Valproic Acid for Perfect Pitch? Steady, Now…

FDA_seizure_drug_DepakoteFor the past few days, the internet has been abuzz with the announcement of the “perfect pitch miracle drug.” Let’s back up a bit, shall we?

Valproic acid has been used alone or in addition to other medications for nearly fifty years to treat epilepsy, and is the active ingredient in drugs such as Valproate and Depakon. It is also used in the prevention of migraines, mania in bipolar disorder and for the treatment of aggression exhibited in children with ADHD. It is in the class of anticonvulsants. To talk a little bit about how it works, our brain is made up of thousands of nerve cells that communicate back and forth via electrical signal, a very intricate and delicate process that need maintain a steady and stable balance for normative functioning. When repetitive and abnormally rapid electrical signals are released, this process becomes disturbed and over stimulated. Anticonvulsants such as Valproate function as a stabilizer by increasing the amount of the natural nerve-calming chemical GABA, (gamma-Aminobutyric acid), as an HDAC (histone deacetlyase) inhibitor (Monti et al., 2009). GABA is one of the brain’s chief inhibitory neurotransmitters, which many researchers believe to regulate anxiety. When the amount of GABA in the brain falls too low, Valproate prevents the breakdown of the chemical and works to stabilize the amount of electrical activity, which explains why the drug has been found effective as a treatment for periods of mania and epileptic seizures.

Unfortunately, valproic acid is far from the ideal end-all. Valproate has been known to potentially cause serious or life threatening damage to the liver, pancreas, and blood cells, and holds an alarmingly high statistic for weight gain. It is not approved for use during pregnancy and breastfeeding, and has recently been the target of a lawsuit due to unforeseen birth defects. It is also known to cause ataxia, thrombocytopenia and leucopenia, so before we all go rushing off to “increase our brain function,” it might be wise to spend a moment thinking critically.

This morning, Tom Ashbrook of On Point, NPR stated “Imagine a pill that could rewire your brain. Would make your brain young again. Able to learn and absorb like a five-year old. Music. Languages. Would you take it?”  Neuroplasticity has risen to near-celebrity status over the past few months, and recent study by Frontiers of Systems Neuroscience is certainly fanning the flame. Carried out by researchers from France, Canada, Maryland, Australia, Massachusetts and England, the study set out to discover whether such periods when enzymes “impose ‘brakes’ on neuroplasticity, might be able to “reopen critical periods of neuroplasticity” via a drug that blocks productions of those enzymes. Absolute pitch was thought to be a solid assessment of this possibility because there are “no known cases of an adult acquiring absolute pitch.”

Absolute pitch (AP) is the ability to identify or produce the pitch of a musical sound without any reference point. Individuals who possess AP, constituting about 0.01% of the general population, are able to identify the pitch class, i.e., one of the 12 notes of the Western musical system, e.g., C, D, G#, of a sound with great accuracy (varying between 70–99%, depending on the task, as compared to 10–40% for non-AP individuals, Takeuchi and Hulse, 1993). The study explains:

“Importantly, acquiring AP has a critical period (Levitin and Zatorre, 2003; Russo et al., 2003). A critical period is a fixed window of time, usually early in an organism’s lifespan, during which experience has lasting effects on the development of brain function and behavior. The principles of critical period phenomena and neural plasticity are increasingly well understood both at the behavioral/experiential (Kleim and Jones, 2008) and at the molecular/cellular level (Hensch, 2005). Specifically, behaviorally induced plasticity in the healthy brain, typically after the end of the relevant critical period, can lead to improvement beyond normal or average performance levels. However, for many tasks, this requires targeted training—simple routine use is often insufficient. The factors known to influence the efficiency of such targeted training include the number of repetitions involved, the intensity of the training as well as the relevance or saliency of the stimuli or task trained. Importantly, such training-induced learning is quite specific to the trained task and to the underlying brain networks, although some transfer to other, related domains of knowledge or skills is sometimes possible. At the cellular level, critical periods close when maturational processes and experiential events converge to cause neuoro-physiological and molecular changes that dampen or eliminate the potential for further change (Hensch, 2005Bavelier et al., 2010), thus imposing “brakes” on neuroplasticity. One of the epigenetic changes leading to decreased plasticity after the critical period involves the action of HDAC, an enzyme that acts as an epigenetic “brake” on critical-period learning (Morishita and Hensch, 2008Qing et al., 2008). Research has shown that inhibition of HDAC can reopen critical-period neuroplasticity in adult mice to enable recovery from amblyopia (Putignano et al., 2007Silingardi et al., 2010), and to facilitate new forms of auditory learning (Yang et al., 2012).” ( ).

The randomized, double blind study was conducted on twenty four men, half of which received Valproate and the other half, a placebo. The men who received Valproate showed advantage in pitch class identification. To come to the conclusion, it is imperative that we acknowledge the fact that these powerful pharmaceuticals were in no way developed for something so “trivial” of the acquisition of perfect pitch – the diagnostic simply was appropriate for a brief and extremely small study and subject pool. The researchers conclude:

If confirmed by future replications, our study will provide a behavioral paradigm for the assessment of the potential of psychiatric drugs to induce plasticity. In particular, the AP task may be useful as a behavioral correlate. If further studies continue to reveal specificity of VPA to the AP task (or to tasks on which training or intervention is provided), critical information will have been garnered concerning when systemic drug treatments may safely be used to reopen neural plasticity in a specific, targeted way.”

It is vital during this time of exponential and rapid advances in the realm of neuroscience that we keep the grounding measures of ethics and morality at the forefront of our minds. There is a reason performance enhancing drugs are strictly forbidden in competitive sports. While it is truly of great interest to deliberate over the implications of a drug altered to target neuroplasticity, with great power (all together now) comes great responsibility. 

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Neural Differences Between Musicians and Non-Musicians

Nature or Nurture, the Chicken or the Egg? The following paper has certainly given me much to think about, and will be addressed in posts soon to come.

Excerpt taken from Enhanced brainstem encoding predicts musicians’ perceptual advantages with pitch.

Musicians have different brains – that fact we have known for a long time. The study of musician and non-musician brains is probably one of the first stories in the science of neural (brain) plasticity; the idea that our brains respond and become modified by the things we experience in everyday life. Nowadays the existence of neural plasticity is beyond doubt: We see regular, remarkable examples of how the human brain, at any age although particularly in childhood, is able to re-organise itself in response to circumstances. For example, we know the brain can adapt after stroke or serious injury, after the loss of any of the senses and even as a result of our career choices. As for the latter, my favourite example is that of London Taxi drivers. Dr. Eleanor Maguire and her team found that the drivers show enlarged posterior hippocampus structures (the memory centre of the brain) which correlate with their possession of ‘the knowledge’, the mental map of London streets that they use to navigate.  As a result of such evidence we take it as a given that our brains will adapt to the world around us and to the demands that we make of it every day. And it therefore makes sense that musicians’ brains would adapt as a result of their exposure to and engagement with music.

But the ease with which we today accept brain plasticity as a result of musical practice is a result of over a century of research, which at first did not have the benefits of the sophisticated brain imaging tools. In fact the evidence goes back to Victorian scientists. Sigmund Auerbach (1860-1923) was a very popular German surgeon and diagnostician who contributed numerous works on the operative treatment of tumours of the brain and spinal marrow/cord, nervous damages, and epilepsy. At the beginning of the twentieth century he conducted a series of post-mortem brain dissections and reported that parts of the temporal and parietal lobe (in particular the superior temporal gyrus) were larger than normal in the brains of 5 famous musicians of the time (1911). However, the problem with simply noting differences between musicians and nonmusicians brains in this way is that you have no evidence for causation – how do you know their musical practice caused these changes? Maybe their brains were different to start with and that is the reason they became successful musicians?

The only way to solve this kind of riddle is with longitudinal, developmental studies. You measure kids’ brains before they start music (or choose not to – that is your control group) and then you determine whether the changes that occur to their brains as they learn match those that we see in adult musicians. I know of only one group braving this kind of study. Gottfried Shlaug’s lab’s results are starting to confirm that the neural differences we see in adult musicians are not present when children start learning – so logic suggests they must be a response to their environment. It is not conclusive yet, but it is a good indicator that musician/non-musician brain differences are largely the result of neural plasticity.

So what are the neural differences between musicians and non-musicians ? Well there are quite a few of them and I want to focus on just one recent study in today’s blog. So you will forgive me, I hope, if I say that if you want to know more about differences in general then I can recommend an article by Dr. Lauren Stewart which gives a great summary of this subjectToday we are interested in the brainstem. This is the oldest part of the brain and the part that is largely in charge of pre-conscious processing.

I first heard about brain stem studies about 4 years ago when I saw talks by Dr Nina Kraus and Dr Patrick Wong. Up until that point I had heard a lot about studying the higher centres of the brain with fMRI, PET and EEG but I have not been introduced to subcortical measures of musical processing. I found it fascinating. Both authors had perfected the technique of measuring the Frequency Following Response (FFR), an evoked potential generated in the upper portion of the brain stem. What happens in an FFR experiment is that a small number of electrodes are placed on the scalp (nowhere near as many as in a typical EEG scan) and then a series of simple sounds are played to one ear. As a participant you don’t have to do anything, in fact you can even fall asleepYour brainstem follows the frequency of the sounds that it hears, even when you are unconscious. It becomes ‘phase locked’, meaning that it displays a characteristic waveform that follows the individual cycles of the stimulus (i.e. its frequency).

Before the FFR paradigm came along we knew that musicians could unconsciously detect smaller changes in pitch than non-musicians (see work by Stefan Koelsch) but we didn’t know where this ability came from; was it coming from the lower pre-conscious levels of the cortex or the much older brainstem regions?  Use of the FFR paradigm has shown that long-term musical experience changes how the brainstem responds to sounds in the environment, and that this correlates with performance in behavioural tasks. For example, Dr Patrick Wong (Wong et al., 2007) showed that musicians show enhanced brain stem responses to tones within speech (in Mandarin Chinese). What about skills that are critical to performing musicians though, such as detecting minute pitch variations thereby being able to tell whether you are in tune?

A paper out in the European Journal of Neuroscience by Gavin Bidelman and team recently looked at this  question using the FFR paradigm. They looked at the properties of the FFR in response to tuned (major and minor) and detuned chordal, triad arpeggios in eleven musicians (vs. 11 controls). Detuning was accomplished by sharpening or flattening the pitch of the chord’s third. Following each note onset the authors took a ‘snapshot’ of the phase-locking in the FFR which occurred 15-20ms post-stimulus onset. Peaks in the FFR were identified by the researchers and confirmed by independent observers. FFR peaks were then quantified and segmented into three sections corresponding to the three notes heard. The authors then completed a separate, standard pitch discrimination task to determine whether the musicians had better responses at the perceptual level. What they found was amazing.

FFR waveforms (image from G. Bidelman’s site, link below) 


1) For the perception test: musicians showed better discrimination performance, and their enhanced ability was the same for major and minor distinctions, as well as for tuned-up vs. tuned-down manipulations of pitch.  The nonmusicians could distinguish major from minor, but could not reliably detect the detunings.

2) For the FFR data: musicians showed faster synchronisation and stronger brainstem encoding for the third of the arpeggios, whether the sequence was in or out of tune (notice the enhanced peak size and regularity in the image above) Nonmusicians on the other hand had much stronger encoding for the major/minor chords compared to that seen for the detuned chords.

The close correspondence between these two results supports the theory that musicians’ enhanced ability to detect out of tune pitches is rooted in pre-conscious processing of pitch that occurs in the brainstem, and specially in the enhancement of phase locked activity.


The thing that fascinates me is that this kind of evidence fills in some of the much needed gaps in our knowledge about how the so-called ‘lower’ centres of the brain are involved in processing jobs that it is very easy to causally attribute to the ‘higher’ centres of the brain, namely the cortex. In reality our perception of music starts at the level of the ear and all the way along its journey to our conscious minds it is carefully dissected, pre-processed and shaped. And it seems that our experience of the world can shape destinations all the way along this pathway, contributing to the overall behavioural differences we see in musicians and nonmusicians when they listen to music.

Bidelman, G.M., Krishnan, A., & Gandour, J.T (2011) Enhanced brainstem encoding predicts musicians’ perceptual advantages with pitch. EJN, 1-9.

Many thanks to Vicky at Victoria Williamson Psychology UK for post.

The Case For Harmony

As I was humming my typical harmonies above the melody line along to Sufjan at work the other day, I realized I really have very little grasp not on how vocal or instrumental harmony is constructed, but how it is learned: acquired, if you will. Now if you know me, you know I spend several blissful (albeit difficult) hours per week teaching young students private voice and piano. So when I say I do not understand how it is learned, let me explain.

In any singer’s intermediate level of coursework, there will come the time when a few different things should take place. They need to acquire a basic knowledge of chord structure, and preferably be able to pick out phrases on the piano. Reading introductory level music, then, also becomes a must. When one is playing two contrasting parts of a melody line together, harmony is created. If they can hear and discern the melody tones from the latter, they are learning harmony. There are also various exercises I assign my students more specifically to improve their note matching and pitch, but the ability to harmonize can also be improved through playing any note on the piano, and trying to sing typically 1.5, 2 or 5 whole steps above it, creating intervals of a minor or Major 3rd, or a perfect 5th. Now singing harmony in perfect 5ths for more than about 2 seconds will only result in parallel 5ths and I would avoid that like the plague…but I digress.

My point is, I have full faith that the majority of people with healthy vocal chords have the capability to learn and sing harmony, because statistics show that cases of amusia, or Tone Deafness, are quite seldom indeed. What I’m not yet grasping, is how does one come “harmony-equipped?” As someone who was singing at the age of three, I cannot recall how I began to form harmonies; main problem being that it must have been before I could remember. I never came to properly read music and understand chordal structure until after High School. It was always solely “by ear”…and thus we come to the crux of my dilemma: Is harmony innate? Is it like absolute pitch, where one simply “has it” and though others may work for years to finally achieve relative pitch, they still fall necessarily short of the natural inclination?