Detecting activity-evoked pH changes in human brain
Vincent A. Magnottaa,b,1, Hye-Young Heoa, Brian J. Dlouhyc, Nader S. Dahdalehc, Robin L. Follmerb, Daniel R. Thedensa,
Michael J. Welshc,d,e,f,g,h,1, and John A. Wemmieb,c,e,f,h,i,1
Departments ofaRadiology,bPsychiatry,cNeurosurgery,dInternal Medicine, andeMolecular Physiology and Biophysics,fInterdisciplinary Graduate Program
in Neuroscience,gHoward Hughes Medical Institute, andhRoy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
andiDepartment of Veterans Affairs Medical Center, Iowa City, IA 52242
Contributed by Michael J. Welsh, April 10, 2012 (sent for review February 28, 2012)
Localized pH changes have been suggested to occur in the brain
during normal function. However, the existence of such pH
changes has also been questioned. Lack of methods for non-
invasively measuring pH with high spatial and temporal resolution
has limited insight into this issue. Here we report that a magnetic
resonance imaging (MRI) strategy, T1relaxation in the rotating
frame (T1ρ), is sufficiently sensitive to detect widespread pH
changes in the mouse and human brain evoked by systemically
manipulating carbon dioxide or bicarbonate. Moreover, T1ρ de-
tected a localized acidosis in the human visual cortex induced by
a flashing checkerboard. Lactate measurements and pH-sensitive
31P spectroscopy at the same site also identified a localized acido-
sis. Consistent with the established role for pH in blood flow re-
cruitment, T1ρ correlated with blood oxygenation level-dependent
contrast commonly used in functional MRI. However, T1ρ was not
directly sensitive to blood oxygen content. These observations in-
dicate that localized pH fluctuations occur in the human brain
during normal function. Furthermore, they suggest a unique func-
tional imaging strategy based on pH that is independent of tradi-
tional functional MRI contrast mechanisms.
brain pH|functional magnetic resonance imaging|T1rho
localized pH changes via several mechanisms. Increased neuronal
activity enhances carbohydrate metabolism producing the pH-
lowering by-products lactic acid and CO2 (2). Activity-evoked
HCO3−transport can alter pH (3). Local field potentials produced
by ion fluxes could change pH (4). In addition, acidic synaptic
vesicles release protons during neurotransmission (5). Such dy-
namic pH fluctuations have the potential to dramatically alter
physiology and behavior through a number of pH-sensitive recep-
tors and channels (6). Acid-sensing ion channels, for example, play
critical roles in synaptic plasticity, learning, memory, pain, and
neurodegeneration (7–10). Superimposed on activity-dependent
buffering systems. Principal among these is the CO2/HCO3−sys-
tem. In a reversible reaction, CO2combines with water to form
carbonic acid, which readily dissociates into HCO3−and H+.
Raising HCO3−shifts the equilibrium away from H+and increases
pH. Conversely, raising CO2shifts the equilibrium toward H+,
thereby lowering pH. The ability to measure these pH changes in
the functioning brain is key for gaining insight into this poorly
understood dimension of CNS physiology and pathophysiology.
Routinely measuring pH in the brain would require novel
noninvasive methods. Traditionally,31P spectroscopy has been
used to estimate brain pH (11); however,31P is limited by poor
spatial resolution (typically 10- to 30-cm3volumes), long acqui-
sition times (often 5–10 min for a single measurement), and the
need for special hardware not typically available on clinical
scanners. Recently,1H MRI pulse sequences have been shown to
detect H+exchange between water and proteins and thus can be
highly pH sensitive. These techniques include amide proton
transfer (APT) and T1in the rotating frame (T1ρ) (12–15). APT
detects H+exchange by taking advantage of differences in res-
onances between amide and water protons. The spin-lock
o what degree pH changes during normal brain function is
unclear (1). However, neuronal activity could cause transient,
preparation pulse used in T1ρ imaging sensitizes the magnetic
resonance (MR) signal to relaxation effects arising from H+
exchange between free water protons and those bound to pro-
teins and macromolecules. Here, we focused on T1ρ because of
its pH sensitivity, high spatial and temporal resolution, and po-
tential to detect dynamic pH changes during brain function.
Validation of pH Sensitivity in Buffered Phantoms. To evaluate T1ρ
sensitivity to pH in the physiological range, we first studied
phantoms [3.5% agar (wt/vol)], 8% BSA (wt/vol), 0.1 M phos-
phate buffered saline pH-adjusted with HCl and NaOH to values
ranging from pH 6.0 to pH 8.0 (Fig. 1A). They were imaged by
using a fast spin-echo sequence with a spin-locking preparation
pulse, which created a B1field of 1,000 Hz, and four spin-lock
times (10, 20, 40, and 60 ms). T1ρ times were inversely pro-
portional to the measured pH (R2= 0.98) (Fig. 1A), suggesting
that T1ρ is sensitive to pH in the physiological range.
T1ρ Insensitivity to Oxyhemoglobin Content. Because current blood
oxygenation level-dependent (BOLD) imaging relies on T2*
contrast to detect changes in blood oxyhemoglobin content,
we compared the specificity of T1ρ and T2* for pH and oxygen
content in fresh sheep blood. Blood pH and O2content were
varied in three test conditions: (i) unaltered, (ii) acidified (25
mM HCl), and (iii) oxygenated with 100% O2. Data from a sin-
gle axial slice were collected by using a T1ρ fast spin-echo se-
quence and T2*-weighted gradient-echo sequence. We found
that T1ρ was sensitive to pH, but not O2 content (Fig. 1B).
Conversely, T2* was sensitive to O2content, but not pH (Fig.
1C). These data suggest that T1ρ changes are unlikely due to
changes in oxyhemoglobin content.
pH Detection in Mouse Brain. To assess pH sensitivity of T1ρ
in vivo, measurements were simultaneously obtained with T1ρ
and a custom-made MRI-compatible pH sensor (pHOptica;
World Precision Instruments; detection range pH 5–9) implan-
ted into the amygdala of mice. Data were collected from anes-
thetized mice under three conditions: (i) room air inhalation,
(ii) 20% CO2inhalation, and (iii) following HCO3−injection (5
mmol/kg, i.p.). Fig. 2A shows examples of T1ρ maps obtained
from a single mouse brain. Direct pH measurements varied from
animal to animal, most likely due to differences in respiratory
suppression from anesthesia. In all cases, CO2inhalation low-
ered pH relative to air and prolonged T1ρ times throughout the
brain, including at the pH-sensing probe tip. HCO3−injection
produced the opposite effect, raising pH and shortening T1ρ
times. Fig. 2B shows the relationship between T1ρ at the sensor
Author contributions: V.A.M., D.R.T., M.J.W., and J.A.W. designed research; V.A.M., H.-Y.H.,
B.J.D., N.S.D., R.L.F., and J.A.W. performed research; V.A.M., H.-Y.H., B.J.D., N.S.D., and
J.A.W. contributed new reagents/analytic tools; V.A.M., H.-Y.H., and J.A.W. analyzed
data; and V.A.M., B.J.D., N.S.D., R.L.F., M.J.W., and J.A.W. wrote the paper.
The authors declare no conflict of interest.
Freely available online through the PNAS open access option.
1To whom correspondence may be addressed. E-mail: email@example.com,
firstname.lastname@example.org, or email@example.com.
| May 22, 2012
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tip and pH measured from the sensor across all mice and con-
ditions (R2= 0.77).
Systemic pH Changes in Human Brain Induced by CO2and Hyper-
ventilation. Qualitatively similar T1ρ responses were observed in
the human brain when pH was manipulated through breathing.
A research participant was imaged on a Siemens 3T scanner
under three conditions: (i) normal breathing of room air, (ii)
breathing 5% CO2, and (iii) paced hyperventilation of room air
(27 breaths per minute). These manipulations changed average
end-tidal CO2(EtCO2) measurements from 4.3% to 7.7% CO2
(Fig. 3B). Consistent with hypercarbic acidosis, CO2inhalation
produced a widespread increase in T1ρ relaxation time (Fig. 3 A
and B). Paced hyperventilation produced the opposite effect,
and consistent with a respiratory alkalosis reduced T1ρ times
(Fig. 3 A and B). Fig. 3C shows the subtracted T1ρ maps between
hyperventilation and room air, and between 5% CO2and room
air, suggesting that these systemic manipulations change pH
throughout the brain.
Localized pH Changes Induced by Flashing Checkerboard. With the
above data suggesting that T1ρ is sensitive to brain pH, we hy-
pothesized that T1ρ might detect localized pH changes evoked by
brain activation. To test this hypothesis, we used a visual flashing
checkerboard task (Fig. 4A). Six participants were presented with
a visual flashing checkerboard (22 × 22 squares) alternating at 8
Hz in a block design (Fig. 4A) (16). For comparison, two runs of
BOLD were interleaved with three runs of T1ρ. Fig. 4B shows the
group activation maps for the T1ρ and BOLD imaging overlaid
on the average T1-weighted anatomical image. Voxels exhibiting
significant activation (P < 0.05, corrected) are shown. The
flashing checkerboard significantly increased T1ρ times in the
occipital cortex. A similar activation region was measured by
functional MRI (fMRI) BOLD. Consistent with the observation
that T1ρ and BOLD detect mutually independent phenomena,
a difference was observed between the size of the T1ρ- and
BOLD-responsive areas. The reason for this apparent difference
is not clear. It is possible that T1ρ detects more focal changes
than BOLD, given that the vascular tree underlying the hemo-
dynamic response is larger than regions of neural activity. For
example, venous drainage of brain areas can extend the BOLD
signal tens of millimeters from the activation site (17). The well-
established effect of acidic pH on blood flow (18) suggests lo-
calized acidosis might even help drive the BOLD response.
Because lactic acid is one potential source of localized pH
change, we measured lactate by1H MR spectroscopy (MRS) in
a voxel positioned at the BOLD site. Consistent with a previous
report (19), we found that the flashing checkerboard significantly
agar phantoms with pH adjusted to different levels (6.0–8.0). The relation-
ship between T1ρ times and pH was linear within this range. The estimated
T1times were calculated within a central 5 × 5 region. (B) T1ρ maps in sheep
blood phantoms (Upper) with corresponding mean and SD in a central 5 × 5
region of interest plotted in Lower. The sheep blood phantoms are arranged
from left to right as follows: unaltered (control), acidified, and hyperoxygen-
ated. (C) Corresponding T2* maps in same sheep blood phantoms (Upper)
with mean and SD in a central 5 × 5 region of interest plotted in Lower.
T1ρ and T2* sensitivity to pH and pO2manipulations. (A) T1ρ maps for
CO2inhalation or i.p. HCO3−injection. (A) T1ρ maps from a mouse brain after
given bicarbonate (Left), exposed to room air (Center), and exposed to 10%
CO2(Right). The position of the fiber-optic pH sensor is shown by the white
arrow, and the open square indicates the location of the ROI used for esti-
mating the T1ρ times. (B) The relationship between the mean T1ρ times and
the corresponding direct pH measurements obtained from the fiber-optic
sensor across four mice. Each mouse is represented by a different symbol.
T1ρ detects pH changes in the anesthetized mouse brain evoked by Fig. 3.
EtCO2manipulation. (A) T1ρ maps of the human brain varied with EtCO2
concentration during hyperventilation, breathing room air, and 5% CO2
challenge. The open box identifies a 7 × 7 region of interest in white matter
where T1ρ time estimates were obtained. (B) The estimated T1ρ times in
white matter varied with measured EtCO2concentrations (module CO2100C;
Biopac). (C) T1ρ subtraction images between the hyperventilation and air
conditions (Left) and 5% CO2and air condition (Right).
T1ρ measurements throughout the human brain are responsive to
Magnotta et al.PNAS
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increased the lactate-to-creatine ratio (Fig. 4C). If the T1ρ and
lactate responses indeed reflect a localized acidosis, we hypoth-
esized that we should be able to detect the pH change with an
measure of pH, and used the T1ρ data to guide voxel positioning.
In six additional subjects, the flashing checkerboard altered visual
cortex31P estimates of pH (Fig. 4D). Like T1ρ, these changes
indicate a transient, activity-dependent localized acidosis.
These results indicate that neuronal activity can change local pH
in the human brain during normal function. Neuronal activation
may lower pH through a variety of processes (20) acting individ-
ually or together to produce the acidosis observed here; further
study will be required to identify the mechanisms underlying this
pH change. Because monocarboxylate transporters cotransport
protons with lactate (21), our studies suggest that lactate pro-
duction and transport might contribute to the localized acidosis.
The localized acidosis observed here might have a number of
consequences for brain physiology and pathophysiology (6, 8).
The reduced pH could activate some ion channels and receptors
and inhibit others, thereby influencing brain function and be-
havior (5, 7, 8, 22). A reduced pH has also been implicated in
ischemic stroke, neurodegenerative disease, seizures, and re-
spiratory control (9, 10, 23–27). Interestingly, in patients with
panic disorder, lactate induction by the flashing checkerboard
was abnormally elevated (19). Others have also suggested lactate
and pH-buffering abnormalities in panic disorder (28). These
observations coupled with our findings support the possibility
that abnormal pH dynamics may contribute to panic disorder (2).
Additional advances in our knowledge of brain pH dynamics
might come from the improved spatial and temporal resolution
provided by T1ρ. The T1ρ sequence used here has an isotropic
spatial resolution of ∼4 mm and temporal resolution of 6 s,
whereas the spatial and temporal resolutions of31P spectroscopy
are 30 mm and several minutes, respectively. Further improve-
ments in the T1ρ scan time may be possible by acquiring only
two spin-lock times and by using parallel imaging. Comparable
temporal and spatial resolution might also be possible with APT
in an echo-planar sequence if only two frequency-offset pulses
were applied about the center imaging frequency.
One limitation of both T1ρ and APT is that they depend on
H+exchange with proteins and amide groups. Thus, either T1ρ
or APT could be affected by appreciable changes in local protein
concentration as well as pH. The observation that T1ρ correlated
closely with direct pH measurements in the mouse brain and with
secondary pH imaging methods in human brain argues that the
T1ρ changes observed here were due at least in part to pH.
In addition to improving the ability to measure brain pH, this
study has unique implications for functional imaging in general.
Because T1ρ showed a linear response to pH, T1ρ may be more
quantifiable than BOLD fMRI, which is not quantifiable other
than percent change and does not address baseline conditions.
In addition, the spatial resolutions of BOLD fMRI and
water positron emission tomography depend on blood flow and
oxyhemoglobin content and are thus limited by the vascular
anatomy. Although T1ρ provided a similar pattern of activation
as BOLD, T1ρ changes were independent of blood oxygenation.
Thus, by measuring functional pH changes, T1ρ MRI might
provide a means for more precisely localizing brain activity.
Sheep Blood Phantom Imaging. All animal care met National Institutes of
Health standards, and the University of Iowa Animal Care andUse Committee
approved all procedures. T1ρ data were collected by using a fast spin-echo
sequence with four spin-lock times (10, 20, 40, and 60 ms) and B1= 400 Hz.
T2*-weighted imaging, which is sensitive to blood oxygenation, was
obtained from a single axial slice by using a gradient-echo sequence with
eight echo-times (1.7, 2, 3, 6, 9, 12, 14, and 16 ms). pH, pO2, and pCO2levels
in the phantoms were confirmed with a blood gas analyzer before and after
imaging (Radiometer ABL 5).
Mouse Brain pH Measurements. pH sensors (pHOptica) were custom-clad in
MRI-compatible PEEK tubing (PlasticsOne) and assembled by World Precision
Instruments and PreSens Inc. Sensors were implanted into the amygdala as
described (7). Twenty-four hours postimplantation, mice were anesthetized
with ketamine/xylazine and imaged on a Varian 4.7-T scanner. CO2(10%
BOLD, and MRS studies. For the T1ρ/BOLD studies, three runs of the T1ρ block sequence where interleaved with two runs of BOLD. (B) T1ρ and BOLD functional
activation maps (P < 0.05, corrected) resulting from the visual flashing checkerboard stimulus. Four contiguous slices are shown. (C) Lactate to total creatine
ratio increased significantly during visual stimulation relative to both baseline and the poststimulus recovery phase. *P < 0.05, paired t test. (D)31P spec-
troscopy estimates of pH in the visual cortex were significantly reduced during flashing checkerboard presentation relative to both baseline and recovery.
*P < 0.05, paired t test.
Flashing checkerboard alters T1ρ, BOLD, lactate, and31P measurements in the visual cortex. (A) Flashing checkerboard paradigms for functional T1ρ,
| www.pnas.org/cgi/doi/10.1073/pnas.1205902109Magnotta et al.
and/or 20%) was administered by nasal cannula to lower brain pH as de- Download full-text
scribed (7), and NaHCO3(5 mmol/kg, i.p.) was administered to raise pH as
described (7, 29). T1ρ images were collected by using a fast spin-echo se-
quence [time to echo (TE) = 12 ms, time to repetition (TR) = 2,000 ms, field of
view (FOV) = 30 × 30 mm, imaging matrix size = 256 × 128, slice thickness = 1
mm] with spin-lock durations of 10, 20, 40, and 60 ms and B1= 1,000 Hz. T1ρ
maps were generated for each condition, and a 5 × 5 region of interest was
placed at the tip of the fiber-optic probe to study the relationship between
T1ρ times and pH measured via the fiber optic sensor.
Functional Brain Imaging (BOLD, T1ρ, and1H MRS). All human research pro-
tocols were approved by the University of Iowa Institutional Review Board.
Multimodal functional imaging was performed on six subjects (four males
and two females, age 28–35 y). Functional T1ρ images were collected by using
an echo-planar spin-echo sequence (TE = 12 ms, TR = 2,200 ms, FOV = 220 ×
220 mm, matrix size = 64 × 64, and slice thickness/gap = 4/1.0 mm) with three
spin-lock pulses (10, 30, and 50 ms) and a B1frequency of 400 Hz. This se-
quence had a temporal resolution of 6.6 s per T1ρ measurement. BOLD im-
aging was performed by using a T2* weighted echo-planar gradient-echo
sequence (TE = 30 ms, TR = 2,000 ms, FOV = 220 × 220 mm, matrix size = 64 ×
64, and slice thickness/gap = 4.0/1.0 mm). For BOLD imaging, seven cycles of
flashing checkerboard and visual fixation were presented with an 80-s pe-
riod. For functional T1ρ imaging, five cycles were collected with a 72-s pe-
riod. The1H MRS data were acquired by using a single-voxel point-resolved
spin-echo sequence with water suppression. For functional1H spectroscopic
imaging, the task began in the baseline task followed by the visual activa-
tion condition and returning to the baseline condition. For all activation
studies, attention was ensured by asking subjects to press a button in re-
sponse to a red square presented in the center of the screen every 4 s.
All BOLD fMRI data were analyzed by using standard preprocessing steps,
including motion correction, slice timing correction, and spatial smoothing. A
general linear model was used to generate individual statistical maps and
calculate signal change. T1ρ data were preprocessed by first performing
motion correction followed by T1ρ map generation. T1ρ data were spatially
smoothed, statistical maps were generated by using a general linear model,
and estimates of T1ρ time changes were computed. BOLD percent signal
change and T1ρ time changes were mapped to MNI space where a t test was
performed across the subjects and corrected for multiple comparisons by
using a false discovery rate analysis.
were frequency and phase corrected and averaged, and the resulting spec-
tral data were analyzed by using LCModel. Ratios of Lactate/Cr and Lac/NAA
were obtained and compared between (i) baseline, (ii) activation, and (iii)
recovery periods using ANOVA.
1H spectroscopic measurements obtained for each condition
31P Spectroscopic Functional Measures. Functional data were acquired in six
subjects (male/female = 4/2; ages = 22–33 y). A 2D31P spectroscopic sequence
used a free induction decay acquisition (TE = 2.3 ms, TR = 4,000 ms, FOV =
240 × 240 mm, matrix = 8 × 8, thickness = 30 mm, averages = 16, vector size =
1,024). This acquisition was repeated three times (baseline, activation,
baseline) with each measurement taking 10 min 24 s.31P data were analyzed
by using the Siemens Syngo software to determine the chemical shift of the
inorganic phosphate (Pi) and phosphocreatine (PCr) peaks in the31P spectra.
The analysis included frequency filtering, frequency and phase correction,
baseline correction, and curve fitting with prior knowledge. Brain pH was
estimated by using the proposed equation (30):
pH ¼ 6:77 þ logfðδ−3:29Þ=ð5:68−δÞg;
where δ is the chemical shift between in ppm between Pi and PCr. The pH
estimates for the baseline, activated, and recovery phases were compared by
ACKNOWLEDGMENTS. This work was supported by grants from the
McKnight Foundation and the Dana Foundation and by a University of
Iowa Clinical and Translational Science Award (to V.A.M. and J.A.W.). M.J.W.
is an Investigator of the Howard Hughes Medical Institute.
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