r Human Brain Mapping 000:00–00 (2011) r

Functional and Structural Correlates of the Aging

Brain: Relating Visual Cortex (V1) Gamma Band
Responses to Age-related Structural Change

William Gaetz,1* Timothy P.L. Roberts,1 Krish D. Singh,2

and Suresh D. Muthukumaraswamy2
1
Lurie Family Foundations MEG Imaging Center, Department of Radiology, Children’s Hospital of
Philadelphia, Philadelphia, Pennsylvania
2
CUBRIC, School of Psychology, Cardiff University, Cardiff, United Kingdom

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Abstract: The gamma band response is thought to be a key neural signature of information processing
in the mammalian brain, yet little is known about how age-related maturation influences the c-band
response. Recent MRI-based studies have shown that brain maturation is accompanied by clear struc-
tural changes in both gray and white matter, yet the correspondence of these changes to brain function
is unclear. The objective of this study was to relate visual cortex (V1) c-band responses to age-related
structural change. We evaluated MEG measured c-band responses to contrast gratings stimuli and
structural MRIs from participants observed from two separate research centers (MEG lab at CUBRIC,
Cardiff University, UK, and the Lurie Family Foundations MEG Imaging Center, (CHOP) at the Child-
ren’s Hospital of Philadelphia). Pooled participant data (N ¼ 59) ranged in age from 8.7 to 45.3 years.
We assessed linear associations between age and MEG c-band frequency and amplitude, as well as
between age and MRI volumetric parameters of the occipital lobe. Our MEG findings revealed a signif-
icant negative correlation for gamma band frequency versus age. Volumetric brain analysis from the
occipital lobe also revealed significant negative correlations between age and the cortical thickness of
pericalcarine and cuneus areas. Our functional MEG and structural MRI findings shows regionally spe-
cific changes due to maturation and may thus be informative for understanding physiological proc-
esses of neural development, maturation, and age-related decline. In addition, this study represents (to
our knowledge), the first published demonstration of multicenter data sharing across MEG centers.
Hum Brain Mapp 00:000–000, 2011. VC 2011 Wiley-Liss, Inc.

Key words: gamma band; development; MEG; magnetoencephalography; visual contrast gratings

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Additional Supporting Information may be found in the online Received for publication 6 July 2010; Revised 6 April 2011;
version of this article. Accepted 8 April 2011
Contract grant sponsors (CHOP): NIH; Contract grant numbers: DOI: 10.1002/hbm.21339
R01DC008871, R01DC008871-02S1; Nancy Lurie Marks Family Published online in Wiley Online Library (wileyonlinelibrary.
Foundation, the Jeffrey and Christina Lurie Family Foundation, com).
Autism Speaks; the Pennsylvania Department of Health
Contract grant sponsors (CUBRIC): School of Psychology at Car-
diff University, Wales Institute of Cognitive Neuroscience.
*Correspondence to: William Gaetz, Department of Radiology,
Children’s Hospital of Philadelphia, 34th St. And Civic Center Bou-
levard, Philadelphia, PA 19104. E-mail: gaetzw@e-mail.chop.edu

C 2011 Wiley-Liss, Inc.

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INTRODUCTION
A growing body of research suggests that the c-band
(
40 Hz) response is a key neural signature of information
processing in the mammalian brain. Invasive and noninva-
sive imaging studies have shown primary cortical c-band
reactivity to auditory [Gurtubay et al., 2004; Steinschneider
et al., 2008], visual [Adjamian et al., 2004; Hoogenboom
et al., 2006; Muthukumaraswamy et al., 2009; Muthukumar-
aswamy and Singh, 2008], somatosensory [Bauer et al., 2006;
Gaetz and Cheyne, 2003], and motor tasks [Cheyne et al.,
2008; Gaetz et al., 2010]. Gamma-band responses have also
been associated with higher-order cognitive functions such
as attention [Fell et al., 2003; Muller et al., 2000], perception
[Keil et al., 1999; Tallon-Baudry et al., 1996, 1997), learning
[Gruber et al., 2001; Miltner et al., 1999] memory [Lutzen-
berger et al., 2002; Tallon-Baudry et al., 1998] and are dis-
turbed in psychiatric disorders such as schizophrenia and
autism [Lewis et al., 2005; Spencer et al., 2003; Uhlhaas and
Mishara, 2007]. Gamma oscillations have also been pro-
posed as a fundamental mechanism for cortical computa-
tion and long-range communication between brain areas
[Fries, 2009; Gregoriou et al., 2009].
Despite the importance of c-band cortical oscillations,
identifying an effective stimulus to elicit a strong, artifact-
free and reliable c-band response has been challenging
[Fries et al., 2008]. Recently, however, simple high-contrast
visual stimuli have gained prominence as a robust method
to elicit cortical c-band activity in primate electrocortico-
graphic (ECoG) studies [Vinck et al., 2010] and noninva-
sively using MEG [Adjamian et al., 2004; Hoogenboom
et al., 2006; Muthukumaraswamy et al., 2009, 2010] in
humans. In human MEG studies, vertical or concentric
circle high-contrast square-wave grating stimuli (
3 cycles
per degree) are presented to central vision, or a single hemi-
field. These stimuli induce a robust c-band response from
primary visual cortex (V1) that persists for the duration of
the presented visual stimulus. These c-band responses
show high between-subject variability in amplitude and fre-
quency, however, within-subject repeated measures appear
remarkably consistent [Hoogenboom et al., 2006; Muthuku-
maraswamy et al., 2010]. Similar between-subject variability
has been noted in ECoG [Rols et al., 2001] and LFP record-
ings [Lima et al., 2010]. Muthukumaraswamy et al. [2009]
recently demonstrated that c-band frequency was corre-
lated with magnetic resonance spectroscopic (MRS) meas-
ures of c-amino-butyric acid (GABA) concentration. In a
study exploring repeatability of gamma cortical oscillations,
the same authors observed that c-band frequency tended to
decrease with age in a healthy adult population [Muthuku-
maraswamy et al., 2010].
MRI imaging studies have described clear changes in
cortical and subcortical brain structures which accompany
normal aging. For example, in a recent study involving 148
healthy adults from three age groups (mean age: 28, 44, and
63 years), Salat et al. [2009] reported considerable regional
changes in neural tissue properties with aging such as
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decreased MR signal intensity from both gray and white
matter and decreased cortical thickness [Salat et al., 2009].
To quantify within-subject changes in brain structure over
time, Raz et al. [2010] investigated brain region of interest
(ROI) volume changes in a population of middle-aged and
older adults on three repeated MRI measures taken over a
30-month period [Raz et al., 2010]. The authors noted that
in healthy individuals, brain volume is known to shrink sig-
nificantly over relatively short time-periods, and with
marked individual variability in the rates of decline [Raz
et al., 2010]. Interestingly, these studies show that age-
related decreases in cortical thickness appear to affect some
cortical areas more than others. For example, Raz et al.
[2010] reported that the greatest mean 30-month change
was observed in the hippocampus, whereas the pons did
not change significantly over this time. Salat et al. [2009]
reported that cortical thickness decreased most significantly
with age in the superior frontal, precentral, postcentral,
superior temporal, and occipital regions and increased with
age in the medial frontal regions. Currently, the mecha-
nisms that contribute to the changes in tissue properties
and the functional and behavioral correlates of age-related
structural change remain unclear.
The purpose of this study was to examine MEG c-band
responses and MRI measures of cortical thickness and vol-
ume in a population of participants over a broader age-
range (from 8 to 46 years) and to directly assess the influ-
ence of the participant’s age on these functional and struc-
tural brain measures. Currently, there are no studies
comparing visual c-band response over the life-span, par-
ticularly in children. However, previous findings from
adults [Muthukumaraswamy et al., 2010] predict that vis-
ual c-band frequency will be inversely related to partici-
pant’s age. A subsidiary purpose, and notable feature of
this article, is that it represents the accumulated efforts of
two MEG laboratories (CUBRIC and CHOP) with data
pooled across international sites. Although multicenter
studies are becomingly increasingly common in large
structural and functional MRI studies, this study repre-
sents (to our knowledge) the first demonstration of multi-
center data sharing across MEG centers.
METHODS
This collaborative study involved the MEG lab at
CUBRIC, Cardiff University, UK, and the Lurie Family
Foundations MEG Imaging Center, at the Children’s Hos-
pital of Philadelphia, PA. Nearly identical data collection
methods, visual stimuli, and analysis methods were used,
with analysis and results across sites pooled (all differen-
ces are noted in Methods).
Participants
One significant challenge embedded in life-span studies
is to disentangle morphological and functional developmen-
tal change from the degenerative changes of late adulthood.
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 r Functional and Structural Correlates of the Aging Brain
Thus, by limiting inclusion of adults in our study up to 50
years (mid-adulthood), we have attempted to limit the influ-
ence of degenerative processes affecting the structural and
functional changes observed with normal aging.
Healthy adult (> 18 years) participants (CUBRIC; N ¼
33, CHOP; N ¼ 13) ranged in age from 18.4 to 45.3 years
(mean age ¼ 31.4 years). In addition healthy child partici-
pants (CHOP; N ¼ 13) ranged in age from 8.7 to 15.6
years. All procedures were approved by the local ethics
committee. Participants were fitted with three electromag-
netic head coils (nasion and preauriculars), which were
used for monitoring within-session head movement and
for subsequent coregistration with each participant’s MRI.
MEG Hardware
Both CHOP and CUBRIC MEG laboratories use the
CTF-Omega 275 channel radial gradiometer system (VSM
MedTech). Whole-head MEG recordings were sampled at
1,200 Hz (0–300 Hz band-pass). Three sensors were turned
off at CUBRIC due to excessive noise. Results from 31
adults participating at CUBRIC have been reported in a
previously published manuscript [Muthukumaraswamy
et al., 2010].
MEG Recording Methods
CUBRIC
MEG/MRI fiducial coregistration at CUBRIC was per-
formed by placing fiduciary markers at fixed distances
from anatomical landmarks identifiable in participants’ an-
atomical MRIs (tragus, eye center). Fiduciary locations
were verified afterwards using high-resolution digital
photographs.
Adult participants run at CHOP were volunteer
researchers with previously acquired brain MRIs. For these
participants, head surface and fiducial coil locations were
digitized using Polhemus (Fastrak; Polhemus, USA). Fidu-
cial coregistration was then based on in-house surface
matching software that aligned the head surface extracted
from each subject’s MRI with the Polhemus measured
head shapes. As age-related MRI/MEG analyses were
planned, we ensured that all participants MRI acquisitions
occurred within 1 year of the MEG recording date.
Pediatric participants at CHOP were enrolled in on-
going studies that included MRI structural scans recorded
directly following the MEG recordings. For these partici-
pants, MRI contrast markers were placed at MEG fiducial
coil locations, prior to the MRI recordings, and were used
for fiducial coregistration.
Visual stimuli
These consisted of vertical, stationary, maximum con-
trast, three cycles per degree, square-wave gratings pre-
sented on a mean luminance background. Stimuli were
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presented in the lower left visual field and subtended 4
both horizontally and vertically, with the upper right cor-
ner of the stimulus located 0.5 horizontally and vertically
from a small red fixation cross [Muthukumaraswamy
et al., 2009]. Participants were instructed to fixate and to
press a response key with the right index finger at the ter-
mination of each stimulation period (varying in duration
1.5–2 s). To ensure that that participant attended to each
trial, the response was required to occur within 700 ms for
the next stimulus to occur. Failure to do so resulted in a
prompt that the response was ‘‘too slow.’’ All stimulus
presentations were controlled by Presentation software
(Neurobehavioral Systems). At CUBRIC stimuli were
directly viewed on a Mitsubishi Diamond Pro 2070 moni-
tor, with a screen size of 1,024 by 768 pixels and a frame-
rate of 100 Hz. The monitor was outside the magnetically
shielded room and viewed directly from within, at 2.15 m,
through a cut-away portal in the shield. At CHOP stimuli
were presented through a back projection system via a
Sanyo Protrax multiverse projector with a screen size of
1,024 by 768 pixels and a frame rate of 60 Hz. A screen
mounted phototransistor was used to synchronize MEG
acquisition with actual time of delivery of visual stimuli,
avoiding latency jitter due to refresh rate.
A pilot study was also conducted to assess the effect of
background room luminance on our c-band measures. This
test showed no significant differences were observed when
running the visual contrast gratings experiment in low and
bright levels of room luminance. Nevertheless, any poten-
tial differences in background room luminance between
MEG laboratories were minimized by first ensuring that all
stimuli were presented in a dimly lit MSR (confirmed with
photographs). The results of the luminance pilot experi-
ment can be found in Supporting Information.
MRI Methods
CUBRIC MRI data were acquired on a 3-T General Elec-
tric HDx scanner using an eight-channel receive only head
RF coil (Medical Devices). A 3D Fast Spoiled Gradient
Recalled (FSPGR) scan was obtained in an oblique-axial
orientation, with maximum field of view ¼ 256  256 
192 and matrix ¼ 256  256  192 to yield 1 mm isotropic
voxel resolution. (TR/TE ¼ 7.9/3.0 ms; inversion time ¼
450 ms; flip angle ¼ 20 ).
CHOP MRI data were acquired on a 3-T Siemens Verio
(TM) scanner using a 32-channel receive only head RF
coil. For each participant we obtained a 3D Magnetization-
Prepared Rapid Acquisition Gradient-Echo (MP-RAGE)
scan in an axial orientation, with field of view ¼ 256 
256  192 and matrix ¼ 256  256  192 to yield 1 mm
isotropic voxel resolution (TR/TE ¼ 1,900/2.87 ms; inver-
sion time ¼ 1,100 ms; flip angle ¼ 9 ).
Cortical reconstruction and volumetric segmentation
was performed with the Freesurfer image analysis suite,
which is documented and freely available (http://surfer.-
nmr.mgh.harvard.edu/). The technical details of these
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procedures are described in prior publications [Dale et al.,
1999; Dale and Sereno, 1993; Fischl and Dale, 2000; Fischl
et al., 1999, 2004; Han et al., 2006; Segonne et al., 2004].
Briefly, this processing includes removal of nonbrain
tissue using a hybrid watershed/surface deformation pro-
cedure [Segonne et al., 2004], automated Talairach trans-
formation, segmentation of the subcortical white matter,
and deep gray matter volumetric structures (including
hippocampus, amygdala, caudate, putamen, ventricles)
[Fischl et al., 2002, 2004] intensity normalization [Sled
et al., 1998], tessellation of the gray matter white matter
boundary, automated topology correction [Fischl et al.,
2001; Segonne et al., 2007], and surface deformation fol-
lowing intensity gradients to optimally place the gray/
white and gray/cerebrospinal fluid borders at the location
where the greatest shift in intensity defines the transition
to the other tissue class [Dale et al., 1999; Dale and Sereno,
1993; Fischl and Dale, 2000]. Once the cortical model is
created, the cerebral cortex is parcellated into units based
on gyral and sulcal structure based on an existing atlas
[Desikan et al., 2006]. The method uses both intensity and
continuity information from the entire three-dimensional
MR volume in segmentation and deformation procedures
to produce representations of cortical thickness, calculated
as the closest distance from the gray/white boundary to
the gray/CSF boundary at each vertex on the tessellated
surface [Fischl and Dale, 2000]. The maps created use spa-
tial intensity gradients across tissue classes and are there-
fore not simply reliant on absolute signal intensity. The
maps produced are not restricted to the voxel resolution
of the original data thus are capable of detecting sub-
millimeter differences between groups. Procedures for the
measurement of cortical thickness have been validated
against histological analysis [Rosas et al., 2002] and man-
ual measurements [Kuperberg et al., 2003; Salat et al.,
2004]. Freesurfer morphometric procedures have been
demonstrated to show good test–retest reliability across
scanner manufacturers and across field strengths [Han
et al., 2006].
A large body of converging evidence exists from LFP
[Gray and Singer, 1989; Henrie and Shapley, 2005; Logo-
thetis et al., 2001] ECOG [Rols et al., 2001] and MEG stud-
ies [Hoogenboom et al., 2006; Muthukumaraswamy and
Singh, 2008] that the source of c-band activity in response
to simple visual stimuli is from V1/V2. To reduce the
number of statistical comparisons, we therefore restricted
our analysis of structural change to the relevant areas of
the occipital lobe in this atlas; lingual, cuneal, and perical-
carine areas. Gray matter cortical reconstructions in these
areas were assessed for three volumetric parameters
(volume, surface area, and cortical thickness).
SAM Source Localization
MEG sources were localized using the differential SAM
beamformer [Robinson and Vrba, 1999]. Visual c-band
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(30–80 Hz) activity was localized using a 0.0 to 1.5 s
(Active) and 1.5 to 0.0 s (Control) time windows
obtained using covariance matrices band-pass filtered
between 30 and 80 Hz. Peak locations of c-band activity
were observed consistently in right hemisphere primary
visual cortex. Each peak location was used to create source
waveforms for time-frequency analysis. The beamformer
weights vector for the peak location was explicitly com-
puted (covariance calculated from 2 to 2 s; 30–80 Hz)
and subsequently, the sensor data were projected through
these weights to obtain a time varying estimate of the ac-
tivity at the image peak location.
Time–Frequency Analysis
Time-frequency analysis assessed both induced and
evoked responses from source waveforms using the Hilbert
transform between 0 and 100 Hz at 0.5 Hz frequency step
intervals, and represented as a percentage change from
baseline values (1.5 to 0 s) for each frequency band. Peak
c-band frequency and amplitude measures (expressed in
units of percent change from baseline) were obtained. Pre-
vious analysis and pilot recordings have shown that the
c-band response from primary visual cortex exhibits both a
‘‘transient’’ component at stimulus onset (0 to
0.3 s) as
well as a ‘‘sustained’’ component that lasts for the duration
of the grating stimulus. From the time-frequency spectro-
grams, we therefore calculated c-band frequency and am-
plitude measures for the transient and sustained response
separately, A time window of 0 to 0.3 s was used to mea-
sure c-band transient frequency and amplitude, whereas
the sustained response was measured using a 0.5 to 1.5 s
analysis window. Reported c-band frequency and ampli-
tudes values were calculated by integrating 5 Hz around
the peak frequency observed in the average TFR for each
peak location and was reported separately for both tran-
sient (0 to 0.3 s) and sustained (0.5 to 1.5 s) c-band time
periods. Analysis of transient c-band responses was not
performed in previous similar work [Muthukumaraswamy
et al., 2010]. An analysis of unbaselined gamma values
(in nAm) can be found in Supporting Information.
The Pearson product–moment correlation coefficient was
used to assess linear associations between age and gamma
band frequency and amplitude, as well as between age
and volumetric parameters of the occipital lobe (noted
above) extracted using FreeSurfer. Linear regression analy-
ses were performed with SPSS (PASW Statistics v.18;
http://www.spss.com).
RESULTS
Source localized c-band differential SAM images are
shown for four representative participants ranging in age
from 8 to 46 years in Figure 1. Consistent with previous
reports using similar stimuli, c-band responses were
observed in individuals to be localized near to the
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Figure 1.
Source localized c-band differential SAM images are shown on amplitude c-band frequency for both the Transient (0 to 0.3 s)
the left for four representative participants of varying age. The Gamma frequency as well as Sustained (0.5 to 1.5 s) gamma
peak location for each source localisation image is indicated by frequency appears to decreases with increasing age. The red *
the green dot in each MRI image. Time–frequency plots from represents the reported peak frequency. [Color figure can be
peak locations and c-band amplitude plots are shown to the viewed in the online issue, which is available at
right. Intersubject variability in c-band amplitude is observed (as wileyonlinelibrary.com.]
reported previously [Muthukumaraswamy et al., 2009]). Peak

pericalcarine area [Adjamian et al., 2004; Brookes et al.,
2005; Hall et al., 2005; Hoogenboom et al., 2006; Muthuku-
maraswamy and Singh, 2008, Muthukumaraswamy et al.,
2010; Swettenham et al., 2009]. The extended area of
source power change observed in these visual cortex
responses is typical of power leakage from the SAM spa-
tial filter, with the amount of leakage dependant on the
SNR ratio, and the threshold applied (see Barnes and Hill-
ebrandt [2003] for more detailed discussion relating to sig-
nal leakage in beamformer images).
Given the heterogenous nature of our participant popu-
lation with respect to age we did not spatially normalize
and average response locations. Time–frequency plots
from early visual cortex peak locations show the character-
istic Transient (0 to 0.3 s) and Sustained responses (0.5 to
1.5 s) to the presented visual stimulus. Given the temporal
lag from stimulus onset, we interpret the Sustained
response as exhibiting primarily induced rhythmic activity
from visual cortex, whereas the Transient response analy-
sis window spans a time period that includes the visual
evoked-response to stimulus onset. Significant correlations
were observed between Transient and Sustained gamma
band Frequency (R2 ¼ 0.65; (P < 0.001) y(Transient) ¼
0.921  (Sustained) þ 10.108), and transient and sustained
gamma band amplitude (R2 ¼ 0.42; (P < 0.001) y(Tran-
sient) ¼ 1.067  (Sustained) þ 14.405).
Although each subject shows the transient and sustained
c-band response, considerable inter-subject variability in c-
band amplitude and frequency is observed [as reported pre-
viously by Muthukumaraswamy et al., 2009; Swettenham

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significant negative correlation was observed for Age vs.

Transient Response Peak Frequency (R2 ¼ 0.37, P < 0.001).
Similarly, a significant negative correlation was also
observed for Age vs. Sustained Gamma Peak Frequency
(R2 ¼ 0.46, P < 0.001) (See Fig. 2a,b). No significant Age
vs. Gamma Amplitude (Transient or Sustained) correlation
was observed. When just the CHOP data were analysed,
similar transient frequency correlations (R2 ¼ 0.73, P <
0.001) and sustained frequency correlations (R2 ¼ 0.58, P
< 0.001) were observed.
The mean peak frequency for the transient gamma was
58.62 Hz and for the sustained gamma was 52.65 Hz and
these were highly correlated (R2 ¼ 0.66, P < 0.001). The
mean change in transient gamma amplitude was 41.01%
and 24.93% for sustained and these were also correlated
(R2 ¼ 0.42, P < 0.001). Two sample paired t-tests of the
mean peak frequency between transient and sustained
gamma frequency was also significant (two tailed; t(58) ¼
8.45, P < 0.001).

Age Versus Structural MR Analysis

Linear regression analysis was conducted to assess the
relationship between participant’s age and MRI-based gray
matter analysis from FreeSurfer. Linear regression analysis
of MRI volumetric brain parameters from the Occipital
lobe revealed a significant negative correlation for Age
versus Pericalcarine Thickness (R2 ¼ 0.07, P < 0.05). Age
versus Cuneus Thickness also showed a significant nega-
tive correlation (R2 ¼ 0.14, P < 0.005) as did Age versus
Cuneus Volume (R2 ¼ 0.08, P < 0.05) (Fig. 3a,b).
Linear regression analysis was then conducted sepa-
rately for the three significant occipital regions (Pericalcar-
ine Thickness, Cuneus Thickness, and Cuneus Volume) in
relation to transient and sustained c-band frequency meas-
ures. For Transient Gamma Peak Frequency, only the
Cuneus Thickness linear regression approached signifi-
Figure 2.
cance (R2 ¼ 0.05, P ¼ 0.08). For Sustained Gamma Peak
(a) A significant negative correlation was observed between the
Frequency, a positive linear trend was observed between
participant’s age and the transient c-band peak frequency (R2 ¼
Pericalcarine Thickness (R2 ¼ 0.06, P ¼ 0.06). Cuneus
0.37, P < 0.001). (b) The significant negative correlation
Thickness correlated significantly with the Sustained
between the participant’s Age and sustained c-band peak fre-
Gamma Peak Frequency (R2 ¼ 0.12, P < 0.01). Finally,
quency (R2 ¼ 0.46, P < 0.001). No significant differences were
Cuneus Volume was also significantly correlated with Sus-
observed between the slopes of these regression lines, thus the
tained Gamma Peak Frequency (R2 ¼ 0.13, P < 0.005). See
correlation and regression equation reported is for all partici-
Table I for a summary of all significant correlations
pants (N ¼ 59).
observed between measures.

et al., 2009]. In addition, young participants show the high-

est frequency c-band responses, whereas c-band power Does Change in Cuneus Thickness or Cuneus
appeared unrelated to the participant’s age. Volume Explain the Decrease in Sustained
Gamma Frequency With Age?

Age Versus Gamma-band Analysis Hierarchical regression analyses was performed to

examined the unique influence of Age and Cuneus Thick-
Linear regression analysis was performed relating the ness on Sustained Gamma Peak Frequency. The full
participant’s age to c-band measures (Transient Gamma regression model (Age and Cuneus Thickness) predicts
Peak Frequency; Sustained Gamma Peak Frequency). A 46.3% of the variance in Sustained Gamma Peak

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Frequency, F(2,56) ¼ 24.16, P < 0.001. Added first, Age

predicted 45.5% of the variance (P < 0.001). Including
Cuneus Thickness explained a nonsignificant 0.8% of addi-
tional variance in the model for Sustained Gamma Peak
Frequency and Age. When Cuneus Thickness was added
to the model first it accounted for 11.5% of the variance in
Sustained Gamma Frequency (P < 0.01), with Age
accounting for an additional 34.8% of the variance (P <
0.001).
Hierarchical regression analyses was also performed to
examined the unique influence of Age and Cuneus Vol-
ume on Sustained Gamma Peak Frequency. The full
regression model (Age and Cuneus Volume) predicts
48.5% of the variance in Sustained Gamma Peak Fre-
quency, F(2,56) ¼ 26.40, P < 0.001. Added first, Age pre-
dicted 45.5% of the variance (P < 0.001). Including Cuneus
Volume explained a nonsignificant 4% of additional var-
iance in the model for Sustained Gamma Peak Frequency
and Age. When Cuneus Volume was added first, it
accounted for 13% of the variance in Sustained Gamma
Frequency (P < 0.001), with Age accounting for an addi-
tional 35.5% of the variance.
For both models, Cuneus Thickness and Cuneus Volume
do not significantly predict Sustained Gamma Peak Fre-
quency after accounting for Age, thus the observed
decrease in Sustained Gamma Peak Frequency with
increasing age is not likely the result of decreased cortical
thickness or cortical volume in visual areas. Rather Sus-
tained Gamma Peak Frequency, Cuneus Thickness and
Cuneus Volume may be related indices of visual cortex
maturation.

Figure 3.
(a, b) A significant negative correlation was observed between
participant’s age and cuneus thickness (R2 ¼ 0.14, P < 0.005), and
a near-significant negative correlation was observed between par-
ticipant’s age and pericalcarine thickness (R2 ¼ 0.07, P ¼ 0.06). 3b
shows the significant positive correlation observed between par-
ticipant’s age and cuneus volume (R2 ¼ 0.08, P < 0.05).
Interlaboratory Comparisons
We performed post-hoc analyses to test for any potential
inter-laboratory differences in our sample (CHOP: n ¼ 26,
CUBRIC: n ¼ 33) for the variables of sustained gamma
power and frequency as well as transient power and fre-
quency. After controlling for age (as younger participants
were collected at CHOP) no interlaboratory differences
were seen (all P > 0.05).

TABLE 1. Summary table of correlation results

Transient gamma (0–0.3 s) Sustained Gamma (0.5–1.5 s)

Age Hz Power HZ Power

Age R2¼ 37 P<0.000 n.s: R2¼0 46, P<0.000 n.s

Peri-Calcarine Thickness (mm) R ¼0.067; P¼0.049
2
n.s n.s. R2¼0.059; P¼0.063 n.s.
Surface Area (mm2) n.s. n.s. n.s n s. n.s
Volume (mm3) n.s n.s. n.s. n.s. n.s.
Cuneus Thickness (mm) R2¼0.142; P¼0 003 R2¼0.054; P¼0 078 n.s R2¼0 115; P¼0 008 n.s
Surface Area (mm2) n.s n.s. n.s.. n.s. n.s.
Volume (mm3) R2¼0.082, P¼0.028 n.s. n.s. R2¼0.13, P¼0.005 n.s.

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DISCUSSION
A growing body of evidence suggests that synchronous
gamma cortical oscillations are integral to variety of per-
ceptual and cognitive functions [Fries, 2009; Uhlhaas et al.,
2009, 2010]. However, less is currently known about how
developmental and maturational changes affect gamma
oscillations observed over the lifespan. The results from
this study show that contrast gratings-evoked gamma os-
cillation frequency decreases with age for both the Tran-
sient (0–0.3 s) and Sustained responses (0.5–1.5 s) to the
presented visual stimulus. Previous research has related
this transient period to input coming from the retina,
through the LGN to cortex. This transient input from the
retina may then initiate a sustained cortico-cortico gamma
synchronization, which is generated and maintained exclu-
sively in cortex [Castelo-Branco et al., 1998]. The precise
and differential roles of these transient and sustained oscil-
lations are not yet known, and the subject of some recent
debate. Some have speculated that oscillations in the
gamma range serve to maintain neural synchrony, enhanc-
ing the transmission and binding of information through
visual cortex to higher-level areas (Fries et al., 2001;
Samonds and Bonds, 2005; Singer, 1999]. Whereas the Sus-
tained response window (0.5 1.5 s) likely represents a pe-
riod dominated by induced cortical responses, the
Transient response window (0–0.3 s) might capture both
evoked and emitted components. However, both Transient
and Sustained frequency and amplitudes were highly cor-
related indicating a tight functional relation. Thus, future
studies might assess the degree to which these responses
dissociate under varied stimulus conditions.
Cortical thickness and volume measures from occipital
lobe, cuneus, and pericalcarine cortex thickness was also
observed to change with age. Although a significant corre-
lation was observed between Cuneus Thickness and
Gamma Sustained Peak Frequency and Cuneus Volume
and Gamma Sustained Peak Frequency, results from hier-
archical regression analysis showed participant’s age
explained the vast majority of the decrease in Gamma Sus-
tained Frequency regression model with age. Previous
analyses of some of these data [Muthukumaraswamy
et al., 2010] showed only a correlation between pericalcar-
ine cortex and gamma frequency (P < 0.05) and while this
is still marginally significant (P ¼ 0.06) the inclusion of a
younger participant pool has shown that neighboring
cuneus thickness and volume are also correlated with
gamma frequencies. We thus interpret the differences
between this study and the Muthukumaraswamy et al.
[2010] as related to the limited sampling of the age range
in the adult study, which hampered uncovering age as a
significant covariate in the relation between cuneus cortical
thickness and GFP. In addition, we note that the neighbor-
ing cuneal and pericalcarine thicknesses are quite strongly
correlated (r ¼ 0.530, P < 1.60  105). This suggests that
both Gamma Frequency and Cuneus Thickness and Vol-
ume measures are sensitive to separate but related proper-
r 8
r
ties of age-dependant maturational change in visual
cortex. These results are important as they show both
functional and structural correlates of maturation are
regionally specific and may serve as an important metric
of neural aging and age-associated neurological disease.
Moreover, these changes may serve as indirect metrics of
histological or pathological processes and may be informa-
tive for understanding physiological processes of neural
development, maturation, and age-related decline.
The current results raise two interesting questions: (1)
what are the known anatomical, neurochemical, and phys-
iological changes that would produce a decrease in c-band
frequency from primary visual cortex with increasing age?
(2) What are the perceptual and behavioral correlates
which can be associated with these structural and func-
tional changes to the occipital lobe observed time?
How Does the Brain Change Structurally With
Age?
Maximal brain weight occurs at approximately 20 years
of age, and declines at approximately 55 years of age
[Dekaban, 1978]. Conversely, white matter volume
increases until approximately the mid-40s [Bartzokis et al.,
2001; Sowell et al., 2003], which coincides with the peak
myelination observed at approximately age 50 [Benes
et al., 1994]. Although the gross morphological structure
(i.e., size) of the brain changes relatively little between
childhood and mid-adulthood, dramatic changes to neural
density and connectivity are known to be taking place
over this time. These morphological changes are largely
dominated by two main neurodevelopmental processes:
synaptic pruning and myelination. In-vivo volumetric studies
show consistent and relatively linear decreases in gray
matter density (an indirect MRI measure related to synap-
tic pruning) from a variety of cortical regions beginning in
late childhood [Giedd et al., 1999; Sowell et al., 2002] and
continuing relatively linearly through old age [Bartzokis
et al., 2003; Courchesne et al., 2000; Ge et al., 2002]. During
adolescence, frontal and parietal lobes show highly signifi-
cant increases in white matter along with concomitant
decreases in gray matter [Giedd et al., 1999; Sowell et al.,
2002]. Gray matter density reduction over the childhood to
adult range appears to show acceleration in the post-ado-
lescent age range, mostly in the dorsal frontal cortices
[Sowell et al., 2001, 2003). These results suggest that
changes in gray matter density between childhood and
young adulthood may index maturation dependent
increases in computational demands as frontal lobe execu-
tive functions develop in adolescence, and thus are not
changing at the same rates over lifespan. Of note, the clear
decrease in gray matter density from dorsal frontal areas
over the 10–40 years range appears to remain relatively
constant in density after
50 years [Sowell et al., 2003]. In
addition to synaptic density, age-dependent neurochemical
r
 r Functional and Structural Correlates of the Aging Brain r

processes are also known to change with development and inhibition balance then we might well predict age-related
maturation [Jansen et al., 2010]. changes in gamma frequency to be correlated with per-
formance on tasks that are thought to be dependent on
GABAergic inhibition. The most compelling case for this is
Neurochemistry Underlying Brain Development orientation discrimination, where animal neurophysiology
and Maturation has shown that intracortical inhibition sharpens neuronal
orientation selectivity [Shapley et al., 2003]. When GABA
Gamma-band responses and long-range synchronization
is blocked by antagonists, neural orientation tuning is
in neocortex are thought to be governed principally by
broadened or even abolished [Sillito, 1975] while the addi-
GABAergic interneurons [Frankle et al., 2009; Uhlhaas
tion of GABA to aged cells restores their orientation tun-
et al., 2009, 2010]. These neocortical interneurons use the
ing [Leventhal et al., 2003]. Using MEG and MRS in
inhibitory neurotransmitter c (gamma)-aminobutyric acid
humans we recently demonstrated that orientation dis-
(GABA) to dampen cortical activity by increasing chloride
crimination performance was predicted by both occipital
(Cl) conductance producing membrane hyperpolarization
GABA concentration and c-band frequency within the
and decreased excitability. In children and adults, GABA
same area—suggesting that variability of GABAergic inhi-
mediates the majority of fast inhibitory neurotransmission
bition can indeed lead to variability in human perform-
in the central nervous system through its activation of the
ance [Edden et al., 2009]. On other tasks, it has been
GABAA receptor. However, both the subunit composition
shown that older subjects are actually better than younger
neuronal GABAA receptors and functional role changes
subjects at discriminating brief, large-field, motion stimuli
during prenatal and postnatal development in humans
[Tadin et al., 2003]—a counterintuitive finding that has
[Andersen et al., 2002; Brooks-Kayal and Pritchett, 1993;
been linked to reduced GABAergic inhibition in the older
Kanaumi et al., 2006; Reichelt et al., 1991]. Because of ele-
cohort, leading to reduced centre-surround suppression.
vated intracellular Cl concentrations in immature neu-
To date, an explicit link between age-related performance
rons, GABA signaling in neonatal brain acts as an
changes and age-related changes in GABA has not been
excitatory neurotransmitter—which switches to an inhibi-
made experimentally. Furthermore, to our knowledge, per-
tory neurotransmitter after about the first 2 years of life
formance changes on these tasks through the early years
[Jansen et al., 2010]. In addition, GABAA receptor a1 and
of development, when the GABA system is maturing,
c2 subunit expression are known to increase over the first
have not been investigated.
56 years of life before reaching a plateau, whereas a4
subunit expression decreases during this same time period
[Jansen et al., 2010]. It is currently not clear how changes
in receptor density correlate with gross non-invasive CONCLUSION
GABA measures such as non-invasive magnetic resonance
To our knowledge, this study is the first published mul-
spectroscopy (MRS). However, widespread decreases in
ticenter MEG study. With this work, we have used nearly
MRS GABA concentration with age have been reported to
identical methods between two research centers, and repli-
correlate negatively with normal aging, in areas such as
cated previously published research findings [Muthuku-
dorsolateral prefrontal cortex (DLPFC), orbito frontal cor-
maraswamy et al., 2010] using an independent sample of
tex (OFC), and sensorimotor cortex (SMC) [Grachev and
adults (CHOP vs. CUBRIC). Moreover, we have extended
Apkarian, 2001], as well as visual cortex [Bigal et al.,
this observation to healthy population of adolescents and
2008]. More recently, a positive correlation was observed
children. This collaborative approach to the study of de-
between MRS resting endogenous GABA concentration in
velopmental neuroscience represents a more efficient and
medial occipital cortex and gratings-induced gamma fre-
statistically powerful path to scientific discovery, particu-
quency [Muthukumaraswamy et al., 2009]. Similar recent
larly when relatively large samples of participants are
findings have also been observed between MRS resting en-
needed.
dogenous GABA concentration and movement-related
Our work has several important implications for basic
gamma synchrony in motor cortex [Gaetz et al., 2011].
and developmental neuroscience. Studies aimed at
Thus, the age-related decreases in gamma frequency
addressing the functional significance of cortical oscilla-
observed in this study may index age-related decreases in
tions should control for maturational processes that may
MRS GABA concentration, or both c-band frequency and
directly affect the frequency of the observed cortical oscil-
GABA concentration may be sensitive to some additional
lations. Future work designed to relate perceptual and be-
and related processes of brain maturation.
havioral consequences of this decrease in c-band
frequency may be important for explaining how c-band
Perceptual and Behavioral Correlates of Visual oscillations contribute to V1 function. In addition, it is
Cortex Maturation clear that age-related changes in cortical thickness affect
some cortical areas more than others, yet the reason for
If, as we speculate earlier, age-related changes in c-band this, and the perceptual and behavioral consequence of
frequency are related to changes in the cortical excitation/ this change remain unclear. Overall, these morphological

r 9 r
 r Gaetz et al.
and functional changes with maturation appear to be
regionally specific, and may thus be informative for under-
standing physiological processes of neural development,
maturation, and age-related decline.
ACKNOWLEDGMENTS
The Cardiff University Brain Research Imaging Centre
was established with support from the UK Department of
Trade and Industry, Cardiff University, and the Welsh As-
sembly government. The content is solely the responsibil-
ity of the authors and does not necessarily represent the
official views of the National Institutes of Health. The
Pennsylvania Department of Health specifically disclaims
responsibility for any analyses, interpretations or conclu-
sions. Dr. Roberts gratefully acknowledges the Oberkircher
Family for the Oberkircher Family Chair in Pediatric Radi-
ology at Children’s Hospital of Philadelphia. We also
thank Dr. James C. Edgar and Dr. Donald Mabbott for
helpful discussions and assistance with statistical analysis.
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