘vigilance regulation model of mania’ where:Unstable vigilance induces a pathogenic circle with vigilance stabilisation syndrome leading to full-blown mania. [NOTE: huh?]The outlined model ... is related to personality theories about extraversion [9] and sensation seeking [10] which comparably explain these traits as an attempt to compensate for low central nervous system arousal. Basically, it works for ADHD, and there are a handful of uncontrolled case reports, so.... let's conduct a clinical trial.Bipolar DepressionDepressive episodes in bipolar disorder are longer in duration and considered more difficult to treat. Again, did not disappoint, revealing a grab bag of "repurposed" treatments:Adjunctive Lisdexamfetamine - another stimulant for ADHD (aka Vyvanse).Adjunctive Isradipine (a calcium channel blocker prescribed for high blood pressure) - this idea — not a new one — deserves a post of its own.Adjunctive Minocycline (an antibiotic) - the proposed mechanism of action is to reduce the production of pro-inflammatory cytokines.Ceftriaxone (another antibiotic) - however, the proposed mechanism here is inactivation of the excitatory neurotransmitter glutamate, via actions on the glutamate transporter.NMDA Antagonists (i.e., club drug ketamine) - this is complicated and again deserving of its own ... Read more »

  • July 22, 2013
  • 10:00 PM

Rorschach inkblots and the neuroscientific basis for pareidolia

by The Neurocritic in The Neurocritic

image via psychpsychbabyA fascinating new historical article in the Journal of Neurology, Neurosurgery, and Psychiatry reviews the aesthetic and perceptual aspects of the Rorschach inkblots and proposes a role for them in understanding pareidolia, the phenomenon of ‘seeing’ objects in amorphous shapes (Schott, 2013). The Rorschach test was developed by handsome Swiss psychoanalyst Hermann Rorschach as a Psychodiagnostic method and only later used as a "projective test" thought to reveal unconscious psychopathology. Although still in use today, it has been widely discredited and shown to be an invalid instrument for assessing personality and mental illness (e.g., see What's Wrong With The Rorschach: Science Confronts the Controversial Inkblot Test). Rorschach Card III via WikipediaRorschach himself viewed the test as perceptual (p. 16 of Lemkau & Kronenberg's 1951 translation of Rorschach, 1921 - PDF):Almost all subjects regard the experiment as a test of imagination. This conception is so general that it becomes, practically, a condition of the experiment. Nevertheless, the interpretation of the figures actually has little to do with imagination, and it is unnecessary to consider imagination a pre-requisite. ...The interpretation of the chance forms falls in the field of perception and apperception rather than imagination.Rorschach denied that it was projective in nature (p. 123, ibid):The test cannot be considered as a means of delving into the unconscious. At best, it is far inferior to the other more profound psychological methods such as dream interpretation and association experiments. This is not difficult to understand. The test does not induce a «free flow from the subconscious» but requires adaptation to external stimuli, participation in the «fonction du réel».Schott (2013) views the inkblots as both artistic entities (noting that Rorschach was a "gifted draughtsman and an excellent art critic") and as visual stimuli for scientific study. Perceptual features of the inkblots are considered in detail:The pivotal graphic features which constitute the blots, and which give rise to the blots’ perceptual effects, include: form: their amorphous shape symmetry the perception of movement: ‘Movement without Motion’ the blank spaces: figure–ground relationships the use of colour shading.Finally, the article summarizes several neuroimaging experiments that have used the inkblots as stimuli. For example, Asari and colleagues reported that unusual or unique perceptions of the blots were associated with greater activation in the right temporal pole (2008) and with larger amygdala volumes (2010).The Virgin Mary TreeThe Neuroscientific Basis for PareidoliaPareidolia is the phenomenon of perceiving a meaningful stimulus (such as a face or a hidden message) in fairly random everyday objects or sounds. We do have quite a propensity to see faces everywhere, and some religious people see the face of god (and other religious iconography) everywhere.Schott (2013) concludes by suggesting that the images merit further investigation by neuroscientists for studies of pareidolia: ...these iconic ink-blots—which straddle iconography, psychology and neuroscience—deserve further study, and may yet illuminate important aspects of cerebral function, and even dysfunction. But DO NOT use them to discriminate psychopaths from non-psychopaths in forensic populations (or for any other clinical diagnostic purpose, for that matter)...ReferencesRorschach, H. (1921). Psychodiagnostics: A Diagnostic Test Based On Perception (1951 translation).Schott, G.D. (2013). Revisiting the Rorschach ink-blots: from iconography and psychology to neuroscience. J Neurol Neurosurg Psychiatry DOI: 10.1136/jnnp-2013-305672
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  • July 13, 2013
  • 10:10 PM

The Destructive Power of Shame

by The Neurocritic in The Neurocritic

Shame is a negative self-conscious emotion that encompasses the feeling that something is terribly wrong with the self as a human being. Feelings of shame are a prominent factor in suicidal thoughts, behaviors, and self-harm (Hastings et al., 2002; Gilbert et al., 2010).  Lately I've encountered several articles saying that shame really isn't that bad for you, after all. The first theme of these commentaries is the spectacle of public shaming, and the second theme concerns private shame as a means of social control.The Futility of Public ShamingOne news article bemoaned the end of shame in American politics. Sex scandals, drug use, and other egregious mistakes just don't have the same permanently negative consequences they used to. If you're a powerful male politician, that is.Where’s the shame? Scandals may no longer end political careers  WASHINGTON — Sex. Drugs. Cheating on a spouse. Those words used to add up to shame. Put them in the same sentence as a politician’s name, and they ended careers.Not anymore. The latest batch of unlikely back-from-the-swamp hopefuls are Anthony Weiner and Eliot Spitzer. Weiner resigned his New York City congressional seat two years ago after revelations that he’d tweeted a sexually suggestive picture of himself to a woman who was following him on Twitter. Spitzer left the state’s governorship in 2008 after reports surfaced that federal investigators had tagged him as “Client 9,” soliciting high-end prostitutes.Read more here:'s the list of prominent male politicians from the article:Anthony Weiner - sent lewd twitpicsEliot Spitzer - prostitution scandalMark Sanford - disappearance and extramarital affairNewt Gingrich - serial cheater; dumper of a wife with cancer; Christian Marion Barry - smoking crackBill Clinton - Monica Lewinsky affair resulted in impeachment of sitting PresidentLarry Craig - arrested for lewd conduct in a men's restroomMark Foley - sent sexually suggestive messages to teenaged male pagesDavid Vitter - D.C. Madam scandalScott DesJarlais - pro-life doctor who had multiple affairs with patients, pushed them to have abortionsThe lesson from all this: Wind up on the ever-increasing roll of tainted celebrities and re-emerge as the friendly, professional politician that vaulted you into office in the first place, and you’ll probably be OK."You'll probably be OK"... if you're a man. Has a female politician ever emerged intact from a federal sex scandal? Or has even been involved in such a scandal? If so, the double standard of slut shaming would likely put an end to her career. One of the few women on the state and local list is:Minnesota Senate Majority Leader Amy Koch (R)... The married mother of one resigned from her leadership position and announced that she would not be seeking reelection shortly before four fellow Republicans indicated that she had been engaged in an "inappropriate" relationship with a male staffer. (2011).Shaming on the InternetHow about for obnoxious offenders in the general public? Does the public shaming of those who spew idiotic sexist, racist, and homophobic comments on social media do any good?The Public Shaming Tumblr aims to draw attention to bad actors on Twitter. Matt Binder says:I started retweeting people complaining about welfare, food stamps, etc. and then following it up with a previous tweet of theirs that makes them look hypocritical/dumb/etc.I discovered that as I would retweet these, my followers would start @replying these people and let them know they were idiots. They would then delete their offending tweet.Well, I couldn’t let that happen. So, I screenshot away.One continuous stream of vile sexist hatred was directed at Women's Wimbledon champion, Marion Bartoli. Why? Because she's not a blond model. Even BBC presenter John Inverdale took part in the insults, saying she "never going to be a looker"... to which Bartoli responded:"It doesn't matter, honestly. I am not blonde, yes. That is a fact. Have I dreamt about having a model contract? No. I'm sorry. But have I dreamed about winning Wimbledon? Absolutely, yes."This is the bottom line. She won Wimbledon, and her detractors will never accomplish anything that monumental. Does shaming the immature little boys for their pathetic cries for attention help anyone?Serious cretins:@Danwatt8 @Willshow95 @LadiesLove_BigD @maxbateman20 @rrruditaylor @Kwikz @EllisKeddie @sumandutta of— Carl Gelderloos (@CGelderloos) July 9, 2013Some of those dudes deleted their accounts (to perhaps reappear another day), but others just go on their merry way with earth-shattering pronouncements like, "I have to untangle my earphones at least 3 times a day" and "Playstation is better than Xbox."Public shaming doesn't seem to cause any lasting change. Does it?Shaming: it’s a bit crap for everyoneIt’s no surprise to anyone that Twitter and Facebook are filled with vile, racist, homophobic, bigoted awfulness. Because humanity is filled with vile, racist, homophobic bigots.. . .The consequence of these shaming sites, is that us “enlightened” folk then pile in on the bigots and abuse them and tell them how awful they are. And I’m willing to bet that the number of individuals who have rescinded what is probably years’ of built up bigotry is the same number of terrorist attacks that the Wellington airport security screeners have stopped: Zero.. . .That’s not to say we should let people get away with awfulness, but when we publicly name and shame and by proxy invite the internet to start tormenting these people, we are becoming them. No better than they are because we now have a figure to poke a stick at.The shame sweepstakes become more costly and damaging once we enter the world of mental illness, addiction, and difference. Yet some still argue in favor of shaming.Has there been a resurgence of shame as a... Read more »

Wiechelt SA. (2007) The specter of shame in substance misuse. Substance use , 42(2-3), 399-409. PMID: 17558937  

Gilbert P, McEwan K, Irons C, Bhundia R, Christie R, Broomhead C, & Rockliff H. (2010) Self-harm in a mixed clinical population: the roles of self-criticism, shame, and social rank. The British journal of clinical psychology / the British Psychological Society, 49(Pt 4), 563-76. PMID: 20109278  

Hastings ME, Northman LM, Tangney JP. (2002) Shame, Guilt, and Suicide. Suicide Science, 67-79. DOI: 10.1007/0-306-47233-3_6  

  • July 8, 2013
  • 04:57 AM

A New Slant on Frontal Connectivity: the Frontal Aslant Tract

by The Neurocritic in The Neurocritic

The frontal aslant tract is shown in yellow (Fig 5, Catani et al., 2012). It's not every day that you hear about a newly described white matter pathway in the human brain. An interesting new study by a group of researchers in London and Chicago found a novel fiber tract implicated in verbal fluency impairments in patients with a lesser known neurodegenerative illness (Catani et al., 2013). This short fiber tract connects two different regions in the frontal lobe. It was recently identified using a combination of diffusion imaging and post-mortem dissection (Lawes et al., 2008; Catani et al., 2012; Thiebaut de Schotten et al., 2012). Dubbed the frontal aslant tract (FAT) by Catani and colleagues, it connects the posterior portion of the inferior frontal gyrus (IFG) to the supplementary motor area (SMA) and pre-SMA on the medial wall.1A number of experiments have already looked at the functional connectivity of these regions, during both resting state and task activation conditions. Statistically correlated fluctuations in the BOLD signal 2 are thought to reflect functional connectivity between two regions, but there is often no evidence that the two regions are directly connected anatomically. Therefore, in vivo structural MRI methods such as diffusion imaging can provide complementary data by visualizing white matter pathways to determine anatomical connections.The diffusion tractography results were then compared to blunt dissection of tracts from post-mortem brains, which helped to validate a method that some view as prone to limitations and potential artifacts.3 Fig. 10 (modified from Catani et al., 2012). Coronal slices of the ‘Digital Dejerine’ maps 4  and post-mortem blunt dissections of the corresponding tracts. E) The frontal aslant tract (FAT) connecting inferior and superior frontal gyri.A comparative study went further, showing that the results obtained from human tractography compared favorably to axonal tracing methods in monkeys (Thiebaut de Schotten et al., 2012).5  Fig. 6 (Thiebaut de Schotten et al., 2012). Reconstructions of the frontal aslant tract: comparison between post-mortem axonal tracing in monkey and human in vivo SD [Spherical Deconvolution] tractography shows simian-human similarities.However, one difference between this tract in monkeys and humans is that the FAT is lateralized in humans, being larger in the left hemisphere than in the right (Catani et al., 2012). In the left hemisphere, posterior IFG is part of Broca's area. This brings us back to the clinical importance of this basic neuoanatomical work.Verbal Fluency and the Frontal Aslant TractPrimary progressive aphasia (PPA) is a neurodegenerative disorder, the hallmark of which is the deterioration of specific speech and language functions. There are three variants, each with characteristic behavioral, neuroanatomical, and pathological features (Gorno-Tempini et al., 2011):Nonfluent/Agrammatic Variant PPA is characterized by halting, effortful speech with difficulties producing grammatical output and/or comprehending syntactically complex sentences. Word comprehension and object knowledge are intact. Atrophy in the left frontal cortex is apparent on MRI.Semantic Variant PPA is marked by impairments that include comprehending the meanings of words, naming objects and understanding their function. Motor speech production and grammatical output are spared. Atrophy is seen in the anterior temporal lobe.Logopenic Variant PPA involves word finding problems, phonological speech errors, and difficulties in repeating words and sentences. Word comprehension, object knowledge, and grammar are spared. Degeneration of left posterior temporal-parietal regions is observed.In the latest study by Catani et al. (2013), 35 patients with PPA and 29 controls participated in behavioral testing and MRI scanning. The tests included standard evaluations of language abilities including the Western Aphasia Battery, the Boston Naming Test, and the Peabody Picture Vocabulary Test. Tractography identified the frontal aslant tract and the uncinate fasciculus, which connects anterior temporal lobe regions to the IFG pars orbitalis and the orbitofrontal cortex. Quantitative measures included the number of streamlines (tract volume), fractional anisotropy, and radial diffusivity (measures of white matter integrity and axonal damage, respectively).Results indicated that patients with Nonfluent/Agrammatic PPA were impaired in a speech production task that required telling the story of Cinderella from a picture book. Poor performance in verbal fluency was associated with the extent of damage in the FAT, but grammatical deficits were not. In contrast, patients with Semantic Variant PPA showed deficits in semantic processing which correlated with degeneration in the uncinate fasciculus.What are the implications for the neuroanatomy of verbal fluency and speech output?...Patients with lesions of the pre-supplementary motor area present with various degrees of speech impairment from a total inability to initiate speech (i.e. mutism) to mild altered fluency. Our findings suggest that these medial regions of the frontal lobe could facilitate speech initiation through direct connection to the pars opercularis of the inferior frontal gyrus. Indirect support of this interpretation comes from the frequent observation of impaired fluency in patients with deep lesions in the frontal periventricular white matter. In these cases, a disconnection of the frontal aslant could explain the emergence of symptoms usually associated with frontal cortical damage. More broadly, characterizing the different pattern... Read more »

Catani M, Dell'acqua F, Vergani F, Malik F, Hodge H, Roy P, Valabregue R, & Thiebaut de Schotten M. (2012) Short frontal lobe connections of the human brain. Cortex; a journal devoted to the study of the nervous system and behavior, 48(2), 273-91. PMID: 22209688  

Catani M, Mesulam MM, Jakobsen E, Malik F, Matersteck A, Wieneke C, Thompson CK, Thiebaut de Schotten M, Dell'acqua F, Weintraub S.... (2013) A novel frontal pathway underlies verbal fluency in primary progressive aphasia. Brain : a journal of neurology. PMID: 23820597  

Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa SF, Ogar JM, Rohrer JD, Black S, Boeve BF.... (2011) Classification of primary progressive aphasia and its variants. Neurology, 76(11), 1006-14. PMID: 21325651  

Thiebaut de Schotten M, Dell'Acqua F, Valabregue R, & Catani M. (2012) Monkey to human comparative anatomy of the frontal lobe association tracts. Cortex; a journal devoted to the study of the nervous system and behavior, 48(1), 82-96. PMID: 22088488  

  • June 14, 2013
  • 05:45 AM

A New Biomarker for Treatment Response in Major Depression? Not Yet.

by The Neurocritic in The Neurocritic

Is a laboratory test or brain scanning method for diagnosing psychiatric disorders right around the corner? How about a test to choose the best method of treatment? Many labs around the world are working to solve these problems, but we don't yet have such diagnostic procedures (despite what some might claim). A new study by McGrath et al. (2013) might be a step in that direction, but the results are very preliminary and await further validation.The principal investigator of that study is Dr. Helen Mayberg, a leader in neuroimaging studies of major depression. She and her colleagues have pioneered the use of deep brain stimulation (DBS) as a treatment for severe, intractable depression, which was "the culmination of 15 years of research using brain imaging technology," says Dr. Mayberg.Psychotherapy or Drugs?The choice of treatment modality in depression, as in other psychiatric disorders, is by trial and error. If one drug doesn't work, switch to another one. If your insurance covers it, a short course of evidence-based psychotherapy1 might be in order.The whole concept of a DSM-based classification scheme for mental illnesses has come under fire, especially with the release of the new Diagnostic and Statistical Manual. In the real world, psychiatric disorders don't always show such clear boundaries; overlap and co-morbidity are common. The National Institute of Mental Health has endorsed a new approach, the Research Domain Criteria project, that incorporates dimensions of observable behavior along with neurobiological measures. Here's where the new work by McGrath et al. (2013) fits in. Their goal was... To identify a candidate neuroimaging “treatment-specific biomarker” that predicts differential outcome to either medication or psychotherapy.Fewer than 40% of depressed patients remit with their first course of treatment, so this would be an important advance. A more scientific way of choosing among possible treatment options would benefit patients and society at large.The study (registered at, NCT00367341) enrolled a total of 82 depressed people. The neuroimaging method might surprise some of you: FDG-PET to measure glucose metabolism -- not the popular and trendy resting state fMRI to examine functional connectivity or any sort of fMRI activation study. However, the authors cite an established literature using this technique in studies of antidepressant treatment response.Patients diagnosed with moderate to severe depression (a score of 18 or more on the Hamilton Depression Rating Scale, HDRS) received a PET scan and were randomized to receive 12 weeks of either cognitive behavioral therapy (CBT, n=41) or escitalopram (Lexapro, n=39), an SSRI antidepressant. Sixty-three patients completed this phase and also had a PET scan. The endpoint considered a successful response to treatment was remission (HDRS score of 7 or less), while non-response was a change in HDRS of 30% or less. Partial responders were omitted, leaving the final groups as follows:CBT remission, n=12escitalopram remission, n=11CBT nonresponse, n=9escitalopram nonresponse, n=6Right away we see that the number of patients in each group is very small, particularly for a study designed to identify biomarkers that will generalize to a larger population. Let me repeat that: a successful biomarker must generalize to an independent population. We haven't seen that here, so any conclusions drawn from this paper must be considered very preliminary.How was the biomarker identified? The PET images were co-registered with the corresponding structural MRIs. A whole brain analysis identified regions showing a treatment × outcome interaction (at a significance level of p<.001 uncorrected). Six regions met this uncorrected standard: right anterior insula, right inferior temporal cortex, left amygdala,2 left premotor cortex, right motor cortex, and precuneus (medial superior parietal lobe). Most of these are pretty surprising, but even more surprising is that the rostral anterior cingulate (and subgenual cingulate, BA 25) were not involved:Contrary to past published studies,63 the rostral anterior cingulate did not discriminate the outcome subgroups in either the main effect or interaction analyses. A post hoc examination of responder and nonresponder differences within each treatment arm did reveal a nonsignificant rostral cingulate activity difference, with metabolism in responders greater than nonresponders, but solely in the escitalopram group. While consistent with past reports, this finding did not meet the TSB [treatment-specific biomarker] criteria defined for the current study, ie, a region whose activity can differentiate both good and poor outcomes for both treatments.- click on image for a larger view -... Read more »

McGrath CL, Kelley ME, Holtzheimer PE, Dunlop BW, Craighead WE, Franco AR, Craddock RC, & Mayberg HS. (2013) Toward a Neuroimaging Treatment Selection Biomarker for Major Depressive Disorder. JAMA psychiatry (Chicago, Ill.), 1-9. PMID: 23760393  

  • June 10, 2013
  • 05:37 AM

How to Measure Female Desire

by The Neurocritic in The Neurocritic

A Sexual Laboratory of One's Own, aka A Clean Well-Lighted Place for SexPsychophysiologic studies of sexual response should be done in a comfortable, well-designed laboratory to minimize subject anxiety and discomfort (Woodard & Diamond, 2009, Fig. 5). How do scientists measure the physiological aspects of sexual arousal in women? A 2009 paper by Woodard and Diamond reviewed 45 years of research using instruments that measure female sexual function. These devices include the vaginal photoplethysmograph (right), vaginal and labial thermistors, pressure/compliance balloons, clitoral electromyography, and the electrovaginogram. For a full list, see Table 1 at the bottom of this post.The authors note that these physiological measures do not correlate very well with subjective ratings of sexual arousal. Furthermore, clinicians who treat women with sexual dysfunctions are of two minds. Some say the distinction between female desire and arousal may be artificial (see DSM-5 changes, p. 13), while others maintain that the merger of female sexual arousal disorder (FSAD) with Hypoactive Sexual Desire Disorder (HSDD) will be disastrous (Clayton et al., 2012).The previous post about Lybrido and Lybridos, the drugs in clinical trials for HSDD, talked briefly about Emotional Brain, the Dutch drug company that is developing them. Putting aside the many objections to the HSDD diagnosis for now, and the fact that the trials pathologize sexual boredom within marriage, the company has conducted some interesting studies1 to assess sexual desire. Foremost among these is the development of an at-home testing environment, or ambulatory lab, to conduct studies of sexual function (Bloemers et al., 2010).Fig. 1 (Bloemers et al., 2010). Schematic overview of the ambulatory measurement setting. (1) Generic laptop, (2) genital probe, (3) wireless sensor system, (4) handheld computer, and (5) secure central database.The participants must be so much more comfortable watching hardcore porn and measuring their own vaginal pulse amplitude and clitoral blood volume in the privacy of their homes, without the prying eyes of hoards of scientists in white lab coats (although some people might be into that).And that's what was found, for the most part (Bloemers et al., 2010):The results of this study support our hypothesis that in healthy controls, clitoral and subjective laboratory measures of sexual arousal show stronger increases to erotic stimuli in the home environment than in the environment of the institutional laboratory. This effect was apparent in response to hardcore stimuli, but not to erotic fantasy. ... To our knowledge, this is the first study that investigates ecological validity of sexual psychophysiological measures by comparing those assessed in the institutional laboratory to those assessed at home with an ambulatory laboratory. Footnote1 Albeit flawed studies, from a cognitive perspective (especially their implementation of an 'Emotional Stroop' task). I am not particularly qualified to comment on other aspects of this research.ReferencesBloemers, J., Gerritsen, J., Bults, R., Koppeschaar, H., Everaerd, W., Olivier, B., & Tuiten, A. (2010). Induction of Sexual Arousal in Women Under Conditions of Institutional and Ambulatory Laboratory Circumstances: A Comparative Study Journal of Sexual Medicine, 7 (3), 1160-1176 DOI: 10.1111/j.1743-6109.2009.01660.xWoodard, T., & Diamond, M. (2009). Physiologic measures of sexual function in women: a review Fertility and Sterility, 92 (1), 19-34 DOI: 10.1016/j.fertnstert.2008.04.041
... Read more »

  • May 27, 2013
  • 07:05 AM

Can Pot Smoking Counter the Negative Metabolic Consequences of Atypical Antipsychotics?

by The Neurocritic in The Neurocritic

DISCLAIMER: This is a hypothetical question and not a medical recommendation. But it might be an idea worth investigating in epidemiological studies.Everyone knows that pot gives you the munchies. So the paradoxical finding that marijuana use is associated with a lower prevalence of obesity and diabetes came as a quite surprise to me. Now, a new study has concluded that pot smokers also have lower fasting insulin levels and smaller waistlines (Penner et al., 2013).I'll let the authors summarize the clinical significance of their study (Penner et al., 2013):Marijuana use is increasingly common, and use of medical marijuana is now legal in 19 states and the District of Colombia.Despite its associations with increased appetite and caloric intake, marijuana use also is associated with lower body mass index and prevalence of diabetes.In a nationally representative survey population, we found current use of marijuana to be associated with lower levels of fasting insulin, lower insulin resistance (homeostasis model assessment of insulin resistance), and smaller waist circumference.More complete descriptions of this article are available at Addiction Inbox and Time Healthland.Marijuana Use and Mental IllnessSome other observations that I will attempt to string together:Cannabis use (and misuse) is higher among individuals with schizophrenia and bipolar disorder (Green et al., 2005; Lev-Ran et al., 2013).I will not address the issue of whether cannabis use is a risk factor for psychosis here.1 In fact, all of my observations will be related to the metabolic effects of marijuana and not to its psychoactive properties and possible detrimental effects on mental health.People with schizophrenia and bipolar disorder are often on atypical antipsychotic drugs, which are notorious for causing significant weight gain that can lead to high cholesterol, hypertension, diabetes and metabolic syndrome. Although cigarette smoking, alcohol use, unhealthy diet, and lack of exercise may contribute to shorter life expectancy in patients with serious mental illnesses (Lawrence et al., 2013), one has to wonder about the effects of atypicals on physical health.2 These drugs can have a very positive effect on mental health, but it comes at a cost.Interestingly, cannabis use is not associated with greater mortality. In fact, the opposite has been reported by Koola et al. (2012), who "observed a lower mortality risk in cannabis-using psychotic disorder patients compared to cannabis non-users despite subjects having similar symptoms and treatments." A total of 762 patients with a psychotic disorder were included in that study. All were on atypical antipsychotics, and 39% used marijuana (although this is often under-reported). The authors speculated on the potential health benefits of cannabis, including its anti-inflammatory effects. However, they didn't mention reductions in obesity and diabetes as possible causes of lower mortality in cannabis users. This association bears further investigation, in my view.Nevertheless, eliminating marijuana to counteract the increase in appetite brought on by atypicals seems like common sense. In fact, this has been proposed as a specific behavioral intervention (Werneke et al., 2013).Those authors assumed that cannabis contributes to the weight gain caused by the prescription medication, which I also assumed (until reading the new papers cited here). But this relationship hasn't really been studied (Werneke et al., 2013):As the endocannabioid system is linked to increased appetite and cannabioid receptor antagonists can induce weight loss [15] cannabis consumption will most likely potentiate antipsychotic-associated weight gain. As the prevalence of cannabis use in people suffering from psychosis is so high, the contribution of cannabis to weight gain in this population is likely to be significant. Surprisingly, this link between cannabis and weight gain remains largely ignored at present. A recent paper in Medical Hypotheses (of all places) takes the opposite stance and proposes cannabis as a weight loss drug (Le Foll et al., 2013):We recently discovered that the prevalence of obesity is paradoxically much lower in cannabis users as compared to non-users and that this difference is not accounted for by tobacco smoking status and is still present after adjusting for variables such as sex and age. Here, we propose that this effect is directly related to exposure to the Δ9-tetrahydrocannabinol (THC) present in cannabis smoke. We therefore propose the seemingly paradoxical hypothesis that THC or a THC/cannabidiol combination drug may produce weight loss and may be a useful therapeutic for the treatment of obesity and its complications.These authors have filed a patent application for 'Use of marihuana and compounds therein for treating obesity' (which they acknowledge in the paper).One of the same authors (Le Foll) has also published on 'Cannabis use and cannabis use disorders among individuals with mental illness' (Lev-Ran et al., 2013), which they found to be particularly high in individuals with Bipolar I disorder (especially in men). Many of these bipolar cannabis users are probably on atypical antipsychotics. This information was not reported in the paper, but it might be available in the National Epidemiologic Survey on Alcohol and Related Conditions (although this is not certain).To be completely clear, I am not advocating the use of marijuana by persons with schizophrenia or bipolar disorder. Rather, I am suggesting that the relationship between atypical antipsychotics and variables such as body mass index, waist circumference, insulin, glucose, and diabetes be compared between groups who do use cannabis vs. those who don't. If there is a benefit in the pot smokers, perhaps there could be a psychiatrically safe, cannabis-derived compound for weight loss in the future. Isn't that more likely than the development of 'third generation' antipsychotics that do not cause substantial weight gain?Footnotes1 Interested readers can consult these articles and posts.2 See also Rising Mortality Rates for People with Serious Mental Illness and Improving the Physical Health of People With Serious Mental Illness.ReferencesGreen B, Young R, Kavanagh D. (2005) Cannabis use and misuse prevalence among people with psychosis. Br J Psychiatry 187:306-13. ... Read more »

  • May 22, 2013
  • 06:19 AM

The Mental Health of Lonely Marijuana Users

by The Neurocritic in The Neurocritic

Mr. Lonely 1Does Smoking Pot Offer Relief to the Lonely?  A new paper by the original Tylenol and social pain researchers claims that it does (Deckman et al., 2013). Let's take a closer look.Comfortably Numb: Marijuana Use Reduces Social Pain, Research FindsMarijuana use buffers people from experiencing social pain, according to research published online on May 14 in Social Psychological and Personality Science."Prior work has shown that the analgesic acetaminophen, which acts indirectly through CB1 receptors, reduces the pain of social exclusion," Timothy Deckman of the University of Kentucky and his colleagues wrote in the study. "The current research provides the first evidence that marijuana also dampens the negative emotional consequences of social exclusion on negative emotional outcomes."You could be forgiven if you thought, as I initially did, that the University of Kentucky IRB must hold a liberal view on the administration of controlled substances to undergrads participating in psychology experiments. But that's not what happened here... the data are entirely correlational, based on self-report, and largely problematic (in my view).Marijuana Lowers Self-Worth and Worsens Mental Health in Those Who Are Not LonelyThat's my interpretation of the article, which is SO clunky compared to the fun and breezy query, Can Marijuana Reduce Social Pain? 2The paper begins with the premise that "Social and physical pain share common overlap at linguistic, behavioral, and neural levels" (Deckman et al., 2013). So let's give a pain reliever to reduce the sting of rejection!  A critique of the original work asked why the authors chose Tylenol, as opposed to an NSAID like aspirin, ibuprofen, or naproxen. In the current study they tried to develop a mechanistic account of why acetaminophen might reduce social pain:Prior research has shown that acetaminophen—an analgesic medication that acts indirectly through cannabinoid 1 receptors—reduces the social pain associated with exclusion. Yet, no work has examined if other drugs that act on similar receptors, such as marijuana, also reduce social pain.The problem is that acetaminophen's mechanism of action is surprisingly unclear (Toussaint et al., 2010). One prominent hypothesis claims that Tylenol might exert its analgesic effects through descending serotonergic pathways at the level of the spinal cord. In fact, the paper that Deckman et al. cited in favor of cannabinoid 1 (CB1) receptors describes a very complex pathway that includes indirect involvement of CB1, with actual pain suppression occurring in the spinal cord. 3An even more basic question: if acetaminophen acts through CB1 receptors, then why isn't it a potential drug of abuse, or known by experienced pharmanauts for its psychoactive properties?  The drug experience vault Erowid says:Acetaminophen is a non-salicylate analgesic and antipyretic (pain killer and fever reducer). It is a common over-the-counter pain medication found in hundreds of products around the world. At higher doses it is known to cause liver-damage and has a low therapeutic index (ratio of effective dose to toxic dose), making it dangerous when included in recreationally used pharmaceuticals [e.g., Tylenol with codeine]. It is not known to be psychoactive.On the other hand, we all know that cannabis is psychoactive. The design of the cannabis study included cross-sectional national survey data, a two year longitudinal survey of 400 high school students, and a Mechanical Turk-implemented version of cyberball, an online game to simulate social exclusion. In all cases, participants reported their marijuana use, and this was related to the variables of interest.I'll focus on the national survey data in this post, which comprised Study 1 (Marijuana Use Buffers Lonely People From Lower Self-Worth and Self-Rated Mental Health) and Study 2 (Marijuana Use Predicts Fewer Major Depressive Episodes Among the Lonely).Study 1 used data from the National Comorbidity Survey: Baseline (NCS-1), 1990-1992 (ICPSR 6693), which you can download for yourself. The survey recruited 8,098 individuals from the ages of 15 to 54 living in the U.S., and included over 4,000 variables. Only four variables were chosen for the present study: self-reported loneliness (1= often, 4 = never), marijuana use (0 = none, 1 = daily, 8 = once or twice a year), self-worth (1 = high, 4 = low), and overall mental health (1 = excellent, 5 = poor).Loneliness was used as a proxy for social pain. Contrary to what the headlines suggested, the impact of pot smoking on social pain was not directly examined. Instead, the study assessed the effects of loneliness (high, low), marijuana use (high, low) and their interaction on self-worth and mental health.Loneliness and pot smoking interacted to predict feelings of self-worth [B = 0.03, t(5609) = 2.20, p = .03]. Given the huge number of participants, this level of statistical significance is not very impressive.Fig. 1 (modified from Deckman et al., 2013). Study 1: Marijuana use moderates the relationship between loneliness and self-reported feelings of self-worth. [NOTE: items were reverse-scored for display purposes.]For lonely people, the amount of pot smoked didn't make too much of a difference in their self-worth (see red arrow above).  For socially connected people, greater marijuana use resulted in lower self-worth, although it's not clear this was significant (pairwise statistical tests were not reported).I also question how the High Marijuana Use and Low Marijuana Use groups were determined, because over 5,000 participants did not smoke pot at all in the last 12 months. Does the heavy use group combine those who smoke 6 joints a year with those who smoke daily?... Read more »

Deckman, T., DeWall, C., Way, B., Gilman, R., & Richman, S. (2013) Can Marijuana Reduce Social Pain?. Social Psychological and Personality Science. DOI: 10.1177/1948550613488949  

  • May 15, 2013
  • 04:50 PM

What RDoC Research Might Look Like

by The Neurocritic in The Neurocritic

The month of May is a violent thingIn the city their hearts start to singWell, some people sing, it sounds like they're screamingI used to doubt it, but now I believe itMonth Of May   ------The Arcade FireToday is Mental Health Month Blog Day, sponsored by the American Psychological Association (APA). It's designed to:...educate the public about mental health, decrease stigma about mental illness, and discuss strategies for making lasting lifestyle and behavior changes that promote overall health and wellness.If the public has been following the recent hullabaloo about how to diagnose mental illnesses, they might be confused about the current and future direction of the field. How did we get here?As most of you know, the American Psychiatric Association (the other APA) is about to release its updated Diagnostic and Statistical Manual of Mental Disorders, the much maligned DSM-5. Weeks before the big launch, however, the National Institute of Mental Health (NIMH) stole the show by announcing that it will be re-orienting its research away from DSM categories:...While DSM has been described as a “Bible” for the field, it is, at best, a dictionary, creating a set of labels and defining each. The strength of each of the editions of DSM has been “reliability” – each edition has ensured that clinicians use the same terms in the same ways. The weakness is its lack of validity. Unlike our definitions of ischemic heart disease, lymphoma, or AIDS, the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure. Instead, the Research Domain Criteria (RDoC) framework would become the preferred method for organizing biologically-based research on mental illnesses, with the ultimate goal of constructing a new classification scheme.This caused quite a commotion, leading many to comment on NIMH's shocking repudiation of DSM-5. However, to long-time observers of RDoC's development, this was not a surprise. And the initial lack of clarity on the distinction between the RDoC Dimensional Approach for Research vs. DSM-5 for Diagnosis didn't help matters, nor did the uncertainty about whether NIMH would fund DSM-based research at all.1NIMH issued a press release on May 13 to clarify its position:DSM-5 and RDoC: Shared InterestsThomas R. Insel, M.D., director, NIMHJeffrey A. Lieberman, M.D., president-elect, APANIMH and APA have a shared interest in ensuring that patients and health providers have the best available tools and information today to identify and treat mental health issues, while we continue to invest in improving and advancing mental disorder diagnostics for the future.Today, the APA's Diagnostic and Statistical Manual of Mental Disorders (DSM), along with the International Classification of Diseases (ICD) represents the best information currently available for clinical diagnosis of mental disorders  Patients, families, and insurers can be confident that effective treatments are available and that the DSM is the key resource for delivering the best available care. The NIMH has not changed its position on DSM-5. As NIMH’s Research Domain Criteria (RDoC) project website states, “The diagnostic categories represented in the DSM-IV and the International Classification of Diseases-10 (ICD-10, containing virtually identical disorder codes) remain the contemporary consensus standard for how mental disorders are diagnosed and treated.”Yet, what may be realistically feasible today for practitioners is no longer sufficient for researchers. Looking forward, laying the groundwork for a future diagnostic system that more directly reflects modern brain science will require openness to rethinking traditional categories. It is increasingly evident that mental illness will be best understood as disorders of brain structure and function that implicate specific domains of cognition, emotion, and behavior. This is the focus of the NIMH’s Research Domain Criteria (RDoC) project. RDoC is an attempt to create a new kind of taxonomy for mental disorders by bringing the power of modern research approaches in genetics, neuroscience, and behavioral science to the problem of mental illness.So what is RDoC, and how might it be applied to new research projects? From the DSM perspective of categorical disorders (e.g, schizophrenia, major depression, and obsessive compulsive disorder), RDoC embraces diagnostic messiness. Patients previously excluded from a study due to comorbidities, or because they don't meet full criteria? Misfits from the "Not Otherwise Specified" (NOS) category? Now they're in. Specifically, the instructions for RFA-MH-14-050 state:Priority will be given to applications that have a well-justified plan to include patients from multiple diagnostic groups (including Not Otherwise Specified and forme fruste diagnoses) as appropriate for explicating the dimensions and constructs of interest in the study design. Studies that include patients from a single diagnostic group may also be considered if there is a particularly strong justification for examining constructs of interest within one diagnostic category.  A defensible approach might be to study all patients presenting themselves at a specialty clinic, e.g., mood disorders clinic, anxiety clinic, or psychotic disorders clinic, regardless of whether they meet criteria for a particular DSM diagnosis.One potential pitfall of this approach is the money required to enroll huge numbers of patients. If commonalities in cognitive function or brain circuitry or especially genetic risk factors are to emerge from studying all patients with mood disorder-like symptoms, then sample sizes must be very large to overcome potential noise in the system(s).The applicant would propose to study one or more of the five different domains, or constructs, that have been fleshed out at NIMH Workshops:Negative Valence SystemsPositive Valence SystemsCognitive SystemsSystems for Social ProcessesArousal/Regulatory SystemsThe possible units of analysis run the gamut from genes to circuits to behavior, and the studies should use specific tasks (paradigms) and self-report measures, as shown in the Negative Valence Systems matrix below.Draft Research Domain Criteria Matrix Animal ... Read more »

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