Biology subjects

Luber, B.

Publications and source records attributed to Luber, B..

9 recordsLinked to original sources

bioRxiv2019

Structural controllability predicts functional patterns and neuromodulatory benefits associated with working memory

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.\n\nHighlights- This study tested the strength of network controllability using fMRI and rTMS\n- Controllability correlates with functional modulation of working memory demand load\n- Controllability is also correlated with the memory improvement from applied rTMS\n- These findings link network control theory with physiology and behavior.\n\n\nIn briefBeynel 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.\n\nAuthor ContributionsConceptualization & 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.

neuroscience↗

bioRxiv2019

Model-based analysis of response and resistance factors of cetuximab treatment in gastric cancer cell lines

Targeted cancer therapies are powerful alternatives to chemotherapies or can be used complementary to these. Yet, the response to targeted treatments depends on a variety of factors, including mutations and expression levels, and therefore their outcome is difficult to predict. Here, we develop a mechanistic model of gastric cancer to study response and resistance factors for cetuximab treatment. The model captures the EGFR, ERK and AKT signaling pathways in two gastric cancer cell lines with different mutation patterns. We train the model using a comprehensive selection of time and dose response measurements, and provide an assessment of parameter and prediction uncertainties. We demonstrate that the proposed model facilitates the identification of causal differences between the cell lines. Furthermore, our study shows that the model provides accurate predictions for the responses to different perturbations, such as knockdown and knockout experiments. Among other results, the model predicted the effect of MET mutations on cetuximab sensitivity. These predictive capabilities render the model a powerful basis for the assessment of gastric cancer signaling and for the development and discovery of predictive biomarkers.\n\nAuthor SummaryUnraveling the causal differences between drug responders and non-responders is an important challenge. The information can help to understand molecular mechanisms and to guide the selection and design of targeted therapies. Here, we approach this problem for cetuximab treatment for gastric cancer using mechanistic mathematical modeling. The proposed model describes multiple gastric cancer cell lines and can accurately predict the response in several validation experiments. Our analysis provides a differentiated view on mutations and explains, for instance, the relevance of MET mutations and the insignificance of PIK3CA mutation in the considered cell lines. The model might provide the basis for understanding the recent failure of several clinical studies.

systems biology↗

bioRxiv2019

Older adults benefit from more widespread brain network integration during working memory

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.\n\nSignificance statementOlder 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.

neuroscience↗

bioRxiv2019

Site-specific effects of online rTMS during a working memory task in healthy older adults.

The process of manipulating information within working memory (WM) is central to many cognitive functions, but also declines rapidly in old age. Given the importance of WM manipulation for maintaining healthy cognition, improving this process could markedly enhance health-span in older adults. The current pre-registered study tested the potential of online repetitive transcranial magnetic stimulation (rTMS) to enhance WM manipulation in healthy elderly adults. Online 5Hz rTMS was applied over the left lateral parietal cortex of 15 subjects to test the hypothesis that active rTMS would significantly improve performance compared to sham stimulation, and that these effects would be most pronounced in conditions with the highest cognitive demand. rTMS was applied while participants performed a delayed-response alphabetization task with two individually-titrated levels of difficulty. Sham stimulation was applied using an electrical sham coil that produced similar clicking sounds and somatosensory sensation as active stimulation but induced negligible effects on the brain. A stimulation site in left lateral parietal cortex was identified from fMRI activation maps and was targeted using individualized electric field modeling, stereotactic neuronavigation, and real-time robotic positioning, allowing optimal coil placement during the stimulation. Contrary to the a priori hypothesis, active rTMS significantly decreased accuracy relative to sham, and only in the hardest difficulty level. These results, therefore, demonstrate engagement of cortical WM processing, but not the anticipated facilitation, and provide a prescription for future studies that may attempt to enhance memory through application of different stimulation parameters.\n\nHighlightsO_LIThis study is one of the first attempts to enhance WM manipulation with online rTMS\nC_LIO_LIOnline 5Hz rTMS and sham were applied over the left parietal cortex of older adults\nC_LIO_LIIndividualized fMRI and electric field modeling were used to optimize targeting\nC_LIO_LIContrary to expectations, rTMS disrupted working memory manipulation abilities\nC_LIO_LIThis demonstrates that parietal cortex is involved in WM and modifiable with rTMS\nC_LI

neuroscience↗

bioRxiv2019

Accuracy of robotic coil positioning during transcranial magnetic stimulation

ObjectiveRobotic positioning systems for transcranial magnetic stimulation (TMS) promise improved accuracy and stability of coil placement, but there is limited data on their performance. This text investigates the usability, accuracy, and limitations of robotic coil placement with a commercial system, ANT Neuro, in a TMS study.\n\nApproach21 subjects underwent a total of 79 TMS sessions corresponding to 160 hours under robotic coil control. Coil position and orientation were monitored concurrently through an additional neuronavigation system.\n\nMain ResultsRobot setup took on average 14.5 min. The robot achieved low position and orientation error with median 1.34 mm and 3.48{degrees}. The error increased over time at a rate of 0.4%/minute for both position and orientation.\n\nSignificanceAfter the elimination of several limitations, robotic TMS systems promise to substantially improve the accuracy and stability of manual coil position and orientation. Lack of pressure feedback and of manual adjustment of all coil degrees of freedom were limitations of this robotic system.

neuroscience↗

bioRxiv2018

Complementary topology of maintenance and manipulation brain networks in working memory

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.\n\nSignificance StatementDespite 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.

neuroscience↗

bioRxiv2018

Spatio-temporally specific transcranial magnetic stimulation to test the locus of perceptual decision making in the human brain

Previous research modeling EEG, fMRI and behavioral data has identified three spatially distributed brain networks that activate in temporal sequence, and are thought to enable perceptual decision-making during face-versus-car categorization. These studies have linked late activation (>300ms post stimulus onset) in the lateral occipital cortex (LOC) to object discrimination processes. We applied paired-pulse transcranial magnetic stimulation (ppTMS) to LOC at different temporal latencies with the specific prediction, based on these studies, that ppTMS beginning at 400ms after stimulus onset would slow reaction time (RT) performance. Thirteen healthy adults performed a two-alternative forced choice task selecting whether a car or face was present on each trial amidst visual noise pre-titrated to approximate 79% accuracy. ppTMS, with pulses separated by 50ms, was applied at one of five stimulus onset asynchronies: -200, 200, 400, 450, or 500ms, and a sixth no-stimulation condition. As predicted, TMS at 400ms resulted in significant slowing of RTs, providing causal evidence in support of LOC contribution to perceptual decision processing. In addition, TMS delivered at -200ms resulted in faster RTs, indicating early stimulation may result in performance enhancement. These findings build upon correlational EEG and fMRI observations and demonstrate the use of TMS in predictive validation of psychophysiological models.

neuroscience↗

bioRxiv2018

Excitatory TMS Boosts Memory Representations

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.

neuroscience↗

bioRxiv2018

A systematic study of repetitive transcranial magnetic stimulation to enhance working memory manipulation abilities

A core element of human working memory (WM) is the ability to perform mental operations on information that is stored in a flexible, limited capacity buffer. Given the profound importance of such WM manipulation (WM-M) abilities, there is a concerted effort aimed at developing approaches to improve them. Past research has identified neural substrates of WM-M centered in the dorsolateral prefrontal cortex (DLPFC), thereby providing a plausible and accessible target for noninvasive neuromodulatory stimulation that can be used to alter cortical excitability and potentially lead to facilitation of WM-M. In the current study, 5Hz online repetitive transcranial magnetic stimulation (rTMS), applied over the left DLPFC, was used to test the hypothesis that active rTMS would lead to significant improvements in memory recall accuracy compared to sham stimulation, and that these effects would be most pronounced in the WM-M conditions with the highest cognitive demand (registered Clinical Trial: #NCT02767323). Participants performed a delayed response alphabetization task with three individually-titrated levels of difficulty during active and sham rTMS. Analyses revealed that active rTMS led to numerically greater accuracy relative to sham stimulation for the hardest condition; however, this effect did not survive Bonferroni correction over all task conditions. Despite the lack of robust, study-wise significant effects, when considered in isolation, the magnitude of behavioral improvement in the hardest condition was negatively correlated with parametric difficulty-related fMRI activity in the targeted brain region, suggesting that individuals with less activation benefit more from rTMS. The present findings therefore suggest evidence towards the hypothesis that active rTMS can enhance performance during difficult memory manipulation conditions; however, firm conclusions cannot be drawn given the lack of overall significant effects. These findings are discussed in the context of individualized targeting and other factors that might moderate rTMS effects.

neuroscience↗