Video games and depression

There’s a lot of talk these days about the harm or benefit of playing video games, a lot of time ignoring the issue of what kind of video games we’re talking about.

Merry et al. (2012) designed a game for helping adolescents with depression. The game is called SPARX (Smart, Positive, Active, Realistic, X-factor thoughts) and is based on the cognitive behavioral therapy (CBT) principles.

CBT has been proven to be more efficacious that other forms of therapy, like psychoanalysis, psychodynamic, transpersonal and so on in treating (or at least alleviating) a variety of mental disorders, from depression to anxiety, form substance abuse to eating disorders. Its aim is to identify maladaptive thoughts (the ‘cognitive’ bit) and behaviors (the ‘behavior’ bit), change those thoughts and behaviors in order to feel better. It is more active and more focused than other therapies, in the sense that during the course of a CBT session, the patient and therapist discuss one problem and tackle it.

SPARX is a simple interactive fantasy game with 7 levels (Cave, Ice, Volcano, Mountain, Swamp, Bridgeland, Canyon) and the purpose is to fight the GNATs (Gloomy Negative Automatic Thoughts) by mastering several techniques, like breathing and progressive relaxation and acquiring skills, like scheduling and problem solving. You can customize your avatar and you get a guide throughout the game that also assess your progress and gives you real-life quests, a. k. a. therapeutic homework. If the player does not show the expected improvements after each level, s/he is directed to seek help from a real-life therapist. Luckily, the researchers also employed the help of true game designers, so the game looks at least half-decent and engaging, not a lame-worst-graphic-ever-bleah sort of thing I was kind of expecting.

To see if their game helps with depression, Merry et al. (2012) enrolled in an intervention program 187 adolescents (aged between 12-19 years) that sought help for depression; half of the subjects played the game for about 4 – 7 weeks, and the other half did traditional CBT with a qualified therapist for the same amount of time.  The patients have been assessed for depression at regular intervals before, during and after the therapy, up to 3 months post therapy. The conclusion?

SPARX “was at least as good as treatment as usual in primary healthcare sites in New Zealand” (p. 8)

Not bad for an RPG! The remission rates were higher for the SPARX group that in treatment as usual group. Also, the majority of participants liked the game and would recommend it. Additionally, SPARX was more effective than CBT for people who were less depressed than the ones who scored higher on the depression scales.

And now, coming back to my intro point, the fact that this game seems to be beneficial does not mean all of them are. There are studies that show that some games have deleterious effects on the developing brain. In the same vein, the fact that some shoddy company sells games that are supposed to boost your brain function (I always wandered which function…) that doesn’t mean they are actually good for you. Without the research to back up the claims, anybody can say anything and it becomes a “Buyer Beware!” game. They may call it cognitive enhancement, memory boosters or some other brainy catch phrase, but without the research to back up the claims, it’s nothing but placebo in the best case scenario. So it gives me hope – and great pleasure – that some real psychologists at a real university are developing a video game and then do the necessary research to validate it as a helping tool before marketing it.

sparx1-copy

Oh, an afterthought: this paper is 4 years old so I wondered what happened in the meantime, is it on the market or what? On the research databases I couldn’t find much, except that it was tested this year on Dutch population with pretty much similar results. But Wikipedia tells us that is was released in 2013 and is free online for New Zealanders! The game’s website says it may become available to other countries as well.

Reference: Merry SN, Stasiak K, Shepherd M, Frampton C, Fleming T, & Lucassen MF. (18 Apr 2012). The effectiveness of SPARX, a computerised self help intervention for adolescents seeking help for depression: randomised controlled non-inferiority trial. The British Medical Journal, 344:e2598. doi: 10.1136/bmj.e2598. PMID: 22517917, PMCID: PMC3330131. ARTICLE | FREE FULLTEXT PDF  | Wikipedia page | Watch the authors talk about the game

By Neuronicus, 15 October 2016

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Tryptophan-rich foods and happiness

angry-woman public domainThe paper I feature today is not an experimental study, but an editorial written as a short review (5 pages). A not very good one, I’m afraid.

Neurochemical imbalances are to be found in virtual any brain disorder. Probably the most known is the serotonin depletion associated to depression, which is the main reason why SSRIs (selective serotonin reuptake inhibitors) are so widely prescribed for the disorder. With the caveats that serotonin is but one player, that it has many receptors involved in different aspects of the disease and “depression” is an umbrella term for a host of behaviors, this editorial focuses on non-pharmacological ways to address the depletion of serotonin. Noble goal, poor execution.

In a nutshell, Young (2007) argues that there are 4 ways to increase serotonin availability in the brain:
1) effortful focusing on positive things, either via psychotherapy, talk, social interactions, mediation or just mental exercises to consciously improve mood. I’m sure that the thought of trying to focus on the positive thoughts never crossed the minds of depressed people! Of course that this is how healthy people regulate their moods, everybody is sad or suffers loss at some point in their life and a lot of people snap out of it by engaging in those suggested behaviors, but the trouble with depression is that it persists despite efforts to be positive. The author should know that crying “Cheer up!” to a depressed person never works, but chances are they would feel even more alienated because they’ve tried that already!
2) exposure to bright light (3000 lux). No contention here. Light therapy is successful in treating seasonal depression. We should all get more light.
3) exercise. It’s unclear which kind, aerobic or to fatigue, but probably either would work.
4) eating tryptophan-rich foods (like meat, cheeses or eggs). Why tryptophan? Because the brain can make serotonin out of tryptophan, but serotonin itself is too big of a molecule to enter the brain (i.e. doesn’t cross the brain blood barrier). But the author admits that “although purified tryptophan increases brain serotonin, foods containing tryptophan do not” (p. 396) soooo,… then eating tryptophan-rich foods will NOT increase the serotonin. But then he goes on saying that drinking milk or eating nixtamalized corn increases serotonin (verbatim: “Acute ingestion of alpha-lactalbumin by humans can improve mood and cognition in some circumstances, presumably owing to increased serotonin” and “Breeding corn with a higher tryptophan content was shown in the 1980s to prevent pellagra; presumably, it also raised brain serotonin” p. 396-397). Utterly confusing and self-contradictory.

I also want to make a big note here:
a) there is no reliable evidence that eating tryptophan-rich foods increases the brain serotonin. Otherwise, instead of paying for Prozac, you would buy a huge bottle of tryptophan pills from the nearest dietary supplements store. Which brings me to my second point:
b) why don’t we give tryptophan supplements instead of SSRIs? Tryptophan is sold in USA as a dietary supplement which I think is a tremendously dangerous thing to allow (in most EU countries is considered a drug, so you can’t buy it from the shoddy dietary supplements stores). Because its efficacy in depression is inconclusive at best, i.e. most studies did not find significant improvements, while others showed improvement only in a subpopulation of depression sufferers. But it can induce nausea, sleepiness, confusion, depression, and even dementia symptoms and death. And interacts badly with other drugs or even with carbohydrate-rich foods, like pizza or pasta.

This is definitely not among the best papers I have read. It has many speculations supported by un-replicated studies. Or, when such studies are sparse, the reasoning relies on evolutionary speculations elevated to the rank of causal explanations (e.g. we spend so much time indoors, therefore depression is on the rise; conversely, our ancestors spent more time outside, therefore they were happier). Although I agree with Young that we should invest more research into non-pharmacological ways to improve brain dysfunctions, we need to do so in a more pragmatical manner that just telling people to think positive. Ok, rant over.

Reference: Young SN (Nov 2007). How to increase serotonin in the human brain without drugs. Journal of Psychiatry and Neuroscience, 32(6):394-399. PMID:18043762, PMCID:PMC2077351. Article | FREE FULLTEXT PDF

By Neuronicus, 3 December 2015

Putative mechanism for decreased spermatogenesis following SSRI

fishThe SSRIs (selective serotonin reuptake inhibitors) are the most commonly prescribed antidepressants around the world. Whether is Prozac, Zoloft or Celexa, chances are that 1 in 4 Americans (or 1 in 10, depending on the study) will be making a decision during their lifetime to start an antidepressant course or not. And yet adherence to treatment is significantly low, as many people get off the SSRI due to their side effects, one of the main complains being sexual dysfunction in the form of low libido and pleasure.

Now a new study finds a mechanism for an even more worrisome effect of citalopram, (Celexa), an SSRI: the reduction of spermatogenesis. Prasad et al. (2015) used male zebrafish as a model and exposed them to citalopram in 3 different doses for 2- or 4-weeks period. They found out that the expression in the brain of the serotonin-related genes (trp2 and sert) and gonadotropin genes (lhb, sdhb, gnrh2, and gnrh3) were differently affected depending on the dose and durations of treatment. In the testes, the “long-term medium- and high-dose citalopram treatments displayed a drastic decrease in the developmental stages of spermatogenesis as well as in the matured sperm cell count” (p. 5). The authors also looked at how the neurons are organized and they found out that the serotonin fibers are associated with the fibers of the neurons that release gonadotropin-releasing hormone 3 (GnRH3) in preoptic area, a brain region in the hypothalamus heavily involved in sexual and parental behavior in both humans and fish.

Shortly put, in the brain, the citalopram affects gene expression profiles and fiber density of the serotonin neurons, which in turn decreases the production of GnRH3, which may account for the sexual dysfunctions that follow citalopram. In the testes, citalopram may act directly by binding to the local serotonin receptors and decrease spermatogenesis.

Reference: Prasad P, Ogawa S, & Parhar IS. (Oct 2015, Epub 8 Jul 2015). Serotonin Reuptake Inhibitor Citalopram Inhibits GnRH Synthesis and Spermatogenesis in the Male Zebrafish. Biololy of Reproduction. 93(4):102, 1-10. doi: 10.1095/biolreprod.115.129965. Article | FREE FULLTEXT PDF

By Neuronicus, 11 November 2015

How long does it take for environmental enrichment to show effects?

From funnyvet.
From funnyvet.

Environmental enrichment is a powerful way to give a boost to neurogenesis and alleviate some anxiety and depression symptoms. For the laboratory rodents, who spend their lives in cages with water and food access, environmental enrichment can refer to as little as a toy or two or as much as large room colonies with different size tubes, different levels to explore, nesting materials, plenty of toys with various shapes, textures, and colors, exercise wheels, and even the occasional fruit or peanut butter snack. But for how long does a mouse need to be exposed to enrichment to show cognitive and emotional improvement?

Leger et al. (2015) ran several anxiety, depression, and long-term memory tests in mice who have been exposed to environmental enrichment for 24 h, 1, 3, or 5 weeks. Although 24 h exposure was enough to improve memory, only after 3-week exposure some anxiety behaviors were attenuated. No effect on depressive behaviors or coticosterone levels, which may be due to that particular strain of mouse (several other studies found that environmental enrichment ameliorates depressive symptoms in other mice strains and rats). The 3-week exposure also increased the levels of serotonin in the frontal cortex. Only after 5-eweek exposure there was a significant survival rate of the hippocampal new cells. Of note, these were normal mice, i.e. they were not suffering from any disorder prior to exposure.

Mice raised in an impoverished environment (a) show less dendrite growth (c) than do mice raised in an enriched environment (b, d). Copyright: BSCS.
Mice raised in an impoverished environment (a) show less dendrite growth (c) than do mice raised in an enriched environment (b, d). Copyright: BSCS.

The findings give us a nice timeline for environmental enrichment to show its desired effects. But… if there are differences in the timeline and effects of environmental enrichment exposure from mouse strain to mouse strain, then what can we say for humans? Probably not much, unfortunately. As the ad nauseam overused phrase goes at the end of so many papers, ‘more research is needed to elucidate this problem’.

Reference: Leger M, Paizanis E, Dzahini K, Quiedeville A, Bouet V, Cassel JC, Freret T, Schumann-Bard P, & Boulouard M. (Nov 2015, Epub 5 Jun 2014). Environmental Enrichment Duration Differentially Affects Behavior and Neuroplasticity in Adult Mice. Cerebral Cortex, 25(11):4048-61. doi: 10.1093/cercor/bhu119. Article | FREE PDF

By Neuronicus, 1 November 2015

Giving up? Your parvalbumin neurons may have something to do with it

Cartoon from http://i393.photobucket.com/albums/pp20/saisi24/dontgivedup.jpg, licensing unknown
Cartoon from Photobucket, licensing unknown.

One of the most ecologically-valid rodent models of depression is the learned helplessness paradigm. You get a rat or a mouse and you confine it in a cage with an electrified grid. Then you apply mild foot shocks at random intervals and of random duration for an hour (which is one session). The mouse initially tries to escape, but there is no escape; the whole floor is electrified. After a couple of sessions, the mouse doesn’t try to escape anymore; it gives up. Even when you put the mouse in a cage with an open door, so it can flee to no-pain freedom, it doesn’t attempt to do so. The interpretation is that the mouse has learned that it cannot control the environment, no matter what he does, he’s helpless, so why bother? Hence the name of the behavioral paradigm: learned helplessness.

All antidepressants on the market have been tested at one point or another against this paradigm; if the drug got the mouse to try to escape more, then the drug passed the test.

Just like in the higher vertebrate realm, there are a few animals who keep trying to escape longer than the others, before they too finally give up; we call these resilient.

Perova, Delevich, & Li (2015) looked at a type of neuron that may have something to do with the capacity of some of the mice to be resilient; the parvalbumin interneurons (PAI) from the medial prefrontal cortex (mPFC). These neurons produce GABA, the major inhibitory neurotransmitter in the brain, and modulates the activity of the nearby neurons. Thanks to the ability to genetically engineer mice to have a certain kind of cell fluoresce, the researchers were able to identify and subsequently record from and manipulate the function of the PAIs. These PAIs’ response to stimulation was weaker in helpless animals compared to resilient or controls. Also, inactivation of the PAI via a designer virus promotes helplessness.

Reference: Perova Z, Delevich K, & Li B (18 Feb 2015). Depression of Excitatory Synapses onto Parvalbumin Interneurons in the Medial Prefrontal Cortex in Susceptibility to Stress. The Journal of Neuroscience, 35(7):3201–3206. doi: 10.1523/JNEUROSCI.2670-14.2015. Article | FREE FULLTEXT PDF

By Neuronicus, 21 October 2015

Cell phones give you hallucinations

A young businessman in a suit screaming at a cell phone. By: Benjamin Miller. License FSP Standard FreeStockPhotos.biz
Photo by Benjamin Miller. License: FSP Standard FreeStockPhotos.biz

Medical doctors (MD) are overworked, particularly when they are hatchlings (i.e. Medical School students) and fledglings (interns and residents). So overworked, that in many countries is routine to have 80-hour weeks and 30-hour shifts as residents and interns. This is a concern as it has been shown that sleep deprivation impairs learning (which is the whole point of residency) and increases the number of medical mistakes (the lack of which is the whole point of their profession).

Lin et al. (2013) show that it can do more than that. Couple internship and cell phones and you get… hallucinations. That’s right. The authors asked 73 medical interns to complete some tests before their internship, then every third, sixth, and twelfth months of their internship, and after the internship. The questionnaires were on anxiety, depression, personality, and cell phone habits and hallucinations. That is: the sensation that your cell phone is vibrating or ringing when, in fact, it is not (which fully corresponds to the definition of hallucination). And here is what they found:

 Before internship, 78% of MDs experienced phantom vibration and 27% experienced phantom ringing.
 During their 1-year internship, about 85 to 95% of MDs experienced phantom vibration and phantom ringing.
 After the internship when the MDs did no work for two weeks, 50% still had these hallucinations.

Composite figure from Lin et al. (2015) showing the interns' depression (above) and anxiety (below) scores before, during, and after internship. The differences are statistically significant.
Fig. 1. Composite figure from Lin et al. (2015) showing the interns’ depression (above) and anxiety (below) scores before, during, and after internship. The differences are statistically significant.

The MDs’ depression and anxiety were also elevated more during the internship than before or after (see Fig. 1), but there was no correlation between the hallucinations and the depression and anxiety scores.

These findings are disturbing on so many levels… Should we be worried that prolonged exposure to cell phones can produce hallucinations? Or that o good portion of the MDs have hallucinations before going to internship? Or that 90% the people in charge with your life or your child’s life are so overworked that are hallucinating on a regular basis? Fine, fine, believing that your phone is ringing or vibrating may not be such a big deal of a hallucination, compared with, let’s say, “the voices told me to give you a lethal dose of morphine”, but as a neuroscientist I beg the question: is there a common mechanism between these two types of hallucinations and, if so, what ELSE is the MD hallucinating about while reassuring you that your CAT scan is normal? Or, forget about the hallucinations, should we worry that your MD is probably more depressed and anxious than you? Or, the “good” news, that the medical interns provide “a model of stress-induced psychotic symptoms” better that previous models, as the authors put it (p. 5)? I really wish there was more research on positive things (… that was a pun; hallucinations are a positive schizophrenic symptom, look it up 🙂 ).

Reference: Lin YH, Lin SH, Li P, Huang WL, & Chen CY. (10 June 2013). Prevalent hallucinations during medical internships: phantom vibration and ringing syndromes. PLoS One, 8(6): e65152. doi: 10.1371/journal.pone.0065152. Article | FREE PDF | First time the phenomenon was documented in press

By Neuronicus, 14 October 2015

Stressed out? Blame your amygdalae

amygdala
Clipart: Royalty free from http://www.cliparthut.com. Text: Neuronicus.

Sooner or later, everyone is exposed to high amounts of stress, whether it is in the form losing someone dear, financial insecurity, or health problems and so on. Most of us manage to bounce right up and continue with our lives, but there is a considerable segment of the population who do not and develop all sorts of problems, from autoimmune disorders to severe depression and anxiety. What makes those people more susceptible to stress? And, more importantly, can we do something about it (yeah, besides making the world a less stressful place)?

Swartz et al. (2015) scanned the brain of 753 healthy young adults (18-22 yrs) while performing a widely used paradigm that elicits amygdalar activation (brain structure, see pic): the subjects had to match a face appearing in the upper part of the screen with one of the faces in the lower part of the screen. The faces looked fearful, angry, surprised, or neutral and amygdalae are robustly activated when matching the fearful face. Then the authors had the participants fill out questionnaires regarding their life events and perceived stress level every 3 months over a period of 2 years (they say 4 years everywhere else in the paper minus Methods & Results, which are the sections that count if one wants to replicate; maybe this is only half of the study and they intend to follow-up to 4 years?).

The higher your baseline amygdalar activation, the higher the risk to develop anxiety disorders later on if expossed to life stressors. Yellow = amygdala. Photo credit: https://www.youtube.com/watch?v=JD44PbAOTy8, presumably copyrighted to Duke University.
The higher your baseline amygdalar activation, the higher the risk to develop anxiety disorders later on if expossed to life stressors. Yellow = amygdala. Photo credit: https://www.youtube.com/watch?v=JD44PbAOTy8, presumably copyrighted to Duke University.

The finding of the study is this: baseline amygdalar activation can predict who will develop anxiety later on. In other words, if your natural, healthy, non-stressed self has a an overactive amygdala, you will develop some anxiety disorder later on if exposed to stressors (and who isn’t?). The good news is that knowing this, the owner of the super-sensitive amygdalae, even if s/he may not be able to protect her/himself from stressors, at least can engage in some preventative therapy or counseling to be better equipped with adaptive coping mechanisms when the bad things come. Probably we could all benefit from being “better equipped with adaptive coping mechanisms”, feisty amygdalae or not. Oh, well…

Reference: Swartz, J.R., Knodt, A.R., Radtke, S.R., & Hariri, A.R. (2015). A neural biomarker of psychological vulnerability to future life stress. Neuron, 85, 505-511. doi: 10.1016/j.neuron.2014.12.055. Article | PDF | Video

By Neuronicus, 12 October 2015

As nutty as Dali, as crazy as van Gogh

Left: Portrait of Salvador Dali (taken in Hôtel Meurice, Paris, by Allen Warren, 1972). Right: Self-portrait with bandaged ear and pipe (van Gogh, 1889). Courtesy of Wikipedia.
Left: Portrait of Salvador Dali (taken in Hôtel Meurice, Paris, by Allen Warren, 1972). Right: Self-portrait with bandaged ear and pipe (van Gogh, 1889). Courtesy of Wikipedia.

Having a brain disease means to have different scores on emotion, cognition, and behavior inventories than the population mean. Also different from the population mean is the ability of an artist to create evocative things. Whether is a piece of music or a painting (or in my case a simple straight line), whether we like it or not, most of us agree that we couldn’t have done it. Also, artists show a decrease in practical reasoning, just like the schizophrenics.

Power et al. (2015) sought to find out if there is a link between being creative and having schizophrenia or bipolar disorder. Lucky for them, the north-European countries keep detailed medical and genetic databases of their population: they had access to 5 databases from Iceland, Sweden, and Netherlands, featuring tens to hundreds of thousands of people.

The authors analyzed hundreds of thousands of individual genetic differences (i.e. SNPs = single nucleotide polymorphisms) that had been previously linked with schizophrenia or bipolar disorder. As a side note, some of this data was obtained by inviting citizens to voluntarily fill out a detailed medical questionnaire and donate blood for DNA analysis. A staggering amount of people agreed. I wonder how many would have done so in U.S.A….

Anyway, the authors defined creative individuals (artists) as “those having (or ever having had) positions in the fields of dance, film, music, theater, visual arts or writing” (online supplemental methods), including those teaching these subjects. And they found out that the same genetic makeup that increases the risk of developing schizophrenia or bipolar disorder also underlies creativity. This link was not explained by education, age, sex, or shared environment.

The study also knocked down an evolutionary explanation for the persistence of schizophrenia and bipolar disorders in the genetic pool. The hypothesis posits that we still have these devastating brain disorders because they come with the side effect of creativity that offsets their negative fitness; but that does not hold, as the artists in this study had less children than the average population. Authors did not offer an alternative speculation.

Reference: Power, R. A., Steinberg, S., Bjornsdottir, G., Rietveld, C. A., Abdellaoui, A., Nivard, M. M., Johannesson, M., Galesloot, T.E., Hottenga, J. J., Willemsen, G., Cesarini, D., Benjamin, D. J., Magnusson, P. K., Ullén, F., Tiemeier, H., Hofman, A., van Rooij, F. J., Walters, G. B., Sigurdsson, E., Thorgeirsson, T. E., Ingason, A., Helgason, A., Kong, A., Kiemeney, L. A., Koellinger, P., Boomsma, D. I., Gudbjartsson, D., Stefansson, H., & Stefansson K. (July 2015, Epub 8 June 2015). Polygenic risk scores for schizophrenia and bipolar disorder predict creativity. Nature Neuroscience, 8(7):953-5. doi: 10.1038/nn.4040. Article + Nature comment

By Neuronicus, 7 October 2015