Physiological Basis of Subjective Time:
Final Report for Nakayama Foundation for Human Science
Jihwan Myung
Taipei Medical University

Time, intuitive and unintuitive
What is time? Time is intuitively obvious—you feel the flow internally. Albert Einstein changed thisworldview with his theory of relativity, and made time as unintuitive as ever.
Time became one of the most fascinating and yet enigmatic topics through the Einstein-Bergson
debate in 1922, where Einstein famously retorted, “Il n’y a donc pas un temps des philosophes,” that
there is no such thing as philosophical time (Canales, 2016). Time did exist, according to Einstein, inphysics and psychology as distinct entities. This statement was certainly disturbing to Bergson. Forhim, time could not be two things. Intuitive or unintuitive, time had to be a single entity.
Time enjoyed a special position in philosophy. Aristotle describes in Physics that time can be definedwith reference to the perceived present moment now, which divides before and after (219 b 33-220 a4). The now moment is completely subjective. Feeling the flow of time is the ultimate conscious
experience. Your being aware always happens now, and it is your self-awareness. When you
introspect, it is immediately obvious that the two are intertwined and inseparable. This idea of now
fascinated many philosophers—and the idea has repeated reincarnations in varioustransmogrifications, probably the most famous version being Martin Heidegger’s temporality. But
before temporality, or maybe time consciousness, there was a word durée, or duration (Bergson,1999). Bergson thought about now in practical terms. When you feel time, you feel the flux, themovement, which never is a frozen instance. But this is time that you feel, and you know it speeds up
and slows down, regardless of how I feel about time, at the same physical time. I still remember one
extremely long night when I was doing my first forced foot march in the army. It felt like several
days, but it was only an overnight. That same exact duration of the night could have been an instantfor someone who was preparing for an exam, or someone who was hosting a wedding reception.
Time that you feel subjectively is a wagomu, a piece rubber band. It sometimes stretches or shrinks.
The span of your temporal wagomu is the extent of your free will. People who narrowly escaped a
traffic accident often testify that right before the moment of collision, time froze and they could
manipulate the handle in minute details, as if they wielded more freewill (Wittmann, 2016). Although
Bergson probably had wanted to keep this special experience of time to be something unique andfundamental, this phenomenon is in many ways physiologically based. The subjective time dilationeven has a name, called tachypsychia, and such state is well associated with epinephrine rush in thebrain. The brain activity bursts in a concentrated timespan, and spares no time for the brain’s time
counter to tick. Neuroscience is in this sense a wonderful area to study, as it describes a dimension
where psychological time meets physical time. But tachypsychia is really just a cheetah run. You
cannot overdrive the brain all the time. There must be a physical and physiological limit that sets thepace of brain activity rhythms, and hence the pace of time, conserved universally across individuals
sharing the same brain structure. Therefore, even though everyone appears to have a different span ofsubjective time in different instances (durée or temporality for that matter), we can still agree on how
we feel about the general scale of passage of time.
Relativity of subjective time
While I was thinking about these issues, the Nakayama Foundation for Human Science made aninteresting challenge to think about the relativity of subjective time. Small animals have fasterheartbeat and shorter lifespan; larger animals have slower heartbeat, slower metabolic rate, and longer
lifespan. Do the higher metabolic activities in the small animal mean in any way, that the small
animal’s subjective time would flow slowly, such that the total amount of subjective time is conserved
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across species? That is, would the one-year lifespan of a mouse feel like 60 years in a human? InJapanese folklore of Urashima Taro (浦島太郞), or Chinese mythology Yu Xi Zhilin (虞喜志林), a
person makes a short visit to the world of gods and later realizes that he had actually spent a very longtime in the human world. If the gods did exist (with extremely long longevity), these stories would beconsistent with our observations so far.
The fact that time perception is physiologically based applies not just across species but also in aging
individuals. We all remember that when we were younger, time flowed extremely slowly. Thirty
years ago, I was sure that the sun will continue to rise and set in its own schedule, and leave me alone
in my teens. Then I do not remember how I have got past my thirties and suddenly became someone
in mid-forties. Psychologists give us good explanations on how this perceptual time warp happens.
You do not count repetitions of daily routines in your accumulative account of time; as you get old,most of what you do becomes SAMO, or same-old-shit, which disappears from your chronologicallog. There are studies that suggest for a genuine change through aging in the scale of time perception,although the results are not so clear-cut. Like an old, stretched wagomu, our older self might find theextent of durée stretched in time, such that elapsing of physical time feels to occur much faster. Thisis difficult to verify directly. In the physiological level, on the other hand, there are some correlatesof these observations: similar to the small and large animals, our maximal (and intrinsic) heart rate
and basal metabolic rate decline gradually with age.
Physiological rhythms underlie subjective timespanThis brings us back to the original question on the relationship between subjective time and rhythmic
physiological parameters. By definition, it is impossible to put subjective time on an objectivetimescale. Nonetheless, we can measure physiological parameters that underlie time perception in anindividual level. The scale of time perception is seconds to minutes, while the timescales ofphysiological rhythms are much longer: most commonly ~24 h, known as the circadian rhythms. The
scales of period itself do not directly correlate; but they do correlate if you look at the phases of time.
Dopamine is the key neurotransmitter that makes you underestimate time intervals (Meck, 1996).
Figure 1 illustrates a schematic choice response trend under dopamine receptor agonist (red) andantagonist (blue) compared to control (gray). Under dopamine agonist administration, subject
underestimates the passage of physical time.

Figure 1. Dopamine distorts subjective estimation of time interval.

This provides an interesting clue to connect time perception with physiological circadian rhythms.
For example, tyrosine hydroxylase (TH), the key dopamine synthesizing enzyme, shows circadian
profile of expression in the brainstem (Chung et al., 2014). The TH production is linked to theexpression peak of a circadian gene Rev-erba, which is a part of the Bmal-Rev loop recently modeledin our own collaboration study, partially supported by Nakayama Foundation for Human Science(Schmal et al., 2019; available at biorxiv.org). The data indicate that the peak phase of dopamine
production must occur in the morning, and the trough should occur in the transition between day andnight (Figure 2). In fact, people usually feel that time flies in the morning, and that we often say “Oh,it’s already time for lunch,” but we rarely say the same for dinner.

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Dopamine is also a key neurotransmitter that underlies psychological modulation of motivation andmood. This makes sense because subjective time does relate to mood: my long night in the army
camp was also a depressing night, while someone’s night at wedding reception must have been an
exciting one.

Figure 2. Brain’s dopamine production (TH) is linked to the molecular circadian clock (Rev-erba).
From Chung et al., 2014.

Subjective time and mood, through seasons
Measurement of time perception is difficult to conduct in mice. Instead, mood state can be measured
using a standard behavioral test such as the tail suspension test (TST) (Figure 3). Like timeperception, mood changes as aging progresses. The dopaminergic system in the brain weakens
through aging, and a tendency towards depression occurs in our later lives. A longitudinal tracing ofmood through a lifespan would take a too much time to conduct. Even a common laboratory mouse
has a longevity span of about 2 years. Would there be a physiological rhythm span that is
experimentally more practical yet theoretically meaningful?

Figure 3. Tail suspension test and basic posture scoring.

Physiological rhythms comprise many timescales: from shorter than 24-h period rhythm called
ultradian rhythm to longer than 24-h period rhythm called infradian rhythms. We are covering all ofthese scales, and a circadian-ultradian rhythm study we performed through an international
collaboration is now under submission (Chrobok et al., 2019). We initially focused on the infradianrhythms of estrous cycles, occurring with a 4-day period in female mice. The computationalmodeling is still on going, but experimental validation process turned out to prolong. We therefore
sought alternative infradian paradigms, and found the seasons of summer and winter to be an ideal
timespan to look at.
We performed TST longitudinally over a 24-h cycle in 4 mice under summer (16-h day and 8-h night)
and in 4 mice under winter (8-h day and 16-h night) day-lengths, simulating the seasonal light-dark
conditions in Northern European cities. We quantified the mood state of a mouse by posture scoring,in the order from demotivated to motivated states (Figure 3). The result came out quite clearly the3/6

morning-midday peak in the posture score (Figure 4), correlated with the expected hindbrain peak ofdopamine production (Figure 1). There also was a seasonal difference, with higher motivation toresist from tail suspension in summer (long day, LD) than winter (short day, SD) (Figure 4, rightmostpanel).

Figure 4. More active posture state observed during summer (long day, LD) than winter (short day,SD). The posture state dips to a demotivated state at the transition point between day and night(unpublished data).

What are the neural correlates of these mood changes, which potentially reflect changes in timeperception? To find out, we have constructed by hand a machine to visually observe circadian gene
expressions in vitro (Figure 5). The system performs real-time measurement of bioluminescenceintensity from luciferase-fused clock proteins that are expressed rhythmically by cellular circadianclocks. We are still working on identifying the correct brain loci to observe.

Figure 5. Imaging setup partially financed by the Nakayama Foundation for Human Science.

Time in the sick bodyIn the meanwhile, we targeted at circadian clock tissues in the brain and the body that are easier totarget. Our own previous work showed that the circadian rhythm accelerates during the summer anddecelerates during the winter (Myung et al., 2015). This finding correlates with our observation thatthe mice are more excited during the summer than winter (Figure 4). Similarly, when we are sick, weare depressed.
The kidney harbors a very robust clock, second only to the liver circadian clock outside the brain.
The kidney clock is easy to prepare and is anatomically and physiologically clearly defined. We
therefore induced a disease state called chronic kidney disease (CKD) by adenine feeding andobserved if the circadian period increases, as in the winter condition. This apparently simple
experimental paradigm proved to be not so simple. The animal developed unstable behavioral

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circadian rhythms (quantified by period standard deviation, period SD), but it did develop a longer
period at the end of adenine diet. The animal was generally sick and preferred to stay in the resting
position, making TST an impractical experimental test. However, we did find something quite
interesting and perplexing. The mice suffering from CKD had the intact “master” circadian clock, thesuprachiasmatic nucleus (SCN), which regulates the sleep-wake cycle in this species. The answer tothis mystery lied in kidneys. The CKD kidneys expressed longer circadian period rhythms withunstable rhythmicity (characterized by higher period SD). These observations led us to believe thatthe kidney clock can feed back its aberrant clock signals to the SCN and affect the behavioral
circadian rhythms under disease states (Figure 6). This work, which is the first experimental workfrom our laboratory and also a result from an international collaboration will be published soon thanks
to the partial financial support from the Nakayama Foundation for Human Science (Myung et al.,2019).

Figure 6. Distributed physiological timers, for example, the kidney circadian clock, and their feedback
to the main clock, the suprachiasmatic nucleus (SCN). Adapted from Myung et al., 2019.

Onward: subjective time and physiological rhythms
The best questions are often philosophical. But the best answers are mostly scientific. Questions
about time, both subjective and objective, touch upon the fundamental domains of our lives and ourworlds. To pursue these questions, I opened a lab called “Laboratory of Braintime.” A novelist
Carey Harrison—we ran a “consciousness club” in Berlin—suggested the name for me. I predict thebest answer to questions on subjective time will come from neuroscience. Multiple scales ofphysiological rhythms modulate mood and time perception at their own respective level. The overall
structure is almost fractal (Figure 7).

Figure 7. Fractal structure of mood, from circadian cycles through seasonal cycles to a life cycle.

5/6With the partial financial support from the Nakayama Foundation for Human Science, we could
purchase critical components for constructing the bioluminescence imaging setup (Figure 5). The
support helped us produce three pending publications (Schmal et al., 2019; Chrobok et al., 2019;Myung et al., 2019) that are expected to appear this year. I am especially proud of my laboratory
members, a research assistant Chun-Ya Lee from Taiwan, a graduate student from Amalia Ridla
Rahim from Indonesia, a graduate student and an MD Vuong Hung Truong from Vietnam, for theprogresses that we made together to get here. I thank all of them, and I thank once again theNakayama Foundation for Human Science for the generous support and for the excellent question onsubjective time.
References
Canales, J. (2016). The Physicist and the Philosopher: Einstein, Bergson, and the Debate that Changed Our
Understanding of Time. Princeton University Press.
Bergson, H. (1999). Duration and Simultaneity: Bergson and the Einsteinian universe. Clinamen Press.
Wittmann, M. (2016). Felt Time: The Psychology of How We Perceive Time. MIT Press.
Meck, W. H. (1996). Neuropharmacology of timing and time perception. Cognitive Brain Research. 3: 227-242.
Chung, S. et al. (2014). Impact of circadian nuclear receptor REV-ERBα on midbrain dopamine production andmood regulation. Cell. 157: 858-868.
Schmal, C., Ono, D., Myung, J. et al. (2019). Weak coupling between intracellular feedback loops explains
dissociation of clock gene dynamics. (Under review)
Chrobok, L., Northeast, R., Myung J. et al. (2019). (Under preparation)
Myung, J. et al. (2015). GABA-mediated repulsive coupling between circadian clock neurons in the SCN
encodes seasonal time. Proceedings of the National Academy of Sciences. 112: E3920-3929.
Myung, J.*, Wu, M. Y., Lee, C. Y. et al. (2019). The kidney clock contributes to timekeeping by the mastercircadian clock. International Journal of Molecular Sciences. (*Corresponding author) (Accepted, 2019/6/3)

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