RESUMO
Human working memory is a key cognitive process that engages multiple functional anatomical nodes across the brain. Despite a plethora of correlative neuroimaging evidence regarding the working memory architecture, our understanding of critical hubs causally controlling overall performance is incomplete. Causal interpretation requires cognitive testing following safe, temporal, and controllable neuromodulation of specific functional anatomical nodes. Such experiments became available in healthy humans with the advance of transcranial alternating current stimulation (tACS). Here, we synthesize findings of 28 placebo-controlled studies (in total, 1,057 participants) that applied frequency-specific noninvasive stimulation of neural oscillations and examined working memory performance in neurotypical adults. We use a computational meta-modeling method to simulate each intervention in realistic virtual brains and test reported behavioral outcomes against the stimulation-induced electric fields in different brain nodes. Our results show that stimulating anterior frontal and medial temporal theta oscillations and occipitoparietal gamma rhythms leads to significant dose-dependent improvement in working memory task performance. Conversely, prefrontal gamma modulation is detrimental to performance. Moreover, we found distinct spatial expression of theta subbands, where working memory changes followed orbitofrontal high-theta modulation and medial temporal low-theta modulation. Finally, all these results are driven by changes in working memory accuracy rather than processing time measures. These findings provide a fresh view of the working memory mechanisms, complementary to neuroimaging research, and propose hypothesis-driven targets for the clinical treatment of working memory deficits.
Assuntos
Memória de Curto Prazo , Estimulação Transcraniana por Corrente Contínua , Adulto , Humanos , Memória de Curto Prazo/fisiologia , Ritmo Gama/fisiologia , Encéfalo , Cognição/fisiologia , Transtornos da Memória , Estimulação Transcraniana por Corrente Contínua/métodosRESUMO
Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation method that is rapidly growing in popularity for studying causal brain-behavior relationships. However, its dose-dependent centrally induced neural mechanisms and peripherally induced sensory costimulation effects remain debated. Understanding how TMS stimulation parameters affect brain responses is vital for the rational design of TMS protocols. Studying these mechanisms in humans is challenging because of the limited spatiotemporal resolution of available noninvasive neuroimaging methods. Here, we leverage invasive recordings of local field potentials in a male and a female nonhuman primate (rhesus macaque) to study TMS mesoscale responses. We demonstrate that early TMS-evoked potentials show a sigmoidal dose-response curve with stimulation intensity. We further show that stimulation responses are spatially specific. We use several control conditions to dissociate centrally induced neural responses from auditory and somatosensory coactivation. These results provide crucial evidence regarding TMS neural effects at the brain circuit level. Our findings are highly relevant for interpreting human TMS studies and biomarker developments for TMS target engagement in clinical applications.SIGNIFICANCE STATEMENT Transcranial magnetic stimulation (TMS) is a widely used noninvasive brain stimulation method to stimulate the human brain. To advance its utility for clinical applications, a clear understanding of its underlying physiological mechanisms is crucial. Here, we perform invasive electrophysiological recordings in the nonhuman primate brain during TMS, achieving a spatiotemporal precision not available in human EEG experiments. We find that evoked potentials are dose dependent and spatially specific, and can be separated from peripheral stimulation effects. This means that TMS-evoked responses can indicate a direct physiological stimulation response. Our work has important implications for the interpretation of human TMS-EEG recordings and biomarker development.
Assuntos
Eletroencefalografia , Estimulação Magnética Transcraniana , Masculino , Humanos , Feminino , Animais , Estimulação Magnética Transcraniana/métodos , Eletroencefalografia/métodos , Macaca mulatta , Potenciais Evocados/fisiologia , Biomarcadores , Potencial Evocado Motor/fisiologiaRESUMO
The ability to simultaneously process and maintain multiple pieces of information is limited. Over the past 50 years, observational methods have provided a large amount of insight regarding the neural mechanisms that underpin the mental capacity that we refer to as "working memory." More than 20 years ago, a neural coding scheme was proposed for working memory. As a result of technological developments, we can now not only observe but can also influence brain rhythms in humans. Building on these novel developments, we have begun to externally control brain oscillations in order to extend the limits of working memory.
Assuntos
Encéfalo , Memória de Curto Prazo , HumanosRESUMO
Among the brain regions involved in the aesthetic evaluation of paintings, the prefrontal cortex seems to play a pivotal role. In particular, consistent neuroimaging evidence indicates that activity in the dorsolateral prefrontal cortex (mainly in the left hemisphere) and in medial and orbital sectors of the prefrontal cortex is linked to viewing aesthetically pleasing images. In this study, we focused on the contribution of the medial prefrontal cortex (mPFC) in mediating aesthetic decisions about paintings. We found that enhancing excitability in this region via anodal tDCS led participants to judge paintings as more beautiful. Although significant, the effects were moderate, possibly due to the neutral affective value of the artworks we used, suggesting that activity in mPFC may be critically dependent on the affective impact of the paintings.
Assuntos
Estética/psicologia , Pinturas , Córtex Pré-Frontal/fisiologia , Estimulação Transcraniana por Corrente Contínua/métodos , Tomada de Decisões , Feminino , Humanos , Masculino , Neuroimagem , Estimulação Luminosa , Adulto JovemRESUMO
Transcranial magnetic stimulation (TMS) and transcranial electric stimulation (TES) are increasingly popular methods to noninvasively affect brain activity. However, their mechanism of action and dose-response characteristics remain under active investigation. Translational studies in animals play a pivotal role in these efforts due to a larger neuroscientific toolset enabled by invasive recordings. In order to translate knowledge gained in animal studies to humans, it is crucial to generate comparable stimulation conditions with respect to the induced electric field in the brain. Here, we conduct a finite element method (FEM) modeling study of TMS and TES electric fields in a mouse, capuchin and macaque monkeys, and a human model. We systematically evaluate the induced electric fields and analyze their relationship to head and brain anatomy. We find that with increasing head size, TMS-induced electric field strength first increases and then decreases according to a two-term exponential function. TES-induced electric field strength strongly decreases from smaller to larger specimen with up to 100x fold differences across species. Our results can serve as a basis to compare and match stimulation parameters across studies in animals and humans.
Assuntos
Modelos Animais , Estimulação Transcraniana por Corrente Contínua/métodos , Estimulação Magnética Transcraniana/métodos , Pesquisa Translacional Biomédica/métodos , Animais , Encéfalo , Cebus , Análise de Elementos Finitos , Humanos , Macaca , CamundongosRESUMO
The aim of this study was to investigate if the blood oxygenation level-dependent (BOLD) changes in the visual cortex can be used as biomarkers reflecting the online and offline effects of transcranial electrical stimulation (tES). Anodal transcranial direct current stimulation (tDCS) and 10Hz transcranial alternating current stimulation (tACS) were applied for 10min duration over the occipital cortex of healthy adults during the presentation of different visual stimuli, using a crossover, double-blinded design. Control experiments were also performed, in which sham stimulation as well as another electrode montage were used. Anodal tDCS over the visual cortex induced a small but significant further increase in BOLD response evoked by a visual stimulus; however, no aftereffect was observed. Ten hertz of tACS did not result in an online effect, but in a widespread offline BOLD decrease over the occipital, temporal, and frontal areas. These findings demonstrate that tES during visual perception affects the neuronal metabolism, which can be detected with functional magnetic resonance imaging (fMRI).
Assuntos
Potenciais Evocados Visuais/fisiologia , Imageamento por Ressonância Magnética/métodos , Lobo Occipital/fisiologia , Oxigênio/metabolismo , Estimulação Transcraniana por Corrente Contínua/métodos , Córtex Visual/fisiologia , Percepção Visual/fisiologia , Adulto , Mapeamento Encefálico/métodos , Feminino , Humanos , Masculino , Plasticidade Neuronal/fisiologia , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
The gradual shifting of preferred neural spiking relative to local field potentials (LFPs), known as phase precession, plays a prominent role in neural coding. Correlations between the phase precession and behavior have been observed throughout various brain regions. As such, phase precession is suggested to be a global neural mechanism that promotes local neuroplasticity. However, causal evidence and neuroplastic mechanisms of phase precession are lacking so far. Here we show a causal link between LFP dynamics and phase precession. In three experiments, we modulated LFPs in humans, a non-human primate, and computational models using alternating current stimulation. We show that continuous stimulation of motor cortex oscillations in humans lead to a gradual phase shift of maximal corticospinal excitability by ~90°. Further, exogenous alternating current stimulation induced phase precession in a subset of entrained neurons (~30%) in the non-human primate. Multiscale modeling of realistic neural circuits suggests that alternating current stimulation-induced phase precession is driven by NMDA-mediated synaptic plasticity. Altogether, the three experiments provide mechanistic and causal evidence for phase precession as a global neocortical process. Alternating current-induced phase precession and consequently synaptic plasticity is crucial for the development of novel therapeutic neuromodulation methods.
Assuntos
Encéfalo , Neurônios , Animais , Neurônios/fisiologia , Primatas , Potenciais de Ação/fisiologiaRESUMO
Transcranial alternating current stimulation (tACS) can modulate human neural activity and behavior. Accordingly, tACS has vast potential for cognitive research and brain disorder therapies. The stimulation generates oscillating electric fields in the brain that can bias neural spike timing, causing changes in local neural oscillatory power and cross-frequency and cross-area coherence. tACS affects cognitive performance by modulating underlying single or nested brain rhythms, local or distal synchronization, and metabolic activity. Clinically, stimulation tailored to abnormal neural oscillations shows promising results in alleviating psychiatric and neurological symptoms. We summarize the findings of tACS mechanisms, its use for cognitive applications, and novel developments for personalized stimulation.
Assuntos
Estimulação Transcraniana por Corrente Contínua , Humanos , Estimulação Transcraniana por Corrente Contínua/métodos , Encéfalo/fisiologiaRESUMO
Transcranial alternating current stimulation (tACS) is a widely used noninvasive brain stimulation (NIBS) technique to affect neural activity. Neural oscillations exhibit phase-dependent associations with cognitive functions, and tools to manipulate local oscillatory phases can affect communication across remote brain regions. A recent study demonstrated that multi-channel tACS can generate electric fields with a phase gradient or traveling waves in the brain. Computational simulations using phasor algebra can predict the phase distribution inside the brain and aid in informing parameters in tACS experiments. However, experimental validation of computational models for multi-phase tACS is still lacking. Here, we develop such a framework for phasor simulation and evaluate its accuracy using in vivo recordings in nonhuman primates. We extract the phase and amplitude of electric fields from intracranial recordings in two monkeys during multi-channel tACS and compare them to those calculated by phasor analysis using finite element models. Our findings demonstrate that simulated phases correspond well to measured phases (r = 0.9). Further, we systematically evaluated the impact of accurate electrode placement on modeling and data agreement. Finally, our framework can predict the amplitude distribution in measurements given calibrated tissuesâ™ conductivity. Our validated general framework for simulating multi-phase, multi-electrode tACS provides a streamlined tool for principled planning of multi-channel tACS experiments.
RESUMO
BACKGROUND: Transcranial alternating current stimulation (tACS) is a widely used noninvasive brain stimulation (NIBS) technique to affect neural activity. TACS experiments have been coupled with computational simulations to predict the electromagnetic fields within the brain. However, existing simulations are focused on the magnitude of the field. As the possibility of inducing the phase gradient in the brain using multiple tACS electrodes arises, a simulation framework is necessary to investigate and predict the phase gradient of electric fields during multi-channel tACS. OBJECTIVE: Here, we develop such a framework for phasor simulation using phasor algebra and evaluate its accuracy using in vivo recordings in monkeys. METHODS: We extract the phase and amplitude of electric fields from intracranial recordings in two monkeys during multi-channel tACS and compare them to those calculated by phasor analysis using finite element models. RESULTS: Our findings demonstrate that simulated phases correspond well to measured phases (r = 0.9). Further, we systematically evaluated the impact of accurate electrode placement on modeling and data agreement. Finally, our framework can predict the amplitude distribution in measurements given calibrated tissues' conductivity. CONCLUSIONS: Our validated general framework for simulating multi-phase, multi-electrode tACS provides a streamlined tool for principled planning of multi-channel tACS experiments.
RESUMO
BACKGROUND: Neural oscillations in the primary motor cortex (M1) shape corticospinal excitability. Power and phase of ongoing mu (8-13 Hz) and beta (14-30 Hz) activity may mediate motor cortical output. However, the functional dynamics of both mu and beta phase and power relationships and their interaction, are largely unknown. OBJECTIVE: Here, we employ recently developed real-time targeting of the mu and beta rhythm, to apply phase-specific brain stimulation and probe motor corticospinal excitability non-invasively. For this, we used instantaneous read-out and analysis of ongoing oscillations, targeting four different phases (0°, 90°, 180°, and 270°) of mu and beta rhythms with suprathreshold single-pulse transcranial magnetic stimulation (TMS) to M1. Ensuing motor evoked potentials (MEPs) in the right first dorsal interossei muscle were recorded. Twenty healthy adults took part in this double-blind randomized crossover study. RESULTS: Mixed model regression analyses showed significant phase-dependent modulation of corticospinal output by both mu and beta rhythm. Strikingly, these modulations exhibit a double dissociation. MEPs are larger at the mu trough and rising phase and smaller at the peak and falling phase. For the beta rhythm we found the opposite behavior. Also, mu power, but not beta power, was positively correlated with corticospinal output. Power and phase effects did not interact for either rhythm, suggesting independence between these aspects of oscillations. CONCLUSION: Our results provide insights into real-time motor cortical oscillation dynamics, which offers the opportunity to improve the effectiveness of TMS by specifically targeting different frequency bands.
Assuntos
Potencial Evocado Motor , Córtex Motor , Adulto , Ritmo beta , Estudos Cross-Over , Eletroencefalografia/métodos , Potencial Evocado Motor/fisiologia , Humanos , Córtex Motor/fisiologia , Estimulação Magnética Transcraniana/métodosRESUMO
BACKGROUND: Long-term recognition memory depends both on initial encoding and on subsequent recognition processes. OBJECTIVE: In this study we aimed at improving long-term memory by modulating posterior parietal brain activity during the encoding process. If this area is causally involved in memory encoding, its facilitation should lead to behavioral improvement. Based on the dual-process memory framework, we also expected that the neuromodulation would dissociate subsequent familiarity-based and recollection-based recognition. METHODS: We investigated the role of the posterior parietal brain oscillations in facial memory formation in three separate experiments using electroencephalography (EEG), functional magnetic resonance imaging (fMRI), and model-driven, multi-electrode transcranial alternating current stimulation (tACS). RESULTS: Using fMRI and EEG, we confirmed that the right posterior parietal cortex is an essential node that promotes the encoding of long-term memories. We found that single-trial low theta power in this region predicts subsequent long-term recognition. On this basis, we fine-tuned the spatial and frequency settings of tACS during memory encoding. Model-driven tACS over the right posterior brain area augmented subsequent long-term recognition memory and particularly the familiarity of the observed stimuli. The recollection process, and short-term task performance as control remained unchanged. Control stimulation over the left hemisphere had no behavioral effect. CONCLUSION: We conclude that the right posterior brain area is crucial in long-term memory encoding.
Assuntos
Memória de Longo Prazo , Modelos Neurológicos , Lobo Parietal/fisiologia , Estimulação Transcraniana por Corrente Contínua/métodos , Adulto , Mapeamento Encefálico , Feminino , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
OBJECTIVE: Real-time approaches for transcranial magnetic stimulation (TMS) based on a specific EEG phase are a promising avenue for more precise neuromodulation interventions. However, optimal approaches to reliably extract the EEG phase in a frequency band of interest to inform TMS are still to be identified. Here, we implement a new real-time phase detection method for closed-loop EEG-TMS for robust phase extraction. We compare this algorithm with state-of-the-art methods and evaluate its performance both in silico and experimentally. APPROACH: We propose a new robust algorithm (Educated Temporal Prediction) for delivering real-time EEG phase-specific stimulation based on short prerecorded EEG training data. This method estimates the interpeak period from a training period and applies a bias correction to predict future peaks. We compare the accuracy and computation speed of the ETP algorithm with two existing methods (Fourier based, Autoregressive Prediction) using prerecorded resting EEG data and real-time experiments. MAIN RESULTS: We found that Educated Temporal Prediction performs with higher accuracy than Fourier-based or Autoregressive methods both in silico and in vivo while being computationally more efficient. Further, we document the dependency of the EEG signal-to-noise ratio (SNR) on algorithm accuracy across all algorithms. SIGNIFICANCE: Our results give important insights for real-time EEG-TMS technical development as well as experimental design. Due to its robustness and computational efficiency, our method can find broad use in experimental research or clinical applications. Through open sharing of code for all three methods, we enable broad access of TMS-EEG real-time algorithms to the community.
Assuntos
Eletroencefalografia , Estimulação Magnética Transcraniana , Algoritmos , Simulação por Computador , DescansoRESUMO
Weak extracellular electric fields can influence spike timing in neural networks. Approaches to noninvasively impose these fields on the brain have high therapeutic potential in neurology and psychiatry. Transcranial alternating current stimulation (TACS) is hypothesized to affect spike timing and cause neural entrainment. However, the conditions under which these effects occur in vivo are unknown. Here, we recorded single-unit activity in the neocortex in awake nonhuman primates during TACS and found dose-dependent neural entrainment to the stimulation waveform. Cluster analysis of changes in interspike intervals identified two main types of neural responses to TACS-increased burstiness and phase entrainment. Our results uncover key mechanisms of TACS and show that the stimulation affects spike timing in the awake primate brain at intensities feasible in humans. Thus, novel TACS protocols tailored to ongoing brain activity may be a tool to normalize spike timing in maladaptive brain networks and neurological disease.
Assuntos
Neocórtex , Estimulação Transcraniana por Corrente Contínua , Animais , Primatas , Estimulação Transcraniana por Corrente Contínua/métodos , VigíliaRESUMO
Neural oscillations play a crucial role in communication between remote brain areas. Transcranial electric stimulation with alternating currents (TACS) can manipulate these brain oscillations in a non-invasive manner. Recently, TACS using multiple electrodes with phase shifted stimulation currents were developed to alter long-range connectivity. Typically, an increase in coordination between two areas is assumed when they experience an in-phase stimulation and a disorganization through an anti-phase stimulation. However, the underlying biophysics of multi-electrode TACS has not been studied in detail. Here, we leverage direct invasive recordings from two non-human primates during multi-electrode TACS to characterize electric field magnitude and phase as a function of the phase of stimulation currents. Further, we report a novel "traveling wave" stimulation where the location of the electric field maximum changes over the stimulation cycle. Our results provide a mechanistic understanding of the biophysics of multi-electrode TACS and enable future developments of novel stimulation protocols.
Assuntos
Fenômenos Biofísicos/fisiologia , Ondas Encefálicas/fisiologia , Encéfalo/fisiologia , Estimulação Transcraniana por Corrente Contínua/métodos , Animais , Cebus , Eletrodos , Feminino , Macaca mulatta , Estimulação Transcraniana por Corrente Contínua/instrumentaçãoRESUMO
BACKGROUND: Phase-amplitude cross-frequency coupling (PAC) is characterized by the modulation of the power of a fast brain oscillation (e.g., gamma) by the phase of a slow rhythm (e.g., theta). PAC in different sub- and neocortical regions is known to underlie effective neural communication and correlates with successful long-term memory formation. OBJECTIVE/HYPOTHESIS: The present work aims to extend earlier observational data, by probing the functional role of theta-gamma PAC in the left temporal cortex in humans during verbal long-term memory encoding. METHODS: In three double-blinded, placebo-controlled experiments (nâ¯=â¯72), we employed cross-frequency transcranial alternating current stimulation (tACS) to externally modulate ongoing PAC during a verbal-associative learning task. Three types of cross-frequency tACS protocols were used: bursts of high gamma tACS were coupled to the peak or trough of the theta tACS cycle, and a control condition where gamma tACS was continuously superimposed at theta tACS cycles. RESULTS: Gamma bursts coupled to the trough of theta tACS induced robust behavioral impairment in memory performance (pâ¯<â¯.01), whereas gamma burst coupled to the peak or continuously superimposed with theta tACS had no significant behavioral effects. CONCLUSIONS: Our results demonstrate direct evidence regarding the importance of theta-gamma coupling in verbal long-term memory formation.
Assuntos
Ritmo Gama/fisiologia , Memória de Longo Prazo/fisiologia , Lobo Temporal/fisiologia , Ritmo Teta/fisiologia , Adolescente , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Estimulação Transcraniana por Corrente Contínua , Adulto JovemRESUMO
BACKGROUND: There is a growing interest in large-scale connectivity as one of the crucial factors in working memory. Correlative evidence has revealed the anatomical and electrophysiological players in the working memory network, but understanding of the effective role of their connectivity remains elusive. OBJECTIVE: In this double-blind, placebo-controlled study we aimed to identify the causal role of theta phase connectivity in visual-spatial working memory. METHODS: The frontoparietal network was over- or de-synchronized in the anterior-posterior direction by multi-electrode, 6âHz transcranial alternating current stimulation (tACS). RESULTS: A decrease in memory performance and increase in reaction time was caused by frontoparietal intrahemispheric desynchronization. According to the diffusion drift model, this originated in a lower signal-to-noise ratio, known as the drift rate index, in the memory system. The EEG analysis revealed a corresponding decrease in phase connectivity between prefrontal and parietal areas after tACS-driven desynchronization. The over-synchronization did not result in any changes in either the behavioral or electrophysiological levels in healthy participants. CONCLUSION: Taken together, we demonstrate the feasibility of manipulating multi-site large-scale networks in humans, and the disruptive effect of frontoparietal desynchronization on theta phase connectivity and visual-spatial working memory.
Assuntos
Sincronização Cortical/fisiologia , Transtornos da Memória/etiologia , Ritmo Teta/fisiologia , Estimulação Transcraniana por Corrente Contínua/efeitos adversos , Adulto , Método Duplo-Cego , Eletroencefalografia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Memória de Curto Prazo/fisiologia , Tempo de Reação/fisiologia , Adulto JovemRESUMO
Previous, albeit correlative, findings have shown that the neural mechanisms underlying working memory critically require cross-structural and cross-frequency coupling mechanisms between theta and gamma neural oscillations. However, the direct causality between cross-frequency coupling and working memory performance remains to be demonstrated. Here we externally modulated the interaction of theta and gamma rhythms in the prefrontal cortex using novel cross-frequency protocols of transcranial alternating current stimulation to affect spatial working memory performance in humans. Enhancement of working memory performance and increase of global neocortical connectivity were observed when bursts of high gamma oscillations (80-100 Hz) coincided with the peaks of the theta waves, whereas superimposition on the trough of the theta wave and low gamma frequency protocols were ineffective. Thus, our results demonstrate the sensitivity of working memory performance and global neocortical connectivity to the phase and rhythm of the externally driven theta-gamma cross-frequency synchronization.
Assuntos
Sincronização Cortical , Memória de Curto Prazo/fisiologia , Córtex Pré-Frontal/fisiologia , Memória Espacial/fisiologia , Adulto , Eletroencefalografia , Feminino , Humanos , Masculino , Estimulação Transcraniana por Corrente Contínua , Adulto JovemRESUMO
There is emerging evidence from imaging studies that parietal and temporal cortices act together to achieve successful recognition of declarative information; nevertheless, the precise role of these regions remains elusive. To evaluate the role of these brain areas in declarative memory retrieval, we applied bilateral tDCS, with anode over the left and cathode over the right parietal or temporal cortices separately, during the recognition phase of a verbal learning paradigm using a balanced old-new decision task. In a parallel group design, we tested three different groups of healthy adults, matched for demographic and neurocognitive status: two groups received bilateral active stimulation of either the parietal or the temporal cortex, while a third group received sham stimulation. Accuracy, discriminability index (d') and reaction times of recognition memory performance were measurements of interest. The d' sensitivity index and accuracy percentage improved in both active stimulation groups, as compared with the sham one, while reaction times remained unaffected. Moreover, the analysis of accuracy revealed a different effect of tDCS for old and new item recognition. While the temporal group showed enhanced performance for old item recognition, the parietal group was better at correctly recognising new ones. Our results support an active role of both of these areas in memory retrieval, possibly underpinning different stages of the recognition process.