Sunday, September 18, 2016

Coming Soon: The Neural Correlates of Procrastination


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Saturday, September 17, 2016

The Neural Lace Tour


Stevie Nicks and Elon Musk finally together in this stunning collection...

Elon
You have the limbic system, 
the cortex 
and a digital layer above the cortex 
that could work well and symbiotically with you



Stevie:
Now here I go again, I see the crystal visions
I keep my visions to myself

--Dreams, Fleetwood Mac




Stevie:
I need you to love me
I need you today
Give to me your leather
Take from me
My lace

--Leather and Lace, Stevie Nicks


Elon:
If you assume any rate of advancement of AI,
um.......
we will be left behind
by a lot

--We are already cyborgs | Elon Musk | Code Conference


Stevie:
It's only me
Who wants to wrap around your dreams and...
Have you any dreams you'd like to sell?

--Dreams, Fleetwood Mac


Neural Lace

The concept was first thought up by Iain M. Banks in his Culture novels. In these novels, a neural lace is a mesh-like device that would be implanted in a person directly through the bloodstream, controlling the release of certain neurons using the power of thought.

Musk’s version of the neural lace doesn’t work exactly like that. Musk’s lace seems to be a mesh that would allow such AI to work symbiotically with the human brain. Signals will be picked up and transmitted wirelessly, but without any interference of natural neurological processes. Essentially, making it a digital brain upgrade. Imagine writing and sending texts just using your thoughts.


Stevie:
And the days go by
Like a strand in the wind
In the web that is my own

--Edge of Seventeen, Stevie Nicks


Elon:
You have a digital version of yourself
a partial version of yourself
online
in the form of your e-mails and social media
and all the things you do...

--We are already cyborgs | Elon Musk | Code Conference


Stevie:
The clouds never expect it
When it rains

--Edge of Seventeen, Stevie Nicks


Elon:
We're IO bound
particularly output bound

--We are already cyborgs | Elon Musk | Code Conference



Stevie:
Heartless challenge
Pick your path and I'll pray

-- Gold Dust Woman, Fleetwood Mac


Elon:
Something
I think
is going to be quite important
— I don't know of a company that's working on it seriously —
is a neural lace



Stevie:
Give to me your leather
Take from me
My lace
Take from me
My lace
Take from me
My lace 

--Leather and Lace, Stevie Nicks


Scientists Just Invented the Neural Lace

A group of chemists and engineers who work with nanotechnology published a paper ... about an ultra-fine mesh that can merge into the brain to create what appears to be a seamless interface between machine and biological circuitry. Called “mesh electronics,” the device is so thin and supple that it can be injected with a needle — they’ve already tested it on mice, who survived the implantation and are thriving. The researchers describe their device as “syringe-injectable electronics,” and say it has a number of uses, including monitoring brain activity, delivering treatment for degenerative disorders like Parkinson’s, and even enhancing brain capabilities.



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Wednesday, September 07, 2016

Pain, Synesthesia, Aging, The Dress, and more


Vote for your favorites in the 2016
Brain Awareness Video Contest!




You can submit up to two votes for The People's Choice Award. You don't need to be a member of the Society for Neuroscience.

Deadline: September 30, 2016.

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Wednesday, August 31, 2016

Music from Your Brain



The journal Brain has a new review on the history of converting the electroencephalogram (EEG) into sound (Lutters & Koehler, 2016). The translation of data into sound, known as sonification, has been applied to brain waves since the 1930s. In addition to early scientific and medical applications, sonification of the EEG has been used in the field of experimental music.




In 1965, physicist Edmond Dewan and composer Alvin Lucier collaborated on Music for the Solo Performer:

Sitting on a chair, eyes closed, Lucier’s brainwaves were recorded from his scalp, amplified and channelled to numerous loudspeakers scattered around the room. As the amplified alpha rhythm was below the human audible range, the loudspeakers were put ‘right up against’ various percussion instruments, which were then activated by means of vibration. While Lucier attempted to refrain from mental activity, percussion sounds slowly started to fill the room, which were suddenly disrupted when he opened his eyes, engaged in mental exercise, or when his attention was drawn towards sounds from the audience (Kahn, 2013).





The article also reviews more contemporary translations of EEG activity into music:

By the end of the century, advances in EEG and sound technology ultimately gave rise to brain–computer music interfaces (BCMIs), a multidisciplinary achievement that has enhanced expressive abilities of both patients and artists (Miranda, 2014).


Image credits:

Edmond Dewan and his brainwave control system (1964). From Kahn D. Earth sound Earth signal: Energies and Earth magnitude in the arts. Los Angeles: University of California Press; 2013. p. 96. Image courtesy of Brian Dewan.

Lucier practicing brainwave control in the Brandeis Music Studio (1965). From Kahn D. Earth sound Earth signal: Energies and Earth magnitude in the arts. Los Angeles: University of California Press; 2013. p. 91. Image courtesy of Alvin Lucier.


Reference

Lutters, B., & Koehler, P. (2016). Brainwaves in concert: the 20th century sonification of the electroencephalogram. Brain DOI: 10.1093/brain/aww207

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Sunday, August 28, 2016

Healing Prayer and the Brain: Not a Match Made in Heaven


Activity of the medial prefrontal cortex after psycho-spiritual healing (Baldwin et al., 2016).


Everything we do and feel and experience changes the brain. Psychotherapy, juggling, taxi driving, poverty, reading, drugs, art, music, anger, love. If it didn't we'd be dead. Why should prayer be any different? The trick is to accurately determine the structural or physiological changes that are unique to a specific activity. And when assessing the effectiveness of clinical interventions, how the changes compare to an adequately matched control intervention. Plenty of high profile studies have failed to do that, including a recent one on emotionally focused therapy.1 

I feel bad about criticizing a study on the neural correlates of healing prayers. I'm not one of those smug atheists who lord their intellectual superiority over the unwashed religious masses. Certain atheist organizations claim they're all about promoting scientific literacy and a secular worldview. But I think these New Atheists are detrimental to science literacy, since they alienate the vast majority of the population.

So why am I blogging about a prayer intervention for depression? It's not to sneer at the authors. And it's especially not to sneer at the participants, who were recruited from Houston-area churches. My interest is the unholy alliance between brain imaging and a psychological intervention with no control condition. As I've said before...
...neuroimaging studies of psychotherapy that have absolutely no control conditions are of limited usefulness. We don't know what sort of changes would have happened over an equivalent amount of time with no intervention. More importantly, we don't know whether the specific therapy under consideration is better than another form of psychotherapy, or better than going bowling once a week.

Healing Prayer, Trauma, and Forgiveness

This is especially true for a treatment that is based on faith and a strong belief that the intervention will work — a Christian form of prayer focused on forgiveness and psycho-spiritual healing (PSFH). A prayer minister “led the subject through three different phases: (1) a prayer of forgiveness for the perpetrator of the hurtful event; (2) a prayer of blessing on the perpetrator; and (3) a prayer to heal the emotional damage caused by the traumatic event.”



Study design for the 6 week healing prayer intervention (Baldwin et al., 2016).

The 18 participants had moderate to severe levels of depression on the Hamilton Depression Scale (HAM-D). Oddly, post-traumatic stress disorder (PTSD) was not assessed before or after the intervention. This was a major weakness, given that the purpose of the intervention was to forgive the perpetrator of childhood abuse and to heal from emotional trauma. In this sense, PSFH is akin to more formalized psychotherapies such as forgiveness therapy.

It's no surprise that a non-randomized, unblinded prayer intervention in religious persons resulted in dramatically reduced HAM-D scores in the 14 participants who completed the study (11 of whom were available for a one year followup).


Who am I to criticize a practice that helps suffering people? I won't do that.

What I will do is point out difficulties in task design that make it nearly impossible to interpret some aspects of their fMRI study. The task used a symptom provocation paradigm using 3 key words to evoke memories of the traumatic event (15 seconds) and feelings of the traumatic event (15 seconds), separated by a 2 second blank screen.2 Is it possible to separate traumatic memories from the feelings they evoke, and to switch between them on such short notice? Certain therapies (such as prolonged exposure) are designed to do just that. The authors stated that anecdotally, this appeared to be the case here as well:
In this and our previous study, subjects frequently mentioned informally that PSFH results in a separation of the traumatic memory and associated feelings: while the memory remains intact, it no longer associates with traumatic feelings.


Activity of the precuneus to Bad Feelings was higher before psycho-spiritual healing (Baldwin et al., 2016).


It is, however, difficult to interpret a 23 voxel decrease in precuneus activity in 14 subjects as a reflection of such a complex therapeutic change, especially since this brain region is involved in both self-referential processing and episodic memory retrieval.

But to be even more fair, the authors listed ten caveats to their admittedly preliminary study.3 When all is said and done, how can this study reveal ANYTHING about the neural correlates of healing prayer?




Or in this case, nothing fails like a non-randomized, unblinded, not-placebo-controlled fMRI study of prayer. Or of any other intervention, for that matter.

Nothing-Fails-Like-Prayer image by Henry Ruddle


Footnotes

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

Also see two blog posts by Dr. James Coyne.

2 These Bad Memory/Feeling blocks were also compared to Neutral Memory/Feeling blocks that evoked memories and feelings about a neutral topic (e.g., the weather). This is the pre/post contrast shown in the first figure of the post.

3 To shorten and paraphrase the overly honest Limitations section of Baldwin et al. (2016):
  • the number of subjects was small (n=14) 
  • recruitment was largely done at churches, which might affect generalizability
  • individual minister effects could not be ruled out
  • there was no control population receiving an alternative therapy
  • only subjects who completed the study were included, which may have skewed the results
  • life events such as changing employment status, marriage stability, family, health, and economic changes were not assessed
  • possible confounding effects between the role of PSFH and intercessory prayer for the participants by others [NOTE: some of us may discount this as a confounder]
  • cannot rule out an effect of being exposed to the task in the MRI twice
  • demand characteristics participants answered worse at the beginning and better at the end to fulfill researcher’s expectations 
  • outcomes were rated by non-blinded observers

Reference

Baldwin, P., Velasquez, K., Koenig, H., Salas, R., & Boelens, P. (2016). Neural correlates of healing prayers, depression and traumatic memories: A preliminary study Complementary Therapies in Medicine, 27, 123-129 DOI: 10.1016/j.ctim.2016.07.002

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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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