Brain Research Bulletin 114 (2015) 56–61

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Brain Research Bulletin

journal homepage: www.elsevier.com/locate/brainresbull

Research report

In vivo evidence for neuroplasticity in older adults

Fábio Henrique de Gobbi Porto a , Anne Murphy Fox a , Erich S. Tusch a , Farzaneh Sorond b ,
Abdul H. Mohammed c,d , Kirk R. Daffner a,∗
a
Laboratory of Healthy Cognitive Aging, Division of Cognitive and Behavioral Neurology and Center for Brain/Mind Medicine,
Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
b
Division of Stroke and Cerebrovascular Disease, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
c
Department of Psychology, Linnaeus University, Växjö, Sweden
d
Center for Alzheimer Research, Department of NVS, Karolinska Institutet, Huddinge, Sweden

a r t i c l e i n f o a b s t r a c t

Article history: Neuroplasticity can be conceptualized as an intrinsic property of the brain that enables modification of
Received 31 December 2014 function and structure in response to environmental demands. Neuroplastic strengthening of synapses
Received in revised form 27 March 2015 is believed to serve as a critical mechanism underlying learning, memory, and other cognitive functions.
Accepted 28 March 2015
Ex vivo work investigating neuroplasticity has been done on hippocampal slices using high frequency
Available online 6 April 2015
stimulation. However, in vivo neuroplasticity in humans has been difficult to demonstrate. Recently, a
long-term potentiation-like phenomenon, a form of neuroplastic change, was identified in young adults
Keywords:
by differences in visual evoked potentials (VEPs) that were measured before and after tetanic visual stim-
Neuroplasticity
Visual evoked potentials (VEPs)
ulation (TVS). The current study investigated whether neuroplastic changes in the visual pathway can
Normal cognitive aging persist in older adults. Seventeen healthy subjects, 65 years and older, were recruited from the com-
Tetanic visual munity. Subjects had a mean age of 77.4 years, mean education of 17 years, mean MMSE of 29.1, and
demonstrated normal performance on neuropsychological tests. 1 Hz checkerboard stimulation, pre-
sented randomly to the right or left visual hemi-field, was followed by 2 min of 9 Hz stimulation (TVS) to
one hemi-field. After 2 min of rest, 1 Hz stimulation was repeated. Temporospatial principal component
analysis was used to identify the N1b component of the VEPs, at lateral occipital locations, in response
to 1 Hz stimulation pre- and post-TVS. Results showed that the amplitude of factors representing the
early and late N1b component was substantially larger after tetanic stimulation. These findings indicate
that high frequency visual stimulation can enhance the N1b in cognitively high functioning old adults,
suggesting that neuroplastic changes in visual pathways can continue into late life. Future studies are
needed to determine the extent to which this marker of neuroplasticity is sustained over a longer period
of time, and is influenced by age, cognitive status, and neurodegenerative disease.
© 2015 Elsevier Inc. All rights reserved.

1. Introduction

Neuroplasticity can be conceptualized as an intrinsic property

Abbreviations: AMNART, American National Adult Reading Test; AMPAR,
␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; GDS, Geriatric
Depression Scale; IQ, intelligence quotient; LTP, long-term potentiation; LTP-lp, LTP-
like phenomenon; MMSE, Mini-Mental State Exam; NMDAR, N-methyl-d-aspartate
receptor; PCA, principal component analysis; PTP, posttetanic potentiation; TMS,
transcranial magnetic stimulation; TVS, tetanic visual stimulation; VEPs, visual
evoked potentials.
∗ Corresponding author at: Division of Cognitive and Behavioral Neurology and
Center for Brain/Mind Medicine, Brigham and Women’s Hospital, Harvard Medical
School, 221 Longwood Avenue, Boston, MA 02115, USA. Tel.: +1 617 732 8060;
fax: +1 617 738 9122.
E-mail addresses: portofhg@gmail.com (F.H.d.G. Porto), afox4@partners.org
(A.M. Fox), etusch@partners.org (E.S. Tusch), fsorond@partners.org (F. Sorond),
Abdul.mohammed@lnu.se (A.H. Mohammed), kdaffner@partners.org (K.R. Daffner).
of the brain that enables modification of function and structure
in response to environmental demands, via the strengthening,
weakening, pruning, or addition of synaptic connections, and by
promoting neurogenesis (Pascual-Leone et al., 2011). There is
presynaptically-mediated short-term plasticity lasting hundreds
of milliseconds to a few minutes (e.g., posttetanic potentiation),
and postsynaptically-mediated long-term plasticity (potentiation
or depression), lasting minutes to months (Nicholls et al., 2011;
Lüscher and Malenka, 2012; Regehr, 2012).
Posttetanic potentiation (PTP) is an example of a presynap-
tic form of short-term neuroplasticity that typically lasts 1–5 min
(Catterall and Few, 2008; Regehr, 2012; Xu et al., 2007). PTP is
driven by an augmented concentration of intracellular Ca2+ that is

http://dx.doi.org/10.1016/j.brainresbull.2015.03.004
0361-9230/© 2015 Elsevier Inc. All rights reserved.
 F.H.d.G. Porto et al. / Brain Research Bulletin 114 (2015) 56–61
associated with increased probability of the release of neurotrans-
mitters such as glutamate (Catterall and Few, 2008; Fioravante and
Regehr, 2011; Habets and Borst, 2006; Korogod et al., 2007; Xu et al.,
2007). Its duration parallels the decay of intracellular Ca2+ (Nicholls
et al., 2011). PTP plays several important regulatory roles in synap-
tic function and information processing (Regehr, 2012), and has
been implicated as a synaptic mechanism underlying a number of
short-term cognitive processes, such as working memory (Hansel
and Mato, 2013; Mongillo et al., 2008).
Long-term potentiation (LTP) is defined as a long-lasting
enhancement in the efficacy of synaptic communication (Malenka
and Nicoll, 1999; Lüscher and Malenka, 2012; Shapiro, 2001)
that serves as a key cellular and biochemical mechanism related
to memory formation (Cavus et al., 2012; Martin et al., 2000).
LTP is triggered by modulation of ionotropic receptors such
as N-methyl-d-aspartate receptor (NMDAR) and ␣-amino-3-
hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), in
the postsynaptic membrane. The most common excitatory neuro-
transmitter involved is glutamate. The early or induction phase of
LTP is stimulus-dependent (e.g., contingent upon tetanic stimula-
tion), and requires the depolarization of the presynaptic neurons
and the presence of glutamate (Byth, 2014). This depolarization
is associated with the removal of Mg2+ from the NMDAR, allow-
ing calcium influx through the receptor, which triggers a complex
intracellular cascade that leads to modifications of synaptic effi-
cacy (Nicholls et al., 2011; Lüscher and Malenka, 2012). Due to
activation of certain kinases and phosphorylation of targeted pro-
teins, the plasticity becomes a long-lasting (i.e., minutes to months),
stimulus-independent postsynaptic process known as LTP. Cal-
cium works as a second messenger, altering the functioning of the
postsynaptic neuron by increasing the sensitivity of AMPAR (via
its phosphorylation) to glutamate, and by insertion of additional
AMPARs in the postsynaptic membrane from a reserve pool (i.e.,
receptor trafficking). The influx of Ca2+ through NMDARs is believed
to be a critical mechanism for the induction of LTP in the hippocam-
pus (Bao et al., 1997; Bliss and Collingridge, 1993; Bliss and Lomo,
1973; Byth, 2014; Lüscher and Malenka, 2012; Malenka and Bear,
2004; Malenka and Nicoll, 1999; Maren et al., 1994). The exact time-
frame of the transition period between presynaptic PTP and early
LTP is uncertain (Byth, 2014).
External “artificial” high frequency stimulation has been shown
to induce neuroplasticity in the form of PTP and LTP in hippocam-
pal slices (Baez et al., 2013; Bliss and Collingridge, 1993; Habets
and Borst, 2005, 2006; Korogod et al., 2007; Martin and Morris,
2002). Although the majority of studies on neuroplasticity have
focused on excitatory synapses in the hippocampus, other areas
of the mammalian brain, such as the visual system, likely share
many of the excitatory synapse’s fundamental properties (Chen
et al., 1996; Huang et al., 2014). Furthermore, although neuroplas-
ticity is vital for understanding mechanisms underlying learning
and memory, most research has investigated the phenomenon ex
vivo–in slices of hippocampal or cortical tissue from animals or
humans. In vivo neuroplasticity has been demonstrated in animals
using invasive techniques (Bliss and Gardner-Medwin, 1973; Bliss
and Lomo, 1973). However, there have been few studies exploring
this process in humans, using in vivo techniques.
Recent reports suggest that an LTP-like phenomenon (LTP-lp)1
can be demonstrated in vivo in young adults, using visual evoked
1
The phenomenon reported by other authors using in vivo models will be labeled
throughout this report as “LTP-like phenomenon” rather than LTP. Despite previ-
ous data showing similarities between results using VEPs and hippocampal slices,
without invasive recordings, is not possible to be sure that the site of plasticity
underlying the changes in VEPs is in the synapse. Therefore, we will use the term
LTP-like phenomenon.
57
potentials (VEPs) as the dependent variable (Cavus et al., 2012;
Clapp et al., 2012, 2005; McNair et al., 2006; Ross et al., 2008;
Teyler et al., 2005). Tetanic visual stimulation (TVS) at a frequency
of 9 Hz induces an augmentation in the N1b component of the
VEP, which has been shown by comparing the amplitude of the
N1 before and after tetanic stimulation. In these studies, the aug-
mented N1b response has been measured within 2 min of a TVS
and has persisted for at least an hour, which was the duration of
the experiments. In subsequent studies, TVS-induced LTP-lp has
been shown to occur only if the stimuli used during tetanic presen-
tation have the same physical properties (e.g., spatial frequency or
orientation) as the visual stimuli presented pre- and post-tetanus
(McNair et al., 2006; Ross et al., 2008). This kind of stimulus speci-
ficity is a core feature of LTP (Malenka and Nicoll, 1999; Lüscher
and Malenka, 2012; Shapiro, 2001). A source modeling study using
functional magnetic resonance imaging indicated that TVS-induced
LTP-lp was most likely generated in the extrastriate cortex (Broad-
mann’s areas 18 and 19) (Clapp et al., 2005). Although ERP studies
of young adults have varied in their use of principal component
analysis (PCA) (Cavus et al., 2012), independent component anal-
ysis (ICA) (Teyler et al., 2005), and averaged waveforms analysis
to identify and measure the N1b component (McNair et al., 2006;
Ross et al., 2008), a robust potentiation of the N1b with TVS has
been consistently observed. In summary, the use of VEPs appears
to be a reliable method for non-invasively measuring TVS-induced
LTP-lp in vivo, a surrogate marker of synaptic plasticity (Clapp et al.,
2012).
An outstanding question involves whether TVS-induced neu-
roplastic changes continue into old age. This issue has important
implications for understanding mechanisms underlying age-
related differences in cognitive processes and synaptic plasticity
(Malenka and Nicoll, 1999; Martin et al., 2000; Shapiro, 2001),
as several predictable changes associated with normal aging may
undermine the biological conditions in which neuroplasticity is
sustained. The glutamatergic system is particularly susceptible to
age-related disruption by oxidative, metabolic, and ionic stresses
(Mattson and Magnus, 2006; Newcomer and Krystal, 2001), raising
uncertainty about whether neuroplasticity would be observed in
the aging brain (Burke and Barnes, 2006). Studies using transcranial
magnetic stimulation (TMS), another model of in vivo neuroplastic-
ity, have shown decreased motor cortex LTP-lp induced by paired
associative stimulation in older adults, as compared to young adults
(Fathi et al., 2010; Müller-Dahlhaus et al., 2008). The response
appears to be more disrupted in older women than in older men
(Tecchio et al., 2008). In sum, the neurochemical and TMS data
suggest that the aging brain may have decreased capacity for
undergoing neuroplasticity. Of note, an abstract presented at the
Society of Neuroscience (Tippett et al., 2011) reported ERP evi-
dence of TVS-induced LTP-lp in some older subjects, lasting at
least 30 min. Interestingly, subjects who demonstrated the LTP-like
phenomenon had better scores on a familiarity-based recognition
memory task. The aim of the current investigation was to use VEPs
to determine if TVS-induced neuroplastic changes are present in
cognitively normal older adults.
2. Methods and materials
2.1. Participants
Subjects 65 and older were recruited through community
announcements in the Boston metropolitan area. All participants
underwent an informed consent process approved by the Partners
Human Research Committee. Inclusion criteria required subjects to
be English-speaking, have 12 or more years of education, a Mini-
Mental State Exam (MMSE) (Folstein et al., 1975) score ≥26, and
58 F.H.d.G. Porto et al. / Brain Research Bulletin 114 (2015) 56–61
Table 1
Subject characteristics.
Variable Mean (SD) Variable Mean (SD)
Age (yrs) 77.4 (6.1) DS 61.1 (14.3)
Gender (F) 16 (94.1%)* FAS 43.6 (11.8)
Educ (yrs) 17 (2.8) CF 42.8 (10.4))
MMSE 29.1 (0.8) LM 28.1 (6.3)
AMNART 122.4 (3.5) GDS 2.6 (2.3)
BNT 14.4 (1.1) VA‡ 0.7 (0.2)
TMTA† 41.8 (17.9)
TMTB† 91.8 (31.2)
AMNART, American National Adult Reading Test; BNT, Boston Naming Test; CF, cat-
egory fluency (fruits, vegetables, and animals; words within each category/1 min);
DS, digit symbol coding, WAIS-IV; Educ, education; F, female; FAS, phonemic fluency
(with the letters “F”, “A” and “S”; words beginning with each letter/1 min); GDS,
Geriatric Depression Scale; LM, logical memory; TMT, trial making test (parts “A”
and “B”); Wechsler Memory Scale-Third Edition; MMSE, Mini-Mental State Exami-
nation; SD, standard deviation; VA, visual acuity; yrs, years.
*
Number of cases and percentage of total.
†
Measured in s.
‡
Binocular visual acuity was measured in all subjects with the Snellen 10 ft model
wall chart and recorded as a decimal representation of 20/x, such that 20/20 = 1.0.
an estimated intelligence quotient (IQ), based on the American
National Adult Reading Test (AMNART) (Ryan and Paolo, 1992) ≥90.
Subjects were excluded if they had a history of clinically signifi-
cant CNS or medical disease, major psychiatric disorders based on
DSM-IV (American Psychiatric Association, 1994) criteria, hearing
or visual impairment that would prevent them from being able to
follow verbal instructions or complete neuropsychological testing,
Geriatric Depression Scale (GDS) (Yesavage et al., 1983) score ≥ 10,
or focal abnormalities on neurological examination consistent with
a CNS lesion.
Seventeen older adults were included in this study. Table 1 sum-
marizes the pertinent demographic and neuropsychological data
on the subjects. Of note, they had completed a mean of 17 (2.8)
years of education and had an estimated IQ of 122.4 (3.5).
2.2. Experimental procedures
Following the methods used by Teyler et al. (2005), and in accor-
dance with the International Society for Clinical Electrophysiology
of Vision recommendations (Odom et al., 2010), VEPs were elicited
by high contrast black and white checkerboard stimuli with 0.4
degrees of arc and boxes measuring 1 cm on each side. Participants
were instructed to fixate on a red cross in the center of the screen
during all data recordings. The viewing distance was approximately
154 cm. Checkerboards were presented randomly to the right or left
visual hemi-field for a total duration of 2 min (50% on each side).
The stimulus duration was 33 ms and the inter-stimulus interval
ranged from 917 to 1017 ms (average presentation rate of ∼1 Hz).
After subjects had rested for 15 s with their eyes open, 2 min of
TVS was presented to one hemi-field (counterbalanced across sub-
jects between the right and left hemi-fields). TVS consisted of a
checkerboard with the same color, contrast, and luminescence of
the previous 1 Hz stimuli, but with a frequency of 9 Hz (which
is below perceptual fusion rate). Following the TVS, participants
were instructed to remain at rest, with their eyes closed for 2 min,
in order to avoid TVS-induced “after-images” in the subsequent
recording. After this rest period, checkerboard stimuli were pre-
sented at 1 Hz for 2 min, following the same procedure used during
the baseline recording.
2.3. ERP recordings
An ActiveTwo electrode cap (Behavioral Brain Sciences Center,
Birmingham, UK) was used to hold to a full array of 128 Ag-AgCl
BioSemi (Amsterdam, The Netherlands) “active” electrodes to the
scalp, at locations determined by a pre-configured montage. Elec-
trodes were arranged in equidistant concentric circles from the
International 10–20 system position Cz. In addition to the 128 elec-
trodes on the scalp, 6 mini bio-potential electrodes were placed,
over the left and right mastoid, beneath each eye, and next to the
outer canthi of the eyes to capture eye blinks and vertical and hor-
izontal eye movements. EEG activity was digitized at a sampling
rate of 512 Hz.
2.4. Data analysis
EEG data were analyzed using ERPLAB (www.erpinfo.
org/erplab) (Lopez-Calderon and Luck, 2014) and EEGLAB
(http://sccn.ucsd.edu/eeglab) toolboxes that operate within
the MATLAB framework (Delorme and Makeig, 2004). Raw EEG
data were resampled to 256 Hz and referenced off-line to the
algebraic average of the right and left mastoids. EEG signals
were filtered using an IIR filter with a bandwidth of 0.03–40 Hz
(12 dB/octave roll-off). Eye artifacts were removed through an
independent component analysis. Individual bad channels were
corrected with the EEGLAB interpolation function. Epochs were
discarded from the analyses if they contained baseline drift or
movement artifacts greater than ±90 ␮V. Data were analyzed
as a function of electrode sites contralateral or ipsilateral to
tetanic stimulation. In the figures, the electrophysiological activity
contralateral to tetanic stimulation is displayed on the right side
of the scalp topographic maps.
2.5. PCA analyses
Following the recommendations of Dien et al. (2007) and Dien
(2010a), a two-step temporospatial procedure (temporal PCA with
Promax rotation followed by a spatial PCA with Infomax rotation,
the latter of which is equivalent to independent component anal-
ysis) was conducted on all subjects’ individual ERP averages, at all
134 electrode sites, using the ERP PCA toolkit 2.39 (Dien et al., 2007;
Dien, 2010b). PCA is a data-driven method that decomposes ERP
waveforms into their underlying components and is particularly
useful in parsing spatially and temporally overlapping components.
Following an approach shown to provide increased sensitivity for
identifying differences between conditions (Cohen, 2014), VEPs
that were recorded before and after TVS were analyzed in separate
PCAs. The time window was limited to 0–350 ms, with a 200 ms
baseline. A parallel test was used to restrict the number of factors
generated for each PCA (Dien, 2012). Examination of the latency and
topography of the PCA output led to the identification of factors of
interest. Factor scores (amplitudes) were submitted to statistical
analysis using paired t-tests.
3. Results
Based on visual inspection of the timing and topography of the
factors, two were of particular interest to the goals of this study,
as they represented N1 subcomponents. One factor peaked around
132 ms (128 ms for pre-TVS and 136 ms for post-TVS VEPs) in the
lateral occipital region contralateral to the side of tetanic stimula-
tion, which was labeled as the early N1b component. Another factor
peaked at 183 ms (for both pre- and post-TVS VEPs) in the lateral
occipital region (just lateral to the location of the early N1b peak),
which was labeled as the late N1b component.
Fig. 1 illustrates the temporospatial factors representing the
early and late N1b components pre- and post-tetanus. The ampli-
tude of the factors representing the early and late N1b components
was larger (more negative) after TVS than before (for the early N1b
component, post: −5.02 (5.6) ␮V; pre: −1.97 (5.8) ␮V; difference:
−3.04 (2.2) ␮V, p < 0.001; for the late N1b component, post: −3.76
 F.H.d.G. Porto et al. / Brain Research Bulletin 114 (2015) 56–61 59

Fig. 1. Scalp topographies (left) and PCA-derived waveforms (right) representing the early N1b and late N1b components for pre-tetanic and post-tetanic visual stimulation.
The right side of the topographic maps represents the hemisphere contralateral to tetanic stimulation.

(2.3) ␮V; pre: −2.48 (2.0) ␮V; difference: −1.28 (1.3) ␮V, p = 0.001).
Of note, there was no correlation between the early and late N1b
values for the post-TVS − pre-TVS amplitude (p = 0.5).
4. Discussion
To the best of our knowledge, this is the first full-length pub-
lished report demonstrating in vivo neuroplastic changes in older
adults using VEPs. Our results show a reliable increase in the
amplitudes of both early and late N1b components after TVS in
cognitively normal older adults, an observation consistent with
previous evidence of in vivo LTP-lp in older adults (Tippett et al.,
2011). Studies of young adults using VEPs to investigate LTP-lp have
relied on different methods for identifying relevant components
(Cavus et al., 2012; McNair et al., 2006; Ross et al., 2008; Teyler
et al., 2005). Most have employed single step ICA or PCA, or mea-
surements based on the amplitude peaking between the N1 and P2
waves of the averaged ERP data. Despite some methodological dif-
ferences, results in young adults have been relatively consistent
across studies, demonstrating TVS-induced augmentation of the
N1b component peaking between 100 and 150 ms (Cavus et al.,
2012) or between 150 and 200 ms (McNair et al., 2006; Ross et al.,
2008). The current study used a two-step procedure, with tem-
poral PCA (with Promax rotation) followed by spatial PCA (with
Infomax rotation), to identify and measure components of inter-
est. This approach was used because it has been shown to produce
results most consistent with simulated data sets (Dien et al., 2007;
Dien, 2010b). TVS-induced neuroplasticity was demonstrated in old
adults for two components, an early and late N1b. Of note, there
was no correlation between the magnitude of TVS-induced aug-
mentation of these two components, indicating that they do not
measure identical underlying operations and are probably derived
from distinct neural sources.
Our data were collected 2 min after the TVS, which is a period
of time most consistent with PTP. There is no consensus regarding
the exact temporal border between PTP and early LTP, and there is
probably a period of overlap between the two forms of neuroplas-
ticity when a tetanic stimulation is the inducting stimulus (Byth,
2014). The methodology used in the current investigation is similar
to that employed in previous studies, which have demonstrated
that neuroplastic changes measured after two minutes, consistent
with PTP, continued to last at least 30 min in young (Cavus et al.,
2012; McNair et al., 2006; Ross et al., 2008; Teyler et al., 2005) and
older adults (Tippett et al., 2011), consistent with LTP-lp. Addi-
tional research is necessary to confirm whether the TVS-induced
VEP potentiation in older adults observed in our study is sustained
for a duration that is consistent with LTP-lp. It is critical to note
that both short-term and long-term plasticity have important
60 F.H.d.G. Porto et al. / Brain Research Bulletin 114 (2015) 56–61
implications for aging and cognition (Cavus et al., 2012; Hansel
and Mato, 2013; Martin et al., 2000; Mongillo et al., 2008). Thus,
the results of studies like the current one would be meaningful,
whether they reflect PTP, LTP, or both. The methodology used may
serve as a promising, non-invasive tool to measure neuroplasticity
and study the brain’s aging process.
Our results are of particular interest, given reports of age-
related changes in the glutamatergic system that may undermine
conditions needed to facilitate neuroplasticity. The glutamater-
gic system appears to be especially susceptible to age-associated
disruption by metabolic, oxidative, and ionic stresses (Mattson
and Magnus, 2006; Newcomer and Krystal, 2001). Notably, the
results of a study using an animal model with invasive in vivo
VEP recordings demonstrated that an NMDAR antagonist com-
pletely abolished LTP, suggesting that the glutamatergic system
needs to be properly functioning to allow for neuroplasticity (Kang
and Vaucher, 2009). Research in humans also has shown an age-
related decrease in NMDAR function, which has been associated
with declines in memory and learning (Newcomer and Krystal,
2001; Newcomer et al., 2000). Given this age-related vulnerabil-
ity, it was unclear whether VEP augmentation would be observed.
Our results demonstrate that some cognitively normal older adults
have the capacity to exhibit TVS-induced neuroplastic changes,
thus providing evidence that their visual pathways are still able
to undergo neuroplasticity. Furthermore, we demonstrated TVS-
induced neuroplastic changes in older women (the majority of our
subjects), a group that was shown to be particularly unrespon-
sive to attempts to induce LTP-lp in a TMS study (Tecchio et al.,
2008).
This study has a few limitations. Our sample size was relatively
small and not representative of the aging population. Participants
were well-educated, highly intelligent, and predominantly female.
Thus, the extent to which our results are generalizable remains
unclear. Although the study demonstrated that neuroplasticity can
persist into late adulthood (mean age of 77), and is supported
by previous research on older individuals (Tippett et al., 2011), it
remains to be determined if this phenomenon is a common fea-
ture of the aging human brain, or if TVS-induced VEP augmentation
is limited to older adults with high cognitive reserve (Barulli and
Stern, 2013). A follow-up investigation with a much larger, more
heterogeneous sample is needed to address this issue. The study
also did not include a comparison group of young adults. Future
studies should determine if there are age-related differences in the
magnitude of TVS-induced neuroplasticity. To determine whether
TVS can induce neuroplastic changes in older adults consistent
with LTP-lp, it is essential to investigate if the augmentation in
N1 amplitude is sustained over a duration of more than a few
minutes and depends on stimulus specificity. Moreover, it would
be informative to examine the links between TVS-induced elec-
trophysiological changes, performance on visually mediated tasks,
and biochemical and imaging markers of synaptic function. Finally,
future studies are also needed to determine whether this pre-
sumed marker of neural plasticity is absent in neurodegenerative
diseases.
5. Conclusion
Neuroplastic changes can be induced by TVS in cognitively nor-
mal older adults, at least in individuals who exhibit “successful”
aging. Additional research is needed to clarify if TVS-induced neu-
roplastic changes are also present in a more heterogeneous older
adult sample and to compare its magnitude across different age
groups. Despite some unanswered questions, this non-invasive
method for measuring neuroplasticity appears to be a promising
tool to study the brain’s aging process.
Acknowledgements
This research was funded by the Kamprad Family Founda-
tion, Vaxjo, Sweden. The Laboratory of Healthy Cognitive Aging
has been sustained by NIA Grant R01 AG017935 and ongoing
support from the Wimberly family, the Muss family, and the
Mortimer/Grubman family. The first author (FHGP) received a
scholarship from the program “Science without Borders” (Coordi-
nation for the Improvement of Higher Education Personnel/Brazil),
number 99999.003029/2014-00, and Lemann Foundation, which
supports advanced training in the USA. The investigators thank Dr.
Timothy J. Teyler and Dr. Wesley C. Clapp for providing additional
information about their experimental methods. Also, the authors
would like to thank Brittany Alperin for early work on the project,
Sarah Fackler for her excellent administrative assistance, and Dr.
Shaomin Li for his invaluable input on the biological mechanisms
underlying neuroplasticity.
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