Friday, July 27, 2012

Online Gaming Addiction, Dysfunctional Families, and the Striatum

Internet addiction is perceived to be an important problem in some Asian countries, including Taiwan and Korea. Fatal marathon sessions of online gaming, in particular, have drawn a lot of media attention. Most recently, a teen in Taiwan died after playing Diablo III for 40 straight hours in an internet cafe.

Yen et al. (2010) speculated on potential cultural contributions to heavy internet use:
Internet addiction has been found to be more prevalent in some Asian countries than in the United States 1. Differences in sociocultural background might partly account for this difference. Among various Internet activities, online gaming is the most developed in many Asian countries. Commercial promotion for online gaming focuses on the adolescent population. Adolescents in high schools of Asian countries usually face a strong academic competition. Internet provides a virtual world in which they can temporarily forget the stress of academic performance.

However, "internet addiction" is a murky and controversial diagnosis that is the subject of intense debate. It is being considered for inclusion in the DSM-5, although some critics find the entire concept to be nonsensical:1
[Dr. Vaughan] Bell has argued that the Internet is not an activity, and therefore Internet addiction is a flawed idea (J Ment Health 2007;16:445–57).

“Fundamentally, the Internet is a medium of communication,” says Bell, who claims that one can no more be addicted to the Internet than to radio waves. “The concept itself doesn’t make sense.”

Nonetheless, internet addiction treatment programs are blossoming in the U.S. and worldwide. Although dodgy Chinese 'boot camps' are grabbing all the headlines, another school of thought looks to family dynamics as the root of the problem.

Online Gaming Addiction: It's the Family's Fault

An unusual new fMRI paper by Han et al. (2012) examined brain activity in adolescents with heavy online game use, both before and after 3 weeks of intensive family therapy. In brief, the results seemed to suggest that activity in the dopamine-rich striatum was increased to family bonding cues after family therapy in the "addicted" gamers.2

Since I've already mentioned dopamine, you can see where this is headed. The authors cited studies on the similarities in brain activity in response to cues of affection and addiction (e.g. Fisher et al., 2005; Frascella et al., 2010), in which the striatum figures prominently. No wonder we see so many ridiculous stories on dopamine and internet addiction in the popular media.

The truth is much more nuanced. It's time to abandon the simplistic notion of dopamine as the feel-good neurotransmitter. To quote the authors of Mesolimbic Dopamine in Desire and Dread (Faure et al., 2008):
It is important to understand how mesocorticolimbic mechanisms generate positive versus negative motivations. Dopamine (DA) in the nucleus accumbens is well known as a mechanism of appetitive motivation for reward. However, aversive motivations such as pain, stress, and fear also may involve dopamine in nucleus accumbens (at least tonic dopamine signals).

The Neurocritic expanded on this thought in Is Mourning Rewarding?, and discussed the distinction between the "wanting" and "liking" aspects of reward (Berridge et al., 2009) in Great and Desperate Cures for Addiction. These two facets of reward can become uncoupled: you can continue to "want" something you no longer "like". But summaries of this research don't make good cover stories for Newsweek.

Dysfunctional Family Circus

Back to Han et al. (2012):
An association between dysfunctional family structure and adolescent substance use has been suggested by several public health studies... . . . In a study of family factors contributing to internet addiction, Yen et al. (2007) reported that higher levels of parent-adolescent conflict and lower family function were associated with internet addiction. China's “left behind children,” due to parental migration from rural to urban areas for work, have been reported to be at increased risk of physical inactivity, internet addiction, and smoking (Gao et al., 2010). In a study of 1369 university students, Tsai et al. (2009) reported that deficient social support was a significant risk factor for internet addiction...

The participants in their study were 15 adolescents with potentially problematic online gaming habits (mean 35 hrs/week), all from dysfunctional families, and 15 adolescents with no gaming issues (mean 3 hrs/week) from intact families. The criteria for problematic online game play were:
1) game playing time greater than four hours per day and 30 hours per week; 2) Young Internet Addiction Scale (YIAS) scores greater than 50. In an epidemiology study of Korean school students, Yoo et al. (2004) reported that 14% of students met the criteria of problematic internet addiction using a standard of IAD > 50; and 3) impaired behaviors or distress due to excessive on-line game play which are modified from DSM-IV criteria for substance abuse.

There were no gaming addicts from happy families in this study. Exclusionary criteria included a history of psychiatric illness, substance abuse, or neurological disorders. This is fairly important, as the literature typically notes a high comorbidity of other psychiatric disorders (e.g. depression, anxiety) along with excessive internet use.

The fMRI study involved passive presentation of pictures in a block design. The stimulus categories were neutral (e.g. tree, book, chair), affectionate families (e.g. parents hugging their child, a mother kissing her child, a family birthday party), and game scenes from the preferred game, which included Lineage®, Sudden Attack®, World of WarCraft®, AION®, Dungeon and Fighter®, and StarCraft®.

The results were so problematic that I'm not sure what you can conclude from this study. Absolutely no regions in the entire brain were significantly activated (p<.05 corrected) by the happy family pictures. This was true in the gamers (both before and after therapy) AND in the control kids. For starters, if you're not going to find significant activation of the fusiform face area in a contrast of faces vs. trees you're in trouble. Also, if you're trying to make the case that affection is (or should be) rewarding, you'd better report activation of reward-related areas.

Furthermore, the game-related stimuli elicited NO significant activation anywhere in the addicted subjects' brains prior to therapy. After treatment, the gaming pictures showed greater activation than the neutral pictures in the right occipital lobe and the left middle frontal gyrus (MFG). However, the authors reported this as a reduction in left MFG from pre- to post-treatment, despite the fact that there was no significant activation in left MFG prior to therapy.

As stated earlier, the other significant treatment effect was an increase in activity in the striatum (specifically, the caudate nucleus) to the happy family photos. But again, this is problematic due to the lack of significant activity when comparing happy families to neutral. Finally, the control participants did not undergo family therapy, nor were they tested again at the 3 week time point.

Although the family therapy intervention did increase family cohesion and reduce the amount of gaming (from 35 to 12 hrs per week), I don't think we've learned anything about the neural correlates of these changes. Extensive gaming may "change your brain" [as does any other activity], but this particular study wasn't especially informative about the nature of these changes.


1 A leading proponent of the concept is Dr. Kimberly Young (of the Internet Addiction Center), who has developed a list of diagnostic criteria. Further, she identifies four main subtypes:
  1. Cybersexual Addiction
  2. Cyber-Affair/Relational Addiction
  3. Net Compulsions
  4. Information Overload
Specific net compulsions include Online Gaming and eBay Addiction. How about Etsy addiction? Regretsy addiction?

2 The results were not actually that straightforward, given the lack of statistical significance in most of the contrasts.


Berridge KC, Robinson TE, Aldridge JW. (2009). Dissecting components of reward: 'liking', 'wanting', and learning. Curr Opin Pharmacol. 9:65-73.

Faure A, Reynolds SM, Richard JM, Berridge KC. (2008). Mesolimbic dopamine in desire and dread: enabling motivation to be generated by localized glutamate disruptions in nucleus accumbens. J Neurosci. 28:7184-92.

Fisher H, Aron A, Brown LL. (2005). Romantic love: an fMRI study of a neural mechanism for mate choice. J Comp Neurol. 493:58-62.

Frascella J, Potenza MN, Brown LL, Childress AR. (2010). Shared brain vulnerabilities open the way for nonsubstance addictions: carving addiction at a new joint? Ann N Y Acad Sci. 1187:294-315.

Han DH, Kim SM, Lee YS, & Renshaw PF (2012). The effect of family therapy on the changes in the severity of on-line game play and brain activity in adolescents with on-line game addiction. Psychiatry research, 202 (2), 126-31 PMID: 22698763

Yen CF, Yen JY, Ko CH. (2010). Internet addiction: ongoing research in Asia. World Psychiatry 9:97.

APM = Actions per minute

Ask a Korean! explains Why is StarCraft Popular in Korea?

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Wednesday, July 18, 2012

Paul Zak, Oxytocin Skeptic?

Could a single molecule—one chemical substance—lie at the very center of our moral lives?

Research that I have done over the past decade suggests that a chemical messenger called oxytocin accounts for why some people give freely of themselves and others are coldhearted louts, why some people cheat and steal and others you can trust with your life, why some husbands are more faithful than others, and why women tend to be nicer and more generous than men. In our blood and in the brain, oxytocin appears to be the chemical elixir that creates bonds of trust not just in our intimate relationships but also in our business dealings, in politics and in society at large.

-Dr. Paul J. Zak in The Moral Molecule (excerpt)

By now, many of you have read Ed Yong's scathing reaction to Paul Zak's new book:
One Molecule for Love, Morality, and Prosperity?

Why the hype about oxytocin is dumb and dangerous.

Imagine a molecule that underlies the virtues that glue societies together. Imagine that it brought out the better angels of our nature with just a sniff and could “rebond our troubled world.” Imagine that it was the “source of love and prosperity” and explained “what makes us good and evil.”

Well, carry on imagining. This is a story about oxytocin, and oxytocin is not that molecule.

The book was published in May, so what was the impetus behind Yong's article, and his #Schmoxytocin commentary (helpfully summarized here)?
He was recently profiled by Oliver Burkeman in the Guardian, the latest episode in a long flirtation with the media in which he regularly expounds on oxytocin’s supposed wonders. You can see why journalists love him. He’s charming, handsome, and infused with that “big ideas” aesthetic that TED so adores. When he delivered his own TED talk in July 2011, he unabashedly claimed that he had found the molecule behind why we’re moral.

The problem with the moral molecule idea is that it turns science—messy, complex, frustrating as it is—into a tidy fable. It’s a bit too ... well ... TED-dy. It not only tells people what they want to hear but also makes them feel delightfully subversive for understanding the secret simplicity of the world.

Yong reviewed a substantial amount of evidence that is counter to that tidy fable, including Conlisk (2011), who concluded that Zak and coauthors "analyzed experimental data in doubtful ways, thus exaggerating results."

However, what you may not know is that Zak took a much more measured approach to oxytocin as recently as 4 years ago, as these quotes from ABC News reveal:
So when it comes to Liquid Trust, do people need a dose of liquid skepticism instead? Zak says perhaps.

"There's probably a big placebo effect. ... It's not a crutch for people who are nervous," he notes. "Having said that, our findings are very exciting. Hopefully, people will just get the straight story and not the hype."

And this:
"I have gotten an enormous number of calls from patients," says Zak, adding that one e-mail he received was from a woman whose social phobia had confined her to her house for the past 10 years. She hoped the oxytocin spray would help her overcome her fear of socializing.

"What do you write back to that kind of message?" Zak says.

The impetus for these calls and e-mails, he says, is his being quoted in a story that ran in the U.K. press [Daily Mail]. The article sported the provocative headline "Scientists Find Childbirth Wonder Drug That Can 'Cure' Shyness."

"They were very much too hyperbolic," Zak says of the piece. "I think media around the world have started to use the word 'cure.' … This hormone does not cure anything."

So 'Trust Drug' Oxytocin Unbelievable For Now (in 2008), but in 2012:
After centuries of speculation about human nature and how we decide what is the right thing to do, we at last have some news we can use—empirical evidence that illuminates the mechanism at the heart of our moral guidance system. So what can we do to shift behavior a bit more toward the expression of oxytocin and thus improve the workings of our entire society?

With hype like that, it's hard to believe that Zak was my source of critical commentary on Liquid Trust:
On that score, a body spray on the market called ''Liquid Trust," is advertised as containing oxytocin that will induce unconscious trust in all who encounter you. But Zak said it's ''totally bogus," because sniffing oxytocin from someone's shirt collar will not get enough of the hormone to the brain. It's also available without a prescription -- unlike the real stuff -- he said, and overpriced: ''Liquid Trust" costs $49.95 for a two-month supply, while Zak and his colleagues made their inhalers for about $5 each.

What happened in the last few years? Was it the TEDification of academic media success and book deals? Repeated use of the first person singular when referring to work done by a multitude of people?

"...The Moral Molecule: The Source of Love and Prosperity details how I discovered a brain chemical, oxytocin, that makes us moral."

Perhaps Dr. Zak should remember the good old days, when he could tell the Boston Globe that...
The dose needed to produce effects on trust was large -- subjects took about three teaspoonsful up their noses. But it appears to be quite safe, said Zak, who is director of the center for Neuroeconomic Studies at Claremont Graduate University in California.

The biggest side effect is that perhaps 20 percent of the men who take it get erections, he said, and, of course, pregnant women would want to avoid it because it could trigger contractions.

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Saturday, July 14, 2012

Brain Responses to Virtual Reality-Induced Hallucinations in Schizophrenia

What is it like to experience the frightening auditory and visual hallucinations characteristic of schizophrenia? Yellowlees and Cook (2006) developed a virtual reality program in Second Life based on interviews with schizophrenic patients. The researchers used this as a tool to educate the general public about schizophrenia, in order to increase understanding and reduce stigma. A video sample of the program can be viewed below.

As you can see, these hallucinations are straight out of a horror movie or a terrible nightmare, except they reflect the reality of living with schizophrenia:
  • Multiple voices, occasionally overlapping, criticizing the user
  • A newspaper in which the word “death” would stand out in a headline
  • A floor that would fall away, leaving the user walking on stepping stones above a bank of clouds
  • A television that would play a political speech, but then criticize the user and encourage suicide
  • A gun that would appear under a cone of light and pulse, with associated voices telling the user to take the gun and commit suicide
  • A mirror in which a person's reflection would appear to die, becoming gaunt with bleeding eyes
The authors also provide information about accessing the Virtual Hallucination environment directly.

Persons with other psychiatric disorders may be plagued by voices saying they're worthless and directing them to commit suicide, but the voice is a self-deprecating internal monologue and clearly identified as their own (as in nonpsychotic unipolar and bipolar depression). The issue in schizophrenia is one of reality monitoring, so that internal thoughts and impulses are interpreted as external to the self.

The most common type of hallucination is hearing voices. To determine which brain regions are implicated, a number of neuroimaging studies have scanned participants with schizophrenia while they are actively experiencing auditory hallucinations, compared to the non-hallucinating state (Allen et al., 2008; Kompus et al., 2011; Jardri et al., 2011). A common finding is increased activation of auditory cortex in the absence of external stimulation, along with greater activity in Broca's area (speech production) and the medial temporal lobe (memory). One interpretation of this pattern is that memory retrieval triggers aberrant auditory perceptual experiences. Another is that inner speech is attributed to external sources due to defective self-monitoring.

A new study by Kim and colleagues (2012) took a different approach. They constructed a virtual reality environment in the scanner to produce the illusion of burning flames, and compared the neural responses of schizophrenic and control participants. The experimental setup is shown below.

Fig. 1A (adapted from Kim et al., 2012). The virtual flame illusion. A participant could see his/her body through a head-mounted display (HMD) during the “flame off” block and watched a superimposed, animated image of a virtual flame on the right or left index finger during the “flame on” block.

The participants were 16 schizophrenic patients with mild to moderately severe symptoms and 17 controls. They were instructed that the purpose of the experiment was to examine the brain's response to “observing the body.” However, they were not informed about the potentially frightening illusion:
Participants were not told about the virtual flame and were instructed to observe their body without closing their eyes. As shown in Fig. 1, the experiment used a blocked paradigm and consisted of two conditions: 1) a ‘flame off’ block (30 s), during which only a real-time body image was presented, and 2) a ‘flame on’ block (16 s), during which the virtual flame was generated by a computer in real-time and superimposed on the participant's index finger. The blocks were alternatively repeated 8 times, and the presentation of the flame on the left or the right finger was counterbalanced.

Fig. 1B (adapted from Kim et al., 2012). fMRI task sequence. The experiment used a blocked design and alternated between ‘flame off’ blocks (30 s) and ‘flame on’ blocks (16 s).

Lest you think this situation skirts the boundaries of unethical (as I did), the study was approved by the local institutional review board and subjects signed [semi-]informed consent statements.

After the fMRI session was over, the participants filled out a questionnaire which indicated (A) the strength of their reactions from 1 (“not at all”) to 7 (“extremely strong”), and (B) how much their feelings changed when the blocks were repeated, rated from 1 (“severely attenuated”) to 7 (“severely augmented”):
After scanning, most participants reported that they initially felt the ‘flame on their finger,’ but then the feeling disappeared after realizing that the flame was not real. . . . ...both patient and control groups showed similar subjective responses to the task stimuli: moderate strength in feeling the flame (4.6 ± 1.9 and 3.8 ± 1.8, respectively) and slight attenuation in flame strength over time (3.3 ± 1.8 and 2.6 ± 1.3, respectively). [The group differences were not statistically significant.]

The data analysis strategy went beyond the standard boxcar comparison between "flame on" and "flame off." Instead, the authors...
...considered that the process of virtual flame-specific learning (i.e., gaining insight into the reality of a visual image) might be reflected as a linear or quadratic function of fMRI signal changes. A linear function could reflect repetition enhancement, sensitization/repetition attenuation, or habituation to the stimulus. A quadratic function could reflect transitions between repetition enhancement and repetition attenuation.

The brain activation differences between groups were not all that spectacular, once you discard all the p<.001 uncorrected regions that were reported in Table 2. What was left?
...only five areas including the left anterior prefrontal cortex, left occipito-temporal junction, left occipital gyrus, right amygdala, and left cerebellum were included. As depicted in Fig. 2, the control group demonstrated transitions from repetition enhancement to attenuation in these five brain regions, in contrast to the lack of enhancement and attenuation in the patient group [i.e., a flat response].

Fig. 2 (Kim et al., 2012). Changing patterns of brain activity related to the virtual flame across time in patients with schizophrenia and in healthy controls. The selected regions were significant in the two-sample tests with the quadratic repetition-variant response at p < 0.05, FDR-corrected: the anterior prefrontal cortex (APFC), occipito-temporal junction (OTJ), occipital cortex (OC), amygdala (AMG), and cerebellum (CER). Rt., right; and Lt., left

Have we come away with a better understanding of the neural processes involved in gaining insight into unreality? Becoming aware of the fact that an unexpected and alarming visual illusion isn't real differs from internally generated hallucinations, of course, but the authors suggest that:
Patients with schizophrenia may use a salience-related region1 instead of reality monitoring-related regions [anterior medial PFC] to react to the unusual stimuli, and this peculiarity of the neural processes may be related to vulnerability to psychosis.


1 The salience-related region (anterior cingulate cortex) did not survive FDR correction for multiple comparisons.


Allen P, Larøi F, McGuire PK, Aleman A. (2008). The hallucinating brain: a review of structural and functional neuroimaging studies of hallucinations. Neurosci Biobehav Rev. 32:175-91.

Kim JJ, Ku J, Lee H, Choi SH, & Kim IY (2012). Distinct neural responses used to gain insight into hallucinatory perception in patients with schizophrenia. Journal of psychiatric research PMID: 22770670

Kompus K, Westerhausen R, Hugdahl K. (2011). The "paradoxical" engagement of the primary auditory cortex in patients with auditory verbal hallucinations: a meta-analysis of functional neuroimaging studies. Neuropsychologia 49:3361-9.

Jardri R, Pouchet A, Pins D, Thomas P. (2011). Cortical activations during auditory verbal hallucinations in schizophrenia: a coordinate-based meta-analysis. Am J Psychiatry 168:73-81.

Yellowlees PM, & Cook JN (2006). Education about hallucinations using an internet virtual reality system: a qualitative survey. Academic Psychiatry, 30 (6), 534-9. PMID: 17139026

When we sit at a table there's fire between the guests
When your hands don't touch there's sand in your face  
And fire under your nails  
Nobody knew so nobody cared
 Nobody knew so nobody cared
Nobody knows

------Throwing Muses

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Sunday, July 08, 2012

EMPowered to Kill

Mentally ill killer tried vitamin therapy, court told

A man with schizophrenia killed his father and gravely injured his mother at their home in North Vancouver, British Columbia. Jordan Ramsay was off his prescribed antipsychotic medication at the time, instead taking an alternative multivitamin preparation called Truehope EMPowerplus™. He believed his parents were aliens and felt compelled to kill them. Ironically, Wendy and Donald Ramsay were in favor of their son's Truehope treatment. But Jordan Ramsay's paternal aunt and grandmother disagreed strongly with this decision:
Leeann Ramsay, the aunt of the accused, believes the family's attempt to control his illness with an alternative therapy rather than his psychiatrist's prescription had a role in his state of mind at the time of the killing.

. . .

...just two days before the murder, a North Vancouver nurse reported, "His mother stated she wanted him on Empower Plus vitamins, and she believed she had permission to reduce his medication."

Leeann Ramsay told CBC News that Jordan's grandmother had serious concerns about the alternative treatment as well.

"My mom had various conversations with them about Jordan weaning off his anti-psychotics and trying this alternative megavitamin therapy, and my mom was very much against it."
Furthermore, Leeann Ramsay wants to launch an investigation into whether EMPowerplus™ played any role in her brother's death, subverting the antipsychiatry paradigm of blaming psychotropic medications for suicides and homicides.

Truehope EMPowerplus™ is no stranger to controversy. In June 2003 Health Canada advised Canadians not to use Empowerplus, and in July 2003 they executed a search warrant to seize imports from the US. The supplement was being marketed to treat bipolar disorder, anxiety, panic attacks, ADHD, schizophrenia, autism, Tourette’s syndrome, fibromyalgia, and OCD without a doctor's supervision and without an approved Drug Identification Number (DIN).
Our main concern deals with the unproven health claims being made about Empowerplus, and the recommendation that patients decrease the dose of, or eliminate altogether, medications prescribed by their doctors. This can result in serious adverse health consequences.

But no matter. The company continues to make false claims. For starters, the current title of the product webpage is still "Depression symptoms reduced or eleminated [sic] by taking EMPowerplus".

But what is EMPowerplus™ exactly? Truehope says it's A Revolutionary Micronutrient Formula...
...proven effective in reducing or eliminating the symptoms of bipolar, anxiety, depression, and ADHD. 16 medical journal publications, plus many individual doctors’ observations, have shown significant reductions in the symptoms of bipolar and other mental disorders.
That's interesting. ONE formulation to treat all of these disorders? Typically, the antidepressants and stimulants used to treat anxiety/depression and ADHD (respectively) are not recommended for bipolar disorder because of the risk of triggering a manic episode. The premise of the Truehope treatment strategy is that a "chemical imbalance" causes all mental illnesses:
The most common explanation for mental disorders is a chemical imbalance in the brain, but how and why these imbalances happen is not yet known. Since a complex web of nutrients, such as zinc, vitamin B6, and vitamin B12, are the building blocks that the brain needs to make the right amounts of important chemicals such as neurotransmitters, it makes sense that a lack of these nutrients could cause the chemical imbalances of mental illnes. [sic]

The thing that I find so fascinating is the simultaneous reliance on a simplistic "chemical imbalance" theory of mental illness and an opposition to traditional pharmaceuticals originally purported to correct those chemical imbalances. This theory has been panned by critics of biological psychiatry and has even fallen out of favor among neuroscientists conducting both basic and clinical research.

However, there is no doubt that vitamin deficiencies can produce neurological and psychiatric disturbances. For instance, a lack of B12 can damage the central nervous system via changes in cytokine and growth factor production (Scalabrino, 2009). Thiamine deficiency is well-known for causing Wernicke's encephalopathy and Korsakoff's syndrome, disorders characterized by severe memory impairments. Previous studies have suggested that vitamins and minerals do have an effect on mood and perhaps even antisocial behavior Kaplan et al., 2007; Bohannon, 2009). The question here is whether broad-spectrum micronutrient treatments (i.e., nutritional supplements) can improve or "cure" bipolar disorder.

Truehope lists 17 published studies on the effectiveness of EMPowerplus™ in treating bipolar, ADHD, autism, and OCD. However, none of these studies is a randomized controlled trial that compares placebo to EMPowerplus™ in a double-blind fashion. Thus, it cannot be established that any improvements are due to the supplement, rather than to expectation or placebo effects.

In one study, Gately and Kaplan (2009) presented results from 358 self-identified bipolar individuals (120 men, 238 women)1 who purchased EMPowerplus™ from the Truehope website and subsequently filled out a symptom reporting checklist using the company's Self-Monitoring Form.2 The diagnosis of bipolar disorder was not confirmed by a mental health professional. We don't know how many have bipolar I vs. bipolar II vs. cyclothymia. Here's a description of how the sample was selected:
There were 682 participants who reported having been diagnosed with bipolar disorder: 378 with no other disorders, 17 with both depression and bipolar disorder,3 and 287 with bipolar disorder as well as additional diagnoses such as ADHD, OCD, anxiety-panic, or schizophrenia. The conservative selection of just the 395 reporting bipolar disorder but no additional disorder except for the 17 also reporting depression was an attempt to reduce the heterogeneity of the sample.

Although physician confirmation of diagnosis was not available, 81% of the sample were taking psychiatric medications at the time they commenced taking the micronutrients, indicating that a physician considered their mood symptoms to be sufficiently severe to warrant medication.
If you're going to ultimately claim that a treatment reduces the symptom severity of an illness, you'd better confirm the clinical diagnosis of that illness (and the presence or absence of any co-morbidities). Of the 358 participants in the primary sample, only 136 were taking a mood stabilizer (e.g., lithium or divalproex sodium), the first-line treatment for bipolar. 145 were taking antidepressants, 75 were on antipsychotics, and 57 on anxiolytics. In addition, reliance on a totally self-selected sample of people who wanted to try an alternative micronutrient treatment is suspect.

Dr. John Grohol made similar points about deficiencies in study design and outcome reporting in a post at PsychCentral:
Some of the published research comes from researchers who have used the company’s own data collection routines through a “Self-Monitoring Form” that’s filled out by customers of the product (a form whose psychometric properties we know nothing of). The majority of customers stop filling out the form after two weeks, however (Rucklidge et al., 2010), suggesting they’ve either stopped using the product or stopped enjoying any positive effects from it.

In the aforementioned study, 120 families (out 709) agreed to monitor symptoms of their children who were taking EMPowerplus over 6 months’ time. Naturally, the researchers found a positive effect for the supplement — a 46% decrease in mean bipolar symptom severity scores at LOCF and a 40% decrease in ADHD symptoms.

But what’s that LOCF thing? Well, it’s a technique called Last Observation Carried Forward that researchers use that carries forward drop-out scores as though they had completed the entire study (in this case, observation of scores over 6 months’ time). In this study, only 49 percent of the participants kept providing the researchers data at 6 months — meaning the majority of them dropped out of the study before the 6 months were up!

LOCF is generally frowned upon in good research unless there’s a very good rationale for its use. Why? Because research conducted on the effects of LOCF shows that this method gives a biased estimate of the treatment effect while underestimating the variability of the result. In other words, it stacks the deck to demonstrate a treatment’s effectiveness — even when the treatment might not be effective. It’s a research slight of hand.

Retention in the Gately and Kaplan study at the 3 month time point was actually quite high (349 out of 358), but this had dropped to 242 at 6 months. What happened to the other 107 participants? Did they feel worse (i.e., depressed) and decide to stop the supplement, or did they just get tired of filling out the checklist? OR did they get worse in an objective sense (i.e., hypo/manic) and decide they were cured?

One troubling (but not unexpected) aspect of the symptom reporting data is the variability of days that were reported: 15% of the 358 participants reported between 60-90 days of the 180 days, 22% between 91-120 days, 21% between 121-150 days, and 42% reported 150 of the 180 days. A related concern is the failure to include specific symptoms or adverse reactions. The words "hypomanic" and "manic" and "psychotic" do not appear in the text. Furthermore, individuals in those states often lack insight into their mental status and may even feel better than ever (in the case of hypomania).

The table below shows that many participants decreased their dose of psychotropic medication or went off their drugs entirely (just like Jordan Ramsay). In fact, this is generally encouraged by the non-medically trained sales staff, called "Truehope Assistants".

- click on image for a larger view -

Sandra Kiume, blogger at Channel N, made these observations about the dangerous lack of medical monitoring:
When you attempt to purchase the product you are forced to sign a terms of agreement that includes:

“Some of the medications I’m currently taking or have taken (if any) may require that I take extra care when starting the EMPowerplus nutrient program and I agree to follow the guidelines of the program as suggested by my Truehope Assistant.”

A Truehope Assistant is essentially a sales rep for the company. They are not mental health professionals. However, based on your checking a box when you order that states “I am taking or have recently taken medication for sleep or a mood disorder,” they advise you to discontinue taking all psych medications before taking Truehope. Why? If it were really a safe nutritional supplement, there wouldn’t be any interaction, and if it’s not, they don’t say what’s in their proprietary formula so we don’t know what’s in it that might pose a risk. Either way, advising people to discontinue medication – without a professional assessment or medical supervision – is a dangerous ploy. To me, this what’s most disturbing about Truehope, even more than their marketing techniques and lack of rigorous research.

In calls to the Truehope sales team, Dr. Terry Polevoy used scripted scenarios to solicit advice about various ailments. It makes for interesting reading (pdf) and listening (mp3). In one scenario, the caller presents with a recent diagnosis of bipolar disorder, and inquires about the product:
. . .

Caller: and if I start the Empower and I still feel good do I stop my lithium, or…?

Truehope: Ok generally what will happen is that after you start on the Empower it gets into your body and it starts to repair that chemical imbalance a little bit at a time. And each time it repairs a little bit your body’s going to go through an adverse drug reaction and you’re going to need just a little bit less medication. And that will continue happening until you wean off all your medication

Caller: I see so there’s really no risk if I stop taking the lithium.

Truehope: Um, we never recommend that you stop your medication before Empower has a chance to get into your system and before your body’s ready. And we always recommend just very slight gradual reduction over a period of anywhere between a month, two months and some people even longer than come off the medication.

And this is done without medical supervision. Later in the conversation, the Truehope Assistant recommends inositol, which can trigger manic episodes (see Levine et al., 1996) at the suggested dose of 6000 mg/day (Red Bull contains 50 mg, to compare):
Truehope: We also, just for your information, we also carry a product called inositol powder and what that is it’s one specific component of the B complex family and what it does is it gives a gentle calming effect over the body. We found it extremely beneficial in helping with anxiety, irritability, withdrawal from coming off of medication, as well as many people have told me they actually find it a lot of help when they are first starting off on Empower just cause it gives them a little bit of a benefit there when they first start off.

Nonetheless, many satisfied customers have provided testimonials on the supplement's effectiveness and how it has improved their lives. These appear not only on the company's website but on numerous blog posts covering the product. The positive comments even appear on the Gately and Kaplan (2009) paper, which is open access and can be read by all.

But testimonials are not the same as double-blind, placebo controlled studies. EMPowerplus™ believers and skeptics alike might ask if there are any ongoing clinical trials. Well there was one registered in the database, but Study NCT00109577 has been terminated.


1 Already we can see this sample is not representative of the general population with bipolar disorder, because women are overrepresented. Bipolar is equally prevalent in men and women, but in this study women outnumber the men 2:1. Also, these participants had the financial means to purchase their own supply of EMPowerplus™ ($150 for one month). This likely rules out many individuals who are unable to work because of the severity of their illness.

2 From the Methods:
...people wanting to take [EMPowerplus™] for amelioration of psychiatric or neurologic symptoms are encouraged to use a checklist to monitor their progress, usually using symptoms specified in the DSM-IV. The Self-Monitoring Form which forms the basis of the current analyses consists of 16 DSM-specified mood symptoms (e.g. loss of interest in hobbies or activities; an excessively high or elated mood). Clients were asked to rate each symptom from 0 (not at all) to 3 (very much), for a maximum score of 48. Use of the Self-Monitoring Form is voluntary, and not all of the company’s clients choose to use it.
3 The diagnosis of bipolar disorder requires both depressive and hypo/manic symptoms, so saying you have both depression and bipolar is redundant.

4 aka the Synergy Group of Canada. The founders said, "We have named this work “TRUEHOPE” because we believe true hope can only be found in the healing sustenance God offers. No man, company, or scientist can ever replicate or replace that which our Creator provides."


Bohannon J (2009). Psychology. The theory? Diet causes violence. The lab? Prison. Science, 325 (5948), 1614-6. PMID: 19779166

Gately D, Kaplan BJ (2009). Database Analysis of Adults with Bipolar Disorder Consuming a Micronutrient Formula. Clinical Medicine: Psychiatry, 2, 3-16. Link

Kaplan BJ, Crawford SG, Field CJ, & Simpson JS (2007). Vitamins, minerals, and mood. Psychological bulletin, 133 (5), 747-60. PMID: 17723028

Levine J, Witztum E, Greenberg BD, Barak Y. (1996). Inositol-induced mania? Am J Psychiatry 153:839.

Rucklidge JJ, Gately D, Kaplan BJ. (2010). Database analysis of children and adolescents with bipolar disorder consuming a micronutrient formula. BMC Psychiatry 10:74.

Scalabrino G. (2009). The multi-faceted basis of vitamin B12 (cobalamin) neurotrophism in adult central nervous system: Lessons learned from its deficiency. Prog Neurobiol. 88:203-20.

Additional Reading - from CIRCARE (Citizens For Responsible Care and Research Inc.):

EmpowerPlus Research I

EmpowerPlus Research II

EmpowerPlus Research VII

Pig Pills, Inc.

Dr. Terry Polevoy has waged a tireless campaign against Empowerplus. His voluminous research on Truehope Nutritional Support Ltd.4 is available at these sites:

Truehope Empowerplus loses lawsuit against Health Canada

Canadian Quackery Watch - Truehope's Empowerplus and other miracles

He also has an ebook: Pig Pills, Inc., The Anatomy of an Academic and Alternative Health Fraud:
It's the unlikely story of a "cure" for psychiatric disorders by "inventors" who were neither doctors nor research scientists. They were, however, seasoned sales people with dubious tragic stories to help them focus their pitch on others in need...

Their pitch was based on the absurd notion that young piglets on their way to becoming ham for your dinner table could be cured of a condition that is know as Ear and Tail Biting Syndrome. They claimed that pigs of course could be healed by just throwing them a haphazard mixture of vitamins, minerals, and herbs - the pig pills. Yes, pig pills! Then in an amazing leap of faith, these two fellows from rural Alberta, Canada, with connections to nutraceutical conglomerates in Utah, came up with the idea that their pig pill formula could help wipe out the scourges of otherwise incurable mental illness in humans.


Four Explanatory Models for how vitamins and minerals may influence mood states (Kaplan et al. 2007, in the highly regarded Psychological Bulletin):
  1. Unstable Mood May Be the Manifestation of Inborn Errors of Metabolism
  2. Unstable Mood May Be the Manifestation of Deficient Methylation Processes
  3. Unstable Mood May Be the Result of the Alteration of Gene Expression by Nutrient Deficiency
  4. Mood Disorders May Be Long-Latency Deficiency Diseases
"The four models described above are entirely compatible ideas that provide overlapping views of how brain metabolic pathways may become deficient and result in mood symptoms."

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Tuesday, July 03, 2012

Justin Bieber Causes Psychosis, says a leading neuroscientist

Well not really, but it's not too much of a stretch to combine two recent pop neuro threads on the evils of dopamine into one dopameme. In the first, heretofore reputable neuroscientist Dr. Daniel Levitin of McGill University is quoted in the Daily Mail:
'Beliebers' suffer a real fever: How fans of the pop sensation have brains hard wired to be obsessed with him

By Mail On Sunday Reporter
PUBLISHED: 18:29 EST, 30 June 2012 | UPDATED: 07:20 EST, 1 July 2012

Justin Bieber fans can’t help their obsession – it’s hardwired into their brain, says a leading neuroscientist.

According to Professor Daniel Levitin ‘Bieber Fever’ (symptoms include screaming, fainting and constantly tracking the teen idol on Twitter) is a real physical compulsion.

When ‘Beliebers’ – as Bieber’s 44 million fans are known – listen repeatedly to his music, a chemical responsible for feelings of pleasure is released in their brains.

‘It triggers a rush of dopamine, the neurotransmitter stimulated by lots of other pleasurable activities such as orgasms or eating chocolate,’ Professor Levitin said last week.

The neuroscientist, of McGill University, Montreal, added: ‘Dopamine is released at much lower levels by music than, say, the use of drugs and the result usually is an obsession, in which you require more and more Justin Bieber.’

In the second part of our dopameme, a recent post by Dr. Victoria L. Dunckley in Psychology Today explained how computers and video games cause psychosis:
Computer, Video Games & Psychosis: Cause for Concern

. . .

In my practice in the past six months, no less than five youths have reported psychotic symptoms that were attributed to, or exacerbated by, electronic screen devices.

The mechanism for this anecdotal deterioration? Dopamine!
Electronic screens, particularly interactive ones (as opposed to passive ones, like television), increase dopamine in the reward center of the brain. This effect has been demonstrated by brain scan (Koepp, 1998: ) Dopamine is known as the brain's "feel good" chemical, but is also related to stress, addiction, anxiety, mood, and attention. Dopamine in excess can lead to psychotic symptoms--voices, delusions, paranoia, or confusion.

Good god. Dirk Hanson has started a comment thread on this irresponsible claim, Screen Time is Melting Our Children’s Brains—Or Something, at Addiction Inbox. I have a [pending] comment there, along with Neuroskeptic and Professor Keith Laws [edited to add].

Let's Go Back Inside the Brains of Bieber Fans

Did Levitin actually say that Bieber fever is "hardwired"? Probably not. [UPDATE (July 9, 2012) - In a comment, Dr. Levitin has confirmed that he was misquoted by the MAIL. What a surprise!] The Daily Mail might be considered a little less reputable than the Wall Street Journal:
What's Behind Bieber Fever? Neuroscience Offers Explanation; a 'Safe' Infatuation


. . .

Hearing familiar, favorite music stimulates the release of dopamine, the neurotransmitter involved in pleasure and addiction, providing the same rush as eating chocolate or that winning does for a compulsive gambler, says neuroscientist Daniel Levitin, who was able to observe the process using fMRI scans in his lab at McGill University in Montreal.

Dr. Levitin's research also showed that musical tastes formed in the teen years become part of the brain's internal wiring, as that is the time when some neural pathways are solidifying and others are being pruned away. That's why the music adults tend to be nostalgic for is the music from their teenage years.

But more importantly, I've received an anonymous tip that another leading neuroscientist bears an uncanny resemblance to Justin Bieber.

Disclaimer: Neither Levitin nor Dunckley actually said that Bieber causes psychosis.

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