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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  • February 20, 2015
  • 02:48 AM

One Brain Network for All Mental Illness

by The Neurocritic in The Neurocritic

What do schizophrenia, bipolar disorder, major depression, addiction, obsessive compulsive disorder, and anxiety have in common? A loss of gray matter in the dorsal anterior cingulate cortex (dACC) and bilateral anterior insula, according to a recent review of the structural neuroimaging literature (Goodkind et al., 2015). These two brain regions are important for executive functions, the top-down cognitive processes that allow us to maintain goals and flexibly alter our behavior in response to changing circumstances. The authors modestly concluded they had identified a “Common Neurobiological Substrate for Mental Illness.”One problem with this view is that the specific pattern of deficits in executive functions, and their severity, differ across these diverse psychiatric disorders. For instance, students with anxiety perform worse than controls in verbal selection tasks, while those with depression actually perform better (Snyder et al., 2014). Another problem is that gray matter volume in the dorsolateral prefrontal cortex, a key region for working memory (a core impairment in schizophrenia and to a lesser extent, in major depression and non-psychotic bipolar disorder), was oddly unaffected in the meta-analysis.The NIMH RDoC movement (Research Domain Criteria) aims to explain the biological basis of psychiatric symptoms that cut across traditional DSM diagnostic categories. But I think some of the recent research that uses this framework may carry the approach too far (Goodkind et al., 2015):Our findings ... provide an organizing model that emphasizes the import of shared endophenotypes across psychopathology, which is not currently an explicit component of psychiatric nosology. This transdiagnostic perspective is consistent...with newer dimensional models such as the NIMH’s RDoC Project.However, not even the Director of NIMH believes this is true:"The idea that these disorders share some common brain architecture and that some functions could be abnormal across so many of them is intriguing," said Thomas Insel, MD... [BUT]"I wouldn't have expected these results. I've been working under the assumption that we can use neuroimaging to help classify the different forms of mental illness," Insel said. "This makes it harder."Anterior Cingulate and Anterior Insula and Everyone We KnowThe dACC and anterior insula are ubiquitously activated 1 in human neuroimaging studies (leading Micah Allen to dub it the ‘everything’ network), and comprise either a “salience network” or “task-set network” (or even two separate cingulo-opercular systems) in resting state functional connectivity studies. But the changes reported in the newly published work were structural in nature. They were based on a meta-analysis of 193 voxel-based morphometry (VBM) studies that quantified gray matter volume across the entire brain in psychiatric patient groups, and compared this to controls.Goodkind et al., (2015) included a handy flow chart for how they selected the papers for their review.I could be wrong, but it looks like 34 papers were excluded because they found no differences between patients and controls. This would of course bias the results towards greater differences between patients and controls. And we don't know which of the six psychiatric diagnoses were included in the excluded batch. Was there an over-representation of null results in OCD? Anxiety? Depression?What Does VBM Measure, Anyway? Typically, VBM measures gray matter volume, which in the cortex is determined by surface area (which can vary due to differences in folding patterns) and by thickness (Kanai & Rees, 2011). These can be differentially related to some ability or characteristic. For example, Song et al. (2015) found that having a larger surface area in early visual cortex (V1 and V2) was correlated with better performance in a perceptual discrimination task, while larger cortical thickness was actually correlated with worse performance. Other investigators warn that volume really isn't the best measure of structural differences between patients and controls, and that cortical thickness is better (Ehrlich et al., 2012):Cortical thickness is assumed to reflect the arrangement and density of neuronal and glial cells, synaptic spines, as well as passing axons. Postmortem studies in patients with schizophrenia showed reduced neuronal size and a decrease in interneuronal neuropil, dendritic trees, cortical afferents, and synaptic spines, while no reduction in the number of neurons or signs of gliosis could be demonstrated.This leads us to the huge gap between dysfunction in cortical and subcortical microcircuits and gross changes in gray matter volume.Psychiatric Disorders Are Circuit DisordersThis motto tells us that mental illnesses are disorder of neural circuits, in line with the funding priorities of NIMH and the BRAIN Initiative. But structural MRI studies tell us nothing about the types of neurons that are affected. Or how their size, shape, and synaptic connections might be altered. Basically, volume loss in dACC and anterior insula could be caused by any number of reasons, and by different mechanisms across the disorders under consideration. Goodkind et al., (2015) state:Our connection of executive functioning to integrity of a well-established brain network that is perturbed across a broad range of psychiatric diagnoses helps ground a transdiagnostic understanding of mental illness in a context suggestive of common neural mechanisms for disease etiology and/or expression.But actually, we might find a reduction in the density of von Economo neurons in the dACC of individuals with early-onset schizophrenia (... Read more »

Goodkind, M., Eickhoff, S., Oathes, D., Jiang, Y., Chang, A., Jones-Hagata, L., Ortega, B., Zaiko, Y., Roach, E., Korgaonkar, M.... (2015) Identification of a Common Neurobiological Substrate for Mental Illness. JAMA Psychiatry. DOI: 10.1001/jamapsychiatry.2014.2206  

  • January 26, 2015
  • 06:23 AM

Is it necessary to use brain imaging to understand teen girls' sexual decision making?

by The Neurocritic in The Neurocritic

“It is feasible to recruit and retain a cohort of female participants to perform a functional magnetic resonance imaging [fMRI] task focused on making decisions about sex, on the basis of varying levels of hypothetical sexual risk, and to complete longitudinal prospective diaries following this task. Preliminary evidence suggests that risk level differentially impacts brain activity related to sexual decision making in these women [i.e., girls aged 14-15 yrs], which may be related to past and future sexual behaviors.”-Hensel et al. (2015) Can the brain activity of adolescents predict whether they are likely to make risky sexual decisions in the future?  I think this is the goal of a new pilot study by researchers at Indiana University and the Kinsey Institute (Hensel et al., 2015). While I have no reason to doubt the good intentions of the project, certain aspects of it make me uncomfortable.But first, I have a confession to make. I'm not an expert in adolescent sexual health like first author Dr. Devon Hensel. Nor do I know much about pediatrics, adolescent medicine, health risk behaviors, sexually transmitted diseases, or the epidemiology of risk, like senior author Dr. J. Dennis Fortenberry (who has over 300 publications on these topics).  His papers include titles such as Time from first intercourse to first sexually transmitted infection diagnosis among adolescent women and Sexual learning, sexual experience, and healthy adolescent sex. Clearly, these are very important topics with serious personal and public health implications. But are fMRI studies of a potentially vulnerable population the best way to address these societal problems?The study recruited 14 adolescent girls (mean age = 14.7 yrs) from health clinics in lower- to middle-income neighborhoods. Most of the participants (12 of the 14) were African-American, most did not drink or do drugs, and most had not yet engaged in sexual activity.  However, the clinics served areas with “high rates of early childbearing and sexually transmitted infection” so the implication is that these young women are at greater risk of poor outcomes than those who live in different neighborhoods.Detailed sexual histories were obtained from the girls upon enrollment (see below). They also kept a diary of sexual thoughts and behaviors for 30 days. Given the sensitive nature of the information revealed by minors, it's especially important to outline the informed consent procedures and the precautions taken to protect privacy. Yes, a parent or guardian gave their approval, and the girls completed informed consent documents that were approved by the local IRB. But I wanted to see more about this in the Methods. For example, did the parent or guardian have access to their daughters' answers and/or diaries, or was that private? This could have influenced the willingness of the girls to disclose potentially embarrassing behavior or “verboten” activities (prohibited by parental mores, church teachings, legal age of consent,1 etc.).  I don't know, maybe the standard procedures are obvious to those within the field of sexual health behavior, but they weren't to me.Turning to more familiar territory, the experimental design for the neuroimaging study involved presentation of four different types of stimuli: (1) faces of adolescent males; (2) alcoholic beverages; (3) restaurant food; (4) household items (e.g., frying pan). My made-up examples of the stimuli are shown below.Each picture was presented with information that indicated the item's risk level (“high” or “low”):Adolescent male faces: number of previous sexual partners and typical condom use (yes/no)Alcoholic beverages: number of alcohol units and whether there was a designated driver (yes/no)Food: calorie content and whether the restaurant serving the food had been cited in the past year for health code violations (yes/no) Household items: whether the object could be returned to the store (yes/no)For each picture, participants rated how likely they were to: (1) have sex with the male, (2) drink the beverage, (3) eat the food, or (4) purchase the product (1 = very unlikely to 4 = very likely). There were 35 exemplars of each category, and each stimulus was presented in both “high” and “low” risk contexts. So oddly, the pizza was 100 calories and from a clean restaurant on one trial, compared to 1,000 calories and from a roach-infested dump on another trial.The faces task was adapted from a study in adult women (Rupp et al., 2009) where the participants gave a mean likelihood rating of 2.45 for sex with low risk men vs. 1.41 for high risk men (significantly less likely for the latter). The teen girls showed the opposite result: 2.85 for low risk teen boys vs. 3.85 for high risk teen boys (significantly more likely) — the “bad boy” effect?But the actual values were quite confusing. At one point the authors say they omitted the alcohol condition: “The present study focused on the legal behaviors (e.g., sexual behavior, buying item, and eating food) in which adolescents could participate.”But in the Fig. 1 legend, they say the opposite (that the alcohol condition was included):Panel (A) provides the average likelihood of young women's endorsing low- and high-risk decisions in the boy, alcohol, food, and household item (control) stimulus categories. Then they say that the low-risk male faces were rated as the most unlikely (i.e., least preferred) of all stimuli.  But Fig. 1 itself shows that the low-risk food stimuli were rated as the most unlikely...Regardless of the precise ratings, the young women were more drawn to all stimuli when they were in the high risk condition. The authors tried to make a case for more "risky" sexual choices among participants with higher levels of overt or covert sexual reporting, but the numbers were either impossibly low (for behavior) or thought-crimes only (for dreams/fantasy). So it's really hard to see how brain activity of any sort could be diagnostic of actual behavior at this point in their lives.And the neuroimaging results were confusing as well. First, the less desirable low-risk stimuli elicited greater responses in cognitive and emotional control regions:Neural activity in a cognitive-affective network, including prefrontal and anterior cingulate (ACC) regions, was significantly greater during low-risk decisions. But then, we see that the more desirable high-risk sexual stimuli elicited greater responses in cognitive/emotional control regions:Compared with other decisions, high-risk sexual decisions elicited greater activity in the anterior cingulate, and low-risk sexual decision elicited greater activity in regions of the visual cortex.&... Read more »

  • January 19, 2015
  • 05:32 AM

Interfering With Traumatic Memories of the Boston Marathon Bombings

by The Neurocritic in The Neurocritic

The Boston Marathon bombings of April 15, 2013 killed three people and injured hundreds of others near the finish line of the iconic footrace. The oldest and most prominent marathon in the world, Boston attracts over 20,000 runners and 500,000 spectators. The terrorist act shocked and traumatized and unified the city.What should the survivors do with their traumatic memories of the event? Many with disabling post-traumatic stress disorder (PTSD) receive therapy to lessen the impact of the trauma. Should they forget completely? Is it possible to selectively “alter” or “remove” a specific memory? Studies in rodents are investigating the use of pharmacological manipulations (Otis et al., 2014) and behavioral interventions (Monfils et al., 2009) to disrupt the reconsolidation of a conditioned fear memory. Translating these interventions into clinically effective treatments in humans is an ongoing challenge.The process of reconsolidation may provide a window to altering unwanted memories. When an old memory is retrieved, it enters a transiently labile state, when it's susceptible to change before becoming consolidated and stored again (Nader & Hardt et al., 2009). There's some evidence that the autonomic response to a conditioned fear memory can be lessened by an “updating” procedure during the reconsolidation period (Schiller et al., 2010).1 How this might apply to the recollection of personally experienced trauma memories is uncertain.Remembering the Boston BombingsCan you interfere with recall of a traumatic event by presenting competing information during the so-called reconsolidation window? A new study by Kredlow and Otto (2015) recruited 113 Boston University undergraduates who were in Boston on the day of the bombings. In the first testing session, participants wrote autobiographical essays recounting the details of their experience, prompted by specific questions. In principle, this procedure re-activated the traumatic memory, rendering it vulnerable to updating during the reconsolidation window (~6 hours).The allotted time for the autobiographical essay was 4 min. After that, separate groups of subjects read either a neutral story, a negative story, or a positive story (for 5 min). The fourth group did not read a story. Presentation of a story that is not one's own would presumably “update” the personal memory of the bombings.A second session occurred one week later. The participants were again asked to write an autobiographical essay for 4 min, under the same conditions as Session #1. They were also asked about their physical proximity to the bombings, whether they watched the marathon in person, feared for anyone's safety, and knew anyone who was injured or killed. Nineteen subjects were excluded for various reasons, leaving the final n=94.One notable weakness is that we don't know anything about the mental health of these undergrads, except that they completed the 10 item Positive and Negative Affective Schedule (PANAS-SF) before each session. And they were “provided with mental health resources” after testing (presumably links to resources, since the study was conducted online).In terms of proximity, 10% of the participants were within one block of the bombings (“Criterion A” stressor), placing them at risk for developing of PTSD. Most (95%) feared for someone's safety and 12% knew someone who was injured or killed (also considered Criterion A). But we don't know if anyone had a current or former PTSD diagnosis.The authors predicted that reading the negative stories during the “autobiographical reconsolidation window” would yield the greatest reduction in episodic details recalled from Session #1 (S1) to Session #2 (S2), relative to the No-Story condition. This is because the negative story and the horrific memories are both negative in valence [although I'm not sure of what mechanism would account for this effect].2Specifically, we hypothesized that learning a negative affective story during the reconsolidation window compared to no interference would interfere with the reconsolidation of memories of the Boston Marathon bombings. In addition, we expected the neutral and positive stories to result in some interference, but not as much as the negative story. The essays were coded for the number of memory details recalled in S1 and S2 (by 3-5 raters3), and the main measure was the number of details recalled in S2 for each of the four conditions. Other factors taken into account were the number of words used in S1, and time between the Boston Marathon and the testing session (both of which influenced the number of details recalled).The results are shown in Table 1 below. the authors reported comparisons between Negative Story vs. No Story (p<.05, d = 0.62), Neutral Story vs. No Story (p=.20, d = 0.39), and Positive Story vs. No Story (p=.83, d = 0.06). The effect sizes are “medium-ish” for both the Negative and Neutral comparisons, but only “significant” for Negative.I would argue that the comparison between Negative Story vs. Neutral Story — which was not reported — is the only way to evaluate the valence aspect of the prediction, i.e. whether the reduction in details recalled was specific to reading a negative story vs. potentially any story. I wasn't exactly sure why they didn't do an ANOVA in the first place, either.Nonetheless, Kredlow and Otto (2015) suggest that their study......represent[s] a step toward translating reconsolidation interference work to the clinic, as, to our knowledge, no published studies to date have examined nonpharmacological reconsolidation interference for clinically-relevant negative memories. Additional studies should examine reconsolidation interference paradigms, such as this one, in clinical populations. If this work was indeed extended to clinical populations, I would suggest conducting the study under more controlled conditions (in the lab, not online), which would also allow close monitoring of any distress elicited by writing the autobiographical essay (essentially a symptom provocation design). As the authors acknowledge, it would be especially important to evaluate not only the declarative, detail-oriented aspects of the traumatic memories, but also any change in their emotional impact.Further ReadingBrief review of memory reconsolidation Media’s role in broadcasting acute stress following the Boston Marathon bombingsAutobiographical Memory for a Life-Threatening Airline DisasterI Forget...Footnotes1 But this effect hasn't replicated in other studies (e.g., Golkar e... Read more »

  • January 2, 2015
  • 08:38 PM

The Futility of Progesterone for Traumatic Brain Injury (but hope for the future)

by The Neurocritic in The Neurocritic

Traumatic Brain Injury (TBI) is a serious public health problem that affects about 1.5 million people per year in the US, with direct and indirect medical costs of over $50 billion. Rapid intervention to reduce the risk of death and disability is crucial. The diagnosis and treatment of TBI is an area of active preclinical and clinical research funded by NIH and other federal agencies. But during the White House BRAIN Conference, a leading neurosurgeon painted a pessimistic picture of current treatments for acute TBI. In response to a question about clinical advances based on cellular neurobiology, Dr. Geoffry Manley noted that the field is on its 32nd or 33rd failed clinical trial. The termination of a very promising trial of progesterone for TBI had just been announced (the ProTECT III, Phase III Clinical Trial “based on 17 years of work with 200 positive papers in preclinical models”), although I couldn't find it at the time (3 months ago).Now, the results from ProTECT III have been published in the New England Journal of Medicine (Wright et al., 2014). 882 TBI patients from 49 trauma centers were enrolled in the study and randomized to receive progesterone, thought to be a neuroprotective agent, or placebo within 4 hours of major head injury. The severity of TBI fell in the moderate to severe range, as indicated by scores on the Glasgow Coma Scale (which rates the degree of impaired consciousness).The primary outcome measure was the Extended Glasgow Outcome Scale (GOS-E) at six months post-injury. The trial was stopped at 882 patients (out of a planned 1140) because there was no way that progesterone would improve outcomes:After the second interim analysis, the trial was stopped because of futility. For the primary hypothesis comparing progesterone with placebo, favorable outcomes occurred in 51.0% of patients assigned to progesterone and in 55.5% of those assigned to placebo.  Analysis of subgroups by race, ethnicity, and injury severity showed no differences between them, but there was a suggestive (albeit non-significant) sex difference.- click on image for a larger view -Modified from Fig. 2 (Wright et al., 2014). Adjusted Relative Benefit in Predefined Subgroups. Note the red box p value for sex differences.Squares to the left of the dotted line indicate that placebo performed better than progesterone in a given patient group, while values to the right favor progesterone. The error bars show confidence intervals, which indicate that nearly all groups overlap with 0 (representing zero benefit for progesterone) The red box indicates a near-significant difference between men and women, with women actually faring worse with progesterone than with placebo. You may quibble about conventional significance, but women on average deteriorated with treatment, while men were largely unaffected.This was a highly disappointing outcome for a well-conducted study that built on promising results in smaller Phase II Clinical Trials (and backed by a boatload of preclinical data). The authors reflect on this gloomy state of affairs:The PROTECT III trial joins a growing list of negative or inconclusive trials in the arduous search for a treatment for TBI. To date, more than 30 clinical trials have investigated various compounds for the treatment of acute TBI, yet no treatment has succeeded at the confirmatory trial stage. Many reasons for the disappointing record of translating promising agents from the laboratory to the clinic have been postulated, including limited preclinical development work, poor drug penetration into the brain, delayed initiation of treatment, heterogeneity of injuries, variability in routine patient care across sites, and insensitive outcome measures.If that isn't enough, a second failed trial of progesterone was published in the same issue of NEJM (Skolnick et al., 2014). This group reported on negative results from an even larger pharma-funded trial (SyNAPse, which is the tortured acronym for Study of a Neuroprotective Agent, Progesterone, in Severe Traumatic Brain Injury). The SyNAPse trial enrolled the projected number of 1180 patients across 21 countries, all with severe TBI. The percentage of patients with favorable outcomes at six months was 50.4% in the progesterone group and 50.5% in the placebo group.The negative result of this study, combined with the results of the PROTECT III trial, should stimulate a rethinking of procedures for drug development and testing in TBI. This led Dr. Lee H. Schwamm (2014) to expound on the flawed culture of research in an Editorial, invoking the feared god of false positive findings (Ioannidis, 2005) and his minions: small effect sizes, small n's, too few studies, flexibility of analysis, and bias. He pointed to problematic aspects of the Phase II Trials that preceded ProTECT III and SyNAPse, including modest effect sizes and better-than expected outcomes in the placebo group.Hope for the Future“And you have to give them hope.”--Harvey Milk When the going gets tough in research, who better to rally the troops than your local university press office? The day after Dr. Manley's presentation at the BRAIN conference on Sept. 30, the University of California San Francisco issued this optimistic news release:$17M DoD Award Aims to Improve Clinical Trials for Traumatic Brain Injury Unprecedented Partnership Joins Universities, FDA, Firms, Philanthropies An unprecedented, public-private partnership funded by the Department of Defense (DoD) is being launched to drive the development of better-run clinical trials and may lead to the first successful treatments for traumatic brain injury, a condition affecting not only athletes and members of the military, but also millions among the general public, ranging from youngsters to elders.Under the partnership, officially launched Oct. 1 with a $17 million, five-year award from the DoD, the research team, representing many universities, the Food and Drug Administration (FDA), companies and philanthropies, will examine data from thousands of patients in order to identify effective measures of brain injury and recovery, using biomarkers from blood, new imaging equipment and software, and other tools.. . .“TBI is really a multifaceted condition, not a single event,” said UCSF neurosurgeon Geoffrey T. Manley, MD, PhD, principal investigator for the new award... “TBI lags 40 to 50 years behind heart disease and cancer in terms of progress and understanding of the actual disease process and its potential aftermath. More than 30 clinical trials of potential TBI treatments have failed, and not a single drug has been approved.”The TED (TBI Endpoints Development) Award is meant to accelerate research to improve TBI diagnostics... Read more »

Skolnick, B., Maas, A., Narayan, R., van der Hoop, R., MacAllister, T., Ward, J., Nelson, N., & Stocchetti, N. (2014) A Clinical Trial of Progesterone for Severe Traumatic Brain Injury. New England Journal of Medicine, 371(26), 2467-2476. DOI: 10.1056/NEJMoa1411090  

Wright, D., Yeatts, S., Silbergleit, R., Palesch, Y., Hertzberg, V., Frankel, M., Goldstein, F., Caveney, A., Howlett-Smith, H., Bengelink, E.... (2014) Very Early Administration of Progesterone for Acute Traumatic Brain Injury. New England Journal of Medicine, 371(26), 2457-2466. DOI: 10.1056/NEJMoa1404304  

  • December 25, 2014
  • 05:00 PM

Eliciting Mirth and Laughter via Cortical Stimulation

by The Neurocritic in The Neurocritic

Ho ho ho!“Laughter consists of both motor and emotional aspects. The emotional component, known as mirth, is usually associated with the motor component, namely, bilateral facial movements.”-Yamao et al. (2014)The subject of laughter has been under an increasing amount of scientific scrutiny.  A recent review by Dr. Sophie Scott and colleagues (Scott et al., 2014) emphasized that laughter is a social emotion. During conversations, voluntary laughter by the speaker is a communicative act. This contrasts with involuntary laughter, which is elicited by external events like jokes and funny behavior.One basic idea about the neural systems involved in the production of laughter relies on this dual process theme:The coordination of human laughter involves the periaqueductal grey [PAG] and the reticular formation [RF], with inputs from cortex, the basal ganglia, and the hypothalamus. The hypothalamus is more active during reactive laughter than during voluntary laughter. Motor and premotor cortices are involved in the inhibition of the brainstem laughter centres and are more active when suppressing laughter than when producing it.Figure 1 (Scott et al., 2014). Voluntary and involuntary laughter in the brain.An earlier paper on laughter and humor focused on neurological conditions such as pathological laughter and gelastic epilepsy (Wild et al., 2003). In gelastic epilepsy, laughter is the major symptom of a seizure. These gelastic (“laughing”) seizures usually originate from the temporal poles, the frontal poles, or from benign tumors in the hypothalamus (Wild et al., 2003). Some patients experience these seizures as pleasant (even mirthful), while others do not:During gelastic seizures, some patients report pleasant feelings which include exhilaration or mirth. Other patients experience the attacks of laughter as inappropriate and feel no positive emotions during their laughter. It has been claimed that gelastic seizures originating in the temporal regions involve mirth but that those originating in the hypothalamus do not. This claim has been called into question, however...In their extensive review of the literature, Wild et al. (2003) concluded that the “laughter‐coordinating centre” must lie in the dorsal midbrain, with intimate connections to PAG and RF. Together, this system may comprise the “final common pathway” for laughter (i.e., coordinating changes in facial muscles, respiration, and vocalizations). During emotional reactions, prefrontal cortex, basal temporal cortex, the hypothalamus, and the basal ganglia transmit excitatory inputs to PAG and RF, which in turn generates laughter.Can direct cortical stimulation produce laughter and mirth? It turns out that the basal temporal cortex (wearing a Santa hat above) plays a surprising role in the generation of mirth, at least according to a recent paper by Yamao et al., (2014). Over a period of 13 years, they recorded neural activity from the cortical surface of epilepsy patients undergoing seizure monitoring, with the purpose of localizing the aberrant epileptogenic tissue. They enrolled 13 patients with implanted subdural grids to monitor for left temporal lobe seizures, and identified induced feelings of mirth in two patients (resulting from electrical stimulation in specific regions).Obviously, this is not the typical way we feel amusement and utter guffaws of delight, but direct stimulation of the cortical surface goes back to Wilder Penfield as a way for neurosurgeons to map the behavioral functions of the brain. Of particular interest is the localization of language-related cortex that should be spared from surgical removal if at all possible.The mirth-inducing region (Yamao et al., 2014) encompasses what is known as the basal temporal language area (BTLA), first identified by Lüders and colleagues in 1986. The region includes the left fusiform gyrus, about 3-7 cm from the tip of the temporal lobe. Stimulation at high intensities produces total speech arrest (inability to speak) and global language comprehension problems. Low stimulation intensity produces severe anomia, an inability to name things (or places or people). Remarkably, however, Lüders et al. (1991) found that “Surgical resection of the basal temporal language area produces no lasting language deficit.”With this background in mind, let's look at the results from the mirthful patients. The location of induced-mirth (shown below) is the white circle in Patient 1 and the black circles in Patient 2.  In comparison, the locations of stimulation-induced language impairment are shown in diamonds. Note, however, that mirth was co-localized with language impairment in Patient 2.Fig. 1 (modified from Yamao et al., 2014). The results of high-frequency electrical cortical stimulation. “Mirth” (circles) and “language” (diamonds) electrodes are shown in white and black colors for Patients 1 and 2, respectively. Note that mirth was elicited at or adjacent to the electrode associated with language impairment.  R = right side. The view is of the bottom of the brain.How do the authors interpret this finding?...the ratio of electrodes eliciting language impairment was higher for the mirth electrodes than in no-mirth electrodes, suggesting an association between mirth and language function. Since the BTLA is actively involved in semantic processing (Shimotake et al., 2014 and Usui et al., 2003), this semantic/language area was likely involved in the semantic aspect of humor detection in our cases.Except there was no external humor to detect, as the laughter and feelings of mirth were spontaneous. After high-frequency stimulation, one patient reported, “I do not know why, but something amused me and I laughed.” The other patient said, “A familiar melody that I had heard in a television program in my childhood came to mind; its tune sounded funny and amused me.”The latter description sounds like memory-induced nostalgia or reminiscence, which can occur with electrical stimulation of the temporal lobe (or TL seizures). But most of the relevant stimulation sites for those déjà vu-like experiences are not in the fusiform gyrus, which has been mostly linked to higher-level visual processing.The authors also found that stimulation of the left ... Read more »

LÜDERS, H., LESSER, R., HAHN, J., DINNER, D., MORRIS, H., WYLLIE, E., & GODOY, J. (1991) BASAL TEMPORAL LANGUAGE AREA. Brain, 114(2), 743-754. DOI: 10.1093/brain/114.2.743  

Scott, S., Lavan, N., Chen, S., & McGettigan, C. (2014) The social life of laughter. Trends in Cognitive Sciences, 18(12), 618-620. DOI: 10.1016/j.tics.2014.09.002  

Wild, B., & et al. (2003) Neural correlates of laughter and humour. Brain, 126(10), 2121-2138. DOI: 10.1093/brain/awg226  

Yamao, Y., Matsumoto, R., Kunieda, T., Shibata, S., Shimotake, A., Kikuchi, T., Satow, T., Mikuni, N., Fukuyama, H., Ikeda, A.... (2014) Neural correlates of mirth and laughter: A direct electrical cortical stimulation study. Cortex. DOI: 10.1016/j.cortex.2014.11.008  

  • December 22, 2014
  • 12:32 AM

Go to Bed Early and Cure Your Negative Ruminations!

by The Neurocritic in The Neurocritic

Source: Alyssa L. Miller, Flickr.For nearly 9 years, this blog has been harping on the blight of overblown press releases, with posts like:Irresponsible Press Release Gives False Hope to People With Tourette's, OCD, and SchizophreniaPress Release: Press Releases Are PrestidigitationNew research provides fresh evidence that bogus press releases may depend largely on our biological make-upSave Us From Misleading Press Releasesetc.So it was heartening to see a team of UK researchers formally evaluate the content of 462 heath-related press releases issued by leading universities in 2011 (Sumner et al., 2014). They classified three types of exaggerated claims and found that 40% of the press releases contained exaggerated health advice, 33% made causal statements based on correlational results, and 36% extrapolated from animal research to humans. A fine duo of exaggerated health advice and causal statements based on correlational results recently caught my eye. Here's a press release issued by Springer, the company that publishes Cognitive Therapy and Research: Don’t worry, be happy: just go to bed earlierWhen you go to bed, and how long you sleep at a time, might actually make it difficult for you to stop worrying. So say Jacob Nota and Meredith Coles of Binghamton University in the US, who found that people who sleep for shorter periods of time and go to bed very late at night are often overwhelmed with more negative thoughts than those who keep more regular sleeping hours.The PR issues health advice (“just go to bed earlier”) based on correlational data: “people who sleep for shorter periods of time and go to bed very late at night are often overwhelmed with more negative thoughts.” But does staying up late cause you to worry, or do worries keep you awake at night? A survey can't distinguish between the two.The study by Nota and Coles (2014) recruited 100 teenagers (or near-teenagers, mean age = 19.4 + 1.9) from the local undergraduate research pool. They filled out a number of self-report questionnaires that assessed negative affect, sleep quality, chronotype (morning person vs. evening person),1  and aspects of repetitive negative thinking (RNT). RNT is a transdiagnostic construct that encompasses symptoms typical of depression (rumination), anxiety (worry), and obsessive-compulsive disorder (obsessions). Thus, the process of RNT is considered similar across the disorders, but the content may differ. The undergraduates were not clinically evaluated so we don't know if any of them actually had the diagnoses of depression, anxiety, and/or OCD. But one can look at whether the types of symptoms that are endorsed (whether clinically relevant or not) are related to sleep duration and timing. Which is what the authors did.Shorter sleep duration and a later bedtime were indeed associated with more RNT. However, when accounting for levels of negative affect, the sleep variables no longer showed a significant correlation.2  Not a completely overwhelming relationship, then.But as expected, the night owls reported more RNT than the non-night owls.  Here's how the findings were interpreted in the Springer press release and conspicuously, by the authors themselves (the study of Sumner et al., 2014 also observed this pattern). Note the exaggerated health advice and causal statements based on correlational results. “Making sure that sleep is obtained during the right time of day may be an inexpensive and easily disseminable intervention for individuals who are bothered by intrusive thoughts,” remarks Nota.The findings also suggest that sleep disruption may be linked to the development of repetitive negative thinking. Nota and Coles therefore believe that it might benefit people who are at risk of developing a disorder characterized by such intrusive thoughts to focus on getting enough sleep.“If further findings support the relation between sleep timing and repetitive negative thinking, this could one day lead to a new avenue for treatment of individuals with internalizing disorders,” adds Coles. “Studying the relation between reductions in sleep duration and psychopathology has already demonstrated that focusing on sleep in the clinic also leads to reductions in symptoms of psychopathology.”As they mentioned, we already know that many psychiatric disorders are associated with problematic sleep, and that improved sleep is helpful in these conditions. Recommending that people suffering with debilitating and uncontrollable intrusive thoughts to “just go to bed earlier” isn't particularly helpful. Not only that, such advice can be downright irritating.Here's a news story from Yahoo that plays up the “sleep reduces worry” causal relationship even more:This Sleep Tweak Could Help You Worry LessCan the time you hit the hay actually influence the types of thoughts you have? Science says yes.Are you a chronic worrier? The hour you’re going to sleep, and how much sleep you’re getting overall, may exacerbate your anxiety, according to a new study published in the journal Cognitive Therapy and Research.The great news here? By tweaking your sleep habits you could actually help yourself worry less. Really. Great! So internal monologues of self-loathing (“I'm a complete failure”, “No one likes me”) and deep anxiety about the future (“My career prospects are dismal”, “I worry about my partner's terrible diagnosis”) can be cured by going to bed earlier!Even if you could forcibly alter your chronotype (and I don't know if this is possible), what do you do when you wake up in the middle of the night haunted by your repetitive negative thoughts?Further ReadingAlexis Delanoir on the RNT paper and much more in Depression And Stress/Mood Disorders: Causes Of Repetitive Negative Thinking And RuminationsScicurious, with an amusingly titled piece: This study of hype in press releases will change journalismFootnotes1 Chronotype was dichotomously classified as evening type vs. moderately morning-type / neither type (not a lot of early birds, I guess). And only 75 students completed questionnaires in this part of the study.2 It's notable that the significance level for these correlations was not corrected for multiple comparisons in the first place.References... Read more »

  • October 30, 2014
  • 07:59 AM

Fright Week: The Stranger in the Mirror

by The Neurocritic in The Neurocritic

In the mirror we see our physical selves as we truly are, even though the image might not live up to what we want, or what we once were. But we recognize the image as “self”. In rare instances, however, this reality breaks down.In Black Swan, Natalie Portman plays Nina Sayers, a ballerina who auditions for the lead in Swan Lake. The role requires her to dance the part of the innocent White Swan (for which she is well-suited), as well as her evil twin the Black Swan — which is initially outside the scope of her personality and technical abilities. Another dancer is favored for the role of the Black Swan. Nina's drive to replace her rival, and her desire for perfection, lead to mental instability (and a breathtaking performance). In her hallucinations she has become the Black Swan.1The symbolic use of mirrors to depict doubling and fractured identity was very apparent in the film:Perhaps Darren Aronofsky [the director's] intentions for the mirror was its power to reveal hidden identities. If you noticed the scenes where Nina saw herself in the mirror, it reflected the illusion of an evil. The mirror presented to her the darkness within herself that metaphorically depicted the evolution into the black swan. How can the recognition of self in a mirror break down?Alterations in mirror self-recognitionThere are at least seven main routes to dissolution or distortion of self-image:psychotic disordersdementiaright parietal-ish or otherwise right posterior cortical strokes and lesionsthe ‘strange-face in the mirror' illusion hypnosisdissociative disorders (e.g., depersonalization, dissociative identity disorderbody image issues (e.g., anorexia, body dysmorphic disorder) Professor Max Coltheart and colleagues have published extensively on the phenomenon of mirrored-self misidentification, defined as “the delusional belief that one’s reflection in the mirror is a stranger.” They have induced this delusion experimentally by hypnotizing highly suggestible participants and planting the suggestion that they would see a stranger in the mirror (Barnier et al., 2011): Following a hypnotic suggestion to see a stranger in the mirror, high hypnotizable subjects described seeing a stranger with physical characteristics different to their own. Whereas subjects' beliefs about seeing a stranger were clearly false, they had no difficulty generating sensible reasons to explain the stranger's presence. The authors tested the resilience of this belief with clinically inspired challenges. Although visual challenges (e.g., the hypnotist appearing in the mirror alongside the subject) were most likely to breach the delusion, some subjects maintained the delusion across all challenges. Ad campaign for the Exelon Patch (rivastigmine, a cholinesterase inhibitor) used to treat Alzheimer's disease. Photographer Tom Hussey did a series of 10 award-winning portraits depicting Alzheimer's patients looking at their younger selves in a mirror (commissioned by Novartis).Mendez et al. (1992) published a retrospective study of 217 patients with Alzheimer's disease. They searched the medical records for caregiver reports of disturbances in person identification of any kind. The most common type was transient confusion of family members that resolved when reminded of the person's identity (found in 33 patients). The charts of five patients contained reports of mirror misidentification, which was always associated with paranoia and delusions. Although not exactly systematic, this fits with other studies reporting that 2–10% of Alzheimer's patients have problems recognizing themselves in a mirror.A very thorough investigation of the topic was actually published 50 years ago, but largely neglected because it was in French. Connors and Coltheart (2011) translated the 1963 paper of Ajuriaguerra, Strejilevitch, & Tissot into English. The Introduction is quite eloquent:The vision of our image in the mirror is a discovery that is perpetually renewed, one in which our being is isolated from the world, from the objects surrounding it, and assumes, despite the fixed quality of reflected images, the significance of multiple personal and potential expressions. The image reflected by the mirror furnishes us not only with that which is, but also how our real image might be changed. It therefore inextricably combines awareness, indulgence and critique.They examined how 30 hospitalized dementia interacted with mirrors in terms of  (1) recognition of their own reflection; (2) use of reflected space; and (3) identifying body parts. The patients sat in front of a mirror and answered the following questions:What is this?Who is that?How old would you say that person is?How do you think you look?Then the experimenter stood behind them and asked questions about himself (e.g., “who is that man?”), and showed them objects in a mirror (e.g., an orange or a pipe – very funny).Eight patients did not recognize themselves in the mirror:Three didn't understand the concept of a mirror. They didn't pay attention to any reflections until directed to do so, and then they became transfixed. They also failed to recognize photos of themselves or their caretakers.Another three eventually admitted it might be themselves when prodded several times.These individuals had severe Alzheimer's disease.The final two recognized themselves the second time, and displayed considerably more anxiety. This sounds terribly frightening:These patients were attentive to their own reflections and those of the researchers, whom they identified. The first patient seemed a bit anxious; she began by touching herself, then laughed, then proclaimed “that is not quite me, it sort of looks like me, but it's not me.” When she was shown her photo head-on and then from the side, she immediately identified herself when the photo was head-on but from the side said “that's not quite me.” These individuals were in an earlier state of dissolution and likely had more awareness of what was happening to them.Other patients with mirrored-self misidentification show greater sparing of cognitive abilities. Chandra and Issac (2014) presented brief case summaries of five mild to moderate dementia patients with “mirror image agnosia, a new observation involving failure to recognize reflected self-images.” This is obviously not a new observation, but the paper includes two videos, one of which is embedded below. Sixty-two-year-old female was brought to the hospital with features of forgetfulness and getting... Read more »

Barnier AJ, Cox RE, Connors M, Langdon R, & Coltheart M. (2011) A stranger in the looking glass: developing and challenging a hypnotic mirrored-self misidentification delusion. The International journal of clinical and experimental hypnosis, 59(1), 1-26. PMID: 21104482  

Chandra SR, & Issac TG. (2014) Mirror image agnosia. Indian journal of psychological medicine, 36(4), 400-3. PMID: 25336773  

Mendez MF, Martin RJ, Smyth KA, & Whitehouse PJ. (1992) Disturbances of person identification in Alzheimer's disease. A retrospective study. The Journal of nervous and mental disease, 180(2), 94-6. PMID: 1737981  

  • October 25, 2014
  • 09:58 PM

Fright Week: The Waking Nightmare of Lord Voldemort

by The Neurocritic in The Neurocritic

Nightmares can seem very real at times, but then we wake up and realize it was all a bad dream. Now imagine having a vivid nightmare with all the reality of waking life and then... it turns out you're actually awake through it all!This happened to an 11 year old Italian boy who reported frightening auditory and visual hallucinations of Voldemort, the archenemy of Harry Potter, for three straight days. These hallucinations began after a bout of sore throat and fever (38°C).  As Vita et al. (2008) report:The day after the resolution of fever, he began to present hallucinations. Hallucinations occurred in the afternoon, after watching TV. They were polymodal: he saw and heard Voldemort (an evil character of the Harry Potter saga). He did not realize his hallucinations were not real; he was extremely frightened, and he cried and searched his parents for protection. The episode lasted several hours, and was not associated with modification of vigilance or consciousness. ... Two days later, a new hallucinatory episode occurred: again, he saw Voldemort, who appeared threatening, and he fought against him. A further episode, with the same features, occurred the following day. He interacted with the characters of the hallucination, and on one occasion, he wore a sword and helmet to fight against Voldemort. When asked to recall the hallucinations, the boy said that they appeared real to him. Neurological exam, EEG, and CSF cultures for bacteria, viruses, and fungi were all negative. CSF titers of antibodies were normal, and there was no evidence of autoantibodies. However, an MRI scan showed abnormal signs in the boy's brainstem. Several small lesions were observed in the pons, in the vicinity of a region implicated in REM sleep.Fig. 1 (modified from Vita et al., 2008). MRI after the onset of hallucinations. Small areas of signal hyperintensity (lesions) are indicated by the arrows.The etiology and phenomenology of the boy's condition seem consistent with peduncular hallucinosis, “a rare form of visual hallucination often described as vivid, colorful visions of people and animals.” The exact cause is unknown, but most cases have been related to lesions in the midbrain, thalamus, or brainstem (Dogan et al. 2013; Penney & Galarneau, 2014; Talih, 2013). In some instances the patients are aware that the hallucinations are not real, but other cases present as a psychiatric disorder and can include auditory or tactile hallucinations, in addition to visual.Here, Vita et al. (2008) speculate that dreaming and REM sleep have become dissociated: the boy was literally dreaming while awake. Fortunately, his nightmarish condition disappeared after treatment with immunoglobulins. The exact diagnosis was unclear, but it might have been a transient demyelinating syndrome, which involves the loss of white matter, or myelin, that surrounds the axon.The authors cited a model of REM sleep in which GABA-containing “REM-on” neurons inhibit GABAergic “REM-off” neurons located in the ventrolateral periaqueductal gray matter (vlPAG) and lateral pontine tegmentum (LPT), and vice versa.Fig. 1 (modified from Vita et al., 2008). MRI after the onset of hallucinations. Three small lesions are indicated by the arrows.Turns out the lesions (shown in gray stippling below) could include some of these neurons, especially those in the REM-off areas (vlPAG and LPT). Fig. 1 (modified from Vita et al., 2008). Schematic of the REM-on and REM-off areas in the pons. Gray stippling indicates the lesions. REM-on region in black, REM-off regions in white.1The authors speculated that transient dysfunction of REM-off cells, caused by the inflammatory demyelinating syndrome, resulted in weaker inhibition of REM-on cells, allowing a dream-like state to ooze into wakefulness. Luckily the boy won out over Voldemort in the end, assisted by a team of doctors at Catholic University in Rome.Footnote1  Detailed figure legend:D: scheme of the REM-on and REM-off areas in the pons. In black: the REM-on region (locus subceruleus-α [sLCα]). In white: the REM-off region: ventrolateral periaqueductal gray (vlPAG) and lateral pontine tegmentum (LPT). In gray the REM modulatory regions: in rostrocaudal order, pedunculopontine tegmentum (PPT), laterodorsal tegmentum (LDT), dorsal raphe nucleus (DRN), and locus ceruleus (LC). Gray dotted areas: sites of the inflammatory lesions.ReferencesDogan VB, Dirican A, Koksal A, Baybas S. (2913). A case of peduncular hallucinosis presenting as a primary psychiatric disorder. Ann Indian Acad Neurol. 16(4):684-6. Penney L, Galarneau D. (2014). Peduncular hallucinosis: a case report. Ochsner J. 14(3):450-2. Talih FR. (2013). A probable case of peduncular hallucinosis secondary to a cerebral peduncular lesion successfully treated with an atypical antipsychotic. Innov Clin Neurosci. 10(5-6):28-31. ... Read more »

Vita MG, Batocchi AP, Dittoni S, Losurdo A, Cianfoni A, Stefanini MC, Vollono C, Della Marca G, & Mariotti P. (2008) Visual hallucinations and pontine demyelination in a child: possible REM dissociation?. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, 4(6), 588-90. PMID: 19110890  

  • October 15, 2014
  • 04:36 AM

Harry Potter and the Prisoner of Mid-Cingulate Cortex

by The Neurocritic in The Neurocritic

What happens in the brain during a highly immersive reading experience? According to the fiction feeling hypothesis (Jacobs, 2014), narratives with highly emotional content cause a deeper sense of immersion by engaging the affective empathy network to a greater extent than neutral narratives. Emotional empathy – in this case, the ability to identify with a fictional character via grounded metarepresentations of ‘global emotional moments’ (Hsu et al., 2014) – relies on  a number of brain regions, including ventromedial prefrontal cortex (PFC), dorsomedial PFC, anterior insula (especially in the right hemisphere), right temporal pole, left and right posterior temporal lobes, inferior frontal gyrus, and midcingulate cortex.A group of researchers in Germany used text passages from the Harry Potter series to test the fiction feeling hypothesis, specifically that readers will experience a greater sense of empathy for and identification with the protagonists when the content is suspenseful and scary (Hsu et al., 2014). This would be accompanied by greater activations in specific brain regions during an fMRI scan.The experimental stimuli were 80 passages from the Harry Potter novels. The authors selected 40 ‘fear-inducing’ and 40 ‘neutral’ passages, each about 4 lines long. 1  These were screened and rated by a set of independent participants. Unfortunately, the authors did not provide any examples, so I'm going to have to improvise here.Given that I've not read any of the Harry Potter books (or seen the movies), I'm not the best person to run a popular blog serial on NeuroReport's Harry Potter and the _______ books.  Or to to launch an academic publishing franchise on fMRI studies of epic fantasy novels. 2 But here's a sampler anyway, based on Ayn Rand’s Harry Potter and the Prisoners of Collectivism: 3He felt the unnatural cold begin to steal over the street. Light was sucked from the environment right up to the stars, which vanished. The cold was biting deeper and deeper into Harry’s flesh [and lighting up his pain matrix in an eerie glow against the dark and lonely night].Then, around the corner, gliding noiselessly, came Dementors, ten or more of them, visible because they were of a denser darkness than their surroundings, with their black cloaks and their scabbed and rotting hands. Could they sense fear [and an overactive amygdala] in the vicinity? ...Suddenly he heard them: Marxists.. . .“Only together, collectively, can we achieve anything of lasting significance,” he heard one of them say. Harry moaned in pain [his anterior cingulate and insular cortices writhing from such cognitive dissonance and social exclusion].“The fortunate owe it to society to contribute to those who cannot work,” another chanted. Harry closed his eyes and collapsed [his ventral posteriorlateral thalamic nuclei and somatosensory cortex no longer able to endure the intolerable battering].My poorly written additions in maroon prefigure the focus of the study – empathy for pain. I'm not exactly sure why this was so (for either literary or scientific reasons). At any rate, Hsu et al. (2014) made the following predictions:we expected (i) higher immersion ratings for fear-inducing passages, which often describe pain or personal distress, as compared with neutral passages, and (ii) significant correlations of immersion ratings with activity in the affective empathy network, particularly AI [anterior insula] and mCC [mid-cingulate cortex], associated with pain empathy for fear-inducing, but not for neutral, passages.AI and mCC have been implicated in the affective component of personally felt pain, as well as in empathy for another person's pain (Jackson et al., 2006). So the expected result would be greater activations in AI and mCC for the Fearful vs. Neutral comparison. They didn't do this exact contrast, but they did look for differential correlations between “immersion ratings” and BOLD responses for Fear > fixation (a low-level control condition) and Neutral > fixation.A separate group of individuals (not the ones who were scanned) rated the Fearful and Neutral passages for immersion by rating their subjective experience, ‘I forgot the world around me while reading’ on a scale from 1 (totally untrue) to 7 (totally true). Although the difference between Fear (mean = 3.75) and Neutral (mean = 3.18) was statistically significant, the level of immersion wasn't all that impressive, being below the midpoint even for the scary texts.The major fMRI result was a cluster in the mid-cingulate cortex (corrected cluster-level P = 0.037) that showed a higher correlation between immersion ratings and BOLD for Fear than for Neutral.Fig. 1B (modified from Hsu et al., (2014). The mid-cingulate gyrus showing a significant correlation difference between passage immersion ratings and BOLD response in the Fear versus Neutral conditions, cross-hair highlighting the peak voxel [8 14 39].No such relation was observed in the anterior insula, which was explained by postulating that “motor affective empathy” was more prominent than “sensory affective empathy”:Craig [12] considered mCC to be the limbic motor cortex and the site of emotional behavioural initiation, whereas AI is the sensory counterpart. With respect to our stimuli from Harry Potter series, in which behavioural aspects of emotion are particularly vividly described, the motor component of affective empathy (i.e. mCC) might predominate during emotional involvement, and facilitate immersive experience.This is obviously a post-hoc explanation, one that's hard to judge in the absence of actual exemplars of the experimental stimuli. Although the results were a bit underwhelming, I was happy the authors did not venture out on a rickety and hyperbolic limb, as the NYT did (gasp!) in ... Read more »

  • September 26, 2014
  • 08:14 AM

Anthropomorphic Neuroscience Driven by Researchers with Large TPJs

by The Neurocritic in The Neurocritic

For immediate release — SEPTEMBER 26, 2014Research from the UCL lab of Professor Geraint Rees has proven that the recent craze for suggesting that rats have “regrets” or show “disappointment” is solely due to the size of the left temporal-parietal junction (TPJ) in the human authors of those papers (Cullen et al., 2014). This startling breakthrough was part of a larger effort to associate every known personality trait, political attitude, and individual difference with the size of a unique brain structure.Cullen and colleagues recruited 83 healthy behavioral neuroscientists and acquired structural brain images using a 1.5-T Siemens Sonata MRI scanner.  The participants completed the Individual Differences in Anthropomorphism Questionnaire (IDAQ), along with 698 other self-report measures. Factor analysis of the IDAQ yielded a two factor solution: anthropomorphism of 1) non-human animals, and 2) non-animals (technology and nature).Voxel-based morphometry (VBM) was to quantify gray matter volume from the structural MRIs. To do this, the authors constructed a “mentalizing mask” to divine which regions of interest (ROIs) would yield the best results.Based on the intuitions of Psychic Love Doctor Anabella (and results from previous studies on theory of mind and social cognition), six 12 mm spheres were drawn in the left and right medial prefrontal cortices (x y z MNI coordinates = ±10, 51, 34), the temporal poles (±43, 8, −34), and the posterior superior temporal sulcus/TPJ (±52, −56, 23). Separate analyses were done using another “mentalizing mask” with different coordinates as well as an anatomically-based mask. But the authors went with the Psychic Love Doctor mask after all. They also did a whole brain analysis, by the way.“You’ll Never Believe What Happened Next.”A tiny little cluster of 24 voxels in the left TPJ correlated with scores on the animal IDAQ scale. This means that the neuroscientists responsible for studies on regret (Steiner & Redish, 2014) and disappointment (Shabel et al., 2014) in rats had the largest L TPJs, by far. Besides publishing in Nature Neuroscience and Science, respectively, these participants were most inclined to attribute human mental states to non-human animals.Fig. 1 (Cullen et al., 2014). The region where grey matter volume showed a correlation with anthropomorphism of non-human animals is shown overlaid on a T1-weighted MRI anatomical image. The cross hair identifies the cluster at the left temporoparietal junction (−45,−54, 27) showing a statistically significant (P < 0.05 FWE-corrected for volume examined) positive correlation with anthropomorphism of non-human animals as measured by the animal IDAQ. However, readers of io9 and The Newer York will be sorely disappointed that no areas of the brain were correlated with anthropomorphization of robots.What does this mean for the future of neuroscience research? Given the prestigious outlets that publish papers in the hot new field of Anthropomorphic Neuroscience, here's what I envision:  transcranial direct current stimulation (tDCS) labs will be overrun with modest scientists who study spatial memory, hoping a stimulating, L TPJ-induced portrayal of rats as taxi drivers will land them in the pages of Nature.-----Disclaimer: Although this post is based on a real study, some of the details are fictionalized. I leave it to the discerning reader to separate fact from fiction. My sincerest apologies to all the authors.Further ReadingOf Mice and Women: Animal Models of Desire, Dread, and Despair – are they really adequate stand-ins for the human condition?Post-modern Anthropomorphism – rat “regret” author A. David Redish, Ph.D. on the use of human cognitive terms for non-human animal behavior.Rats Regret Making the Wrong Decision – accessible summary.Scientists Discover “Dimmer Switch” For Mood Disorders – strains credulity to go from rat “disappointment” to a depression dimmer switch in humans.Not tonight dear, I had zymosan A injected into my hind paw – Hypoactive Sexual Desire Disorder, in rats. You decide.Liberals Are Conflicted and Conservatives Are Afraid – discusses the Colin Firth study on political orientation and brain structure (Kanai, Feilden, Firth & Rees, 2011). References... Read more »

  • September 16, 2014
  • 06:36 AM

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

by The Neurocritic in The Neurocritic

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

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

  • September 8, 2014
  • 02:41 AM

A Dangerous New Dish

by The Neurocritic in The Neurocritic

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

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

  • August 31, 2014
  • 06:36 PM

Whitman Was Not a Neuroscientist

by The Neurocritic in The Neurocritic

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

  • August 25, 2014
  • 02:39 AM

Autobiographical Memory for a Life-Threatening Airline Disaster

by The Neurocritic in The Neurocritic

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

  • July 31, 2014
  • 07:10 PM

Twitter Psychosis as a Cultural Artifact

by The Neurocritic in The Neurocritic

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

... Read more »

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

  • July 10, 2014
  • 07:17 AM

Can a Failed Schizophrenia Drug Prevent PTSD?

by The Neurocritic in The Neurocritic

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

  • June 1, 2014
  • 07:59 AM

Feeling Mighty Unreal: Derealization in Kleine-Levin Syndrome

by The Neurocritic in The Neurocritic

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

  • May 26, 2014
  • 04:41 PM

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

by The Neurocritic in The Neurocritic

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

... Read more »

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

  • May 18, 2014
  • 10:44 PM

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

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