By identifying how stimulation frequency governs the mechanism of neural engagement and how behavioral state selectively gates brain-wide entrainment but not local inhibitory recruitment, the results provide a mechanistic foundation for designing targeted, reproducible neuromodulation strategies.
Abstract
Electrical stimulation is widely used to modulate neuronal activity, yet its effects on neuronal circuits in vivo remain poorly understood. This, in turn, has hindered the principled design of stimulation protocols and raised questions about reproducibility that constrain the field’s translational impact. Here we combine cortical sinusoidal electrical stimulation (sES) with Neuropixels recordings to characterize stimulation-driven responses in more than 2,700 well-isolated neurons across 53 brain areas in 14 behaving, head-fixed mice. We uncover two distinct, concurrent modes of neural modulation. First is a sustained, brain-wide spike-phase entrainment effect that depends on stimulation frequency: entrainment to slow stimulation is supported by non-synaptic electric field propagation while anatomical connectivity dominates entrainment to higher stimulation frequencies. Second, we find a transient, spatially localized spike-rate modulation mainly mediated through anatomical connectivity that only emerges at high stimulation frequencies by selectively recruiting inhibitory neurons. We show that the two distinct modes are differentially shaped by behavior. By identifying how stimulation frequency governs the mechanism of neural engagement and how behavioral state selectively gates brain-wide entrainment but not local inhibitory recruitment, our results provide a mechanistic foundation for designing targeted, reproducible neuromodulation strategies.
Background Deep brain stimulation (DBS) is widely used to treat neurological disorders, but how it exerts its therapeutic effects remains an open question. Although DBS primarily acts through stimulated subcortical structures and their networks, recent studies have demonstrated that cortical electric field (E-field) strengths generated during DBS are comparable to, and can exceed, those shown to modulate neuronal activity with transcranial alternating current stimulation. We therefore investigated whether and how these weak DBS fields can directly modulate cortical spike timing. Methods We used multi-compartment computational models of five neuron types across all cortical layers and exposed them to E-fields modeled as DBS pulses. E-field amplitudes spanned the typical range of cortical E-field strengths during DBS, while frequency and orientation were varied. Entrainment was assessed using peri-stimulus time histograms and quantified by the phase locking value (PLV). Results Weak DBS fields modulated spike timing of some neurons by either increasing or decreasing the likelihood of firing immediately following the stimulation pulse. This modulation reflected entrainment to the stimulation, with the PLV increasing with E-field amplitude and frequency. The magnitude and direction of spike-timing modulation varied across neuron types and depended on the orientation of the field. Conclusion These findings suggest that cortical E-fields of DBS may directly influence activity of some cortical neurons, alongside the established indirect cortical effects mediated by subcortical targets and their networks. This provides a new perspective on how DBS may influence cortical activity and offers insights into its potential mechanisms of therapeutic and/or side effects. Highlights Multi-compartment models to study how DBS E-fields affect cortical neuron dynamics. E-fields of DBS can directly affect cortical neuron spike timing. Probability of firing increases or decreases following DBS pulses. Some pyramidal neurons can phase-lock to weak electric fields as low as 1 V/m. Weak fields of DBS may play a role in therapeutic and/or side effects. Graphical Abstract
Maud Bosman, Nina Doorn, H. G. Meijer et al.· bioRxiv· 0 citations
Temporal interference brain stimulation (TIBS) is a non-invasive neuromodulation approach that can reach deep brain targets by delivering two kilohertz-frequency currents through scalp electrodes, producing a low- frequency amplitude envelope where the fields intersect. Conventional deep brain stimulation suppresses its targets at 130 Hz, and TIBS studies of epilepsy have adopted the same range. However, which neurons TIBS recruits at different frequencies has never been measured. Here, we recorded from genetically defined populations in the mouse hippocampus across envelope frequencies from 10 to 130 Hz, using cell-type- specific fiber photometry, retrograde viral labelling, and immunohistochemistry. A 10 Hz envelope drives both glutamatergic pyramidal neurons and GABAergic interneurons. From 20 Hz onward pyramidal activity falls below baseline while interneuron activity keeps rising, and the two separate maximally at 100 Hz. Retrogradely labelled cortical neurons projecting to CA2 respond weakly and show no frequency dependence, placing the switch inside the local circuit, and c-fos co-staining identifies parvalbumin interneurons as the population recruited at 100 Hz. Overall, this study provides the first in vivo cell-type-resolved evidence for envelope-frequency-dependent neuromodulation and shows that TIBS envelope frequency is a tunable parameter for excitation-inhibition balance. These findings can guide the choice of envelope frequency in the clinical research of TIBS.
Yi-Cheng Fang, Lin Chou, Yao-Yi Tseng et al.· bioRxiv· 0 citations
Electrical microstimulation provides high-resolution control of neural circuits for causal studies and restoration of impaired functions, yet how responses to artificial activation evolve with learning remains unclear. Here, we deploy a detection task and pair ultraflexible electrodes for stable intracortical microstimulation (ICMS) with longitudinal imaging and recordings to track single-cell and population responses across weeks of learning. Detection thresholds decreased with learning, indicating plasticity. Chronic imaging showed that stimulus-evoked recruitment expanded at a fixed current, while a consistent number of neurons continued to underlie behavioral responses. A subset of learning-sensitive cells enhanced modulation and reduced latency. Electrophysiological recordings further distinguished two forms of adaptation: Directly activated, pulse-locked neurons strengthened their excitability, whereas polysynaptically recruited neurons expanded in number and were predictive of behavioral outcomes. These results show that learning in an ICMS task reshapes cortical circuits through activation-mechanism–dependent plasticity, underscoring the need for stimulation paradigms that adapt to both cell-intrinsic and network dynamics.
Robin Kim, Roy Lycke, Pavlo Zolotavin et al.· Science Advances· 0 citations
Temporal interference stimulation (TIS) is a promising non-invasive technique for reaching deep brain regions that are difficult to modulate with conventional transcranial electrical stimulation. A critical question is whether TIS can reliably induce neural modulation at its envelope frequency in humans.
As an initial step toward applications targeting deeper structures, we investigated whether TIS can modulate cortical oscillations at the envelope frequency within the primary somatosensory cortex (S1). We also examined how electric fields in off-target regions contribute to interindividual variability in stimulation efficacy using individualized simulations based on each participant’s magnetic resonance imaging (MRI).
Forty-nine healthy participants were enrolled (24 TIS, 25 active sham without envelope modulation). TIS was applied over the left S1 hand area using a stimulation protocol designed to generate a 10 Hz envelope frequency. Brain activity was recorded with magnetoencephalography (MEG) before and after stimulation. Electric field simulations were conducted using individualized head models reconstructed from each participant’s structural MRI.
The primary mixed two-way ANOVA revealed no significant group-by-time interaction for alpha-band power, with a sensitivity analysis indicating that the study was slightly underpowered to detect this interaction effect. Subsequent exploratory within-group analyses showed a post-stimulation increase in alpha band power around 10 Hz in the targeted S1 in the TIS group (Cohen’s
d
= 0.570), whereas no significant change was observed in the active sham group. No clear changes were observed in the beta or gamma bands, and the increase was descriptively largest in the alpha band, although a direct statistical comparison across frequency bands did not reach significance. Furthermore, exploratory analyses based on individualized electric field simulations suggested that off-target electric fields may attenuate the relationship between local field strength in S1 and changes in alpha-band oscillations.
These findings provide preliminary evidence suggesting that TIS may modulate cortical oscillations in humans in accordance with the envelope frequency, although the evidence remains limited. Furthermore, its effectiveness may be influenced by off-target electric fields.
Koshi Iimuro, Naofumi Otsuru, Y. Akazawa et al.· Journal of NeuroEngineering...· 0 citations
Transcranial Magnetic Stimulation is widely used to probe and modulate human brain function, yet the neural effects of stimulation delivered at very low intensities remain unclear. Here, we show that very low intensity magnetic pulses can alter ongoing oscillatory activity in the human primary motor cortex. In healthy participants, we combined transcranial magnetic stimulation with electroencephalography to assess neural responses to single pulses and rhythmic stimulation in the motor cortex. Conventional high intensity stimulation produced robust evoked responses and synchronized beta-frequency oscillations. Low-intensity rhythmic stimulation, despite generating much weaker direct responses, modified local oscillatory activity in a manner consistent with phase-dependent enhancement of ongoing rhythms. These findings suggest that cortical oscillations can be influenced by magnetic fields substantially weaker than those typically used in human studies. Low-intensity stimulation may therefore offer a route towards portable, energy-efficient technologies for investigating and modulating brain networks
Xavier Corominas-Teruel, Martina Bracco, A. Lohof et al.· bioRxiv· 1 citation
Introduction Sensory processing depends on interactions between neural circuits that convey and regulate information across cortical and subcortical networks. Classical frameworks distinguish driving inputs, which transmit sensory content via suprathreshold activation, from modulatory inputs, which alter neuronal excitability without directly eliciting spiking. However, physiological signatures of these circuit types that generalize widely across distributed brain regions remain unclear. Methods We functionally differentiated driving and modulatory circuits in the awake macaque brain by jointly quantifying suprathreshold multiunit activity (MUA) and oscillatory phase coherence (inter-trial coherence, ITC) across eight cortical and thalamic structures during auditory, visual, and eye-movement conditions. Results Preferred sensory stimuli elicited broadband ITC increases accompanied by robust MUA, yielding relatively uniform spectral distributions across adjacent frequency bands, consistent with driving inputs. In contrast, non-preferred sensory and eye-movement related events produced narrowband, frequency-specific ITC modulation without concurrent firing, characterized by dominant peaks at stimulation or event rates, consistent with modulatory inputs. These two response types were observed within individual regions, revealing two separable modes of neural activity. Discussion This narrowband ITC modulation is indicative of coordinated phase alignment, capable of dynamically regulating information transfer mediated by driving inputs across thalamocortical circuits. These findings identify distinct spectrotemporal signatures of driving and modulatory circuit properties across cortical and thalamic levels and demonstrate that subthreshold oscillatory modulation is a widespread phenomenon reflecting cross-modal and saccadic-related influences on neural excitability.
M. N. O'Connell, A. Barczak, C. A. Mackey et al.· Frontiers in Human Neuroscie...· 0 citations
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