The Neurocritic

290 posts · 278,778 views

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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  • September 16, 2014
  • 06:36 AM
  • 411 views

Should Policy Makers and Financial Institutions Have Access to Billions of Brain Scans?

by The Neurocritic in The Neurocritic

"Individual risk attitudes are correlated with the grey matter volume in the posterior parietal cortex suggesting existence of an anatomical biomarker for financial risk-attitude," said Dr Tymula.This means tolerance of risk "could potentially be measured in billions of existing medical brain scans." 1 -Gray matter matters when measuring risk toleranceLet's pretend that scientists have discovered a neural biomarker that could accurately predict a person's propensity to take financial risks in a lottery. Would it be ethical to release this information to policy makers? That seems to be the conclusion of a new paper published in the Journal of Neuroscience (Gilaie-Dotan et al., 2014):The results will also provide a simple measurement of risk attitudes that could be easily extracted from abundance of existing medical brain scans, and could potentially provide a characteristic distribution of these attitudes for policy makers.If we accept this line of thinking, it's not much of a stretch to imagine that financial institutions, employers, consumer reporting agencies, and dating services could use this information in a discriminatory, preemptive fashion to screen out potentially risky applicants. Or perhaps casinos, lotteries, and predatory lending companies could target these individuals with personalized ads.Conversely, investment firms could vie for traders with the largest right posterior parietal cortices, since they would have the highest tolerance for risk.Or am I being alarmist about the breach of ethics involved in releasing protected medical information to outside entities? Although the authors subtly deter extrapolation to this invasive scenario by using phrases like "characteristic distribution" and "risk attitudes of populations" (as opposed to risk attitudes of individuals), they're pretty clear about the promise of their gray matter measure to inform policy (Gilaie-Dotan et al., 2014):Our finding suggests the existence of a simple biomarker for risk attitude, at least in the midlife [sic] population we examined in the northeastern United States. ...  If generalized to other groups, this finding will also imply that individual risk attitudes could, at least to some extent, be measured in many existing medical brain scans, potentially offering a tool for policy makers seeking to characterize the risk attitudes of populations.Now let's all take a step back and evaluate whether this is currently feasible. The short answer is no (in my view, at least).First, we have to be somewhat skeptical of the study's major conclusion. Voxel-based morphometry (VBM) was to quantify cortical volume from structural MRIs.2 Gray matter volume in a small chunk of the right posterior parietal cortex (PPC) was the only place in the entire cerebral cortex that correlated with individual attitudes toward financial risk. In humans, right lateralized PPC has been strongly implicated in visuospatial attention.Doesn't it seem more plausible that a region like the orbitofrontal cortex (OFC), which has been activated in numerous functional neuroimaging studies of decision making and risk, would show such an association? Studies in primates have demonstrated that economic risk is coded by single neurons in the OFC (O'Neill & Schultz, 2014), and in rats risk preference can be differentiated by OFC neuronal responses (Roitman & Roitman, 2010).The authors do cite an extensive literature on the role of parietal neurons in decision making, but fMRI studies have observed effects of risk preference in left PPC, and uncertainty in bilateral PPC (Huettel et al., 2005, 2006).But what is the purpose of having a larger gray matter volume in PPC in relation to financial risk attitude? Does it allow for a higher "computational capacity" that can accommodate greater risk tolerance? We don't actually know, as Gilaie-Dotan et al. (2014) explain:We do not know precisely how GM volume translates to the neural level. It is possible that volume differences reflect synaptogenesis and dendritic arborization (Kanai and Rees, 2011), but to-date there is no clear evidence of correlation between GM volume measured by VBM and any histological measure, including neuronal density (Eriksson et al., 2009). In contrast to the neural correlate of risk attitude, a participant's attitude toward ambiguity was not associated with structural differences anywhere in the cortex (Gilaie-Dotan et al., 2014). How were these attitudes (or preferences) measured? Experimental economics methods were used to estimate individual preferences for risk (uncertainty with known probabilities) and ambiguity (uncertainty with unknown probabilities).Participants played a game where they could choose between lotteries that varied in monetary value and in the degree of either risk or ambiguity. In the example trial below, the participant chooses either this option, where they stand a 38% chance of winning $18, or the reference option that offers a 50% chance of winning $5.Modified from Fig. 1A (Gilaie-Dotan et al., 2014).There were five reward levels ($5, $9.50, $18, $34, and $65), each fully crossed with three probabilities of winning and three levels of ambiguity around the winning probability, as shown below.Figure 1 (Levy et al., 2012). Risky and ambiguous stimuli. A) In risky stimuli the red and blue areas of each image are proportional to the number of red and blue chips. Three outcome probabilities were used: 13, 25 and 38%. B) In ambiguous stimuli the central part of the image is obscured with a gray occluder. In the gray area the number of chips of each color is unknown, and thus the probability of drawing a chip of a certain color is not precisely known. Three levels of ambiguity were used, where 25, 50 or 75% of the image is occluded.Using a maximum likelihood procedure, the choice data of each participant was fit to a logistic function. Fitting the choice data with a choice function provided estimates for the risk attitude (α) and ambiguity attitude (β) for each person. These were included in multiple regression analyses to determine the neuroanatomical correlates of risk (α) and ambiguity (β) based on the model estimates.3 Two populations of subjects w... Read more »

Gilaie-Dotan, S., Tymula, A., Cooper, N., Kable, J., Glimcher, P., & Levy, I. (2014) Neuroanatomy Predicts Individual Risk Attitudes. Journal of Neuroscience, 34(37), 12394-12401. DOI: 10.1523/JNEUROSCI.1600-14.2014  

  • September 8, 2014
  • 02:41 AM
  • 433 views

A Dangerous New Dish

by The Neurocritic in The Neurocritic

Bibimbop Brugmansia ** Do NOT try this at home.Edible flowers can make for a beautiful garnish on salads and trendy Brooklyn cocktails, but those decorative flourishes can be a disaster for the oblivious amateur. An unusual case report in BMC Research Notes summarizes what happens when you sprinkle toxic flower petals on your bibimbop (Kim et al., 2014).A 64 year old Koren woman came to the emergency room with incoherent speech and fluctuations in attention, orientation and comprehension. She had called her daughter for help but couldn't remember why. (Hint: that's because she ingested flowers containing scopolamine and atropine, two potent anticholinergic compounds that can cause amnesia).In contrast to these alterations in her mental state, she did not show dilated pupils, dry mouth, increased heart rate, or other changes to the autonomic nervous system typically observed with anticholinergics [which seems odd to me]. After 10 hours had elapsed, she became fully conscious and remembered that she had added a few flowers to her bowl of bibimbop, a traditional Korean dish. Twenty-four hours later, her memory for the entire episode was hazy.Angel's Trumpet (Brugmansia), a popular ornamental shrub, has a long history in ethnobotany and toxicology as a deliriant, differentiated from the psychedelic and dissociative hallucinogens. There are numerous case reports of presumed Angel's Trumpet poisoning in the literature. A 2003 review reported on 33 patients, 31 of whom deliberately consumed a brewed tea (Isbister et al., 2003). Dilation of the pupils (mydriasis) was seen in 100% of the patients, which is why it's odd that Kim et al. did not observe this.In fact, one paper reported on accidental unilateral mydriasis in a 11 year old girl who touched “a nice pink flower, similar to a trumpet” and then rubbed her eye (Andreola et al., 2008).But the most infamous case of deliberate Angel's Trumpet abuse is the young man who severed his own penis and tongue after drinking a tea, “illustrating that consuming this beautiful flower with the name of an angel and the poison of the devil can be very dangerous” (Marneros et al., 2006).Scopolamine blocks M1 muscarinic acetylcholine receptors that are prominently distributed in the cerebral cortex, amygdala, and hippocampus. The septo-hippocampal cholinergic system plays an important role in learning and memory, accounting for the oft-observed amnesia. Brugmansia was (and is) used by Native groups in South America for religious ceremonies. According to Lockwood (1979), the Jivaro in eastern Ecuador used Brugmansia in a boyhood rite of passage. The adults understood the potential danger of the delirious and hallucinatory state and closely supervised the child:When a Jivaro reaches the age of six he seeks an arutam wakani, an acquired soul. ... To acquire an arutam soul, the boy, usually accompanied by his father, makes a pilgrimage to a sacred waterfall where he bathes, fasts, and drinks infusions of fresh tobacco water. If no vision or apparition appears, recourse may be to drink maikua, the juice of Brugmansia.... . .The arutam seeker is watched over by men not taking the maikua, in order to protect him from accidents or self-inflicted harm that might occur during the initial violent stages when the drug is taking effect. If the boy is fortunate, the arutam will appear to him, usually in the form of a pair of large creatures, often animals such as jaguars or anacondas.In more recent times, the street drug 'burundanga' has been used by criminals to incapacitate potential victims, as Vaughan Bell has explained.So the question arises, with such a long and distinguished literature, why was a new case study of Brugmansia poisoning published? Obviously, there are vast cultural differences between indigenous South American peoples, curious German and Australian youth, and elderly Korean women.Heungmi kkotjeon (Pan-fried Sweet Black Rice Cake with Flower Petals)CC BY-SA 2.0The beautiful Korean dish above is made with non-toxic edible flowers. Another (similar?) dish is hwajeon, or "flower cake". Might this lead to a greater danger in accidentally eating toxic flowers? Kim et al. conclude:This case is unique in that AT was ingested as an ingredient of a traditional Korean dish.  ...  Considering the fact that one can purchase it from virtually any florist without much difficulty, and that the number of adolescent recreational drug users is increasing, AT could be misused in the near future. The flowers of AT are occasionally used to garnish foods, so raising the awareness of the toxicities of this plant to the general public is important.Further ReadingThe tree of drunkenessHallucinations and hospitalizations: Angel’s TrumpetThe plant of human puppetsCultural Chemistry - the plant that robs you of your free will?Is free will spent by a knock-out drug?Mind controller: What is the 'burundanga' drug?... Read more »

Evans Schultes, R., & Plowman, T. (1979) The ethnobotany of Brugmansia. Journal of Ethnopharmacology, 1(2), 147-164. DOI: 10.1016/0378-8741(79)90004-7  

  • August 31, 2014
  • 06:36 PM
  • 539 views

Whitman Was Not a Neuroscientist

by The Neurocritic in The Neurocritic

Do I contradict myself?Very well then I contradict myself,(I am large, I contain multitudes.)-Walt Whitman, "Song of Myself" (from Leaves of Grass)Science is the search for objective truth based on physical laws of the universe. Scientific theories try to explain the consistent and predictable behavior of natural systems. They are generally reductionist, meaning that complex systems are reduced to simpler and more fundamental elements. The principles of physics, for instance, are expressed in the form of beautiful equations that are the envy of the softer sciences.xkcd: PurityThe enterprise of explaining how human brains produce complex thought (or how any nervous system produces observable behavior, for that matter) is notably lacking in the realm of grand unifying theories, a topic of discussion recently in the New York Times: “What would a good theory of the brain actually look like?”But the “search for a general ‘bridging theory’ may be a fruitless one” – like Awaiting a theory of neural weather. The “bridge, some way of connecting two separate scientific languages — those of neuroscience and psychology” may not exist.I'm not sure why the question, “What would a good theory of the brain actually look like?” was even posed in the first place (or posed in that fashion, like a single theory should be expected to explain “the brain”). Adam Calhoun asked what I think is a more productive question:  Are these the equations of the brain?English theoretical physicist Paul Dirac said, “A physical law must possess mathematical beauty.” Are these equations beautiful? 1 I cannot say. I am neither physicist nor mathematician. I traffic in matters less sublime. All I can do here is to include this citation from neuroaesthetician Semir Zeki and colleagues (2014), who reported that the neural correlates of perceiving mathematical beauty are the same as those that appreciate fine visual art. To be more precise, ratings of mathematical beauty were parametrically related to BOLD signal in field A1 of the medial orbitofrontal cortex, a part of the brain involved in  emotion, reward, and decision making.At the phenomenological level of subjective experience, this knowledge of brain activity does no more to explain what it's like to behold Dirac’s wave equation than the Temporal Difference Learning equation describes what it's like to feel this emotionally rewarding experience — the Nagelian conundrum of qualia.We sail the arctic sea, it is plenty light enough,Through the clear atmosphere I stretch around on the wonderful beauty,The enormous masses of ice pass me and I pass them, the scenery is plain in all directions,-Whitman, ibid What does any of this have to do with Walt Whitman? Yesterday I saw a pair of articles that encapsulate Whitman's principle of “I am large, I contain multitudes” when applied to neuroimaging studies of unclear psychological phenomena.“The results obtained suggest that dysfunctional [lower] activation of the SMA [supplementary motor area] for response inhibition is one of the candidate mechanisms of IGD [internet gaming disorder].”“...adults with IGD have ... greater activation of the fronto-striatal network in order to maintain their response inhibition performance.”The first study claimed that reduced recruitment of the SMA (a motor control area) could be responsible for the impulsivity seen in individuals with internet gaming disorder (an actual “Condition for Further Study” in the DSM-5). The second study suggested that enhanced activity in the fronto-striatal network (implicated in motor control as well, but also in reward) was necessary for IGD participants to maintain the same restrained behavior as control participants.So which is it?These results are not consistent. They contradict themselves. This is not unusual. The greater problem is that the discrepant results were reported by the same lab, each without any reference to the other study.Do I contradict myself?Very well then I contradict myselfThis world view makes for profound and transcendent poetry, but unacknowledged internal contradiction should not be adopted as the optimum path to scientific enlightenment.Empirical falsification, on the other hand, is a staple of the scientific method.I don't mean to single out this particular lab (which is why I did not include in-line citations), but this is a pet peeve of mine, along with a refusal to acknowledge any and all evidence that refutes one's signature theory. There's no shame in obtaining inconsistent results (or at least, there shouldn't be). But at least say so, try to come up with a plausible explanation, and do more experiments.Clear and sweet is my soul, and clear and sweet is all that is not my soul.... Read more »

  • August 25, 2014
  • 02:39 AM
  • 432 views

Autobiographical Memory for a Life-Threatening Airline Disaster

by The Neurocritic in The Neurocritic

“My attention shifts to the fact that the comforting engine hum is eerily gone. Where has the comforting hum of the engines gone. Something has gone very, very wrong, the plane continued to shake.” -Daniel Goncalves, recalling the terror of Air Transat Flight 236I'm sitting here in an airport, reading a harrowing first person account of Air Transat Flight 236, which fell out of the sky when it lost all power on Aug. 24, 2001.The plane was bound from Toronto, Ontario to Lisbon, Portugal when a fuel leak in the right engine began 3 hrs and 46 min after takeoff (at 04:38 UTC). The leak went undetected by the flight crew for over an hour, when it finally became apparent that the remaining fuel was insufficient to reach their destination in Lisbon. At 05:45 UTC, the pilot diverted the flight to Lajes Field on Terceira Island in the Azores, a cluster of islands about 850 miles west of Portugal.Image: Humberta Augusto/AP – via The Globe and MailAir Transat Flight 236 with its emergency slides deployed, sitting on the tarmac of Lajes Field in the Azores island of Terceira, after an emergency landing on Friday, Aug, 24, 2001.Here, Mr. Goncalves' gripping narrative should speak for itself.“All lights turn off, TV's off, P.A. system off, emergency lights light up the floors marking the emergency exit door. What the hell is going on? Is this a joke? Another clearly tense voice takes over and tried to address the 300+ passengers without the aid of a P.A. system. "Everyone put on their life vest and prepare for emergency ditching at sea." Huh? What the hell does that mean? Are you kidding me? Disbelief. "The captain has informed us that we are two hours away from Lisbon and we will not make it. We are preparing for an emergency ditch at sea. When you hear BRACE, BRACE, BRACE, lean against the seat in front of you, fold your arms and brace yourself." WHAT WHAT WHAT WHAT????? Oh my God, what is happening. We're going into the cold and black Atlantic? Now? Why? Is this a Joke? Are we part of that Just for Laughs show? Stop playing, come on. No joke. I was in denial. This fully loaded Airbus A330 was going into the ocean and all I knew was that my poor family were there with me. It hit me. This wasn't going to go away. This was it. This really was it. The end. Unimaginable death by catastrophe.”-Daniel Goncalves, My Air Transat flight 236 storyI'm reading this story because of a very unique paper published recently in Clinical Psychological Science (McKinnon et al. 2014), a study of  post-traumatic stress disorder (PTSD) and memory in survivors of the near-fatal Air Transat flight. Fifteen of the individuals WHO WERE ACTUALLY ON THAT FLIGHT participated in an experiment of autobiographical memory for the event, a shared horror of impending death. The comparison events were the terrorist attacks of September 11, 2001 (9/11) and a neutral event from around the same time.1 Seven of the survivors had been diagnosed with PTSD, six did not have PTSD, and the status of the remaining two was unknown. This immediately raises the caveat of very small comparison groups, further complicated by the fact that some of the assessment instruments were missing from various participants (e.g., the NEO-Five Factor Inventory of personality was missing from four).The study was conducted in the lab of Dr. Brian Levine, a well-known memory researcher at the Rotman Research Institute in Toronto. Adding another unexpected twist, the first author of the paper, Dr. Margaret C. McKinnon, was a passenger on Flight AT236!Now I'm flying in an Airbus 319, returning home. The setting sun to my right is blinding across the aisle.Here is the series of events on AT236 as recounted by Goncalves:Timeline: 4:38am-fuel started leaking5:45am- diverted to Lages Air Base in Azores5:48am- emergency declared6:13am- engine no 2 flamed out 217 km from Lages Air Base, full thrust to engine #1 on left wing and plane descended 6,000 feet (this was scary and when when the passengers first found out something was very wrong).6:23am- Mayday declared6:26am- engine no 1 flamed out 120 km from Lages Air Base6:45am- plane touched down hard on runway 33Then a flight attendant came over the PA system on my flight: “Ladies and gentlemen, we are experiencing a little turbulence, please return to your seats and fasten your seat belts.”OK, there's the turbulence, good thing I took an anti-emetic...But the bumpiness was quite short-lived, so back to our main story.Image via ... Read more »

  • July 31, 2014
  • 07:10 PM
  • 470 views

Twitter Psychosis as a Cultural Artifact

by The Neurocritic in The Neurocritic

The creation of the category “Twitter Psychosis" tells us more about the culture of contemporary psychiatry than it does about the purported dangers of social media overuse. Can Twitter really “cause” psychotic symptoms in predisposed individuals? Or is Twitter merely the latest technical innovation that influences “the form, origin and content of delusional beliefs” (Bell et al., 2005)? Twitter as the new telephone tower, radio waves, microchip implant or personal TV show, if you will.Via Twitter (@DrShock, @vaughanbell), of course, comes news of a one page paper entitled, Twitter Psychosis: A Rare Variation or a Distinct Syndrome? (Kalbitzer et al., 2014): The authors report the development of psychosis in a young woman coinciding with excessive use of the online communication system Twitter and the results of an experimental account to argue that Twitter may have a high potential to induce psychosis in predisposed users.The authors presented the case of a 31 year old woman who was hospitalized for intensive suicidal thoughts and compulsions. She had no previous history of psychiatric illness and denied current hallucinations.1 Her friends and family said the symptoms began about 8 months earlier. Approximately 4 months prior to that she started using Twitter “excessively” (defined as “several hours a day reading and writing messages, neglecting her social relationships and, sometimes, even meals and regular sleeping hours”).2 At some point she came to believe that a famous actor was communicating to her personally (a common delusion), and to see hidden symbolic messages in Tweets:During the next couple of weeks, Mrs. C increasingly felt that the messages of other users were “meant in a symbolic way” and that she had to react to these “tasks” in a certain manner. After approximately 2 months, she started to discover the same symbols in her real-world environment. She then started to feel that there “must be some organization behind these tasks” and started to suspect a sect, pointing to the development of systematized paranoid delusion. None of this really seems like a Distinct Syndrome, and I doubt it's even a Rare Variation any more. The authors wanted to discuss (with the larger medical community) “whether they already have to speak of a distinct syndrome of social media-induced psychosis.”And in fact, Dr. Vaughan Bell is one of the top experts to discuss this issue, and I imagine he will address the authors over at Mind Hacks.But then the Brief Report completely derails with an “experiment” reported in the remaining paragraphs...The Ben Goldacre Experiment"This is a path of brotherhood and love" says the new pope, immediately excluding a cool 4 billion people.— ben goldacre (@bengoldacre) March 13, 2013Someone (it's not clear who) created a fake account to address whether “Twitter communication responds to changes in communication style.” [NOTE: I'm not sure what this means.]To test this, a test person created an account and responded to the messages of Ben Goldacre, the maker of the blog http://badscience.net. Our test person responded to a message of Mr. Goldacre about the pope, but Mr. Goldacre did not reply. However, the authors received an answer from an unknown participant, writing "<our username> Cold blooded RT. XXX: I am in the church: <link>." The link led to different Web pages with commercials....when the authors followed the link, they were confused about a flood of useless information (commercials). The authors understood that this was a spam message, but this might not be the case for a person who is predisposed to psychosis and, in addition, in a stressful psychosocial situation.So from this ill-defined, bizarre and staged interaction with a test person, the authors concluded that “Twitter might combine several aspects that could induce or further aggravate psychosis.” In a presumably peer-reviewed publication.3This is preposterous. Hopefully we will not see “Twitter causes psychosis” headlines any time soon. Vaughan should have the last Tweet here:How did this get published? "Twitter may have a high potential to induce psychosis in predisposed users" http://t.co/uHCcuxFB6S via @DrShock— Vaughan Bell (@vaughanbell) July 31, 2014Further ReadingReturning to the title of the post, here's more on Twitter and cultural artifacts:Twitter as a Cultural Artifact Tools for Tech Thinking: McLuhan on TwitterFootnotes1 However, Bell et al. (2008) showed that individuals with delusions do not always have anomalous perceptual experiences.2 I imagine “several hours a day” could apply to many individuals without a formal diagnosis of mental illness. I will not deny that Twitter and other forms of social media can have an addictive quality for some people, but the “Twitter addiction” construct is not very useful.3 Can I put this blog post on my CV?? Here we learn about academic publishing in psychiatry and the propensity to categorize.ReferenceKalbitzer J, Mell T, Bermpohl F, Rapp MA, & Heinz A (2014). Twitter Psychosis: A Rare Variation or a Distinct Syndrome? The Journal of nervous and mental disease, 202 (8) PMID: 25075647

... Read more »

Kalbitzer J, Mell T, Bermpohl F, Rapp MA, & Heinz A. (2014) Twitter Psychosis: A Rare Variation or a Distinct Syndrome?. The Journal of nervous and mental disease, 202(8), 623. PMID: 25075647  

  • July 10, 2014
  • 07:17 AM
  • 493 views

Can a Failed Schizophrenia Drug Prevent PTSD?

by The Neurocritic in The Neurocritic

In the 2000s, enthusiasm was high that a novel class of drugs would reach the market as blockbuster treatments for psychiatric disorders. These drugs act on receptors for a group of neuropeptides known as tachykinins (or neurokinins). These peptides — substance P (SP), neurokinin A (NkA), and neurokinin B (NkB) — function as neurotransmitters or neuromodulators in the central nervous system, but are quite different from the usual monoamines targeted by current psychotropic medications prescribed for schizophrenia, depression, and other mental illnesses.The tachykinin receptors (NK1, NK2, NK3) have varying affinities for the different peptides, being greatest for SP, NkA, and NkB respectively. A series of clinical trials with NK1 antagonist compounds (i.e., SP blockers) was conducted as potential treatments for major depression, generalized anxiety disorder, alcohol craving, and post-traumatic stress disorder (PTSD). Substance P is released during times of increased stress and localized in brain regions implicated in the stress response (Ebner et al., 2009), so the idea was that dampening the effects of SP would lead to symptom amelioration in these disorders.  However, except for some mildly promising results in stressed alcoholics, the trials were disappointing in patients with generalized anxiety and PTSD. Results were mixed in major depression. But those trials, with a GSK compound called orvepitant, were terminated to due serious adverse events (seizures) in several patients.In contrast, the most promising target for schizophrenia seemed to be the neurokinin 3 (NK3) receptor. This was because of prominent expression on the midbrain dopamine (DA) cells implicated in the pathophysiology of schizophrenia, and because selective NK3 antagonists can block NkB-induced excitation of dopamine neurons (Spooren et al., 2005). The original “typical” antipsychotic medications are DA antagonists, which can have untoward side effects with chronic use. Because NK3 antagonists lack the major extrapyramidal and metabolic side effects of typical and atypical antipsychotics, they were heralded as “the next generation of antipsychotics” in 2005. How well have they fared since then?(1) The NK3 antagonist osanetant was under development by Sanofi-Synthélabo as a potential treatment for schizophrenia:In October 1999, Lehman Brothers predicted that the probability of the product reaching the market was 10%, with a possible launch in 2003 and potential peak sales of US $200 million in 2011.However, Sanofi-Aventis stopped any further development of osanetant in 2005.(2) The NK3 antagonist talnetant was under development by GlaxoSmithKline, with several clinical trials conducted between 2002 and 2005. But it too was discontinued (in 2007).In other words, these drugs have not lived up to their original promise as novel treatments for schizophrenia.“Repurposing” of Drugs“We should continue to repurpose treatments and to recognise the role of serendipity,” said Geddes and Miklowitz (2013) in a recent review on new treatments for bipolar disorder. Although the article did not hint at any impending pharmacological breakthroughs, the idea that existing drugs can find new indications is especially pertinent in this era of shrinking investment in neuro/psych drug development. Sometimes the serendipity and repurposing comes from mechanistic preclinical studies that can then be retranslated back to the clinic. Jumping ahead to that possibility, a press release from Emory declares:Potential drug target for PTSD preventionScientists at Yerkes National Primate Research Center, Emory University have identified a drug that appears to make memories of fearsome events less durable in mice.The finding may accelerate the development of treatments for preventing PTSD. The drug, called osanetant, targets a distinct group of brain cells in a region of the brain that controls the formation and consolidation of fear memories.. . .“Potentially, drugs that act on this group of cells could be used to block fear memory consolidation shortly after exposure to a trauma, which would aid in preventing PTSD,” says Kerry Ressler, MD, PhD, professor of psychiatry and behavioral sciences... “PTSD is unique among psychiatric disorders in that we know when it starts – at the time of the trauma. Finding ways to prevent its development in the first place – in the emergency department or the battlefield - is an important and exciting avenue of research in this area.”NkB and the Consolidation of Fear Memories  A new study in mice found that osanetant could block the consolidation of fear memories when administered within a narrow time window (Andero et al., 2014):Notably, when osanetant is dosed from 30 min before auditory FC [fear conditioning] up to 1 hr after training, it does not affect fear acquisition but impairs fear memory consolidation as shown by decreased freezing in the fear expression test.  Furthermore, mice previously traumatized by 2 hours of immobilization (a rodent model of PTSD-like behaviors that include impaired fear extinction) also showed reductions in fear memory consolidation when given osanetant (IMO-Osa), compared to placebo (IMO-Veh).... Read more »

  • June 1, 2014
  • 07:59 AM
  • 512 views

Feeling Mighty Unreal: Derealization in Kleine-Levin Syndrome

by The Neurocritic in The Neurocritic

I went on this trip once, back to my hometown after a long absence. Have you ever felt that your surroundings seem odd and distant, and that you're completely detached from them? That the things and places around you aren't real? This can happen to me, on occasion.It did on this trip, perhaps because I've dreamed about those places so many times that the real places and the dream places are blurred in memory.Of course time marches on. The stores in the strip mall have changed, and you go to Starbucks with your father. But sometimes new and surprising things appear in the landscape.Or maybe old and unexpected things pop up in the background, renewing a long-standing confusion between rural and suburban.These nostalgic travel vignettes illustrate the phenomenon of derealization, a subjective alteration in one's perception or experience of the outside world. The pervasive unreality of the external environment is a key feature, along with emotional blunting. The world loses its vividness, coloring, and tone. Some even report seeing things as if they're looking through a fog or a haze. Or a pane of blurry glass.Derealization is often (but not always) associated with depersonalization, a feeling of detachment from oneself, as if you yourself are unreal or even outside your body. Both of these phenomena can be mild and transient, or the symptoms can be chronic and disturbing in Depersonalization Disorder, which is considered a dissociative disorder.Not surprisingly, these dissociative states can be induced by drugs such as ketamine (a dissociative anesthetic) and hallucinogens (e.g., LSD, psilocybin). The symptoms can also be induced by stress and anxiety, or by trauma, or by sleep deprivation. Not all instances of derealization and depersonalization qualify as a disorder, however.The DSM-5 diagnostic criteria for Depersonalization/Derealization Disorder are as follows:A. An individual consistently has a feeling of both or either depersonalization or derealization. Depersonalization: Experiences of unreality, detachment, or being an outside observer with respect to one's thoughts, feelings, sensations, body, or actions (e.g.,perceptual alterations, distorted sense of time, unreal or absent self, emotional and/or physical numbing.)" Derealization: "Experiences of unreality or detachment with respect to surroundings (e.g., individuals or objects are experienced as unreal, dreamlike, foggy, lifeless, or visually distorted." B. "During the depersonalization or derealization experiences, reality testing remains intact." C. "The disturbance is not attributable to the physiological effects of a substance (e.g., a drug of abuse, medication or other medical condition (e.g., seizures)." D. "The disturbance is not better explained by another mental disorder."What other mental disorders can manifest as derealization (included as one of a core set of symptoms)? Among the most curious of these is an unusual neurological disorder called Kleine-Levin syndrome (KLS).Kleine-Levin SyndromeImagine sleeping 20 hours a days for days end, with your limited waking hours spent confused, disoriented, cognitively impaired, and voraciously hungry. Sometimes referred to as “Sleeping Beauty” syndrome in the media, KLS is a very rare sleep disorder (1-2 cases per million) characterized by intermittent bouts of hypersomnia (Arnulf et al., 2012). Other symptoms can include hyperphagia (compulsive overeating), hypersexuality, apathy, behavioral disturbances, depression, delusions, and derealization.1Considered a relapsing/remitting disease that typically onsets during adolescence, there is no known cause, no objective laboratory findings, and no cure. In the review by Arnulf et al. (2012), episodes lasted 10-12 days on average, followed by almost 6 months of normal sleep, cognition, and behavior. The disease can resolve spontaneously once the patient reaches their 30s. Those with childhood or adult onset can show a different disease course.The review suggested that confusion, apathy, and/or derealization are the best diagnostic indicators, when coupled with recurrent hypersomnia.The Phenomenology of Derealization in KLSSince derealization is such a prominent symptom of KLS, Arnulf et al. (2012) provided examples reported by patients during Kleine-Levin episodes:Patients feel as though they are in a dream or a bubbleThey claim sight, sound, smell, taste, and perception of cold, hot, and pain feel wrongThe environment feels flat and two-dimensionalIn the shower, patients might see the water flowing on their bodies, but not feel its temperaturePatients who injure themselves might not understand when or how the injury happened or that it has happened at allActions do not have consequencesPatients might do something to test for a normal action, such as breaking an object (eg, a cup)Patients might ask whether they are dead or aliveAre there any changes in brain activity during symptomatic periods in KLS? A Paris-based research group led by Dr. Isabelle Arnulf recently reported on a functional imaging study in 41 asymptomatic patients (Kas et al., 2014), 11 of whom were also scanned during an episode. The authors used SPECT (single photon emission computed tomography) to measure blood perfusion in the brain. SPECT is a relatively inexpensive... Read more »

  • May 26, 2014
  • 04:41 PM
  • 410 views

Let's Face It: Publishing Weak Data on Face Processing in Pedophiles Is Pointless

by The Neurocritic in The Neurocritic

Modified from Fig. 2 (Ponseti et al., 2014). Brain areas that selectively respond to faces of the sexually preferred age. Just when we thought it was safe to bury the dead salmon of uncorrected statistical thresholds in neuroimaging studies, a new and incendiary study on face processing in pedophiles emerges (Ponseti et al., 2014). Even if it were surprising and informative that “Human face processing is tuned to sexual age preferences” (Ponseti et al., 2014), the fMRI data analyses failed to correct for multiple statistical comparisons, which is standard in the field. Therefore, by using a very liberal statistical threshold of p < 0.01 uncorrected for the large number of tests, the results could be a series of untrustworthy false positives.1 Importantly, the basic pattern of findings, that visual parts of the brain are more responsive to pictures of faces that fall within the broad category of “sexual attractiveness”, does not tell us why someone has a particular sexual orientation, nor does it tell us if this preference is “hard wired” (i.e., innate).The participants in the study were 56 men, 11 of whom were heterosexual pedophiles (prefer young girls), 13 homosexual pedophiles (prefer young boys), 18 heterosexual teleiophiles (prefer adult women) and 14 homosexual teleiophiles (prefer adult men). These are small groups, but to complicate matters, half of the pedophiles had committed sexual offenses and the other half had not. This is a critical difference, as one might expect differences between men who could refrain from acting on their impulses and those who could not. Yet, activation in the dorsal striatum was interpreted as a potential indicator of “efforts in withholding actions”. Furthermore, the results presented here were part of a larger study that aimed to classify pedophiles solely on the basis of their brain responses to nude photos showing whole-body frontal views or genitals only (Ponseti et al., 2012).2 The authors claimed an astounding 95% accuracy in distinguishing between pedophiles and non-pedophiles.Overall, the participants viewed 14 different kinds of stimuli in these two papers, so you can see that the number of potential statistical comparisons is astronomical.The take-home message is that the participants' subjective attractiveness ratings of each face (completed after the fMRI study) were much more reliable at identifying their sexual preferences (p < 0.001) than the brain imaging data. Neuroscientists working with such controversial populations need to be especially careful in analyzing their data, and aware of how their work may be used in a broader social context.Footnotes1 Thanks to commenter Com__Truise on reddit who alerted me to this paper and who noted:Published cognitive Neuroscientist here. This should not have gotten through peer review. The fMRI analysis is invalid. The study uses an uncorrected threshold (not corrected for multiple comparisons) of p< 0.01 (considered very liberal!) and all the results are probably false positives. This is not to say that the theory is not correct - however, the statistics are invalid and meaningless. You can read more here: http://neurocritic.blogspot.de/2012/03/how-much-of-neuroimaging-literature.html http://www.danielbor.com/dilemma-weak-neuroimaging/Here is another cautionary note from Professor James Ogloff, Director of the Centre for Forensic Behavioural Science and Legal Studies at Swinburne University of Technology, Victoria.2 Critical and ethical evaluation of this study is beyond the scope of the present post.ReferencesPonseti J, Granert O, Jansen O, Wolff S, Beier K, Neutze J, Deuschl G, Mehdorn H, Siebner H, Bosinski H. (2012). Assessment of pedophilia using hemodynamic brainresponse to sexual stimuli. Arch Gen Psychiatry 69(2):187-94.Ponseti, J., Granert, O., van Eimeren, T., Jansen, O., Wolff, S., Beier, K., Deuschl, G., Bosinski, H., & Siebner, H. (2014). Human face processing is tuned to sexual age preferences Biology Letters, 10 (5), 20140200-20140200 DOI: 10.1098/rsbl.2014.0200

... Read more »

Ponseti, J., Granert, O., van Eimeren, T., Jansen, O., Wolff, S., Beier, K., Deuschl, G., Bosinski, H., & Siebner, H. (2014) Human face processing is tuned to sexual age preferences. Biology Letters, 10(5), 20140200-20140200. DOI: 10.1098/rsbl.2014.0200  

  • May 18, 2014
  • 10:44 PM
  • 539 views

Does Gamma tACS Really Induce Lucid Dreaming?

by The Neurocritic in The Neurocritic

Dream scene from InceptionDIY brain stimulation geeks were supercharged last week by the finding that dream awareness could be enhanced by transcranial alternating current stimulation (tACS)1 at frequencies of 25 and 40 Hz (Voss et al., 2014). Headlines were abuzz with zingers like Brain Zaps Can Trigger Lucid Dreams and A Jolt to the Brain Triggers Lucid Dreams and Brain Zap Could Help You Control Your Dreams. Visualize all the incipient Kickstarter campaigns ready to capitalize on the lucid dreaming market...Except did the stimulation really induce lucid dreaming? The only critical evaluation of this claim (that I'm aware of) came from Christian Jarrett in his post, Psychologists Give People Control of Their Dreams Using Brain Stimulation. Really? He closely examined the Lucidity and Consciousness in Dreams scale (LuCiD) used by the experimenters (Voss et al., 2013) and saw that the participants' self-ratings weren't actually indicative of lucid dreaming.Although the scores on some LuCiD factors were indeed significantly higher after frontal stimulation at 25 Hz (beta, actually) and/or 40 Hz (gamma) frequencies (relative to sham or other frequencies), this did not mean the dreams were technically “lucid”.Fig. 3 (Voss et al., 2014). Mean scores for three LuCiD factors [NOTE: each self-rating scale goes from 0: strongly disagree to 5: strongly agree].The LuCiD scale consists of 28 statements, each followed by a 6-point rating scale (0: strongly disagree, 5: strongly agree). Insight is the awareness that one is currently dreaming, Dissociation is taking a third-person perspective, and Control is control over the dream plot.Of the eight LuCiD factors, Insight is the single most important criterion for lucid dreaming (Voss et al., 2013).  However, the mean Insight score in the current study is well below that reported for lucid dreams in the earlier study used to construct the scale. modified from Fig. 5 (Voss et al., 2013). Mean scores for LuCiD scales for non-lucid vs. lucid dream reports [NOTE: each scale goes from 0: strongly disagree to 5: strongly agree. The yellow bars indicate means after 25 or 40 Hz tACS in Voss et al. 2014].In other words, the 25 Hz and 40 Hz brain stimulation significantly increased Insight and Control, but not to the levels reported in lucid dreams (according the authors' previous definition). The definition in the present study was less stringent: “Lucidity was assumed when subjects reported elevated ratings (>mean + 2 s.e.) on either or both of the LuCiD scale factors insight and dissociation.”Nonetheless, induced gamma band oscillations did result in a heightened perception of self-awareness during REM sleep, in particular the ability to view the ongoing dream activities as a detached observer. But don't waste your money investing in the latest neurocrap that claims to induce lucid dreaming... As Seen On Nature Neuroscience.Further ReadingPsychologists Give People Control of Their Dreams Using Brain Stimulation. Really? Neurocrap Funded by the Masses: NeuroOn and No More WoofFootnote1 Note that tACS is different from the usual DIY tDCS (transcranial direct current stimulation). tACS is thought to modulate and entrain brain oscillations in a frequency-specific manner, although others are much more cautious in their interpretation.ReferencesVoss, U., Holzmann, R., Hobson, A., Paulus, W., Koppehele-Gossel, J., Klimke, A., & Nitsche, M. (2014). Induction of self awareness in dreams through frontal low current stimulation of gamma activity. Nature Neuroscience DOI: 10.1038/nn.3719Voss, U., Schermelleh-Engel, K., Windt, J., Frenzel, C., & Hobson, A. (2013). Measuring consciousness in dreams: The lucidity and consciousness in dreams scale. Consciousness and Cognition, 22 (1), 8-21 DOI: 10.1016/j.concog.2012.11.001... Read more »

Voss, U., Holzmann, R., Hobson, A., Paulus, W., Koppehele-Gossel, J., Klimke, A., & Nitsche, M. (2014) Induction of self awareness in dreams through frontal low current stimulation of gamma activity. Nature Neuroscience. DOI: 10.1038/nn.3719  

Voss, U., Schermelleh-Engel, K., Windt, J., Frenzel, C., & Hobson, A. (2013) Measuring consciousness in dreams: The lucidity and consciousness in dreams scale. Consciousness and Cognition, 22(1), 8-21. DOI: 10.1016/j.concog.2012.11.001  

  • May 12, 2014
  • 12:59 AM
  • 485 views

The Seductive Allure of Spintronics™ Neuroimaging mock mind reading scanner

by The Neurocritic in The Neurocritic

Spintronics™ Neuroimaging mock scanner used in experiment by Ali, Lifshitz & Raz (2014)A new study has tricked undergraduates into believing that “Spintronics,” a whimsical new “mind reading” technology constructed using an old hair dryer, was able to accurately read their thoughts  (Ali et al., 2014). This held even for students enrolled in a class on the pros and cons of neuroimaging methods taught by the senior author (McGill Professor Amir Raz). The paper coined the phrase “empirical neuroenchantment” to explain why a highly dubious experimental setup would lead to such a deficit in critical thinking.The participants were 58 McGill students, 26 of whom were upper-level psychology, neuroscience or cognitive science majors enrolled in a skeptical neuroimaging course that warned them about overblown claims. Furthermore, the professor had lectured about his experience as a “mind reading” magician who fools audiences into believing he has paranormal abilities: The professor in the course (AR) repeatedly harped on the present impossibility of mind-reading and tested this information on the final examination verifying that students internalized these points. He also spoke about his background as a mentalist – a magician who performs psychological tricks, such as mind-reading – and led class demonstrations to exemplify why the public often misinterprets these effects and takes them for genuine paranormal powers.And in fact, sleight of hand was used to further the ruse that the hair dryer contraption was able to read their minds. Subjects were told they were participating in a study on “The Neural Correlates of Thought” (amusingly described in the Methods) where they......encountered a rickety mock brain scanner built from discarded medical scraps from the 1960s and adorned with an old-fashioned hair-dryer dome [shown in the figure above]. We told participants that scientists at the Montreal Neurological Institute had developed new experimental technology to decode resting state brain activity and read the human mind. We labeled the technology Spintronics and displayed warning signs around the scanning equipment similar to those found in MRI environments. The participants were told to think of a two-digit number, a three-digit number, a color, and a country and to write down their answers on a piece of paper. The first author cleverly pocketed their answers, then participants were told to think about their choices while their brains were faux scanned. During this time, “a pre-recorded video displayed rotating three-dimensional brain slices with accompanying scanner-like audio, lending the appearance of collecting and analyzing patterns of brain activity.”Afterwards, the subjects were shown the results of the scan. Lo and behold, the machine could read their minds! A brief questionnaire rated their level of belief on a 0 to 6 point scale (from “not at all” to “extremely”).How did the informed students fare against the non-Neuro controls? The Neuro students found the results significantly less believable (3.96 vs. 4.96), and they rated themselves as more skeptical (3.42 vs, 1.94) than the controls. However, they were not immune to ascribing even greater mind-reading capabilities to Spintronics© after being shown that the contraption successfully “read” their thoughts.Can we conclude from the present study that neuroimaging is special in the realm of scientific technology in its ability to dupe even those who should know better? No, and the authors acknowledge as much. We don't know whether the dual phenomena of deferring to experts in a professional laboratory, and overriding scientific knowledge on the basis of one compelling experience, would occur in other fields of study. We could potentially see meteoroenchantment or roboenchantment in the realms of weather prediction and artificial intelligence, respectively.Nonetheless, the Spintronics study ups the ante in the Brainwashed sweepstakes on The Seductive Appeal of Mindless Neuroscience, which maintains that the media can easily dupe an unsuspecting public into believing nearly anything couched in the guise of neuroscience.The Seductive Allure of Neuroscience ExplanationsRemember the “seductive allure” of colorful brain images? This was the idea that college undergraduates could be swayed to believe implausible explanations for psychological phenomena if accompanied by brain images (McCabe & Castell, 2008). For example, a fictitious news article explaining that ‘Watching TV is Related to Math Ability’ — since watching television and completing math problems both lead to activation in the temporal lobe, watching TV will of course improve math skills — was more believable when accompanied by a brain scan than by a bar graph.The Not So Seductive Allure of Colorful Brain ImagesHowever, this finding was not replicated in more recent studies (Farah & Hook, 2013; Michael et al., 2013; Schweitzer et al., 2013). Is this because participants in psychology experiments have gotten more sophisticated in the past 5 years? 1 Or is it because the results weren't that strong to begin with?It'll be much more difficult for other labs to replicate the present results of Ali and colleagues (2014), namely because (1) most Principal Investigators aren't magicians, and (2) recruiting 1,068 participants via the online marketplace Mechanical Turk just won't work here...Further ReadingAre Brain Scans Really So Persuasive?The Not So Seductive Allure of Colorful Brain ImagesFootnote1 More sophisticated, say, from reading critical neuroscience blogs?  Or much more likely, reading critical coverage in places like the New York Times? Or am I living in a bubble which assumes way too much public interest in these topics?References... Read more »

Sabrina Ali, Michael Lifshitz, and Amir Raz. (2014) Empirical Neuroenchantment: From Reading Minds to Thinking Critically. Frontiers in Human Neuroscience. info:/10.3389/fnhum.2014.00357

  • May 4, 2014
  • 11:31 PM
  • 553 views

Not tonight dear, I had zymosan A injected into my hind paw

by The Neurocritic in The Neurocritic

We now have definitive proof that the propensity of womankind to postpone sex due to a headache is of evolutionary origin! This annoying habit has been traced back directly to a strain of ovariectomized CD-1® IGS mice supplied by Charles River.In a naturalistic design that precisely mimics the mating habits of humans, sexual receptivity was induced in the female mice with subcutaneous injections of estradiol. Then the female mice and their preferred male partners were injected in various body parts with two different compounds to induce inflammatory pain. Lo and behold, the mounting behaviors of male mice were hardly deterred by these painful treatments, but the females declined sexual congress and hid from the males.“These findings suggest that the well known context sensitivity of the human female libido can be explained by evolutionary rather than sociocultural factors, as female mice can be similarly affected,” concluded the authors (Farmer et al., 2014). Of Mice and WomenThis study was published in the Journal of Neuroscience, and the strongly worded quote above is how the authors chose to conclude their abstract. They go to great lengths to “prove” that the loss of libido was due to lack of sexual motivation in the female mice, rather than a direct consequence of pain. The authors also stretch the clinical applicability (and evolutionary validity) of their work a bit beyond belief, in my view. Why? Perhaps it's because promoting a viable animal model of low sexual motivation in women will ultimately serve drug development purposes (Farmer et al., 2014):The link between pain and sexual motivation is evident in human sexual relations. The widespread aphorism, “Not tonight, dear, I have a headache” refers to a lack of sexual motivation due to pain. No clinical data exist on the direct impact of pain on sexual motivation, yet high prevalence of reduced sexual desire in chronic pain populations (Basson et al., 2010; Fine, 2011) suggest that pain may adversely influence sexual motivation. It's not actually true that “No clinical data exist on the direct impact of pain on sexual motivation...” (as we'll see later), but first let's take a look at the actual study.1 Pairs of vigorously mating mice were assigned to either male “open field” or female “paced mating” situations, which mimics their respective natural preferences. One member of each pair was injected with a pain-inducing inflammatory compound (zymosan A or λ-carrageenan) into their genital or nongenital (hind paw, tail, cheek) regions. Sexual behavior was measured by mounting in open field (for males) or in paced mating (for females) conditions. In the latter situation, the smaller females could run into their safe room to avoid the males.  The results generally indicated that the females hid from the males when injected with painful substances (Fig. 1A), but the males were not bothered (based on the total number of mounts) with the exception of a non-significant decline when the penis was injected with zymosan (Fig. 1C). Fig. 1 (modified from Farmer et al., 2014). Reduction of sexual behavior in female but not male mice by inflammatory pain. A. Decreased mounting behavior in a paced mating paradigm when female mice receive zymosan (ZYM) or carrageenan (CARR) injections to the vulva, hind paw, tail, or cheek, compared with uninjected female mice (No Inj.). Bars represent mean ± SEM mounts with (shaded) or without (open) intromissions. C. No decreases in mounting behavior in an open field when male mice are treated in a similar fashion. *p < 0.05, **p < 0.01 compared with vehicle [NOTE: using uncorrected t-tests].[As an aside, one could imagine that the mating behavior of human males might be more greatly affected by penile injections of any sort, and by inflammogen injections into the hand or cheek than what we're seeing here in the male mice.]In addition to mounts, Table 1 in Farmer et al. lists 8 other behaviors × 2 treatments. Of these 16 comparisons to the vehicle control, five indicated reductions and one indicated an increase in activity of some sort, meaning that certain behaviors (number of ejaculations, latency to first mount, number of crossings to the male side, latency to return to the male side) were unaffected by one or both treatments [NOTE: using Dunnett's post-hoc comparisons that do correct for multiple comparisons]. Make of that what you will.However, the pained females did indeed spend significantly less time in their male partner's side of the apparatus.Next, some of the pained female mice were given pregabalin (Lyrica), an anticonvulsant drug used to treat neuropathic pain (kindly provided by one of the study sponsors, Pfizer). You'll be comforted to hear that analgesic administration and concomitant pain relief will lead to increased sexual activity in injured female mice (and probably in injured creatures of any sort).On the other hand, administration of the non-selective dopamine agonist apomorphine, which is “pro-sexual” in mice but strongly emetic in humans, is unlikely to be welcomed by women as an antidote to a pain-quashed libido. Apomorphine (not related to morphine) is sometimes given to Parkinson's patients, but always in conjunction with other drugs to prevent vomiting. In fact, apomorphine is so unpleasant to humans that it has been used for aversion therapy in gay people (an “anti-sexual” agent if there ever was one).Anyway, it was interesting to learn that rodents do not vomit, and that apomorphine reverses the pain-induced reduction in sexual behavior exhibited by female mice. This was interpreted to mean that sexual motivation was enhanced. But since apomorphine also increases locomotion in rodents, I wonder if other appetitive behaviors were enhanced as well.The other pro-sexual drug used in the current study was melanotan-II, which is converted to the melanocortin-3/melanocortin-4 receptor agonist, bremelanotide (formerly known as PT-141, developed by Palatin Technologies). Intranasal bremelanotide underwent clinical testing to treat sexual dysfunction in humans (male and female), but trials were halted in 2008 because of untoward elevations of blood pressure in some individuals.When given to injured female mice, melanotan-II reversed the reduction in sexual behavior. Unlike apomorphine, however, melanotan-II: (1) does not increase locomotion, and (2) is undergoing further testing in humans via a subcutaneous route of administration that doesn't increase blood pressure. Moreover, the authors are highly aware of their potential animal model:Thus, the reversal of pain-induced reductions in female-paced sexual behavior likely re... Read more »

Ambler N, Williams AC, Hill P, Gunary R, & Cratchley G. (2001) Sexual difficulties of chronic pain patients. Clinical Journal of Pain, 17(2), 138-45. PMID: 11444715  

Farmer, M., Leja, A., Foxen-Craft, E., Chan, L., MacIntyre, L., Niaki, T., Chen, M., Mapplebeck, J., Tabry, V., Topham, L.... (2014) Pain Reduces Sexual Motivation in Female But Not Male Mice. Journal of Neuroscience, 34(17), 5747-5753. DOI: 10.1523/JNEUROSCI.5337-13.2014  

  • April 21, 2014
  • 04:08 AM
  • 407 views

The Life and Brain of H.M.

by The Neurocritic in The Neurocritic

Dr. Suzanne Corkin on H.M.One of the highlights of this year's Cognitive Neuroscience Society Meeting was Dr. Corkin's keynote address about Henry Molaison the person and his lasting contribution to the neurobiology of memory. In her more timely recap of the meeting, Daisy Yuhas included this moving quote from H.M., who could not remember meeting Corkin even after decades of testing:Corkin also discussed the man behind the initials, describing his gentle and remarkably upbeat disposition, given that he was repeatedly confronting a confusing, context-free present. Her talk included a poignant and powerful audio recording of Corkin and H.M. chatting in 1992. In the excerpt, H.M. professes to “not mind” all of the tests and studies, saying simply, “I figure what’s wrong about me helps you help others.”Henry Molaison died on December 6, 2008. Corkin described the post-mortem handling of H.M.'s brain, which was first scanned before autopsy. Then the brain was removed and preserved in formaldehyde for 10 weeks, and later scanned in a 7T magnet (see Annese et al., 2014 for details).1H.M.'s brain flew Jet BlueH.M.'s brain was transported across the country, where it underwent lengthy processing prior to sectioning into 2,401 slices on a heavy duty frozen microtome (Annese et al., 2014).2 This event was webcast live at the Brain Observatory, which she said was “like watching paint dry.”  I beg to differ.  I thought the live coverage was like the Stanley Cup of Neuroscience, as mesmerizing as watching the Zamboni clean the ice at a hockey game. At the time, I noted that “H.M.'s ventricles are quite enlarged. Then again, he was 82 when he died (so that's not unexpected).”H.M. was, in fact, demented when he died. His cerebellum was severely atrophied after years on the anticonvulsant drug Dilantin. Cerebellar dysfunction on its own can be associated with explicit memory deficits (Baillieux et al., 2008). And finally, his amygdalae were gone bilaterally (Annese et al., 2014):  The excision of the anterior hippocampus, together with the bulk of the amygdala, may explain H.M.’s dampened expression of emotions, poor motivation and lack of initiative19. The fact that he was impaired in reporting internal states such as pain, hunger and thirst and his apparent lack of initiative was ascribed to the almost complete removal of the amygdala...Dr. Corkin has long said that “H.M.'s amnesia was pure.” But these additional issues, along with some reports that his language production and visual cognition were not entirely normal, raise questions about his status as the definitive hippocampal amnesic. Nonetheless, there's no denying the immense importance of what H.M. so generously taught us about memory. “It’s a funny thing,” he said, “you live and learn. I’m living and you’re learning.” Footnotes1 H.M's brain was......fixed in standard buffered formalin (4% formaldehyde; postmortem interval of ∼14 h). The brain was fixed for 10 weeks at 4 °C with three changes of fixative during that time; it was suspended upside down, hung by the basilar artery. When the tissue was firm enough, the brain was immersed in fixative laying on a cushion of hydrophilic cotton. Subsequently, multiple series of MRI scans of the fixed specimen were acquired in 3T and 7T scanners.2 Annese et al., 2014:The results of our examination are based on 2,401 digital anatomical images and selected corresponding histological sections that were collected at an interval of 70 μm over the course of an uninterrupted 53-hour procedure. The series of digital images of the block’s surface was obtained using a digital camera mounted directly above the microtome stage. Volumetric reconstruction from these images was the basis for subsequent visualization and 3D measurements along arbitrary planes. The dissection of the brain was video-recorded and streamed live on the web to permit scientific scrutiny and to foster public engagement in the study.

... Read more »

Annese, J., Schenker-Ahmed, N., Bartsch, H., Maechler, P., Sheh, C., Thomas, N., Kayano, J., Ghatan, A., Bresler, N., Frosch, M.... (2014) Postmortem examination of patient H.M.’s brain based on histological sectioning and digital 3D reconstruction. Nature Communications. DOI: 10.1038/ncomms4122  

  • March 30, 2014
  • 07:05 PM
  • 498 views

Contest to Reduce Implicit Racial Bias Shows Empathy and Perspective-Taking Don't Work

by The Neurocritic in The Neurocritic

NCAA college basketball isn't the only hot competition involving a team at the University of Virginia.  UVa Psychology Professor Brian Nosek is one of three founders of Project Implicit, a collaborative nonprofit dedicated to the study of implicit social cognition — how unconscious thoughts and feelings can influence attitudes and behavior.Prof Nosek is also heavily involved in the Open Science and Replication movements. Along with graduate student Calvin Lai, he led a multinational group of 22 other researchers in a competition to see who could devise the best intervention to reduce racial bias scores on a widely administered implicit test, the race IAT (Lai et al, 2014).The Implicit Association Test (IAT) is a mainstay of social psychology research that assesses implicit (unconscious) attitudes towards outgroups (based on race, sexual orientation, body size, age, etc.), stereotypes (e.g., men are in science, women are in arts/humanities), opposing ideologies (e.g, Democrat vs. Republican), and a staggering array of other binary preferences (Classical-Hip hop IAT, Astrology-Science, Britney Spears-50 cent, Boxers-Briefs, Harry Potter-Lord of the Rings and on and on).  Or does it... ? There have been some vocal critics of the IAT over the years who have questioned what the test actually measures. I'll return to this point later, but for now let's look at the impressive aspects of the new paper.Performance on the Black-White IAT was compared after 17 brief interventions aimed at changing pro-White bias (and a "faking" condition) relative to a control condition of no pre-test intervention. Participants were over 20,000 non-Black individuals registered at the Project Implicit website, randomized into groups of 300-400. Most of the interventions were tested in four different studies. The contest rules allowed changes to the design between studies. The goal was to lower pro-White bias scores to the point of no preference between Blacks and Whites.In the IAT, participants classify faces as Black or White and words as good or bad. Some blocks contain only faces or only words. The two critical conditions are shown in the figure above. The stimulus-response mappings are rotated in different blocks to either reinforce stereotypes (bottom) or go against stereotype (top). In the Stereotype condition, participants press the same key when they see White faces or “good” words. They press the other key when they see Black faces or “bad” words. Most White participants (and many African Americans) show a pro-White “preference” or bias, with faster responses when White/good and Black/bad are mapped to the same key (than vice versa).Conversely, in the Against Stereotype condition, Black faces and positive words are mapped to one key, and White faces and negative words are mapped to the other key. In essence, this induces a response conflict similar to that seen in many classic cognitive psychology tasks such as the color-word Stroop task, e.g. BLUE (say “red”) and the Eriksen flanker task, e.g. ← ← → ← ← (press right button). Slower response times in the IAT conflict conditions has been interpreted as an implicit bias against Black people (Greenwald et al., 2009), although one could argue that executive control abilities play a role here, just as they do in the Stroop task (Siegel et al, 2012).1The InterventionsThe interventions were divided into six different descriptive categories. Although the descriptions were based on existing hypotheses in the literature, they do not imply the operation of any specific psychological mechanism. The interventions had to be brief in length (5 min or less), yield interpretable scores, and have a low attrition rate. See Appendix 1 at the end of this post for a detailed list.(1) Engage with others’ perspectives: imagine the thoughts, feelings, and actions of Black individuals (Interventions #1–3).(2) Exposure to counterstereotypical exemplars: assigned to fictional groups with positive Black ingroup members and/or negative White outgroup members; OR think about famous Black people and infamous White people (Interventions #4–8).(3) Appeals to egalitarian values: activate egalitarian goals (e.g., thinking about failures to be objective or egalitarian); OR think about multicultural values (Interventions #9–13).(4) Evaluative conditioning: strengthen counterstereotypical associations by pairing White faces with Bad words and Black faces with Good words (Interventions #14 and #15).(5) Inducing emotion: the positive emotion of elevation (Intervention #16).(6) Intentional strategies to overcome biases: provide strategies to override or suppress the influence of automatic biases, rather than trying to shift associations directly (Interventions #17 and #18).To reveal my own a priori biases regarding these descriptive categories, I favor (6) Intentional strategies to overcome biases, which I have written about previously (in 2008). These were interventions #17 Using Implementation Intentions, and #18 Faking the IAT as proposed by Calvin K. Lai, the first author of the manuscript.Results indicated that nine of the interventions were effective, and nine were ineffective. The interventions that tried to change attitudes (Appeals to egalitarian values), increase empathy or perspective-taking (Engage with others’ perspectives), or elicit an elevated sense of morality (Inducing emotion - Haidt) were completely ineffective.I note here that the failed interventions all tried to challenge the racially biased attitudes and prejudice purportedly measured by the IAT. These interventions are below the red line in the figure below.- click on image for a larger view -Figure 1 (modified from Lai et al, 2014). Effectiveness of interventions on implicit racial preferences, organized from most effective to least effective. Cohen’s d = reduction in implicit preferences relative to control; White circles = the meta-analytic mean effect size; Black circles = individual study effect sizes; Lines = 95% confidence intervals around meta-analytic mean effect sizes. IAT = Implict Association Test; GNAT = go/no-go association task.Some of the most effective interventions showed variability across studies, because the parameters were altered between studies (which was allowed). Importantly, some of the interventions included multiple manipulations. The top three, Vivid Counters... Read more »

Lai CK, Marini M, Lehr SA, Cerruti C, Shin JE, Joy-Gaba JA, Ho AK, Teachman BA, Wojcik SP, Koleva SP.... (2014) Reducing Implicit Racial Preferences: I. A Comparative Investigation of 17 Interventions. Journal of experimental psychology. General. PMID: 24661055  

  • March 24, 2014
  • 12:21 AM
  • 512 views

Hippocampal Pathology in California Sea Lions with Domoic Acid-Induced Temporal Lobe Epilepsy

by The Neurocritic in The Neurocritic

In 1987, over 100 Canadians became ill after eating cultivated mussels from Prince Edward Island. Symptoms included the typical gastrointestinal issues, but serious neurological findings such as disorientation, confusion, and memory loss were also observed (Perl et al., 1990). In the worst cases, the patients developed seizures or went into coma. Three elderly people died. The cognitive changes were persistent, and had not resolved within a two year follow-up.The toxin was identified as domoic acid, which received the well-deserved moniker of Amnesiac Shellfish Poison. Domoic acid is a potent excitatory amino acid that activates kainate and AMPA receptors, the binding sites for the ubiquitous excitatory neurotransmitter glutamate. It acts as an excitotoxin by overstimulating these receptors, causing a flood of calcium ions into the cells. Particularly vulnerable are neurons in medial temporal lobe structures such as the amygdala and the hippocampus, which is critical for memory. Postmortem examination of four brains revealed hippocampal pathology that could account for the clinically significant anterograde amnesia seen in other (still living) patients (Teitelbaum et al., 1990). The pattern of neuronal loss was consistent with the damage observed in kainic acid animal models of epilepsy.Fig. 3 (modified from Teitelbaum et al., 1990).  Panel A: Section of Hippocampus from a Patient Who Died 24 Days after Mussel-Induced Intoxication, showing severe loss of neurons in all fields except CA2 (arrow), and tissue collapse is evident in part of field CA1 (double arrow).  Panel B: Control Subject.What was the source of the Amnesiac Shellfish Poison that had accumulated in the mussels? A "red tide" of phytoplankton created a harmful algal bloom that produced domoic acid, which accumulates not only in shellfish but also in fish such as anchovies and sardines. This is where the California sea lions make their noisy entrance... {click here to play mp3}Live Sea Lion Web Cam at Pier 39 in San Francisco.Domoic Acid Toxicity in California Sea LionsThe Marine Mammal Center in Sausalito, California rescues and rehabilitates sick, stranded, and malnourished marine mammals, including seals, sea lions, and cetaceans. An up-to-date list of their current patients is available here. They are the premiere institution for the diagnosis, treatment, and scientific study of domoic acid toxicity in California sea lions:The Marine Mammal Center was the first group to definitively diagnose DA posioning in marine mammals because of a large outbreak in California sea lions in 1998. In September 2004, the Center received a grant from the Oceans and Human Health Initiative to study the long term effects of domoic acid in sea lions. This project studied the impact of DA on health, survival, and reproduction. Part of this project focused on the neurological effects of DA. Effects were evaluated using magnetic resonance imaging (MRI), cognitive behavior tests (how the animal behaves), and histopathology (tissue samples from dead animals).Their website on the topic is highly recommended, and contains links to published papers such as Magnetic resonance imaging quality and volumes of brain structures from live and postmortem imaging of California sea lions with clinical signs of domoic acid toxicosis [PDF].Most recently, a team of researchers from Stanford University collaborated with the Marine Mammal Center to conduct a detailed neuropathological investigation of the brains of sea lions who suffered from seizures due to domoic acid toxicity (Buckmaster et al., 2014). Unfortunately, this is not an uncommon occurrence, since the current census of pinniped patients includes five sea lions diagnosed with acute domoic acid toxicity. In the chronic state, the animals can experience recurrent seizures, leading to a failure to thrive and poor prognosis. The authors hypothesize that the animals develop temporal lobe epilepsy, which can serve as an unfortunate accidental model of temporal lobe epilepsy in humans.The researchers examined the brains of 14 domoic acid-exposed (DA) animals and 9 control animals. Five of the affected sea lions were admitted in status epilepticus, a state of continual seizure that causes severe brain damage and even death. The study expanded on earlier work by using stereological methods to obtain an unbiased estimate of the total number of neurons in each hippocampus (left and right hemispheres).In control sea lions, Buckmaster and colleagues (2014) estimated that each hippocampus contains over 6 million neurons! For the comparative hippocampal anatomy aficionados, sea lions had a relatively small proportion of neurons in the dentate gyrus granule cell layer relative to other mammals (i.e., macaque monkeys, squirrel monkeys, dogs, rats, and mice), and the granule cell layer was thinner than in other species.Importantly, the authors observed significa... Read more »

Buckmaster, P., Wen, X., Toyoda, I., Gulland, F., & Van Bonn, W. (2014) Hippocampal neuropathology of domoic acid-induced epilepsy in California sea lions. . Journal of Comparative Neurology, 522(7), 1691-1706. DOI: 10.1002/cne.23509  

Perl, T., Bédard, L., Kosatsky, T., Hockin, J., Todd, E., & Remis, R. (1990) An Outbreak of Toxic Encephalopathy Caused by Eating Mussels Contaminated with Domoic Acid. New England Journal of Medicine, 322(25), 1775-1780. DOI: 10.1056/NEJM199006213222504  

Teitelbaum, J., Zatorre, R., Carpenter, S., Gendron, D., Evans, A., Gjedde, A., & Cashman, N. (1990) Neurologic Sequelae of Domoic Acid Intoxication Due to the Ingestion of Contaminated Mussels. New England Journal of Medicine, 322(25), 1781-1787. DOI: 10.1056/NEJM199006213222505  

  • March 5, 2014
  • 06:15 AM
  • 459 views

Warning about Ketamine in the American Journal of Psychiatry

by The Neurocritic in The Neurocritic

The dissociative anesthetic and ravey club drug ketamine has been hailed as a possible “miracle” cure for depression. In contrast to the delayed action of standard antidepressants such as SSRIs, the uplifting effects of Special K are noticeable within an hour. “Experimental Medication Kicks Depression in Hours Instead of Weeks,” says the National Institute of Mental Health. NIMH has been bullish on ketamine for years now. Prominent researchers Duman and Aghajanian called it the “the most important discovery in half a century” in a recent Science review.But in 2010, I pondered whether this use of ketamine was entirely positive:Drawbacks include the possibility of ketamine-induced psychosis (Javitt, 2010), limited duration of effectiveness (aan het Rot et al., 2010), potential long-term deleterious effects such as white matter abnormalities (Liao et al., 2010), and an inability to truly blind the ketamine condition due to obvious dissociative effects in many participants.Ketamine can also cause memory impairments, and abuse of the drug can result in severe bladder damage. There's even a model of schizophrenia based on antagonism of glutamate NMDA receptors, ketamine's main mechanism of action.Now, in the latest issue of the American Journal of Psychiatry, Dr. Alan F. Schatzberg of Stanford University School of Medicine has a commentary entitled, A Word to the Wise About Ketamine. He first acknowledges the excitement about acute ketamine for refractory depression, then raises several cautionary notes and warns:“This unbridled enthusiasm needs to be tempered by a more rational and guarded perspective.”He notes that the drug is administered off-label in free-standing private psychiatry clinics without regulation by the FDA. Some leading proponents have advocated for strictly inpatient use, but that cat is already out of the bag. Another potential issue is abuse liability.  The antidepressant effects of ketamine are short-lived (less than a week), which means that repeated infusions are required. The published literature suggests a relatively safe profile over two weeks in a hospital setting, but patients at commercial clinics are unlikely to be monitored as closely.The commentary also suggests that “We Need To Know More About the Mechanism of Action of the Mood-Elevating Effects” – but that is true of all drugs with antidepressant properties. The Slippery Ketamine SlopeIn response to the question, “Should Clinicians Prescribe Ketamine for Patients With Refractory Depression?” Dr. Schatzberg answers:Without more data on what ketamine can do clinically, except to produce brief euphoriant effects after acute administration, and knowing it can be a drug of abuse, it is difficult to argue that patients should receive an acute trial of ketamine for refractory depression. ... The recent ketamine studies are exciting, and they open up important avenues for investigation that should be supported; however, until we know more, clinicians should be wary about embarking on a slippery ketamine slope.However, in the midst of all this naysaying, it's important to note that Dr. Schatzberg has extensive ties to the pharaceutical and biotech industries. He receives consulting fees from 19 different companies and has equity in 16 different companies, including one for which he is a co-founder. Ketamine of course is not under patent and is cheap to purchase. Perhaps not coincidentally, he does not receive fees from AstraZeneca, which (until recently) was developing a “low-trapping” NMDA antagonist that does not cause the hallucinogenic effects of ketamine (AZD6765, aka lanicemine).In the past, I have suggested that short-term use for immediate relief of life-threatening symptoms (i.e. suicidal ideation) or end-of-life depression seem to be the best indications. Neuroskeptic has argued for the use of an active placebo condition (i.e, a non-dissociative comparison drug) in clinical trials, which has happened only rarely (Murrough et al., 2013), and for better assessment of dissociative behavioral effects.At this point, the long-term ramifications of ketamine use for treatment-resistent depression remain to be seen...In a future post I'll investigate the potential side effects in more detail. DeclarationI have no financial conflicts to declare. But if some company wants to employ a critic for some bizarre reason, I'll take this under advisement. Further ReadingKetamine for Depression: Yay or Neigh?Chronic Ketamine for Depression: An Unethical Case Study?While I Was Away... (more on ketamine for depression)Update on Ketamine in Palliative Care SettingsReferenceSchatzberg AF (2014). A word to the wise about ketamine. The American journal of psychiatry, 171 (3), 262-4 PMID: 24585328
... Read more »

Schatzberg AF. (2014) A word to the wise about ketamine. The American journal of psychiatry, 171(3), 262-4. PMID: 24585328  

  • February 23, 2014
  • 12:25 AM
  • 527 views

"Love at first sight is a myth," say Chicago researchers

by The Neurocritic in The Neurocritic

Social Neuroscience power couple, John T. Cacciopo and Stephanie CacciopoThis, my friends, is a belated Valentine's Day tale that went oh so wrong...On Feb 14, Scientific American ran a piece about When Scientists Are Mad about Each Other. The cutesy narrative on the Cacciopos described a wonderful story of love at first sight:He was studying loneliness and isolation. She was studying love and desire. When they found themselves together, they gravitated toward her end of the continuum of social connection.John Cacioppo was living in Chicago and Stephanie Ortigue in Geneva when they met—in Shanghai. ... On the last night of the conference, they happened to be seated next to one another at an official dinner, and soon became absorbed in conversation. “She was wonderful and brilliant and funny and I was completely taken by her,” Cacioppo says.They both felt the chemistry but had to return to their respective homes the next day. Before parting ways they walked out of the restaurant together and noticed a beautiful moon hanging over the city. He snapped a picture of it. “A couple weeks later, she e-mailed me and asked if I could send her the picture,” Cacioppo says—a request his wife now confesses was just an excuse to strike up another conversation.Within weeks they arranged to meet again, and from there their love unfurled. ... Within eight months they were engaged, and a season later they had married.Their romantic story and collaborative work has been covered by a number of professional and popular media outlets, including the press office at the University of Chicago. The newsroom issued a press release on February 13, 2014 to coincide with Valentine's Day:Researchers find brain’s ‘sweet spot’ for love in neurological patientA region deep inside the brain controls how quickly people make decisions about love, according to new research at the University of Chicago. The finding, made in an examination of a 48-year-old man who suffered a stroke, provides the first causal clinical evidence that an area of the brain called the anterior insula “plays an instrumental role in love,” said UChicago neuroscientist Stephanie Cacioppo, lead author of the study. The study (Cacioppo et al., 2013) showed no such thing (in my opinion), and I'll return that in a moment. But for now I'll point out the Cacioppo spin didn't translate so well to other reports about this neurological patient. According to the Fox News affiliate in Little Rock, AK:Love at first sight does not exist, claim researchers in the Current Trends in Neurology journal.A stroke patient had a damaged anterior insula -- which is the part of the brain which controls how quickly we fall for someone.They found that he could make decisions about lust normally but needed longer to think about love.The researchers say this finding "makes it possible to disentangle love from other biological drives".The Chicago researchers never said that love at first sight is a myth. But that didn't stop the British tabloid Metro from running that headline, while the Times of India declared:'Love at first sight' doesn’t exist!Feb 18, 2014, 04.52 PMA new study suggests that love at first sight is a myth and it does not exist.According to the study, the speed at which we fall for someone is controlled by a region in the brain called the anterior insula, Metro.co.uk reported.All this curt tabloid fodder contradicts the meet-cute trope of the Cacciopo's own relationship. But their study itself is also quite problematic. It doesn't support the authors' contention, in my view, and here's why.The Martin Lindstrom School of Anterior Insula StudiesRemember this classic op-ed piece in the New York Times?You Love Your iPhone. Literally.By MARTIN LINDSTROMPublished: September 30, 2011WITH Apple widely expected to release its iPhone 5 on Tuesday, Apple addicts across the world are getting ready for their latest fix.But should we really characterize the intense consumer devotion to the iPhone as an addiction? A recent experiment that I carried out using neuroimaging technology suggests that drug-related terms like “addiction” and “fix” aren’t as scientifically accurate as a word we use to describe our most cherished personal relationships. That word is “love.”. . ....most striking of all was the flurry of activation in the insular cortex of the brain, which is associated with feelings of love and compassion. The subjects’ brains responded to the sound of their phones as they would respond to the presence or proximity of a girlfriend, boyfriend or family member. Here Lindstrom committed the logical fallacy of reverse inference – one cannot directly infer the participants' cognitive or emotional state from the observed pattern of brain activity in neuroimaging experiments. 1 Fortunately, Russ Poldrack and Tal Yarkoni (and I) wrote posts about the debacle: NYT Editorial + fMRI = complete crap and the New York Times blows it big time on brain imaging and Neuromarketing means never having to say you're peer reviewed. We all corrected the completely erroneous assumption that activation of insular cortex = love. As Dr. Poldrack said:In Tal Yarkoni’s recent paper in Nature Methods [PDF], we found that the anterior insula was one of the most highly activated part of the brain, showing activation in nearly 1/3 of all imaging studies!Here's where the Cacciopos and their anterior insulae come in...The Common Neural Bases Between Sexual Desire and LoveThat was the title of a review article that conducted a statistical meta-analysis of the neuroimaging literature on "love" compared to "lust" (Cacioppo et al., 2012). The emphasis was on the similarity of brain regions activated by purported experimental elicitors of these complex behavioral and cognitive states (e.g., "look at a picture of your spouse" vs. close friend, or "watch porn" vs. non-porn). However, they did report a "gradient" of differential activation from the anterior "love" ... Read more »

S Cacioppo, B Couto, M Bolmont. (2013) Selective decision-making deficit in love following damage to the anterior insula. Current Trends in Neurology, 15-19. info:other/

  • February 9, 2014
  • 08:21 PM
  • 458 views

I Wanna Hold Your Hand (after 23 sessions of Emotionally Focused Therapy)

by The Neurocritic in The Neurocritic

Can neuroscience illuminate the nature of human relationships? Or does it primarily serve as a prop to sell self-help books? The neurorelationship cottage industry touts the importance of brain research for understanding romance and commitment. But any knowledge of the brain is completely unnecessary for issuing take-home messages like tips on maintaining a successful marriage.In an analogous fashion, we can ask whether successful psychotherapy depends on having detailed knowledge of the mechanisms of “neuroplasticity” (a vague and clichéd term). Obviously not (or else everyone's been doing it wrong). Of course the brain changes after 12 sessions of psychotherapy, just as it changes after watching 12 episodes of Dexter. The important question is whether knowing the pattern of neural changes (via fMRI) can inform how treatment is administered. Or whether pre-treatment neuroimaging can predict which therapy will be the most effective.However, neuroimaging studies of psychotherapy that have absolutely no control conditions are of limited usefulness. We don't know what sort of changes would have happened over an equivalent amount of time with no intervention. More importantly, we don't know whether the specific therapy under consideration is better than another form of psychotherapy, or better than going bowling once a week.Enter Love Sense: The Revolutionary New Science of Romantic Relationships, a new book by Dr. Sue Johnson, the clinical psychologist who developed Emotionally Focused Therapy (EFT).1 The book is reviewed by Dr. Helen Fisher in the New York Times:Love in the Time of NeuroscienceBy HELEN FISHER  FEB. 7, 2014In “The Devil’s Dictionary,” Ambrose Bierce defined love as “a temporary insanity curable by marriage.” Enter Sue Johnson, a clinical psychologist and couples therapist who says that relationships are a basic human need and that “a stable, loving relationship is the absolute cornerstone of human happiness and general well-being.” To repair ailing partnerships, she has developed a new approach in marriage counseling called Emotionally Focused Therapy, or EFT, which she introduces in her new book, “Love Sense.”...Johnson believes EFT can help couples break out of patterns, “interrupting and dismantling these destructive sequences and then actively constructing a more emotionally open and receptive way of interacting.” She aims to transform relationships “using the megawatt power of the wired-in longing for contact and care that defines our species,” and offers various exercises to restore trust.Most interesting to me was Johnson’s brain-scanning study. Before EFT therapy, unhappily married women participating in the study reported considerable pain from an electric shock to the ankle as they held their husbands’ hands. After 20 sessions of EFT, however, these now more securely attached women judged their pain as only “uncomfortable” and their brain scans showed no alarm response. Secure attachment appears to change brain function and reduce pain.Initial questions:Is there a “wired-in longing for contact and care that defines our species”? {my needy cat seems to long for contact and care}What's with that hand-holding ankle shock brain-scanning study? {did EFT really eliminate the “alarm response” in these women?}  Then Fisher continues:But Johnson too often focuses on attachment to the exclusion of other “megawatt” brain systems. Remarkably, she lumps romantic love with attachment, saying “adult romantic love is an attachment bond, just like the one between mother and child.” In reality, romantic love is associated with a constellation of thoughts and motivations that are strikingly different from those of attachment. My research bears out that humankind evolved distinct but interrelated brain systems for mating and reproduction: the sex drive (to seek a range of partners); feelings of romantic love (to focus one’s mating energy on a single partner); and feelings of attachment (to drive our forebears to form a pair-bond to rear their young together). Each brain system is associated with different neurochemicals; each is a powerful drive that still plays a continuing role in partnership stability.More questions:Are there distinct (but interrelated) brain systems for the sex drive, romantic love, and feelings of attachment? {I actually find this to be plausible}Is each brain system associated with different neurochemicals? {i.e. testosterone, dopamine, and oxytocin, respectively. I find this to be less plausible, or at least a bit simplistic.} It's time to correct the misperceptions and overinterpretations that have arisen from this research!!This is a job for...MagnetoThis looks like a job for @sarcastic_f! (I imagine him as some sort of BS-fighting super hero) http://t.co/z29q00G80u— Adam J Calhoun (@neuroecology) February 8, 2014Since there are a number of issues to tackle here – too many for a single post – I'll concentrate on only one of them here.I Wanna Hold Your HandIn 2006, Dr. James Coan and colleagues published a neuroimaging paper suggesting that the brains of happily married women showed an attenuation of activity related to emotion and threat when they held the hands of their husbands (Coan et al., 2006). Threat was induced experimentally by presenting a stimulus which occasionally signaled that a mild electric shock would be delivered to the ankle (20% of the time). Holding the hand of a male stranger also attenuated the hemodynamic response in some of these regions, relative to a no hand-holding control condition.2Backing up a bit, the participants in the study were 16 heterosexual couples who rated their marital satisfaction as at least 40 on the Satisfaction subscale of the 50 point Dyadic Adjustment Scale (DAS). Total scores on the DAS were 126 for husbands (on a 151 point scale) and 127 for wives.3 The experimental design is illustrated below. The red X indicated a 20% chance of shock.... Read more »

Coan JA, Schaefer HS, & Davidson RJ. (2006) Lending a hand: social regulation of the neural response to threat. Psychological science, 17(12), 1032-9. PMID: 17201784  

Johnson SM, Moser MB, Beckes L, Smith A, Dalgleish T, Halchuk R, Hasselmo K, Greenman PS, Merali Z, & Coan JA. (2013) Soothing the threatened brain: leveraging contact comfort with emotionally focused therapy. PloS one, 8(11). PMID: 24278126  

  • December 30, 2013
  • 10:36 PM
  • 507 views

How Can We Forget?

by The Neurocritic in The Neurocritic

** This post is meant to be read in tandem with its more complimentary cousin, Electroconvulsive Therapy Impairs Memory Reconsolidation, at The Neurocomplimenter. **spECTrum 5000Q® ECT device (MECTA)Bad memories haunt a significant number of people with serious mental illnesses, such as chronic major depression and post-traumatic stress disorder (PTSD). If it were possible to undergo an experimental procedure that selectively impairs your memory for an extremely unpleasant event, would you do it? If this sounds like the plot of Eternal Sunshine of the Spotless Mind, you're not alone.A pet peeve of mine is reference to this excellent but far-fetched film in scientific journals and popular media coverage of “memory erasure.” The idea that it's possible to selectively remove a complex autobiographical memory that has become intimately entwined with the fabric of our constructed selves is utter science fiction.At some level, even Michel Gondry knew it. One incident in Eternal Sunshine is suggestive of how memories might actually be stored. It was after one of the main characters (Joel) had his memories of his ex-girlfriend Clementine erased, and he couldn't remember who Huckleberry Hound was. He had associated the cartoon character and the song "Darling Clementine" with her. That resembles a semantic network, where an overlapping network of neurons and synapses code different but semantically related things. Take out all episodic and semantic memories of Clementine, and knowledge of Huckleberry Hound goes with it.The latest incarnation of this particular memory erasure meme was provoked by publication of a paper (Kroes et al., 2013) that examined the process of memory reconsolidation in depressed patients administered a course of electroconvulsive therapy (ECT). Here are some of the headlines:Zapping the brain can help to spot-clean nasty memories Absolutely shocking: electrocuting brain can wipe unpleasant memoriesUnwanted Memories Erased in Electroconvulsive Therapy ExperimentShocking Memories AwayMy companion post at The Neurocomplimenter reviews the literature on memory reconsolidation and describes the experiment of Kroes et al. (2013) in some detail. What I'd like to do here is to point out possible weaknesses in the results that could undermine the authors' conclusions. I'll also discuss a much earlier ECT study which did not support the notion that reactivated memories are especially vulnerable to disruption (Squire et al., 1976).To briefly reiterate the methods used in the new paper (Kroes et al., 2013), the participants were 39 patients with moderate to severe major depression. They were either at the end of an acute treatment cycle or receiving maintenance ECT. The study used a between-subjects design with three different experimental conditions, with patients randomly assigned to one of the three groups (n=13 in each). The within-subjects factor was whether or not the patients received a reminder of previously learned material before treatment.All participants learned two different emotionally charged slide stories with audio narration, each consisting of 11 images. In one, a boy is in an accident that severs his feet, which are reattached at the hospital. In the other, two sisters leave their home at night, and one is kidnapped at knife point and attacked by an escaped convict.Memory for one of the stories was reactivated a week later by presenting part of the first slide, and then giving a test for this slide. Only four minutes later, Groups A and B were anesthetized and received ECT. Group C received their ECT treatment at a later date. The final memory test for Groups A and C was 24 hrs after the reminder, while Group B was tested as soon as they woke up from the procedure (mean = 104 min later). The final test consisted of 40 multiple choice questions about each of the stories. The basic idea is that reconsolidation of the reactivated story isn't complete within 104 min, so Group B's test performance should be the same for the two stories. In contrast, reconsolidation is complete by 24 hrs, so for Group A the disruptive effect of ECT should selectively impair memory for the transiently reactivated story, which is in a labile state (relative to the "consolidated" story learned 7 days earlier).Is that what was observed? Statistically speaking, yes. But two patients in Group B (out of 13 total) performed very well on the reactivated story (see purple box in the figure below). Fig. 1 (modified from Kroes et al. 2013). ECT disrupts reconsolidation. Memory scores on the multiple choice test are expressed as percentage correct (y axis). Memory for the reactivated story shown in solid bars and non-reactivated story in open bars. Each circle is the score for an individual patient. The horizontal dotted line is chance performance. Group A is in red, Group B in blue, and Group C in orange. Edited to add: The purple box highlights 2 outliers in ... Read more »

  • December 30, 2013
  • 10:24 PM
  • 514 views

Electroconvulsive Therapy Impairs Memory Reconsolidation

by The Neurocritic in The Neurocritic

** This post is meant to be read in tandem with its more critical cousin, How Can We Forget? at The Neurocritic. **Thymatron® System IV (Somatics, LLC)“Memories are constantly changing, each time we recall them they're physically different.”- me, July 7, 2006The precision of memory over time is a quaint idea. A large body of research shows us that memories are not fixed entities (Alberini & Ledoux, 2013). Every time a specific memory “trace” is reactivated, it enters a transiently unstable state where it's subject to change before becoming consolidated and stored again (Nader & Hardt et al., 2009). In the most widely studied model systems, new protein synthesis in the hippocampus and/or amygdala is required for reconsoldation of fear memories. Fig. 1 (Alberini & Ledoux, 2013). Two Views of Memory. In the reconsolidation view (bottom), when a memory is activated, the version stored during the last retrieval (rather than the version stored after the original experience) is called up.Although these concepts and mechanisms of memory reconsolidation are not universally accepted, they've formed the basis for a thriving area of basic neuroscience research. Furthermore, the principles learned from animal studies have been applied to Pavlovian fear conditioning in humans (Schiller et al., 2010).By precisely timing the presentation of a fear memory reminder (i.e., within the reconsolidation window), extinction of the skin conductance response to a conditioned stimulus (a colored square previously associated with a mild shock) occurred when tested 24 hours later (Schiller et al., 2010). A subset of participants returned one year later, and the “extinction-during-reconsolidation” procedure prevented reinstatement of the fear response, unlike in the group where extinction training was conducted outside the reconsolidation window.This finding was greeted with optimism for potential future applications in treating anxiety disorders, including PTSD. However, sweaty palms in anticipation of a mild shock is not exactly the same as the trauma of a disfiguring accident or a sexual assault.Now, a group of Dutch researchers (Kroes et al., 2013) has taken a completely different approach to disrupt reconsolidaton in humans – namely, by reactivating recently learned memories in depressed patients immediately before administration of clinically prescribed electroconvulsive therapy (ECT).ECT is sometimes used as a last resort in treating chronically depressed patients who've failed to respond to pharmaceutical and psychological therapies. Despite its floridly negative depiction in Hollywood movies, ECT is generally accepted within the psychiatric community as a highly effective treatment for intractable major depression (Kellner et al., 2012).1The participants were 39 patients (mean age = 57 yrs) diagnosed primarily with moderate to severe recurrent major depressive disorder. They were either at the end of an acute treatment cycle or receiving maintenance ECT. The study used a between-subjects design with 3 different experimental conditions, with patients randomly assigned to Group A, B, or C (n=13 in each). The within-subjects factor was whether or not the patients received a reminder of previously learned material before treatment.All participants learned two different emotionally charged slide stories with audio narration, each consisting of 11 images. In one, a boy is in an accident that severs his feet, which are reattached at the hospital. In the other, two sisters leave their home at night, and one is kidnapped at knife point and attacked by an escaped convict.Memory for one of the stories was reactivated a week later by presenting part of the first slide, and then giving a test for this slide. The most surprising part comes next: only 4 minutes later (on average), Groups A and B were anesthetized and received ECT, which induced a seizure. Group C received their ECT treatment at a later date. The final memory test for Groups A and C was 24 hrs after the reminder, while Group B was tested as soon as they woke up from the procedure (mean = 104 min later). The final test consisted of 40 multiple choice questions about each of the stories.Supplementary Fig. 1 (modified from Kroes et al. 2013). Study design. During the first study session, all groups were shown two emotional slide-show stories. During the second session, memory for one of the two stories was reactivated. Immediately after memory reactivation, patients in Groups A and B received ECT. For Group B, memory was tested immediately upon recovery from ECT (blue box). For Groups A and C, memory was tested one day after reactivation (red and orange respectively).The basic idea here is that reconsolidation of the reactivated story isn't complete at 30 or 90 minutes, so Group B's test performance should be the same for the two stories. In contrast, reconsolidation is complete by 24 hrs, so for Group A the disruptive effect of ECT should selectively impair memory for the transiently reactivated story, which is in a labile state (relative to the "consolidated" story learned 7 days earlier).And in fact, this is what the authors observed, as shown in the figure below. The horizontal dotted line depicts chance performance (25% accuracy) – no better than guessing. Group A performed at chance for the reactivated story, but remembered at least some of the non-reactivated story. In contrast, Group B performed significantly better than chance for both stories. Finally, Group C (the control group) remembered significantly more details about the reactivated story (relative to the non-reactivated s... Read more »

  • December 21, 2013
  • 11:58 PM
  • 691 views

When Waking Up Becomes the Nightmare: Hypnopompic Hallucinatory Pain

by The Neurocritic in The Neurocritic

Most of us have had frightening nightmares – someone is chasing after us trying to kill us, or the world is coming to an end. Other disturbing dreams are based on real life anxieties – our partner leaves us, we lose our job, we become homeless. One specific psychiatric condition includes nightmares as part of the diagnosis. Individuals with post-traumatic stress disorder (PTSD) often have terrible nightmares that relive the traumatic event (Pigeon et al., 2013)We're always glad to wake up from such nightmares, whether they were of the supernatural or mundane or terrifying variety. "Thank god it was only a dream," we say.But what if waking up from sleep was the nightmare? Hypnopompic hallucinations are unusual sensory phenomena experienced just before or during awakening. Their better known mirror image, hypnagogic hallucinations, are vivid and frightening episodes of seeing or hearing or feeling phantom sensations while falling asleep (or in early stage 1 sleep). Both are frequently associated with sleep paralysis, the terrifying condition of being half awake but unable to move. This is because the complete muscle atonia typically experienced during REM sleep has oozed into lighter stages of non-REM sleep.Hypnagogic and hypnopompic hallucinations are usually associated with narcolepsy, but 37% of a representative community sample reported frequent hypnagogic hallucinations, and 12.5% reported hypnopompic hallucinations (Ohayon et al., 1996).1 This went well beyond the low incidence of narcolepsy in that population. Both types of hallucinations were more common in those with insomnia, excessive daytime sleepiness, anxiety disorders, and depression (according to self-report).Night Terrors 1, by Beth RobinsonNocturnal Episodes of Pain and ScreamingA new case study in the journal Sleep (Mantoan et al., 2013) reports on the terrifying hypnopompic hallucinations of a 43 year old woman who experiences intense limb pain when waking up, which vanishes within 30 seconds. This is a very unusual manifestation of a non-REM parasomnia, a sleep disorder involving partial arousal during the transition between non-REM and wakefulness. The phenomenology might be best characterized as a night terror. According to the case report (Mantoan et al., 2013), the patient had......a history of nocturnal screaming episodes within 1–2 h of sleep onset from the age of 30 years. Her husband was habitually awoken by his wife screaming loudly, usually flapping either her right or left hand against the bed in a semi-purposeful fashion. Her husband reported that the events were sometimes heralded by an inspiratory sigh, she looked terrified and would not respond to him. The screaming would usually last 5–10 sec, and she would then complain to her husband of intense pain affecting the fingers of either hand or arm and occasionally her legs, with no associated numbness or paraesthesia. She would become fully orientated within 30 sec and would be partially amnesic for the event, but would recall an accompanying sense of “fighting to stay alive” associated with intense panic and often accompanied by fast regular palpitations. Otherwise no dream mentation or visualizations were reported in association with the episodes. She initially had these episodes monthly, but they increased in frequency to 2-5 times a week with 1-2 episodes per night.She was unable to identify any triggers for the episodes, and neither she nor her husband considered her to be stressed, anxious, or depressed. There was no history of sleep violence, sleep sex, sleep eating, or any other NREM parasomniac automatisms. The authors could not identify any standard physical source for the pain. Thoracic outlet syndrome, cervical radiculopathy, focal nerve entrapment, and median neuropathy (carpal tunnel syndrome) were all ruled out.Pharmacological treatments were unsuccessful. A low dose (0.5–1 mg) of clonazepam was poorly tolerated (it made her feel depressed) and had no effect on her symptoms. Paroxetine was poorly tolerated (due to sedative effects), and gabapentin was also a complete failure. Trazodone, a sedating antidepressant most often prescribed for insomnia, actually made the symptoms worse.An MRI ruled out a thalamic or hypothalamic lesion. Sleep EEG revealed sudden arousals from deep sleep, accompanied by looks of pain and/or fear on the patient's face. The episodes were consistent with a NREM parasomnia. In the example below, the patient was shaking her arm – muscle activity (EMG) is shown in the green trace.adapted from Fig. 1B (Mantoan et al., 2013). EEG showing delta waves of stage 3 sleep before an episode of arousal with shaking of one arm and looks of fear. Channels 1-12 are EEG; channels 13 and 14 are electro-oculogram (EOG) activity; channel 15 is electromyography (EMG); channel 16 is electrocardiogram (ECG); channel 17 is oxygen saturation by pulse oximetry (SpO2). What did the doctors do to help this poor woman? Nothing, it seems. A few more musculoskeletal causes need to be ruled out. The authors end on a vague note about the possible mechanism(s):In conclusion, to our knowledge this is the first report of a NREM parasomnia associated with painful paroxysms, for which we postulate the following underlying pathophysiological mechanism: an internal or external stimulus triggers arousal, facilitating the activation of innate motor pattern generators in the brainstem and activating somatosensory cortical areas to produce hypnopompic hallucinatory pain.So instead of the more typical visual hallucinations, the patient experiences pain hallucinations that originate.... where?? It seems to me that the sleep EEG could be analyzed more thoroughly, beyond merely ruling out seizure occurrence. Perhaps another imaging modality like PET could be tried (PET would be quieter than fMRI and would better tolerate movement). Identifying the neurophysiological correlates of her phantom night terr... Read more »

Ohayon MM, Priest RG, Caulet M, & Guilleminault C. (1996) Hypnagogic and hypnopompic hallucinations: pathological phenomena?. The British journal of psychiatry : the journal of mental science, 169(4), 459-67. PMID: 8894197  

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