An ex vivo platform that integrates microelectrode array stimulation with simultaneous recording and single-nucleus genomics from resected temporal cortex obtained from patients undergoing neurosurgery finds that stimulation strengthens cell assemblies and then linked this effect to cell-type-specific gene regulatory networks.
Neural stimulation, such as electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS), is highly effective clinical intervention for a broad spectrum of psychiatric disorders, including depression and schizophrenia. However, their mechanism of action at the cellular level remains poorly understood. Here, we model ECT with repeated optogenetic neuronal stimulation in the mouse dentate gyrus, and observe ECT-relevant behavioral changes, including decreased depression-like behavior and increased locomotor activity. At the cellular level, we identify dematuration to a long-term stable state, persisting for more than one month, defined by changes in nuclear structure, gene expression patterns resembling the G2/M phase of the cell cycle, and altered neural coding of navigational information. Moreover, knockout of the G2/M master regulator Cyclin B attenuates some of behavioral and cellular effects. These findings demonstrate that chronically-repeated brain stimulation triggers plasticity of the cellular state, revealing a form of stimulus-regulated nuclear reprogramming with potential clinical utility. Here, the authors find repeated stimulation of dentate gyrus neurons in mice reverts post-mitotic mature neurons to an immature-like state through reactivation of cell-cycle-like programs—a previously unrecognized form of cellular plasticity termed “nuclear reprogramming.
Tomoyuki Murano, H. Hagihara, K. Tajinda et al.· Nature Communications· 2 citations
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.
I. Rembado, Soo Yeun Lee, L. Marks et al.· bioRxiv· 0 citations
Alzheimer's disease (AD) is increasingly characterized as a disorder of large-scale brain networks driven by synaptic dysfunction, excitation-inhibition imbalance, and progressive breakdown of hippocampal-cortical communication. While recently developed disease-modifying therapies target molecular pathology, their clinical benefits remain modest, underscoring the need for interventions that target dysfunctional circuits. Neuromodulatory techniques such as transcranial magnetic stimulation, transcranial electrical stimulation, and deep brain stimulation demonstrate safety and act at network/system levels to engage target sites yet are limited by their ability to modulate deep anatomic structures and/or their invasiveness. Focused ultrasound (FUS) offers the distinct capability of modulating cortical and deep subcortical networks noninvasively and with anatomic precision. Preclinical studies demonstrate that FUS neuromodulation can influence mechanosensitive ion channels, synaptic plasticity, neurotrophic signaling, and oscillatory dynamics, with downstream effects on distributed memory networks. Early human investigations similarly suggest FUS neuromodulation can alter functional connectivity within default mode, frontoparietal, and limbic networks. Together, these findings support a framework in which FUS may help reshape pathological network states that emerge prior to irreversible neurodegeneration. Here, we present a narrative review of evidence across neuromodulation approaches to define principles of circuit engagement in AD and discuss a network-based rationale for ultrasound interventions. As an illustration of this framework, we also report preliminary findings from a Phase I pilot study of FUS neuromodulation in amyloid-positive mild cognitive impairment demonstrating safety, tolerability, and measurable modulation of hippocampal connectivity. We conclude mechanistic biomarkers of network response may accelerate translational development and guide future controlled trials.
Marc W. Haut, Camila Vieira Ligo Teixeira, M. Ranjan et al.· Biological Psychiatry· 0 citations
Neurostimulation techniques can powerfully modulate neural circuit activity and provide causal insights into the relationship between brain function and behavior. Macaque monkeys have long been a key animal model for brain stimulation studies. While stimulating the macaque brain with one or a few electrodes has already taught us much about brain function and dysfunction, recent technological advances promise a future with more precise stimulation using many more electrodes. However, such possibilities also increase the number of choices an experimenter has when designing their study. We can learn from a rich past, but a comprehensive overview of which brain regions have been studied and with what stimulation parameters is lacking. Here, we present a PRISMA-compliant systematic review of 734 macaque brain stimulation studies using electrical and/or optogenetic stimulation. We find a striking bias in which brain areas have traditionally been stimulated: a mere 10 brain regions account for half of all studies, with the remainder of studies investigating approximately 150 other areas. Across studies, stimulation frequency robustly predicted direct behavioral effects independent of brain region, while amplitude did not. Future studies could more systematically explore less studied regions through lower stimulation frequencies (e.g., 20-50Hz) alongside established ranges (~200Hz).Tools such as fMRI or optical imaging can capture neural circuit engagement evoked by these frequencies, even when behavioral effects are absent or remain subtle. Our synthesis offers a guide towards the next steps in high-channel-count, high-precision stimulation approaches.
S. Murris, J. Westerberg, P. C. Klink et al.· Neuroscience and Biobehavior...· 0 citations
BACKGROUND
High-frequency deep-brain stimulation can reduce seizure burden but imposes a large stimulation load on the tissue, and its effects depend on both frequency and temporal patterning. We tested whether a compact reservoir model could generate a hippocampal-inspired event schedule and whether that schedule could modulate neuronal activity in vitro with fewer nominal pulses than 50-Hz stimulation.
METHODS
A 10-unit leaky reservoir with a one-dimensional affine ridge readout transformed cortical input recordings into CA3-inspired outputs. Retrospective computational validation used paired cortical-CA3 recordings, training-only scaling, removal of at least the first 10 s of every generated trace, date-grouped held-out evaluation, multiple spectral and temporal metrics, objective-function ablation and surrogate signals. One offline biomimetic schedule was then delivered open loop to primary rat cortical cultures on multielectrode arrays and compared with periodic 0.16-Hz and 50-Hz stimulation.
RESULTS
17 of 19 paired recordings passed the pre-specified transient diagnostic. In 11 scorable date-grouped held-out recordings, the reservoir had modestly lower median log-PSD RMSE and autocorrelation error than linear and lagged-ridge baselines. When applied to primary cortical cultures, the primary pooled analysis of all 11 biomimetic-stimulated MEAs yielded a mean firing-rate slope of 0.7655 relative to the null value of 1 (95% CI for the mean slope, 0.491-1.040; p = 0.0865). In separate MEA-level fold-change analyses of all 11 biomimetic-stimulated MEAs, normalized firing rate was 0.8458 and normalized burst rate was 0.7792, both significantly reduced relative to baseline. A post hoc exploratory classification identified reduced firing-rate slopes in 4 of 11 MEAs.
CONCLUSION
These results provide an open-loop in vitro proof of concept that a low-event, irregular stimulation schedule can be associated with heterogeneous modulation of cortical-network activity. Periodic stimulation at the same nominal mean event rate did not produce a statistically significant modulation under the conditions tested. The irregular schedule may contain timing-related properties that contribute to the observed response, but the specific contribution of ESN-derived temporal ordering remains unresolved. Future work should test appropriate temporal controls and evaluate the approach in closed-loop and epilepsy-model experiments.
Ángel Canal-Alonso, Adam Armada-Moreira, Alessio Di Clemente et al.· Brain Stimulation· 0 citations
Highlights What are the main findings? Magnetic stimulation regulates hippocampal synaptic plasticity in a frequency- and state-dependent manner: ELF-MF commonly exerts bidirectional effects with developmental sensitivity, whereas HF-rTMS more consistently restores impaired LTP and related cognitive function under pathological conditions. The effects of cross-frequency magnetic stimulation converge on a multilevel mechanistic framework involving Ca2+ dynamics, BDNF/TrkB-associated neurotrophic and structural remodeling, and system-level adaptation; micromagnetic stimulation extends this modulation to focal, subregional control of the hippocampus. What are the implications of the main findings? The biological effects of hippocampal magnetic stimulation should be interpreted within the combined context of stimulation parameters and network state, rather than on the basis of frequency alone. Standardized parameter mapping, biomarker-guided stratification, and miniaturized or multisite stimulation platforms are needed to support the development of individualized and closed-loop precision neuromodulation strategies. Abstract Magnetic stimulation modulates hippocampal synaptic plasticity in a parameter-dependent manner with effects shaped by stimulation frequency, intensity, waveform, and exposure conditions. Low-intensity magnetic fields generate induced electric fields that can influence neuronal membrane excitability and neural network activity. Hippocampal long-term potentiation (LTP) and long-term depression (LTD) are widely used as important readouts for evaluating the neurobiological effects of magnetic stimulation. Previous studies have shown that extremely low-frequency magnetic fields (ELF-MFs) may enhance, inhibit, or have no effect on LTP. These divergent effects appear to depend on stimulation conditions, developmental stage, and the baseline state of the neural network. High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) has been reported to promote the recovery of LTP-like plasticity, improve synaptic structure, and regulate the expression of neurotrophic factors in some aging or pathological models. However, its effects are still influenced by both stimulation parameters and biological states. The underlying mechanisms may involve multiple levels of regulation, including Ca2+ dynamics, neurotrophic signals, glutamate receptor dynamics, mitochondrial function, and network oscillations. However, these mechanisms have been inferred mainly from various experimental models, and their interactions, temporal sequence, and causal relationships still need further clarification. Micro-magnetic stimulation (μMS) offers a potential technical approach for improving the spatial selectivity of local regulation in the hippocampus. Arrayed and wireless μMS platforms have further expanded their potential applications. However, available evidence has been obtained primarily from in vitro experiments and animal models. This review summarizes the effects of magnetic stimulation with different parameter configurations on hippocampal synaptic plasticity, integrates the biological mechanisms underlying cross-frequency magnetic neuromodulation, and discusses current challenges in the field of magnetic neuromodulation and future directions toward translational development.
Shuaitao Deng, Lei Tian, Jian-hai Song et al.· Brain Science· 0 citations
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