The Neurocritic

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

The Neurocritic
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  • May 18, 2014
  • 10:44 PM

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

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

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

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

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

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

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

"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, 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

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)— 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

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

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

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  

  • December 14, 2013
  • 04:26 PM

The Manifestation of Migraine in Wagner's Ring Cycle

by The Neurocritic in The Neurocritic

German Composer Richard Wagner (1813-1883) wasn't the healthiest guy. He suffered from heart disease, skin disorders, acute infections, minor ailments, and most prominently, recurring headaches – the “main plague” of his life (Göbel et al., 2013). He complained of “Headache, ‘sick headache,’ ‘dyspepsia,’ ‘nervousness,’ melancholy, insomnia, indescribable suffering... Wagner had all of them all of the time.” (Gould, 1903). Wagner wrote many letters to his doctor, Dr. Pusinelli, over a 35 year period (Gould, 1903): They begin with, "I have headache," and continue with complaints of bad weather and bad health; of growing old and loss of joy (aged 33 years); of increase of illness; working at composition with consequent frightful suffering; with prayers for peace, peace; moans at the uselessness of life; regrets at inability to get a good photograph; and sleeplessness. Baths and douches drive him nearly crazy. There is longing for his natural joyfulness; reiteration of physical and mental exhaustion; the thought of suicide ; emphasis of his irritability and of his inability to write another line, etc.A new article in the Christmas edition of BMJ by a trio of Göbels (Göbel, Göbel, & Göbel, 2013) focuses on Wagner's migraines and how he incorporated the attacks and auras into his operas. The specific example of interest is the opera Siegfried (1876), which is the third part of the Ring Cycle.The first scene of act 1 of the opera Siegfried provides an extraordinarily concise and strikingly vivid headache episode. The music begins with a pulsatile thumping, first in the background, then gradually becoming more intense. This rises to become a directly tangible almost painful pulsation. While the listener experiences this frightening headache sensation, Mime is seen pounding with his hammer, creating the acoustic trigger for the musically induced throbbing, painful perception. At the climax Mime cries out: “Compulsive plague! Pain without end!” A contemporary staging of Siegfried by Anthony Pilavachi portrays the character of Mime as a scientist in a white lab coat. Göbel et al. (2013) identify a “migraine aura leitmotif” that occurs in act 1, scene 3. It depicts the visual disturbances that accompany migraine aura. Mime sings, “Loathsome light! Is the air aflame? What is it flaring and flashing, glittering and whirring, what is swirling and whirling there and flickering around? It glistens and gleams in the sunlight’s glow. What is it rustling and humming and blustering there?”Wagner's disabling migraines contributed to a 12 year disruption in his work on Siegfried, which was finally completed in 1871. In a January 1857 letter to Franz Liszt, he wrote (Gould, 1903):My health, too, is once more so bad that for ten days after I had finished the sketch for the first act of Siegfried, I was literally not able to write a single bar without being driven away from my work by a most alarming headache. Every morning I sit down, stare at the paper, and am glad enough when I get as far as reading Walter Scott. The fact is I have once more overtaxed myself, and how am to recover my strength? With Rheingold I got on well enough but the Valkyrie caused me much pain. At present my nervous system resembles a pianoforte very much out of tune. The Göbels summarize their paper in the video below. Here's hoping that your holiday season is headache-free!References Carl H Göbel, Anna Göbel, Hartmut Göbel (2013). “Compulsive plague! pain without end!” How Richard Wagner played out his migraine in the opera Siegfried BMJ DOI: 10.1136/bmj.f6952... Read more »

  • November 29, 2013
  • 03:29 AM

The Phases of Shopping Addiction

by The Neurocritic in The Neurocritic

The blight of Black Friday is upon us. What better time to look at a recent paper on compulsive shopping? Sohn and Choi (2013) adopted a qualitative approach and recruited a small group of Korean housewives with problematic shopping habits via consumer news websites. These nine women ranged in age from 22 to 40. The authors identified their target group as individuals with compulsive buying disorder, who reported a "preoccupation with shopping, pre-purchase tension or anxiety, and sense of relief following the purchase defined by Faber and O’Guinn (1992)." The participants all had high scores on the Faber and O’Guinn 14 item "compulsive buying checklist."The authors conducted in-depth 2 hour interviews with each participant and analyzed the data according to a six-step contents analysis (Kim et al. 1999) that derived concept clusters, subcategories, and categories. Of note are these Five Sequential Phases of Shopping Addiction (Sohn & Choi, 2013):Phase 1. Retail therapy, “Filling up emptiness with shopping”Phase 2. Denial, “Ignoring overconsumption”Phase 3. Debt-ridden, “Ran out of money, while nothing left”Phase 4. Impulsive buying, “Driving ones-self to hasty buying”Phase 5. Compulsive buying, “It is crazy but I cannot stop” Accompanying these phases are 5 themes, 15 subthemes, and 43 codes (shown in detail below).- click on image for a larger view -Do you have a strong urge to purchase the latest Xbox One or PS4 before they sell out? Would you feel anxious if you didn't get one? If so, then you may be in Phase IV, Impulsive Buying.But if you go to the mall every morning and shop online every day, it's all over. You've reached Phase V, Compulsive Buying.ReferenceSang-Hee Sohn and Yun-Jung Choi (2013). Phases of Shopping Addiction Evidenced by Experiences of Compulsive Buyers. International Journal of Mental Health and Addiction DOI: 10.1007/s11469-013-9449-y

... Read more »

  • November 21, 2013
  • 05:13 AM

New Deep Brain Stimulation System Measures Neurotransmitter Release

by The Neurocritic in The Neurocritic

Wireless Instantaneous Neurotransmitter Concentration Sensing System (WINCS) Patient Module printed circuit board & sterilizable case. (Fig. 1, Kimble et al. 2009). Last month, the New York Times reported that the Defense Advanced Research Projects Agency (DARPA) will spend $70 million to further the development of technologies that use deep brain stimulation (DBS), which has been highly successful in treating Parkinson's Disease (PD). The SUBNETS program (Systems-Based Neurotechnology for Emerging Therapies) is part of the BRAIN Initiative that aims to "revolutionize our understanding of the human mind."DARPA issued their call for proposals on October 25. My original take was that the goals were overly ambitious and nearly impossible to achieve within the specified time frame:To elaborate, over a 5 year period, the successful applicants must conduct clinical trials in human patients with 7 specified psychiatric and neurological disorders (not including PD), some of which have never been treated with DBS. The successful teams will use devices that both stimulate and record neural activity, and provide real-time data that can be decoded as reflecting a particular behavioral state... basically, a futuristic implant that can adjust its own stimulation parameters based on how the patient is doing. At least, that's how I interpret it.  How close are we to seeing a DBS implant that not only stimulates neural tissue, but also records electrical or chemical signals and then uses this information to adjust the stimulation parameters? Closer than I originally suspected. A recent Nature News article reported on the Mayo Clinic's efforts to develop a DARPAesque, state-of-the-art implant that aims to track brain signals in real time:Researchers hope that the device will identify the electrical and chemical signals in the brain that correlate in real time with the presence and severity of symptoms, including the tremors experienced by people with Parkinson’s disease. This information could help to uncover where and how DBS exerts its therapeutic effects on the brain, and why it sometimes fails, says Kendall Lee, a neurosurgeon at the Mayo Clinic in Rochester, Minnesota, who is leading the project.. . ....Using a method called fast-scan cyclic voltammetry, the device applies a localized voltage change in the brain. This transiently pulls electrons off certain neurotransmitters — the brain chemicals that activate or inhibit neurons — giving rise to electrical currents that can be measured. Each neurotransmitter molecule produces a different electrochemical signature, which can be used to identify it and estimate its concentration every 10 milliseconds.Studies in awake behaving rats have used fast-scan cyclic voltammetry to measure phasic dopamine release associated with burst firing (Robinson et al., 2003).Fig, 3 (Robinson et al., 2003). Heterogeneity of electrically evoked dopamine release in the nucleus accumbens of a freely moving rat.Further information about the device is provided in this article from the Mayo Clinic, which indicates that the WINCS has already been tested in 15 human patients with Parkinson's disease or essential tremor. The study registered in is described as an Efficacy Study whose primary purpose is basic science:Neurotransmitter Measurements Using Wireless Instantaneous Neurotransmitter Concentration System (WINCS) During Deep Brain Stimulation NeurosurgeryIn this study, the investigators will monitor extracellular neurotransmitter levels using a probe that is able to perform real time electrochemical detection during deep brain stimulation surgery. The overall question this study is designed to answer is: Are there neurotransmitters released during deep brain stimulation? Interestingly, the primary outcome measure is adenosine1 release recorded by WINCS, and the secondary outcome measure is dopamine release (pre-, during, and post-DBS, over a time frame of 30 min). Adenosine A2A antagonists may extend the duration of action of L-dopa, a primary treatment for PD. Preliminary studies in rats were able to detect subsecond dopamine and adenosine release at an implanted sensor in the striatum during high-frequency stimulation of ascending fibers (Kimble et al., 2009). It seems the early results in patients were also successful in measuring neurotransmitter release.The WINCS will be integrated with another device, the MINCS (Mayo Investigational Neuromodulation Control System), which is optically linked to WINCS. The entire system is being tested in animal models to deliver brain stimulation wirelessly. Fig 1B (Chang et al., 2013). Photograph of the MINCS-WINCS hardware showing relative size, optical connection, and recording and stimulating electrode leads. ADC = analog-to-digital converter; DAC = digital-to-analog converter; LPF = low-pass filter; MC = microcontroller; TIA = transimpedance amplifier; V/I Sense = voltage/current sense. Numbers 1 and 4 indicate the microcontrollers; 2 and 3 are the Bluetooth modules.These developments in DBS devices for Parkinson's disease are very impressive indeed, but DARPA wants to go 7 steps further by developing similar clos... Read more »

Kimble CJ, Johnson DM, Winter BA, Whitlock SV, Kressin KR, Horne AE, Robinson JC, Bledsoe JM, Tye SJ, Chang SY.... (2009) Wireless Instantaneous Neurotransmitter Concentration Sensing System (WINCS) for intraoperative neurochemical monitoring. Conference proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society., 4856-9. PMID: 19963865  

  • November 9, 2013
  • 09:15 PM

Now Is That Gratitude?

by The Neurocritic in The Neurocritic

Now is that Gratitude,Or is it really love?Some kind of reality That fits just like a glove--Danny Elfman, GratitudePraise and condemnation serve a powerful purpose in our social and internal lives. They prop us up and tear us down. We reward ourselves (and others) when we perform good deeds, give a pat on the back for a job well done. Conversely, we punish bad behavior. Some people are more vengeful than others when they're wronged; other individuals might be more inclined to blame themselves, even when it's not their fault.Laws and religions and etiquette and complex ethical systems enforce the rules of behavior. For most human beings of a certain age, moral emotions are the result of abiding by or violating these social norms. Moral emotions can be defined as “those emotions that are linked to the interests or welfare either of society as a whole or at least of persons other than the judge or agent” (Haidt, 2003). They can entail reacting to events that don't directly involve the self, as in the case of sympathy or contempt.Zahn and colleagues (2013) refer to these feelings and reactions as moral sentiments, “following philosophers of the Scottish enlightenment who pointed to their role as key motivators of moral behaviour (Bishop, 1996).” In a recent study, they conceptualized four of these moral sentiments in a 2 x 2 grid, depending upon whether the emotion involved praise or blame, of oneself or of another (Zahn et al., 2013).                          SELF        OTHER     PRAISE      Pride       Gratitude BLAME      Guilt        Indignation Their goal was to determine whether there are individual differences in cortical gray matter volumes associated with self-reports on the Value-related Moral Sentiment Task (VMST), which attempts to quantify personally felt human emotions.Moral PhrenologyDoes the tendency to experience each of these moral sentiments correlate with the size of different regions of the brain? The strong form of this question assumes the brain is modular and divisible into separate regions that oversee distinct processes. It also reflects a belief in the “brain is like a muscle” analogy, with discrete regions growing larger with use and smaller with disuse. In Franz Gall's original formulation of phrenology, there were 27 “organs” or mental faculties that could be measured by palpating bumps on the skull. The list of faculties was further refined and developed by Spurzheim (1815), Combe (1834 & 1847), and Lundie (1844). 1 Phrenological Chart, via Wikimedia CommonsFor example, the organ of Benevolence is “situated at the upper part of the frontal bone... When it is large, the frontal bone rises with an arched appearance; when small, the forehead is low and retreating.”Zahn et al. (2013) didn't palpate bumps on the skull, of course. Instead, they used voxel-based morphometry (VBM) to quantify regional gray matter (GM) volumes in 63 participants. In turn, these GM volumes were related to scores for each moral sentiment, controlled for positive and negative valence (Zahn et al., 2013):We examined the effects of each moral sentiment measure (e.g. pride-proneness) on GM volume across the whole brain while using the other moral sentiment of equal valence (e.g. gratitude-proneness) as a covariate of no interest to control for effects of valence. We thus used two separate models to test for positive and negative emotions. All reported results were thus partial effects of one moral sentiment controlled for the adjusted effect of the equal-valence moral sentiment.The Value-related Moral Sentiment Task (VMST) consisted of 180 descriptions of positive or negative interactions between a participant and their best friend in which either they (self-agency, N=90), or their best friend (other-agency, N=90), acted in accord with (N=90) or counter to (N=90) social and moral values. The four conditions thus measured proneness to:Pride (POS_SELF): positive self-agency (e.g. ‘Yourself acting in a generous way towards Sam [best friend]’)Gratitude (POS_OTHER): positive other-agency (e.g. ‘Sam acting in a generous way towards you’)Guilt (NEG_SELF): negative self-agency (e.g. ‘Yourself acting in a stingy way towards Sam’)Indignation (NEG_OTHER): negative other-agency (e.g. ‘Sam acting in a stingy way towards you’)The task was to choose the most fitting label (pride, gratitude, embarrassment [not examined here], guilt, indignation/anger, or none/other) for what they'd feel in response to each example. Participants then rated the unpleasantness or pleasantness of their projected feelings on a scale of -4 to +4.Based on the authors' previous s... Read more »

  • October 29, 2013
  • 06:12 AM


by The Neurocritic in The Neurocritic

Image credits. Left: SUBNETS program (DARPA). Right: BRAIN interim report presentation (NIH).In April, the White House announced the $100 million Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. The goals of this bold new research effort are to "revolutionize our understanding of the human mind and uncover new ways to treat, prevent, and cure brain disorders like Alzheimer's, schizophrenia, autism, epilepsy, and traumatic brain injury." A series of high-profile journal articles traced the genesis of this initiative from the Brain Activity Map idea to develop nanotechnologies and "image every spike from every neuron" (Alivisatos et al., 2012) to its current emphasis on neural circuits and systems neuroscience more broadly construed (Insel et al., 2013). In the first year (FY 2014),1 $50 million will be allocated to DARPA and $40 million to NIH.2The two federal agencies have taken starkly different approaches to the challenge, in terms of timing and scope. They also address different levels of nervous system function. Both are ambitious, but one surpasses earlier calls for a "moon shot" to the mind.  IF successful,3 it would render much of pre-clinical neuroscience research quaint and obsolete (except for providing mechanistic details).The Tale of Two BRAINS1. The National Institute of Health (NIH) sponsored a series of meetings and solicited public feedback. The NIH Director's BRAIN Advisory Committee issued its Interim Report (PDF) on September 16. The report focuses primarily on animal models, including improved technologies for recording neuronal activity and manipulating circuit function.4 Here are the high-priority research areas for FY 2014:#1.  Generate a Census of Cell Types.#2.  Create Structural Maps of the Brain.  #3.  Develop New Large-Scale Network Recording Capabilities. #4.  Develop A Suite of Tools for Circuit Manipulation.#5.  Link Neuronal Activity to Behavior. #6.  Integrate Theory, Modeling, Statistics, and Computation with Experimentation.   #7.  Delineate Mechanisms Underlying Human Imaging Technologies.#8.  Create Mechanisms to Enable Collection of Human Data.#9.  Disseminate Knowledge and Training. These are very ambitious projects, each delineated in more detail in the full report (PDF). However, the NIH has yet to issue a Request for Applications that outlines the requirements for grant proposals submitted through this program.2. On the other hand, the Defense Advanced Research Projects Agency (DARPA) announced their goals for the BRAIN Initiative via the New York Times on October 24 and and issued a broad agency announcement (call for proposals) on October 25. The focus is on developing technologies and treatments that use deep brain stimulation (DBS), which has been highly successful in Parkinson's Disease. There are 3 Technical Areas that are covered in the announcement. All applicants must address Area One, and teams of investigators are encouraged to address all three.TA One is comprised of clinical trials in order to establish mechanistic models of awake, behaving human brain activity. TA Two encompasses the hardware development component in order to create safe and effective sensing and stimulation systems.In TA Three, investigators will use human-relevant animal models [primates, not rodents] to generate safety and efficacy data as well as establish preliminary theories and rapidly prototype hypotheses regarding the links between neural data and clinical outcomes.  To elaborate, over a 5 year period, the successful applicants must conduct clinical trials in human patients with 7 specified psychiatric and neurological disorders (not including PD), some of which have never been treated with DBS. The successful teams will use devices that both stimulate and record neural activity, and provide real-time data that can be decoded as reflecting a particular behavioral state... basically, a futuristic implant that can adjust its own stimulation parameters based on how the patient is doing. At least, that's how I interpret it. Brainstorm (1983). Brain-computer interfaces have improved a bit in the last 30 yrs.Systems-Based Neurotechnology for Emerging Therapies (SUBNETS)Let's take a closer look at TA One of DARPA's SUBNETS program.SUBNETS is distinct from current therapeutic approaches as it seeks to develop the ability to create a closed-loop diagnostic and therapeutic system. Through measuring pathways involved in complex systems-based brain disorders such as depression, compulsion, debilitating impulse control, and chronic pain, SUBNETS will attempt to establish the capability to record and model how these systems function in both normal conditions, among volunteers seeking treatment for unrelated neurologic disorders, as well as impaired clinical research participants. SUBNETS will then use these models to determine appropriate therapeutic stimulation methodologies that meet guidelines for both safety and efficacy in human participants. These models will be adapted onto next-generation, closed-loop neural stimulators that exceed currently developed capacities for simultaneous stimulation and recording and provide a research investigator, a clinician, and a human research participant with the ability to record, analyze, and stimulate multiple brain regions for therapeutic purposes. Seven disorders are targeted: Post-Traumatic Stress Disorder (PTSD), Major Depression, Borderline Personality Disorder (BPD), General Anxiety Disorder (GAD), Traumatic Brain Injury (TBI), Substance Abuse/Addiction, and Fibromyalgia/Chronic Pain. To the best of my knowledge, there is no published literature on DBS for PTSD, BPD, GAD [as opposed to OCD], or TBI [except for minimally conscious state]. At, a Pilot Study of DBS of the Amygdala for Treatment-Refractory Combat PTSD was withdrawn prior to enrollment. There's one DBS ... Read more »

Alivisatos AP, Chun M, Church GM, Greenspan RJ, Roukes ML, & Yuste R. (2012) The brain activity map project and the challenge of functional connectomics. Neuron, 74(6), 970-4. PMID: 22726828  

Insel TR, Landis SC, & Collins FS. (2013) Research priorities. The NIH BRAIN Initiative. Science, 340(6133), 687-8. PMID: 23661744  

  • October 12, 2013
  • 05:38 AM

Existential Neuroscience: a field in search of meaning

by The Neurocritic in The Neurocritic

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

  • September 30, 2013
  • 04:42 AM

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

by The Neurocritic in The Neurocritic

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

  • September 27, 2013
  • 03:44 AM

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

by The Neurocritic in The Neurocritic

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