Brain Stimulation

BackgroundHigh-frequency (10 Hz) repetitive transcranial magnetic stimulation (rTMS) to the primary motor cortex (M1) is used to treat several neuropsychiatric disorders, but its main mechanism of action remains unclear. ObjectiveTo probe four cortical hubs used for rTMS (M1; dorsolateral-prefrontal cortex, DLPFC; anterior cingulate cortex, ACC; posterosuperior insula, PSI) with TMS coupled with high-density electroencephalography (TMS-EEG) and measure cortical excitability and oscillatory dynamics before and after active and sham rTMS to M1. MethodsBefore and immediately after active or sham M1-rTMS (15 min, 3,000 pulses at 10 Hz), single-pulse TMS evoked EEG were recorded at the four targets in 20 healthy individuals. Measures of cortical excitability and oscillatory dynamics were extracted at the main frequency bands ( [8-13 Hz], low-{beta} [14-24 Hz], high-{beta} [25-35 Hz]). ResultsComparing active and sham M1 rTMS, M1 TMS-EEG demonstrated an increase in high-{beta} synchronization in electrodes around M1 stimulation area and remotely in the contralateral hemisphere (p=0.026). The increase in high-{beta} synchronization (48-83 ms after TMS-EEG stimulation) was succeeded by an enhancement in low-{beta} power (86-144 ms after TMS-EEG stimulation) both locally and in the contralateral hemisphere (p=0.006). No significant differences were observed in TMS-EEG responses probing DLPFC, ACC, or PSI. ConclusionM1-rTMS engaged a sequence of enhanced phase synchronization, followed by an increase in power occurring within M1, that spread to remote areas and was measurable after the end of the stimulation session. These results are relevant to understanding the M1 neuroplastic effects of rTMS and associated changes in cortical activity dynamics.

Transcranial direct-current stimulation (tDCS) is a non-invasive brain stimulation technique consisting in the application of weak electric currents on the scalp. Although previous studies have demonstrated the clinical value of tDCS for modulating sensory, motor, and cognitive functions, there are still huge gaps in the knowledge of the underlying physiological mechanisms. To define the immediate impact as well as the after-effects of tDCS on sensory processing, we first performed electrophysiological recordings in primary somatosensory cortex (S1) of alert mice during and after administration of S1-tDCS, and followed up with immunohistochemical analysis of the stimulated brain regions. During the application of cathodal and anodal transcranial currents we observed polarity-specific bidirectional changes in the N1 component of the sensory-evoked potentials (SEPs) and associated gamma oscillations. Regarding the long-term effects observed after 20 min of tDCS, cathodal stimulation produced significant after-effects including a decreased SEP amplitude for up to 30 min, a power reduction in the 20-80 Hz range and a decrease in gamma event related synchronization (ERS). In contrast, no significant long-term changes in SEP amplitude or power analysis were observed after anodal stimulation except for a significant increase in gamma ERS after tDCS cessation. The polarity-specific differences of these long-term effects were corroborated by immunohistochemical analysis, which revealed an unbalance of GAD 65-67 immunoreactivity between the stimulated vs. non-stimulated S1 region only after cathodal tDCS. These results highlight the differences between immediate and long-term effects of tDCS, as well as the asymmetric long-term changes induced by anodal and cathodal stimulation. Significance StatementHere we provide a first glimpse at the immediate and long-term impact of tDCS on neural processing in alert animals. The obtained results highlight the complexity of tDCS-associated effects, which include both bidirectional as well as asymmetrical modulation depending on the polarity of the stimulation. This asymmetry suggests the implication of different mechanisms underlying the long-term effects induced by anodal and cathodal transcranial currents. Identifying and defining these effects and its associated mechanisms is crucial to help design effective protocols for clinical applications.

BackgroundRepetitive brain stimulation is hypothesized to bidirectionally modulate excitability, with low-frequency trains decreasing and high-frequency (>5 Hz) trains increasing activity. Most insights on the neuroplastic effects of repetitive stimulation protocols stem from non-invasive human studies (TMS/EEG) or data from rodent slice physiology. Here, we developed a rodent experimental preparation enabling simultaneous imaging of cellular activity during stimulation in vivo to understand the mechanisms by which brain stimulation modulates excitability of prefrontal cortex. MethodsRepetitive trains of intracortical stimulation were applied to the medial prefrontal cortex using current parameters mapped to human rTMS electric-field estimates. Calcium imaging of glutamatergic (CamKII) and GABAergic (mDLX) neurons was performed before, during, and after stimulation in awake rodents (n=9 females). Protocols included low-frequency (1 Hz, 1000 pulses) and high-frequency (10 Hz, 3000 pulses), with sham stimulation as a control. ResultsGlutamatergic neurons were differentially modulated by stimulation frequency, with 10 Hz increasing and 1 Hz decreasing activity. Post-stimulation, 1 Hz suppressed both glutamatergic and GABAergic activity, whereas 10 Hz selectively suppressed GABAergic neurons. ConclusionsThese findings provide direct evidence that clinical brain stimulation protocols induce long-term modulation of cortical excitability, with low-frequency stimulation broadly suppressing activity and high-frequency stimulation preferentially inhibiting GABAergic neurons after stimulation.

BackgroundTranscranial ultrasonic stimulation (TUS) is an emerging non-invasive neuromodulation technique with the potential to target both cortical and subcortical brain regions. This study investigates the effects of theta-burst TUS (tb-TUS), a neuromodulatory pattern characterized by bursts of pulses repeated at a theta frequency, on cerebral blood flow, functional connectivity, and metabolite concentrations in the primary motor cortex (M1). The aim of this study is to take a first step towards the mechanistic and methodological feasibility of tb-TUS at the M1 using multimodal neuroimaging. MethodsSeventeen healthy participants underwent a double-blind, sham-controlled crossover design, receiving both active and sham tb-TUS to the left M1 over three days. Multimodal MRI, including pseudo-continuous arterial spin labeling (PCASL), resting-state functional MRI (rs-fMRI), and magnetic resonance spectroscopy (MRS), was conducted at baseline, pre-, and post-stimulation. Acoustic simulations and finger-tapping BOLD-peak signal guided individualized TUS targeting. ResultsActive tb-TUS significantly reduced cerebral blood flow (p < .001) and within-region functional connectivity (p < .001) in the M1 compared to sham stimulation. A non-significant trend towards decreased GABA was observed, with no significant session x condition interaction found for GABA, Glutamate, or Glx concentrations. ConclusionThis pilot study demonstrates that tb-TUS of the M1 induces reductions in cerebral blood flow and functional connectivity in healthy participants. Our findings indicate that tb-TUS may be mitigating neural hyperactivity patterns, but preliminary studies so far arrive at differing results, highlighting the need for further research to replicate our findings, elucidate the underlying mechanisms, and optimize stimulation protocols.

BackgroundClinical intracranial electrical stimulation often deploys trains of high frequency pulses. While brief bursts of stimulation are known to heterogeneously modulate neuronal spiking, it is unclear how trains of high frequency pulses influence neural dynamics. ObjectiveAs fast spiking interneurons (FSIs) can support rapid firing, we seek to determine how high frequency stimulation modulates FSIs. MethodsWe characterized the real-time effect of one-second-long local stimulation at 40 versus 140 Hz on parvalbumin positive interneurons, known as FSIs, in motor and visual cortices in awake mice using near kilohertz voltage imaging, free of electrical stimulation artifact. ResultsStimulation at 140 Hz, like 40 Hz, heterogeneously modulates individual FSIs membrane voltage in both cortices, leading to complex temporal dynamics. FSIs in both cortices are robustly entrained by 40 Hz stimulation, even though 40 Hz led to prominent membrane hyperpolarization in visual cortex but not motor cortex. Intriguingly, visual cortical FSIs, but not motor cortical ones, were reliably entrained by 140 Hz stimulation. Finally, while stimulation consistently reduced the response amplitude of visual cortical FSIs to visual flickers, response temporal precision is bidirectionally modulated. ConclusionHigh frequency electrical stimulation mediates brain-region specific entrainment of FSIs, and bidirectionally modulates FSI temporal processing of synaptic inputs. Thus, high frequency stimulation can differentially engage inhibitory neurons in different brain regions to modulate network information processing. HighlightsO_LIEvoked membrane potential (Vm) responses are frequency and brain region specific C_LIO_LI140 Hz stimulation entrains the Vm of visual, but not motor, cortical FSIs C_LIO_LI140 Hz, but not 40 Hz, is effective at reducing Vm amplitude to visual flickers C_LIO_LIStimulation bidirectionally modulates Vm response timing to visual inputs C_LIO_LIVisual cortical FSIs are suppressed by 40 Hz stimulation, unlike other conditions C_LI

A leading theory for how psychedelics are able to produce robust clinical improvement and preclinical behavioral changes is that psychedelics act through neuroplastic mechanisms to induce lasting structural and functional alterations in neural circuits. However, psychedelics produce these effects across wide swaths of the brain. Based on our prior work, we hypothesized that engaging a specific brain circuit with focal brain stimulation during the window of enhanced plasticity produced by psychedelics would lead to more persistent alterations in the activity of that circuit. To test this, we administered either saline (SAL) or lysergic acid diethylamide (LSD) to rats 24 hours prior to electrical stimulation targeting the rat medial prefrontal cortex (mPFC). Brain activity was recorded before, during, and after stimulation using depth electrodes implanted in four bilateral frontostriatal regions. To assess changes in neural activity, we trained general logistic classifiers to distinguish between time points (e.g., pre-stimulation vs. post-stimulation) and then compared model performances across groups (e.g., LSD vs. SAL). As such, model performance represents the degree of difference between the two neural states (pre vs. post), and a significant difference between groups indicates a larger change in brain activity in one group. We found that LSD pretreatment, compared to SAL, resulted in larger and longer-lasting changes in brain activity following stimulation. Immunohistochemistry revealed that stimulation led to the activation of the mTOR signaling pathway, and the combination of LSD and stimulation led to alterations in perineuronal net (PNN) integrity. Regardless of pretreatment, brain activity states recorded during stimulation did not capture the brain state that persisted in the minutes or days that followed. This work has important implications for understanding the general effects of brain stimulation and provides strong support for the development of psychedelic-assisted brain stimulation approaches. By increasing the durability of brain stimulation-induced changes in activity, this approach could lead to a reduction in relapse rates, which currently limit the impact of non-invasive stimulation treatments.

Graphical AbstractVarying inter-train intervals (ITIs) during theta burst stimulation (TBS) differentially modulates neuronal activity in the medial prefrontal cortex. Short ITIs (e.g., ITI 4 s) induce strong glutamatergic excitation but fail to induce long-term changes post-stimulation. By contrast, an extended ITI of 20 seconds (eTBS, green star) optimally enhances long-term excitability in glutamatergic neurons while suppressing GABAergic interneurons, indicating a shift in excitation-inhibition balance that promotes cortical plasticity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/608693v2_ufig1.gif" ALT="Figure 1000"> View larger version (38K): org.highwire.dtl.DTLVardef@113f13dorg.highwire.dtl.DTLVardef@4317d7org.highwire.dtl.DTLVardef@d25dd5org.highwire.dtl.DTLVardef@10e6e3f_HPS_FORMAT_FIGEXP M_FIG C_FIG SummaryElectrical theta burst stimulation (TBS) with different inter-train intervals (ITIs) was first used to characterize bidirectional synaptic plasticity in brain slices. Despite a lack of understanding of mechanism, TBS has been adopted by rTMS research and clinical protocols to drive plasticity in the human brain, with variable results. To uncover how TBS modulates excitability in vivo, we systematically screen the impact of electrical TBS with different ITIs on rodent cortical neurons. Short inter-train intervals (4-10s) increased calcium activity in both glutamatergic and GABAergic neurons during stimulation, whereas extended ITIs (20s) yielded modest but significant activation of glutamatergic cells and minimal activation of GABAergic cells. TBS with an ITI of 20s emerged as a plasticity "sweet spot" that maximized long-term activation of glutamatergic neurons, potentially through suppression of GABAergic neurons(1-3). Translating our novel iTBS electrical stimulation protocol to rTMS interventions has the potential to deliver heightened plasticity and improved therapeutic outcomes. HighlightsSystematic manipulation of inter-train intervals (ITIs) reveals an optimal 20s ITI for TBS-induced plasticity. Extended ITIs enhance excitability in glutamatergic neurons while suppressing GABAergic activity. PV interneurons are preferentially recruited during short-interval TBS, limiting sustained plasticity.

IntroductionTranscranial direct current stimulation (tDCS) is a non-invasive neuromodulation method using low amplitude current (1-2 mA) to create weak electric fields (<1 V/m) in the brain, influencing cognition, motor skills, and behavior. However, the neural mechanisms remain unclear, as prior studies used high electric field strengths (10-40 V/m) unrepresentative of human tDCS. ObjectiveThis study aimed to develop an in-vivo rat model replicating human tDCS electric field strengths to examine effects of weak electric fields on cortical neurons. MethodCurrents of 0.005-0.3 mA were applied in 9 rats, generating electric fields of 0.5-35 V/m in the somatosensory cortex. Neural activity across cortical layers was recorded using a multichannel silicone probe. Somatosensory evoked potentials (SSEP) elicited by foot shocks assessed membrane polarization. Regular spiking (RS) and fast-spiking (FS) neurons were identified via spike shapes. Effects of tDCS on SSEP, spontaneous spiking activity (SSA), and evoked spiking activity (ESA) were analyzed. ResultsAnodal tDCS caused hyperpolarization (SSEP increase) in superficial layers and depolarization (SSEP decrease) in deeper layers, reversing asymmetrically for cathodal stimulation. Weak fields (<1 V/m) altered SSA in RS but not FS neurons, while stronger fields affected ESA in RS neurons. Effects correlated with field strength and were well described by linear mixed-effect models. Changes in SSA were correlated with changes in SSEP. ConclusionThis study demonstrates that realistic tDCS fields induce complex cortical polarization patterns linked to SSA changes. Increasing electric field strength amplifies effects, suggesting higher amplitude tDCS could enhance efficacy in humans. HighlightsO_LINewly developed in-vivo rodent model to replicate the weak electric field strengths characteristic of human tDCS, probe localized membrane polarization effects and simultaneously monitor spontaneous and evoked spiking activity. C_LIO_LIResults provide the first direct in-vivo confirmation of several tDCS mechanistic predictions derived from computational models and brain slice work. C_LIO_LIComplex Membrane Polarization Patterns: tDCS induces simultaneous hyperpolarization and depolarization in distinct neuronal compartments. C_LIO_LINeuron-Specific Effects: Weak electric fields preferentially modulate excitatory neurons, with no significant impact on inhibitory neurons at low electric field strengths. C_LIO_LIPolarity asymmetric effects: Anodic stimulation produces stronger effects than cathodic stimulation. C_LIO_LIMembrane polarization is linked to changes in spiking activity: Changes in membrane polarization are correlated with changes in spontaneous spiking activity. C_LIO_LIAll the tDCS neural mechanisms showed effects that were linearly related to electric field strength, underscoring the translational importance of novel tDCS protocols that can increase electric field strength, potentially improving the robustness and reproducibility of tDCS protocols in humans. C_LI

Transcranial alternating current stimulation (tACS) can influence human perception and behavior, with recent evidence also suggesting its potential impact in clinical settings, but the underlying mechanisms are poorly understood. Behavioral and indirect physiological evidence indicates that phase-dependent constructive and destructive interference between the tACS electric field and ongoing brain oscillations may play an important role, but direct in-vivo validation was infeasible because stimulation artifacts impeded such assessment. Using stimulation artifact source separation (SASS), a real-time compatible artifact suppression approach, we overcame this limitation and provide direct evidence for millisecond-by-millisecond phase-dependent enhancement and suppression of ongoing brain oscillations during amplitude-modulated tACS (AM-tACS) across 29 healthy human volunteers. We found that AM-tACS enhanced and suppressed targeted brain oscillations by 11.7 {+/-} 5.14% and 10.1 {+/-} 4.07% respectively. Millisecond-precise modulation of oscillations predicted modulation of behavior (r = 0.65, p < 0.001). These results not only provide direct evidence for constructive and destructive interference as a key mechanism of AM-tACS but suggest superiority of phase-locked (closed-loop) AM-tACS over conventional (open-loop) AM-tACS to purposefully enhance or suppress brain oscillations. SignificanceThe presented data provide direct evidence for a key mechanism underlying neurophysiological and behavioral effects of transcranial alternating current stimulation (tACS), a broadly used neuromodulation approach that yields promising clinical results but also raised controversies because of its variable effects. Our findings not only elucidate the underlying mechanisms of tACS, but also provide the rationale for closed-loop tACS protocols that will enable targeted enhancement and suppression of brain oscillations related to various brain functions such perception, memory or cognition. Towards this end, we introduce the technical prerequisites to establish millisecond-to-millisecond precise closed-loop tACS protocols that will be important to advance tACS as a neuroscientific and clinical tool, for example in the treatment of neuropsychiatric disorders.

Although stimulation with ultrasound has been shown to modulate brain activity at multiple scales, it remains unclear whether transcranial focused ultrasound stimulation (tFUS) exerts its influence on specific cell types. Here we propose a novel form of tFUS where a continuous waveform is amplitude modulated (AM) at a slow rate (i.e., 40 Hz) targeting the temporal range of electrophysiological activity: AM-tFUS. We stimulated the rat hippocampus while recording multi-unit activity (MUA) followed by classification of spike waveforms into putative excitatory pyramidal cells and inhibitory interneurons. At low acoustic intensity, AM-tFUS selectively reduced firing rates of inhibitory interneurons. On the other hand, higher intensity AM-tFUS increased firing of putative excitatory neurons with no effect on inhibitory firing. Interestingly, firing rate was unchanged during AM-tFUS at intermediate intensity. Consistent with the observed changes in firing rate, power in the theta band (3-10 Hz) of the local field potential (LFP) decreased at low-intensity, was unchanged at intermediate intensity, and increased at higher intensity. Temperature increases at the AM-tFUS target were limited to 0.2{degrees}C. Our findings indicate that inhibitory interneurons exhibit greater sensitivity to ultrasound, and that cell-type specific neuromodulation may be achieved by calibrating the intensity of AM-tFUS.

Repetitive Transcranial Magnetic Stimulation (rTMS) is an established neuromodulation technique, using electromagnetic pulses that, depending on the precise parameters, are assumed to lead to lasting neural excitability changes. rTMS has widespread applications in both research and therapy, where it has been FDA approved and is considered a first-line treatment for depression, according to recent North American and European guidelines. However, these assumed excitability effects are often difficult to replicate, and highly unreliable on the single subject/patient level. Given the increasing application of rTMS, especially in clinical practice, the absence of a method to unequivocally determine effects of rTMS on human neuronal excitability is problematic. We have taken a first step in addressing this bottleneck, by administering excitatory and inhibitory rTMS protocols, iTBS and cTBS, to a human in vitro neuron model; differentiated SH-SY5Y cells. We use live calcium imaging to assess changes in neural activity following stimulation, through quantifying fluorescence response to chemical depolarization. We found that iTBS and cTBS have opposite effects on fluorescence response; with iTBS increasing and cTBS decreasing response to chemical depolarization. Our results are promising, as they provide a clear demonstration of rTMS after-effects in a living human neuron model. We here present an in-vitro live calcium imaging setup that can be further applied to more complex human neuron models, for developing and evaluating subject/patient-specific brain stimulation protocols.

Theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation (TMS), is capable of non-invasively modulating cortical excitability. TBS is gaining popularity as a therapeutic tool for psychiatric disorders such as depression, in which the dorsolateral prefrontal cortex (DLPFC) is the main therapeutic target. However, the neuromodulatory effects of TBS on prefrontal regions remain unclear. An emerging tool to assess neuromodulation in non-motor regions is concurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG) to measure TMS-evoked potentials (TEPs). We assessed twenty-four healthy participants (13 males, mean age 25.2{+/-}9.9 years) following intermittent TBS, continuous TBS, and sham applied to the left DLPFC using a double-blinded crossover design. TEPs were obtained at baseline and 2-, 15-, and 30-min post-stimulation. Four TEP components (N40, P60, N100 and P200) were analysed using mixed effects repeated measures models (MRMM). Results indicate no significant effects for any assessed components (all p>.05). The largest effect size (Cohens d = -0.5) comparing iTBS and sham was obtained for the N100 component at 15 minutes post-stimulation. This result was in the same direction but smaller than found in previous studies, suggesting that the true effect size may be lower than previously reported. Accurate estimates of the effects sizes and inter-individual heterogeneity will critically inform clinical applications using TEPs to assess the neuromodulatory effects of TBS.

BackgroundDeep brain ultrasound offers a novel means of modulating human cognition by noninvasively targeting subcortical structures that were previously accessible only through invasive procedures. While decades of research have mapped cortical circuits of attention, the causal roles of deep hubs such as the basal ganglia and thalamus remain poorly understood in the healthy human brain. Objectives/HypothesisTo test whether low intensity transcranial ultrasound stimulation (TUS) of two nodes in the basal ganglia-thalamic network, the globus pallidus internus (GPi) and the pulvinar, causally alters visual attention. We hypothesized that TUS-induced modulations in attentional performance would be site specific, reflecting distinct circuit functions. ResultsAcross sessions, focal TUS accelerated reaction time in a visual search task, indicating augmented attention. Reaction time improvements were observed after stimulation relative to baseline. A dissociation emerged across sites: both GPi and pulvinar enhanced reaction times, but pulvinar yielded more robust benefits for target present trials at peripheral eccentricities, and improved search efficiency in the same trials. ConclusionsThese findings provide causal evidence that human attentional control can be steered at deep subcortical sites. TUS offers a practical approach for dissecting circuit level contributions to cognition and a potential noninvasive avenue for enhancing attention and other cognitive or affective functions.

Transcranial alternating current stimulation (tACS) is a noninvasive technique for modulating brain oscillations. While sinusoidal tACS (sin-tACS) delivers current at a constant amplitude, amplitude-modulated tACS (AM-tACS) uses a high-frequency carrier modulated by a low-frequency envelope. We systematically compared the acute effects of sin-tACS at theta (5 Hz), alpha (10 Hz), beta (20 Hz), and gamma (140 Hz) frequencies, and AM-tACS (140 Hz carrier frequency modulated at theta, alpha, or beta) on corticospinal excitability. Healthy participants received 2 mA peak-to-peak tACS to the primary motor hand area (M1HAND) via a bipolar montage (M1HAND-Pz). Each tACS block consisted of ten 30-second stimulation periods interleaved with 6-second pauses, followed by 11 minutes without stimulation. Corticospinal excitability was assessed during each block using single-pulse transcranial magnetic stimulation (TMS), delivered at the peak and trough of tACS. MEP amplitudes were generally larger at the trough. Only beta sin-tACS and theta AM-tACS significantly modulated corticospinal excitability. Beta sin-tACS increased MEP amplitudes in early stimulation epochs, while theta AM-tACS facilitated MEPs in later stimulation epochs and this facilitation persisted briefly after stimulation ended. Participants with stronger early responses to beta sin-tACS also tended to show greater delayed effects with theta AM-tACS. These excitability changes during tACS were not predicted by simulated electric field strength. A follow-up EEG experiment revealed that beta sin-tACS increased beta power over left sensorimotor cortex, while theta AM-tACS decreased beta power over midline parietal cortex. These EEG changes were restricted to tACS pauses. The results show that sin-tACS and AM-tACS can both modulate corticospinal excitability, but functional changes differ in temporal dynamics, frequency specificity, and cortical region engagement.

BackgroundEmotion regulation is a core transdiagnostic process in mood, anxiety, and stress-related disorders. While existing non-invasive brain stimulation approaches, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), can modulate affective networks, their clinical use is limited by restricted spatial precision and depth penetration. Transcranial focused ultrasound stimulation (tFUS) offers submillimeter focality and access to both cortical and deep subcortical structures, making it a promising tool for affective neuromodulation. MethodsWe systematically searched PubMed, Embase, and PsycINFO for human studies using tFUS to modulate emotion regulation, affective processing, or related symptoms. Eligible studies included randomized controlled trials (RCTs), open-label, and within-subject designs. Data on stimulation parameters, target regions, outcomes, and safety were extracted. Effect sizes were calculated and pooled using a random-effects model, with subgroup analyses by clinical domain. ResultsEleven studies met inclusion criteria, targeting the amygdala (n = 5), prefrontal cortex (n = 5), or subcallosal cingulate cortex (n = 1), with protocols varying in frequency (250-650 kHz), duty cycle (0.5-70%), and number of sessions (1-25). Across six studies reporting behavioral symptom outcomes, the pooled effect was moderate-to-large (Hedges g = 0.88, 95% CI [0.47, 1.29]), with larger effects in depression-related measures (g = 1.31) than in anxiety-related measures (g = 0.67). Imaging outcomes were reported in a smaller subset of studies and were not included in the pooled estimates. No serious adverse events were reported. ConclusionstFUS is a safe and well-tolerated intervention capable of engaging deep affective circuits. Future large-scale, harmonized, and mechanistically informed trials are warranted to refine protocols, establish durability, and optimize translation into clinical practice.

Transcranial magnetic stimulation (TMS) is increasingly deployed in the treatment of neuropsychiatric illness, under the presumption that stimulation of specific cortical targets can alter ongoing neural activity and cause circuit-level changes in brain function. While the electrophysiological effects of TMS have been extensively studied with scalp electroencephalography (EEG), this approach is most useful for evaluating low-frequency neural activity at the cortical surface. As such, little is known about how TMS perturbs rhythmic activity among deeper structures - such as the hippocampus and amygdala - and whether stimulation can alter higher-frequency oscillations. Recent work has established that TMS can be safely used in patients with intracranial electrodes (iEEG), allowing for direct neural recordings at sufficient spatiotemporal resolution to examine localized oscillatory responses across the frequency spectrum. To that end, we recruited 17 neurosurgical patients with indwelling electrodes and recorded neural activity while patients underwent repeated trials of single-pulse TMS at several cortical sites. Stimulation to the dorsolateral prefrontal cortex (DLPFC) drove widespread low-frequency increases (3-8Hz) in frontolimbic cortices, as well as high-frequency decreases (30-110Hz) in frontotemporal areas, including the hippocampus. Stimulation to parietal cortex specifically provoked low-frequency responses in the medial temporal lobe. While most low-frequency activity was consistent with brief evoked responses, anterior frontal regions exhibited induced theta oscillations following DLPFC stimulation. Taken together, we established that non-invasive stimulation can (1) provoke a mixture of low-frequency evoked power and induced theta oscillations and (2) suppress high-frequency activity in deeper brain structures not directly accessed by stimulation itself.

Cerebellar transcranial direct current stimulation (Cb-tDCS) is a promising tool for non-invasive modulation of cerebellar function and is under investigation for treating cerebellum-related disorders. However, its local and remote effects on sensory processing remain poorly understood. We investigated the immediate and long-term effects of Cb-tDCS on sensory-evoked responses in the cerebellum and primary somatosensory cortex (S1) of awake mice. Sensory-evoked potentials (SEPs) were recorded in Crus I/II and S1 during and after short (15 s) or long (20 min) sessions of anodal or cathodal Cb-tDCS. In addition, the excitation/inhibition balance was assessed by quantifying vGLUT1 and GAD 65-67 immunoreactivity, and spectral changes in local field potentials were analyzed using FFT-based analysis. Anodal and cathodal Cb-tDCS respectively induced an immediate increase and decrease in the trigeminal component in Crus I/II but no aftereffects were observed 20 minutes post-stimulation. In S1, Cb-tDCS resulted in polarity-dependent modulation of the N1 component during stimulation, which was opposite to the changes induced in Crus I/II and a sustained increase after anodal Cb-tDCS, accompanied by reduced GAD 65-67 immunoreactivity. While power spectrum analysis revealed no changes in Crus I/II, cathodal Cb-tDCS significantly modulated gamma (30-45 Hz) and high-frequency oscillations (255-300 Hz) in S1. These findings show that Cb-tDCS differentially modulates sensory input processing in cerebellar and cortical circuits. While cerebellar effects are transient, stimulation elicits lasting changes in remote cortical areas. This underscores the need to consider both local and distant network effects when applying Cb-tDCS in translational and clinical settings.

BackgroundThe therapeutic effects of transcranial magnetic stimulation (TMS) likely stem from neuroplasticity induced by repeated sessions over time. While animal models offer insights into TMS-induced plasticity, a rodent model that faithfully replicates prolonged TMS conditions in humans is still lacking. Objective/HypothesisDevelop a rat model that mimics the spatial and temporal patterns of TMS in humans. MethodsExperiments were conducted on two cohorts of healthy adult rats (N=33). In cohort 1, rats underwent surgical implantation of microelectrodes for motor evoked potential (MEP) recording. With a rodent-specific coil and the high-density theta burst stimulation (hdTBS) paradigm, under awake condition, rats received daily TMS at 100% motor threshold for five days (days 1-5) to the hindlimb motor cortex. Cortical excitability was measured by input-output (I-O) curves on Day 0 (pre-hdTBS baseline) and Day 6 (post-hdTBS). The second cohort received identical TMS and underwent fMRI to map cerebral blood volume (CBV) on Days 0 and 6. ResultsDaily hdTBS session for 5 days significantly up-shifted I-O curves only in the TMS group (N=9), not in the sham group (N=7), indicating enhanced cortical excitability. fMRI data showed that, compared to sham group (N=9), rats receiving hdTBS (N=8) had increased basal CBV in several brain regions proximal and distal to the stimulation site, suggesting enhanced basal metabolism. Conclusion(s)Daily hdTBS session for 5 days focally delivered to the motor cortex of naive rats significantly altered basal brain activity in a network of brain regions, opening a novel platform for further investigating TMS-induced plasticity.

BackgroundLow-intensity transcranial ultrasound stimulation (TUS) is a novel non-invasive brain-stimulation technique offering high spatial precision and depth penetrance. Theta burst TUS (tbTUS), featuring a temporal theta burst stimulation pattern, has been reported to facilitate corticomotor excitability, when applied to the human primary motor hand area (M1-HAND). However, replication attempts have yielded inconsistent results. MethodsFifteen healthy human participants underwent neuronavigated tbTUS targeting the left M1-HAND in the anterior wall of the precentral sulcus, as well as anterior and posterior active control sites. The three tbTUS conditions were applied in counterbalanced order on separate days. Corticospinal excitability was assessed via motor evoked potentials (MEPs) recorded before and 5, 15, 30, and 60 minutes after tbTUS, and analyzed using an rmANOVA. ResultsNone of the tbTUS conditions produced consistent group-level changes in MEP amplitude at any time point. Both intra- and inter-subject variability were high, and individual MEP changes following precentral tbTUS did not correlate with changes after control-site stimulation. ConclusionsWe did not observe reliable modulatory effects of neuronavigated tbTUS on corticospinal excitability. Methodological and hardware differences may account for discrepancies across studies. Our findings align with recent reports questioning the robustness of tbTUS-induced facilitation.

Transcranial focused ultrasound stimulation (tFUS) has been proven capable of altering focal neuronal activities and neural circuits non-invasively in both animals and humans. The abilities of tFUS for cell-type selection within the targeted area like somatosensory cortex have been shown to be parameter related. However, how neuronal subpopulations across neural pathways are affected, for example how tFUS affected neuronal connections between brain areas remains unclear. In this study, multi-site intracranial recordings were used to quantify the neuronal responses to tFUS stimulation at somatosensory cortex (S1), motor cortex (M1) and posterior medial thalamic nucleus (POm) of cortico-thalamo-cortical (CTC) pathway. We found that when targeting at S1 or POm, only regular spiking units (RSUs, putative excitatory neurons) responded to specific tFUS parameters (duty cycle: 6%-60% and pulse repetition frequency: 1500 and 3000 Hz ) during sonication. RSUs from the directly connected area (POm or S1) showed a synchronized response, which changed the directional correlation between RSUs from POm and S1. The tFUS induced excitation of RSUs activated the feedforward and feedback loops between cortex and thalamus, eliciting delayed neuronal responses of RSUs and delayed activities of fast spiking units (FSUs) by affecting local network. Our findings indicated that tFUS can modulate the CTC pathway through both feedforward and feedback loops, which could influence larger cortical areas including motor cortex.