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1.  Differences in Brain Activity during a Verbal Associative Memory Encoding Task in High- and Low-fit Adolescents 
Journal of cognitive neuroscience  2012;25(4):595-612.
Aerobic fitness is associated with better memory performance as well as larger volumes in memory-related brain regions in children, adolescents, and elderly. It is unclear if aerobic exercise also influences learning and memory functional neural circuitry. Here, we examine brain activity in 17 high-fit (HF) and 17 low-fit (LF) adolescents during a subsequent memory encoding paradigm using fMRI. Despite similar memory performance, HF and LF youth displayed a number of differences in memory-related and default mode (DMN) brain regions during encoding later remembered versus forgotten word pairs. Specifically, HF youth displayed robust deactivation in DMN areas, including the ventral medial PFC and posterior cingulate cortex, whereas LF youth did not show this pattern. Furthermore, LF youth showed greater bilateral hippocampal and right superior frontal gyrus activation during encoding of later remembered versus forgotten word pairs. Follow-up task-dependent functional correlational analyses showed differences in hippocampus and DMN activity coupling during successful encoding between the groups, suggesting aerobic fitness during adolescents may impact functional connectivity of the hippocampus and DMN during memory encoding. To our knowledge, this study is the first to examine the influence of aerobic fitness on hippocampal function and memory-related neural circuitry using fMRI. Taken together with previous research, these findings suggest aerobic fitness can influence not only memory-related brain structure, but also brain function.
doi:10.1162/jocn_a_00344
PMCID: PMC3786681  PMID: 23249350
2.  Consciousness, brain, neuroplasticity 
Subjectivity, intentionality, self-awareness and will are major components of consciousness in human beings. Changes in consciousness and its content following different brain processes and malfunction have long been studied. Cognitive sciences assume that brain activities have an infrastructure, but there is also evidence that consciousness itself may change this infrastructure. The two-way influence between brain and consciousness has been at the center of philosophy and less so, of science. This so-called bottom-up and top-down interrelationship is controversial and is the subject of our article. We would like to ask: how does it happen that consciousness may provoke structural changes in the brain? The living brain means continuous changes at the synaptic level with every new experience, with every new process of learning, memorizing or mastering new and existing skills. Synapses are generated and dissolved, while others are preserved, in an ever-changing process of so-called neuroplasticity. Ongoing processes of synaptic reinforcements and decay occur during wakefulness when consciousness is present, but also during sleep when it is mostly absent. We suggest that consciousness influences brain neuroplasticity both during wakefulness as well as sleep in a top-down way. This means that consciousness really activates synaptic flow and changes brain structures and functional organization. The dynamic impact of consciousness on brain never stops despite the relative stationary structure of the brain. Such a process can be a target for medical intervention, e.g., by cognitive training.
doi:10.3389/fpsyg.2013.00412
PMCID: PMC3706726  PMID: 23847580
consciousness; neuroplasticity; memory
3.  Beyond vascularization: aerobic fitness is associated with N-acetylaspartate and working memory 
Brain and Behavior  2012;2(1):32-41.
Aerobic exercise is a promising form of prevention for cognitive decline; however, little is known about the molecular mechanisms by which exercise and fitness impacts the human brain. Several studies have postulated that increased regional brain volume and function are associated with aerobic fitness because of increased vascularization rather than increased neural tissue per se. We tested this position by examining the relationship between cardiorespiratory fitness and N-acetylaspartate (NAA) levels in the right frontal cortex using magnetic resonance spectroscopy. NAA is a nervous system specific metabolite found predominantly in cell bodies of neurons. We reasoned that if aerobic fitness was predominantly influencing the vasculature of the brain, then NAA levels should not vary as a function of aerobic fitness. However, if aerobic fitness influences the number or viability of neurons, then higher aerobic fitness levels might be associated with greater concentrations of NAA. We examined NAA levels, aerobic fitness, and cognitive performance in 137 older adults without cognitive impairment. Consistent with the latter hypothesis, we found that higher aerobic fitness levels offset an age-related decline in NAA. Furthermore, NAA mediated an association between fitness and backward digit span performance, suggesting that neuronal viability as measured by NAA is important in understanding fitness-related cognitive enhancement. Since NAA is found exclusively in neural tissue, our results indicate that the effect of fitness on the human brain extends beyond vascularization; aerobic fitness is associated with neuronal viability in the frontal cortex of older adults.
doi:10.1002/brb3.30
PMCID: PMC3343297  PMID: 22574272
Aging; brain; exercise; fitness; human; N-acetylaspartate; working memory
4.  Aerobic fitness relates to learning on a virtual morris water task and hippocampal volume in adolescents 
Behavioural Brain Research  2012;233(2):517-525.
In rodents, exercise increases hippocampal neurogenesis and allows for better learning and memory performance on water maze tasks. While exercise has also been shown to be beneficial for the brain and behavior in humans, no study has examined how exercise impacts spatial learning using a directly translational water maze task, or if these relationships exist during adolescence – a developmental period which the animal literature has shown to be especially vulnerable to exercise effects. In this study, we investigated the influence of aerobic fitness on hippocampal size and subsequent learning and memory, including visuospatial memory using a human analogue of the Morris Water Task, in 34 adolescents. Results showed that higher aerobic fitness predicted better learning on the virtual Morris Water Task and larger hippocampal volumes. No relationship between virtual Morris Water Task memory recall and aerobic fitness was detected. Aerobic fitness, however, did not relate to global brain volume, or verbal learning, which might suggest some specificity of the influence of aerobic fitness on the adolescent brain. This study provides a direct translational approach to the existing animal literature on exercise, as well as adds to the sparse research that exists on how aerobic exercise impacts the developing human brain and memory.
doi:10.1016/j.bbr.2012.05.012
PMCID: PMC3403721  PMID: 22610054
exercise; adolescence; neuroimaging; spatial memory; hippocampus
5.  The response of face-selective cortex with single face parts and part combinations 
Neuropsychologia  2012;50(10):2454-2459.
A critical issue in object recognition research is how the parts of an object are analyzed by the visual system and combined into a perceptual whole. However, most of the previous research has examined how changes to object parts influence recognition of the whole, rather than recognition of the parts themselves. This is particularly true of the research on face recognition, and especially with questions related to the neural substrates. Here, we investigated patterns of BOLD fMRI brain activation with internal face parts (features) presented singly and in different combinations. A preference for single features over combinations was found in the occipital face area (OFA) as well as a preference for the two-eyes combination stimulus over other combination stimulus types. The fusiform face area (FFA) and lateral occipital cortex (LO) showed no preferences among the single feature and combination stimulus types. The results are consistent with a growing view that the OFA represents processes involved in early, feature-based analysis.
doi:10.1016/j.neuropsychologia.2012.06.016
PMCID: PMC3423083  PMID: 22750118
object recognition; face recognition; fmri; occipital face area; feature-based processing
6.  Decoding information in the human hippocampus: A user's guide 
Neuropsychologia  2012;50(13):3107-3121.
Multi-voxel pattern analysis (MVPA), or ‘decoding’, of fMRI activity has gained popularity in the neuroimaging community in recent years. MVPA differs from standard fMRI analyses by focusing on whether information relating to specific stimuli is encoded in patterns of activity across multiple voxels. If a stimulus can be predicted, or decoded, solely from the pattern of fMRI activity, it must mean there is information about that stimulus represented in the brain region where the pattern across voxels was identified. This ability to examine the representation of information relating to specific stimuli (e.g., memories) in particular brain areas makes MVPA an especially suitable method for investigating memory representations in brain structures such as the hippocampus. This approach could open up new opportunities to examine hippocampal representations in terms of their content, and how they might change over time, with aging, and pathology. Here we consider published MVPA studies that specifically focused on the hippocampus, and use them to illustrate the kinds of novel questions that can be addressed using MVPA. We then discuss some of the conceptual and methodological challenges that can arise when implementing MVPA in this context. Overall, we hope to highlight the potential utility of MVPA, when appropriately deployed, and provide some initial guidance to those considering MVPA as a means to investigate the hippocampus.
Highlights
► Multi-voxel pattern analysis (MVPA) is increasingly used to analyse fMRI data. ► We review the relatively few studies that have used MVPA to examine the hippocampus. ► We consider methodological challenges related to implementing this approach. ► We conclude that fMRI MVPA can offer new insights into the role of the hippocampus.
doi:10.1016/j.neuropsychologia.2012.07.007
PMCID: PMC3500691  PMID: 22820344
fMRI; Hippocampus; Decoding; MVPA; Autobiographical memory; Episodic memory; Navigation; Scenes
7.  Harnessing brain and cognitive reserve for the prevention of dementia 
Indian Journal of Psychiatry  2009;51(Suppl1):S16-S21.
The concepts of brain and cognitive reserve capture several elements of common wisdom – that we all differ in the neural resources we are endowed at birth, that experience and especially complex mental activities then modify how these neural resources are organized and cultivated, and that after any form of brain injury there is significant individual variation in the degree to which clinical deficits may manifest. Transforming these insights into a formal and refutable working definition, however, has been more challenging. Depending on the scale of analysis, brain and cognitive reserve have been defined from neurocentric, neuropsychological, computational, and behavioral perspectives. In our research, we have focused on the behavioral definition, whereby an individual’s lifetime exposure to complex mental activities is used for prediction of longitudinal cognitive and neurological change. This approach also benefits from a wealth of epidemiological studies linking heightened complex mental activity with reduced dementia risk. Research in the field of cognitive training is also beginning to indicate that incident cognitive decline can be attenuated, with recent clinical trials addressing the major challenges of transfer of gain and durability of effect. High quality randomized clinical trials are therefore the most urgent priority in this area so that the promise of brain and cognitive reserve can be harnessed for the purpose of the primary prevention of dementia.
PMCID: PMC3038530  PMID: 21416010
Brain reserve; cognitive exercise; cognitive reserve; cognitive training; dementia; prevention
8.  Do hormonal control systems produce evolutionary inertia? 
Hormonal control systems are complex in design and well integrated. Concern has been raised that these systems might act as evolutionary constraints when animals are subject to anthropogenic environmental change. Three systems are examined in vertebrates, especially birds, that are important for assessing this possibility: (i) the hypothalamic–pituitary–gonadal (HPG) axis, (ii) the activational effects of sex steroids on mating effort behaviour, and (iii) sexual differentiation. Consideration of how these systems actually work that takes adequate account of the brain's role and mechanisms suggests that the first two are unlikely to be impediments to evolution. The neural and molecular networks that regulate the HPG provide both phenotypic and evolutionary flexibility, and rapid evolutionary responses to selection have been documented in several species. The neuroendocrine and molecular cascades for behaviour provide many avenues for evolutionary change without requiring a change in peripheral hormone levels. Sexual differentiation has some potential to be a source of evolutionary inertia in birds and could contribute to the lack of diversity in certain reproductive (including life history) traits. It is unclear, however, whether that lack of diversity would impede adaptation to rapid environmental change given the role of behavioural flexibility in avian reproduction.
doi:10.1098/rstb.2007.0005
PMCID: PMC2606723  PMID: 18048293
hypothalamic–pituitary–gonadal axis; mating behaviour; hormonal activation; sexual differentiation; Japanese quail; constraint
9.  Arterial Baroreflex Control of Cardiac Vagal Outflow in Older Individuals Can Be Enhanced by Aerobic Exercise Training 
Hypertension  2009;53(5):826-832.
Maintained cardiac vagal function is critical to cardiovascular health in human aging. Aerobic exercise training has been thought an attractive intervention to increase cardiovagal baroreflex function however, the data are equivocal. Moreover, if regular exercise does reverse the age-related decline in cardiovagal baroreflex function, it is unknown how this might be achieved. Therefore, we assessed the effects of a 6-month aerobic training program on baroreflex gain and its mechanical and neural components in older individuals (5 women and 7 men, aged 55–71 years).
We assessed baroreflex function using pharmacologic pressure changes (bolus nitroprusside followed by bolus phenylephrine) and estimated the integrated gain (ΔR-R interval/Δsystolic blood pressure) and mechanical (Δ diameter/Δ pressure) and neural (ΔR-R interval/Δ diameter) components via measurements of carotid artery diameter in previously sedentary older individuals before and after 6-months of aerobic training. There was a significant 26% increase in baroreflex gain that was directly related to the amount of exercise performed and that derived mainly from an increase in the neural component of the arterial baroreflex (p<0.05). We did find changes in the mechanical component but unlike integrated gain and the neural component, these were not related to the magnitude of the exercise stimulus.
These results suggest that exercise training can have a powerful effect on cardiovagal baroreflex function, but a sufficient stimulus is necessary to produce the effect. Moreover, adaptations in the afferent efferent baroreflex control of cardiac vagal outflow may be crucial for the improvement in arterial baroreflex function in older humans.
doi:10.1161/HYPERTENSIONAHA.109.130039
PMCID: PMC2696114  PMID: 19332656
baroreflex; aging; exercise; nervous system; autonomic; carotid arteries
10.  Second-language learning and changes in the brain 
Journal of neurolinguistics  2008;21(6):509-521.
Presumably, second-language (L2) learning is mediated by changes in the brain. Little is known about what changes in the brain, how the brain changes, or when these changes occur during learning. Here, we illustrate by way of example how modern brain-based methods can be used to discern some of the changes that occur during L2 learning. Preliminary results from three studies indicate that classroom-based L2 instruction can result in changes in the brain’s electrical activity, in the location of this activity within the brain, and in the structure of the learners’ brains. These changes can occur during the earliest stages of L2 acquisition.
doi:10.1016/j.jneuroling.2008.01.001
PMCID: PMC2600795  PMID: 19079740
Second language; plasticity; ERPs; N400; P600; VBM; language processing
11.  Training-Induced Improvement of Response Selection and Error Detection in Aging Assessed by Task Switching: Effects of Cognitive, Physical, and Relaxation Training 
Cognitive control functions decline with increasing age. The present study examines if different types of group-based and trainer-guided training effectively enhance performance of older adults in a task switching task, and how this expected enhancement is reflected in changes of cognitive functions, as measured in electrophysiological brain activity (event-related potentials). One hundred forty-one healthy participants aged 65 years and older were randomly assigned to one of four groups: physical training (combined aerobic and strength training), cognitive training (paper–pencil and computer-aided), relaxation and wellness (social control group), and a control group that did not receive any intervention. Training sessions took place twice a week for 90 min for a period of 4 months. The results showed a greater improvement of performance for attendants of the cognitive training group compared to the other groups. This improvement was evident in a reduction of mixing costs in accuracy and intraindividual variability of speed, indexing improved maintenance of multiple task sets in working memory, and an enhanced coherence of neuronal processing. These findings were supported by event-related brain potentials which showed higher amplitudes in a number of potentials associated with response selection (N2), allocation of cognitive resources (P3b), and error detection (Ne). Taken together, our findings suggest neurocognitive plasticity of aging brains which can be stimulated by broad and multilayered cognitive training and assessed in detail by electrophysiological methods.
doi:10.3389/fnhum.2012.00130
PMCID: PMC3349932  PMID: 22593740
aging; cognitive training; physical training; task switching; response selection; ERPs; N2; Ne
12.  The effects of aging on the neural basis of implicit associative learning in a probabilistic Triplets Learning Task 
Journal of cognitive neuroscience  2011;24(2):451-463.
Few studies have investigated how aging influences the neural basis of implicit associative learning and available evidence is inconclusive. One emerging behavioral pattern is that age differences increase with practice, perhaps reflecting the involvement of different brain regions with training. Many studies report hippocampal involvement early on with learning becoming increasingly dependent on the caudate with practice. We tested the hypothesis that the contribution of these regions to learning changes with age, due to differential age-related declines in the striatum and hippocampi. We assessed age-related differences in brain activation during implicit associative learning using the Triplets Learning Task. Over 3 event-related fMRI runs, 11 younger and 12 healthy older adults responded to only the third (target) stimulus in sequences of three stimuli (“triplets”) by corresponding key press. Unbeknownst to participants, the first stimulus’ location predicted one target location for 80% of trials and another target location for 20% of trials. Both age groups learned associative regularities, but differences in favor of the younger adults emerged with practice. The neural basis of learning (response to predictability) was examined by identifying regions that showed a greater response to triplets that occurred more frequently. Both age groups recruited the hippocampus early, but with training the younger adults recruited their caudate whereas the older adults continued to rely on their hippocampus. This pattern enables older adults to maintain near-young levels of performance early in training but not later, and adds to evidence that implicit associative learning is supported by different brain networks in younger and older adults.
doi:10.1162/jocn_a_00116
PMCID: PMC3629094  PMID: 21861675
Implicit Learning; Implicit associative learning; Striatum; Hippocampus; Functional Neuroimaging
13.  Age-related changes in the cerebral substrates of cognitive procedural learning 
Human Brain Mapping  2009;30(4):1374-1386.
Cognitive procedural learning occurs in three qualitatively different phases (cognitive, associative and autonomous). At the beginning of this process, numerous cognitive functions are involved, subtended by distinct brain structures such as the prefrontal and parietal cortex and the cerebellum. As the learning progresses, these cognitive components are gradually replaced by psychomotor abilities, reflected by the increasing involvement of the cerebellum, thalamus and occipital regions. In elderly subjects, although cognitive studies have revealed a learning effect, performance levels differ during the acquisition of a procedure. The effects of age on the learning of a cognitive procedure have not yet been examined using functional imaging. The aim of this study was therefore to characterize the cerebral substrates involved in the learning of a cognitive procedure, comparing a group of older subjects with young controls. For this purpose, we performed a positron emission tomography activation study using the Tower of Toronto task. A direct comparison of the two groups revealed the involvement of a similar network of brain regions at the beginning of learning (cognitive phase). However, whereas the engagement of frontal and cingulate regions persisted in the older group as learning continued, it ceased in the younger controls. We assume that this additional activation in the older group during the associative and autonomous phases reflected compensatory processes and the fact that some older subjects failed to fully automate the procedure.
doi:10.1002/hbm.20605
PMCID: PMC2935916  PMID: 18537110
Age Factors; Aged; Aging; Brain Mapping; Cerebral Cortex; physiology; radionuclide imaging; Cognition; physiology; Female; Humans; Learning; physiology; Male; Middle Aged; Multivariate Analysis; Neuropsychological Tests; Photic Stimulation; Positron-Emission Tomography; methods; Reference Values
14.  The effects of neural gain on attention and learning 
Nature neuroscience  2013;16(8):1146-1153.
Attention is commonly thought to be manifest through local variations in neural gain. However, what would be the effects of brain-wide changes in gain? Here, we hypothesize that global fluctuations in gain modulate the breadth of attention, and thus, the degree to which processing is focused on aspects of the environment to which one is predisposed to attend. In accordance with this hypothesis, we show that measures of pupil diameter, which are thought to track levels of LC-NE activity and neural gain, are correlated with the degree to which learning is focused on stimulus dimensions that individual human participants are more predisposed to process. In support of our interpretation of this effect in terms of global changes in gain, we further show that the measured pupillary and behavioral variables are strongly correlated with global changes in the strength and clustering of functional connectivity, as brain-wide fluctuations of gain would predict.
doi:10.1038/nn.3428
PMCID: PMC3725201  PMID: 23770566
15.  Imaging Learning: The Search for a Memory Trace 
Learning is associated with structural changes in the human brain that can be seen and studied by MRI. These changes are observed in gray matter and surprisingly also in white matter tissue. Learning a wide range of skills, from sports, computer games, music, and reading, to abstract intellectual learning, including classroom study, is associated with structural changes in appropriate cortical regions or fiber tracts. The cellular changes underlying modifications of brain tissue during learning include changes in neuronal and glial morphology as well as vascular changes. Both alterations in axon morphology and myelination are thought to contribute to white matter plasticity during learning but to varying degrees depending on age. Structural changes in white matter could promote learning by improving the speed or synchrony of impulse transmission between cortical regions mediating the behavior. Action potentials can stimulate oligodendrocyte development and myelination by at least three known mechanisms that involve signaling molecules between axons and oligodendrocytes, which do not require neurotransmitter release from synapses. Integrating information from cellular/molecular and systems-level research on normal cognitive function, development, and learning is providing new insights into the biological mechanisms of learning and the structural changes produced in the brain.
doi:10.1177/1073858410383696
PMCID: PMC3163891  PMID: 21403182
white matter; gray matter; learning and memory; MRI; DTI; brain imaging; myelin; NG2; activity-dependent plasticity; neuron-glia interactions; oligodendrocytes; enriched environment
16.  BRAIN ACTIVITY DURING BLADDER FILLING IS RELATED TO WHITE MATTER STRUCTURAL CHANGES IN OLDER WOMEN WITH URINARY INCONTINENCE 
NeuroImage  2010;51(4):1294-1302.
Evidence from longitudinal studies in community-dwelling elderly links complaints of urgency and urinary incontinence with structural white matter changes known as white matter hyperintensities (WMH). How WMH might lead to incontinence remains unknown, since information about how they relate to neural circuits involved in continence control is lacking. The aim of this study was to investigate the role of WMH in altered brain activity in older women with urgency incontinence. In a cross-sectional study, we measured WMH, globally and in specific white matter tracts, and correlated them with regional brain activity measured by fMRI (combined with simultaneous urodynamic monitoring) during bladder filling and reported 'urgency'. We postulated that increase in global WMH burden would be associated with changes (either attenuation or reinforcement) in responses to bladder filling in brain regions involved in bladder control. Secondly, we proposed that such apparent effects of global WMH burden might be specifically related to the burden in a few critical white matter pathways. The results showed that regional activations (e.g. medial/superior frontal gyrus adjacent to dorsal ACG) and deactivations (e.g. perigenual ACG adjacent to ventromedial prefrontal cortex) became more prominent with increased global WMH burden, suggesting that activity aimed at suppressing urgency was augmented. Secondary analyses confirmed that the apparent effect of global WMH burden might reflect the presence of WMH in specific pathways (anterior thalamic radiation and superior longitudinal fasciculus), thus affecting connections between key regions and suggesting possible mechanisms involved in continence control.
doi:10.1016/j.neuroimage.2010.03.016
PMCID: PMC2880617  PMID: 20302947
17.  Exercise-Induced Noradrenergic Activation Enhances Memory Consolidation in Both Normal Aging and Patients with Amnestic Mild Cognitive Impairment 
Journal of Alzheimer's disease : JAD  2012;32(4):1011-1018.
Post-trial pharmacological activation of the noradrenergic system can facilitate memory consolidation. Because exercise activates the locus coeruleus and increases brain norepinephrine release, we hypothesized that post-trial exercise could function as a natural stimulus to enhance memory consolidation. We investigated this in amnestic mild cognitive impairment (aMCI) and cognitively normal elderly individuals by examining the effects of an acute bout of post-learning, aerobic exercise (6 minutes at 70% VO2 max on a stationary bicycle) on memory for some emotional images. Exercise significantly elevated endogenous norepinephrine (measured via the biomarker, salivary alpha-amylase) in both aMCI patients and controls. Additionally, exercise retrogradely enhanced memory in both aMCI patients and controls. Acute exercise that activates the noradrenergic system may serve as a beneficial, natural, and practical therapeutic intervention for cognitive decline in the aging population.
doi:10.3233/JAD-2012-121078
PMCID: PMC3951984  PMID: 22914593
Cognition; exercise; memory; noradrenaline; noradrenergic
18.  The BDNF effects on dendritic spines of mature hippocampal neurons depend on neuronal activity 
The fine tuning of neural networks during development and learning relies upon both functional and structural plastic processes. Changes in the number as well as in the size and shape of dendritic spines are associated to long-term activity-dependent synaptic plasticity. However, the molecular mechanisms translating functional into structural changes are still largely unknown. In this context, neurotrophins, like Brain-Derived Neurotrophic Factor (BDNF), are among promising candidates. Specifically BDNF-TrkB receptor signaling is crucial for activity-dependent strengthening of synapses in different brain regions. BDNF application has been shown to positively modulate dendritic and spine architecture in cortical and hippocampal neurons as well as structural plasticity in vitro. However, a global BDNF deprivation throughout the central nervous system (CNS) resulted in very mild structural alterations of dendritic spines, questioning the relevance of the endogenous BDNF signaling in modulating the development and the mature structure of neurons in vivo. Here we show that a loss-of-function approach, blocking BDNF results in a significant reduction in dendritic spine density, associated with an increase in spine length and a decrease in head width. These changes are associated with a decrease in F-actin levels within spine heads. On the other hand, a gain-of-function approach, applying exogenous BDNF, could not reproduce the increase in spine density or the changes in spine morphology previously described. Taken together, we show here that the effects exerted by BDNF on the dendritic architecture of hippocampal neurons are dependent on the neuron's maturation stage. Indeed, in mature hippocampal neurons in vitro as shown in vivo BDNF is specifically required for the activity-dependent maintenance of the mature spine phenotype.
doi:10.3389/fnsyn.2014.00005
PMCID: PMC3960490
dendrites; spines; structural plasticity; hippocampus; neurotrophins
19.  Neural Plasticity in Human Brain Connectivity: The Effects of Long Term Deep Brain Stimulation of the Subthalamic Nucleus in Parkinson’s Disease 
PLoS ONE  2014;9(1):e86496.
Background
Positive clinical outcomes are now well established for deep brain stimulation, but little is known about the effects of long-term deep brain stimulation on brain structural and functional connectivity. Here, we used the rare opportunity to acquire pre- and postoperative diffusion tensor imaging in a patient undergoing deep brain stimulation in bilateral subthalamic nuclei for Parkinson’s Disease. This allowed us to analyse the differences in structural connectivity before and after deep brain stimulation. Further, a computational model of spontaneous brain activity was used to estimate the changes in functional connectivity arising from the specific changes in structural connectivity.
Results
We found significant localised structural changes as a result of long-term deep brain stimulation. These changes were found in sensory-motor, prefrontal/limbic, and olfactory brain regions which are known to be affected in Parkinson’s Disease. The nature of these changes was an increase of nodal efficiency in most areas and a decrease of nodal efficiency in the precentral sensory-motor area. Importantly, the computational model clearly shows the impact of deep brain stimulation-induced structural alterations on functional brain changes, which is to shift the neural dynamics back towards a healthy regime. The results demonstrate that deep brain stimulation in Parkinson’s Disease leads to a topological reorganisation towards healthy bifurcation of the functional networks measured in controls, which suggests a potential neural mechanism for the alleviation of symptoms.
Conclusions
The findings suggest that long-term deep brain stimulation has not only restorative effects on the structural connectivity, but also affects the functional connectivity at a global level. Overall, our results support causal changes in human neural plasticity after long-term deep brain stimulation and may help to identify the underlying mechanisms of deep brain stimulation.
doi:10.1371/journal.pone.0086496
PMCID: PMC3899266  PMID: 24466120
20.  Reversal of Glial and Neurovascular Markers of Unhealthy Brain Aging by Exercise in Middle-Aged Female Mice 
PLoS ONE  2011;6(10):e26812.
Healthy brain aging and cognitive function are promoted by exercise. The benefits of exercise are attributed to several mechanisms, many which highlight its neuroprotective role via actions that enhance neurogenesis, neuronal morphology and/or neurotrophin release. However, the brain is also composed of glial and vascular elements, and comparatively less is known regarding the effects of exercise on these components in the aging brain. Here, we show that aerobic exercise at mid-age decreased markers of unhealthy brain aging including astrocyte hypertrophy, a hallmark of brain aging. Middle-aged female mice were assigned to a sedentary group or provided a running wheel for six weeks. Exercise decreased hippocampal astrocyte and myelin markers of aging but increased VEGF, a marker of angiogenesis. Brain vascular casts revealed exercise-induced structural modifications associated with improved endothelial function in the periphery. Our results suggest that age-related astrocyte hypertrophy/reactivity and myelin dysregulation are aggravated by a sedentary lifestyle and accompanying reductions in vascular function. However, these effects appear reversible with exercise initiated at mid-age. As this period of the lifespan coincides with the appearance of multiple markers of brain aging, including initial signs of cognitive decline, it may represent a window of opportunity for intervention as the brain appears to still possess significant vascular plasticity. These results may also have particular implications for aging females who are more susceptible than males to certain risk factors which contribute to vascular aging.
doi:10.1371/journal.pone.0026812
PMCID: PMC3201977  PMID: 22046366
21.  Neuroimaging of Cerebrovascular Disease in the Aging Brain 
Aging and Disease  2012;3(5):414-425.
Cerebrovascular disease remains a significant public health burden with its greatest impact on the elderly population. Advances in neuroimaging techniques allow detailed and sophisticated evaluation of many manifestations of cerebrovascular disease in the brain parenchyma as well as in the intracranial and extracranial vasculature. These tools continue to contribute to our understanding of the multifactorial processes that occur in the age-dependent development of cerebrovascular disease. Structural abnormalities related to vascular disease in the brain and vessels have been well characterized with CT and MRI based techniques. We review some of the pathophysiologic mechanisms in the aging brain and cerebral vasculature and the related structural abnormalities detectable on neuroimaging, including evaluation of age-related white matter changes, atherosclerosis of the cerebral vasculature, and cerebral infarction. In addition, newer neuroimaging techniques, such as diffusion tensor imaging, perfusion techniques, and assessment of cerebrovascular reserve, are also reviewed, as these techniques can detect physiologic alterations which complement the morphologic changes that cause cerebrovascular disease in the aging brain.Further investigation of these advanced imaging techniques has potential application to the understanding and diagnosis of cerebrovascular disease in the elderly.
PMCID: PMC3501396  PMID: 23185721
Neuroradiology; neuroimaging; aging; cerebrovascular disease; white matter; cerebral infarction
22.  Fine Discrimination Training Alters the Causal Contribution of Macaque Area MT to Depth Perception 
Neuron  2008;60(2):367-377.
When a new perceptual task is learned, plasticity occurs in the brain to mediate improvements in performance with training. How do these changes affect the neural substrates of previously learned tasks? We addressed this question by examining the effect of fine discrimination training on the causal contribution of area MT to coarse depth discrimination. When monkeys are trained to discriminate between two coarse absolute disparities (near vs. far) embedded in noise, reversible inactivation of area MT devastates performance. In contrast, after animals are trained to discriminate fine differences in relative disparity, MT inactivation no longer impairs coarse depth discrimination. This effect does not result from changes in the disparity tuning of MT neurons, suggesting plasticity in the flow of disparity signals to decision circuitry. These findings show that the contribution of particular brain area to task performance can change dramatically as a result of learning new tasks.
doi:10.1016/j.neuron.2008.08.023
PMCID: PMC2642520  PMID: 18957227
23.  A Time for Atlases and Atlases for Time 
Advances in neuroanatomy and computational power are leading to the construction of new digital brain atlases. Atlases are rising as indispensable tools for comparing anatomical data as well as being stimulators of new hypotheses and experimental designs. Brain atlases describe nervous systems which are inherently plastic and variable. Thus, the levels of brain plasticity and stereotypy would be important to evaluate as limiting factors in the context of static brain atlases. In this review, we discuss the extent of structural changes which neurons undergo over time, and how these changes would impact the static nature of atlases. We describe the anatomical stereotypy between neurons of the same type, highlighting the differences between invertebrates and vertebrates. We review some recent experimental advances in our understanding of anatomical dynamics in adult neural circuits, and how these are modulated by the organism's experience. In this respect, we discuss some analogies between brain atlases and the sequenced genome and the emerging epigenome. We argue that variability and plasticity of neurons are substantially high, and should thus be considered as integral features of high-resolution digital brain atlases.
doi:10.3389/neuro.06.017.2009
PMCID: PMC2831630  PMID: 20204142
brain atlas; stereotypy; in vivo imaging; structural plasticity; experience-dependent plasticity; genome; epigenome
24.  Dissociating hippocampal and striatal contributions to sequential prediction learning 
The European Journal of Neuroscience  2012;35(7):1011-1023.
Behavior may be generated on the basis of many different kinds of learned contingencies. For instance, responses could be guided by the direct association between a stimulus and response, or by sequential stimulus-stimulus relationships (as in model-based reinforcement learning or goal-directed actions). However, the neural architecture underlying sequential predictive learning is not well-understood, in part because it is difficult to isolate its effect on choice behavior. To track such learning more directly, we examined reaction times (RTs) in a probabilistic sequential picture identification task. We used computational learning models to isolate trial-by-trial effects of two distinct learning processes in behavior, and used these as signatures to analyze the separate neural substrates of each process. RTs were best explained via the combination of two delta rule learning processes with different learning rates. To examine neural manifestations of these learning processes, we used functional magnetic resonance imaging to seek correlates of timeseries related to expectancy or surprise. We observed such correlates in two regions, hippocampus and striatum. By estimating the learning rates best explaining each signal, we verified that they were uniquely associated with one of the two distinct processes identified behaviorally. These differential correlates suggest that complementary anticipatory functions drive each region's effect on behavior. Our results provide novel insights as to the quantitative computational distinctions between medial temporal and basal ganglia learning networks and enable experiments that exploit trial-by-trial measurement of the unique contributions of both hippocampus and striatum to response behavior.
doi:10.1111/j.1460-9568.2011.07920.x
PMCID: PMC3325519  PMID: 22487032
hippocampus; striatum; associative learning; model-based fmri
25.  Structural plasticity of the adult brain 
The adult brain has long been considered stable and unchanging, except for the inevitable decline that occurs with aqinq. This view is now being challenged with clear evidence that structural changes occur in the brain throughout life, including the generation of new neurons and other brain cells, and connections between and among neurons. What is as remarkable is that the changes that occur in the adult brain are influenced by the behaviors an individual engages in, as well as the environment in which an individual lives, works, and plays. Learning how behavior and environment regulate brain structure and function will lead to strategies to live more effective lives and perhaps protect from, or repair, brain damage and brain disease.
PMCID: PMC3181802  PMID: 22034393
neurogenesis; adult stem cell; brain structure; neurological disease; depression

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