The phase of plasticity-induced neurochemical changes of high-frequency repetitive transcranial magnetic stimulation are different from visual perceptual learning.

Numerous studies have found that repetitive transcranial magnetic stimulation (rTMS) modulates plasticity. rTMS has often been used to change neural networks underlying learning, often under the assumption that the mechanism of rTMS-induced plasticity should be highly similar to that associated with learning. The presence of visual perceptual learning (VPL) reveals the plasticity of early visual systems, which is formed through multiple phases. Hence, we tested how high-frequency (HF) rTMS and VPL modulate the effect of visual plasticity by investigating neurometabolic changes in early visual areas. We employed an excitatory-to-inhibitory (E/I) ratio, which refers to glutamate concentration divided by GABA+ concentration, as an index of the degree of plasticity. We compared neurotransmitter concentration changes after applying HF rTMS to the visual cortex with those after training in a visual task, in otherwise identical procedures. Both the time courses of the E/I ratios and neurotransmitter contributions to the E/I ratio significantly differed between HF rTMS and training conditions. The peak E/I ratio occurred 3.5 h after HF rTMS with decreased GABA+, whereas the peak E/I ratio occurred 0.5 h after visual training with increased glutamate. Furthermore, HF rTMS temporally decreased the thresholds for detecting phosphene and perceiving low-contrast stimuli, indicating increased visual plasticity. These results suggest that plasticity in early visual areas induced by HF rTMS is not as involved in the early phase of development of VPL that occurs during and immediately after training.

The Flexibility of Physio-Cognitive Decline Syndrome: A Longitudinal Cohort Study.

The mutual presence of impairments in physical and cognitive functions in older adults has been reported to predict incident disability, dementia, and mortality. The longitudinal transitions of phenotypes between these functional impairments, either individually or in combination, remain unclear. To investigate the natural course and prevalence of physical and/or cognitive impairments (CIs), we enrolled participants from a community-based population. Data were retrieved from the first (August 2011 and December 2012) and second wave (August 2013 and June 2015) of the I-Lan Longitudinal Aging Study (ILAS). All participants were classified into four groups: robust, mobility impairment (MI), CI, and physio-cognitive decline syndrome (PCDS). MI was diagnosed with weakness and/or slowness. CI was diagnosed if a subject met a cutoff below 1.5 standard deviations (SDs) of age-, sex-, and education-matched norms of any neuropsychological assessments. PCDS was combined with MI and CI. Our results showed that 38, 14, 30, and 18% of the participants were on the robust, MI, CI, and PCDS at the first wave, respectively. After 2.5 years, 17% robust, 29% MI, and 37% CI progressed to PCDS. In contrast, 33% of PCDS was reversed to non-PCDS. Predictors of conversion to PCDS included worse memory and language functions, older age, lower muscle mass, and the presence of diabetes. In PCDS, a stronger hand-grip strength, younger age, and better memory functions predicted reversion to non-PCDS status. In summary, we probed the transition of PCDS. The skeletal muscle mass/function and memory function are crucial factors associated with PCDS reversion or progression.

Baseline Cerebro-Cerebellar Functional Connectivity in Afferent and Efferent Pathways Reveal Dissociable Improvements in Visuomotor Learning.

Visuomotor coordination is a complex process involving several brain regions, primarily the cerebellum and motor cortex. Studies have shown inconsistent resting-state functional magnetic resonance imaging (rsfMRI) results in the cerebellar cortex and dentate nucleus of the cerebro-cerebellar connections. Echoing anatomical pathways, these two different cerebellar regions are differentially responsible for afferent and efferent cerebro-cerebellar functional connections. The aim of this study was to measure the baseline resting-state functional connectivity of different cerebellar afferent and efferent pathways and to investigate their relationship to visuomotor learning abilities. We used different cerebellar repetitive transcranial magnetic stimulation (rTMS) frequencies before a pursuit rotor task to influence visuomotor performance. Thirty-eight right-handed participants were included and randomly assigned to three different rTMS frequency groups (1 Hz, 10 Hz and sham) and underwent baseline rsfMRI and pursuit rotor task assessments. We report that greater baseline functional connectivity in the afferent cerebro-cerebellar pathways was associated with greater accuracy improvements. Interestingly, lower baseline functional connectivity in the efferent dentato-thalamo-cortical pathways was associated with greater stability in visuomotor performance, possibly associated with the inhibitory role of the dentate nucleus and caused a reduction in the efferent functional connectivity. The functional dissociation of the cerebellar cortex and dentate nucleus and their connections, suggests that distinct mechanisms in the cerebellum regarding visuomotor learning, which should be investigated in future research.

Frequency-Dependent Effects of Cerebellar Repetitive Transcranial Magnetic Stimulation on Visuomotor Accuracy.

The cerebellum plays a critical role in acquiring visuomotor skills. Visuomotor task mastery requires improving both visuomotor accuracy and stability; however, the cerebellum's contribution to these processes remains unclear. We hypothesized that repetitive transcranial magnetic stimulation (rTMS) of the cerebellum exerts frequency-dependent modulatory effects on both accuracy and stability in subjects performing a visuomotor coordination task (i.e., pursuit rotor task). We recruited 43 healthy volunteers and randomly assigned them to the high-frequency (HF), low-frequency (LF), and sham rTMS groups. We calculated changes in performance of the pursuit rotor task at the highest rotation speed and the minimum distance from target as indices of accuracy. We also calculated the intertrial variability (standard deviations) of time on target and distance from target as indices of stability. Visuomotor accuracy was significantly enhanced in the HF group and disrupted in the LF group compared to the sham group, indicating frequency-dependent effects of rTMS. In contrast, both HF and LF rTMS demonstrated no significant change in visuomotor stability. Surprisingly, our findings demonstrated that the accuracy and stability of visuomotor performance may be differentially influenced by cerebellar rTMS. This suggests that visuomotor accuracy and stability have different underlying neural mechanisms and revealed the possibility of training strategies based on cerebellar neuromodulation.

The Relationship Between Zebrin Expression and Cerebellar Functions: Insights From Neuroimaging Studies.

The cerebellum has long been known to play an important role in motor and balance control, and accumulating evidence has revealed that it is also involved in multiple cognitive functions. However, the evidence from neuroimaging studies and clinical observations is not well-integrated at the anatomical or molecular level. The goal of this review is to summarize and link different aspects of the cerebellum, including molecular patterning, functional topography images, and clinical cerebellar disorders. More specifically, we explored the potential relationships between the cerebrocerebellar connections and the expression of particular molecules and, in particular, zebrin stripe (a Purkinje cell-specific antibody molecular marker, which is a glycolytic enzyme expressed in cerebellar Purkinje cells). We hypothesized that the zebrin patterns contribute to cerebellar functional maps-especially when cerebrocerebellar circuit changes exist in cerebellar-related diseases. The zebrin stripe receives input from climbing fibers and project to different parts of the cerebral cortex through its cerebrocerebellar connection. Since zebrin-positive cerebellar Purkinje cells are resistant to excitotoxicity and cell injury while zebrin-negative zones are more prone to damage, we suggest that motor control dysfunction symptoms such as ataxia and dysmetria present earlier and are easier to observe than non-ataxia symptoms due to zebrin-negative cell damage by cerebrocerebellar connections. In summary, we emphasize that the molecular zebrin patterns provide the basis for a new viewpoint from which to investigate cerebellar functions and clinico-neuroanatomic correlations.

Structural and Functional Connectivity Changes Beyond Visual Cortex in a Later Phase of Visual Perceptual Learning.

The neural mechanisms of visual perceptual learning (VPL) remain unclear. Previously we found that activation in the primary visual cortex (V1) increased in the early encoding phase of training, but returned to baseline levels in the later retention phase. To examine neural changes during the retention phase, we measured structural and functional connectivity changes using MRI. After weeks of training on a texture discrimination task, the fractional anisotropy of the inferior longitudinal fasciculus, a major tract connecting visual and anterior areas, was increased, as well as the functional connectivity between V1 and anterior regions mediated by the ILF. These changes were strongly correlated with behavioral performance improvements. These results suggest a two-phase model of VPL in which localized functional changes in V1 in the encoding phase of training are followed by changes in both structural and functional connectivity in ventral visual processing, perhaps leading to the long-term stabilization of VPL.

Overlearning hyperstabilizes a skill by rapidly making neurochemical processing inhibitory-dominant.

Overlearning refers to the continued training of a skill after performance improvement has plateaued. Whether overlearning is beneficial is a question in our daily lives that has never been clearly answered. Here we report a new important role: overlearning in humans abruptly changes neurochemical processing, to hyperstabilize and protect trained perceptual learning from subsequent new learning. Usually, learning immediately after training is so unstable that it can be disrupted by subsequent new learning until after passive stabilization occurs hours later. However, overlearning so rapidly and strongly stabilizes the learning state that it not only becomes resilient against, but also disrupts, subsequent new learning. Such hyperstabilization is associated with an abrupt shift from glutamate-dominant excitatory to GABA-dominant inhibitory processing in early visual areas. Hyperstabilization contrasts with passive and slower stabilization, which is associated with a mere reduction of excitatory dominance to baseline levels. Using hyperstabilization may lead to efficient learning paradigms.

Reduction in the retinotopic early visual cortex with normal aging and magnitude of perceptual learning.

Although normal aging is known to reduce cortical structures globally, the effects of aging on local structures and functions of early visual cortex are less understood. Here, using standard retinotopic mapping and magnetic resonance imaging morphologic analyses, we investigated whether aging affects areal size of the early visual cortex, which were retinotopically localized, and whether those morphologic measures were associated with individual performance on visual perceptual learning. First, significant age-associated reduction was found in the areal size of V1, V2, and V3. Second, individual ability of visual perceptual learning was significantly correlated with areal size of V3 in older adults. These results demonstrate that aging changes local structures of the early visual cortex, and the degree of change may be associated with individual visual plasticity.

Age-related declines of stability in visual perceptual learning.

One of the biggest questions in learning is how a system can resolve the plasticity and stability dilemma. Specifically, the learning system needs to have not only a high capability of learning new items (plasticity) but also a high stability to retain important items or processing in the system by preventing unimportant or irrelevant information from being learned. This dilemma should hold true for visual perceptual learning (VPL), which is defined as a long-term increase in performance on a visual task as a result of visual experience. Although it is well known that aging influences learning, the effect of aging on the stability and plasticity of the visual system is unclear. To address the question, we asked older and younger adults to perform a task while a task-irrelevant feature was merely exposed. We found that older individuals learned the task-irrelevant features that younger individuals did not learn, both the features that were sufficiently strong for younger individuals to suppress and the features that were too weak for younger individuals to learn. At the same time, there was no plasticity reduction in older individuals within the task tested. These results suggest that the older visual system is less stable to unimportant information than the younger visual system. A learning problem with older individuals may be due to a decrease in stability rather than a decrease in plasticity, at least in VPL.

White matter in the older brain is more plastic than in the younger brain.

Visual perceptual learning (VPL) with younger subjects is associated with changes in functional activation of the early visual cortex. Although overall brain properties decline with age, it is unclear whether these declines are associated with visual perceptual learning. Here we use diffusion tensor imaging to test whether changes in white matter are involved in VPL for older adults. After training on a texture discrimination task for three daily sessions, both older and younger subjects show performance improvements. While the older subjects show significant changes in fractional anisotropy (FA) in the white matter beneath the early visual cortex after training, no significant change in FA is observed for younger subjects. These results suggest that the mechanism for VPL in older individuals is considerably different from that in younger individuals and that VPL of older individuals involves reorganization of white matter.

Consolidated learning can be susceptible to gradually-developing interference in prolonged motor learning.

When multiple items are learned in sequential order, learning for one item tends to be disrupted by subsequently learned items. Such retrograde interference has been studied with paradigms conducted over a relatively short term. Resistance to interference is generally believed to be a measure of learning or consolidation. Here, we used a finger-tapping motor sequence paradigm to examine interference in prolonged motor learning. Three groups of nine subjects participated in training sessions for 16 days, and practiced three different sequences in different orders and combinations. We found that a well-trained motor sequence was subject to a gradual interference when the subsequent learning was paired in a particular order. The results suggest that a well-learned motor memory is still susceptible to interference, and that resistance to interference in one condition does not necessarily imply full, permanent consolidation.

Decoding reveals plasticity in V3A as a result of motion perceptual learning.

Visual perceptual learning (VPL) is defined as visual performance improvement after visual experiences. VPL is often highly specific for a visual feature presented during training. Such specificity is observed in behavioral tuning function changes with the highest improvement centered on the trained feature and was originally thought to be evidence for changes in the early visual system associated with VPL. However, results of neurophysiological studies have been highly controversial concerning whether the plasticity underlying VPL occurs within the visual cortex. The controversy may be partially due to the lack of observation of neural tuning function changes in multiple visual areas in association with VPL. Here using human subjects we systematically compared behavioral tuning function changes after global motion detection training with decoded tuning function changes for 8 visual areas using pattern classification analysis on functional magnetic resonance imaging (fMRI) signals. We found that the behavioral tuning function changes were extremely highly correlated to decoded tuning function changes only in V3A, which is known to be highly responsive to global motion with human subjects. We conclude that VPL of a global motion detection task involves plasticity in a specific visual cortical area.

Resetting capacity limitations revealed by long-lasting elimination of attentional blink through training.

As with other cognitive phenomena that are based upon the capacity limitations of visual processing, it is thought that attentional blink (AB) cannot be eliminated, even after extensive training. We report in this paper that just 1 h of specific attentional training can completely eliminate AB, and that this effect is robust enough to persist for a few months after training. Results of subsequent behavioral and functional magnetic resonance imaging (fMRI) experiments indicate that this learning effect is associated with improvements in temporal resolution, which are mainly due to processing in the prefrontal areas. Contrary to prior wisdom, we conclude that capacity limitations can be overcome by short-term training.

Interference and feature specificity in visual perceptual learning.

Perceptual learning (PL) often shows specificity to a trained feature. We investigated whether feature specificity is related to disruption in PL using the texture discrimination task (TDT), which shows learning specificity to background element but not to target element. Learning was disrupted when orientations of background elements were changed in two successive training sessions (interference) but not in a random order from trial to trial (roving). The presentation of target elements seemed to have reversed effect; learning occurred in two-parts training but not with roving. These results suggest that interference in TDT is feature specific while disruption by roving is not.