Neu
ron
al A
cti
vit
y
“Ele
ctr
ical E
ven
ts”
Fu
ncti
on
al
Imag
ing
“BO
LD
Effect”
Neurovascular
Coupling
Vascular
Dynamics
Linear System
Linear Convolution Model r
BOLD k HRF ky t h t d • Relation with physiology? • Dysfunctions? Diseases
Physiology of the neurovascular coupling Biophysical models for vascular dynamics
Particulars for Dementia (AD) & Epilepsy
Topics for this talks
Physiology of the neurovascular coupling Biophysical models for vascular dynamics
Particulars for Dementia (AD) & Epilepsy
Topics for this talks
Hamel, J Appl Physiol, 2006
EXTRINSIC INNERVATION
superior cervical (SCG) sphenopalatine (SPG) otic (OG) trigeminal (TG)
Ganglion
SUBCORTICAL VASOACTIVE PATHWAYS
NA- norepinephrine NKA- neurokinin A NPY- neuropeptide Y VIP- vasointentinal polypeptide SP- substance P CGRP- calcitonin gene-related peptide PACAP- pituitary adenylate-cyclase activating polypeptide NOS- nitric oxide synthase ACh- Acetylcholine 5-HT- serotonin SOM- somatostatin
Cauli et al., J Neurosci, 2004
Single interneuron stimulation induces
dilation or constriction of cortical blood
vessels
Hamel, J Appl Physiol, 2006
SUBCORTICAL VASOACTIVE PATHWAYS
Drew
el al. P
NA
S, 20
11
Phasic Pathway (NO, PGE2)
Tonic Pathway (Astrocytes)
Riera, Brain Product Press Release, 2011
Gas Diffusion
NO
NO NO
1
nNOS
Phasic Pathway NADPHd-positive
neuron
Cortical neurons synthetizing NO
Estrada and DeFelipe, Cerebral Cortex, 1998
Nitrergic Neurons
Stefanovic et al., JCBFM 2007
7NI – Inhibitor nNOS (specific)
killed
PGE2 Lipid Diffusion
2
PGE2 Lipid Diffusion
Phasic Pathway
Glutamatergic Neurons
Wang et al., Cerebral Cortex, 2005
Large COX-2 labeled dendrites (COX-d1 and d2) are apposed (black block arrows) by nNOS-
containing terminals (NOS-t1 and t2)
W, Whisker; F, forepaw; H, hindpaw; T, trunk; VC, visual cortex.
Boorman et al., J Neurosci, 2010
Goense et al., (2012)
PBR
NBR
CBF and CBV increased in the center of the cortex
“Laminar Differences in Neurovascular Coupling
For positive BOLD responses:
For negative BOLD responses: CBF decreased superficially while CBV increased in the center
Patrick Drew (Personal Communication) Penn State
Neuronal Astrocytes
Vascular Astrocytes
Cx43 (blue) and Cx30 (red)
Gia
um
e e
t al
., N
RN
, 20
10
Domains do not overlap
Differentially expressed in barrels (dark) and septa (light)
G βPLC
R
IP3R [Ca2+]ER
Cytosol [Ca2+]
Agonist
SERCA
[Ca2+] Extrusion
SCO
PLC
influx
micro-domain
[Ca2+] CCE
[Ca
2+]
Multiple-Channel Patches
IP3R “hot regions” (clusters) ~ 10 M
Channel
Cluster
Riera et al., Biophysical J (2010)
A biophysical model (astrocytes)
Population Astrocytic Ca2+ activity (WT mice)
Nimmerjahn et al., Nat Methods (2004)
Cerebral Cortex (in vivo)
Ca2+ activity
Propagation
Hippocampus (in vitro)
Riera et al., unpublished
1
2
Fluo-4 AM
10 m
Takano et al., Nature Neuroscience 2006
FITC-Dextran (green) Rhod-2 (red)
Wang et al., Nature Neuroscience 2006
Neuronal Activity
Neuronal ATP Consumption
Neuronal O2
Consumption
Tissue
pO2
Level
Ca2+
Waves
Glu Glu
Glu Glu
NO NO
NO
NO
Gas Diffusion
AA AA
AA
AA
AA
Acid Diffusion
AA
CYP2C
COX-1
PGT
PGE2 PGE2
LACTATE LACTATE
LACTATE
glycolysis LDH
MCT-1&4
NO +
EET
+
PGE2
+
AA
20-HETE
-
+
NO -
NO
cGMP Modulation
Astrocyte
Riera & Sumiyoshi, CON 2010
Tonic Pathway
soluble Guanylate Cyclase
lactate dehydrogenase (LDH) monocarboxylate transporter (MCT)
Gordon et al., Nature 2008
• NO-mediated 20-HETE/EET unbalance hypothesis for vasoconstriction and vasodilations
• Lactate–PGE2 coupling hypothesis
Tonic Pathway
Physiology of the neurovascular coupling Biophysical models for vascular dynamics
Particulars for Dementia (AD) & Epilepsy
Topics for this talks
, , , , , ,r t r t t r t r fx x i
,k kt k tr t gy x ε
a) Performing statistical inference about the states,
exogenous inputs and network topology
b) Combining different modalities of functional neuroimaging
data
Why Are Model Needed?
State-Space Model
Discrete nonparametric models
Continuous parametric models , ,l l l l l
l ld t t t dt d t fx x u G w
, 0, , , ,k k k k k
l l l l
t l t l t l tk N
fx x u
,, 2l l
l lE t t
Dw w
The Fokker-Planck equation describes the time evolution of the probability density function
2, 1, , , ,
2
l
l l l l l l
l l l ij l
ij i j
dp tt t p t dt H p t
dt x x
f
xx u x x
2l l lH DGG
The high-dimensionality of the Fokker-Planck equation can be reduced by using the mean-field approximation
, ,l k l
l l kkp t p tx x
, , , ,k l l l
l k k k k lt t t f x u
l l
k kt E t x
Riera, Encyclopedia Computation Neuroscience, 2014
Hemodynamic Model
Riera et al., Hum Brain Map, 2006
Windkessel Theory
Capillary OEF Mass Balance Equation
Wn
ag e
t al
., N
eu
roIm
age
, 20
06
spike-density function
Transient Neural Response
Logothetis et al., Nature ,2001
BOLD signal & EEG recordings
X = -40 mm Y = 8 mm Z = -24 mm
Sumiyoshi et al., Neuroimage, 2011
Wistar Rats (Adult)
Sumiyoshi et al., Neuroimage 2012, In Press
Coefficient P-value
Intercept (b0) -5.27000 0.100
Regression slope for "PaO2" (bO2) +0.00037 0.700
Regression slope for "PaCO2" (bCO2) -0.00067 0.800
Regression slope for "pH" (bpH) +0.78000 0.060
Regression slope for "MABP" (bMABP) -0.00140 0.070
Regression slope for "HR" (bHR) +0.00094 0.007
Multiple Compartmental Model
Lay
er V
Py
ram
idal
Cel
l
Riera et al., Hum Brain Map, 2006
Dendrite + Soma
Dendrite
(Tuft)
Dendrite
(Basal)
Soma
Electrotonic Propagation
Intra- & Extra- Cellular Components
GA
BA
ergic
In
tern
euro
ns
Neurona Mass Model
Phasic (NO) Hemodynamic Model
NO
W
u t t C d
,
lIN PC
NO IN IN PC PC
l T F
C t g S g S
Lin
ear F
ilte
r
(Diffu
sio
n a
nd S
cavenges)
21 exp /k C k C kg I I
Estrada and DeFelipe, Cerebral Cortex, 1998
(NADPHd)
histochemistry
Riera et al., Hum Brain Map, 2006
Visual Integration
Contrast SPM2 t-test
PCD Orientations
BOLD Effect (Time Course)
Riera et al., Hum Brain Map, 2007
PCD Amplitude (Time Course) Where are these components
coming from?
C1
C2
C3
C4
C2
Riera et al., Hum Brain Map, 2007
Mes
o-s
co
pic
Vari
ab
les
NO
dHb
CBF
CBV
Synaptic Inputs
Visual Integration
INTEGRATOR
(apical trunk)
LENGTH
MEAN±SD(μm)
DIAMETER
MEAN±SD(μm)
Branch 1 205.89±25.00 1.26±0.05
Last Compartment 2.48±0.61 2.48±0.61
PROPAGATOR (dendritic trunk)
LENGTH
MEAN±SD(μm)
DIAMETER
MEAN±SD(μm)
Compartment 10 61.64±4.99 2.76±0.25
Compartment 9 60.47±7.68 2.69±0.55
Compartment 8 62.05±5.71 2.80±0.48
Compartment 7 61.66±8.69 2.71±0.38
Compartment 6 63.29±7.01 2.91±0.47
Compartment 5 62.51±7.44 3.01±0.79
Compartment 4 61.43±8.69 2.99±0.45
Compartment 3 61.93±6.68 3.05±0.45
Compartment 2 61.47±5.12 3.33±0.20
Compartment 1 60.66±9.06 4.34±0.46
DIAMETER
MEAN±SD(μm)
COLLECTOR
(soma) 13.40±1.40
Electrotonic Characteristics of layer V PCs
Wang et al., Neural Comp, 2013
10
0
m
Crivaro et al., J Microscopy, 2011
Extended Split-Gradient Deconvolution Method
0 1 2 3
1 1 1k
k
t k k
k
q tb V k q t k k v t
v t
van der Zwaag et al., (2009) & Uludag et al., (2009)
BOLD Signal Model 1 0
12k E
20k
31k
7T MRI
Scanner
1
0
0
0
, 1 1 11
f t
EE f E g
g
00.49g g
Vazquez et al., JCBM (2009)
10
0
,dq t E f Ef t v t q t
dt E
11dv t
f t v tdt
Windkessels Theory
4
f t r t Generalized Poiseuille's Equation
2sNO NO PGE PGE EET EET HETE HETE d
dr tn n n n r t
dt
Phasic Response
Stephenson et al., (1994); Golanov et al., (1994);
Alkayed et al., (1995); Ma et al., (1996); Lindauer et al., (1996);
Alonso-Galicia et al., (1997); Sun et al., (2000);
Niwa et al., (2001); Bakalova et al., (2002); Peng et al., (2002);
Xu et al., (2003); Takano et al., (2006); Stefanovic et al., (2007);
Hoffmeyer et al., (2007); Leithner et al., (2009)
34%sPGE
34%
EET
19%HETE
13%NO
2
2 2 2
2
1 0 0 2
PGE
PGE PGE COX PGT in PGE COX
dn tn t Ca t C L t L n t E t
dt
2
0
EET
EET EET
dn tn t Ca t C
dt P2C
2
0
NOHETE n t
HETE HETE
dn tn t Ca t C e
dt
P4A
2
2
NO O f
NO NO NO NO O NO E I
dn tn t n t n t n f t E t I t
dt
2 2 2 2
2 2 2 0,
O O O O
O O pp E E O
dn tn t l t E t I t E f E
dt
2
2
0 0in in in
in G NO f
L L L NO L PGT in PGE
E I pp
TCA TCA TCA
dL tn t Ca t C n t f t L t L n t
dt
E t I t l t
Dynamic Model Metabolites Astrocytes
Blinder et al. Nature, 2013
Communities Resistances
Vascular-steal/leakage effect
CBF CBV
CBF CBV CBF CBV
NA
O2
Pa
PIC = PCV
CW1 RW1
Ra1(t)
CW2 RW2
Ra2
Rv Rv R12
Windkessel Model Parallel Compartment
Rak (t0)+ RWk0
+ Rv = 1
0.60 % 0.30 % 0.10 %
bA
-β1
kk
V V WkC
0
k
kk
V
VV RR W0Wk
bwo0RF
0V A
- Laminar Flow b - Diminished Volume Reserve P
0 2 4 6 8 10 12 14 16 18 200.985
0.99
0.995
1
1.005
1.01
1.015
Time (Sec)
[Hb
r]
2 4 6 8 10 12 14 16 18 20
1
1.05
1.1
2 4 6 8 10 12 14 16 18
0.994
0.996
0.998
1
Time (Sec)
CB
F
0 2 4 6 8 10 12 14 16 18 200.9
1
1.1
0 2 4 6 8 10 12 14 16 18 200.995
1
1.005
1.01
1.015
Time (Sec)
CB
V
0 2 4 6 8 10 12 14 16 18 20-0.03
-0.02
-0.01
0
0.01
0.02
0.03
Time (Sec)
BO
LD
PBR
NBR
R12 =[.1, .45, .8, 1.15, 1.5]
Physiology of the neurovascular coupling Biophysical models for vascular dynamics
Particulars for Epilepsy and Dementia (AD)
Topics for this talks
L R
A
P D V
A
B
C
D
R L
2.08 mm
Song et al. OHBM Poster 2264
32 Channel EEG
Mini-Cap
MRI based template
Sharp-Wave
Spikes
EEG Waveforms Topography Tomography
EEG Source Analysis
Bae et al. OHBM Poster 2198
Magnetic Resonance Research
Center
Yale University
sL
OR
ETA
(Co
rtica
l)
EE
G-T
rigg
ere
d B
OL
D
BOLD Effect
vs.
Current Source Imaging
Yinchen Song, PhD Candidate
1 2
Electrophysiological Recording
Laser Doppler Flowmetry
System
for R
eco
rdin
g In
trinsic O
ptical Sign
als
A B
Electrocorticography (ECoG)
Pediatric Focal Epilepsy
500 nm 700 nm
Intrinsic Optical Imaging
Low-Frequency Oscillations
Out-of-phase
Rat FCD
WT APP-Tg
Mouse strain C57BL/6J C57BL/6J
Genotype WT BE-APP65Sw/Lo
Phenotype normal Promotion of Ab deposition Increase in senile plaque Being prone to dementia
Early: 6-10 months
Middle: 11-20 months
Late: 21-28 months
GROUPS
Animal Model
Riera et al., J Biophysics, 2011
Pike et al., Exp. Neurol., (1995)
Gliosis in Alzheimer’s Disease
Astrocytes surround the area of
diffuse amyloid accumulation with
long processes
Primitive “Classic” Plaques
- Increases in relation to neurite
dystrophy (Mrak et al., J Neuropathol
Exp Neurol., 1996)
- Contributes to the immunological
cascade, e.g., by initiating an
inflammation with increased IL-6 release
(Huell et al., Acta Neuropathol, 1995;
Wood et al., Brain Res., 1993)
Advanced Stage Plaques
Takano et al., Ann. N.Y. Acad. Sci., (2007)
Age: 2-4 months
fluo-4 AM
Sulforhodamine 101
Fluorescent Indicators
Triple transgenic (3XTg-AD)
Dutch/Iowa mutation (DI)
APP Sweden Tg-2576 (APP)
Mouse Stream
Kuchibhotla et al., Science, (2009)
• Mutant human Ab precursor
protein (APP)
• Mutant presenilin 1 (PS1) in
neurons
(APPswe:PS1ΔE9)
Mouse Stream
Age: 6-8 months OGB-1 AM + (FLIM)
methoxy-XO4 (Ab)
Sulforhodamine 101
Fluorescent Indicators
Dysfunctions in Alzheimer disease
Riera et al. Biophysical Journal, 2011
De
ns
ity o
f C
on
ne
cti
on
s
WT APP-Tg
Str
en
gth
o
f c
on
ne
cti
on
s
0.025
0.020
0.015
0.010
0.005
0 APP-Tg WT
mean±SD
Astrocytic connections: density (WT<APP) and strength (WT=APP)
Percentage of active cells with age: increase (WT) and reduce (APP)
High frequency: > 6 transients / 10 min
WT APP-Tg
Pe
rce
nta
ge
of
ce
lls
Wit
h h
igh
fre
qu
en
cy (
%)
Perc
enta
ge o
f active c
ells
(%
) mean±SD
APP-Tg
WT
Early Middle Late
Hippocampus L
ate
Ag
e
1.0
0.8
0.6
0.4
0.2
0.0
Probability Map
(White Noise)
WT APP
Long-term neuronal activity deprivation decreased Aβ plaque formation/growth
Bero et al., Nat Neurosci (2011)
Sustained Metabolic Activation in the
brain’s default-mode networks
Early Middle Late
age
Ca
2+
activity
APP
WT Reactivity Dysfunction
Functionality of astrocytes is very
compromised in AD Development
Plasticity
A severely impairment of the cerebral autoregulation in AD
Claassen & Zhang, Cereb Blood Flow Metab (2011)
Model
“Neurons”
Vasculature
LFP/Unit-Activity
EEG/MEG
Large-Scale
Small-Scale
fMRI-BOLD
Large-Scale
Astrocytes
Vasomotions
Neuronal
Modulation
Thanks