Structural Controllability Predicts Functional Patterns and Brain Stimulation 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 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.SIGNIFICANCE STATEMENT The network controllability concept proposes that specific cortical nodes are able to steer the brain into certain physiological states. By applying external perturbation to these control nodes, it is theorized that brain stimulation is able to selectively target difficult-to-reach states, potentially aiding processing and improving performance on cognitive tasks. The current study used rTMS and fMRI during a working memory task to test this hypothesis. We demonstrate that network controllability correlates with fMRI modulation because of working memory load and with the behavioral improvements that result from a multivisit intervention using 5 Hz rTMS. This study demonstrates the validity of network controllability and offers a new targeting approach to improve efficacy.

Network-based rTMS to modulate working memory: The difficult choice of effective parameters for online interventions.

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.

Using Transcranial Magnetic Stimulation to Test a Network Model of Perceptual Decision Making in the Human Brain.

Previous research has suggested that the lateral occipital cortex (LOC) is involved with visual decision making, and specifically with the accumulation of information leading to a decision. In humans, this research has been primarily based on imaging and electroencephalography (EEG), and as such only correlational. One line of such research has led to a model of three spatially distributed brain networks that activate in temporal sequence to enable visual decision-making. The model predicted that disturbing neural processing in the LOC at a specific latency would slow object decision-making, increasing reaction time (RT) in a difficult discrimination task. We utilized transcranial magnetic stimulation (TMS) to test this prediction, perturbing LOC beginning at 400 ms post-stimulus onset, a time in the model corresponding to LOC activation at a particular difficulty level, with the expectation of increased RT. Thirteen healthy adults participated in two TMS sessions in which left and right LOC were stimulated separately utilizing neuronavigation and robotic coil guidance. Participants performed a two-alternative forced-choice task selecting whether a car or face was present on each trial amidst visual noise pre-tested to approximate a 75% accuracy level. In an effort to disrupt processing, pairs of TMS pulses separated by 50 ms were presented at one of five stimulus onset asynchronies (SOAs): -200, 200, 400, 450, or 500 ms. Behavioral performance differed systematically across SOAs for RT and accuracy measures. As predicted, TMS at 400 ms resulted in a significant slowing of RT. TMS delivered at -200 ms resulted in faster RT, indicating early stimulation may result in priming and performance enhancement. Use of TMS thus causally demonstrated the involvement of LOC in this task, and more broadly with perceptual decision-making; additionally, it demonstrated the role of TMS in testing well-developed neural models of perceptual processing.

Site-Specific Effects of Online rTMS during a Working Memory Task in Healthy Older Adults.

The process of manipulating information within working memory is central to many cognitive functions, but also declines rapidly in old age. Improving this process could markedly enhance the health-span in older adults. The current pre-registered, randomized and placebo-controlled study tested the potential of online repetitive transcranial magnetic stimulation (rTMS) applied at 5 Hz over the left lateral parietal cortex to enhance working memory manipulation in healthy elderly adults. rTMS was applied, while participants performed a delayed-response alphabetization task with two individually titrated levels of difficulty. Coil placement and stimulation amplitude were calculated from fMRI activation maps combined with electric field modeling on an individual-subject basis in order to standardize dosing at the targeted cortical location. Contrary to the a priori hypothesis, active rTMS significantly decreased accuracy relative to sham, and only in the hardest difficulty level. When compared to the results from our previous study, in which rTMS was applied over the left prefrontal cortex, we found equivalent effect sizes but opposite directionality suggesting a site-specific effect of rTMS. These results demonstrate engagement of cortical working memory processing using a novel TMS targeting approach, while also providing prescriptions for future studies seeking to enhance memory through rTMS.

Application of long-interval paired-pulse transcranial magnetic stimulation to motion-sensitive visual cortex does not lead to changes in motion discrimination.

The perception of visual motion is dependent on a set of occipitotemporal regions that are readily accessible to neuromodulation. The current study tested if paired-pulse Transcranial Magnetic Stimulation (ppTMS) could modulate motion perception by stimulating the occipital cortex as participants viewed near-threshold motion dot stimuli. In this sham-controlled study, fifteen subjects completed two sessions. On the first visit, resting motor threshold (RMT) was assessed, and participants performed an adaptive direction discrimination task to determine individual motion sensitivity. During the second visit, subjects performed the task with three difficulty levels as TMS pulses were delivered 150 and 50 ms prior to motion stimulus onset at 120% RMT, under the logic that the cumulative inhibitory effect of these pulses would alter motion sensitivity. ppTMS was delivered at one of two locations: 3 cm dorsal and 5 cm lateral to inion (scalp-based coordinate), or at the site of peak activation for "motion" according to the NeuroSynth fMRI database (meta-analytic coordinate). Sham stimulation was delivered on one-third of trials by tilting the coil 90°. Analyses showed no significant active-versus-sham effects of ppTMS when stimulation was delivered to the meta-analytic (p = 0.15) or scalp-based coordinates (p = 0.17), which were separated by 29 mm on average. Active-versus-sham stimulation differences did not interact with either stimulation location (p = 0.12) or difficulty (p = 0.33). These findings fail to support the hypothesis that long-interval ppTMS recruits inhibitory processes in motion-sensitive cortex but must be considered within the limited parameters used in this design.

Effects of online repetitive transcranial magnetic stimulation (rTMS) on cognitive processing: A meta-analysis and recommendations for future studies.

Online repetitive transcranial magnetic stimulation (rTMS), applied while subjects are performing a task, is widely used to disrupt brain regions underlying cognition. However, online rTMS has also induced "paradoxical enhancement". Given the rapid proliferation of this approach, it is crucial to develop a better understanding of how online stimulation influences cognition, and the optimal parameters to achieve desired effects. To accomplish this goal, a quantitative meta-analysis was performed with random-effects models fitted to reaction time (RT) and accuracy data. The final dataset included 126 studies published between 1998 and 2016, with 244 total effects for reaction times, and 202 for accuracy. Meta-analytically, rTMS at 10 Hz and 20 Hz disrupted accuracy for attention, executive, language, memory, motor, and perception domains, while no effects were found with 1 Hz or 5 Hz. Stimulation applied at and 10 and 20 Hz slowed down RTs in attention and perception tasks. No performance enhancement was found. Meta-regression analysis showed that fMRI-guided targeting and short inter-trial intervals are associated with increased disruptive effects with rTMS.

The effect of body mass and diet composition on torpor patterns in a Malagasy primate (Microcebus murinus).

One of the most obvious physiological changes accompanying seasonal heterothermy in mammals is a fattening stage preceding periods of resource scarcity. This phenomenon reflects the interplay of both diet and physiology. Though the accrual of fat stores is known to be essential for overwintering in some species, the influence of diet on the physiology of torpor is not fully understood. Results from captive studies in heterothermic rodents and marsupials have indicated that when autumn diets are enriched with polyunsaturated fatty acids (PUFAs), animals receiving these diets experience deeper and more frequent torpor bouts than their counterparts receiving a control diet. Our study investigates this potential effect of dietary composition in animals that use daily torpor rather than prolonged torpor (i.e., hibernation). In so doing, we investigate the degree to which dietary effects on torpor are restricted to cold-adapted rodents and marsupials, or are a more general feature of mammalian heterothermy. We examined the effects of a PUFA diet and a control diet on the thermoregulation of one of the few species of primates known to use daily torpor: the grey mouse lemur (Microcebus murinus). Though the results of this study are largely inconclusive regarding the impact of dietary manipulations on torpor frequency and duration, we nonetheless find that the propensity of animals to enter torpor is directly influenced by age and seasonal changes in body mass, and thus reflect important physiological aspects of flexible thermoregulatory responses.