Download Spontaneous activity in developing sensory circuits

YNIMG-09254; No. of pages: 10; 4C:
NeuroImage xxx (2012) xxx–xxx
Contents lists available at SciVerse ScienceDirect
NeuroImage
journal homepage: www.elsevier.com/locate/ynimg
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Review
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Matthew Colonnese a, b, c,⁎, Rustem Khazipov a, b, d
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INSERM, U29, INMED, Marseille 13009, France
Aix Marseille Université, Faculté des Sciences, Marseille, F-13000, France
Department of Pharmacology and Physiology, Institute for Neuroscience, George Washington University, Washington DC 20037, USA
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Kazan Federal University, Kazan, Russia
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Spontaneous activity in developing sensory circuits: Implications for resting
state fMRI
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a b s t r a c t
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Article history:
Accepted 13 February 2012
Available online xxxx
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The immature brain spontaneously expresses unique patterns of electrical activity that are believed to contribute to the development of neuronal networks. Certain electrographic features of this activity, particularly
modulation on an infraslow time scale, resemble activity patterns observed in the mature brain at ‘rest’,
loosely defined as the absence of an investigator imposed task. However, it is not clear whether the immature
activity patterns observed at rest are precursors of the spontaneous neuronal activity that forms resting state
networks in the adult. Here, we review recent studies that have explored the generative mechanisms of resting state activity during development in the primary sensory systems of premature human neonates and
neonatal rodents. The remarkable hypothesis suggested by this work is that while resting state activity during the pre- and possibly near-term period can bear superficial resemblance to adult activity it is fundamentally different in terms of function and origin. During early development spontaneous thalamocortical activity
in primary sensory regions is determined largely by transitory generators in the sensory periphery. This is in
contrast to the adult, where spontaneous activity generated within thalamocortex, particularly by corticocortical connections, dominates. We therefore suggest a conservative interpretation of developmental mapping studies which are based on indirect measurement of activity (e.g. fMRI), or on the partitioning of EEG
frequency using bands derived from adult studies. The generative mechanisms for brain activity at early
ages are likely different from those of adults, and may play very different roles; for example in circuit formation as opposed to attention.
© 2012 Published by Elsevier Inc.
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Keywords:
Development
Resting state
Preterm
Neonatal
Spindle burst
Spontaneous activity
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Contents
Resting state activity in neonates and adults . . . . . . . . . . .
Discontinuous temporal organization of early activity . . . . . . .
Unique activity patterns in preterm infants . . . . . . . . . . . .
Appearance . . . . . . . . . . . . . . . . . . . . . . . .
Modulation . . . . . . . . . . . . . . . . . . . . . . . .
Developmental separation . . . . . . . . . . . . . . . . .
Generative mechanisms . . . . . . . . . . . . . . . . . .
Peripheral dominance of resting activity during early development
Development of intrinsic thalamocortical activities . . . . . . . .
Early cortical function and implications for resting state fMRI . . .
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . .
Uncited references . . . . . . . . . . . . . . . . . . . . . . .
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⁎ Corresponding author at: INSERM, U29, INMED, Marseille 13009, France.
E-mail address: [email protected] (M. Colonnese).
1053-8119/$ – see front matter © 2012 Published by Elsevier Inc.
doi:10.1016/j.neuroimage.2012.02.046
Please cite this article as: Colonnese, M., Khazipov, R., Spontaneous activity in developing sensory circuits: Implications for resting state fMRI,
NeuroImage (2012), doi:10.1016/j.neuroimage.2012.02.046
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M. Colonnese, R. Khazipov / NeuroImage xxx (2012) xxx–xxx
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The cerebral cortex is never quiet (Fox and Raichle, 2007). Even primary sensory regions are consistently active in the absence of sensory
input, including during states of unconsciousness such as non-REM
sleep and anesthesia (Bianciardi et al., 2009; Hasenstaub et al., 2007;
Leopold and Logothetis, 2003). Neurophysiologists have a tradition of
labeling such non-task related activity ‘spontaneous’ or even ‘background’, while similar fluctuations have been categorized as ‘resting
state’ by the human fMRI community. The origins and functions of
this activity are a mystery, but are thought to include replay of sensory
information in cortical circuits during sleep and attention, visual
learning and ongoing cogitation during waking (Berkes et al., 2011;
Haider and McCormick, 2009; Ji and Wilson, 2007). And, resting state
activity fluctuations have themselves become a powerful tool in
defining the functional connections between cortical and sub-cortical
regions. Measuring the co-modulation of activity in multiple regions
with fMRI or EEG during ‘rest’, i.e. in the absence of directed goals, has
revealed multiple independent networks linked to sensory processing,
movement, and higher functions such as attention. Perhaps most striking
is the discovery of ‘default-mode’ networks inversely correlated with
directed behavior and perceptual tasks (Raichle and Snyder, 2007).
Understanding when these networks form is an important goal, because their disruption during development is predicted to be causally
linked to the onset of neurological disorders. The question has two components: when do the anatomical connections that link brain regions
together form, and when are the network properties sufficiently mature
to allow for mature function? This latter question is critically important
because network properties change constantly during development.
Animal models have shown that during the initial formation of neural
circuits a number of transitory properties exist to generate spontaneous
activity in the local circuits, despite a poverty of local interconnectivity
and adult functional connectivity (Blankenship and Feller, 2010). For
example, isolated slices of rodent cortex and hippocampus exhibit multiple stages of network activity during the first postnatal weeks (Allene
et al., 2008; Moody and Bosma, 2005). In addition, both the retina and
cochlea generate transitory activity bursts that synchronize firing in
local neuronal populations on an infraslow timescale (Demas et al.,
2003; Tritsch et al., 2007; Wong, 1999). This process has been studied
extensively in the visual system, where genetic and pharmacological
manipulation of spontaneous retinal activity has been shown to be critical for visual map formation in central visual structures including the
cortex (Huberman et al., 2008). Sensorimotor systems also engage in
a similar process, but instead of generating activity spontaneously in
the sense organ, spontaneous bursts of activity in the spinal cord
cause myclonic jerks in the various muscles, resulting in ‘spontaneous’
sensory input that is carried to the cortex (Khazipov et al., 2004;
Kreider and Blumberg, 2000).
In short, data from animal models predict significant ‘resting-state’
activity during early developmental time periods equivalent to the
fetal stage in humans. This review examines the evidence that this activity is not equivalent to resting-state modulations in adults, either in
terms of generative mechanisms or function. This is important because
understanding the development of resting state networks requires not
just a demonstration of co-modulation of various brain regions, but
also an understanding of the generative mechanisms of these modulations, which are likely to change dramatically during development.
Humans are born in the midst of a surge of cortical synaptogenesis
that will continue throughout the first year after birth (Huttenlocher
and Dabholkar, 1997). This synaptic burst is coincident with a rapid increase in the continuity of cortical activity and a maturation of activity
patterns, as many EEG grapho-elements disappear in the first couple of
months, and adult patterns of activity including sleep spindles, delta
waves and strong gamma-band modulations emerge within the first
year (Andre et al., 2010; Curzi-Dascalova, 1977; Ellingson and Peters,
1980). As might be expected, these rapid changes in synaptic density,
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connectivity and electrical activity are accompanied by rearrangements
in resting state cortical networks as assayed by fMRI. Resting state networks, organized locally around hubs in sensory and motor cortex,
have been demonstrated in term infants (Fransson et al., 2011), as well
as preterm infants (Doria et al., 2010; Smyser et al., 2010). By contrast,
resting state networks involving distant regions, particularly frontal
and associative regions such as the default state and attention networks,
develop later than local networks. One study identified the adult complement of resting state networks by term (Doria et al., 2010), while other
studies observed an incomplete default state network at term
(Fransson et al., 2007, 2011; Gao et al., 2009; Smyser et al., 2010).
These data suggest that some important property of sensory networks forms in utero, while the development of associational networks
is likely part of the rapid synaptogenesis and maturation of cortical
activity patterns observed postnatally. Thus a close examination of activity in primary sensory cortex during the fetal period will be necessary
to determine to what extent the resting state fMRI detects adult-like
functional networks or immature activity patterns, and what this
would mean for the processing capacity of the infant brain.
Determining the patterns of activity expressed in the fetal brain is
a challenging task. Due to the technical difficulty of performing EEG
and MEG through the uterine wall, the main approach consists of
scalp EEG recordings from premature neonates. One should question
whether cortical activity in premature neonates is the same as in the
fetus. Certainly, the extra-uterine environment is very different, and
the function of many systems (cardiovascular, respiratory, and digestive) undergo significant development after birth regardless of gestational age. However, the major characteristics of preterm EEG, such as
those used for clinical monitoring, are primarily determined by gestational, and not postnatal, age (Andre et al., 2010); the length of time
ex utero does not exert a large effect on the gross patterns of brain
activity maturation. Moreover, the temporal organization of spontaneous activity as shown by fetal MEG studies is remarkably consistent
with data obtained from gestational age matched premature neonates
(Eswaran et al., 2004, 2007). A number of caveats apply, however. The
development of a number of neurological markers is accelerated by preterm birth, while others are delayed or unaffected (Ellingson and Peters,
1980; Smyser et al., 2010) and these can vary depending on the extrauterine experience (Guzzetta et al., 2009). Furthermore, the fetus,
under the influence of maternal hormones and lack of stimuli, is maintained in a sleep-promoting environment. Therefore, scalp EEG from
healthy premature neonates should be considered as an approximation
of fetal brain activity, and hopefully further technical developments will
provide further verification for this model.
A mechanistic understanding of resting state network development
requires appropriate animal models. Pioneering studies describing the
phenomenology of EEG development were performed in fetal and neonatal pigs, sheep, guinea pigs, cats, rabbits, rats and dogs (Bergstrom et
al., 1962; Bernhard et al., 1959; Charles and Fuller, 1956; Crain, 1952;
Deza and Eidelberg, 1967; Fox, 1967; Jouvet-Mounier et al., 1970;
Marty and Thomas, 1963; Pampiglione, 1977; Petersen et al., 1964;
Rose and Ellingson, 1968; Scherrer and Oeconomos, 1954; Tuge et al.,
1960; Yoshii and Tsukiyama, 1951). These studies led to conclusion
that EEG pattern maturation is similar between species and determined
more by relative maturation than by time of birth. In all species, at first
appearance EEG activity consists of bursts of activity lasting around 1 s
with intervening periods of electrical silence that can last up to 10 s.
Interhemispheric synchrony is lacking. No changes associated with
the sleep-wake cycle can be detected. As described by Ellingson
(1970) EEG patterns then undergo a series of universal developmental
trends in the postnatal EEG: (1) low frequency activity becomes less
abundant with increasing age; (2) frequency of rhythmic (alpha- or
alpha-like) activity during wakefulness increases with age; (3) interhemispheric synchrony improves with age; (4) overall amplitude increases during infancy and then declines somewhat to maturity; and
(5) complexity of sleep patterns increases with age (Ellingson, 1970).
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Resting state activity in neonates and adults
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Please cite this article as: Colonnese, M., Khazipov, R., Spontaneous activity in developing sensory circuits: Implications for resting state fMRI,
NeuroImage (2012), doi:10.1016/j.neuroimage.2012.02.046
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We have considered the differences in the nature of the infraslow
oscillations observed at rest during early development and in adults,
namely the alternation between network silence and activity that characterizes the immature brain, as opposed to waxing and waning of
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The adult brain is constantly active, though the patterns and amount
of this activity are modulated differentially between brain networks by
a number of factors including vigilance state, mental task and sensory
input (Steriade and McCarley, 2005). The basis of functional connectivity mapping appears to be the waxing and waning of ongoing activity on
an ‘infraslow’ timescale (0.01–0.2 Hz), rather than the cessation and reinduction of activity itself (Baria et al., 2011; Jann et al., 2010; Laufs et
al., 2003; Sadaghiani et al., 2010; Vincent et al., 2007; Zuo et al.,
2010). Since the first recordings of human neonates using scalp electrographic recordings by Dreyfus-Brisac and Monod (1965) and DreyfusBrisac et al., (1956), a pronounced infraslow modulation of activity in
preterm infants has also been noted. However, close examination of
this oscillation reveals that it is of a fundamentally different character
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from adult: it arises not from the modulation of ongoing activity or
brain states as in adults, but from alternating periods of complete network silence and activity. This temporal organization in preterms was
named tracé discontinu, and is most prominent during the second half
of gestation, particularly during quiet sleep. During tracé discontinu,
the cortical EEG is organized in intermittent bursts separated by periods
of isoelectric EEG that could last for tens of seconds (Dreyfus-Brisac and
Larroche, 1971). With maturation, the flat periods between bursts become progressively shorter, first during active (pre-REM) sleep and
then during quiet sleep. By 30 weeks post-conception periods of tracé
discontinu become interleaved with periods of low-voltage activity (indicative of continuous activity) observed between the bursts. These periods, so called tracé alternant, become more common, resulting in
longer periods of continuous activity. Continuous cortical activity is observed from 1 to 2 months after birth (Andre et al., 2010).
Thus infraslow modulation in preterm infants results from the apparent cessation of activity, while in adults it results from more modest
increases and decreases in ongoing activity. Recent rodent studies have
examined whether these isoelectric ‘silent’ periods result from true network silence, or from asynchronous neuronal activity that poorly registers at the scalp. Extracellular recordings of multiple unit activity in
somatosensory and visual cortex of rats showed that neurons fire virtually no action potentials during these isoelectric EEG epochs (Fig. 1). In
agreement with this result, patch-clamp recordings revealed that neurons stay relaxed at their resting membrane potential and receive
very few synaptic inputs during the isoelectric EEG periods
(Colonnese and Khazipov, 2010; Khazipov et al., 2004; Rochefort et al.,
2009). This means that isoelectric EEG epochs reflect a synchronous
neuronal silence which is never observed in a healthy adult. The closest
the adult cortex comes to such collective silence is during so called
‘down states’, observed during unconsciousness brought on by slowwave sleep or anesthesia. In adults, natural down states observed
during sleep last only on the order of hundreds of milliseconds
(Steriade and McCarley, 2005), whereas they can last for tens of seconds
in neonatal rats and preterm humans.
Oscillations between periods of neuronal depolarization associated
with synaptic barrages (called UP-states) and the DOWN state generates slow waves on EEG (Steriade et al., 1993), giving name to the
state of sleep when they are most commonly observed. In adults this
so-called ‘slow’ oscillation between up and down states is too rapid to
account for resting state connectivity (though the number or power of
such transitions over a 10 s period could in theory (Jann et al., 2010)).
In contrast, in preterm infants and neonatal rats a singular burst of activity against a background of network silence could conceivably contribute to infraslow modulations and resting state connectivity.
Why do immature networks produce such long-lasting periods of
network silence? Intracellular studies in adults indicate that down
states result when the level of mutual excitation in the cortical network
falls below the critical level necessary to maintain the UP-state, allowing neurons to return to their resting membrane potential (Contreras
et al., 1996; Sanchez-Vives and McCormick, 2000; Shu et al., 2003). Immature networks, which are much less densely connected, likely require much greater network activation before generating an up-state,
and thus spend much longer periods of time in network silence. Combined with the evidence outlined below that the majority of activity
that does occur in immature sensory cortex is related to thalamic
input, it appears that the default state of cortical networks during the
fetal period is network silence, rather than the continuous ‘spontaneous’ activity characteristic of healthy mature cortex.
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Pampiglione (1977) also pointed out that “from the evolution of E.E.G.
features it seems that the underlying mechanisms during maturation
do not evolve according to a uniformly continuous process but proceed,
like the main E.E.G. features, in irregular steps, with plateaus lasting
days or weeks, followed by a more rapid change over a period of a
very few days before reaching the next plateau which then may last
several weeks or months before changing again into a final adult
phase. The evolution process therefore seems to be much more like a series of changes of uneven duration rather than a smooth curve.”
To move beyond these phenomenological observations and construct
a mechanistic understanding of the early activity patterns and their
physiological roles in brain development, recent efforts have focused
on neonatal rodents, and to a lesser extent ferrets, as a model system
for human EEG development. In rodents invasive recordings of brain activity, including intra-cellular recordings, can be combined with pharmacological and genetic manipulations to identify network mechanisms of
early activity generation (Khazipov and Luhmann, 2006). Rats and
mice are altricial; that is, they are born in an immature state. Although
it is difficult to provide exact comparisons between human and rodents,
the degree of rat cortical development on the day of birth (P0) can be
roughly compared to the stage of human cortex at mid-gestation
(Clancy et al., 2001). Multi-factor estimates based primarily on neurogenetic times (Clancy et al., 2007), and direct comparisons of neural activity
patterns in humans and rats (Colonnese et al., 2010) disagree on the rat
equivalent of term in humans. This is in part because there is likely no
single age equivalent useful for all brain regions, as even primates exhibit
profound heterogeneity between cortical and sub-cortical developmental times (Clancy et al., 2000). For hippocampus, term in human was suggested to correspond to postnatal day P5–7 in the rat (Avishai-Eliner et
al., 2002). For cortex however, both the timing of the surge in synaptogenesis in primary sensory regions, and changes in neural activity appear
to develop on a time course that diverges from other developmental
markers. Such heterochrony may have implications for resting state network development, as networks may become ‘functional’ at different developmental points in different species. For visual cortex, in terms of
function, we suggest that term in humans roughly corresponds to postnatal day P12-14 (roughly the time of eye opening) in the rat or mouse.
The invasive animal studies completed so far suggest that in primary
sensory systems neuronal activity during the preterm period is categorically different from adult activity, even when there are superficial similarities in terms of temporal modulation and frequencies. In particular,
while adult resting activity appears generated by the dense corticocortical interconnectivity modulated by the neuromodulatory systems
(Destexhe et al., 2003; Haider and McCormick, 2009), early sensory networks are driven largely by spontaneous activity in the periphery, interacting with thalamocortical network properties unique to the time
period. We will review this evidence below, focusing on two features:
the lack of continuous cortical–cortical activity, which causes a discontinuous pattern of resting activity, and the generation of unique activity
patterns in cortex during early development.
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Please cite this article as: Colonnese, M., Khazipov, R., Spontaneous activity in developing sensory circuits: Implications for resting state fMRI,
NeuroImage (2012), doi:10.1016/j.neuroimage.2012.02.046
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Quiet Inter-SAT
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unique rhythmic, oscillations and intermittent, fast events that are
expressed during restricted ages. These immature patterns are notable
for their poor modulation by specific behaviors or vigilance states. Because they are clearly different in structure and occurrence from adult
patterns, these events have been given unique names, which include
temporal theta bursts, encoches frontales, and delta brush (Andre et al.,
2010; Mizrahi et al., 2003). The earliest activity, detected at 24–25
post-menstrual weeks (the earliest age that reliable recordings are
made), appears in clinical EEG as intermittent ‘delta’ waves, either
smooth or with more rapid rhythms superimposed. By the seventh
month, these slow oscillations are reliably intermixed with rapid
rhythms, and are abundant in central, temporal and occipital regions,
fading first in central regions and lastly on occipital electrodes around
term.
Our understanding of the organization and development of early activity patterns is still evolving. Recent observations using direct-current
(DC) recordings to reveal activity modulation on long timescales show
that delta brushes and other rapid oscillations often occur sequentially,
contained within a negative potential of unusually large amplitude (up
to 800 μV; (Vanhatalo et al., 2002)). During standard EEG such ‘DC
shifts’ are not observed due to the use of conventional high-pass
(>0.5–1 Hz) filters. These studies suggest that the subdivision of various oscillations into discrete events such as individual delta brushes
should be questioned, and that they would be better considered a singular class of unique developmental events termed ‘spontaneous activity transients’ (SATs), which consist of slow and infraslow waves that
group rapid oscillations of various frequencies (Vanhatalo and Kaila,
2006). Evidence from animal studies, reviewed below, supports this
classification.
Wide Band EEG
500μV
40 s
200 μV
2s
P10
Bursting Inter-SAT
∗
∗
∗
500μV
O
F
40 s
200 μV
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Activity
No retinal activity
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40 s
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Fig. 1. Development of resting state activity in the rat visual cortex. Spontaneous depth
EEG recorded from layer 4 from three different ages of rat, roughly equivalent to midgestation (P6), third trimester (P10) and term (P13) in human. Direct current recordings
of the field potential reveal infraslow activity dynamics. During the first postnatal week all
activity consists of recurrent infraslow waves that contain rapid (alpha-beta) oscillations
and delta waves, together called a delta brush or spindle burst (P6). These events are
often linked together to form spontaneous activity transients (SATs). Between SATs, cortical networks are largely silent (‘inter-SAT’). SATs continue during the second postnatal
week (P10), but short bursts of activity are now present between SATs. Elimination of retinal activity eliminates SATs, but short activity bursts remain (P10 lower left). Conversely,
pharmacological initiation of constant retinal activity causes constant SAT activity in cortex (P10 lower right). Thus SATs (and therefore 90% of spiking) are not generated spontaneously in cortex but driven by the retina, while the short activity bursts result from true
intrinsic spontaneous activity in thalamocortical circuits. Continuous inter-SAT activity
begins at the end of the second postnatal week (P13), and the size of the now infrequent
SATs is reduced.
Figure modified from Colonnese and Khazipov (2010).
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Appearance
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In adults, cortical activity patterns are notable for their diversity and
modulation by vigilance state. Some examples are the production of
delta waves of increasing amplitude as the depth of non-REM sleep increases, spindle oscillations during light sleep, alpha oscillations during
eye closure, and gamma-band oscillations during sensory vigilance
(Buzsáki, 2006). Homologues of none of these patterns have been identified in preterm infants. Preterm activity is instead dominated by a few
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continuous activity in the adult. The next question is whether the activity bursts that interrupt network silences are fragments of the corticocortical activity that composes the adult resting state, or are of a qualitatively different sort. Along with Pampiglione's ideas quoted above, a
number of facts argue for the latter. In particular (1) the appearance
of the activity is different, (2) the modulation of the cortical activities
by sleep, ‘rest’, and vigilance is poorly developed, (3) adult resting activity does not emerge from immature bursts, and (4) studies in sensory
cortex show that the generative mechanisms are different.
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Cortical activity in preterm infants is weakly modulated by vigilance
state. Until approximately 32 weeks post-conception both quiet and active sleep (thought to be equivalent to non-REM and REM sleep respectively) are poorly differentiated in EEG and display prominent delta
waves, brushes and SATs as described above. By 32 weeks delta activity
becomes more restricted to quiet sleep and active sleep becomes defined by low amplitude rapid activity, yet as much as 30% of sleep at
these ages is characterized as indeterminate, or containing characteristics of each (Andre et al., 2010). This developmental pattern is matched
in neonatal rats, which display little modulation of cortical activity. Cortical EEG in rats starts to exhibit some sleep/awake state-dependent differentiation of delta activity beginning approximately at P10–11,
becoming robust at the end of the second postnatal week (Frank and
Heller, 1997; Gramsbergen, 1976; Jouvet-Mounier et al., 1970; Seelke
and Blumberg, 2008).
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Developmental separation
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Simple difference in appearance between the immature and adult
EEG is not sufficient evidence to declare them to be independent phenomena. Functionally similar activity patterns could appear superficially different as a result of changing circuitry or even current source
relationships. In this case we expect that early activity patterns, if followed through development, would transform into adult patterns.
However, in every case examined so far the opposite occurs. The first
studies to identify delta brushes in preterm infants noted their structural similarity to sleep spindles (Dreyfus-Brisac, 1962; Ellingson, 1958;
Watanabe and Iwase, 1972) However, it became rapidly apparent that
delta brushes do not develop into sleep spindles, because sleep spindles
appear a full two months after delta brushes have ceased (Ellingson,
1982). In keeping with these clinical findings, sleep spindles in thalamic
slices from ferrets and mice also appear after the disappearance of delta
brushes (McCormick et al., 1995; Warren and Jones, 1997). A second example is gamma oscillations, which have been proposed to be a
384
Please cite this article as: Colonnese, M., Khazipov, R., Spontaneous activity in developing sensory circuits: Implications for resting state fMRI,
NeuroImage (2012), doi:10.1016/j.neuroimage.2012.02.046
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Peripheral dominance of resting activity during
early development
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Investigators have used the somatosensory and visual cortex of
rats and ferrets to ask the following question: Is resting activity in neonates driven by cortico-cortical connections as it is in adults, or is it
driven by other mechanisms such as spontaneous activity in the sense
organ? These studies have revealed that the large majority of cortical
activity during the period of discontinuity results from input generated spontaneously at the sensory periphery, not within cortex. Examination of electrographic signatures of sensory stimulation in both
neonatal rats and human preterm infants has provided evidence
that a similar peripheral generation of resting activity may occur in
the neonates and fetuses.
This conserved peripheral dominance was first identified in rat primary somatosensory cortex where spontaneous muscle twitches are
associated with local, transient bursts of rhythmic, 5–25 Hz activity,
originally termed ‘spindle burst’(Khazipov et al., 2004)(Fig. 2A). Use of
wide-band recording techniques revealed a very large (up to 1 mV)
negative slow potential associated with rapid oscillations (MarcanoReik and Blumberg, 2008; Minlebaev et al., 2009), thus electrographically resembling delta brushes in human preterms. This was confirmed
in a follow up study in preterm infants that showed delta brushes were
triggered in the somatotopically appropriate region at GW28–32
U
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O
The final evidence that early and late resting activities are different is
that they have fundamentally different pacemakers and generators.
One clear example in cortex is gamma oscillations. In young rodents
gamma oscillations take the form of EGOs, and are primarily determined by gamma-rhythmic excitatory input from thalamus. In the
adult, gamma oscillations depend on perisomatic inhibition within the
cortex. (Minlebaev et al., 2011). This difference in generation leads to
significant differences in the physiological roles of EGOs and adult
gamma oscillations. Whereas EGOs enable the vertical synchronization
of the topographically aligned thalamic and cortical neurons necessary
for the development of thalamocortical units, adult gamma oscillations
synchronize larger areas of the cortex horizontally. A detailed understanding of the thalamic and cortical pacemakers of other early resting
activity patterns is not complete. However, as reviewed in the next section, it is clear that the production of the great majority of activity in the
early sensory cortex is dependent on external drive of thalamus; a fact
that stands in contrast to adult resting activity.
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Generative mechanisms
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(Fig. 2B) (Milh et al., 2007; see also Hrbek et al. (1973) for earlier demonstration of similar phenomenon). Thus in both species direct stimulation of the same body regions induces delta brushes in somatic cortex,
suggesting that it is the sensory feedback produced by the twitch
which triggers delta brushes. In rats spindle bursts do persist after sensory deafferentation (e.g., spinal cord transection), although at a much
reduced frequency (Khazipov et al., 2004). These results suggest that
some component of spindle bursts is endogenous to the thalamocortical
circuit. However, under normal, intact circumstances, they are controlled by the external stimuli brought about by the thalamocortical afferents that trigger these oscillations in the somatosensory cortex in a
somatotopic manner.
Spindle bursts are also the dominant pattern in early postnatal rat
visual cortex (Fig. 1). However, spindle bursts in visual cortex are longer
and less frequent than those in somatosensory cortex. This difference is
due largely to the influence of the retina, not differences intrinsic to the
cortical region. Following enucleation, visual cortex strongly resembles
somatosensory cortex after spinal cord transections, producing shortduration network bursts with long inter-burst periods (Colonnese and
Khazipov, 2010; Hanganu et al., 2006; Khazipov et al., 2004). Retinal involvement in spindle bursts is also indicated by evoked responses. Spindle bursts can be evoked by visual stimulation in preterm infants and
neonatal rats once photoreceptor mediated light responses occur in
the retina (Figs. 2C and D) (Colonnese et al., 2010; Ellingson, 1960;
Hrbek and Mares, 1964), or in rats by electrical stimulation of the eye
before this point (Hanganu et al., 2006). The importance of visual induction of human delta brushes (the homolog of spindle bursts) under normal circumstances is unknown, but is likely to be minimal because the
fetus is relatively visually isolated and spindle occurrence does not depend on the presence of fluctuations of environmental illumination or
movement that might change luminance on the retina. Furthermore,
in rats, the retina is insensitive to light during the first postnatal week,
while spindle bursts are prevalent.
Rather than ambient illumination, spontaneous retinal activity,
which propagates as wave fronts and synchronizes retinal activity within
local domains (Wong, 1999) provides the primary drive for spindle
bursts, at least in rats. A role for these retinal waves in driving visual cortex spindle bursts was demonstrated by simultaneous recordings from
the retina and V1 cortex (Hanganu et al., 2006), which revealed a strong
correlation between the occurrence of spindle bursts in visual cortex and
spontaneous retinal waves. Furthermore, pharmacological manipulations to increase retinal wave generation increased spindle-burst activity
(Colonnese and Khazipov, 2010; Hanganu et al., 2006). Perhaps most
tellingly, the temporal structure of spindle bursts in visual cortex is not
constant during development, but undergoes a profound change during
the second postnatal week, as spindle bursts begin to occur in groups
that together form long-lasting (5–10 s) events associated with large
amplitude DC shifts, highly reminiscent of SATs observed in human preterm neonates. The occurrence of V1 SATs at this time is highly regular,
repeating approximately every 60 s. This change exactly parallels
changes in the structure of spontaneous retinal activity (Blankenship et
al., 2009; Demas et al., 2003; Kerschensteiner and Wong, 2008). Multiunit recordings made from the cortex and thalamus of freely moving ferrets during the same developmental period revealed similar long-lasting
macro-burst behavior eliminated by enucleation (Chiu and Weliky,
2001; Weliky and Katz, 1999).
Thus the differences in the initiation, duration, and intra-burst structure of activity between visual and somatosensory cortex, as well as between visual cortex at different ages, appears to result from differences
inherent in the sense organ input. In total, activity in immature cortex
appears to have a two-tiered generative mechanism: short-duration inputs such as muscle twitches, light flashes, electrical stimulation, and
perhaps even endogenous cortical activity in the absence of peripheral
input, trigger spindle bursts/delta brushes. However, elongated activity
such as retinal waves drives similarly elongated spindle bursts or even
their agglomeration into SATs.
D
421
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403
T
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mechanism for horizontal synchronization and large scale binding necessary for perception and thought in adults (Buzsáki, 2006). Traditionally thought to emerge relatively late in development, recent
observations in the neonatal rats revealed robust local oscillations at
gamma frequency (Minlebaev et al., 2011). However, despite a similar
frequency and potential to be evoked by sensory stimuli as those of the
adult, the early gamma oscillations (EGOs) are transiently expressed.
They abruptly disappear at the end of the first postnatal week, while
the earliest adult gamma oscillations cannot be observed until days
later, thus arguing against their identity as the same class of activity. A
final example is SATs, introduced above. SATs become elongated in duration but reduced in amplitude with gestational age (Colonnese and
Khazipov, 2010; Tolonen et al., 2007), suggesting that the continuous activity of maturity may emerge due to elongated SATs becoming linked
during development. However, close examination of activity using DC
recordings in both humans and rats showed that continuous resting activity actually emerges from the quiet periods between SATs, and not
from their elongation (Fig. 1). We are not aware of any evidence demonstrating transformation of an identified early activity pattern into a mature network activity. The activities of immaturity studied in detail so
far are clearly temporally independent from adult activity.
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Please cite this article as: Colonnese, M., Khazipov, R., Spontaneous activity in developing sensory circuits: Implications for resting state fMRI,
NeuroImage (2012), doi:10.1016/j.neuroimage.2012.02.046
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A
P5Rat Somatosensory
Cortex
Hindlimb S1 EEG
+
+
-
-
0.1 mV
0.2 s
Hindlimb S1 MUA
0.1 mV
Hindlimb Movement
4s
Right Hand Stimulation
Somatosensory
Cortex
-
F
B GW 30
Twitch - evoked
delta-brush
+
100 µV
T3
FP1 FP2
C3 Cz C4
O
0.5 s
T4
Depth EEG
+
-
*
Sleep
C
+
-
T4
40 µV
Evoked 200 ms
delta-brush
Electrode O2
+
> 2Hz
T3
O1
Cz
500 mV
Evoked
delta-brush
100 mV
500 ms
5s
O
R
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MUA
EEG (0.05-40 Hz)
R
FP1 FP2
C3 Cz C4
FP2
C4
T4
O2
FP1
C3
+
400 µV
E
GW 30 Visual
Cortex
T
light flash
T3
Depth EEG
D
400 µV
200 ms
light flash
D
Awake
Evoked
delta-brush
P
P10Rat Visual
Cortex
E
C
R
O
O1 O2
+
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Fig. 2. Conserved drive of early network oscillations by sensory periphery. In the human and rat somatosensory and visual systems, spontaneous early network oscillations can also be
reliably evoked in a topographically restricted manner by sensory input. A. Simultaneous recording in hindlimb S1 while monitoring hindlimb motion. Spontaneous delta brushes in rats
are associated with spontaneous myclonic jerks, which precede the delta brush. Expanded time scale (right) shows rapid oscillations of delta brushes and associated unit activity following
movements. Direct stimulation of the hind-paw also elicits delta brushes (not shown). B. Direct stimulation of the hand in a preterm infant produces delta brushes in contralateral central
cortex (center panel). Expanded time scale (right) shows delta brush (negative is up) restricted to single electrode. C. Visual stimulation produces delta brushes in visual cortex. Responses
to 6 light flashes in layer 4 of V1 from the same animal during different vigilance states (central traces). A spontaneous delta brush occurs before one of the stimulus trials (asterisk). Note
the similarity of spontaneous and evoked patterns. Expanded time scale (right) shows field potential and evoked unit activity. D. Visual stimulation produces delta brushes in occipital
electrodes of preterm infants (center panel). Expanded time scale (right) shows evoked potentials similar to the rodent visual response.
Modified from Khazipov et al. (2004); Milh et al. (2007); and Colonnese et al. (2010).
Recent studies suggest that regions outside of the primary sensory
regions follow similar developmental patterns. Prefrontal cortex demonstrates alternating periods of silence and rapid oscillation that are
driven by the hippocampus and become continuous around the same
time as sensory cortex (Brockmann et al., 2011). Similar activity patterns have also been described in dysgranular and temporal cortex
(Adelsberger et al., 2005; Seelke and Blumberg, 2010), though their
generative mechanisms are still unclear.
In summary, recent rodent work, partially confirmed in human preterm infants, shows that the resting state neural events (SATs/spindle
bursts/delta brushes) which constitute the majority of early neural activity (>90% in rat visual cortex) have as their primary driver input
from the peripheral sense organ (Fig. 3). In adults the proportion of
resting activity contributed by sensory input to primary sensory cortex
is likely to be small, as sensory input is specifically kept minimal during
testing and ongoing activity in visual cortex is only minimally modulated by visual inputs (Fiser et al., 2004).
541
Development of intrinsic thalamocortical activities
545
If the basis of resting state activity modulations in sensory cortex during early development is spontaneous activation at the periphery, then
they result from different functional circuits from those generating resting activity in the adult. The activity patterns most closely associated
with resting state modulations in sensory cortex are delta waves (Jann
et al., 2010; Lu et al., 2007), which result from spontaneous activation
546
Please cite this article as: Colonnese, M., Khazipov, R., Spontaneous activity in developing sensory circuits: Implications for resting state fMRI,
NeuroImage (2012), doi:10.1016/j.neuroimage.2012.02.046
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M. Colonnese, R. Khazipov / NeuroImage xxx (2012) xxx–xxx
Immature
Pre-resting state
7
Adult
Resting state
Higher SC
and other Ctx
Higher
VC and
other Ctx
Higher
SC and
other Ctx
Visual
Cortex
Somatosensory
Cortex
Visual
Cortex
SC
Thalamus
Thalamus
Thalamus
Thalamus
Retina
(spontaneous
waves)
Somatic
Receptors
(spontaneous
twitches)
Retina
F
HigherVC
and other Ctx
O
Somatic
Receptors
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Q13571
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D
in rodents (Gramsbergen, 1976). This rapid increase in spontaneous activity does not emerge simultaneously in entire cortex, but instead occurs first in somatosensory and then in visual cortex in both the rat
and human. In both species it coincides with the elimination of delta
brushes and spindle bursts in these areas (Andre et al., 2010).
At least two developmental factors relevant to the generation of
resting state connectivity are likely involved in the emergence of
the activated cortical state: the development of arousal systems and
intra-cortical connections. Isolating the forebrain from ascending
neuromodulatory arousal inputs at P13–15 rats reverses the developmental increase in spontaneous cortical activity, reinstating the immature discontinuity (Colonnese et al., 2010). The mature activity
state is re–instated by application of norepinephrine, a key initiator
of the activated cortical state (Constantinople and Bruno, 2011).
This is consistent with the critical role for noradrenergic systems for
the development of sleep-wake transitions (Gall et al., 2009) and
the maturation of cholinergic (Mechawar and Descarries, 2001;
Robertson et al., 1985) and noradrenergic afferents and receptor distributions (Latsari et al., 2002; Venkatesan et al., 1996) around this
time. However, arousal system activity alone is incapable of inducing
a continuous active state in the immature cortex (Hanganu et al.,
2007). Thus the acquisition of brainstem control of cortical rest states
likely requires thalamocortical inputs as well. A prominent candidate
is the strengthening of the long and short range intra-cortical connectivity, required for maintenance of the activated cortical state
(Sanchez-Vives and McCormick, 2000; Steriade and McCarley, 2005;
Timofeev et al., 2000). The network of horizontal connections between cortical columns emerges shortly before eye opening in cats
and ferrets (Durack and Katz, 1996; Ruthazer and Stryker, 1996) independently of visual input (Callaway and Katz, 1990; Durack and
Katz, 1996; Ruthazer and Stryker, 1996). In mice feedback connections to V1 are observed just before eye opening (Berezovskii et al.,
2011). In humans, dense horizontal connections are also first observed at GW37 (Burkhalter et al., 1993). Emergence of the continuous mode of cortical activity thus likely results from a coincidence
of two developmentally regulated factors: (i) maturation of the brainstem arousal input to thalamus and cortex, which provides tonic neuronal depolarization and (ii) formation of excitatory synaptic
connections among local and distant cortical neurons, required for
initiation and maintenance of the activated cortical state, and for resting state modulations.
E
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of thalamocortical circuits during sleep or periods of low vigilance
(Steriade and McCarley, 2005). Not surprisingly, the development of
delta activity induced by non-REM sleep parallels the loss of early activity
patterns in rats and humans (Andre et al., 2010; Gramsbergen, 1976;
Seelke and Blumberg, 2008). Thus, the question of when adult resting
state develops a question of when intrinsic activity generated within cortical circuits develops (Fig. 3). In adults, intrinsically generated activity in
thalamocortical circuits is characterized by the presence of activated cortical states (aka desynchronized- or up-state) (Destexhe et al., 2003,
2007). This intrinsic activity is generated via recurrent cortical connectivity, which drives balanced excitatory and inhibitory input to neurons,
and is regulated by neuromodulatory input, particularly acetylcholine
and norephinephrine (Steriade and McCarley, 2005). The active state occurs during waking, REM sleep and even slow wave sleep, when it is broken up by very short periods of network silence, or down states.
Intracellular recordings show little difference between continuous cortical activity during awake, REM sleep and UP-states during slow wave
sleep. As described in Sections Discontinuous temporal organization of
early activity, Unique activity patterns in preterm infants, and
Peripheral dominance of resting activity during early development, the
current evidence suggests that the activated cortical state is not present
in neonatal rats and young premature neonates, as the majority of activity is driven directly by the periphery, not intra-cortical circuits. Furthermore, the early sensory driven SAT and delta brushes do not develop
into activated cortical states. Instead it appears that primitive active
states, which resemble those observed in isolated cortical slabs, develop
independently during the second postnatal week in the rat, which show
increased delta activity during quiet sleep (Seelke and Blumberg, 2008),
calcium bursts under anesthesia (Golshani et al., 2009; Rochefort et al.,
2009) and short 200–500 ms bursts of cortical activity that are insensitive to eye-removal (Colonnese and Khazipov, 2010). This may correspond to the increase in delta activity observed during quiet sleep
during third trimester preterm infants, or the tracé alternant pattern
which becomes increasingly prevalent during active sleep toward the
end of gestation. Interestingly, rat cortical slices begin to produce spontaneous synaptic activity around the same time (Allene et al., 2008;
Rheims et al., 2008), demonstrating a basic change in the ability of isolated cortex to generate activity. In visual cortex these early delta/slow
waves become rapidly more frequent around eye opening (Colonnese
and Khazipov, 2010; Colonnese et al., 2010; Rochefort et al., 2009), coinciding with the emergence of clearly differentiable EEG sleep states
U
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R
O
Fig. 3. Changing drive of resting state activity during development of sensory systems. Diagram shows hypothesized circuits influencing cortical activity during preterm and adult
resting states in primary sensory systems. During early development in the absence of visual input spontaneous waves cause the retina to be synchronously active. Spontaneous
jerks serve a similar purpose in the somatosensory system. During this period spontaneous intra-cortical activity (both local and feedback) is minimal. The majority of resting activity thus results from the transmission of spontaneous retinal activity. This is in contrast to adults, whose resting activity is largely independent of retinal or somatic input and is
instead generated via recurrent interactions between and within cortex and thalamus. Because of these substantial differences in drive and function between the immature and
adult systems, we propose that the preterm infant and neonatal rat be considered to be in a pre-resting state.
Please cite this article as: Colonnese, M., Khazipov, R., Spontaneous activity in developing sensory circuits: Implications for resting state fMRI,
NeuroImage (2012), doi:10.1016/j.neuroimage.2012.02.046
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Summary
744
Electrophysiological evidence in human preterm infants and animal
models reviewed here is consistent with the hypothesis that early circuit development is characterized by a unique state of cortical network
dynamics, in which adult-like thalamocortical resting state activity is
minimal, allowing inputs from the periphery to be amplified by cortical
oscillatory bursts (Fig. 3). This period appears tightly regulated to coincide with the sensory deprivation experienced in the womb (or maintained by eye or ear canal closure in rodents), and to end when active
sensory processing is initiated. It is only when this early period ends
that many of the gross characteristics of adult resting state activity can
be discerned, including clear regulation of cortical EEG by sleep state
and the reduction and eventual elimination of SATs in counterpoint to
continuous activity (Gramsbergen, 1976; Seelke and Blumberg, 2008;
Vanhatalo et al., 2005), and perhaps not surprisingly, elements of complex cortico-cortical resting state networks (Doria et al., 2010; Fransson
et al., 2011; Gao et al., 2009). Of course, the development of cortical activity is by no means complete by this point; in essence it has only just
745
746
F
We have presented evidence that ‘resting state’ modulations of activity in sensory cortex during early ages are not the same infraslow
modulation present in the adult. This is supported by two characteristics of neocortical activity during the fetal and early neonatal period
(1) unique early network activities driven by the sensory periphery
and (2) the lack of intrinsic activity generated in thalamocortical circuits. The young resting state activities represent a unique network
state that is limited to early development. We propose this state is optimized to drive synaptic plasticity in thalamocortical networks in response to spontaneous activity generated in the sense organs. To
support this function, ‘resting’ activity at these ages largely reflects activity generated in the sensory periphery, despite its independence
from changes in the external environment. As a result, cortical activity
at these early ages is poorly modulated by vigilance state or the environment; in effect the cortex is always ‘at rest’ in the sense that there
are no task or attention based modulations of the cortex. Unlike adults,
however, rest is a singular condition, at least during early development.
A key implication of this hypothesis for imaging studies is that while
powerful activity modulations are present during early development,
they are incapable of conveying graded and high-frequency information
transfer as in adults.
Two examples support this assertion. Using two-photon calcium imaging of the superficial layers of visual cortex in anesthetized mice
Rochefort et al. (2009) and Golshani et al. (2009) traced the development of cortical slow waves. They observed a rapid developmental decrease in neuronal synchrony during individual slow waves by the end
of the second postnatal week. Why is this important? Generation of active states is proposed to be a primary mode of intra-cortical communication, by activation of particular circuits and not others during waking
and by driving replay of memories during sleep (Destexhe et al., 2003; Ji
and Wilson, 2007), both of which require differential firing of neurons
based on behavioral or sensory experience. Thus synchronous firing
by all neurons is poorly adapted for information processing, though it
is well adapted for the stabilization of grossly refined connectivity during early development.
Such all or none responses are found during early sensory processing. Colonnese et al. (2010) examined the role of early thalamocortical
networks properties in determining visual responses in preterm
humans and rat. Despite weak or absent retinal visual responses in
vitro, robust light responses could be evoked as early as P8 in rats. As
discussed previously, cortical light responses consisted of a complex
group of network oscillations including delta brushes (Fig. 2C). These
visual responses were ‘all-or-none’ bursts, effectively registering the
presence of an even minimal stimulation, but not its intensity. Measurement of the spiking responses of retinal ganglion cells in acutely excised
retina allowed further quantification of the input-output relationships,
which showed that these early bursting responses massively amplified
retinal activity within the cortical circuit. Only with the development of
continuous activity in cortex were graded responses to light observed.
Thus we suggest that the primary role of early activity patterns, in addition to precisely synchronizing activity, is to amplify weak, tentative inputs. Such amplification is incompatible with visual processing. These
changes in bursting and amplification observed in the visual system
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Early cortical function and implications for resting state fMRI
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(where they can be quantified) are likely also to occur in other, nonsensory, cortical areas, where we would predict that early activity
might be similarly ’non-coding’, but instead serve more limited synapse
stabilization goals at these early ages.
In short these data strongly argue that while correlated activity within and between various brain regions is undoubtedly present during the
fetal period, they are much more likely to reflect the presence of anatomical connections rather than a functional transfer of information. In fact
two pieces of evidence suggest that early connectivity studies may
‘over-estimate’ connectivity in preterm infants relative to adult. First,
the lack of continuous activity should increase signal to noise, leading
to detection of connectivity levels below those apparent in adults. Second, the amplification of weak inputs should result in activity levels
with much lower anatomical connectivity indexes.
By contrast, fMRI has a potential to underestimate connectivity in
young brains relative to electrophysiological measurements because
neurovascular coupling is still immature. While relatively tight coupling
of neuronal activity and the Blood Oxygen Level Dependent (BOLD) signal in adults has been established in animal models (Logothetis and
Wandell, 2004), the developmental timing of this coupling is poorly explored. In rat somatosensory cortex, evoked BOLD signal in anesthetized
rats could not be observed before the 13th postnatal day (Colonnese et
al., 2008). Even after the development of functional coupling, the time
course of hemodynamic responses evolved over an extended time period, which should change the relevant frequencies of resting state modulations. Combined studies of spontaneous cortical EEG and blood flow
measured with near infrared spectroscopy in preterm infants show that
SATs are accompanied by increased oxygen extraction leading to a large
and extended decrease in oxy-hemoglobin which is followed by a
delayed hyperfusion of oxygenated blood relative to the adult value
(Roche-Labarbe et al., 2007), somewhat resembling early BOLD signals
in rats. fMRI studies in term infants have suggested a changing developmental relationship between evoked neural activity and the BOLD signal. Pattern vision evoked BOLD signals undergo an inversion, moving
from positive to negative around 8 weeks (Muramoto et al., 2002).
The authors suggest this is a result of rapid synaptogenesis out-pacing
vascular development at these ages, causing oxygen extraction to exceed reactive blood flow. This effect has seen mixed support in other
studies (Anderson et al., 2001; Dehaene-Lambertz et al., 2002; Erberich
et al., 2003). Thus until the development of the neurovascular unit is
better understood in humans and animal models, methods relying on
neurovascular dynamics in the infant, particularly preterm infants, do
not have the same experimental support as currently exists for adults,
and have the potential to underestimate connectivity, while the activity
and electrical characteristics of young tissue may provide a counter balancing amplification.
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In summary, spontaneous activity generated within thalamocortical
circuits, i.e. the true ‘resting state’, is developmentally delayed relative
to cortical responses to spontaneous activity in the periphery, which
generate transient excitatory waves on an infraslow timescale during
early development. Only after the establishment of basic cortical circuits, such as topographic mapping of thalamic inputs, does significant
intra-cortical connectivity and modulation by vigilance state emerge.
It is perhaps then not surprising that resting state networks involving
multiple, distant cortical regions emerge after local, primarily sensory,
networks (Doria et al., 2010; Power et al., 2010).
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NeuroImage (2012), doi:10.1016/j.neuroimage.2012.02.046
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Please cite this article as: Colonnese, M., Khazipov, R., Spontaneous activity in developing sensory circuits: Implications for resting state fMRI,
NeuroImage (2012), doi:10.1016/j.neuroimage.2012.02.046