Coexisting Spatio-Temporal Scales In Neuroscience

ALFREDO PEREIRA, JÚNIOR

Instituto de Biociências, UNESP/Campus de Botucatu, São Paulo, Brasil; E-mail: apj@ibb.unesp.br
Abstract. In this study I propose an epistemological discussion of multiple spatio-temporal scales in
neuroscience. Are such scales merely convenient levels of description of structure and function, or do
they correspond to irreducible levels of brain organization? What criteria should we employ in order
to reduce one level to another, or to identify levels that are not reducible to others? Should we think of
these criteria as based on empirical and/or theoretical reasons? Beginning with an empirical criterion
– the necessity of different experimental methodologies for the measurement of different phenomena
in the same system – I summarize spatial and temporal scales currently used in neuroscience and
discuss the possibility of a more general theoretical criterion. I conclude that multiscaling should be
recognized as a central concept in the epistemology of neuroscience.

1. Introduction
Recent philosophical discussion of the cognitive functions of the animal brain –
including the search for neural correlates of consciousness – has relied on the as-
sumption of an ultimate level of description where the biological basis of cognition
could be identified. Neuroscientific research, on the other hand, has worked with
the tacit assumption of multiple coexisting spatial and temporal scales that should
be tied together to form an approximate picture of brain cognitive function.
The problem of multiscaling has been raised in a number of scientific areas.
It may be understood as an attempt to study coexisting spatio/temporal scales
of phenomena relative to the same system. Glimm and Sharp (1997) consider
multiscale science “a challenge for the twenty-first century”, insofar as it plays
a central role in “such diverse fields as fluid dynamics, materials science, biology,
environmental science, chemistry, geology, meteorology, and high-energy physics”
(1997, 1). Grossberg writes that “all of the self-adapting behavioral and brain sys-
tems that I have ever derived are nonlinear feedback systems with large number of
components operating over multiple spatial and temporal scales” (1999, 5).
However, when considering the use of multiple levels of description, a prelim-
inary epistemological question arises: is the existence of multiple levels in science
merely a convenient choice of the observer, or does it imply the real existence of
multiple levels of organization? Two criteria which could help to decide between
such alternatives are proposed here, the first being empirical and the second a
theoretical. This distinction provides a way to clarify what multiscaling means: the
consideration of multiple scales that directly derive from the existence of multiple
levels of organization in a system. Therefore, it is not restricted to the equally
important issue of how one might describe the structure and function of a complex
system as the brain.

Minds and Machines 11: 457–465, 2001.

© 2001 Kluwer Academic Publishers. Printed in the Netherlands.
458 ALFREDO PEREIRA, JÚNIOR

After presenting the empirical criterion, I will summarize spatial and temporal
scales in neuroscience and claim that in some aspects they are irreducible, relatively
to this criterion. In the final section I will discuss a theoretical criterion and its
applicability to empirically-based scales.

2. The Empirical Criterion

The empirical criterion that I propose for distinguishing between two levels of
organization is relatively straightforward. If experimental access to two levels of
description requires different technical strategies and tools, then they constitute
two levels of organization; but if only one methodology gives experimental access
to both levels, they are merely levels of description. For example, if measurement
of the electrical activity in the living brain requires methods such as scalp EEG,
while measurement of chemical processes require methods as ‘in vitro’ micro-
dialysis then given the current state of our knowledge and technology, electrical
and chemical activities should be considered as occurring at two distinct levels of
organization.
I have chosen the limits of current technology as the parameter for the experi-
mental irreducibility of levels. Of course, given that technology will change with
time, our determination of distinct levels will also have to change. In this respect,
the epistemology of neuroscience has to evolve with the science; it is radically
different from the philosophy of mind in the sense that it isn’t directed toward
finding metaphysical truths about the mind. It is concerned with understanding data
about the brain discovered by neuroscientific research and putting them together in
provisional models of biological cognition.
One might ask, why provide an empirical criterion for the determination of
levels when most discussions of reducibility in the philosophy of science have
focused on inter-theoretic relations? The simple reason is that assumptions in neur-
oscience have not been elaborated to the point of forming broad theories.

3. Levels of Spatial Resolution in Neuroscience

There is large evidence in the literature that the brain works at different spatial
scales simultaneously: peripheral sensors are sensitive to microscopic particles
such as photons and electrons; neurons receive electrochemical information and
transport it to the molecular level, activating signal transduction pathways and
triggering quantum phenomena. The result of all such processing is used to control
the motor and endocrine systems that act upon the environment in several ways.
As neuroscientific investigation progresses toward the study of microscopic
processes in neurons, new levels of organization are discovered. One tendency
of contemporary research is to focus on synaptic and intra-cellular biochemistry
and its related molecular and quantum processes. Academic specialization has also
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promoted new lines of research in several fields of micro-neurobiology, with related

disciplines and journals.
A realistic categorization of spatial levels of resolution in contemporary neur-
oscience would have to include at least the following seven levels:
a) Cerebral Regions: this level is focused in studies of Neuropsychology and
Systems Neuroscience, by interpreting data from scalp multielectrode elec-
troencephalogram (EEG), magnetoencephalography (MEG), functional mag-
netic resonance imaging (fMRI) and scanning by positron emission tomo-
graphy (PET-scanners);
b) Large Neuronal Networks: this level focus on large networks detected by
means of the above methodologies, and also by “single neuron” invasive elec-
trode measurement in experimental animals, allowing a more detailed analysis
and the formation of models that cover several cerebral regions. It is found
in integrative Cognitive Neuroscience, a good example being the Working
Memory model (see e.g. D’Esposito and Grossman, 1996; Miller et al., 1996);
c) Micro Networks: relative to this level computational models are built, cov-
ering the scale of cortical layers and columns (by “cortical” I mean the neo-
cortex as well as hippocampal and cerebellar cortex), or reticular-thalamic-
cortical connections. Typical examples are connectionist models based on
neural action potential communication; the dynamics of such models is proved
by computer simulation rather than by brain electrical measurement (very
hard at this level of resolution, as shown by results from measurement with
invasive microelectrode arrays), and compared to the corresponding behavior
that such networks are presumed to subserve;
d) Synaptic Mechanisms: this level focus on transmitters-receptors-modulators
biochemistry at the synapses. Because of the complexity of such processes
(involving hundreds of different macromolecules) the approach is highly in-
ductive – e.g., reasoning by generalization from ‘in vitro’ data – and partial
– e.g., the identification of the contribution of a couple or triplet of elements
relative to some neuronal function, without modeling the activity of the whole
synapse. This level of analysis has higher resolution than the network one,
since the former finds its lower boundary at the action potential level, while
the latter includes sub-threshold levels of synaptic activity that influence the
neuron without producing axonal pulses to another neurons. Pharmacological
methods are largely used at this level, to test the effect of drugs similar to
transmitters/modulators and/or agonists or antagonists to the receptors;
e) Membrane Mechanisms: this level includes microscopic mechanical and
chemical processes, the gating of membrane channels and the movement of
ions through them, producing not only depolarization and – eventually – ac-
tion potentials, but also triggering several metabolic and transcriptional pro-
cesses inside the cells. The methodology includes mathematical models as the
classical one by Hodgkin and Huxley (1952), ‘in vitro’ cell cultures, and ‘in
vivo’ techniques using experimental animals with large neurons;
460 ALFREDO PEREIRA, JÚNIOR

f) Signal Transduction Pathways: this level corresponds to a recent area of

research focusing on internal pathways, controlled by signaling molecules,
that subserve a variety of functions, ranging from the economy of energy
to immune defense and dendrite growth. One of the new techniques used to
access this level is the use of genetically modified animals (e.g., mice) with a
mutation at a subunit of a membrane receptor protein that controls the pathway
being studied;
g) Sub-Chemical Processing: this is still a hypothetical level of organization
where quantum computational processes are assumed to occur, connecting
elements from a large number of neurons by means of non-local commu-
nication and supporting unitary conscious experience. A popular proposal
is Hameroff’s (1998) hypothesis of quantum computation in microtubules,
although other biologically plausible proposals exist, as DNA and/or meta-
bolic proteins quantum computation. In order to stabilize as a scientific area,
this kind of approach needs to find the right kind of methodology to access
the quantum level in neurons. Several recent publications (e.g. Brassard et
al., 1998) have indicated the possibility of quantum computing in systems
of proteins and/or ions at biologically compatible temperatures, although the
methods of preparation of entangled states in such systems are still being
improved.

4. The Example of Multiscale Mechanisms of Memory

For many years learning and memory were considered the simplest cognitive pro-
cesses to be studied in neuroscience, but progress of knowledge has revealed that
such processes are as much complex as anything that the brain does. Memory
is basically the capacity of keeping an informational item for some time and re-
trieving it later. The retrieval may involve consciousness (the case of declarative
memory) or merely the capacity to perform a behavior (procedural memory). Such
a classification is the roughest one; each of the above classes were found to support
many subdivisions (see Squire, 1992).
One of the factors that make memory a complex issue is the coexistence of
multiple temporal scales. Three temporal scales of mnemonic processes have been
identified, both at the phenomenological and neural levels. First I will draw the
classification at the phenomenological level:
a) Short-Term Memory (STM): lasts from milliseconds to hours, as in the
famous working memory examples of memorizing a new telephone number
or keeping a number in mind while performing an arithmetic operation;
b) Long-Term Potentiation (LTP): lasts from hours to a days. The original
concept was suggested by the fact that the repetition of a stimulus facilitates
learning (before habituation mechanisms operate). An experimental design
was developed, where tetanization of a neuron was observed to lead to post-
synaptic as well as presynaptic modifications. The current concept of LTP
COEXISTING SPATIO-TEMPORAL SCALES IN NEUROSCIENCE 461

also incorporates data from cognitive neuroscience showing that during sleep
the hippocampal system works to “consolidate” some of the items that were
previously kept in STM. Such a scientific construction corresponds to our
common experience, after a period of sleep, of remembering some items better
than immediately after they were first learned;
c) Long-Term Memory (LTM): lasts from days to years, even if the memorized
items are not recalled during the period. A good example is our capacity of
recalling the name of our neighbors many years ago, even if during this period
we have never met with or talked about these people.
There are well corroborated neurobiological theories that relate each of the three
temporal scales above with specific neuronal mechanisms. One such theory was
based on the famous case of H.M. H.M. had most of his hippocampus surgically
removed and lost the mnemonic capacity described in the item B above, but not the
capacities described in A and C. Such mechanisms are physically interconnected,
since all of them are part of the same functioning system, the brain. It is remarkable
that the putative neuronal correlates of each phenomenological scale of memory
works at a similar temporal scale in physical time. Of course, this may be an
artifact of the theoretical framework of neuroscientists, who surely try to match the
proposed neuronal categories with their intuitive experiential categories. However,
before drawing a rash conclusion it is worth taking a look at some current models
which are very convincingly arguing for specific correlates of STM, LTP and LTM:
a) LTM has been proposed to involve a whole cellular cycle: transmitter-
receptor binding, the activation of signal transduction pathways leading to the
activation of transcriptional factors, gene activation and inter-gene regulation,
protein production and influences on dendrite growth. This whole cellular
cycle has been documented by Kandel and his group (see Bailey and Kandel,
1995) in the study of the withdrawal reflex of Aplysia;
b) LTP has been studied mostly in hippocampal neurons, although it is well
understood today that it should conjointly mobilize associative areas of the
neocortex (see Eichenbaum, 1997). The standard model (Bliss and Collin-
gridge, 1993) proposes that LTP sequentially mobilizes AMPA/kainate and
NMDA glutamate receptors, leading to Ca ions entry in the neuron, phosphor-
ilation of metabolic proteins and retroactivation of glutamate metabotropic
receptors, but without mobilizing transcriptional factors that could produce
changes in gene activation. Therefore, LTP would work only with the cells’
preexisting proteins, which are recycled by means of the entering Ca; if a
longer lasting process that leads to the production of new proteins is trigered,
then the mnemonic phenomena moves to the LTM scale;
c) STM was considered in EEG studies in the sixties (Roy John, 1967) as
being supported by “reverberatory circuits”; this idea evolved to Grossberg’s
concept of “resonance”, that could be understood to imply the existence of
sustained spiking (action potentials) activity in some brain region. In fMRI
experimental studies, such activity is measured as the hemodynamic response
462 ALFREDO PEREIRA, JÚNIOR

(a increase of influx of arterial blood to a brain area). Both concepts – sus-

tained spiking and increased hemodynamic response – can be explained by the
local action of retrograde messengers (as nitric oxide) able to produce network
activation and arterial dilation (Flohr, 1995). A synthesis of our knowledge
about different time scales of processes triggered by calcium ions, regarding
associative memory and its putative neuronal mechanisms, was presented by
Alkon et. al (1998).

5. The Theoretical Criterion

The concept of theoretical reduction in the philosophy of biology has always been
a focus of controversy (beginning with a classical discussion in Hull, 1970). If a
naive conception of deduction is used – the notion that biological facts could be de-
rived from physical laws alone – the notion would turn out to be void; i.e., nothing
in biology (or in neuroscience) could be strictly deduced from the laws of nature.
Moreover, such a naive approach is misleading in the sense that if larger structures
and their functions (macroscopic phenomena) are deductible from smaller ones
(laws of microphysics) then they would better be considered merely epiphenomena.
However, this is not the case in biological and other complex systems, where lar-
ger and smaller structures/functions constitute different mechanisms that interact,
e.g., in the digestion process both macro (mechanical movements of the stom-
ach and intestine) and micro processes (chemical action of enzymes) constitute
complementary mechanisms.
But the Nagelian concept of theoretical deduction (Nagel, 1961) is far more
sophisticated than the naive one: any theoretical deduction must incorporate in its
premises, besides universal laws, also particular “initial conditions”. The concept
of “initial conditions” (IC) is admittedly vague, but such vagueness is convenient
for the Nagelian approach in biology since it can accommodate any biological
particularity which cannot be deduced from the physical laws alone. A reductionist
project in the philosophy of biology is therefore not impossible. However, the in-
clusion of initial conditions generates another problem for the theory of scientific
explanation insofar as the inclusion of new premises (in the form of strategically
chosen initial conditions) in principle makes possible any theoretical deduction.
The discovery of new degrees of difficulty in theoretical deduction, in the math-
ematical modeling of the dynamics of complex systems, has raised new discussion
of Nagel’s concept of initial condition. The discovery I’m referring to is the now-
famous “sensitivity to initial conditions” that characterizes the behavior of complex
systems. More precisely, it has been claimed that even in macroscopic deterministic
systems, initial conditions cannot be exactly defined as to assure the deductibility of
the whole trajectory. Any coarse-graining in the specification of initial conditions
in chaotic systems leads to different trajectories in the evolution of the system.
This restriction is serious because in any empirical study (taken in opposition to
idealized models) the specification of initial conditions cannot be completely exact
COEXISTING SPATIO-TEMPORAL SCALES IN NEUROSCIENCE 463

since measurement operations always involve some uncertainty (ultimately due to

quantum constraints on the instruments and their interaction with human sensors).
Besides the proper initial conditions problem, the development of new integra-
tion techniques reveal new difficulties in inter-level deduction. Following Rueger’s
paper (in this volume) I will use the term “non-uniformity” to characterize this
difficulty. In the philosophy of classical physics space and time were believed
to be “uniform” in the sense that the chosen scale of description would not alter
the mathematical properties of the system under description. However, classical
physics focused only on “simple” systems that are exactly those which are uniform.
When studying “complex” systems a mathematical problem arose. Let’s call X and
Y two empirical levels of description of a complex system Z. When deducing X
from Y (or vice-versa) two kinds of mathematical problems may occur:
a) computational difficulties
or
b) even if the deduction is effectively computed the final mathematical expres-
sion shows discontinuities in the domain of real numbers that make it unintell-
igible or intractable for practical purposes.
Such mathematical difficulties, that also contaminate the attempts to achieve
the theoretical unity of physics, have led researchers in some scientific areas to
reconceptualize the universal laws of nature as being in fact restricted to specific
spatio-temporal scales.
A theoretical criterion to distinguish different levels of organization in a com-
plex system would then be based on two pillars. First, if a level of description is
sufficiently exact to play the role of an initial condition for the description of other
levels, it should be regarded as a level of organization. Second, if the deduction of
a level X from a level Y displays mathematical non-uniformity, then X should be
regarded as a level of organization. Does such framework apply to the previously
described spatio-temporal scales, empirically used in neuroscience? This is the big
question that can be formulated but not answered at this point. Progress in this issue
would first need an adequate mathematical modeling of each spatial and temporal
scale; as such models are still not available any attempt to answer the question
would be premature.

6. Conclusion: Multiscaling and Neural Correlates of Cognition

An examination of muiltiscaling in empirical studies of brain processes, and its
close correspondence with dimensions of cognitive processing – as I summarized
for the case of memory – suggests that such a concept should play a central role
in any discussion of the mind/brain problem. An apparent flaw in the discussion of
such problem has been the assumption of (structural and functional) reductionism,
in the sense of the existence of a fundamental level of analysis where the correlates
of mental processes could be found. A lesson for epistemology coming from the
464 ALFREDO PEREIRA, JÚNIOR

study of complex systems is that although any phenomena at higher organizational

levels could in principle be deduced from phenomena at lower levels and laws
of nature, in practice the determination of exact initial conditions is problematic,
the deduction itself may be computationally intractable and the results when using
sophisticated mathematical techniques may be unintelligible. Such lessons imply
the existence of unexpected obstacles for theoretical reductions (in the Nagelian
sense of the expression – perhaps not to other versions of reductionism, as John
Bickle’s).
I would like to point to the fact that as the brain is, by any standard, a complex
system, then it should display the same kind of multiscale organization found in
other areas of science. In this view, the concept of multiscaling, replacing reduc-
tionism, could help to find better correlation between brain and cognitive processes.
A cognitive process (that usually or always has a rich spatial and temporal di-
versity) would correlate with a myriad of brain processes, in multiple spatial and
temporal scales.

Acknowledgements
I would like to express my gratitude to Armando Rocha and John Symons for
helpful comments and discussion.

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