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Abstract

A growing literature has focused on the brain's ability to augment processing in local regions by recruiting distant communities of neurons in response to neural decline or insult. In particular, both younger and older adult populations recruit bilateral prefrontal cortex (PFC) as a means of compensating for increasing neural effort to maintain successful cognitive function. However, it remains unclear how local changes in neural activity affect the recruitment of this adaptive mechanism. To address this problem, we combined graph theoretical measures from functional MRI with diffusion weighted imaging and repetitive transcranial magnetic stimulation (rTMS) to resolve a central hypothesis: how do aged brains flexibly adapt to local changes in cortical activity? Specifically, we applied neuromodulation to increase or decrease local activity in a cortical region supporting successful memory encoding (left dorsolateral PFC or DLPFC) using 5 or 1 Hz rTMS, respectively. We then assessed a region's local within-module degree, or the distributed between-module degree (BMD) between distant cortical communities. We predicted that (1) local stimulation-related deficits may be counteracted by boosting BMD between bilateral PFC, and that this effect should be (2) positively correlated with structural connectivity. Both predictions were confirmed; 5 Hz rTMS increased local success-related activity and local increases in PFC connectivity, while 1 Hz rTMS decreases local activity and triggered a more distributed pattern of bilateral PFC connectivity to compensate for this local inhibitory effect. These results provide an integrated, causal explanation for the network interactions associated with successful memory encoding in older adults. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc.

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... Structural connectivity. Information on the structural connections based on diffusion tractography, between each pair of regions in our data were assessed with a standard DWI processing pipeline used previously in our group 40,41 . DWI data were analyzed utilizing FSL (https://fsl.fmrib.ox.ac.uk/fsl/fslwiki) and MRtrix (http:// mrtrix.org) ...
... Functional connectivity. Functional connection matrices representing task-related connection strengths were estimated using a correlational psychophysical interaction (cPPI) analysis 40,41 in order to estimate a whole-brain connectivity matrix that describes task-related interactions between brain regions. Briefly, the model relies on the calculation of a PPI regressor for each region (or node), based on the product of that region's timecourse and a task regressor of interest, in order to generate a term reflecting the psychophysical interaction between the seed region's activity and the specified experimental manipulation. ...
... Task-related connectivity was estimated from the resulting output matrices; negative connections were included in these analyses, as they may inform important, explicit interpretations about how networks may be segregated 44 . Graph metrics, including modularity (describing the modular organization of the whole-brain graph) and strength (describing a sum of the connectivity strengths for each node) were computed using the Brain Connectivity Toolbox as described previously 40 and, when appropriate, summed across all nodes within a task-related network. ...
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Abstract Working memory (WM) is assumed to consist of a process that sustains memory representations in an active state (maintenance) and a process that operates on these activated representations (manipulation). We examined evidence for two distinct, concurrent cognitive functions supporting maintenance and manipulation abilities by testing brain activity as participants performed a WM alphabetization task. Maintenance was investigated by varying the number of letters held in WM and manipulation by varying the number of moves required to sort the list alphabetically. We found that both maintenance and manipulation demand had significant effects on behavior that were associated with different cortical regions: maintenance was associated with bilateral prefrontal and left parietal cortex, and manipulation with right parietal activity, a link that is consistent with the role of parietal cortex in symbolic computations. Both structural and functional architecture of these systems suggested that these cognitive functions are supported by two dissociable brain networks. Critically, maintenance and manipulation functional networks became increasingly segregated with increasing demand, an effect that was positively associated with individual WM ability. These results provide evidence that network segregation may act as a protective mechanism to enable successful performance under increasing WM demand.
... rTMS of left dlPFC has produced moderately consistent effects on RSFC but less consistent cognitive outcomes. Regarding cognitive changes associated with left dlPFC rTMS, eight of twelve studies reviewed here reported significant cognitive improvements associated with high-frequency stimulation [14,33,34,37,38,40,41,[43][44][45]70,71]. Further, one study using low-frequency rTMS reported acute cognitive impairment [42]. ...
... Their study observed a response similar to an inverted U-shaped curve, with no significant results at 50%, cognitive enhancement at 75%, and intermediate enhancement at 100%. In a similar study, Davis and colleagues applied 5 Hz rTMS at 120% MT to left dlPFC but observed no significant change in cognitive ability [41]. Together, these studies suggest that the greater the rTMS stimulation intensity does not directly correspond to greater outcomes, and that there may be ideal intensities for specific frequencies of rTMS. ...
... In these two studies [40,41], rTMS was associated with changes in RSFC or EEG variables. Further, Davis and colleagues observed that RSFC changes were associated with better cognitive performance, including increased representational similarity during encoding and retrieval during a memory task [41,43]. ...
Article
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Human memory systems are imperfect recording devices that are affected by age and disease, but recent findings suggest that the performance of these systems may be modifiable through interventions using non-invasive brain stimulation such as repetitive transcranial magnetic stimulation (rTMS). The translational potential of these rTMS interventions is clear: memory problems are the most common cognitive complaint associated with healthy aging, while pathological conditions such as Alzheimer’s disease are often associated with severe deficits in memory. Therapies to improve memory or treat memory loss could enhance independence while reducing costs for public health systems. Despite this promise, several important factors limit the generalizability and translational potential of rTMS interventions for memory. Heterogeneity of protocol design, rTMS parameters, and outcome measures present significant challenges to interpretation and reproducibility. However, recent advances in cognitive neuroscience, including rTMS approaches in addition to a new understanding of functional brain networks and related insights, may offer methodological tools necessary to design new interventional studies with enhanced experimental rigor, improved reproducibility, and greater likelihood of successful translation to clinical settings. In this review, we first discuss the current state of the literature on memory modulation with rTMS, then offer a commentary on developments in cognitive neuroscience that are relevant to rTMS interventions, and finally close by offering several recommendations for the design of future investigations using rTMS to modulate human memory performance.
... A similar pattern of effects of 1 Hz rTMS on episodic memory that was revealed in the meta-analysis on young adults was found in 1 Hz rTMS studies on older adults with below-MTI stimulation enhancing performance (Turriziani et al., 2012) while above-MTI had no effect (Davis et al., 2017). Turriziani et al. (2012) administered offline 1 Hz rTMS at 90% MT to the left or right DLPFC of patients with mild cognitive impairment following encoding of faces, buildings, and words and found enhanced recognition memory. ...
... Turriziani et al. (2012) administered offline 1 Hz rTMS at 90% MT to the left or right DLPFC of patients with mild cognitive impairment following encoding of faces, buildings, and words and found enhanced recognition memory. In contrast, Davis et al. (2017) administered offline 1 or 5 Hz rTMS at 120% MT to the left DLPFC of healthy older adults prior to an encoding task and observed null effects on associative memory (although there were differential effects on brain network activity related to successful memory performance, for details see Davis et al., 2017). Although several parameters differed between these studies, the difference in outcomes of 1 Hz rTMS as a function of MTI is consistent with the findings of studies included in the meta-analysis irrespective of differences among those studies. ...
... Turriziani et al. (2012) administered offline 1 Hz rTMS at 90% MT to the left or right DLPFC of patients with mild cognitive impairment following encoding of faces, buildings, and words and found enhanced recognition memory. In contrast, Davis et al. (2017) administered offline 1 or 5 Hz rTMS at 120% MT to the left DLPFC of healthy older adults prior to an encoding task and observed null effects on associative memory (although there were differential effects on brain network activity related to successful memory performance, for details see Davis et al., 2017). Although several parameters differed between these studies, the difference in outcomes of 1 Hz rTMS as a function of MTI is consistent with the findings of studies included in the meta-analysis irrespective of differences among those studies. ...
Article
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A systematic review and meta-analysis were conducted to synthesize the existing literature on how transcranial magnetic stimulation (TMS) has been used to modulate episodic memory. Given the numerous parameters of TMS protocols and experimental design characteristics that can be manipulated, a mechanistic understanding of how changes in the combination of parameters (e.g., frequency, timing, intensity, targeted brain region, memory task) modulate episodic memory is needed. To address this, we reviewed 59 studies and conducted a meta-analysis on 245 effect sizes from 37 articles on healthy younger adults (N = 1,061). Analyses revealed generally more beneficial effects of 1-Hz rTMS vs. other frequencies on episodic memory. Moderation analyses revealed complex interactions as online 20-Hz rTMS protocols led to negative effects, while offline 20-Hz rTMS led to enhancing effects. There was also an interaction between stimulation intensity and frequency as 20-Hz rTMS had more negative effects when applied below- vs. at-motor threshold. Conversely, 1-Hz rTMS had more beneficial effects than other frequencies when applied below- vs. at- or above-motor threshold. No reliable aggregate or hypothesized interactions were found when assessing stimulation site (frontal vs. parietal cortex, left vs. right hemisphere), stimulated memory process (during encoding vs. retrieval), the type of retrieval (associative/recollection vs. item/familiarity), or the type of control comparison (active vs. sham or no TMS) on episodic memory. However, there is insufficient data to make strong inference based on the lack of aggregate or two-way interactions between these factors, or to assess more complex (e.g., 3-way) interactions. We reviewed the effects on other populations (healthy older adults and clinical populations), but systematic comparison of parameters was also prevented due to insufficient data. A database of parameters and effects sizes is available as an open source repository so that data from studies can be continuously accumulated in order to facilitate future meta-analysis. In conclusion, modulating episodic memory relies on complex interactions among the numerous moderator variables that can be manipulated. Therefore, rigorous, systematic comparisons need to be further investigated as the body of literature grows in order to fully understand the combination of parameters that lead to enhancing, detrimental or null effects on episodic memory.
... A final 2 studies examined the effects of rTMS on associative memory performance (53,60). Manenti et al. (60) applied rTMS (20 Hz) to either the left or right DLPFC during encoding or recalling of word-pairs and found that stimulation significantly impeded word-pair recall accuracy. ...
... In terms of stimulation montages, those that aimed at one area were favoured in relation to those targeting several nodes within a network. Some evidence did appear to exist for stimulation of temporoparietal regions augmenting performance, which appeared to last for up to a week (e.g., 53). This is consistent with the right temporoparietal junction being particularly involved with integrating sensory and contextual stimuli (81), hence making it a likely neuroanatomical correlate for associative memory. ...
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It has long been acknowledged that memory changes over the course of one's life, irrespective of diseases like dementia. Approaches to mitigate these changes have however yielded mixed results. Brain stimulation has been identified as one novel approach of augmenting older adult's memory. Thus far, such approaches have however been nuanced, targeting different memory domains with different methodologies. This has produced an amalgam of research with an unclear image overall. This systematic review therefore aims to clarify this landscape, evaluating, and interpreting available research findings in a coherent manner. A systematic search of relevant literature was conducted across Medline, PsycInfo, Psycarticles and the Psychology and Behavioral Sciences Collection, which uncovered 44 studies employing non-invasive electrical brain stimulation in healthy older adults. All studies were of generally good quality spanning numerous memory domains. Within these, evidence was found for non-invasive brain stimulation augmenting working, episodic, associative, semantic, and procedural memory, with the first three domains having the greatest evidence base. Key sites for stimulation included the left dorsolateral prefrontal cortex (DLPFC), temporoparietal region, and primary motor cortex, with transcranial direct current stimulation (tDCS) holding the greatest literature base. Inconsistencies within the literature are highlighted and interpreted, however this discussion was constrained by potential confounding variables within the literature, a risk of bias, and challenges defining research aims and results. Non-invasive brain stimulation often did however have a positive and predictable impact on older adult's memory, and thus warrants further research to better understand these effects.
... Such findings suggest evidence of compensation, a concept particularly developed within the field of cognitive neuroscience of aging, and which refers to the capacity of engaging additional neural resources (i.e., such as reflected by increased fMRI BOLD signal) to counteract the lack of functionality of the typical brain resources in a given situation [56][57][58] . Compensation has been frequently associated with increases in contralateral recruitment as an adaptative shift [57][58][59] and is a term associated to enhanced cognitive performance. However, a task-related increase in cognitive demands may be completely counteracted by the recruitment of additional neural resources, or it may reduce but do not completely eliminate the gap between task demands and available resources 57 . ...
... The present findings using rTMS as a technique to directly manipulate neural activity are aligned with previous rTMS studies conducted amongst older adults (i.e., 59,62,64 ) showing that a disruption of local resources resulted in a shift of brain activity positively associated with task performance. However, it should be noted that in the present study we employed an rTMS 'online' stimulation protocol during the memory encoding phase, using very brief (i.e., 900 ms) trains of a high frequency stimulation (20 Hz), that in principle should not induce after-effects. ...
Article
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The BDNF Val66Met gene polymorphism is a relevant factor explaining inter-individual differences to TMS responses in studies of the motor system. However, whether this variant also contributes to TMS-induced memory effects, as well as their underlying brain mechanisms, remains unexplored. In this investigation, we applied rTMS during encoding of a visual memory task either over the left frontal cortex (LFC; experimental condition) or the cranial vertex (control condition). Subsequently, individuals underwent a recognition memory phase during a functional MRI acquisition. We included 43 young volunteers and classified them as 19 Met allele carriers and 24 as Val/Val individuals. The results revealed that rTMS delivered over LFC compared to vertex stimulation resulted in reduced memory performance only amongst Val/Val allele carriers. This genetic group also exhibited greater fMRI brain activity during memory recognition, mainly over frontal regions, which was positively associated with cognitive performance. We concluded that BDNF Val66Met gene polymorphism, known to exert a significant effect on neuroplasticity, modulates the impact of rTMS both at the cognitive as well as at the associated brain networks expression levels. This data provides new insights on the brain mechanisms explaining cognitive inter-individual differences to TMS, and may inform future, more individually-tailored rTMS interventions.
... have been at least four published studies that have administered low-and high-frequency rTMS with an expectation of changing RSFC rTMS without a sham control (Cocchi et al., 2015;Davis et al., 2017;Eldaief et al., 2011;Watanabe et al., 2014), and only one study mentions this as a potential limitation (Davis et al., 2017). Our results showing no rTMS frequency differences on RSFC also underscore some inconsistencies and gaps in knowledge regarding the relationships between MEPs, BOLD activation, and RSFC that impede the formulation of accurate hypotheses. ...
... have been at least four published studies that have administered low-and high-frequency rTMS with an expectation of changing RSFC rTMS without a sham control (Cocchi et al., 2015;Davis et al., 2017;Eldaief et al., 2011;Watanabe et al., 2014), and only one study mentions this as a potential limitation (Davis et al., 2017). Our results showing no rTMS frequency differences on RSFC also underscore some inconsistencies and gaps in knowledge regarding the relationships between MEPs, BOLD activation, and RSFC that impede the formulation of accurate hypotheses. ...
Article
The insular cortex supports the conscious awareness of physical and emotional sensations, and the ability to modulate the insula could have important clinical applications in psychiatry. Repetitive transcranial magnetic stimulation (rTMS) uses transient magnetic fields to induce electrical currents in the superficial cortex. Given its deep location in the brain, the insula may not be directly stimulated by rTMS; however, rTMS may modulate the insula via its functional connections with superficial cortical regions. Furthermore, low- versus high-frequency rTMS is thought to have opposing effects on cortical excitability, and the present study investigated these effects on brain activity and functional connectivity with the insula. Separate groups of healthy participants (n = 14 per group) received low (1 Hz)- or high (10 Hz)-frequency rTMS in five daily sessions to the right postcentral gyrus, a superficial region known to be functionally connected to the insula. Resting-state functional connectivity (RSFC) was measured pre- and post-rTMS. Both 1 and 10 Hz rTMS increased RSFC between the right postcentral gyrus and the left insula. These results suggest that low- and high-frequency rTMS has similar long-term effects on brain activity and RSFC. However, given the lack of difference, we cannot exclude the possibility that these effects are simply due to a nonspecific effect. Given this limitation, these unexpected results underscore the need for acoustic- and stimulation-matched sham control conditions in rTMS research.
... However, Vidal-Piñeiro et al. (2014) used off-line TMS targeting the left inferior frontal gyrus, and the results showed no difference in recognition memory accuracy between the TMS group and the sham group. Davis et al. (2017) conducted both low-frequency (1 Hz) and high-frequency (5 Hz) rTMS in healthy older adults, the stimulation site was the left DLPFC, and the results showed no differences in recognition memory performance between 1 and 5 Hz rTMS. The current contradictory results make it difficult to conclude that rTMS could improve the cognitive ability in healthy elderly, and more studies are needed. ...
... The improvement of source memory was consistent with previous studies that implemented the multi-session offline rTMS in MCI and Alzheimer's disease patients (Cotelli et al., 2012;Drumond Marra et al., 2015;Koch et al., 2018). Only few studies investigated the rTMS off-line effect in healthy adults, which have not found that rTMS significantly improves episodic memory in healthy older adults (e.g., Vidal-Piñeiro et al., 2014;Davis et al., 2017), perhaps because those studies have used a single-session stimulus protocol. The present findings suggested multi-session off-line stimulus protocol could produce accumulated intervention effects in healthy older adults. ...
Article
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Source memory is one of the cognitive abilities that are most vulnerable to aging. Luckily, the brain plasticity could be modulated to counteract the decline. The repetitive transcranial magnetic stimulation (rTMS), a relatively non-invasive neuro-modulatory technique, could directly modulate neural excitability in the targeted cortical areas. Here, we are interested in whether the application of rTMS could enhance the source memory performance in healthy older adults. In addition, event-related potentials (ERPs) were employed to explore the specific retrieval process that rTMS could affect. Subjects were randomly assigned to either the rTMS group or the sham group. The rTMS group received 10 sessions (20 min per session) of 10 Hz rTMS applying on the right dorsolateral prefrontal cortex (i.e., F4 site), and the sham group received 10 sessions of sham stimulation. Both groups performed source memory tests before and after the intervention while the electroencephalogram (EEG) was recorded during the retrieval process. Behavioral results showed that the source memory performance was significantly improved after rTMS compared with the sham stimulation; ERPs results showed that during the retrieval phase, the left parietal old/new effect, which reflected the process of recollection common to both young and old adults, increased in the rTMS group compared with the sham stimulation group, whereas the late reversed old/new effect specific to the source retrieval of older adults showed similar attenuation after intervention in both groups. The present results suggested that rTMS could be an effective intervention to improve source memory performance in healthy older adults and that it selectively facilitated the youth-like recollection process during retrieval. This study was registered in the Chinese Clinical Trial Registry (ChiCTR) with the identifier chictr-ire-15006371.
... the task regressor, to control for co-activation effects; the regions' time courses, to control for intrinsic or task-unrelated coupling; the regressor for incorrect trials, from the GLM model; and nuisance signals. Specifically, nuisance signals included: the 6 realignment parameters (3 translations and 3 rotations), regressors for outlier volumes (i.e., volumes with differential motion d > 3 mm or global intensity z > 6, identified as described above), and concurrent signals from within the white matter and cerebrospinal fluid (i.e., average signals across each individuals' masks resulted from segmentation); for similar approaches see Davis et al. (2017), Davis et al. (2018), Wang et al. (2018). Correlation coefficients were then Fisher-z transformed to allow statistical testing. ...
Article
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Brain activity typically increases with increasing working memory (WM) load, regardless of age, before reaching an apparent ceiling. However, older adults exhibit greater brain activity and reach ceiling at lower loads than younger adults, possibly reflecting compensation at lower loads and dysfunction at higher loads. We hypothesized that WM training would bolster neural efficiency, such that the activation peak would shift towards higher memory loads after training. Pre-training, older adults showed greater recruitment of the WM network than younger adults across all loads, with decline at the highest load. Ten days of adaptive training on a verbal WM task improved performance and led to greater brain responsiveness at higher loads for both groups. For older adults the activation peak shifted rightward towards higher loads. Finally, training increased task-related functional connectivity in older adults, both within the WM network and between this task-positive network and the task-negative/default-mode network. These results provide new evidence for functional plasticity with training in older adults and identify a potential signature of improvement at the neural level.
... These behavioral changes may reflect direct effects on AG, which has an important role in episodic memory retrieval in its own right (4), or indirect effects on HC and the core network. The rTMS effects can spread to distant regions, including the contralateral hemisphere, and can also trigger compensatory network responses (13). This is why it is optimal to measure and confirm TMS effects on the brain by following TMS application with functional neuroimaging, as Thakral et al. do (7). ...
... It is made available under a The copyright holder for this preprint this version posted June 6, 2020. . https://doi.org/10.1101/2020.06.05.136531 doi: bioRxiv preprint striatum and the hippocampus, during resting-state Esslinger et al., 2014;Gratton et al., 2013;Iwabuchi et al., 2017;Mastropasqua et al., 2014;Shang et al., 2019) and during working and episodic memory tasks Davis, Luber, Murphy, Lisanby, & Cabeza, 2017;Esslinger et al., 2014). In line with this earlier work, our connectivity analyses revealed that DLPFC stimulation before learning altered connectivity in fronto-hippocampal and striatal networks during motor sequence learning. ...
Preprint
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While it is widely accepted that motor sequence learning (MSL) is supported by a prefrontal-mediated interaction between hippocampal and striatal networks, it remains unknown whether the functional responses of these networks can be modulated in humans with targeted experimental interventions. The present proof-of-concept study employed a comprehensive multimodal neuroimaging approach, including functional magnetic resonance (MR) imaging and MR spectroscopy, to investigate whether individually-tailored theta-burst stimulation of the dorsolateral prefrontal cortex can modulate responses in the hippocampus and striatum during motor learning. Our results indicate that stimulation influenced task-related connectivity patterns within hippocampo-frontal and striatal networks. Stimulation also altered the relationship between the levels of gamma-aminobutyric acid (GABA) in the stimulated prefrontal cortex and learning-related changes in both activity and connectivity in fronto-striato-hippocampal networks. This study provides the first experimental evidence that brain stimulation can alter motor learning-related functional responses in the striatum and hippocampus.
... Where Ζ is the mean r-values between nodes of one partition, module, or system (similar to within-284 module degree or WMD), and Ζ is the mean of r-values between nodes of separate partitions (similar 285 to between-module degree or BMD, Davis et al., 2017). Accordingly, values greater than 0 reflect 286 relatively lower between-system correlations in relation to within-system correlations (i.e., stronger 287 integration of systems), and values less than 0 reflect higher between-system correlations relative to 288 within-system correlations (i.e., diminished integration of systems). ...
Article
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Neuroimaging evidence suggests that the aging brain relies on a more distributed set of cortical regions than younger adults in order to maintain successful levels of performance during demanding cognitive tasks. However, it remains unclear how task demands give rise to this age-related expansion in cortical networks. To investigate this issue, functional magnetic resonance imaging was used to measure univariate activity, network connectivity, and cognitive performance in younger and older adults during a working memory (WM) task. Here, individuals performed a WM task in which they held letters online while reordering them alphabetically. WM load was titrated to obtain four individualized difficulty levels with different set sizes. Network integration—defined as the ratio of within- versus between-network connectivity—was linked to individual differences in WM capacity. The study yielded three main findings. First, as task difficulty increased, network integration decreased in younger adults, whereas it increased in older adults. Second, age-related increases in network integration were driven by increases in right hemisphere connectivity to both left and right cortical regions, a finding that helps to reconcile existing theories of compensatory recruitment in aging. Lastly, older adults with higher WM capacity demonstrated higher levels of network integration in the most difficult task condition. These results shed light on the mechanisms of age-related network reorganization by demonstrating that changes in network connectivity may act as an adaptive form of compensation, with older adults recruiting a more distributed cortical network as task demands increase.
... Or the other way around, the long-range communication being weakened by the inability to generate strong output signals due to the lack of local synchronization. Alternatively, there is evidence from brain stimulation studies that local underconnectivity might coexist with longrange overconnectivity, as the result of a compensation effect (Davis et al. 2017). It is clear that more research is needed to unravel the link between local and distributed connectivity alterations and their causality. ...
Article
Autism spectrum disorder (ASD) is diagnosed more often in males with a ratio of 1:4 females/males. This bias is even stronger in neuroimaging studies. There is a growing evidence suggesting that local connectivity and its developmental trajectory is altered in ASD. Here, we aim to investigate how local connectivity and its age-related trajectories vary with ASD in both males and females. We used resting-state fMRI data from the ABIDE I and II repository: males (n = 102) and females (n = 92) with ASD, and typically developing males (n = 104) and females (n = 92) aged between 6 and 26. Local connectivity was quantified as regional homogeneity. We found increases in local connectivity in participants with ASD in the somatomotor and limbic networks and decreased local connectivity within the default mode network. These alterations were more pronounced in females with ASD. In addition, the association between local connectivity and ASD symptoms was more robust in females. Females with ASD had the most distinct developmental trajectories of local connectivity compared with other groups. Overall, our findings of more pronounced local connectivity alterations in females with ASD could indicate a greater etiological load for an ASD diagnosis in this group congruent with the female protective effect hypothesis.
... Therefore, the application of graph theory to structural networks is likely crucial to developing a comprehensive understanding of the brain basis of episodic memory. Support for this assertion is evident in a study applying graph theory methods to both functional and structural (derived from diffusion-weighted imaging) networks and using repetitive transcranial magnetic stimulation (rTMS) to investigate the impact of prefrontal cortex (PFC) connectivity on episodic memory encoding [15]. Results revealed that the impact of rTMS on functional connectivity depended on the level of structural connectivity, with high structural connectivity associated with a larger magnitude of impact of rTMS on functional connectivity. ...
Article
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Episodic memory is supported by a distributed network of brain regions, and this complex network of regions does not operate in isolation. To date, neuroscience research in this area has typically focused on the activation levels in specific regions or pairwise connectivity between such regions. However, research has yet to investigate how the complex interactions of structural brain networks influence episodic memory abilities. We applied graph theory methods to diffusion-based anatomical networks in order to examine the structural architecture of the medial temporal lobe needed to support effective episodic memory functioning. We examined the relationship between performance on tests of verbal and non-verbal episodic memory with node strength, which indexes how well connected a brain region is in the network. Findings mapped onto the Posterior Medial memory system, subserved by the parahippocampal cortex and overlapped with findings of previous studies of episodic memory employing different methodologies. This expands our current understanding by providing independent evidence for the importance of identified regions and suggesting the particular manner in which these regions support episodic memory.
... How do age-related changes in synaptic plasticity, discussed below, affect DRT performance? Might neuromodulation (Arnsten et al., 2012;Davis et al., 2017;Wang et al., 2019) during working memory task performance reduce the pyramidal neuron hyperexcitability observed in vitro? Computational models provide an essential means for testing and refining hypotheses as future data become available. ...
Article
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Behavioral studies have shown spatial working memory impairment with aging in several animal species, including humans. Persistent activity of layer 3 pyramidal dorsolateral prefrontal cortex (dlPFC) neurons during delay periods of working memory tasks is important for encoding memory of the stimulus. In vitro studies have shown that these neurons undergo significant age-related structural and functional changes, but the extent to which these changes affect neural mechanisms underlying spatial working memory is not understood fully. Here, we confirm previous studies showing impairment on the Delayed Recognition Span Task in the spatial condition (DRSTsp), and increased in vitro action potential firing rates (hyperexcitability), across the adult life span of the rhesus monkey. We use a bump attractor model to predict how empirically observed changes in the aging dlPFC affect performance on the Delayed Response Task (DRT), and introduce a model of memory retention in the DRSTsp. Persistent activity—and, in turn, cognitive performance—in both models was affected much more by hyperexcitability of pyramidal neurons than by a loss of synapses. Our DRT simulations predict that additional changes to the network, such as increased firing of inhibitory interneurons, are needed to account for lower firing rates during the DRT with aging reported in vivo. Synaptic facilitation was an essential feature of the DRSTsp model, but it did not compensate fully for the effects of the other age-related changes on DRT performance. Modeling pyramidal neuron hyperexcitability and synapse loss simultaneously led to a partial recovery of function in both tasks, with the simulated level of DRSTsp impairment similar to that observed in aging monkeys. This modeling work integrates empirical data across multiple scales, from synapse counts to cognitive testing, to further our understanding of aging in non-human primates.
... rTMS therefore provides an ideal means to test the assumption that a localized change in energy to a modal controller could affect a global change in brain states and concomitant behavior. The effects of neuromodulation are typically observed not only in the stimulated site, but also in distal connected regions (Bestmann et al., 2004;Davis et al., 2017;Ruff et al., 2008;Wang et al., 2014;Wang et al., 2018), and thus the controllability framework offers an opportunity to test the hypothesis that network-level activation due to exogenous neuromodulation can be estimated by the network properties of the stimulated site (Muldoon et al., 2016;Spiegler et al., 2016). ...
Preprint
The brain is an inherently dynamic system, and much work has focused on the ability to modify neural activity through both local perturbations and changes in the function of global network ensembles. Network controllability is a recent concept in network science that purports to predict the influence of individual cortical sites on global network states and state changes, thereby creating a unifying account of local influences on global brain dynamics. Here, we present an integrated set of multimodal brain–behavior relationships, acquired from functional magnetic resonance imaging during a transcranial magnetic stimulation intervention, that demonstrate how network controllability influences network function, as well as behavior. This work helps to outline a clear technique for integrating structural network topology and functional activity to predict the influence of a potential stimulation target on subsequent behaviors and prescribes next steps towards predicting neuromodulatory and behavioral responses after brain stimulation. Highlights - This study tested the strength of network controllability using fMRI and rTMS - Controllability correlates with functional modulation of working memory demand load - Controllability is also correlated with the memory improvement from applied rTMS - These findings link network control theory with physiology and behavior. In brief Beynel et al. show that the benefits of functionally targeted brain stimulation on working memory performance can be predicted by network control properties at the stimulated site. Structural controllability and functional activity independently predict this cognitive benefit. Author Contributions Conceptualization & Methodology: L.B, S.W.D., B.L., R.C., L.G.A.; Investigation: L.B., L.D., S.W.D., C.A.C., M.D., H.P., S.H.; Writing—Original Draft: L.B., L.D., S.W.D.; Writing—Review & Editing: L.B., L.D., S.W.D., L.G.A., A.V.P.; Funding Acquisition: S.W.D., R.C., B.L., S.H.L., A.V.P.; Resources: L.G.A., B.L., R.C.; Supervision: L.G.A., S.W.D.
... How central a role does synaptic facilitation play during the task? Might neuromodulation (Arnsten et al. 2012;Davis et al. 2017;Wang et al. 2019) during working memory task performance reduce the pyramidal neuron hyperexcitability observed in vitro? Computational models provide an essential means for testing and refining hypotheses as future data become available. ...
Preprint
Behavioral studies have shown spatial working memory impairment with aging in several animal species, including humans. Persistent activity of layer 3 pyramidal dlPFC neurons during delay periods of working memory tasks is important for encoding memory of the stimulus. In vitro studies have shown that these neurons undergo significant age-related structural and functional changes, but the extent to which these changes affect neural mechanisms underlying spatial working memory is not understood fully. Here we confirm previous studies showing impairment on the Delayed Recognition Span Task in the spatial condition (DRSTsp), and increased action potential firing rates, across the adult life span of the rhesus monkey. We use a bump attractor model to predict how empirically observed changes in the aging dlPFC affect performance on the Delayed Response Task, and introduce a model of memory retention in the DRSTsp. Persistent activity in both models was severely affected by pyramidal neuron hyperexcitability (Chang et al. 2005), but not by a loss of synapses (Peters et al. 2008), and was enhanced by synaptic facilitation. Modeling hyperexcitability and synapse loss simultaneously led to a partial recovery of function, so that the simulated level of DRSTsp impairment was consistent with that observed in aging monkeys.
... Where Ζ ̅ is the mean r-values between nodes of one partition, module, or system (similar to within-266 module degree or WMD), and Ζ ̅ is the mean of r-values between nodes of separate partitions (similar 267 to between-module degree or BMD, Davis et al., 2017). Accordingly, values greater than 0 reflect 268 All rights reserved. ...
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Neuroimaging evidence suggests that the aging brain relies on a more distributed set of cortical regions than younger adults in order to maintain successful levels of performance during demanding cognitive tasks. However, it remains unclear how task demands give rise to this age-related expansion in cortical networks. To investigate this issue, we used functional magnetic resonance imaging to measure univariate activity, network connectivity, and cognitive performance in younger and older adults during a working memory (WM) task. In the WM task investigated, participants hold letters online (maintenance) while reordering them alphabetically (manipulation). WM load was titrated to obtain four individualized difficulty levels. Network integration—defined as the ratio of within-versus between-network connectivity—was linked to individual differences in WM capacity. The study yielded three main findings. First, as task difficulty increased, network integration decreased in younger adults, whereas it increased in older adults. Second, age-related increases in network integration were driven by increases in right hemispheric connectivity to both left and right cortical regions, a finding that helps to reconcile extant theories of compensatory recruitment in aging to address the multivariate dynamics of global network functioning. Lastly, older adults with higher WM capacity demonstrated higher levels of network integration in the most difficult condition. These results shed light on the mechanisms of age-related network reorganization by suggesting that changes in network connectivity may act as an adaptive form of compensation, with older adults recruiting a more distributed cortical network as task demands increase. Significance statement Older adults often activate brain regions not engaged by younger adults, but the circumstances under which this widespread network emerges are unclear. Here, we examined the effects of aging on network connectivity between task regions recruited during a working memory (WM) manipulation task, and the rest of the brain. We found an age-related increase in the more global network integration in older adults, and an association between this integration and working memory capacity in older adults. The findings are generally consistent with the compensatory interpretation of these effects.
... Puis confirmés à de nombreuses reprises chez l'animal (Seewoo et al., 2018) et chez l'Homme (Tracy et al., 2010) où il a été montré qu'une stimulation à 1Hz diminuait l'activité corticale sous-jacente à la stimulation mais également à distance de la cible ( Figure 5.2). Par ailleurs, il a été retrouvé de manière cohérente avec les études sur le neurone une distinction d'effets entre les fréquences de stimulation, les basses fréquences (1Hz) étant inhibitrices de l'activité cérébrale alors que les hautes fréquences (5Hz) étaient excitatrices (Davis et al., 2017). Enfin, (Esser et al., 2005;Radman et al., 2009;Silva et al., 2008) proposent à travers leur modèles de connexion thalamo-corticale un mécanisme d'action mettant en jeu des activations indirectes (I-waves) permettant de faire le lien entre activations neuronales locales et activations à distance, notamment thalamique. ...
Thesis
La douleur neuropathique centrale est une séquelle fréquente après une atteinte du système nerveux centrale. L’impact négatif de ces douleurs sur la qualité de vie des patients ainsi que l’efficacité modérée (40% de répondeurs) des traitements de 1ère intention font de la recherche de thérapies alternatives un enjeu clinique majeur. Depuis plusieurs années, la technique de stimulation magnétique transcrânienne répétée (rTMS) est présentée comme un outil intéressant pour soulager ce type de douleur sans pour autant que son efficacité clinique n’ait été clairement démontrée. Ce travail de thèse s’attache donc à investiguer l’efficacité de la rTMS pour traiter les douleurs neuropathiques centrales.Nous avons dans un premier temps mis en évidence, dans une étude observationnelle, qu’un minimum de 4-5 séances sur deux mois de rTMS à 20HZ sur le cortex moteur primaire (M1) produit un soulagement de la douleur pouvant se maintenir même après une année de stimulation. Afin d’écarter un possible effet placebo, nous avons objectivé l’efficacité antalgique en répliquant ce protocole dans une étude clinique randomisée, contrôlée, en groupes croisés. Les résultats obtenus confirment ceux de l’étude observationnelle puisque que l’effet antalgique de la rTMS active était significativement supérieure à la stimulation placebo pour le critère principal (% de soulagement, +33%) ou l’intensité douloureuse (EVA, -19%), avec 47% de répondeurs. Pour les patients non-répondeurs à la stimulation de M1, nous avons également testé contre placebo, dans une étude randomisée, l’efficacité d’une cible alternative : le cortex somesthésique secondaire (S2). Aucun des patients n’a été soulagé par cette stimulation mais le faible effectif de cette étude ne nous permet pas de conclure définitivement à l’absence d’effet antalgique. Enfin, compte tenu de l’utilisation croissante de nouvelles cibles corticales plus profondes, nous avons à partir de l’enregistrement du champ-magnétique produit par la rTMS dans différents milieux (l’air et modèle ex-vivo), proposé un modèle de distribution de ce champ selon la profondeur de la cible et le type de sonde de stimulation utilisé.Pour conclure, ces travaux objectivent l’effet antalgique de 4 séances de rTMS à 20Hz de M1 sur les douleurs neuropathiques centrales, validant ainsi son utilisation lorsque les traitements de 1ère intention ont échoué. Les résultats obtenus par la stimulation de S2 ainsi que par la modélisation du champ magnétique doivent permettre à de futures études d’explorer de nouvelles cibles corticales pour les patients qui restent encore en échec de traitement.
... Task-related 322 connectivity was estimated from the resulting output matrices; negative connections were included in these 323 analyses, as they may inform important, explicit interpretations about how networks may be segregated (Yeh 324 et al., 2016). Graph metrics, including modularity (describing the modular organization of the whole-brain 325 graph) and strength (describing a sum of the connectivity strengths for each node) were computed using the 326 Brain Connectivity Toolbox as described previously (Davis et al., 2017) and, when appropriate, summed 327 across all nodes within a task-related network. ...
Preprint
Working memory (WM) is assumed to consist of a process that sustains memory representations in an active state ( maintenance ) and a process that operates on these activated representations ( manipulation ). Prior fMRI studies have examined maintenance and manipulation in separate task conditions, whereas in real life these processes operate simultaneously. In the current study, the neural mechanisms of maintenance and manipulation were disentangled during the same task by parametrically varying these processes. During fMRI, participants maintained consonant letters in WM while sorting them in alphabetical order. Maintenance was investigated by varying the number of letters held in WM and manipulation by varying the number of moves required to sort the list alphabetically. The study yielded three main findings. First, the degree of both maintenance and manipulation demand had significant effects on behavior that were associated with different cortical regions: maintenance was associated with bilateral prefrontal and left parietal cortex, and manipulation with right parietal activity, a link that is consistent with the role of parietal cortex in symbolic computations. Second, univariate fMRI and tractography based on diffusion-weighted imaging showed that maintenance and manipulation regions are supported by two dissociable structural networks. Finally, maintenance and manipulation functional networks became increasingly segregated with increasing demand, possibly reflecting the protection of information held in WM from interference generated by manipulation operations. These results represent a novel approach to study the brain as an adaptive system that coordinates multiple ongoing cognitive processes. Significance Statement Despite the importance of working memory (WM) in everyday life, little is known about how the brain is able to simultaneously maintain and manipulate information stored in short-term memory buffers. We examined evidence for two distinct, concurrent cognitive functions supporting maintenance and manipulation abilities by testing brain activity as participants performed a WM alphabetization task. We found behavioral and neural evidence in support of dissociable cognitive functions associated with these two operations. Furthermore, we found that connectivity between these networks was increasingly segregated as difficulty increased, and that this effect was positively related to individual WM ability. These results provide evidence that network segregation may act as a protective mechanism to enable successful performance under increasing WM demand.
... This finding is consistent with prior results showing that small adjustments in stimulation frequency affects which nodes within a single resting state network (RSN) are engaged [36,37], the extent to which rTMS stimulation changes local vs. distant network modules [38], and the degree of engagement between a RSN and an affiliated brain region. For example, different stimulation frequencies applied to a parietal node can change interactions of the frontoparietal control network (FCN) with the default mode network (DMN) from excitatory to inhibitory [39]. ...
Article
Background: The individual α frequency (IAF) has been associated with the outcome of repetitive Transcranial Magnetic Stimulation (rTMS) treatment of Major Depressive Disorder (MDD), but the association has been inconsistent. Hypothesis: Proximity of IAF to the stimulation frequency, rather than the value of IAF per se, is associated with outcome for patients receiving 10 Hz rTMS. Methods: We examined the relationships between IAF, rTMS stimulation frequency, and treatment outcome in 147 patients. All patients initially received 10 Hz rTMS unilateral treatment delivered to left dorsolateral prefrontal cortex (DLPFC) (10UL), with subsets of patients changed to unilateral 5 Hz to left DLPFC (5UL) or sequential bilateral (SB) stimulation (10 Hz/1Hz) to left and right DLPFC based upon worsening symptoms with or intolerance of 10UL. Outcome was percent change in total score on the Inventory of Depressive Symptomatology – Self Report (IDS-SR) scale from pre-treatment baseline to the 30th treatment. IAF values and absolute difference between IAF and 10 Hz (|IAF-10Hz|) were examined in relation to outcome for the overall sample and for each stimulation group separately. Results: There was no correlation between IAF value, or |IAF-10Hz| and outcome in the overall sample. ANCOVA showed a significant interaction between IAF measures and treatment type. Post-hoc analyses revealed that IAF and |IAF-10Hz| were both significantly associated with degree of improvement (IDS-SR % change) for patients who received 10UL (P
... Both clinical and basic science targeting approaches for TMS should consider the consequences of regional brain stimulation in manipulating more global functional and structural networks connected to the stimulation site (J. X. Wang and Voss, 2015;Davis et al., 2017;W. C. Wang et al., 2018). ...
Article
The brain is an inherently dynamic system, and much work has focused on the ability to modify neural activity through both local perturbations and changes in the function of global network ensembles. Network controllability is a recent concept in network neuroscience that purports to predict the influence of individual cortical sites on global network states and state changes, thereby creating a unifying account of local influences on global brain dynamics. While this notion is accepted in engineering science, it is subject to ongoing debates in neuroscience as empirical evidence linking network controllability to brain activity and human behavior remains scarce. Here, we present an integrated set of multimodal brain–behavior relationships derived from fMRI, diffusion tensor imaging, and online repetitive transcranial magnetic stimulation (rTMS) applied during an individually calibrated working memory task performed by individuals of both sexes. The modes describing the structural network system dynamics showed direct relationships to brain activity associated with task difficulty, with difficult-to-reach modes contributing to functional brain states in the hard task condition. Modal controllability (a measure quantifying the contribution of difficult-to-reach modes) at the stimulated site predicted both fMRI activations associated with increasing task difficulty and rTMS benefits on task performance. Furthermore, fMRI explained 64% of the variance between modal controllability and the working memory benefit associated with 5 Hz online rTMS. These results therefore provide evidence toward the functional validity of network control theory, and outline a clear technique for integrating structural network topology and functional activity to predict the influence of stimulation on subsequent behavior.
... Although there are many approaches to TMS targeting [11][12][13] , including the 5-cm rule commonly used to target the dorsolateral prefrontal cortex (dlPFC) in depression protocols [14][15][16] , greater precision can be achieved by defining subject-specific targets with fMRI and using neuronavigation [17][18][19] . fMRI, a widely used method for studying brain activity during cognitive paradigms, can deliver subject-specific, high-resolution maps of the entire brain that reflect changes in metabolic activity due to task demands [20][21][22] . ...
Article
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Transcranial magnetic stimulation (TMS) is a noninvasive method to stimulate the cerebral cortex that has applications in psychiatry, such as in the treatment of depression and anxiety. Although many TMS targeting methods that use figure-8 coils exist, many do not account for individual differences in anatomy or are not generalizable across target sites. This protocol combines functional magnetic resonance imaging (fMRI) and iterative electric-field (E-field) modeling in a generalized approach to subject-specific TMS targeting that is capable of optimizing the stimulation site and TMS coil orientation. To apply this protocol, the user should (i) operationally define a region of interest (ROI), (ii) generate the head model from the structural MRI data, (iii) preprocess the functional MRI data, (iv) identify the single-subject stimulation site within the ROI, and (iv) conduct E-field modeling to identify the optimal coil orientation. In comparison with standard targeting methods, this approach demonstrates (i) reduced variability in the stimulation site across subjects, (ii) reduced scalp-to-cortical-target distance, and (iii) reduced variability in optimal coil orientation. Execution of this protocol requires intermediate-level skills in structural and functional MRI processing. This protocol takes ~24 h to complete and demonstrates how constrained fMRI targeting combined with iterative E-field modeling can be used as a general method to optimize both the TMS coil site and its orientation.
... The study overall indicates that anatomic bilateral symmetry is preserved in the aging human brain, supporting recent findings that postulate increased communication between distant brain areas as a mechanism to compensate for the deleterious effects of aging [Davis et al., 2017]. The characterization of brain subcortical symmetry proposed here allows new views of interhemispheric and intrahemispheric volume variation, setting the basis for future studies of anatomical symmetry and asymmetry in healthy brain aging. ...
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Here we address the hemispheric interdependency of subcortical structures in the aging human brain. In particular, we investigate whether volume variation can be explained with the adjacency of structures in the same hemisphere or is due to the interhemispheric development of mirror subcortical structures in the brain. Seven subcortical structures in both hemispheres were automatically segmented in a large sample of over three 3,312 magnetic resonance imaging (MRI) studies of elderly individuals in their 70s and 80s. We perform Eigenvalue analysis to find that anatomic volumes in the limbic system and basal ganglia show similar statistical dependency when considered in the same hemisphere (intrahemispheric) or in different hemispheres (interhemispheric). Our results indicate that anatomic bilaterality is preserved in the aging human brain, supporting the hypothesis that coupling between non-adjacent brain areas could act as a mechanism to compensate for the deleterious effects of aging.
... This CTG algorithm summarizes connectivity in canonical, well-characterized fiber systems. Streamline connectivity between regions of interest (ROIs) of a subparcellated version of the Harvard-Oxford Atlas (Tzourio-Mazoyer et al., 2002), defined originally in MNI space, and used previously in our work (Beynel et al., 2020;Davis et al., 2017) and others (Hall et al. 2021). One disadvantage of this standard atlas is that the ROIs could have different sizes. ...
Article
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Multiple sclerosis (MS) is a progressive disease characterized by widespread white matter lesions in the brain and spinal cord. In addition to well-characterized motor deficits, MS results in cognitive impairments in several domains, notably in episodic autobiographical memory. Recent studies have also revealed that patients with MS exhibit deficits in episodic future thinking, i.e., our capacity to imagine possible events that may occur in our personal future. Both episodic memory and episodic future thinking have been shown to share cognitive and neural mechanisms with a related kind of hypothetical simulation known as episodic counterfactual thinking: our capacity to imagine alternative ways in which past personal events could have occurred but did not. However, the extent to which episodic counterfactual thinking is affected in MS is still unknown. The current study sought to explore this issue by comparing performance in mental simulation tasks involving either past, future or counterfactual thoughts in relapsing-remitting MS. Diffusion weighted imaging (DWI) measures were also extracted to determine whether changes in structural pathways connecting the brain’s default mode network (DMN) would be associated with group differences in task performance. Relative to controls, patients showed marked reductions in the number of internal details across all mental simulations, but no differences in the number of external and semantic-based details. It was also found that, relative to controls, patients with relapsing-remitting MS reported reduced composition ratings for episodic simulations depicting counterfactual events, but not so for actual past or possible future episodes. Additionally, three DWI measures of white matter integrity—fractional anisotropy, radial diffusivity and streamline counts—showed reliable differences between patients with relapsing-remitting MS and matched healthy controls. Importantly, DWI measures associated with reduced white matter integrity in three association tracts on the DMN—the right superior longitudinal fasciculus, the left hippocampal portion of the cingulum and the left inferior longitudinal fasciculus—predicted reductions in the number of internal details during episodic counterfactual simulations. Taken together, these results help to illuminate impairments in episodic simulation in relapsing-remitting MS and show, for the first time, a differential association between white matter integrity and deficits in episodic counterfactual thinking in individuals with relapsing-remitting MS.
... Older adults with comparable memory performance showed more bilateral prefrontal activation, while older adults with lower performance maintained asymmetric activation (Cabeza et al., 2002). To support the idea that cognitive reserve in older adults is dependent on an ability to recruit a more distributed neural network, Cabeza et al. (2002) applied a low frequency stimulation to depress prefrontal activity during a memory encoding and retrieval task and found bilateral prefrontal recruitment compensating for local inhibition (Davis et al., 2017). However, increased neural activity in dentate/CA3 region and decreased neural activity in anterolateral EC in older adults can lead to pattern separation impairments (Yassa et al., 2011;Reagh et al., 2018). ...
Article
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With aging comes a myriad of different disorders, and cognitive decline is one of them. Studies have consistently shown a decline amongst aged subjects in their ability to acquire and maintain temporal associative memory. Defined as the memory of the association between two objects that are separated in time, temporal associative memory is dependent on neocortical structures such as the prefrontal cortex and temporal lobe structures. For this memory to be acquired, a mental trace of the first stimulus is necessary to bridge the temporal gap so the two stimuli can be properly associated. Persistent firing, the ability of the neuron to continue to fire action potentials even after the termination of a triggering stimulus, is one mechanism that is posited to support this mental trace. A recent study demonstrated a decline in persistent firing ability in pyramidal neurons of layer III of the lateral entorhinal cortex with aging, contributing to learning impairments in temporal associative memory acquisition. In this work, we explore the potential ways persistent firing in lateral entorhinal cortex (LEC) III supports temporal associative memory, and how aging may disrupt this mechanism within the temporal lobe system, resulting in impairment in this crucial behavior.
... Evidence supports transsynaptic action of superficial TMS into deep brain regions. TMS studies utilizing concurrent neuroimaging with fMRI ( Baudewig et al., 2001 ;Bestmann et al., 2003 ;Roberts et al., 1997 ;Bohning et al., 1998 ;Davis et al., 2017 ;Tik et al., 2017 ), PET ( Fox et al., 1997 ;Ferrarelli et al., 2004 ), and EEG ( Ilmoniemi et al., 1997 ), have demonstrated that TMS stimulation of superficial cortical targets can re-sult in measurable effects at remote sites including those that are deep relative to the surface of the brain such as the hippocampus and other limbic regions ( Denslow et al., 2005 ;Li et al., 2004 ;Bestmann et al., 2004 ;Wang et al., 2018 ). For example, TMS of the motor cortex induced measurable dopamine release in the putamen while rTMS of the DLPFC induced dopamine release in the head of the caudate ( Strafella et al., 2003( Strafella et al., , 2005Cho and Strafella, 2009 ). ...
Article
TMS has become a powerful tool to explore cortical function, and in parallel has proven promising in the development of therapies for various psychiatric and neurological disorders. Unfortunately, much of the inference of the direct effects of TMS has been assumed to be limited to the area a few centimeters beneath the scalp, though clearly more distant regions are likely to be influenced by structurally connected stimulation sites. In this study, we sought to develop a novel paradigm to individualize TMS coil placement to non-invasively achieve activation of specific deep brain targets of relevance to the treatment of psychiatric disorders. In ten subjects, structural diffusion imaging tractography data were used to identify an accessible cortical target in the right frontal pole that demonstrated both anatomic and functional connectivity to right Brodmann area 25 (BA25). Concurrent TMS-fMRI interleaving was used with a series of single, interleaved TMS pulses applied to the right frontal pole at four intensity levels ranging from 80% to 140% of motor threshold. In nine of ten subjects, TMS to the individualized frontal pole sites resulted in significant linear increase in BOLD activation of BA25 with increasing TMS intensity. The reliable activation of BA25 in a dosage-dependent manner suggests the possibility that the careful combination of imaging with TMS can make use of network properties to help overcome depth limitations and allow noninvasive brain stimulation to influence deep brain structures.
... Information on the structural connections based on diffusion tractography between each pair of regions in our data was assessed with a standard DWI processing pipeline used previously in our group Davis et al., 2018;Davis et al., 2017). DWI data were analyzed using FSL and MRtrix (http://mrtrix.org) ...
Article
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Background Online repetitive transcranialmagnetic stimulation (rTMS) has been shown to modulate working memory (WM) performance in a site‐specific manner, with behavioral improvements due to stimulation of the dorsolateral prefrontal cortex (DLPFC), and impairment from stimulation to the lateral parietal cortex (LPC). Neurobehavioral studies have demonstrated that subprocesses of WM allowing for the maintenance and manipulation of information in the mind involve unique cortical networks. Despite promising evidence of modulatory effects of rTMS on WM, no studies have yet demonstrated distinct modulatory control of these two subprocesses. The current study therefore sought to explore this possibility through site‐specific stimulation during an online task invoking both skills. Methods Twenty‐nine subjects completed a 4‐day protocol, in which active or sham 5Hz rTMS was applied over the DLPFC and LPC in separate blocks of trials while participants performed tasks that required either maintenance alone, or both maintenance and manipulation (alphabetization) of information. Stimulation targets were defined individually based on fMRI activation and structural network properties. Stimulation amplitude was adjusted using electric field modeling to equate induced current in the target region across participants. Results Despite the use of advanced techniques, no significant differences or interactions between active and sham stimulation were found. Exploratory analyses testing stimulation amplitude, fMRI activation, and modal controllability showed nonsignificant but interesting trends with rTMS effects. Conclusion While this study did not reveal any significant behavioral changes in WM, the results may point to parameters that contribute to positive effects, such as stimulation amplitude and functional activation.
... The sustained physiologic and behavioral effects of rTMS are highly dependent upon the frequency of stimulation [17][18][19][20][21]. Different frequencies of stimulation applied to a single site in the brain may have distinct effects on task performance, as well as the connectivity of that site to other brain regions [16,22]. Modifying the frequency of stimulation affects which nodes within a network are engaged [23,24], the extent to which rTMS engages local vs. ...
Article
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Background Repetitive Transcranial Magnetic Stimulation (rTMS) is an effective treatment for Major Depressive Disorder (MDD), but therapeutic benefit is highly variable. Clinical improvement is related to changes in brain circuits which have preferred resonant frequencies (RFs) and vary across individuals. Objective We developed a novel rTMS-electroencephalography (rTMS-EEG) interrogation paradigm to identify RFs using the association of power/connectivity measures with symptom severity and treatment outcome. Methods 35 subjects underwent rTMS interrogation at 71 frequencies ranging from 3-17 Hz administered to left dorsolateral prefrontal cortex (DLPFC). TMS-EEG was used to assess resonance in oscillatory power/connectivity changes (phase coherence (PC), envelope correlation (EC), and spectral correlation coefficient (SCC)) after each frequency. Multiple regression was used to detect relationships between 10 Hz resonance and baseline symptoms as well as clinical improvement after 10 sessions of 10 Hz rTMS treatment. Results Baseline symptom severity was significantly associated with SCC resonance in left sensorimotor (SM; p < 0.0004), PC resonance in fronto-parietal (p = 0.001), and EC resonance in centro-posterior channels (p = 0.002). Subjects significantly improved with 10 sessions of rTMS treatment. Only decreased SCC SM resonance was significantly associated with clinical improvement (r = 0.35, p = 0.04). Subjects for whom 10 Hz SM SCC was highly ranked as an RF among all stimulation frequencies had better outcomes from 10 Hz treatment. Conclusions Resonance of 10 Hz stimulation measured using SCC correlated with both symptom severity and improvement with 10 Hz rTMS treatment. Research should determine whether this interrogation paradigm can identify individualized rTMS treatment frequencies.
... The study overall indicates that anatomic bilateral symmetry is preserved in the aging human brain, supporting recent findings that postulate increased communication between distant brain areas as a mechanism to compensate for the deleterious effects of aging (Davis et al. 2017). The characterization of brain subcortical symmetry proposed here allows new views of interhemispheric and intrahemispheric volume variation, setting the basis for future studies of anatomical symmetry and asymmetry in healthy brain aging. ...
Article
Full-text available
Here, we address the hemispheric interdependency of subcortical structures in the aging human brain. In particular, we investigated whether subcortical volume variations can be explained by the adjacency of structures in the same hemisphere or are due to the interhemispheric development of mirror subcortical structures in the brain. Seven subcortical structures in each hemisphere were automatically segmented in a large sample of 3312 magnetic resonance imaging (MRI) studies of elderly individuals in their 70s and 80s. We performed Eigenvalue analysis, and found that anatomic volumes in the limbic system and basal ganglia show similar statistical dependency whether considered in the same hemisphere (intrahemispherically) or different hemispheres (interhemispherically). Our results indicate that anatomic bilaterality of subcortical volumes is preserved in the aging human brain, supporting the hypothesis that coupling between non-adjacent subcortical structures might act as a mechanism to compensate for the deleterious effects of aging.
... High rsFC between regions can occur via intermediate nodes (Honey et al., 2009) where anatomical connectivity exists (Davis et al., 2017;Gong et al., 2009), and models based on anatomical connectivity account for the effects of TMS on network rsFC (Muldoon et al., 2016). Individual differences in pathway anatomy also have potential to explain the wide variability in the physiological (López-Alonso et al., 2014) and behavioral (Nicolo et al., 2015) responses to rTMS. ...
Article
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Repetitive transcranial magnetic stimulation (rTMS) of the inferior parietal cortex (IPC) increases resting-state functional connectivity (rsFC) of the hippocampus with the precuneus and other posterior cortical areas and causes proportional improvement of episodic memory. The anatomical pathway(s) responsible for the propagation of these effects from the IPC is unknown and may not be direct. In order to assess the relative contributions of candidate pathways from the IPC to the MTL via the parahippocampal cortex and precuneus, to the effects of rTMS on rsFC and memory improvement, we used diffusion tensor imaging to measure the extent to which individual differences in fractional anisotropy (FA) in these pathways accounted for individual differences in response. FA in the IPC-parahippocampal pathway and several MTL pathways predicted changes in rsFC. FA in both parahippocampal and hippocampal pathways was related to changes in episodic, but not procedural, memory. These results implicate pathways to the MTL in the enhancing effect of parietal rTMS on hippocampal rsFC and memory.
... Brain imaging analyses revealed that DLPFC stimulation before learning altered connectivity in fronto-hippocampal and striatal networks during motor sequence learning. These results are in line with previous research in both the motor (Herz et al., 2014) and the declarative memory domain (Bilek et al., 2013;Esslinger et al., 2014;Davis et al., 2017) showing that frontal stimulation can alter task-related connectivity patterns of frontal areas with other cortical areas as well as with deep regions including the basal ganglia and the hippocampus. ...
Article
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While it is widely accepted that motor sequence learning (MSL) is supported by a prefrontal-mediated interaction between hippocampal and striatal networks, it remains unknown whether the functional responses of these networks can be modulated in humans with targeted experimental interventions. The present proof-of-concept study employed a multimodal neuroimaging approach, including functional magnetic resonance (MR) imaging and MR spectroscopy, to investigate whether individually-tailored theta-burst stimulation of the dorsolateral prefrontal cortex can modulate responses in the hippocampus and the basal ganglia during motor learning. Our results indicate that while stimulation did not modulate motor performance nor task-related brain activity, it influenced connectivity patterns within hippocampo-frontal and striatal networks. Stimulation also altered the relationship between the levels of gamma-aminobutyric acid (GABA) in the stimulated prefrontal cortex and learning-related changes in both activity and connectivity in fronto-striato-hippocampal networks. This study provides the first experimental evidence, to the best of our knowledge, that brain stimulation can alter motor learning-related functional responses in the striatum and hippocampus.
... In the future, a larger sample size is needed to explore the therapeutic pathways pertaining to the network connectivity of anterior hippocampus. Lastly, this study only investigated high-frequency effects [48]. Previous studies indicated that there were frequency-specific neuromodulation effects on improving episodic memory. ...
Article
Hippocampal subregions (HIPsub) and their network connectivities are generally aberrant in patients with subjective cognitive decline (SCD). This study aimed to investigate whether repetitive transcranial magnetic stimulation (rTMS) could ameliorate HIPsub network connectivity by modulating one node of HIPsub network in SCD. In the first cohort, the functional connectivity (FC) of three HIPsub (i.e., hippocampal emotional, cognitive, and perceptual regions: HIPe, HIPc, and HIPp) were analyzed so as to identify alterations in HIPsub connectivity associated with SCD. Afterwards, a support vector machine (SVM) approach was applied using the alterations in order to evaluate to what extent we could distinguish SCD from healthy controls (CN). In the second cohort, a 2-week rTMS course of 5-day, once-daily, was used to activate the altered HIPsub network connectivity in a sham-controlled design. SCD subjects exhibited distinct patterns alterations of HIPsub network connectivity compared to CN in the first cohort. SVM classifier indicated that the abnormalities had a high power to discriminate SCD from CN, with 92.9% area under the receiver operating characteristic curve (AUC), 86.0% accuracy, 83.8% sensitivity and 89.1% specificity. In the second cohort, changes of HIPc connectivity with the left parahippocampal gyrus and HIPp connectivity with the left middle temporal gyrus demonstrated an amelioration of episodic memory in SCD after rTMS. In addition, SCD exhibited improved episodic memory after the rTMS course. rTMS therapy could improve the posterior hippocampus connectivity by modulating the precuneus in SCD. Simultaneous correction of the breakdown in HIPc and HIPp could ameliorate episodic memory in SCD. Thus, these findings suggested that rTMS manipulation of precuneus-hippocampal circuit might prevent disease progression by improving memory as the earliest at-risk state of Alzheimer's disease in clinical trials and in practice.
... There are many different types of TMS protocols: repetitive TMS (rTMS), used to induce changes in brain activity even after the stimulation period 12 , single-pulse TMS (sTMS), used to explore brain functioning, and deep TMS (dTMS), which can modulate cortical excitability up to a maximum depth of 6 cm from the scalp, interfering, therefore, with deeper neural circuits 13 . The effect of TMS stimulation can be activating (Hz ≥ 10) or inhibiting (Hz ≤ 5) and it may vary according to the area stimulated and the coil type used [14][15][16][17] . Coils, which differ in shapes, are chosen in relation to their proprieties and the aim of the treatment. ...
Article
Objective. The aim of the present meta-analysis was to investigate the safety of different Transcranical Magnetic Stimulation (TMS) protocols in pathological and healthy samples. Methods. We used the following search words on Pubmed and Scopus, alone or in combination: TMS, side effects, secondary effects, adverse events (AEs). Comprehensive Meta-Analysis Software version 2 was used for data analysis. Results. One-hundred and nine original papers were included in our quantitative synthesis, involving both healthy (N = 475) and pathological subjects (N = 4880). The pooled rate of dropouts due to side effects was 3.0%; subjects reporting at least one side effect were 13.7%. Headache, painful sensations, muscle twitching, ocular problems and discomfort were significantly related to active stimulation. Conclusions. The results of our meta-analysis state that TMS is usually a safe technique, with mild and transient adverse events, that rarely provoke dropouts. Beside a complete assessment of the efficacy of TMS in different pathological conditions, it's also important to report in a clear and standardized way the occurrence of AEs.
... There are other techniques, such as measures of glucose utilization [257], beta-amyloid burden [258], synaptic density [259], optical imaging [260], PET markers of neuroinflammation [261,262], MR spectroscopic measures of the neurotransmitters [263,264] and even non-invasive brain stimulation [265,266] that may further help understand the basis of BOLD signals, but are beyond the scope of this review. ...
Article
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Accurate identification of brain function is necessary to understand the neurobiology of cognitive ageing, and thereby promote well-being across the lifespan. A common tool used to investigate neurocognitive ageing is functional magnetic resonance imaging (fMRI). However, although fMRI data are often interpreted in terms of neuronal activity, the blood oxygenation level-dependent (BOLD) signal measured by fMRI includes contributions of both vascular and neuronal factors, which change differentially with age. While some studies investigate vascular ageing factors, the results of these studies are not well known within the field of neurocognitive ageing and therefore vascular confounds in neurocognitive fMRI studies are common. Despite over 10 000 BOLD-fMRI papers on ageing, fewer than 20 have applied techniques to correct for vascular effects. However, neurovascular ageing is not only a confound in fMRI, but an important feature in its own right, to be assessed alongside measures of neuronal ageing. We review current approaches to dissociate neuronal and vascular components of BOLD-fMRI of regional activity and functional connectivity. We highlight emerging evidence that vascular mechanisms in the brain do not simply control blood flow to support the metabolic needs of neurons, but form complex neurovascular interactions that influence neuronal function in health and disease. This article is part of the theme issue ‘Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity’.
... Connectomes were generated by using FLIRT to apply a linear registration to a 471-region subparcellated version of the Harvard-Oxford atlas (HOA) (Davis et al., 2017) to register it to each subject's native diffusion space. The sub-parcellated HOA has the advantage of full cortical and subcortical coverage and relatively uniform, isometric ROI sizes. ...
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Brain regions within a posterior medial network (PMN) are characterized by sensitivity to episodic tasks, and they also demonstrate strong functional connectivity as part of the default network. Despite its cohesive structure, delineating the intranetwork organization and functional diversity of the PMN is crucial for understanding its contributions to multidimensional event cognition. Here, we probed functional connectivity of the PMN during movie watching to identify its pattern of connections and subnetwork functions in a split-sample replication of 136 participants. Consistent with prior findings of default network fractionation, we identified distinct PMN subsystems: a Ventral PM subsystem (retrosplenial cortex, parahippocampal cortex, posterior angular gyrus) and a Dorsal PM subsystem (medial prefrontal cortex, hippocampus, precuneus, posterior cingulate cortex, anterior angular gyrus). These subsystems were anchored by two complementary regions: Retrosplenial cortex mediated communication between parahippocampal cortex and the Dorsal PM system, and posterior cingulate cortex mediated communication among Dorsal PM regions. Finally, the distinction between PMN subsystems is functionally relevant: whereas both Dorsal and Ventral PM connectivity tracked the movie content, only Ventral PM connections increased in strength at event transitions and appeared sensitive to episodic memory. Overall, these findings provide a model of PMN pathways and reveal distinct functional roles of intranetwork subsystems associated with event cognition.
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Repetitive transcranial magnetic stimulation (rTMS) has gained considerable importance in the treatment of disorders, e.g. depression. However, it is not yet understood how rTMS alters brain's functional connectivity. Here we report the changes captured by resting state functional magnetic resonance imaging (rsfMRI) within the first hour after 10Hz rTMS in (1) nodes, where the strongest functional connectivity of regions is seen, and (2) boundaries, where functional transitions between regions occur. We use support vector machines (SVM), a widely used machine learning algorithm that has been proven to be robust and effective, for the classification and characterization of time intervals of major changes in node and boundary maps, while respecting the variability between subjects. Particularly in the posterior cingulate cortex and precuneus, our results reveal that the changes in connectivity at the boundaries are slower and more complex than in those observed in the nodes, but of similar magnitude according to accuracy confidence intervals. As the network boundaries are under studied in comparison to nodes in connectomics research, our results highlight their contribution for functional adjustments to rTMS.
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The ability of repetitive transcranial magnetic stimulation (rTMS) to non-invasively induce neuroplasticity in the human cortex has opened exciting possibilities for its application in both basic and clinical research. Changes in the amplitude of motor evoked potentials (MEPs) elicited by single-pulse transcranial magnetic stimulation has so far provided a convenient model for exploring the neurophysiology of rTMS effects on the brain, influencing the ways in which these stimulation protocols have been applied therapeutically. However, a growing number of studies have reported large inter-individual variability in the mean MEP response to rTMS, raising legitimate questions about the usefulness of this model for guiding therapy. Although the increasing application of different neuroimaging approaches has made it possible to probe rTMS-induced neuroplasticity outside the motor cortex to measure changes in neural activity that impact other aspects of human behaviour, the high variability of rTMS effects on these measurements remains an important issue for the field to address. In this review, we seek to move away from the conventional facilitation/inhibition dichotomy that permeates much of the rTMS literature, presenting a non-standard approach for measuring rTMS-induced neuroplasticity. We consider the evidence that rTMS is able to modulate an individual’s moment-to-moment variability of neural activity, and whether this could have implications for guiding the therapeutic application of rTMS.
Chapter
Numerous interrelated factors on the causal pathway to falls in older adults—from gait and balance decline to cognitive dysfunction, depression, and chronic pain—arise at least in part from ineffective and/or inappropriate activation of brain networks. Transcranial electrical stimulation (tES) and transcranial magnetic stimulation (TMS) are two forms of noninvasive brain stimulation capable of selectively modulating the excitability of brain regions of interest and their connected neural networks. While no studies to date have directly examined the effects of tES or TMS interventions on falls in older adults, mounting evidence suggests that each technology holds promise to enhance gait and balance, improve certain aspects of cognitive function, and combat symptoms associated with depression and chronic pain in both aging and disease. This chapter will thus introduce tES and TMS technologies and their application to clinical research in aging, review available literature with potential relevance to falls prevention, and highlight important areas of future research needed to maximize the potential of noninvasive brain stimulation to alleviate the burden of cognitive–motor decline and falls in older adults.
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During demanding cognitive tasks, older adults (OAs) frequently show greater prefrontal cortex (PFC) activity than younger adults (YAs). This age-related increase in PFC activity is often associated with enhanced cognitive performance, suggesting functional compensation. However, the brain is a complex network of interconnected regions, and it is unclear how network connectivity of PFC regions differs for OAs versus YAs. To investigate this, we examined the age-related difference on the functional brain networks mediating episodic memory retrieval. YAs and OAs participants encoded and recalled visual scenes, and age-related differences in network topology during memory retrieval were investigated as a function of memory performance. We measured both changes in functional integration and reconfiguration in connectivity patterns. The study yielded three main findings. First, PFC regions were more functionally integrated with the rest of the brain network in OAs. Critically, this age-related increase in PFC integration was associated with better retrieval performance. Second, PFC regions showed stronger performance-related reconfiguration of connectivity patterns in OAs. Finally, the PFC reconfiguration increases in OAs tracked reconfiguration reductions in the medial temporal lobe (MTL)-a core episodic memory region, suggesting that PFC connectivity in OAs may be compensating for MTL deficits.
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As aging population is increasing, new methodologies to apprehend and enhance the mechanisms related to optimal brain function in advancing age become urgent. This review describes how the combined use of non‐invasive brain stimulation (NIBS) with functional magnetic resonance imaging (fMRI) provides novel experimental data on the putative neurophysiological mechanisms underlying inter‐individual differences in cognitive status among older adults, also further illuminating our understanding of theoretical models proposed within the cognitive neuroscience of aging literature. In addition, it explores published evidence of how this combined procedure entails the capacity to modify the activity and connectivity of specific brain networks in older adults, potentially leading to improvements in cognitive function and other measures reflecting mental health status. Although additional research is needed, combining NIBS with fMRI might provide innovative understanding of how fundamental brain plasticity mechanisms operate in advancing age, a knowledge that may be eventually used to refine more individually tailored approaches to promote brain health in aged populations.
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Brain stimulation technologies have seen increasing application in basic science investigations, specifically towards the goal of improving memory functioning. However, proposals concerning the neural mechanisms underlying cognitive enhancement often rely on simplified notions of excitation and, most applications examining the effects of transcranial magnetic stimulation (TMS) on functional neuroimaging measures have been limited to univariate analyses of brain activity. We present here analyses using representational similarity analysis (RSA) and encoding-retrieval similarity (ERS) analysis in order to quantify the effect of TMS on memory representations. To test whether an increase in local excitability in PFC can have measurable influences on upstream representations in earlier temporal memory regions, we compared 1Hz and 5Hz stimulation to the left dorsolateral PFC. We found that 10 minutes of 5Hz rTMS, relative to 1Hz, had multiple effects on neural representations: 1) greater RSA during both encoding and retrieval, 2) greater ERS across all items, and, critically, 3) increasing ERS in MTL with increasing univariate activity in DLPFC, and greater functional connectivity for hits than misses between these regions. These results provide the first evidence of rTMS enhancing semantic representations and strengthen the idea that rTMS may affect the reinstatement of previously experienced events in upstream regions.
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Repetitive transcranial magnetic stimulation (rTMS) of the inferior parietal cortex (IPC) increases resting-state functional connectivity (rsFC) of the hippocampus with the precuneus and other posterior cortical areas and causes proportional improvement of episodic memory. The anatomical pathway responsible for the propagation of these effects from the IPC is unknown and may not be direct. Using diffusion tensor imaging, we examined whether individual differences in fractional anisotropy (FA), a tensor-derived quantity related to white matter properties, in pathways between the IPC and medial temporal lobe (MTL), via the parahippocampal cortex and the precuneus, accounted for individual differences in hippocampal rsFC and memory change after rTMS. FA in the IPC-parahippocampal pathway was associated with rsFC change in a few small cortical clusters, while FA in the IPC-precuneus pathway was strongly linked to widespread changes in rsFC. FA in both pathways was related to episodic memory, but not to procedural memory. These results implicate pathways to the MTL and to the precuneus in the enhancing effect of parietal rTMS on hippocampal rsFC and memory.
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Episodic memory is thought to rely on interactions of the hippocampus with other regions of the distributed hippocampal‐cortical network (HCN) via interregional activity synchrony in the theta frequency band. We sought to causally test this hypothesis using network‐targeted transcranial magnetic stimulation. Healthy humans participants completed four experimental sessions, each involving a different stimulation pattern delivered to the same individualized parietal cortex location of the HCN for all sessions. There were three active stimulation conditions, including continuous theta‐burst stimulation, intermittent theta‐burst stimulation, and beta‐frequency (20‐Hz) repetitive stimulation, and one sham condition. Resting‐state fMRI and episodic memory testing were used to assess the impact of stimulation on hippocampal fMRI connectivity related to retrieval success. We hypothesized that theta‐burst stimulation conditions would most strongly influence hippocampal‐HCN fMRI connectivity and retrieval, given the hypothesized relevance of theta‐band activity for HCN memory function. Continuous theta‐burst stimulation improved item retrieval success relative to sham and relative to beta‐frequency stimulation, whereas intermittent theta‐burst stimulation led to numerical but nonsignificant item retrieval improvement. Mean hippocampal fMRI connectivity did not vary for any stimulation conditions, whereas individual differences in retrieval improvements due to continuous theta‐burst stimulation were associated with corresponding increases in fMRI connectivity between the hippocampus and other HCN locations. No such memory‐related connectivity effects were identified for the other stimulation conditions, indicating that only continuous theta‐burst stimulation affected memory‐related hippocampal‐HCN connectivity. Furthermore, these effects were specific to the targeted HCN, with no significant memory‐related fMRI connectivity effects for two distinct control brain networks. These findings support a causal role for fMRI connectivity of the hippocampus with the HCN in episodic memory retrieval and indicate that contributions of this network to retrieval are particularly sensitive to continuous theta‐burst noninvasive stimulation. This article is protected by copyright. All rights reserved.
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Brain stimulation technologies have seen increasing application in basic science investigations, specifically toward the goal of improving memory function. However, proposals concerning the neural mechanisms underlying cognitive enhancement often rely on simplified notions of excitation. As a result, most applications examining the effects of transcranial magnetic stimulation (TMS) on functional neuroimaging measures have been limited to univariate analyses of brain activity. We present here analyses using representational similarity analysis (RSA) and encoding-retrieval similarity (ERS) analysis to quantify the effect of TMS on memory representations. To test whether an increase in local excitability in PFC can have measurable influences on upstream representations in earlier temporal memory regions, we compared 1Hz and 5Hz stimulation to the left dorsolateral PFC (DLPFC). We found that 5Hz rTMS, relative to 1Hz, had multiple effects on neural representations: 1) greater representational similarity during both encoding and retrieval in ventral stream regions, 2) greater ERS in the hippocampus, and, critically, 3) increasing ERS in MTL was correlated with increasing univariate activity in DLPFC, and greater functional connectivity for hits than misses between these regions. These results provide the first evidence of rTMS modulating semantic representations and strengthen the idea that rTMS may affect the reinstatement of previously experienced events in upstream regions.
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Purpose: To evaluate the additive effect of Transcranial Direct Current Stimulation (tDCS) associated with multi-component training (MT) on the functional capacity (FC) of older adults and to assess whether these effects remain after the end of training. The secondary objectives were to evaluate the locomotion capacity, balance, functional independence, and quality of life and correlate them with functional capacity. Methodology: Twenty-eight older adults were randomized into two groups: experimental (MT associated with active tDCS - a-tDCS) and control (MT associated with sham tDCS - s-tDCS). The FC was measured by the Glittre-ADL test, locomotion capacity by the 6-minute walk test, balance by the BESTest, functional independence by the FIM, and quality of life by the WHQOL. The assessments were performed pre-, post-intervention, and 30-day follow-up. Results: There was a significant decrease in the time to the Glittre-ADL test when comparing the a-tDCS and s-tDCS groups after the interventions (139.77 ± 21.62, 205.10 ± 43.02, p < .001) and at the 30-day follow-up (142.74 ± 17.12, 219.55 ± 54.05, p < .001), respectively. There was a moderate correlation between FC and locomotion capacity and balance. Conclusions: The addition of tDCS potentiated the results of MT to impact FC, maintaining the positive results longer. Locomotion and balance influenced the improvement of functional capacity.
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Although the medial temporal lobes (MTLs) are critical for both item memory (IM) and source memory (SM), the lateral prefrontal cortex and posterior parietal cortex play a greater role during SM than IM. It is unclear, however, how these differences translate into shared and distinct IM versus SM network components and how these network components vary with age. Within a sample of younger adults (YAs; n = 15, Mage = 19.5 years) and older adults (OAs; n = 40, Mage = 68.6 years), we investigated the functional networks underlying IM and SM. Before functional MRI scanning, participants encoded nouns while making either pleasantness or size judgments. During functional MRI scanning, participants completed IM and SM retrieval tasks. We found that MTL nodes were similarly interconnected among each other during both IM and SM (shared network components) but maintained more intermodule connections during SM (distinct network components). Also, during SM, OAs (compared to YAs) had MTL nodes with more widespread connections. These findings provide a novel viewpoint on neural mechanism differences underlying IM versus SM in YAs and OAs.
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Within the primate visual system, areas at lower levels of the cortical hierarchy process basic visual features, whereas those at higher levels, such as the frontal eye fields (FEF), are thought to modulate sensory processes via feedback connections. Despite these functional exchanges during perception, there is little shared activity between early and late visual regions at rest. How interactions emerge between regions encompassing distinct levels of the visual hierarchy remains unknown. Here we combined neuroimaging, non-invasive cortical stimulation and computational modelling to characterize changes in functional interactions across widespread neural networks before and after local inhibition of primary visual cortex or FEF. We found that stimulation of early visual cortex selectively increased feedforward interactions with FEF and extrastriate visual areas, whereas identical stimulation of the FEF decreased feedback interactions with early visual areas. Computational modelling suggests that these opposing effects reflect a fast-slow timescale hierarchy from sensory to association areas.
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The standard clinical technique for using repetitive transcranial magnetic stimulation (rTMS) for major depressive disorder (MDD) is associated with limited efficacy to date. Such limited efficacy may be due to reliance on scalp-based targeting rather than state-of-the-science methods which incorporate fMRI-guided neuronavigation based on a specific model of neurocircuit dysfunction. In this review, we examine such a specific model drawn from regulatory focus theory, which postulates two brain/behavior systems, the promotion and prevention systems, underlying goal pursuit. Individual differences in these systems have been shown to predict vulnerability to MDD as well as to comorbid generalized anxiety disorder (GAD). Activation of an individual's promotion or prevention goals via priming leads to motivational and affective responses modulated by the individual's appraisal of their progress in attaining the goal. In addition, priming promotion vs. prevention goals induces discriminable patterns of brain activation that are sensitive to the effects of depression and anxiety: MDD is associated with promotion system failure, anhedonic/dysphoric symptoms, and hypoactivation in specific regions in left prefrontal cortex, whereas GAD is associated with prevention system failure, hypervigilant/agitated symptoms, and hyperactivation in right prefrontal cortex (PFC). These left and right PFC locations can be directly targeted in an individualized manner for TMS. Additionally, this individually targeted rTMS can be integrated with cognitive interventions designed to activate the neural circuitry associated with promotion vs. prevention, thus allowing the neuroplasticity induced by the rTMS to benefit the systems likely to be involved in remediating depression. Targeted engagement of cortical systems involved in emotion regulation using individualized fMRI guidance may help increase the efficacy of rTMS in depression.
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Functional interactions in the brain are constrained by the underlying anatomical architecture, and structural and functional networks share network features such as modularity. Accordingly, age-related changes of structural connectivity (SC) may be paralleled by changes in functional connectivity (FC). We provide a detailed qualitative and quantitative characterization of the SC-FC coupling in human aging as inferred from resting-state blood oxygen-level dependent functional magnetic resonance imaging and diffusion-weighted imaging in a sample of 47 adults with an age range of 18-82. We revealed that SC and FC decrease with age across most parts of the brain and there is a distinct age-dependency of regionwise SC-FC coupling and network-level SC-FC relations. A specific pattern of SC-FC coupling predicts age more reliably than does regionwise SC or FC alone (r = 0.73, 95% CI = [0.7093, 0.8522]). Hence, our data propose that regionwise SC-FC coupling can be used to characterize brain changes in aging. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.
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Brain connectivity analysis have shown great promise in understanding of how aging affects functional connectivity, however, an explanatory framework to study healthy aging in terms of network efficiency is still missing. Here we study network robustness i.e., resilience to perturbations, in resting state functional connectivity networks (rs-fMRI) in young and elder subjects. We apply analytic measures of network communication efficiency in the human brain to investigate the compensatory mechanisms elicited in aging. Specifically, we quantify the effect of "lesioning" (node cancelling) of either single regions-of-interest (ROI) or whole networks on global connectivity metrics (i.e., efficiency). We find that young individuals are more resilient than old ones to random "lesioning" of brain areas, global network efficiency is over 3 times lower in older subjects relative to younger subjects. On the other hand, the "lesioning" of central and limbic structures in young subjects yield a larger efficiency loss than in older individuals. Overall our study shows a more idiosyncratic response to specific brain network "lesioning" in elder compared to young subjects, and that young adults are more resilient to random deletion of single nodes compared to old adults.
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A common approach in memory research is to isolate the function(s) of individual brain regions, such as the hippocampus, without addressing how those regions interact with the larger network. To investigate the properties of the hippocampus embedded within large-scale networks, we used functional magnetic resonance imaging and graph theory to characterize complex hippocampal interactions during the active retrieval of vivid versus dim visual memories. The study yielded 4 main findings. First, the right hippocampus displayed greater communication efficiency with the network (shorter path length) and became a more convergent structure for information integration (higher centrality measures) for vivid than dim memories. Second, vivid minus dim differences in our graph theory measures of interest were greater in magnitude for the right hippocampus than for any other region in the 90-region network. Moreover, the right hippocampus significantly reorganized its set of direct connections from dim to vivid memory retrieval. Finally, beyond the hippocampus, communication throughout the whole-brain network was more efficient (shorter global path length) for vivid than dim memories. In sum, our findings illustrate how multivariate network analyses can be used to investigate the roles of specific regions within the large-scale network, while also accounting for global network changes.
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The development of new technologies for mapping structural and functional brain connectivity has led to the creation of comprehensive network maps of neuronal circuits and systems. The architecture of these brain networks can be examined and analyzed with a large variety of graph theory tools. Methods for detecting modules, or network communities, are of particular interest because they uncover major building blocks or subnetworks that are particularly densely connected, often corresponding to specialized functional components. A large number of methods for community detection have become available and are now widely applied in network neuroscience. This article first surveys a number of these methods, with an emphasis on their advantages and shortcomings; then it summarizes major findings on the existence of modules in both structural and functional brain networks and briefly considers their potential functional roles in brain evolution, wiring minimization, and the emergence of functional specialization and complex dynamics. Expected final online publication date for the Annual Review of Psychology Volume 67 is January 03, 2016. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
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A recent trend in functional magnetic resonance imaging is to test for association of clinical disorders with every possible connection between selected brain parcels. We investigated the impact of the resolution of functional brain parcels, ranging from large-scale networks to local regions, on a mass univariate general linear model (GLM) of connectomes. For each resolution taken independently, the Benjamini-Hochberg procedure controlled the false-discovery rate (FDR) at nominal level on realistic simulations. However, the FDR for tests pooled across all resolutions could be inflated compared to the FDR within resolution. This inflation was severe in the presence of no or weak effects, but became negligible for strong effects. We thus developed an omnibus test to establish the overall presence of true discoveries across all resolutions. Although not a guarantee to control the FDR across resolutions, the omnibus test may be used for descriptive analysis of the impact of resolution on a GLM analysis, in complement to a primary analysis at a predefined single resolution. On three real datasets with significant omnibus test (schizophrenia, congenital blindness, motor practice), markedly higher rate of discovery were obtained at low resolutions, below 50, in line with simulations showing increase in sensitivity at such resolutions. This increase in discovery rate came at the cost of a lower ability to localize effects, as low resolution parcels merged many different brain regions together. However, with 30 or more parcels, the statistical effect maps were biologically plausible and very consistent across resolutions. These results show that resolution is a key parameter for GLM-connectome analysis with FDR control, and that a functional brain parcellation with 30 to 50 parcels may lead to an accurate summary of full connectome effects with good sensitivity in many situations. Copyright © 2015. Published by Elsevier Inc.
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Although it is known that brain regions in one hemisphere may interact very closely with their corresponding contralateral regions (collaboration) or operate relatively independent of them (segregation), the specific brain regions (where) and conditions (how) associated with collaboration or segregation are largely unknown. We investigated these issues using a split field-matching task in which participants matched the meaning of words or the visual features of faces presented to the same (unilateral) or to different (bilateral) visual fields. Matching difficulty was manipulated by varying the semantic similarity of words or the visual similarity of faces. We assessed the white matter using the fractional anisotropy (FA) measure provided by diffusion tensor imaging (DTI) and cross-hemispheric communication in terms of fMRI-based connectivity between homotopic pairs of cortical regions. For both perceptual and semantic matching, bilateral trials became faster than unilateral trials as difficulty increased (bilateral processing advantage, BPA). The study yielded three novel findings. First, whereas FA in anterior corpus callosum (genu) correlated with word-matching BPA, FA in posterior corpus callosum (splenium-occipital) correlated with face-matching BPA. Second, as matching difficulty intensified, cross-hemispheric functional connectivity (CFC) increased in domain-general frontopolar cortex (for both word and face matching) but decreased in domain-specific ventral temporal lobe regions (temporal pole for word matching and fusiform gyrus for face matching). Last, a mediation analysis linking DTI and fMRI data showed that CFC mediated the effect of callosal FA on BPA. These findings clarify the mechanisms by which the hemispheres interact to perform complex cognitive tasks. Copyright © 2015 the authors 0270-6474/15/358191-10$15.00/0.
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We present a visualization technique for brain fiber tracts from DTI data that provides insight into the structure of white matter through visual abstraction. We achieve this abstraction by analyzing the local similarity of tract segment directions at different scales using a stepwise increase of the search range. Next, locally similar tract segments are moved toward each other in an iterative process, resulting in a local contraction of tracts perpendicular to the local tract direction at a given scale. This not only leads to the abstraction of the global structure of the white matter as represented by the tracts, but also creates volumetric voids. This increase of empty space decreases the mutual occlusion of tracts and, consequently, results in a better understanding of the brain’s three-dimensional fiber tract structure. Our implementation supports an interactive and continuous transition between the original and the abstracted representations via various scale levels of similarity. We also support the selection of groups of tracts, which are highlighted and rendered with the abstracted visualization as context.
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Neurobiological theories of awareness propose divergent accounts of the spatial extent of brain changes that support conscious perception. Whereas focal theories posit mostly local regional changes, global theories propose that awareness emerges from the propagation of neural signals across a broad extent of sensory and association cortex. Here we tested the scalar extent of brain changes associated with awareness using graph theoretical analysis applied to functional connectivity data acquired at ultra-high field while subjects performed a simple masked target detection task. We found that awareness of a visual target is associated with a degradation of the modularity of the brain's functional networks brought about by an increase in intermodular functional connectivity. These results provide compelling evidence that awareness is associated with truly global changes in the brain's functional connectivity.
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Normal brain function depends on a dynamic balance between local specialization and large-scale integration. It remains unclear, however, how local changes in functionally specialized areas can influence integrated activity across larger brain networks. By combining transcranial magnetic stimulation with resting-state functional magnetic resonance imaging, we tested for changes in large-scale integration following the application of excitatory or inhibitory stimulation on the human motor cortex. After local inhibitory stimulation, regions encompassing the sensorimotor module concurrently increased their internal integration, and decreased their communication with other modules of the brain. There were no such changes in modular dynamics following excitatory stimulation of the same area of motor cortex; nor were there changes in the configuration and interactions between core brain hubs after excitatory or inhibitory stimulation of the same area. These results suggest the existence of selective mechanisms that integrate local changes in neural activity, while preserving ongoing communication between brain hubs. Copyright © 2014, Journal of Neurophysiology.
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The influential notion that the hippocampus supports associative memory by interacting with functionally distinct and distributed brain regions has not been directly tested in humans. We therefore used targeted noninvasive electromagnetic stimulation to modulate human cortical-hippocampal networks and tested effects of this manipulation on memory. Multiple-session stimulation increased functional connectivity among distributed cortical-hippocampal network regions and concomitantly improved associative memory performance. These alterations involved localized long-term plasticity because increases were highly selective to the targeted brain regions, and enhancements of connectivity and associative memory persisted for ~24 hours after stimulation. Targeted cortical-hippocampal networks can thus be enhanced noninvasively, demonstrating their role in associative memory.
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"The Scaffolding Theory of Aging and Cognition (STAC)", proposed in 2009, is a conceptual model of cognitive aging that integrated evidence from structural and functional neuroimaging to explain how the combined effects of adverse and compensatory neural processes produce varying levels of cognitive function. The model made clear and testable predictions about how different brain variables, both structural and functional, were related to cognitive function, focusing on the core construct of compensatory scaffolding. The present paper provides a revised model that integrates new evidence about the aging brain that has emerged since STAC was published 5 years ago. Unlike the original STAC model, STAC-r incorporates life-course factors that serve to enhance or deplete neural resources, thereby influencing the developmental course of brain structure and function, as well as cognition, over time. Life-course factors also influence compensatory processes that are engaged to meet cognitive challenge, and to ameliorate the adverse effects of structural and functional decline. The revised model is discussed in relation to recent lifespan and longitudinal data as well as emerging evidence about the effects of training interventions. STAC-r goes beyond the previous model by combining a life-span approach with a life-course approach to understand and predict cognitive status and rate of cognitive change over time.
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Relating the brain's structural connectivity (SC) to its functional connectivity (FC) is a fundamental goal in neuroscience because it is capable of aiding our understanding of how the relatively fixed SC architecture underlies human cognition and diverse behaviors. With the aid of current noninvasive imaging technologies (e.g., structural MRI, diffusion MRI, and functional MRI) and graph theory methods, researchers have modeled the human brain as a complex network of interacting neuronal elements and characterized the underlying structural and functional connectivity patterns that support diverse cognitive functions. Specifically, research has demonstrated a tight SC-FC coupling, not only in interregional connectivity strength but also in network topologic organizations, such as community, rich-club, and motifs. Moreover, this SC-FC coupling exhibits significant changes in normal development and neuropsychiatric disorders, such as schizophrenia and epilepsy. This review summarizes recent progress regarding the SC-FC relationship of the human brain and emphasizes the important role of large-scale brain networks in the understanding of structural-functional associations. Future research directions related to this topic are also proposed.
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A balance of mutual tonic inhibition between bi-hemispheric posterior parietal cortices is believed to play an important role in bilateral visual attention. However, experimental support for this notion has been mainly drawn from clinical models of unilateral damage. We have previously shown that low-frequency repetitive TMS (rTMS) over the intraparietal sulcus (IPS) generates a contralateral attentional deficit in bilateral visual tracking. Here, we used functional magnetic resonance imaging (fMRI) to study whether rTMS temporarily disrupts the inter-hemispheric balance between bilateral IPS in visual attention. Following application of 1 Hz rTMS over the left IPS, subjects performed a bilateral visual tracking task while their brain activity was recorded using fMRI. Behaviorally, tracking accuracy was reduced immediately following rTMS. Areas ventro-lateral to left IPS, including inferior parietal lobule (IPL), lateral IPS (LIPS), and middle occipital gyrus (MoG), showed decreased activity following rTMS, while dorsomedial areas, such as Superior Parietal Lobule (SPL), Superior occipital gyrus (SoG), and lingual gyrus, as well as middle temporal areas (MT+), showed higher activity. The brain activity of the homologues of these regions in the un-stimulated, right hemisphere was reversed. Interestingly, the evolution of network-wide activation related to attentional behavior following rTMS showed that activation of most occipital synergists adaptively compensated for contralateral and ipsilateral decrement after rTMS, while activation of parietal synergists, and SoG remained competing. This pattern of ipsilateral and contralateral activations empirically supports the hypothesized loss of inter-hemispheric balance that underlies clinical manifestation of visual attentional extinction.
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Diffusion Imaging in Python (Dipy) is a free and open source software project for the analysis of data from diffusion magnetic resonance imaging (dMRI) experiments. dMRI is an application of MRI that can be used to measure structural features of brain white matter. Many methods have been developed to use dMRI data to model the local configuration of white matter nerve fiber bundles and infer the trajectory of bundles connecting different parts of the brain. Dipy gathers implementations of many different methods in dMRI, including: diffusion signal pre-processing; reconstruction of diffusion distributions in individual voxels; fiber tractography and fiber track post-processing, analysis and visualization. Dipy aims to provide transparent implementations for all the different steps of dMRI analysis with a uniform programming interface. We have implemented classical signal reconstruction techniques, such as the diffusion tensor model and deterministic fiber tractography. In addition, cutting edge novel reconstruction techniques are implemented, such as constrained spherical deconvolution and diffusion spectrum imaging (DSI) with deconvolution, as well as methods for probabilistic tracking and original methods for tractography clustering. Many additional utility functions are provided to calculate various statistics, informative visualizations, as well as file-handling routines to assist in the development and use of novel techniques. In contrast to many other scientific software projects, Dipy is not being developed by a single research group. Rather, it is an open project that encourages contributions from any scientist/developer through GitHub and open discussions on the project mailing list. Consequently, Dipy today has an international team of contributors, spanning seven different academic institutions in five countries and three continents, which is still growing.
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The aging brain shows a progressive loss of neuropil, which is accompanied by subtle changes in neuronal plasticity, sensory learning and memory. Neurophysiologically, aging attenuates evoked responses-including the mismatch negativity (MMN). This is accompanied by a shift in cortical responsivity from sensory (posterior) regions to executive (anterior) regions, which has been interpreted as a compensatory response for cognitive decline. Theoretical neurobiology offers a simpler explanation for all of these effects-from a Bayesian perspective, as the brain is progressively optimized to model its world, its complexity will decrease. A corollary of this complexity reduction is an attenuation of Bayesian updating or sensory learning. Here we confirmed this hypothesis using magnetoencephalographic recordings of the mismatch negativity elicited in a large cohort of human subjects, in their third to ninth decade. Employing dynamic causal modeling to assay the synaptic mechanisms underlying these non-invasive recordings, we found a selective age-related attenuation of synaptic connectivity changes that underpin rapid sensory learning. In contrast, baseline synaptic connectivity strengths were consistently strong over the decades. Our findings suggest that the lifetime accrual of sensory experience optimizes functional brain architectures to enable efficient and generalizable predictions of the world.
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