Author: James B. Ackman  
Date: 2013-09-04 10:54:02  
Tags: paper, draft, manuscript, literature, research, #results, retinal waves, spontaneous activity, development, calcium domains  

# Structured population activity across developing isocortex  
Structured neural activity across developing cerebral hemispheres  
Mesoscale mapping of neural activity across developing cerebral hemispheres  

# Abstract  

The cerebral cortex exhibits spontaneous and sensory evoked patterns of activity during fetal and postnatal development that are crucial for the activity-dependent formation and refinement of circuits [#Katz:1996]. Knowing the source and flow of these activity patterns locally and globally is crucial to understanding self-organization in the developing brain. Here we show that neural population activity within newborn mice in vivo is characterized by spatially discrete domains that are coordinated in a state dependent and areal dependent fashion throughout developing isocortex. Whole brain optical recordings from neonatal mice expressing a genetic calcium reporter showed that ongoing activity in the cerebral cortex was characterized by discrete and repetitively active domains measuring hundreds of microns in diameter. Cortical domain activity depended on brain state with periods of localized and global domain synchrony exhibiting positive and negative correlations to motor behavior respectively. Furthermore, domain activity exhibited mirror-symmetric patterns between the hemispheres, with strong correlations between cortical areas that correspond to the default-mode network in primates. This study provides the first comprehensive description of population activity in the developing isocortex at a scope and scale that bridges the microscopic or macroscopic spatiotemporal resolutions provided by traditional neurophysiological or neuroimaging techniques. The data provided by mesoscale mapping of population dynamics among cortical areas in animal models will be crucial to engineering repair strategies and brain-machine interfaces for neurodevelopmental disorders.




# Introduction  

<!--- This should be one paragraph. Some of this intro material could be combined with intro or concl sentences in abstract for a Nature letter (should be referenced and up to 300 words; 200 words preferred) --->

- Activity and development
- Neural activity, drugs, and birth defects
	- epilepsy
	- autism
- What is the activity?
     - instructive or permissive?
     - EEG slow oscillations not detectable until P10 in rodent.
     - slice work
     - leinekukel and khazipov work [#Leinekugel:2002][#Khazipov:2004a]
     - ucla konnerth imaging work [#Golshani:2009][#Adelsberger:2005]
     - human occipital cortex and my retinal wave paper [#Vanhatalo:2005][#Tolonen:2007][#Ackman:2012]
     - is the activity completely random? Or Is it organized in space and time, and at what scale?
     - the little that we know is from work in second postnatal week, not earlier, olavarria work, interneuon migration, synaptic formation, and anatomical studies indicates significant development decisions are being made in first postnatal week




# Results

## Ongoing activity in the developing cerebral cortex is characterized by discrete domains

* Cortical column (mini/meso/super columns) history (20th century anatomists-- sherrington, valverde, rakic, etc). 
* Column physiology-- Hubel and Wiesel. Rodent V1?
* Developmental studies-- fetal monkey ODCs. 
* Rodent barrels (early anatomical emergence from TC input, functional/physiological emergence?). 
	* What is known about columns/domains in secondary/association/non-primary sensory representations? Rest of rodent S1 (non-barrel cortex?). 
* Calcium domains of Yuste, Science 1992 paper. [#Yuste:1992]
* Other slice calcium recordings, patch/gap junctions. In vivo physiology? (Not too many multisite electrode recordings in cortex, spatial resolution issue). 
* Calcium imaging-- Konnerth 'waves' in Ent cortex [#Adelsberger:2005]. For visual cortex, domains activity in extrastriate cortex (Ackman Nature 2012). But S1-- [#Golshani:2009] work in later postnatal-- but activity not obeying domains in barrel cortex-- problem with spatial sampling in the xy and the z for this study?


![**Figure 1.** Calcium domains throughout neonatal mouse isocortex. **a** Experimental schematic. **b** Single image frame showing calcium domains in both hemispheres at P3 and automatically detected domain masks. **c** Domain overlay map for a single 10 min recording. 3D binary masks were flattened for each domain and colored by time and transparently overlaid. Notice the non-uniform distribution of boundaries and color intensities across each hemisphere, as well as local maxima and minima that indicate matched areal boundaries bilaterally. **d** Histograms showing the distribution of spatial diameters and durations for calcium domains.](figure1.png)

metric | mean  | min  | max    | unit                  
------------- | ----- | ---- | ------ | --------------------  
diameter      | 396.0 | 22.7 | 2383.5 | µm           
duration      | 0.6   | 0.2  | 14.6   | s             
frequency     | 2.9   |      |        | domains/sec/hemisphere
[**Table 1: Domain statistics**]






## Cortical domain activity is state dependent  ##

* Previously demonstrated that general anesthesia abolishes spontaneous activity in visual system [#Ackman:2012]. 
* What about ongoing activity in other cortical areas during early brain development? Surgical procedure relevance.
* No population calcium activity found during gen'l anesthesia, only slow traveling waves.
* During anesthesia induction, rapid (<30 s) knock down of discrete domain activity (P3 mouse <120518_09.tif>). Cingulate, retrosplenial activations the last to go-- default mode/resting state network areas last.
<120518_09_mjpeg.mov>


![**Figure 2.** Cortical domains are state dependent. **a** Experimental schematic. Red light illumination measured with a photodiode (PD) was used to monitor motor activity. **b** dF/F image sequence showing cortical domain activity before and after isoflurane anesthesia within a single recording. **c** Cortical activity (active fraction) in each hemisphere after onset of gas anesthetic. **d** Hemispheric autocorrelation and cross-correlation functions for cortical activity at all and short time lags. Notice the peaks above gaussian distributed noise (blue traces). **e** Cortical activity and coincident motor activity signals. Moving averages of cortical and motor activity at 10 s and >70 s windows. **f** Single frame domain masks for times indicated in **e**. **g** Autocorrelation and cross-correlation functions for cortical and motor activity for the whole recording or during just the active-motor-period. Notice the correlation between cortical and motor activity above random noise and that motor activity generally follows cortical activity (shift towards right).](figure2.png)


Conclusions: The two hemispheres seem to be mostly synchronized, though it’s possible the R hemispshere (which is also the slightly more ‘active’ hemisphere, see stats table below) leads the left by a bit. The asymmetric peak at –150–175frames is interesting. That would be about 30–35 sec.

The big secondary peaks around ±30 sec is present in both autocorrs and xcorrs and is far above the random normal xcorr baseline (blue trace). In fact there is a periodicity seen in the autocorrs and the xcorrs where there is a dampening oscillation about on this interval! (See ideal dampening frequency in random sine wave example above). This corresponds to a 1/30sec == 0.033 Hz ultra-slow oscillation.

Looking at the above plot showing lags from [–1000, 1000] frames which is ± 200 s, we can see about 5.5 cycles of this underlying dampening oscillation in both autocorr plots. This corresponds to (1000fr*0.2sec/fr)/5.5 => 36.36 sec/cycle => 0.0275 cycles/sec or ~0.03 Hz





### Percentage of cortical activity which exhibits corr with motor signal?

lenActvFraction>0 | fracCorr | timeCorr_s | fracCorrPos | timeCorrPos_s | fracCorrNeg | timeCorrNeg_s
 --- | --- | --- | --- | --- | --- | ---
2161 | 0.30032 | 129.8 | 0.27441 | 118.6 | 0.025914 | 11.2








## Cortical activity is mirrored between the hemispheres ##

* Inter hemispheric functional connectivity, importance for autism, schizophrenia. Maybe an activity-dependent mechanism for commisural connectivity.
* [#Hanganu:2006], 30% of spindle bursts correlated across hemispheres
* Activity correlated in anterior-posterior and medial-lateral directions
* Mirror symmetric and non-mirror symmetric patterns
* Regional effects, more corr anticorr in certain regions?
* State dependent corr?

<!--- * Each hemisphere 'training' the other one in preparation for behaviorally relevant sensory-motor imitations '[[mirror_neurons]]' hypothesis? --->

![**Figure 3.** Cortical domain activity exhibits bilateral symmetry. **a** Examples of domains exhibiting spatially symmetric activations. Notice most timepoints contain a mixture of symmetric and asymmetric domain activations. **b** Hemispheric domain centers of mass for coactive frames in a recording along medial-lateral (ML) and anterior-posterior (AP) extents. Bottom panels show the periods indicated by black bars at expanded view. **c** Plot of hemispheric domain centers of mass for coactive frames. **d** Correlation matrix of domain activity among cortical areas.](figure3.png)




xy pearson corr coef ML | xy pearson corr coef AP
--- | ---
p = 1.1591e-28 | p = 7.0982e-07
*scatterplots in figure 3* ||



**Conclusions:** So the activity in both hemispheres at postnatal day 3 (P3) clearly exhibits significant spatial correlations in  both in the medial-lateral and anterior-extent. This is consistent with and complementary to the fact that the active pixel fraction in each hemisphere exhibits a strong temporal correlation as I found earlier in this report [Temporal correlation of activity][]. The medial-lateral positional correlation is stronger than the anterior-posterior (higher *R* and lower *p* value).   The total number of coactive frames is `numel(y1(~isnan(y1)&~isnan(y2)))` == **1114 frames**. This is accounts to **37.13%** of the movie or **222.8 s**. Cortex.L had 1635 actvFrames and cortex.R had 1677 actvFrames which means that each hemisphere was coactive with the other hemisphere 1114/1635 == **68.13%** and 1114/1677 == **66.43%** of the active time respectively. 



<!--- # References --->
<<[references.txt]

<!---Figure 1 metadata
* neonate_ms_fig.png
* binary masks: Screen_Shot_2013-03-29_at_12.06.25_PM_crop.png, ..._crop1.png, ..._crop2.png
* domain map: Screen_Shot_2013-05-14_at_4.11.51_PM_crop.png
* hists: 120518_07_connComponents_BkgndSubtr60px-20130327-163111domains20130402-151440-crop.png
--->

<!--- TODO: add a domain centroid size/duration map similar to: ![](../figures/Screen_Shot_2013-04-03_at_8.42.49_AM.png)
![](../figures/Screen_Shot_2013-04-03_at_10.04.36_AM.png)
--->

<!---Figure 2 metadata 
Temporal correlation of activity between the hemispheres and preceding motor activation:  
![](../figures/Screen_Shot_2013-04-30_at_3.02.20_PM.png)
hemisphere active fraction traces: Screen_Shot_2013-04-08_at_8.47.19_AM.png

### Cortical activity and motor activity is periodic
hemi auto & xcorr:
Screen_Shot_2013-04-08_at_2.31.33_PM.png
Screen_Shot_2013-04-08_at_2.34.50_PM.png
Moving average signals color coded at diff lags: Screen_Shot_2013-05-02_at_10.53.40_AM.png

### Cortical activity is correlated with the motor signal
Rho and pvalues whole trace: ![](../figures/Screen_Shot_2013-04-25_at_5.18.36_PM.png)
Rho and pvalues subset trace: ![](../figures/Screen_Shot_2013-04-25_at_3.59.05_PM.png)

### Cross-correlation of cortical activity and motor activity
auto, xcorr for whole. 
Screen_Shot_2013-04-24_at_2.39.50_PM.png
auto, xcorr during motor period. 
Screen_Shot_2013-04-24_at_3.11.10_PM.png
--->


<!---Figure 3 metadata
binary mask snapshots, cropped from screen shots in [[2013-04-19_analysis]]
Screen_Shot_2013-04-19_at_8.26.00_AM_fr1786.png
Screen_Shot_2013-04-19_at_8.27.49_AM_fr2134.png
Screen_Shot_2013-04-19_at_8.30.27_AM_fr759.png
Screen_Shot_2013-04-19_at_8.30.51_AM_fr373.png
Screen_Shot_2013-04-19_at_8.38.54_AM_fr177.png

activefraction hemis AP & ML all: ![](../figures/Screen_Shot_2013-04-23_at_8.45.18_AM.png)
activefraction hemis AP & ML segment: ![](../figures/Screen_Shot_2013-04-23_at_8.46.27_AM.png)
activefraction hemis AP & ML segment: ![](../figures/Screen_Shot_2013-04-23_at_8.51.55_AM.png)
scatterplot ML Screen_Shot_2013-04-22_at_4.29.28_PM.png
scatterplot AP 
--->
