Monday, August 08, 2016

Scientific Study Shows Mediums Are Wrong 46.2% of the Time

Not a very good showing, eh?


In the study,
“Participants were asked to press a button if they thought the person in a photo was living or deceased. Overall mean accuracy on this task was 53.8%, where 50% was expected by chance (p < 0.004, two-tail). Statistically significant accuracy was independently obtained in 5 of the 12 participants.”

The abstract claims the participants showed better than chance performance, but even if we accept this level of accuracy at face value (so to speak), the mediums were wrong 46.2% of the time. Remember that before your next psychic reading.

And of course we should not accept the results at face value. Let's take a closer look at the paper (Delorme et al., 2016), which was published in Frontiers in Human Neuroscience



Actually, let's take a closer look at the authors first. Arnaud Delorme, Alan Pierce, Leena Michel,  and Dean Radin are all affiliated with the Institute of Noetic Sciences (IONS), a parapsychology research institute in California. Dr. Delorme is also affiliated with UC San Diego. Along with Scott Makeig, he developed EEGLAB, a Matlab toolbox that's widely used to analyze EEG data. Delorme and Makeig (2004) has been cited 5738 times (as of this writing).

Why is Delorme doing parapsychology research?? He's a long-time Zen meditator, according to his IONS biography. Why is Frontiers publishing parapsychology research? Here's one opinion.


Dead or Alive?


Figure 1 (Delorme et al., 2016). Process involved in creating a group of photographs of “Alive” and “Deceased” individuals.


Photographs of known alive and dead people were selected from three internet databases: (D1) school portraits from 1939–1941; (D2) school portraits from 1962–1968; and (D3) politicians (US senators excluded) and businessmen. Why? Why use pictures of US Representatives and state politicians outside of California? Even though the subjects said they didn't recognize them, there could be a vague sense of familiarity with some of these faces.

Photos of 404 individuals were presented, and the 12 participants pressed keys to indicate “deceased,” “living,” or “do not know”. 1

The participants all “claimed to be able to experience feelings of vitality from facial photographs alone. ... They were required to have been performing professional ‘readings’ for clients...” THERE WAS NO CONTROL GROUP.  In other words, participants who did not claim any psychic or clairvoyant abilities were not included in this study. Thus, there was no way to know if the marginal ability to discern whether a person was alive or dead was based on mediumship.

And marginal it was. Basically, they were terrible at determining whether people in old yearbook photos were dead or alive. Terrible. No better than guessing. 2




Given the number of statistical tests, we should only consider values with *** (p<.001), of which there were two (out of 35 possible comparisons). Therefore, the evidence for mortality prediction (clairvoyance) should not be taken seriously, despite the authors' conclusion:
We do not rule out the hypothesis that subjects might have had access to information in ways that are not currently understood by modern physics and could potentially go beyond classical information delivered by facial features.

Paranormal physics do not apply to old photographs, however.

And the EEG data were equally unconvincing. The face-specific N170 component did not differ based on dead or alive, correct or incorrect. The earlier P1 component showed a small difference between correct and incorrect responses for the deceased only, but there was no good explanation for this (“Future research could assess if low-level visual image characteristics and attentional modulation were important factors in leading to this difference in electrocortical activity”).

The truth is out there, but this study provides no proof that the ‪#‎Supernatural‬ actually exists.


Footnote

The “do not know” responses were not included in the analyses, and we have no idea of how many such responses were recorded.

2 Oh here's a fun fact. S06 indicated that 90% of the people in the photos were dead.


Reference

Delorme, A., Pierce, A., Michel, L., & Radin, D. (2016). Prediction of Mortality Based on Facial Characteristics. Frontiers in Human Neuroscience, 10.  DOI: 10.3389/fnhum.2016.00173




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Friday, July 29, 2016

Clinical Trial for Alzheimer's Disease - Is LMTX Ineffective or Unprecedented?






So which is it? Ineffective or unprecedented?

TauRx Alzheimer's Drug LMTX Fails in Large Study Although Some Benefit Seen

Wednesday, 27 Jul 2016 | 11:23 AM ET

TauRx Pharmaceuticals' experimental Alzheimer's drug LMTX failed to improve cognitive and functional skills in patients with mild to moderate Alzheimer's disease, a large, late-stage study showed.

But in a perplexing twist, the drug did show a significant benefit in about 15 percent of patients in the trial who were not taking other standard Alzheimer's drugs, according to the findings released on Wednesday at the Alzheimer's Association International Conference in Toronto.


LMTX was ineffective in a clinical trial of 891 patients with Alzheimer's disease (AD), although a post hoc analysis in a small subgroup of patients showed a benefit for those taking no other medications for AD (when compared to an inappropriate control group).


Ben Goldacre, Chris Chambers, and others on Twitter took the UK media to task for their misleading articles on the outcome of the trial conducted by TauRx Pharmaceuticals.

As the name implies, TauRx is developing Alzheimer's treatments based on disrupting tau protein, which accumulates in pathological tangles in the brain. Tau aggregation inhibitors are presumed to disrupt these tangles, thereby slowing neurodegeneration and memory loss. The degradation of tau aggregates in vitro was first demonstrated 20 years ago (Wischik et al., 1996), using the stain methylene blueLMTX is a variant of methylene blue, which turns urine blue. For that reason, the placebo group in the TauRx trial received a tiny amount of the drug for blinding purposes.

The clinical trial protocol is NCT01689246, Safety and Efficacy Study Evaluating TRx0237 in Subjects With Mild to Moderate Alzheimer's Disease. The original enrollment across 121 sites was estimated at 833, and the original duration was 12 months. The duration was changed to 15 months about a year later, and five other outcome measures were added. And a secondary outcome measure (ADCS-ADL23) and a primary outcome measure (ADCS-CGIC) were swapped.

The company press release used a vague headline (TauRx Reports First Phase 3 Results for LMTX®) to announce the results, but led off with the subgroup analysis (no surprise):

TauRx Therapeutics Ltd today announced Phase 3 clinical trial results that show treatment with LMTX®, the company's novel tau aggregation inhibitor, had a marked beneficial effect on key measures of Alzheimer's disease in patients with mild or moderate forms of the disease.

While the TRx-237-015 study in 891 subjects failed to meet its co-primary endpoints, clinically meaningful and statistically significant reductions in the rate of disease progression were observed across three key measures in patients who were treated with LMTX® as their only Alzheimer's disease medication. These three key measures comprised a cognitive assessment (ADAS-Cog), a functional assessment (ADCS-ADL) and an assessment of the level of brain atrophy (lateral ventricular volume, LVV, as measured by MRI). An abstract of the results will be presented during an open session at the 2016 Alzheimer's Association International Conference (AAIC) in Toronto, Canada this afternoon by Dr. Serge Gauthier, CM, MD.

The ADCS-ADL was originally a secondary outcome measure, and hippocampal volume (not reported) was included as an “Other” outcome measure along with the lateral ventricle volume measurements. Keep in mind these results are preliminary (not peer-reviewed). However, given the possibility of a true positive treatment effect, I can understand why publication would be of secondary importance. There should be no delay in starting AD patients on an effective new and proven treatment (which this is not).

It took a while to find the conference abstract by Gaultier et al. (2016), but an excerpt is below. The actual results were not included the abstract aimed to “highlight the potential therapeutic value” of LMTX (also called LMTM and TRx-0237)  but the text did mention the “85% were taking approved AD treatments” aspect of the study.

Gaultier et al., AAIC 2016

LMTM (TRx-0237) is a novel stabilized reduced form of the methylthioninium moiety with potential for efficacy in treatment of Alzheimer's disease. ... It acts as a selective tau aggregation inhibitor in vitro and in transgenic mouse models  The present 15-month double-blind, placebo-controlled trial (NCT01689246) was performed in patients with probable AD, MMSE score in the range 14-26, Clinical Dementia Rating 1-2 and age < 90 years. Patients were randomized 3:3:4 to receive oral LMTM at doses of 150 or 250 mg/day or placebo (containing 8 mg/day, to maintain blinding) respectively. Primary efficacy outcomes were change from baseline on cognitive (ADAS-Cog) and functional (ADCS-ADL) scores. Three-monthly assessment included magnetic resonance imaging (MRI) as a disease modifying outcome. Other secondary outcomes included ADCS-CGIC and MMSE. Results: A total of 891 patients were randomized, of whom 62% were female. Approved AD treatments were being taken in 85%. The mean age was 70.6 (SD 9.0) years and baseline MMSE score was 18.7 (SD 3.4). ... The study efficacy and safety outcomes will be reported. The outcomes of this phase 3 trial will highlight the potential therapeutic value of tau aggregation inhibitor therapy in AD. A second phase 3 trial of LMTM for AD will be completed and reported later in 2016.

[The entire abstract with authors and affiliations is at the end of this post.]

The 15% who benefited from LMTX® were the patients who were not taking any other medications for dementia (e.g., acetylcholinesterase inhibitors). This monotherapy subgroup was compared to the entire placebo group, not to the subgroup of placebo patients not on any other dementia meds (as pointed out by @bengoldacre). It was nice to read critical coverage of the TauRx spin (and media reporting) at Forbes, BuzzFeed, and Quartz.


Meanwhile, New Scientist updated their headline (and url) to more accurately reflect reality.




Is it worthwhile for TauRx to pursue a proper clinical trial of LMTX as a monotherapy?  Maybe. The big mystery is why LMTX didn't work in patients taking the usual medications for dementia. There's no convincing mechanism to explain that odd result (Wischik: “other Alzheimer’s treatments help to clear toxic material out of the brain, and may also clear away LMTX too”). Or it could be a p-hacked false positive, or a function of milder severity or diagnostic issues or study site in the 15%. If TauRx is truly confident that LMTX taken alone can slow the progression of AD by 80%, then run another randomized controlled study where LMTX + no AD meds is compared to placebo + no AD meds.

Meanwhile, exaggerated reporting on “the first drug to halt Alzheimer’s” is highly unethical.


ADDENDUM (Aug 2 2016): A damning article at Alzforum says, In First Phase 3 Trial, the Tau Drug LMTM Did Not Work. Period.
On the main primary results slide, disease progression curves for both doses of drug and the placebo were practically identical. Scientists’ disappointment at this finding soon turned into disbelief when Gauthier went on to present a subgroup analysis that held no statistical credence yet purported to show a strong benefit on cognition and brain atrophy.
 
Thanks to @MaikWallas for the link.


AAIC Conference Abstract

Phase 3 Trial of the Tau Aggregation Inhibitor Leuco-Methylthioninium-Bis(hydromethanesulfonate) (LMTM) in Mild to Moderate Alzheimer's Disease

Serge Gauthier, MD1; Howard H Feldman, MD2; Lon S Schneider, MD, MS3; Gordon Wilcock, MD4; Giovanni B Frisoni, MD5; Jiri Hardlund, MD6; Karin Kook, PhD7; Damon J Wischik, PhD6; Bjoern O Schelter, PhD8; John M Storey, PhD6,8; Charles R Harrington, PhD6,8 and Claude M Wischik, MD, PhD6,8, (1)McGill University Research Centre for Studies in Aging, Verdun, QC, Canada, (2)University of British Columbia, Vancouver, BC, Canada, (3)Keck School of Medicine of USC, Los Angeles, CA, USA, (4)Oxford University, Oxford, United Kingdom, (5)Universite de Geneve, Geneve, Switzerland, (6)TauRx Therapeutics Ltd, Aberdeen, United Kingdom, (7)Salamandra LLC, Bethesda, MD, USA, (8)University of Aberdeen, Aberdeen, United Kingdom

Background: Leuco-methylthioninium-bis(hydromethanesulfonate) (LMTM; TRx-0237) is a novel stabilized reduced form of the methylthioninium (MT) moiety (Harrington et al. J Biol Chem 2015;290:10862) with potential for efficacy in treatment of Alzheimer's disease (AD). A previous trial using the oxidized form of MT identified dose dependent absorption limitations (Wischik et al. J Alzheimers Dis 2015;44:705). LMTM is better absorbed and tolerated (Baddeley et al. J Pharmacol Exptl Therapeutics 2015;352:110) permitting higher doses to be tested. It acts as a selective tau aggregation inhibitor in vitro (Harrington et al. J Biol Chem 2015;290:10862) and in transgenic mouse models (Melis et al. Behav Pharmacol 2015;26:353). Methods: The present 15-month double-blind, placebo-controlled trial (NCT01689246) was performed in patients with probable AD, Mini-Mental State Examination (MMSE) score in the range 14-26, Clinical Dementia Rating (CDR) 1-2 and age < 90 years. Patients were randomized 3:3:4 to receive oral LMTM at doses of 150 or 250 mg/day or placebo (containing 8 mg/day, to maintain blinding) respectively. Primary efficacy outcomes were change from baseline on cognitive (Alzheimer's Disease Assessment Scale cognitive subscale; ADAS-Cog) and functional (Alzheimer's Disease Cooperative Study Activities of Daily Living; ADCS-ADL) scores. Three-monthly assessment included magnetic resonance imaging (MRI) as a disease modifying outcome. Other secondary outcomes included ADCS-CGIC and MMSE. Results: A total of 891 patients were randomized, of whom 62% were female. Approved AD treatments were being taken in 85%. The mean age was 70.6 (SD 9.0) years and baseline MMSE score was 18.7 (SD 3.4). Dementia was of moderate severity (MMSE score 14-19) in 61%. The study efficacy and safety outcomes will be reported. Conclusions: The outcomes of this phase 3 trial will highlight the potential therapeutic value of tau aggregation inhibitor therapy in AD. A second phase 3 trial of LMTM for AD will be completed and reported later in 2016.

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Friday, July 22, 2016

A New Twist on Some Old Brain Myths



1. We only use 4 to 5% of our brains.

The usual ten percent myth is wrong, according to Brain Vizion. We have even more untapped potential waiting to be unlocked!
Brain is the most complex organ in the human body & serves as the center of the nervous system. Brain is the amazing organ as we go deeper we realize the miracles of the GOD. If all information of all books in the world is loaded into the brain, human brain will never be full. Do you know, we are using at the most 4% to 5% of potential of our brain?. Potential of human brain is beyond our imagination. Full potential is a result of proper education (mental development). Think what will happen if we use whole brain?





2. Left Brain, Right Brain, Mid Brain

Everyone knows the left brain/right brain myth. But did you know that you should stimulate your mid brain?
Mid-brain activation is a method to stimulate and balance the left and right brains. Mid brain Activation allows the middle brain act as a control panel for left and right hemispheres. This activates both parts of the brain and enhances the capacity and ability to learn.

What is the middle brain?
Mid brain manages functions of left and right brain. Mid brain is the ‘bridge’ between left and right hemispheres. [No, that would be the corpus callosum.] Once the mid brain gets activated, information will exchange more efficiently in between both hemispheres which leads to more efficient in learning and absorbing information.Mid brain activation allows the brain to function as a whole, rather than only utilizing one part of the brain.




3. Left Brain is Beta, Right Brain is Alpha.

Did you know that each hemisphere has a unique pattern of oscillatory brain activity, operating at separate frequency bands?
One type of brain function belongs to left brain which operates at Beta wave frequency (14Hz to 30Hz cycles/sec). This is the brain we are most familiar with, having developed this brain in traditional academy settings. ... The right brain works at Alpha wave frequency (8 to 13 hertz cycles per second). This is the frequency of the brain associated with a relaxed alert state of mind such as in meditation, just before getting out of bed or while listening to music. It is not the type of brain activity which determines whether something is right or left brain oriented, but rather the brain wave that is operating at the time (Alpha or Beta).




4. Move over theta, it's time for THEATA wave learning.

Back to our magical friend, Mid Brain Activation:
In order to awaken this part of the brain, it is necessary to stimulate a hormonal discharge by sending a special vibration. For this scientific alpha-theta level music are played where apparently only children can receive these waves effectively. In general, theta and alpha waves belong to babies and children. Since these waves belong to the subconscious mind babies and children feel easier to learn something or receive and follow somebody else’s words.  

Wait, I thought alpha waves belong to the right hemisphere...

Mystical brain training outlet Brain Vizion has clearly moved from common brain myths into ESP territory here:
During the mid-brain activation, a child learns how to enter the condition of meditative trans in order to be able to ”see” with eyes closed (Blind-folded).
. . .

Blindfold activation ... is a form of extra sensory perception.Our activated mid-brain’s brain-wave may detect objects nearby & appears in our mind as a form of visualization.Science have proven that even animals are able to perform such ability when moving around or looking for food.e.g.Bats.In human beings , in Blind-fold activation intuition play an important role.

OK then. What can THEATA wave training do for you?
Children will be given an opportunity to do activities of ALPHA & THEATA level vigorously throughout the workshop.Conventional school emphasize predominantly on BETA waves & neglect the importance of ALPHA & THEATA wave learning environment which are for more conducive.


The benefits of their Brain Stimulation program also include improvements in attention, mood, motivation, energy, pain, sleep, performance enhancement, and stress reduction.

It gets even weirder, with the quackery known as the Dermatoglyphics Multiple Intelligence Test (DMIT).




What is the Relation between Human Brain and Fingerprints? Don't click unless you want to see pictures of anencephalic babies. Instead, if you really want to read more about DMIT, Hand Reading News & Reports has a comprehensive review of its history, pseudoscientific claims, and scams.

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Saturday, July 16, 2016

Professor Richard Frackowiak on Retirement (and the Human Brain Project)


A neuroimaging pioneer, distinguished Professor Richard Frackowiak, has come out in favor of retirement:
I retired aged 65 – I am known for being very pro-retirement. Older scientists should advise, if asked, by the next generation, which they trained. They should refrain from occupying leadership positions or directing implementation – the time for that is past.

This is an important public stance to take in a time of dwindling resources and opportunities for junior scientists. On the one hand, with the steady increase in life expectancy since 1935, many aging Boomers plan to work well into their 70s. But on the other hand, this glut of working elders deprives many talented young researchers entrée into tenure track positions. The fact that a senior scientist wants to move aside to allow the next generation to occupy leadership positions is notable, in my view.

Prof Frackowiak's opinion on retirement was included in his comment on a post about Henry Markam and the Human Brain Project (HBP). In The laborious delivery of Markram’s brainchild, science journalist Leonid Schneider takes Markram to task for his dictatorial HBP leadership, his publishing empire (Frontiers), and most of all his hubris (e.g., 2009 TED talk):
“I hope that you are at least partly convinced that it is not impossible to build a brain. We can do it within 10 years, and if we do succeed, we will send to TED, in 10 years, a hologram to talk to you”.

Frackowiak found the post “scurrilous” and specifically objected to Schneider's mischaracterization of his own retirement as “resigning” from the HBP:
I note one mistake that could easily have been checked. Makes me wonder about the accuracy of this scurrilous blog. I did not resign from the HBP. I remain a task leader in the Medical Informatics Platform.  




But many have objected to the goals and governance of the HBP from the very beginning. In fact, two years ago, 156 Principal Investigators (eligible for HBP funding) and 660 others signed an Open message to the European Commission concerning the Human Brain Project. I won't rehash those issues (see further reading below).

Schneider ends with some pointed links to highly embarrassing Frontiers papers, including one endorsing chemtrail conspiracy theories. Frontiers has issued an Expression of Concern about this paper:
An expression of concern on
Human and Environmental Dangers Posed by Ongoing Global Tropospheric Aerosolized Particulates for Weather Modification
by Herndon, J.M. (2016). Front. Public Health 4:139. doi: 10.3389/fpubh.2016.00139

With this notice, Frontiers states its awareness of several complaints and serious allegations surrounding the article “Human and Environmental Dangers Posed by Ongoing Global Tropospheric Aerosolized Particulates for Weather Modification” published on 30 June 2016. Our Chief Editors, Joav Merrick and Anwar Huq, will direct an investigation in full accordance with our complaints procedures. The situation will be updated as soon as the investigation is complete.

UPDATE (17 July 2016): The chemtrails article has been retracted by Frontiers (via @Neuro_Skeptic):
Based on information discovered after publication and reported to Frontiers in July 2016, the article was examined, revealing that the complaints were valid and that the article does not meet the standards of editorial and scientific soundness for Frontiers in Public Health. The retraction of the article was approved by the Field Chief Editor of Frontiers in Public Health and the Specialty Chief Editor of Environmental Health. The author considers the retraction to be unwarranted and therefore does not agree to the statement. 


What does this have to do with the HBP?? Nothing. It came along as part of the larger anti-Markram package.


Further Reading

Guest post: Dirty Rant About The Human Brain Project

Interview: What’s wrong with the Human Brain Project?

Markram et al. (2015). Reconstruction and Simulation of Neocortical Microcircuitry. Cell. 2015 Oct 8;163(2):456-92.

Behold, The Blue Brain

More Fringe Science from Borderline Publisher Frontiers




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Friday, July 01, 2016

Newly Discovered EEG Rhythm Related to Texting, or Cell Phone Artifact?

Texting Zombie (by Ian Aberle)


Contemporary consumers of science infotainment “need” to understand that the brain responds to modern technology in an unprecedented and potentially sinister way. Or at least, that's what you'd think, based on the number of books and essays on how The Internet and Digital Technologies are destroying our brains. The latest entrée into this lucrative genre of mild techno-paranoid is from Elsevier, with their press release about a poorly controlled observational study in a relatively obscure journal:

Sending text messages on a smartphone can change the rhythm of brain waves, according to a new study published in Epilepsy & Behavior.
. . .

Dr. Tatum, professor of neurology and director of the epilepsy monitoring unit and epilepsy center at Mayo Clinic in Jacksonville, Florida found a unique 'texting rhythm' in approximately 1 in 5 patients who were using their smartphone to text message while having their brain waves monitored.

The publishing giant spawned a flood of news stories which claim that texting triggers a Unique, Never-Before-Seen Brain Rhythm that Actually Changes the Way Your Brain Thinks.

But here's what we don't know about the 'texting rhythm'. We don't know:
  • That the signal represents brain activity, rather than a biological artifact (e.g., eye movements) or an electromagnetically-induced artifact produced by the smartphone
  • That the 'texting rhythm' has never been seen before, given the lack of systematic studies
  • That it occurs in people without epilepsy
  • That it has any direct relation to how we think

In a series of two [largely overlapping] studies, Tatum and colleagues (2016a, 2016b) recorded noninvasive EEG (brainwave) activity from inpatients undergoing continuous video monitoring for potential seizure activity. In the more recent paper (2016b), records from 129 texting patients were reviewed for the presence of a reproducible texting rhythm (TR), defined as “a distinct, paroxysmal, time-synched, rhythmic, generalized, frontocentral, 5–6 Hz, monomorphic, theta rhythm repeatedly induced by text messaging” (based on their 2016a study with 100 patients).



Fig. 1 (adapted from Tatum et al., 2016b). (B) unilateral texting with the right hand (picture insert) during video-EEG monitoring. Note the presence of the TR as a 5–6-Hz frontocentral monomorphic rhythm (blue boxes) at the start and termination of texting (solid blue arrows).


It's hard to see what's going on here, so I've zoomed in on the lower box, which shows activity from two bipolar derivations. The Fp1-F3 trace shows eye movements and the F3-C3 trace shows the TR. It appears to be more rhythmic in these left hemisphere electrodes contralateral to the texting hand, but the TR can also be seen in the F4-C4 derivation in Fig 1B.


Although I'm just making qualitative guesses here, I don't think the EEG was quantified with spectral power or time-frequency analyses. In other words, epochs of EEG during texting vs. other activities (audio telephone use, thumb/finger movements, cognitive testing/calculation, scanning eye movements, and speech/language tasks) were eyeballed for the presence or absence of TR. We learn that the TR lasted from 2 sec to continuous runs of  >10 sec. We don't know the number or duration of epochs during the various control activities, but the authors declared a startling significance level:
The TR was highly specific to this text messaging (p < 0.0001). A similar waveform during baseline activation with motor, speech/language, and cognitive tasks performed independently was absent in all patients and was not observed during auditory–verbal smartphone communication (p < 0.0001).

The TR didn't habituate with repeated texting, wasn't specific to iPhone vs. Android, and “was observed in a patient using an iPad, though we did not observe it during the use of a laptop.”

But most texting patients undergoing video EEG monitoring did not show a TR. The percentage of patients with a TR was 24.5% (24 out of 98) and 22.6% (7 out of 31) in a separate Chicago cohort (Tatum et al, 2016a), and only 20.9% (27 of 129) in the 2016b paper. Having a TR wasn't related to age, sex, type of seizure (focal, generalized, epileptic, non-epileptic), or presence/absence of brain lesion on MRI. And we have absolutely no explanation for why that might be, which inspired this hilarious, overly honest headline:

Neuroscientists just found that texting alters your brainwaves, but they can’t explain why

Does using a smartphone fundamentally alter the way that your brain works? ...a group of researchers at the Mayo Clinic recently discovered that text messaging elicits a change in the regular rhythm of brain waves, completely different than the waveforms created by any other activity.

“The big deal with discovering this ‘texting rhythm’ is that the number of new brain waves that are identified on EEG are extremely rare at this point in time,” Dr. William Tatum, the lead author of the study, tells Digital Trends.

Dr. Tatum says that the new brain waves were discovered by accident when analyzing the day-to-day cortical rhythms of people suffering from epilepsy. This discovery triggered an investigation into the neurological effects of smartphone use, which ultimately grew to include nearly 130 participants over a period of 16 months. Only around one in five participants demonstrated the “texting rhythm,” although it didn’t appear to conform to any single gender, ethnicity or age group. Nor is it known exactly what aspect of texting prompts the effect: since text messaging includes a variety of different skills, such as finger dexterity, formulating succinct communications and more.

What we do know is that cell phones and other devices can produce artifacts in EEG recordings (Sethi et al., 2007; Rasquinha et al., 2012; Myers et al., 2016), and this was not discussed in the paper.


Dr. Ranjith Polusani, Artifacts in EEG


EEG Artifact Recognition: Electrical and Environmental Artifacts [cellphone]


But I don't mean to be so pedantic. William O. Tatum, D.O. is a neurologist and member of the American Board of Clinical Neurophysiology who has published Handbook of EEG Interpretation, Second Edition, How not to read an EEG (Neurology, 2013), Artifact-related epilepsy (Neurology, 2013), and more (see References). In fact, here's another image of a telephone artifact from Tatum et al. (2011). Dr. Tatum presumably knows a non-physiological artifact when he sees one.



So does that mean I believe the TR is real? I'll withhold judgment until the results from carefully controlled, quantitatively analyzed, statistically rigorous experiments in participants with and without epilepsy are in. Meanwhile, speculating on the origin, meaning, or relevance of the 'texting rhythm' is premature...

“The question we’re trying to answer right now is whether this is a destructive process or an active process,” Dr. Tatum says. “We think it’s probably an active process through an entrainment of normal cortical rhythms. What’s strange is that it appears to be a destructive frequency that’s more typically identified in people that have a slowing of their brain waves.”


References

Myers KA (2016). Cell Phone Saccades: EEG Artifact for the 21st Century. Pediatric Neurology. Available online 25 June 2016.

Rasquinha RJ, Moszczynski AJ, Murray BJ. (2012). A modern artifact in the sleep laboratory. J Clin Sleep Med. 8(2):225-6.

Sethi NK, Sethi PK, Torgovnick J, Arsura E. (2007). Telephone artifact in EEG recordings. The Internet Journal of Neuromonitoring. 5(1).

Tatum WO, Dworetzky BA, Schomer DL. (2011). Artifact and recording concepts in EEG. J Clin Neurophysiol. 28(3):252-63.

Tatum WO. (2013). How not to read an EEG: introductory statements. Neurology 80(1 Suppl 1):S1-3.

Tatum WO. (2013). Artifact-related epilepsy. Neurology 80(1 Suppl 1):S12-25.

Tatum WO, DiCiaccio B, Kipta JA, Yelvington KH, Stein MA. (2016a). The Texting Rhythm: A Novel EEG Waveform Using Smartphones. J Clin Neurophysiol. Jan 7. [Epub ahead of print]

Tatum WO, DiCiaccio B, Yelvington KH. (2016b). Cortical processing during smartphone text messaging. Epilepsy Behav. 59:117-21.

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Thursday, June 23, 2016

In Oxytocin We Trust



Oh oxytocin, you cuddly hug drug, you fine upstanding moral molecule, why are you so maligned by critics? That's because you're overrated, and misunderstood by those who look to you as a beacon of empathy, trust, love, peace, and prosperity. Sure, you're all about pair bonding in monogamous prairie voles — we have no beef with rigorous animal studies — but in humans, you're downright complicated. Yes, you can be magnanimous and romantic some of the time. But you're not always a moral molecule. You can promote antisocial behaviors such as envy and schadenfreude and aggressive tendencies. And even in voles, too much of a good thing can backfire.

Four new papers on oxytocin in humans have been published this week.1 Collectively, there's something for nearly everyone to complain about:

Oxytocin and Epigenetics

Of the four, the one that has garnered the most media attention is on epigenetics and sociability (Haas et al., 2016, published in PNAS). DNA methylation in the promoter region of the oxytocin gene (OXT) was quantified as an indicator of OXT expression. Lower methylation is presumably associated with higher OXT expression, and all sorts of sociable characteristics such as “more secure attachment styles, improved ability to recognize emotional facial expressions, greater superior temporal sulcus activity during two social-cognitive functional MRI tasks, and larger fusiform gyrus gray matter volume.”

Are these findings plausible from a mechanistic standpoint? Assuming that OXT expression was higher in the sociable sorts, which in turn assumes that methylation in saliva is a good proxy for expression in brain, how did “more“ oxytocin have all these effects? And on what time scale?

The Daily Mail was predictably credulous and hyperbolic,2 using terms like “breakthrough”, “a ‘chatty’ gene which makes people sociable”, and [the kicker] “new treatments for autism”. The autism reference comes from the paper itself (and from the university press release):
"Participants with greater methylation of the OXT gene were less accurate in describing the emotional states of the people they saw in pictures," [first author Brian W. Haas] said. "That's a typical characteristic associated with autism, for example."

But it's not that simple. Let's look at the relationship between emotion recognition and OXT methylation. The task was to view 10 sec video clips of human faces morphing from neutral expressions to happy, sad, fearful and angry, and to identify the emotion as soon as it was detected. This led to 10 different dependent measures: reaction time and accuracy for each of the individual expressions, and for the mean of all expressions. The (conservative) Bonferroni corrected significance level is α = .05/10 = .005 [but the authors said it should be .025]. Overall accuracy is shown below.




Not all that impressive, eh? Another scatterplot was based on self-report questionnaires. The association between an anxious and insecure attachment style and OXT methylation fared better (p=.005), but the association between OXT methylation and avoidant attachment style was not significant. Why?


Oxytocin and Spirituality

The next paper, on oxytocin and spirituality (Van Cappellen et al., 2016), has gained traction on Twitter. Dan Quintana has already written an inspired blog post about it (Spray and pray: Does intranasal oxytocin increase spirituality?), so you should go and check it out. Dan has published at least 7 papers on oxytocin, so his critique is more informed than mine. I'll highlight his main points and then add a few of my own.

Good news:
First, the authors should be congratulated for posting the data for the paper on Open Science Framework (OSF). It’s great to see this dataset online considering the hype surrounding oxytocin...

Here’s a few other things I liked about this paper (or a list of things that oxytocin papers often don’t do): i) Effect sizes and confidence intervals are reported, ii) the alpha for the main outcome was adjusted for multiple tests, and iii) the placebo spray was a “true” placebo that contained all the same ingredients as the oxytocin spray, except the actual oxytocin (i.e, not just saline spray). It’s much easier to taste the difference between oxytocin and saline so this is an important point.

Bad news, genetics:
The authors included an “exploratory analysis” (their words in the intro and a section of the results) of three oxytocin pathway polymorphisms (rs53576, rs6449182, and rs3796863). There are about 10–15 candidate oxytocin pathway SNPs the could be analysed so it’s not clear why these three were chosen rather than others. Sure, rs53576 has been studied a lot, but so have many other oxytocin pathway SNPs (especially rs2254298).

Bad news, religious affiliation:
...it appears that there was a main effect of condition on both spirituality scales. However, a close read of table 1 reveals that this was after correcting for religious affiliation. Now this is reasonable when you consider that someone who’s an atheist is likely to report that spiritually is “not at all” important in my life. In fact, the data bears this out as the average spiritual rating (which can range from 0 to 7) for the atheist/agnostic group was 1.97 during the experimental visit and 1.88 a week later, whereas the average rating for the religiously affiliated group was 4.8 during the first visit and 4.9 during the second visit (I was able to calculate this from their posted dataset — isn’t open data great!).

It’s plausible for someone who identifies as agnostic or atheist to report “not at all” on both occasions — and many did. In fact, when you look at the agnostics/atheist group alone, there’s a statistically significant increase in spirituality after oxytocin compared to placebo both during the lab visit and 1 week later... However, there was no significant difference when assessing the religiously affiliated group.

(or not)

 Dr. Quintana concluded his post by advocating pre-registration and replication.


Oxytocin, Meditation, Positive Emotions, Negative Emotions, Oxytocin Receptor Gene (OXTR rs53576), CD38 (rs6449182 and rs3796863), Religious Affiliation, and Spirituality After Intranasal Oxytocin Administration in 83 Predominantly White Middle Aged Men

My unwieldy subheading includes only a small subset of the 161 variables in the study of Van Cappellen et al. (2016). Granted, some of these variables (e.g, the answers to individual items on questionnaires) were never examined in isolation — they were part of a composite score. Nonetheless, I think we can tick the “Ridiculously large numbers of variables” bullet point. We also have “Intranasal oxytocin administration” and “Small n candidate gene studies” (with n's below 20 in some cells). Bonus bullet point of “Between subjects design” is a personal pet peeve. I'd really like to see some within-subjects studies.

And there's a mysterious element to some of the data not included in this paper:
The data presented here are part of a larger study testing additional hypotheses not related to the present ones. For the larger study and to test a larger model, based on power calculation, a sample of 240 participants was targeted with a breakdown female-male of 125-115... Data collection ... stopped at 239 but despite recruitment effort, the sample is skewed toward females. This report focuses only on the 83 males who took part in the study... Growing evidence suggests that the effects of oxytocin are different for males and females (Feng et al., 2015) and most of the current evidence on intranasal oxytocin’s psychological effects, which support the current hypotheses, come from studies with exclusively male samples. A separate analysis of female participants, controlling for a series of additional variables related to natural variations in oxytocin is ongoing.

The larger study also included a task using Chinese pictographs, since the ability to read Chinese pictographs was an exclusionary criterion “applied to another task unrelated to the current investigation.” I'm generally not a study pre-registration evangelist, but one can really see the point here.




In Oxytocin We Doubt

I'll conclude on a pessimistic note (what else is new?). Some highly critical reviews of the oxytocin literature have appeared recently.

Evans SL, Dal Monte O, Noble P, Averbeck BB. Intranasal oxytocin effects on social cognition: a critique. Brain Res. 2014 Sep 11;1580:69-77.

Leng G, Ludwig M. Intranasal Oxytocin: Myths and Delusions. Biol Psychiatry. 2016 Feb 1;79(3):243-50.
Despite widespread reports that intranasal application of oxytocin has a variety of behavioral effects, very little of the huge amounts applied intranasally appears to reach the cerebrospinal fluid. However, peripheral concentrations are increased to supraphysiologic levels, with likely effects on diverse targets including the gastrointestinal tract, heart, and reproductive tract. The wish to believe in the effectiveness of intranasal oxytocin appears to be widespread and needs to be guarded against with scepticism and rigor. Preregistering trials, declaring primary and secondary outcomes in advance, specifying the statistical methods to be applied, and making all data openly available should minimize problems of publication bias and questionable post hoc analyses. Effects of intranasal oxytocin also need proper dose-response studies, and such studies need to include control subjects for peripheral effects, by administering oxytocin peripherally and by blocking peripheral actions with antagonists. Reports in the literature of oxytocin measurements include many that have been made with discredited methodology. Claims that peripheral measurements of oxytocin reflect central release are questionable at best.
--- there is a retort to Leng and Ludwig by Quintana and Woolley:  Intranasal Oxytocin Mechanisms Can Be Better Understood, but Its Effects on Social Cognition and Behavior Are Not to Be Sniffed At.

Walum H, Waldman ID, Young LJ. Statistical and Methodological Considerations for the Interpretation of Intranasal Oxytocin Studies. Biol Psychiatry. 2016 Feb 1;79(3):251-7.
...Our conclusion is that intranasal OT studies are generally underpowered and that there is a high probability that most of the published intranasal OT findings do not represent true effects. Thus, the remarkable reports that intranasal OT influences a large number of human social behaviors should be viewed with healthy skepticism...

McCullough ME, Churchland PS, Mendez AJ. Problems with measuring peripheral oxytocin: can the data on oxytocin and human behavior be trusted? Neurosci Biobehav Rev. 2013 Sep;37(8):1485-92.


It might be time to order Liquid Trust...



Footnotes

1 Actually, the number of articles is closer to ten, but I'll just list these four for now.
  1. Van Cappellen P, Way BM, Isgett SF, Fredrickson BL. Effects of Oxytocin Administration on Spirituality and Emotional Responses to Meditation. Soc Cogn Affect Neurosci. 2016 Jun 17. PMID: 27317929.
  2.  
  3. Haas BW, Filkowski MM, Cochran RN, Denison L, Ishak A, Nishitani S, Smith AK. Epigenetic modification of OXT and human sociability. Proc Natl Acad Sci. 2016 Jun 20. PMID: 27325757.
  4.  
  5. Simons RL, Lei MK, Beach SR, Cutrona CE, Philibert RA. Methylation of the oxytocin receptor gene mediates the effect of adversity on negative schemas and depression. Dev Psychopathol. 2016 Jun 20:1-12. PMID: 27323309.
  6.  
  7. Gao S, Becker B, Luo L, Geng Y, Zhao W, Yin Y, Hu J, Gao Z, Gong Q, Hurlemann R, Yao D, Kendrick KM. Oxytocin, the peptide that bonds the sexes also divides them. Proc Natl Acad Sci. 2016 Jun 20. PMID: 27325780.
2 Hyperbolic and inaccurate. They called methyl groups "proteins".


References

Haas BW, Filkowski MM, Cochran RN, Denison L, Ishak A, Nishitani S, Smith AK. Epigenetic modification of OXT and human sociability. Proc Natl Acad Sci. 2016 Jun 20. PMID: 27325757.

Van Cappellen P, Way BM, Isgett SF, Fredrickson BL. Effects of Oxytocin Administration on Spirituality and Emotional Responses to Meditation. Soc Cogn Affect Neurosci. 2016 Jun 17. PMID: 27317929.


Further Reading

The Ed Yong Collection:

Oxytocin: the hype hormone

One Molecule for Love, Morality, and Prosperity?

Oxytocin: Still Not a Moral Molecule

The Weak Science Behind the Wrongly Named Moral Molecule

The Neurocritic Back Catalogue:

Oxytocin and Mind Reading...

LEARN TO TRUST YOUR OWN EYES

ABC News Says: 'Trust Drug' Oxytocin Unbelievable For Now

Paul Zak, Oxytocin Skeptic?

Your Brain on Coupons?

Neuroskeptic Posts:

More Doubts Over The Oxytocin And Trust Theory
(about: Failed Replication of Oxytocin Effects on Trust)

Psychologists Throw Open The “File Drawer”
(about: Is there a publication bias in behavioral intranasal oxytocin research on humans?)

Sofia Deleniv: The Dark Side of Oxytocin

Nature News: Neuroscience: The hard science of oxytocin


Old ad for Liquid Trust

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Monday, June 06, 2016

Advil Increases Social Pain (if you're male)




A recent neuroessay in the New York Times asked, Can Tylenol Help Heal a Broken Heart?
What’s crazy about the pain of a broken heart is that your body perceives it as physical pain.
No it does not. Do you feel heartbroken every time you stub your toe?


Well... I guess the social pain = physical pain isomorphism is a one way street. Anyway, the author continued:
In research published in 2010, scientists found that acetaminophen can reduce physical and neural responses associated with the pain of social rejection, whether in romantic relationships, friendships or otherwise.
The pain reliever Tylenol (acetaminophen) lessens the pain of social rejection, according to the 2010 study in Psychological Science [except when it doesn't].1 Acetaminophen also purportedly soothes the existential angst of watching a David Lynch film, blunts your emotions, and kills your empathy.2


So if you’re hurting from heartache, try popping some Tylenol.
Do not pop Tylenol after a breakup. It can cause serious liver damage if you take too much.


But What About Advil?

A 2014 study in the journal Personal Relationships was the first to break the stranglehold of acetaminophen (Vangelisti et al., 2014). The paper made few headlines (an exception was the Daily Mail), and it was not cited by the Tylenol researchers after its publication. Yet I saw no difference in quality, and even found more to like about it compared to the Tylenol papers (all of which appeared in higher impact journals). One of the Advil authors was Dr. James Pennebaker, chair of Psychology at the University of Texas. Dr. Pennebaker is well-known for his research on text analysis and what word choice can reveal about sex, age, social class, personality, mood, and affective state.

The focus of the study by Dr. Anita Vangelisti and colleagues was on potential sex differences in the effects of a physical pain reliever on social pain. They cited evidence suggesting that women are more sensitive to physical pain, and men might be more responsive to pain relievers like ibuprofen (Walker & Carmody, 1998).

Proposed explanations for sex differences in pain and analgesia include the bullet list below (Mogil & Bailey, 2010). These could potentially influence the effects of ibuprofen (and acetaminophen) on social pain.3
  • Sociocultural manly and stoic machismo
  • Psychological greater negative affect and catastrophizing in women
  • Experiential women may have more experience with clinical pain, which affects current pain perception
  • Opioid receptors and especially their interactions with gonadal hormones
  • Other potential biological factors a long list

Advil Worsened Social Pain in Men

Ibuprofen did indeed increase ratings of social pain in male participants, but decreased ratings in female participants Vangelisti et al. (2014). For more details, read on.

Read more »

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