Transcranial Direct Current Stimulation

Epistemic status: rough-draft, I wouldn’t be surprised if my conclusions reversed

tDCS consists of a pair of sponge electrodes on the head, through which constant current is placed, at about 0.029-0.08 mA per square centimeter. Locations vary based on the intended effect of the treatment.  Extending treatment is usually done by prolonging duration rather than increasing intensity, as higher currents cause more cutaneous pain. When done correctly, the stimulation is painless, and therefore can be compared to sham stimulation as a control.[1]

Bottom lines: there are some serious methodological flaws in tCDS studies.  “Sham” stimulation isn’t a perfect control, so some significant proportion of the effect may be placebo. And there’s quite significant variation in how much a given application of current increases the evoked potential in the brain.  Also, almost all the studies are quite small.

Given that, though, the effect sizes on working memory are quite good — comparable or better to the best nootropics (caffeine, modafinil, and amphetamine.)

As a treatment for depression, tCDS looks less impressive; aggregating the best-quality studies gives no net effect compared to sham stimulation.

As a treatment for chronic pain, tCDS looks quite good, though there’s not very many studies.

Cognition

A study of 15 healthy females found a slight improvement on a working memory task from anodal stimulation to the DLPFC, but not from cathodal stimulation of the DLPFC, stimulation of M1, or sham stimulation.  Cohen’s d is 0.66. [2]

18 patients with Parkinson’s given 1-2 mA of tCDS to the DLPFC for 20 min found a 20% increase in correct answers on a 3-back task compared to sham stimulation for 2 mA.  Stimulation with 1 mA improved accuracy by only 5%. Stimulation of M1 had a significant improvement of reaction time but not accuracy. Cohen’s d is 3.5.[3]

32 patients given sham, anodal, or cathodal stimulation of the DLPFC or M1 found that accuracy on a word-memorization task was significantly better with anodal DLPFC stimulation than sham (88% correct vs. 80% correct), while cathodal stimulation was worse than sham.  Sham and M1 stimulation were similar.  Cohen’s d was 3.5. [7]

18 subjects given a verbal-associative task with anodal DLPFC tCDS vs sham or cathodal tCDS significantly improved mean scores (9 vs. 7 out of 12 correct). There was no effect on verbal fluency scores (a test of how many unique words one can produce in a short timespan).  Cohen’s d was 0.8.[8]

12 patients given a 2-back task with sham, anodal DLPFC tCDS, or transcranial random noise stimulation found a significant improvement in speed but not accuracy for 2-back anodal tCDS vs. sham.  Cohen’s d was 0 for accuracy, 0.36 for speed.[9]

10 Alzheimer’s patients treated with tCDS on the DLPFC and left temporal cortex found significantly more correct responses with tCDS vs sham on a memorization task (30 vs. 35 correct responses out of 55) but no improvement in Stroop or digit span tests.  Cohen’s d was 1.[12]

16 Parkinson’s patients given tCDS to the DLPFC significantly improved phonemic verbal fluency relative to sham and TPC stimulation (p < 0.002) but did not improve semantic verbal fluency.[17]

In a study of 12 healthy subjects given a naming task, reaction times were decreased with anodal tCDS to the DLPFC and increased with cathodal tCDS to the DLPFC.[18]

15 healthy subjects given a 3-back working memory task given anodal tCDS to the DLPFC significantly improved accuracy with tCDS vs sham (80% correct vs 69% correct).  Cohen’s d of 0.87.[18]

10 stroke patients given a 2-back working memory task, treated with anodal DLPFC tCDS or sham, found significant improvement in accuracy in anodal but not sham groups. Cohen’s d of 2.4.[19]

28 patients with major depression given a 2-back task given tCDS or sham on the DLPFC found a significant improvement in accuracy with the active version vs. sham: 58% vs 42% correct, p = 0.04, Cohen’s d about 4.[20]

58 healthy subjects given working memory training had an effect size of DLPFC tCDS vs. sham of 1.5 on digit span (p = 0.025) , 1.35 for Stroop accuracy, 1.3 on the CVLT, no effect on Raven’s.[21]

30 healthy older adults were given sham or real anodal tCDS to the left DLPFC and given a 3-back test; there was no significant effect of stimulation on working memory performance.[24]

37 patients with temporal lobe epilepsy had no improvement in working or episodic memory from anodal tCDS to the left DLPFC.[25]

Mean Cohen’s d for working memory accuracy, weighted by sample size: 1.5.

A meta-analysis of 16 studies of anodal DLPFC tCDS found a mean effect size of 0.14 for accuracy and 0.15 for reaction time.[22]

I’m not certain why I’m getting such different numbers, except that my “review” seems to have included different studies than the meta-analysis did.  If you averaged the results, you’d still get a mean effect size of 0.75, which corresponds to a strong effect.

Speech

10 aphasic stroke patients treated with anodal tCDS over Wernicke’s area vs. sham: significantly improved accuracy on a picture-naming task (40% vs 20% correct before training, and 70% vs 50% after training.)  Anodal tCDS also improved mean reaction time (1.8 sec vs 2.5 sec.)  The improvement persisted 3 weeks after treatment.[6]

In 10 healthy subjects, anodal tCDS over Broca’s area vs sham increased verbal fluency: mean number of words were 22 vs. 16, and mean number of syllables was 15 vs. 14.  There was no effect when the tCDS was switched to the right-hemisphere analogue of Broca’s area.[10]

Pain

A study of 17 patients with central pain due to traumatic spinal cord injury, given 2 mA of tCDS to the motor cortex M1 or sham tCDS found a significant improvement of pain scores — from a 7 (out of 9) to a 4.  The effects of consecutive sessions were cumulative.  There was no significant effect of treatment on anxiety or cognitive function.

32 female patients with fibromyalgia were treated with sham tCDS, tCDS of M1, or tCDS of the DLPFC.  M1 stimulation worked, sham and DLPFC did not. Out of a subjective improvement scale (where 2 is “much improvement”,  3 is “minimal improvement”, and 4 is “no change”, the group treated with M1 tCDS was at 2.5 and the sham group was at 3.5; the DLPFC group was at 3.  This was 2 mA, 20 min/day, for 5 days.[4]

41 female patients with fibromyalgia treated with tCDS on M1, DLPFC, or sham found that M1 stimulation significantly improved pain scores compared to DLPFC or sham: from about a 6 (which was baseline) to a 4.  No significant effect on depression scores.[11]

A meta-analysis of tCDS for chronic pain found a pooled effect size of 2.29 on pain symptoms.[23]

Depression

A meta-analysis of the use of tCDS in depression (directed to the DLPFC) found that the mean effect on depressive symptoms was significant: a Hedges’ g score of 0.743, significant at a p-value of 0.006. There’s a bit of a bias in the data: the Fregni and Boggio labs had significantly larger effect sizes than the other labs, and there was significant heterogeneity in results. Only a minority of patients (10-30%) were responders.  The average reduction in symptom severity was about 30%.[5]

Another meta-analysis of 6 RCTs of tCDS in depression found no significant effect of tCDS vs. sham on response rates or remission rates for depression.[13]

Blinding issues

There are more frequent reports of itching and burning with real than sham tCDS, suggesting that blinding may not be sufficient.[14]  Participants are able to guess more accurately than chance whether they are in the active or sham treatment.[15]

Other problems

The MEP (electrical activity change) due to tCDS is extremely variable both between individuals and within the same individual. The MEP effect of tCDS can be abolished by moving or thinking while the current is being administered.[16]

DIY

If you want to zap your brain, there are a variety of places that sell tCDS devices.

The Brain Stimulator is $59.95

The foc.us  stimulator is $249, plus headsets and cables.

The Apex is $139.99

The Fisher Wallace Stimulator is $699.

Soterix Medical makes the standard clinical-use device, for investigational use only.

And, of course, a lot of people make DIY versions.

Safety issue to keep in mind: high voltage to your brain is not good. Anything above 2 mA is outside the range of what’s been studied and probably a bad idea.  If it hurts your skin, it’s too strong. A TENS unit is too strong.  A 9-volt battery is too strong. Do not do the thing.

References

[1]Nitsche, Michael A., et al. “Transcranial direct current stimulation: state of the art 2008.” Brain stimulation 1.3 (2008): 206-223.

[2]Fregni, Felipe, et al. “Anodal transcranial direct current stimulation of prefrontal cortex enhances working memory.” Experimental brain research 166.1 (2005): 23-30.

[3]Boggio, Paulo S., et al. “Effects of transcranial direct current stimulation on working memory in patients with Parkinson’s disease.” Journal of the neurological sciences 249.1 (2006): 31-38.

[4]Fregni, Felipe, et al. “A randomized, sham‐controlled, proof of principle study of transcranial direct current stimulation for the treatment of pain in fibromyalgia.” Arthritis & Rheumatism 54.12 (2006): 3988-3998.

[5]Kalu, U. G., et al. “Transcranial direct current stimulation in the treatment of major depression: a meta-analysis.” Psychological medicine 42.09 (2012): 1791-1800.

[6]Fiori, Valentina, et al. “Transcranial direct current stimulation improves word retrieval in healthy and nonfluent aphasic subjects.” Journal of Cognitive Neuroscience 23.9 (2011): 2309-2323.

[7]Javadi, Amir Homayoun, and Vincent Walsh. “Transcranial direct current stimulation (tDCS) of the left dorsolateral prefrontal cortex modulates declarative memory.” Brain stimulation 5.3 (2012): 231-241.

[8]Cerruti, Carlo, and Gottfried Schlaug. “Anodal transcranial direct current stimulation of the prefrontal cortex enhances complex verbal associative thought.” Journal of Cognitive Neuroscience 21.10 (2009): 1980-1987.

[9]Mulquiney, Paul G., et al. “Improving working memory: exploring the effect of transcranial random noise stimulation and transcranial direct current stimulation on the dorsolateral prefrontal cortex.” Clinical Neurophysiology 122.12 (2011): 2384-2389.

[10]Cattaneo, Z., A. Pisoni, and C. Papagno. “Transcranial direct current stimulation over Broca’s region improves phonemic and semantic fluency in healthy individuals.” Neuroscience 183 (2011): 64-70.

[11]Valle, Angela, et al. “Efficacy of anodal transcranial direct current stimulation (tDCS) for the treatment of fibromyalgia: results of a randomized, sham-controlled longitudinal clinical trial.” Journal of pain management 2.3 (2009): 353.

[12]Boggio, Paulo S., et al. “Temporal cortex direct current stimulation enhances performance on a visual recognition memory task in Alzheimer disease.” Journal of Neurology, Neurosurgery & Psychiatry 80.4 (2009): 444-447.

[13]Berlim, Marcelo T., Frederique Van den Eynde, and Z. Jeff Daskalakis. “Clinical utility of transcranial direct current stimulation (tDCS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials.” Journal of psychiatric research 47.1 (2013): 1-7.

[14]Kessler, Sudha Kilaru, et al. “Differences in the experience of active and sham transcranial direct current stimulation.” Brain stimulation 5.2 (2012): 155-162.

[15]O’connell, Neil E., et al. “Rethinking clinical trials of transcranial direct current stimulation: participant and assessor blinding is inadequate at intensities of 2mA.” PloS one 7.10 (2012): e47514.

[16]Horvath, Jared Cooney, Olivia Carter, and Jason D. Forte. “Transcranial direct current stimulation: five important issues we aren’t discussing (but probably should be).” Frontiers in systems neuroscience 8 (2014): 2.

[17]Pereira, Joana B., et al. “Modulation of verbal fluency networks by transcranial direct current stimulation (tDCS) in Parkinson’s disease.” Brain stimulation 6.1 (2013): 16-24.

[18]Ohn, Suk Hoon, et al. “Time-dependent effect of transcranial direct current stimulation on the enhancement of working memory.” Neuroreport 19.1 (2008): 43-47.

[19]Jo, Jung Mi, et al. “Enhancing the working memory of stroke patients using tDCS.” American Journal of Physical Medicine & Rehabilitation 88.5 (2009): 404-409.

[20]Oliveira, Janaina F., et al. “Acute working memory improvement after tDCS in antidepressant-free patients with major depressive disorder.” Neuroscience letters 537 (2013): 60-64.

[21]Richmond, Lauren L., et al. “Transcranial direct current stimulation enhances verbal working memory training performance over time and near transfer outcomes.” Journal of Cognitive Neuroscience (2014).

[22]Hill, Aron T., Paul B. Fitzgerald, and Kate E. Hoy. “Effects of anodal transcranial direct current stimulation on working memory: a systematic review and meta-analysis of findings from healthy and neuropsychiatric populations.” Brain stimulation 9.2 (2016): 197-208.

[23]Luedtke, Kerstin, et al. “Transcranial direct current stimulation for the reduction of clinical and experimentally induced pain: a systematic review and meta-analysis.” The Clinical journal of pain 28.5 (2012): 452-461.

[24]Nilsson, Jonna, Alexander V. Lebedev, and Martin Lövdén. “No significant effect of prefrontal tDCS on working memory performance in older adults.” Frontiers in aging neuroscience 7 (2015).

[25]Liu, Anli, et al. “Exploring the efficacy of a 5-day course of transcranial direct current stimulation (TDCS) on depression and memory function in patients with well-controlled temporal lobe epilepsy.” Epilepsy & Behavior 55 (2016): 11-20.

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Nootropics

Epistemic status: medium

There are a lot of drugs and supplements reputed to improve cognitive function.  I was sick of relying on hearsay and anecdote, so I did my best attempt at a systematic overview of what works and what doesn’t.

BOTTOM LINES

Caffeine, modafinil, amphetamine, methylphenidate, and maybe a discontinued nicotinic-receptor agonist drug called ispronicline, have really big effects on cognitive function in healthy people.

Caffeine and modafinil work significantly better in sleep-deprived than non-sleep-deprived people.

Caffeine, nicotine, and amphetamine, in contrast to methylphenidate and modafinil, do not improve memory performance or accuracy on cognitive tasks in healthy people, but only reaction time.  In other words: caffeine, nicotine, and amphetamine make you more alert but not smarter; methylphenidate and modafinil also seem to improve memory.

Amphetamine and modafinil work better on people with the COMT val/val phenotype (who tend to be less intelligent) and may be ineffective or counterproductive on COMT met/met phenotype people.

All of the above (caffeine, nicotine, modafinil, amphetamine, and methylphenidate) cause some tolerance.

Cerebrolysin, a mixture of neural growth factors, apparently works really well on Alzheimer’s patients, though there’s fewer studies of it than more common Alzheimer’s drugs.  It might extrapolate to people with other kinds of neurodegenerative problems, or to slow the effects of aging.

Cognitive training (memorization practice including spaced repetition) works moderately well on Alzheimer’s patients and schizophrenics.  It’s quite plausible that it’s also good for healthy people.

Healthy people can get small positive effects from nicotine, possibly the herb Bacopa monniera, and from transcranial magnetic stimulation.

Alzheimer’s patients can get small effects from cholinesterase inhibitors (which are standard Alzheimer’s drugs); from a mixture of vitamins, fatty acids, choline, and uridine; from melatonin, the hormone which regulates sleep; and from the amino acid derivative acetyl-l-carnitine. Apart from the cholinesterase inhibitors (which have GI side effects) these are safe for healthy people to take, but it’s not known whether they affect cognitive function in healthy people.

METHODOLOGY

only looked at published studies on cognitive outcomes in humans: tests of memory, reaction time, and the like.  No animal studies. No measurements of neural correlates or biomarkers. To show up in my list, it has to make humans perform better.  I didn’t restrict attention to healthy humans, however; a lot of the studies on cognitive enhancement are performed on subjects with diseases like Alzheimer’s or schizophrenia, so I included some of those, under the suspicion that they might generalize to healthy people.

I ranked nootropics by effect size. That is, Cohen’s d, the difference in mean outcome between treatment and control groups divided by the pooled standard error.

Assume that a trait, like your score on an exam, has a Gaussian distribution. Suppose you have some treatment that increases the mean score in the treatment vs. the control group. Then you can divide by the (pooled) standard deviation of the score to get an estimate of how big a difference the treatment makes, compared to the population variation in the trait. Does it increase your score by one standard deviation? That’s an effect size of one.  Does it increase your score by half a standard deviation? That’s an effect size of 0.5.

This allows us to compare “how big an effect” different interventions have, along one scale, even if they’re acting on different traits. If drug A improves your reaction times by two standard deviations, and drug B improves your memory by half a standard deviation, you can still say that drug A has a larger effect than drug B, even though the effect isn’t on the same thing.

Conventionally, an effect size of 0.2-0.3 is a “small” effect, around 0.5 is a “medium” effect, and anything greater than 0.8 is a “large” effect. Most drugs used in psychiatry have effect sizes around 0.5.  Intuitively, effect sizes of about 0.5 look like “sorta works” to the naked eye. Effect sizes greater than 1 look like “holy shit, that’s an unmistakable effect” to the naked eye.

Anything with a p-value of <0.05 (but not <0.01) I didn’t include in the table of best nootropics, because the vast majority of studies with such high p-values don’t replicate.  I also didn’t include things in the table if they were shown to not work on healthy subjects (even if they did work on ill subjects).  When there was conflict between studies, I erred on the conservative side and chose smaller effect sizes.

 

Drug Effect Size Trait
Modafinil, Caffeine 2-3 Executive function in sleep deprived people
Modafinil, Caffeine 2-3 Wakefulness in sleep deprived people
Ispronicline 2.5 Attention and episodic memory in healthy people
Amphetamine 2.3 Reaction time in healthy people
Cerebrolysin 1.8-2.2 ADAS-cognitive test in Alzheimer’s patients
Methylphenidate 1.4 Memory in healthy non-sleep-deprived people
Modafinil 1.22 Working memory in sleep deprived people
Caffeine 0.7 Reaction time in non-sleep-deprived healthy people
Nicotine 0.7 Attention in schizophrenics
Modafinil 0.56 Attention in non-sleep-deprived healthy people
Melatonin 0.56 ADL’s for Alzheimer’s patients
Cognitive training (including spaced repetition) 0.43-0.47 Various cognitive tests and ADL’s for Alzheimer’s patients and schizophrenic patients
Bacopa monniera 0.32 Learning rate in healthy people
Nicotine 0.3 Reaction times in smokers and nonsmokers
Cholinesterase inhibitors 0.2-0.5 ADAS-cognitive test in Alzheimer’s patients
rTMS 0.2-0.3 Working memory and reaction time in healthy subjects
Souvenaid 0.23 Memory in Alzheimer’s patients
Acetyl-L-carnitine 0.2 Various cognitive tests in Alzheimer’s patients

EFFECTIVE THERAPIES

ALCAR

ALCAR, or acetylcarnitine, is an amino acid derivative used in the metabolism of fatty acids.

A meta-study of 21 studies of Alzheimer’s patients found a median effect size of 0.2, with a total of 499 patients, across various cognitive tests.

Amphetamine

Amphetamine is a dopaminergic stimulant drug.

Amphetamine improved working-memory performance in healthy subjects only if they had low performance at baseline, and worsened it in those who had high performance at baseline.[4]

Improves working memory on healthy val/val COMT subjects, doesn’t, or deteriorates it, on met/met subjects. (“Warriors” benefit, “worriers” do not.)[38]

Improves reaction time on a movement estimation task (effect size: 2.3) but not digit span.[39]

Bacopa monniera

Bacopa monniera is a plant traditionally supposed to improve memory. The active ingredient is bacoside, a triterpenoid saponin.

Randomized study of 46 healthy adults, AVLT learning rate after 12 weeks is better, effect size 0.32, a significant effect at p < 0.01.  State anxiety also lower, p < 0.001. No effect on digit span.[33] No effects on memory.[34]

Caffeine

Caffeine is the most commonly used psychoactive chemical worldwide, and is a stimulant that works by adenosine receptor antagonism.

Cross-sectional study of 9003 adults finds that higher habitual coffee and tea consumption has a significant dose-response relationship (p < 0.001) with performance tests of memory, visuospatial reasoning, and reaction time, suggesting that tolerance to caffeine is incomplete and caffeine does cause higher absolute levels of cognitive performance.[1]

Metastudy found that caffeine had no effect on free recall in most short-term memory studies. It does reliably improve reaction time.  Reduces the risk of sleep-deprivation-related work accidents by about two-fold.  Generally improves cognitive performance more in sleep-deprived than in non-sleep-deprived subjects. Caffeine improves cognitive function in elderly subjects more than in young (20-60) subjects, and regular caffeine consumers have less (half as much) age-related cognitive decline.[20]

Caffeine improves reaction time over placebo with an effect size of 0.7[21]

Cerebrolysin

Cerebrolysin is a mixture of neurotrophic peptides derived from pig brains, including BDNF, GDNF, NGF, and CNTF. It may have a neuroprotective or neurorestorative effect.

Randomized study of 279 Alzheimer patients found scores on the cognitive subscale of the ADAS improved by 4 points on Cere vs. placebo, effect size of 1.86, p = 0.03.  Global clinical outcome significantly better than placebo (p < 0.001).[27]  A randomized trial of 149 Alzheimer patients found an effect size of 2.22, improvement of 3.2 on the ADAS-cog on Cerebrolysin vs. placebo, p < 0.001.[28]  Effect size of 2 on elderly controls on the ADAS-cog.[67]

Cholinesterase inhibitors

This is a class of drugs used for Alzheimer’s disease, including donepezil and galantamine.  A meta-study found they had median effect size 0.28 on the ADAS-Cog for high-dose studies, 0.15 for low dose.[48]  Another meta-study found they had mean effect size 0.1 for ADLs in Alzheimer’s and there’s no difference between cholinesterase inhibitors.

Cognitive Training

For Alzheimer’s disease. Mostly these are memory practice games or drills, many of which are spaced repetition. Across various measurements of outcome (CPT, memory tests, IADLs, etc) median effect size was 0.47.[50] A metastudy of cognitive remediation for schizophrenia found a median effect size of 0.43 across various cognitive tests.[56]

Donepezil

Donepezil is an acetylcholinesterase inhibitor used in Alzheimer’s.

Effect size of 1.25 on ADAS-Cog in Alzheimer’s patients (p < 0.001).[51]  Odd that it is so much better than “cholinesterase inhibitors” as a class.  Doesn’t affect progression to Alzheimer’s in mild cognitive impairment.[53] Effect size of 0.6 on the MMSE in Parkinson’s patients, p = 0.0013.[54]  One study showed that donepezil did not have an effect in mild cognitive impairment.[55] Doesn’t work on schizophrenics either. [58]  Did not have an effect on healthy elderly volunteers on cognitive tasks.[66]  I’m going to take the conservative, lower estimates that effect sizes are around 0.2 or 0.5.

Erythropoietin

Erythropoietin is a hormone that increases red blood cell production.

It improves working memory, verbal processing, and Wisconsin Card Sorting scores significantly over placebo in schizophrenic patients.[8]  Significantly improves (p < 0.01) sustained attention and information processing speed in bipolar patients.[72] “EPO acts in an antiapoptotic, anti-inflammatory, antioxidant, neurotrophic, angiogenetic, stem cell–modulatory fashion” so it’s investigated as a neuroprotective for stroke and neurodegenerative diseases, but so far mostly in animals.[42]

Galantamine

Galantamine is an acetylcholinesterase inhibitor used in Alzheimer’s.

Effect size of 8.18 (?!) in Alzheimer’s patients after 6 months; slows cognitive decline.[59] After 3 months, effect size of 2.4 in Alzheimer’s patients, p = 0.002.[63] Galantamine is better than donepezil for Alzheimer’s ADAS-Cog and MMSE.[64] On schizophrenics, effect size of 0.89 in schizophrenic patients on RBANS test, one standard deviation up on the memory subscale, effectively normalizing performance.[60] A much larger randomized study on schizophrenics, however, found no overall effect. [61]  Metastudy on galantamine vs. donezepil for Alzheimers found much weaker effects: 0.48 effect size for donepezil and 0.52 for galantamine.[65]

Ginseng

Panax ginseng is a plant traditionally used as an “adaptogen” to increase alertness and endurance; the active ingredients are triterpinoid saponins called ginenosides.

In a controlled trial of Alzheimer’s, ginseng improves performance on MMSE and ADAS scales after 12 weeks (p = 0.009 and 0.029 respectively) and declined to baseline after discontinuation.[6] Reduces blood glucose acutely (p < 0.001) in 30 healthy volunteers [40] and improves performance at p < 0.05 at “repeated sevens” task. Effect size of 1-2, but since effects were only slightly significant here and were not in other tasks, there’s some reason for skepticism.  This study found that it didn’t improve working memory or reaction time but did improve the “quality of memory” subscore.[41]

Ispronicline

Ispronicline is a nicotinic receptor agonist.  The company that produced it, Targacept, appears to have gone out of business, and the drug was discontinued after it failed to make progress on Alzheimer’s.

It significantly improves measures of attention & episodic memory on healthy male volunteers vs. placebo. Also increases upper alpha peak on EEGs.[44]  2.5 effect size, p < 0.01 for 50 mg AZD vs. placebo for elderly patients on attention, episodic memory, and SDI-cog.[46]   Not statistically significantly effective on Alzheimer’s.[45] 

L-Dopa

This is a precursor to dopamine, used as a treatment for Parkinson’s disease.

Slightly reduces reaction time in healthy subjects, p < 0.05.[74]  Some healthy subjects develop side effects of nausea and excitation under L-Dopa, and these have slower reaction time than placebo; those who don’t have adverse effects have faster reaction times, p = 0.02.[75]

Melatonin

Melatonin is the hormone that regulates sleep cycles, often taken as a sleep aid.

Significant (p = 0.004) improvement in IADL score (activities of daily living, effect size 0.56) on 80 Alzheimer’s patients.[25]

Methylphenidate

Methylphenidate is a stimulant that works by dopamine reuptake inhibition and is used as a treatment for ADD.

Meta-analysis finds a large effect size (1.4) in memory on healthy non-sleep-deprived subjects, but no other improvements on executive function, attention, or mood.  Does not reduce sleepiness after sleep deprivation.[17]

Modafinil

Modafinil is a stimulant that works primarily by histamine agonism.

Significantly improves digit span (by 1-2 digits) and improved pattern recognition (by 8 percentage points), fewer stop errors & lower stop signal reaction time, better spatial planning.[11]

Significant effects (in a meta-study) on working memory, digit span, reaction time, in most studies; no effect on Stroop, spatial planning, verbal fluency; no effect at all on high-IQ population.[14]

Does not cause overconfidence vs. placebo.[15]

Improves performance in a mean 100 IQ group, but not a mean 115 IQ group.[16]

Meta-study founds a moderate improvement on attention (0.56) in healthy non-sleep-deprived individuals. No changes in mood, memory, or motivation.  In sleep-deprived individuals, has a large (2-3) effect size on executive function, a large effect size (1.22) on memory, and a large effect size on wakefulness (2-3).[17]

Comparable alertness and performance effects for 200 or 400 mg modafinil vs. 600 mg caffeine (6 cups of coffee) in sleep-deprived patients.[18]  Caffeine, amphetamine, and modafinil are comparably effective in increasing alertness & reaction time in sleep-deprived patients.[9]

Nicotine

Nicotine is a stimulant and nicotinic acetylcholine receptor agonist.

4-week nicotine skin patch improves performance on continuous performance test vs. placebo in 8-person trials of Alzheimer’s.[3]

In abstinent smokers, nicotine improves performance on all tests; in never-smokers, produces faster reaction times but more errors.

6-month trial on schizophrenics improves performance on the CPT with an effect size of 0.7.[22]

A meta-analysis found that nicotine improved working memory reaction time in both smokers and nonsmokers, effect size 0.34, but did not improve accuracy; also improved reaction time in orienting attention, effect size 0.34, and alerting attention, 0.3

Oxygen

Breathing high-oxygen air increases blood oxygen concentration.

It improves word recall vs. placebo in healthy subjects, but only at a p < 0.05 level.  Reaction time lowered, p < 0.0005.  No effect on working memory.[10]  Effect size on word recall and reaction time in another study on healthy subjects was ~2.5, p < 0.05.[43]

Piracetam

Piracetam has an unknown mechanism of action but is sometimes used as a nootropic.

In a metastudy of piracetam for cognitive impairment (mostly age-related), 63.9% were improved on piracetam vs. 34.1% on placebo. Fixed-effects model OR is 3.35.[29]  Doesn’t work on Alzheimer’s.[69]

PRL-8-53

PRL-8-53 is an experimental compound with some cholinergic properties.

Significant (p < 0.01) improvement in word retention over placebo; 30-45% improvements in # of words retained.[26]

rTMS

Repetitive transcranial magnetic stimulation involves placing a magnetic coil near the head of the subject and produces small electric currents in the brain.

A meta-study found improvements with effect size of 0.2-0.3 in working memory and response times on healthy subjects on n-back tasks.[12]

Semax

Semax is a Russian nootropic that seems to work by stimulate nerve growth factors.

Significant 74% improvement over placebo on memorization exam in power plant operators.[24]  Most of the other evidence about Semax is from Russian rat studies.

Souvenaid

Souvenaid is a cocktail containing essential fatty acids, vitamins, uridine, and choline, used to treat Alzheimer’s.  

A randomized 24-week trial on Alzheimer’s patients found that it improved the memory subscore on the NTB with an effect size of 0.23.[68]

Tandospirone

Tandospirone is a serotonin partial agonist, similar to buspirone, used for anxiety and depression.

In schizophrenic patients, improves performance on Wechsler Memory Scale and Wisconsin Card Sorting, p < 0.001 and 0.0001 respectively, effect sizes of 0.63 and 0.7.[4]  However, tandospirone impaired memory in healthy subjects.[71]

Tianeptine

Tianeptine is an antidepressant that seems to work by enhancing dopamine release, enhancing BDNF, and/or targeting opioid receptors.

In an uncontrolled trial of depressed patients, tianeptine improved working memory and reaction time.[23]  Did not affect memory, attention, or psychomotor performance on young healthy volunteers.

Tolcapone

Tolcapone is a COMT inhibitor used in the treatment of Parkinson’s.

Tolcapone improves memory for val/val COMT healthy subjects, but worsens it for met/met. (“Warriors” benefit, “worriers” don’t.)  Effect size of about 0.8, p < 0.05 on the val/val’s.[73]
INEFFECTIVE THERAPIES

B vitamins

No effect on elderly subjects. [7]

Creatine

Creatine is a compound that occurs naturally in vertebrates and supplies ATP to muscles.

No effect on cognitive function on healthy young adults.[35]  Does have effects on memory in the elderly [36] (d = 1.5, p < 0.001 for backward digit span) and vegetarians [37]

D-Cycloserine

D-cycloserine is an amino acid derivative and antibiotic.

Doesn’t improve cognitive function/digit span in schizophrenics.[57]

DHEA

DHEA is a steroid hormone and precursor to estrogen and testosterone.

No effect on elderly subjects.[5]

Dual N-Back

Dual N-back is a memory practice game.

Metastudy shows that, while performance on the N-back task improves, no crossover improvement on IQ tests occurs.[13]

Gingko Biloba

Fails to find effect on cognitive performance on Stroop test in MS patients.[2]  Also fails to prevent cognitive decline in older adults.[76]g

Oxiracetam

Oxiracetam is in the racetam class of drugs, unknown mechanism of action.

Doesn’t work on Alzheimer’s. [32]

Selegiline

Selegiline is an MAOB inhibitor used in Parkinson’s and depression.

Not effective on cognitive performance in Alzheimer’s.[30]  Doesn’t help in Parkinson’s either.[31]

Tarenflurbil

Tarenflurbil is a discontinued putative Alzheimer’s drug that destroys amyloid plaques.

Doesn’t slow cognitive decline in Alzheimer’s.[49]

NOTES

Unsurprisingly, the classic stimulants do quite well. (Caffeine, nicotine, amphetamine, methylphenidate, modafinil.)  Ispronicline is less well known and its evidence base is much smaller, but since it’s also a nicotinic receptor agonist, it’s possible that it also belongs in this category.

Cerebrolysin is interesting. It’s a legal anti-Alzheimer’s drug in Europe, and one of the few drugs that directly focuses on neural growth factors. These are known (mostly in animal studies) to be protective against brain damage, as from stroke or Parkinson’s.  Deficiency in BDNF is also one of the current hypotheses for what’s going wrong in depression.  “Just give people some growth factors” might be one of these simple obvious-in-retrospect things that could pan out to be widely effective.  In animal studies, growth factor gene therapy often has neuroprotective effects, and Nobel Prize-winning neuroscientist Rita Levi-Montalcini took daily NGF eyedrops.

There’s a common pattern in anything dopaminergic (such as: amphetamines, tolcapone, L-dopa, etc) that they improve cognitive performance in people who have “too little dopamine” (Parkinson’s patients, ADHD patients, val/val COMT genotypes) but are useless or worse in those who have “too much dopamine” (met/met COMT genotypes.)  This seems like a fairly robust finding, across many drugs as well as a lot of fMRI studies about dorsolateral prefrontal cortex activation.  How good dopaminergics are for your mental performance may depend a lot on who you are.

 

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Dopamine, Perception, and Values

The pop-neuroscience story is that dopamine is the “reward” chemical.  Click a link on Facebook? That’s a hit of dopamine.

And there’s obviously an element of truth to that. It’s no accident that popular recreational drugs are usually dopaminergic.  But the reality is a little more complicated. Dopamine’s role in the brain — including its role in reinforcement learning — isn’t limited to “pleasure” or “reward” in the sense we’d usually understand it.

The basal ganglia, located at the base of the forebrain, below the cerebral cortex and close to the limbic system, have a large concentration of dopaminergic neurons.  This area of the brain deals with motor planning, procedural learning, habit formation, and motivation.  Damage causes movement disorders (Parkinson’s, Huntington’s, tardive dyskinesia, etc) or mental illnesses that have something to do with “habits” (OCD and Tourette’s).  Dopaminergic neurons are relatively rare in the brain, and confined to a smal number of locations: the striatal area (basal ganglia and ventral tegmental area), projections to the prefrontal cortex, and a few other areas where dopamine’s function is primarily neuroendocrine.

Dopamine, in other words, is not an all-purpose neurotransmitter like, say, glutamate (which is what the majority of neurons use.)  Dopamine does a specific thing or handful of things.

The important thing about dopamine response to stimuli is that it is very fast.  A stimulus associated with a reward causes a “phasic” (spiky) dopamine release within 70-100 ms. This is faster than the gaze shift (mammals instinctively focus their eyes on an unexpected stimulus).  It’s even faster than the ability of the visual cortex to distinguish different images.  Dopamine response happens faster than you can feel an emotion.  It’s prior to emotion, it’s prior even to the more complicated parts of perception.  This means that it’s wrong to interpret dopamine release as a “feel-good” response — it happens faster than you can feel at all.

What’s more, dopamine release is also associated with things besides rewards, such as an unexpected sound or an unpredictably flashing light.  And dopamine is not released in response to a stimulus associated with an expected reward; only an unexpected reward.  This suggests that dopamine has something to do with learning, not just “pleasure.”

Redgrave’s hypothesis is that dopamine release is an agency detector or a timestamp.  It’s fast because it’s there to assign a cause to a novel event.  “I get juice when I pull the lever”, emphasis on when.  There’s a minimum of sensory processing; just a little basic “is this positive or negative?”  Dopamine release determines what you perceive.  It creates the world around you.  What you notice and feel and think is determined by a very fast, pre-conscious process that selects for the surprising, the pleasurable, and the painful.

Striatal dopamine responses are important to perception.  Parkinson’s patients and schizophrenics treated with neuroleptics (both of whom have lowered dopamine levels) have abnormalities in visual contrast sensitivity.  Damage to dopaminergic neurons in rats causes sensory inattention and inability to orient towards new stimuli.

A related theory is that dopamine responds to reward prediction errors — not just rewards, but surprising rewards (or surprising punishments, or a surprisingly absent reward or punishment).  These prediction errors can depend on models of what the individual expects to happen — for example, if the stimulus regularly reverses on alternate trials, the dopamine spikes stop coming because the pattern is no longer surprising.

In other words, what you perceive and prioritize depends on what you have learned.  Potentially, even, your explicit and conscious models of the world.

The incentive salience hypothesis is an attempt to account for the fact that damage to dopamine neurons does not prevent the individual from experiencing pleasure, but damages his motivation to work for desired outcomes.  Dopamine must have something to do with initiating purposeful actions.  The hypothesis is that dopamine assigns an “incentive value” to stimuli; it prioritizes the signals, and then passes them off to some other system (perceptual, motor, etc.)  Dopamine seems to be involved in attention, and tonic dopamine deficiency tends to be associated with inattentive behavior in humans and rats.  (Note that the drugs used to treat ADHD are dopamine reuptake inhibitors.)  A phasic dopamine response says “Hey, this is important!”  If the baseline is too low, you wind up thinking everything is important — hence, deficits in attention.

One way of looking at this is in the context of “objective” versus “subjective” reality.  An agent with bounded computation necessarily has to approximate reality.  There’s always a distorting filter somewhere.  What we “see” is always mediated; there is no place in the brain that maps to a “photograph” of the visual field.   (That doesn’t mean that there’s no such thing as reality — “objective” probably refers to invariants and relationships between observers and time-slices, ways in which we can infer something about the territory from looking at the overlap between maps.)

And there’s a sort of isomorphism between your filter and your “values.”  What you record and pay attention to, is what’s important to you. Things are “salient”, worth acting on, worth paying attention to, to the extent that they help you gain “good” stuff and avoid “bad” stuff.  In other words, things that spike your dopamine.

Values aren’t really the same as a “utility function” — there’s no reason to suppose that the brain is wired to obey the Von Neumann-Morgenstern axioms, and in fact, there’s lots of evidence suggesting that it’s not.  Phasic dopamine release actually corresponds very closely to “values” in the Ayn Rand sense.  They’re pre-conscious; they shape perceptions; they are responses to pleasure and pain; values are “what one acts to gain and keep”, which sounds a whole lot like “incentive salience.”

Values are fundamental, in the sense that an initial evaluation of something’s salience is the lowest level of information processing. You are not motivated by your emotions, for instance; you are motivated by things deeper and quicker than emotions.

Values change in response to learning new things about one’s environment. Once you figure out a pattern, repetition of that pattern no longer surprises you. Conscious learning and intellectual thought might even affect your values, but I’d guess that it only works if it’s internalized; if you learn something new but still alieve in your old model, it’s not going to shift things on a fundamental level.

The idea of identifying with your values is potentially very powerful.  Your striatum is not genteel. It doesn’t know that sugar is bad for you or that adultery is wrong.  It’s common for people to disavow their “bestial” or “instinctive” or “System I” self.  But your values are also involved in all your “higher” functions.  You could not speak, or understand language, or conceive of a philosophical idea, if you didn’t have reinforcement learning to direct your attention towards discriminating specific perceptions, motions, and concepts. Your striatum encodes what you actually care about — all of it, “base” and “noble.”  You can’t separate from it.  You might be able to rewire it.  But in a sense nothing can be real to you unless it’s grounded in your values.

Glimcher, Paul W. “Understanding dopamine and reinforcement learning: the dopamine reward prediction error hypothesis.” Proceedings of the National Academy of Sciences 108.Supplement 3 (2011): 15647-15654.

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Redgrave, Peter, Kevin Gurney, and John Reynolds. “What is reinforced by phasic dopamine signals?.” Brain research reviews 58.2 (2008): 322-339.

Schultz, Wolfram. “Updating dopamine reward signals.” Current opinion in neurobiology 23.2 (2013): 229-238.