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Davis, S. W.

Publications and source records attributed to Davis, S. W..

At least 19 recordsLinked to original sources

Not all memory declines with age: Neural correlates of implicit associative memory in younger and older adults.

While explicit associative memory declines with age, implicit associative memory remains preserved. Few studies have examined the neural basis of implicit associative memory in aging, and it remains unclear whether the hippocampus is required as it is more often associated with explicit associative memory. While undergoing functional magnetic resonance imaging, young and old adults completed a speeded object categorization task in which they viewed pictured objects with superimposed words. Implicit memory was tested by presenting intact (original pairs) and rearranged pairs (items previously presented, but not together) from encoding while participants did the same categorization task. Associative priming was defined as faster reaction times (behavioural associative priming) and less activation for intact than rearranged pairs at retrieval (neural associative priming). Whole-brain analyses revealed neural associative priming in occipitotemporal and frontal regions that did not differ by age. A region of interest analysis (using subject-specific masks of medial temporal lobe regions) showed that only older adults had greater posterior hippocampal activation to intact than rearranged items at test, though activation in the hippocampus did not relate to behavioural associative priming. In contrast, greater behavioural associative priming was related to greater neural associative priming in the perirhinal cortex in both age groups. Together, these findings suggest that implicit associative priming remains intact with age, possibly because it relies on additional processes outside the hippocampus such as perirhinal-dependent unitization.

neuroscience↗

Understanding the mechanisms of lateral parietalmemory modulation in Mild Cognitive Impairment

The application of transcranial magnetic stimulation (TMS) to lateral parietal cortex has shown promise in improving episodic memory in older adults with Mild Cognitive Impairment (MCI). Previous work has suggested that such improvements are achieved by activating hippocampus at a distance with TMS, though this explanation is incomplete. We hypothesized that the mnemonic benefits arise from an additional mechanism: the modulation of semantic representations. Nineteen participants with amnestic MCI received either active intermittent theta-burst stimulation (iTBS) to angular gyrus or control vertex stimulation over three consecutive days while viewing object stimuli and completing relational memory encoding tasks during fMRI, followed by conceptual and perceptual recognition memory tests. We found that active TMS (relative to control TMS) significantly modulated conceptual memory performance. Using Representational Similarity Analysis with semantic embeddings derived from a large language model, we examined how TMS affects neural representations in inferior parietal lobule and hippocampus. We found that TMS enhanced semantic representational strength in inferior parietal lobule and reduced representational strength in hippocampus. Surprisingly, both effects supported successful memory. Neural pattern similarity analyses suggested that reduced hippocampal similarity supported successful memory, perhaps by promoting pattern separation mechanisms. These findings demonstrate that parietal TMS modulates semantic processing in a region-specific manner, by strengthening semantic integration at the stimulation site while promoting representational differentiation in medial temporal regions. This work advances our mechanistic understanding of memory neuromodulation and has implications for the optimization of therapeutic interventions in age-related memory disorders. Significance StatementTranscranial Magnetic Stimulation (TMS) applied to parietal cortex can improve memory in patients with Mild Cognitive Impairment (MCI), a population at high risk for Alzheimers Disease, yet the mechanisms underlying this benefit remain poorly understood. Using fMRI and Representational Similarity Analysis (RSA), we examined how TMS alters the neural representation of semantic stimulus information in parietal cortex and hippocampus during memory encoding. Our results show that TMS selectively modulates semantic representations at the stimulation site and in hippocampus, and that these representational changes predict memory improvement. These findings advance our mechanistic understanding of parietal memory neuromodulation and lay the groundwork for more targeted and effective TMS-based interventions for age-related memory disorders.

neuroscience↗

White-matter connectivity shapes visual and semantic representations in the aging brain

Multiple lines of evidence indicate that aging is associated with a reduction in the quality of sensory information coupled with increased reliance on semantic information. Consistent with this evidence, functional MRI studies have repeatedly found that, compared to younger adults, older adults show weaker visual representations but stronger semantic representations. However, the factors that engender this visuo-semantic representational shift (VSRS) remain unclear. Here, we test whether structural connectivity within the representational network predicts these shifts. In the face of typical age-related declines in visual memory and structural connectivity, we find that structural connectivity (i) mediates age-related decline in perceptual representation, and (ii) supports semantic and perceptual mnemonic representations in older adults. These findings outline a potential mechanism of age-related perceptual processing declines and highlight the adaptability of the memory system with age.

neuroscience↗

When knowledge interferes with perception: Neural mechanisms of the semantic amplification of visual false memory

Visual false memory refers to our tendency to falsely recognize novel stimuli that are visually similar to seen stimuli. Visual false memory also occurs when stimuli are meaningful, suggesting that semantic information interferes with the encoding of visual details. However, the neural mechanisms of this semantic interference effect are largely unknown. In the present fMRI study, participants were scanned while encoding visually similar fonts presented with words (word-fonts) or pseudowords (pseudoword-fonts), and later, when recognizing old, new similar (lures), and new dissimilar (novel) fonts displayed in the same meaningless letter string. We performed (1) representational similarity analysis (RSA) at encoding to identify visual, visuosemantic, and semantic representations associated with subsequent visual true and false font recognition, (2) encoding-retrieval similarity (ERS) analysis to assess their reinstatement during retrieval, and (3) mediational analyses to examine hippocampal contributions. The study yielded three main findings. First, visuosemantic representations supported true font recognition when stored in right fusiform gyrus, but false recognition of word-fonts when stored in the left fusiform gyrus. Second, mirroring this pattern, reinstatement in right fusiform gyrus was associated with true font recognition, whereas reinstatement in left fusiform gyrus was linked to false recognition of word-fonts. Finally, posterior hippocampal activation reduced false font memory mainly for pseudoword-associated fonts via decreased reinstatement in perceptual regions, while anterior hippocampal activity increased false memory of word-fonts via enhanced reinstatement in semantic regions. Taken together, these findings reveal how distinct hippocampal-cortical pathways differentially bias memory towards perceptual specificity or semantic generalization. Significance StatementFalse memories are often triggered by visual similarity, but this study shows that meaning encoded during learning can distort memory for visual details, even when retrieval cues are meaningless. Participants learned fonts associated with words or pseudowords and judged whether similar lure fonts, shown on a meaningless letter string, were seen before. Although behavioral performance was similar across conditions, brain imaging revealed a key dissociation: the left fusiform gyrus and anterior hippocampus promote semantic generalization that increases false recognition, whereas the right fusiform gyrus and posterior hippocampus support perceptual specificity that protects against it. These findings reveal how distinct hippocampal-cortical pathways differentially bias memory toward truth or illusion.

neuroscience↗

From Sensory Details to Verbal Codes: Visual Memory Reinstatement of Location and Color Features

Successful episodic memory depends on the reinstatement of encoding content and processes during retrieval. However, it remains unclear how such reinstatement (1) differs for various perceptual features, (2) supports subjective versus objective memory retrieval, and (3) relies on linguistic information. To investigate these three issues, we designed an fMRI study in which participants encoded and recalled the colors and spatial locations of object pictures, and provided subjective vividness and objective precision measures. We used encoding-retrieval similarity (ERS) to identify feature-level reinstatement for location or color features, and trial-specific reinstatement for individual location trials or individual color trials. The study yielded three main findings. First, feature-level reinstatement in frontoparietal and visual regions supported both location and color memory, whereas trial-specific reinstatement in early visual cortex contributed to location memory and feature-level reinstatement in lateral/anterior temporal cortices, to color memory. Second, trial-specific reinstatement in early visual cortex supported both location vividness and precision, while feature-level reinstatement in inferior frontal gyrus contributed to color vividness, and trial-specific reinstatement in posterior inferior temporal gyrus (including the color area), to color precision. Finally, color name richness (the number of names associated with a particular color) enhanced color memory precision and modulated trial-specific color reinstatement in right anterior inferior temporal gyrus. Together, these findings suggest that perceptual and linguistic reinstatement play complementary roles in visual episodic memory: perceptual replay provides fine-grained sensory details, whereas linguistic replay can scaffold and refine these representations, especially for features that are easier to verbalize such as colors. Significance StatementNeural reinstatement has been associated with the quality of episodic memory for complex visual images. However, it remains unclear how neural reinstatement varies across perceptual features, memory subjectivity, and linguistic accessibility. Here, we examine how neural reinstatement supports memory for color and location, whether it plays different roles in memory vividness versus precision, and the role of language in color memory. We showed that location memory relies primarily on trial-specific reinstatement in early visual cortex, supporting precise and vivid recall, whereas color memory is supported by a more complex and complementary interplay between perceptual and linguistic reinstatement. Together, these results advance our understanding of how distinct reinstatement mechanisms support the precision and vividness of episodic memory for basic visual features.

neuroscience↗

Disruption of the Wnt-antagonist Apc in the pituitary stem cells drives the development of adamantinomatous craniopharyngioma.

Adamantinomatous craniopharyngiomas (aCPs) are complex intracranial neoplasms that generally arise in the sellar and suprasellar region of the brain which affect the endocrine and nervous systems causing severe sequelae. Activating mutations resulting in degradation-resistant forms of {beta}-catenin (CTNNB1) have been shown to be the main driver for many of these neoplasms. However, the underlying genetic driver for a proportion of these tumours is still unknown. Using murine transgenic models, we show that genetic disruption of the Wnt-antagonist and tumour suppressor, adenomatous polyposis coli (Apc), within the pituitary progenitors/stem cells, leads to pituitary tumours that closely resemble human aCPs. These tumours present classic histopathological hallmarks of aCPs, such as large deposits of wet keratin, stellar-reticular-like cells, large cystic components and clusters of accumulating nucleo-cytoplasmic {beta}-catenin that are slow-dividing and exhibit a secretory phenotype. We show that a hypomorphic allele of Apc is sufficient for tumour development, indicating that disruption of Apc function can lead to aCP formation. Moreover, we identify that bi-allelic loss of Apc in the Sox2+ve pituitary stem cells is sufficient to initiate tumour formation, indicating that Sox2+ve stem cells are the cell origin of these Apc-driven aCPs. Transcriptomic analyses of early tumour-initiating cells revealed that Apc-driven clusters of accumulating {beta}-catenin undergo senescence-associated secretory phenotype (SASP), which is p21-mediated and results in secretion of inflammasome, angiosome and developmental growth factors. Our data unequivocally show a causal role for the disruption of the tumour suppressor Apc as a primary driver of aCPs independent of mutations in {beta}-catenin. We provide murine models representing a novel genetic subtype of human aCPs offering insights into aCP pathogenesis. Our work reinforces the importance of genetic testing for mutations in APC in patients with aCPs and identifies a potential need to screen patients with familial adenomatous polyposis (FAP) or spectrum of APC-pathogenic syndromes for aCPs in early life.

cancer biology↗

Mapping concept and relational semantic representation in the brain using large language models

How the brain organizes semantic information is one of the most challenging and expansive questions in cognitive neuroscience. To shed light on this issue, prior studies have attempted to decode how the brain represents concepts. We instead examined how relational information is encoded, which we pursued by submitting texts to a contemporary large language model and extracting relational embeddings from the model. Using behavioral data (N = 636), we found these embeddings capture independent information about scenes and objects, along with relational information on their semantic links. Turning to fMRI data (N = 60), we leveraged these embeddings for representational similarity analysis: The occipitotemporal cortex represents concepts in isolation, whereas the dorsolateral prefrontal cortex and basal ganglia principally encode relational information. Relational coding within prefrontal and striatal areas also tracks how participants reason about scenes and objects. Altogether, this research maps how information progresses from concept-level to integrative forms and how this translates into behavior.

neuroscience↗

Trial-Level Representational Similarity Analysis

Neural representation refers to the brain activity that stands in for ones cognitive experience, and in cognitive neuroscience, a prominent method of studying neural representations is representational similarity analysis (RSA). While there are several recent advances in RSA, the classic RSA (cRSA) approach examines the structure of representations across numerous items by assessing the correspondence between two representational similarity matrices (RSMs): usually one based on a theoretical model of stimulus similarity and the other based on similarity in measured neural data. However, because cRSA cannot weigh the contributions of individual trials (RSM rows/columns), it is fundamentally limited in its ability to assess subject-, stimulus-, and trial-level variances that all influence representation. Here, we formally introduce trial-level RSA (tRSA), an analytical framework that estimates the strength of neural representation for singular experimental trials and evaluates hypotheses using multi-level models. First, we verified the correspondence between tRSA and cRSA in quantifying the overall representation strength across all trials. Second, we compared the statistical inferences drawn from both approaches using simulated data that reflected a wide range of scenarios. Compared to cRSA, the multi-level framework of tRSA was both more theoretically appropriate and significantly sensitive to true effects. Third, using real fMRI datasets, we further demonstrated several issues with cRSA, to which tRSA was more robust. Finally, we presented some novel findings of neural representations that could only be assessed with tRSA and not cRSA. In summary, tRSA proves to be a robust and versatile analytical approach for cognitive neuroscience and beyond.

neuroscience↗

Intrinsic fluctuations in global connectivity reflect transitions between states of high and low prediction error

While numerous researchers claim that the minimization of prediction error (PE) is a general force underlying most brain functions, others argue instead that PE minimization drives low-level, sensory-related neuronal computations but not high-order, abstract cognitive operations. We investigated this issue using behavioral, fMRI, and EEG data. Studies 1A/1B examined semantic- and reward-processing PE using task-fMRI, yielding converging evidence of PEs global effects on large-scale connectivity: high-PE states broadly upregulated ventral-dorsal connectivity, and low-PE states upregulated posterior-anterior connectivity. Investigating whether these global patterns characterize cognition generally, Studies 2A/2B used resting-state fMRI and showed that individuals continuously fluctuate between ventral-dorsal (high-PE) and posterior-anterior (low-PE) dynamic connectivity states. Additionally, individual differences in PE task responses track differences in resting-state fluctuations, further endorsing that these fluctuations represent PE minimization at rest. Finally, Study 3 combined fMRI and EEG data, and the study found that the fMRI fluctuation amplitude correlates most strongly with EEG power at 3-6 Hz, consistent with the PE network fluctuations occurring at Delta/Theta oscillation speeds. This whole-brain layout and timeline together are consistent with high/low-PE fluctuations playing a role in integrative and general sub-second cognitive operations.

neuroscience↗

Local and distributed information coding in the ventral stream

Neuroscience is replete with evidence that cognitive representations are distributed across many cortical regions. Yet, the scale and content of such distributed processing is unclear. Do findings of widespread information coding suggest a large-scale "forest" of regions interacting to represent information or instead imply a multitude of small-scale trees, processing information as localized modules. To investigate this distinction, we used visual and semantic representational analysis of fMRI data from 60 participants viewing everyday objects in multiple task contexts, and we examined the relationships between regions in terms of information coding. We demonstrate that coding of visual content in the occipital lobe is overwhelmingly modular, such that different occipital structures show limited coordination and tend to encode information redundantly. By contrast, the coding of semantic content in the inferior temporal lobe involves a high degree of coordination between regions, which optimize their coding to collectively represent a large semantic space with minimal redundancy between regions. No other brain area - neither the parietal nor prefrontal cortices - shows the preference for large-scale coding seen in the inferior temporal lobe. Taken together, these results outline a framework of how the ventral stream transitions from small-scale to large-scale coding as information progresses from visual to semantic representations. Significance statementHow does the brain convert incoming signals into usable information? Many studies have investigated this question by attempting to clarify which brain regions encode what information (e.g., V4 encodes color information). We instead aimed to shed light on the degree of coordination among information coding regions. We find that the visual-to-semantic transition as information flows anteriorly in the occipitotemporal cortex is accompanied by a shift from modular to distributed coding. That is, occipital regions encode perceptual information relatively independently with redundancy, while inferior temporal lobe regions cooperate to most efficiently represent a large space of semantic information. By leveraging ideas from information theory, our work introduces coding scale as a new dimension for understanding the architecture of information coding.

neuroscience↗

Nucleoredoxin regulates WNT signaling during pituitary stem cell differentiation

Nucleoredoxin (Nxn) encodes a multi-functional enzyme with oxidoreductase activity that regulates many different signaling pathways and cellular processes in a redox-dependent manner. Rare NXN mutations are reported in individuals with recessive Robinow syndrome, which involves mesomelic skeletal dysplasia, short stature, craniofacial dysmorphisms, and incompletely penetrant heart and palate defects. Here we report that Nxn is expressed in the ventral diencephalon and developing pituitary gland, and that Nxn deficient mice have pituitary dysmorphology and craniofacial abnormalities that include defects in the skull base and cleft palate. Nxn mutant mice exhibit reduced WNT signaling and reduced differentiation of pituitary stem cells into hormone-producing cells. These results suggest patients with Robinow syndrome could benefit from evaluation by endocrinologists for pituitary structural imaging and hormone insufficiency. HighlightsNxn deficiency causes neonatal lethality, cleft palate, craniofacial abnormalities, and other structural birth defects. Nxn deficiency causes pituitary dysmorphology. Analysis of scRNA seq reveals delayed trajectory during early pituitary cell differentiation. Nxn deficiency reduces canonical and non-canonical Wnt signaling in developing pituitary glands. Nxn deficiency reduces stem cell differentiation into pituitary hormone-producing cells.

developmental biology↗

TIME-CoExpress: Temporal Trajectory Modeling of Dynamic Gene Co-expression Patterns Using Single-Cell Transcriptomics Data

The rapid advancements of single-cell RNA sequencing (scRNAseq) technology provide high-resolution views of transcriptomic activity within a single cell. Most routine analyses of scRNAseq data focus on individual genes; however, the one-gene-at-a-time analysis is likely to miss meaningful genetic interactions. Gene co-expression analysis addresses this issue by identifying coordinated gene expression changes in response to cellular conditions, such as developmental or temporal trajectory. Identifying differential co-expression gene combinations along the cell temporal trajectory using scRNAseq data can provide deeper insight into the biological processes. Existing approaches for gene co-expression analysis assume a restrictive linear change of gene co-expression. In this paper, we propose a copula-based approach with proper data-driven smoothing functions to model non-linear gene co-expression changes along cellular temporal trajectories. Our proposed approach provides flexibility to incorporate characteristics such as over-dispersion and zero-inflation rate observed in scRNAseq data into the modeling framework. We conducted a series of simulation analyses to evaluate the performance of the proposed algorithm. We demonstrate the implementation of the proposed algorithm using a scRNAseq dataset and identify differential co-expression gene pairs along cell temporal trajectory in pituitary embryonic development comparing Nxn-/- mutated versus wild-type mice.

genetics↗

Semantic Dimensions Support the Cortical Representation of Object Memorability

Recent work in vision sciences contends that objects carry an intrinsic property, memorability, that describes the likelihood that an object can be successfully encoded and later retrieved from memory. It has been shown that object memorability is supported by semantic information, but the neural correlates involved are largely unexplored. The present study explores these premises and asks whether neural correlates of object memorability can be accounted for by semantic dimensions. To investigate these questions, we combine three datasets: (1) feature norms for a database of [~]1000 natural object images, (2) normative conceptual and perceptual memory data for those objects, and (3) neuroimaging data from an fMRI study collected using a subset (n=360) of those objects. We found that object-wise memorability elicits consistent brain activation across participants in key mnemonic regions (e.g., hippocampus and rhinal cortex), and that a substantial portion of the variance in this brain activity is mediated by the semantic factors describing these images. Regions with the strongest mediation effects are associated with sensory, motor, and visual processes, suggesting that the relationship between memorability and semantics may align with a sensory-functional account of the representation of concepts in the brain.

neuroscience↗

Cortico-hippocampal interactions underlie schema-supported memory encoding in older adults

Although episodic memory is typically impaired in older adults (OAs) compared to young adults (YAs), this deficit is attenuated when OAs can leverage their rich semantic knowledge, such as their knowledge of schemas. Memory is better for items consistent with pre-existing schemas and this effect is larger in OAs. Neuroimaging studies have associated schema use with the ventromedial prefrontal cortex (vmPFC) and hippocampus (HPC), but most of this research has been limited to YAs. This fMRI study investigated the neural mechanisms underlying how schemas boost episodic memory in OAs. Participants encoded scene-object pairs with varying congruency, and memory for the objects was tested the following day. Congruency with schemas enhanced object memory for YAs and, more substantially, for OAs. FMRI analyses examined how cortical modulation of HPC predicted subsequent memory. Congruency-related vmPFC modulation of left HPC enhanced subsequent memory in both age groups, while congruency-related modulation from angular gyrus (AG) boosted subsequent memory only in OAs. Individual differences in cortico-hippocampal modulations indicated that OAs preferentially used their semantic knowledge to facilitate encoding via an AG-HPC interaction, suggesting a compensatory mechanism. Collectively, our findings illustrate age-related differences in how schemas influence episodic memory encoding via distinct routes of cortico-hippocampal interactions.

neuroscience↗

Using Dual-Coil TMS-EEG to Probe Bilateral Brain Mechanisms in Healthy Aging and Mild Cognitive Impairment

BackgroundA widespread observation in the cognitive neuroscience of aging is that older adults show a more bilateral pattern of task-related brain activation. These observations are based on inherently correlational approaches. The current study represents a targeted assessment of the role of bilaterality using repetitive transcranial magnetic stimulation (rTMS). ObjectiveWe used a novel bilateral TMS-stimulation paradigm, applied to a group of healthy older adults (hOA) and older adults with mild cognitive impairment (MCI), with two aims: First, to elucidate the neurophysiological effects of bilateral neuromodulation, and second to provide insight into the neurophysiological basis of bilateral brain interactions. MethodsElectroencephalography (EEG) was recorded while participants received six forms of transcranial magnetic stimulation (TMS): unilateral and bilateral rTMS trains at an alpha (8 Hz) and beta (18 Hz) frequency, as well as two sham conditions (unilateral, bilateral) mimicking the sounds of TMS. ResultsFirst, time-frequency analyses of oscillatory power induced by TMS revealed that unilateral beta rTMS elicited rhythmic entrainment of cortical oscillations at the same beta-band frequency. Second, both bilateral alpha and bilateral beta stimulation induced a widespread reduction of alpha power. Lastly, healthy older adults showed greater TMS-related reductions in alpha power in response to bilateral rTMS compared to the MCI cohort. ConclusionOverall, these results demonstrate frequency-specific responses to bilateral rTMS in the aging brain, and provide support for inhibitory models of hemispheric interaction across multiple frequency bands.

neuroscience↗

A frameshift mutation in the murine Prkra gene causes dystonia and exhibits abnormal cerebellar development and reduced eIF2α phosphorylation.

Mutations in Prkra gene, which encodes PACT/RAX cause early onset primary dystonia DYT-PRKRA, a movement disorder that disrupts coordinated muscle movements. PACT/RAX activates protein kinase R (PKR, aka EIF2AK2) by a direct interaction in response to cellular stressors to mediate phosphorylation of the subunit of the eukaryotic translation initiation factor 2 (eIF2). Mice homozygous for a naturally arisen, recessively inherited frameshift mutation, Prkralear-5J exhibit progressive dystonia. In the present study, we investigate the biochemical and developmental consequences of the Prkralear-5J mutation. Our results indicate that the truncated PACT/RAX protein retains its ability to interact with PKR, however, it inhibits PKR activation. Furthermore, mice homozygous for the mutation have abnormalities in the cerebellar development as well as a severe lack of dendritic arborization of Purkinje neurons. Additionally, reduced eIF2 phosphorylation is noted in the cerebellums and Purkinje neurons of the homozygous Prkralear-5J mice. These results indicate that PACT/RAX mediated regulation of PKR activity and eIF2 phosphorylation plays a role in cerebellar development and contributes to the dystonia phenotype resulting from this mutation. Summary StatementThis study shows, for the first time, a role of reduced eIF2 phosphorylation in DYT-PRKRA and the cerebellum development in a mouse model.

molecular biology↗

Cognition's dependence on functional network integrity with age is conditional on structural network integrity

Maintaining good cognitive function is crucial for well-being across the lifespan. We proposed that the degree of cognitive maintenance is determined by the functional interactions within and between large-scale brain networks. Such connectivity can be represented by the white matter architecture of structural brain networks that shape intrinsic neuronal activity into integrated and distributed functional networks. We explored how the function-structure connectivity convergence, and the divergence of functional connectivity from structural connectivity, contribute to the maintenance of cognitive function across the adult lifespan. Multivariate analyses were used to investigate the relationship between function-structure connectivity convergence and divergence with multivariate cognitive profiles, respectively. Cognitive function was increasingly dependent on function-structure connectivity convergence as age increased. The dependency of cognitive function on connectivity was particularly strong for high-order cortical networks and subcortical networks. The results suggest that brain functional network integrity sustains cognitive functions in old age, as a function of the integrity of the brains structural connectivity.

neuroscience↗

Concurrent fMRI demonstrates propagation of TMS effects across task-related networks

Transcranial magnetic stimulation (TMS) has become an important technique in both scientific and clinical practices, and yet our understanding of how the brain responds to TMS is still limited. Concurrent neuroimaging during TMS may bridge this gap, and emerging evidence suggests widespread that modulatory effects of TMS may be best captured through changes in functional connectivity between distributed networks, rather than local changes in cortical activity. However, the relationship between TMS stimulation parameters and evoked changes in functional connectivity is unknown. In this study, 24 healthy volunteers received concurrent TMS-fMRI while performing a dot-motion direction discrimination task. An MR-compatible coil was used to apply trains of three pulses at 10 Hz rTMS over the primary visual cortex (V1) at the onset of the dot stimuli with four levels of stimulation intensity (20%, 40%, 80%, and 120% of resting motor threshold, RMT). Behavioral results demonstrated impairment of motion discrimination at 80% RMT. FMRI results yielded three findings. First, functional connectivity between visual and non-visual areas increased as a function of rTMS intensity. Second, connectivity within the visual network was positively associated with motion accuracy, while the connectivity between visual and non-visual regions was negatively associated with motion accuracy. Lastly, we found that reductions in the similarity between functional and structural connectivity associated with increasing TMS intensity were constrained to the visual network. These findings demonstrate spatially dependent nonlinear effects of TMS intensity on brain functional connectivity that proceed beyond the site of stimulation and influence associated behavior.

neuroscience↗