Dynamic corticothalamic modulation of the somatosensory thalamocortical circuit during wakefulness.

The feedback projections from cortical layer 6 (L6CT) to the sensory thalamus have long been implicated in playing a primary role in gating sensory signaling but remain poorly understood. To causally elucidate the full range of effects of these projections, we targeted silicon probe recordings to the whisker thalamocortical circuit of awake mice selectively expressing Channelrhodopsin-2 in L6CT neurons. Through optogenetic manipulation of L6CT neurons, multi-site electrophysiological recordings, and modeling of L6CT circuitry, we establish L6CT neurons as dynamic modulators of ongoing spiking in the ventral posteromedial nucleus of the thalamus (VPm), either suppressing or enhancing VPm spiking depending on L6CT neurons' firing rate and synchrony. Differential effects across the cortical excitatory and inhibitory sub-populations point to an overall influence of L6CT feedback on cortical excitability that could have profound implications for regulating sensory signaling across a range of ethologically relevant conditions.

[A study on the regulation of motor behavior in mouse based on temporal interference].

Temporal interference (TI) as a new neuromodulation technique can be applied to non-invasive deep brain stimulation. In order to verify its effectiveness in the regulation of motor behavior in animals, this paper uses the TI method to focus the envelope electric field to the ventral posterior lateral nucleus (VPL) of the thalamus in the deep brain of mouse to regulate left- and right-turning motor behavior. The focusability of TI in the mouse VPL was analyzed by finite element method, and the focus area and volume were obtained by numerical calculation. A stimulator was used to generate TI current to stimulate the mouse VPL to verify the effectiveness of the TI stimulation method, and the accuracy of the focus location was further determined by c-Fos immunofluorescence experiments. The results showed that the electric field generated by TI stimulation was able to focus on the VPL nuclei when the stimulation current reached 800 µA; the mouse were able to make corresponding left and right turns according to the stimulation position; and the c-Fos positive cell markers in the VPL nuclei increased significantly after stimulation. This study confirms the feasibility of TI in regulating animal motor behavior and provides a non-invasive stimulation method for brain tissue for animal robots.

Mapping Subcortico-Cortical Coupling-A Comparison of Thalamic and Subthalamic Oscillations.

BACKGROUND: The ventral intermediate nucleus of the thalamus (VIM) is an effective target for deep brain stimulation in tremor patients. Despite its therapeutic importance, its oscillatory coupling to cortical areas has rarely been investigated in humans. OBJECTIVES: The objective of this study was to identify the cortical areas coupled to the VIM in patients with essential tremor. METHODS: We combined resting-state magnetoencephalography with local field potential recordings from the VIM of 19 essential tremor patients. Whole-brain maps of VIM-cortex coherence in several frequency bands were constructed using beamforming and compared with corresponding maps of subthalamic nucleus (STN) coherence based on data from 19 patients with Parkinson's disease. In addition, we computed spectral Granger causality. RESULTS: The topographies of VIM-cortex and STN-cortex coherence were very similar overall but differed quantitatively. Both nuclei were coupled to the ipsilateral sensorimotor cortex in the high-beta band; to the sensorimotor cortex, brainstem, and cerebellum in the low-beta band; and to the temporal cortex, brainstem, and cerebellum in the alpha band. High-beta coherence to sensorimotor cortex was stronger for the STN (P = 0.014), whereas low-beta coherence to the brainstem was stronger for the VIM (P = 0.017). Although the STN was driven by cortical activity in the high-beta band, the VIM led the sensorimotor cortex in the alpha band. CONCLUSIONS: Thalamo-cortical coupling is spatially and spectrally organized. The overall similar topographies of VIM-cortex and STN-cortex coherence suggest that functional connections are not necessarily unique to one subcortical structure but might reflect larger frequency-specific networks involving VIM and STN to a different degree. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Inhibitory Gating of Thalamocortical Inputs onto Rat Gustatory Insular Cortex.

In primary gustatory cortex (GC), a subregion of the insular cortex, neurons show anticipatory activity, encode taste identity and palatability, and their activity is related to decision-making. Inactivation of the gustatory thalamus, the parvicellular region of the ventral posteromedial thalamic nucleus (VPMpc), dramatically reduces GC taste responses, consistent with the hypothesis that VPMpc-GC projections carry taste information. Recordings in awake rodents reported that taste-responsive neurons can be found across GC, without segregated spatial mapping, raising the possibility that projections from the taste thalamus may activate GC broadly. In addition, we have shown that cortical inhibition modulates the integration of thalamic and limbic inputs, revealing a potential role for GABA transmission in gating sensory information to GC. Despite this wealth of information at the system level, the synaptic organization of the VPMpc-GC circuit has not been investigated. Here, we used optogenetic activation of VPMpc afferents to GC in acute slice preparations from rats of both sexes to investigate the synaptic properties and organization of VPMpc afferents in GC and their modulation by cortical inhibition. We hypothesized that VPMpc-GC synapses are distributed across GC, but show laminar- and cell-specific properties, conferring computationally flexibility to how taste information is processed. We also found that VPMpc-GC synaptic responses are strongly modulated by the activity regimen of VPMpc afferents, as well as by cortical inhibition activating GABAA and GABAB receptors onto VPMpc terminals. These results provide a novel insight into the complex features of thalamocortical circuits for taste processing.SIGNIFICANCE STATEMENT We report that the input from the primary taste thalamus to the primary gustatory cortex (GC) shows distinct properties compared with primary thalamocortical synapses onto other sensory areas. Ventral posteromedial thalamic nucleus afferents in GC make synapses with excitatory neurons distributed across all cortical layers and display frequency-dependent short-term plasticity to repetitive stimulation; thus, they do not fit the classic distinction between drivers and modulators typical of other sensory thalamocortical circuits. Thalamocortical activation of GC is gated by cortical inhibition, providing local corticothalamic feedback via presynaptic ionotropic and metabotropic GABA receptors. The connectivity and inhibitory control of thalamocortical synapses in GC highlight unique features of the thalamocortical circuit for taste.

Layer 5 of cortex innervates the thalamic reticular nucleus in mice.

Neurons in the thalamic reticular nucleus (TRN) are a primary source of inhibition to the dorsal thalamus and, as they are innervated in part by the cortex, are a means of corticothalamic regulation. Previously, cortical inputs to the TRN were thought to originate solely from layer 6 (L6), but we recently reported the presence of putative synaptic terminals from layer 5 (L5) neurons in multiple cortical areas in the TRN [J. A. Prasad, B. J. Carroll, S. M. Sherman, J. Neurosci. 40, 5785-5796 (2020)]. Here, we demonstrate with electron microscopy that L5 terminals from multiple cortical regions make bona fide synapses in the TRN. We further use light microscopy to localize these synapses relative to recently described TRN subdivisions and show that L5 terminals target the edges of the somatosensory TRN, where neurons reciprocally connect to higher-order thalamus, and that L5 terminals are scarce in the core of the TRN, where neurons reciprocally connect to first-order thalamus. In contrast, L6 terminals densely innervate both edge and core subregions and are smaller than those from L5. These data suggest that a sparse but potent input from L5 neurons of multiple cortical regions to the TRN may yield transreticular inhibition targeted to higher-order thalamus.

Vim-Thalamic Deep Brain Stimulation for Cervical Dystonia and Upper-Limb Tremor: Quantification by Markerless-3D Kinematics and Accelerometry.

Background: Deep Brain Stimulation (DBS) for dystonia is usually targeted to the globus pallidus internus (GPi), though stimulation of the ventral-intermediate nucleus of the thalamus (Vim) can be an effective treatment for phasic components of dystonia including tremor. We report on a patient who developed a syndrome of bilateral upper limb postural and action tremor and progressive cervical dystonia with both phasic and tonic components which were responsive to Vim DBS. We characterize and quantify this effect using markerless-3D-kinematics combined with accelerometry. Methods: Stereo videography was used to record our subject in 3D. The DeepBehavior toolbox was applied to obtain timeseries of joint position for kinematic analysis [1]. Accelerometry was performed simultaneously for comparison with prior literature. Results: Bilateral Vim DBS improved both dystonic tremor magnitude and tonic posturing. DBS of the hemisphere contralateral to the direction of dystonic head rotation (left Vim) had greater efficacy. Assessment of tremor magnitude by 3D-kinematics was concordant with accelerometry and was able to quantify tonic dystonic posturing. Discussion: In this case, Vim DBS treated both cervical dystonic tremor and dystonic posturing. Markerless-3D-kinematics should be further studied as a method of quantifying and characterizing tremor and dystonia.

Ventral Intermediate Nucleus of the Thalamus versus Posterior Subthalamic Area: Network Meta-Analysis of DBS Target Site Efficacy for Essential Tremor.

BACKGROUND: Deep brain stimulation (DBS) targeting the ventral intermediate nucleus (Vim) of the thalamus or the posterior subthalamic area (PSA) are effective treatments for essential tremor (ET). However, their relative efficacy is unknown. OBJECTIVE: Here, we present the first systematic review and network meta-analysis, examining the efficacy of Vim versus PSA DBS for treating medically refractory ET. METHODS: We included all primary studies that reported validated Fahn-Tolosa-Marin Tremor Rating Scale (FTM-TRS) scores pre-/postimplantation or on-/off-stimulation postimplantation, for patients receiving either Vim or PSA DBS. The primary outcome was FTM-TRS score reduction; the secondary outcome was percent reduction in score. We categorized all outcomes as short-term (≤12 months) or long-term (>12 months). RESULTS: For pre-/postimplantation comparisons, 19 and 11 studies met inclusion criteria for short- and long-term follow-ups, respectively. For on-/off-stimulation tremor score comparisons, 8 studies met inclusion criteria for short-term follow-up. Network meta-analysis of pre-/postimplantation tremor scores showed greater tremor reduction with PSA implantation short-term (absolute tremor reduction: PSA: -30.94 [95% confidence interval (CI): -34.93, -26.95]; Vim: -26.26 [95% CI: -33.39, -19.12]; relative tremor reduction: PSA: 63.3% [95% CI: 61.8%-64.8%]; Vim: 57.8% [95% CI: 56.5%-59.0%]). However, there was no difference in efficacy between PSA and Vim DBS when comparing tremor on-versus off-stimulation at short-term follow-up or pre- versus postimplantation tremor reduction long-term. CONCLUSION: Our systematic review highlighted both heterogeneity in scoring systems used and lack of transparency in reporting total scores, limiting direct comparison across studies. We found a modestly superior efficacy with PSA stimulation in the short term, but no difference in tremor reduction long-term.

Divergent outputs of the ventral lateral geniculate nucleus mediate visually evoked defensive behaviors.

Rapid alternations between exploration and defensive reactions require ongoing risk assessment. How visual cues and internal states flexibly modulate the selection of behaviors remains incompletely understood. Here, we show that the ventral lateral geniculate nucleus (vLGN)-a major retinorecipient structure-is a critical node in the network controlling defensive behaviors to visual threats. We find that vLGNGABA neuron activity scales with the intensity of environmental illumination and is modulated by behavioral state. Chemogenetic activation of vLGNGABA neurons reduces freezing, whereas inactivation dramatically extends the duration of freezing to visual threats. Perturbations of vLGN activity disrupt exploration in brightly illuminated environments. We describe both a vLGN→nucleus reuniens (Re) circuit and a vLGN→superior colliculus (SC) circuit, which exert opposite influences on defensive responses. These findings reveal roles for genetic- and projection-defined vLGN subpopulations in modulating the expression of behavioral threat responses according to internal state.

Circuit organization of the excitatory sensorimotor loop through hand/forelimb S1 and M1.

Sensory-guided limb control relies on communication across sensorimotor loops. For active touch with the hand, the longest loop is the transcortical continuation of ascending pathways, particularly the lemnisco-cortical and corticocortical pathways carrying tactile signals via the cuneate nucleus, ventral posterior lateral (VPL) thalamus, and primary somatosensory (S1) and motor (M1) cortices to reach corticospinal neurons and influence descending activity. We characterized excitatory connectivity along this pathway in the mouse. In the lemnisco-cortical leg, disynaptic cuneate→VPL→S1 connections excited mainly layer (L) 4 neurons. In the corticocortical leg, S1→M1 connections from L2/3 and L5A neurons mainly excited downstream L2/3 neurons, which excite corticospinal neurons. The findings provide a detailed new wiring diagram for the hand/forelimb-related transcortical circuit, delineating a basic but complex set of cell-type-specific feedforward excitatory connections that selectively and extensively engage diverse intratelencephalic projection neurons, thereby polysynaptically linking subcortical somatosensory input to cortical motor output to spinal cord.

Distinct functional developments of surviving and eliminated presynaptic terminals.

For neuronal circuits in the brain to mature, necessary synapses must be maintained and redundant synapses eliminated through experience-dependent mechanisms. However, the functional differentiation of these synapse types during the refinement process remains elusive. Here, we addressed this issue by distinct labeling and direct recordings of presynaptic terminals fated for survival and for elimination in the somatosensory thalamus. At surviving terminals, the number of total releasable vesicles was first enlarged, and then calcium channels and fast-releasing synaptic vesicles were tightly coupled in an experience-dependent manner. By contrast, transmitter release mechanisms did not mature at terminals fated for elimination, irrespective of sensory experience. Nonetheless, terminals fated for survival and for elimination both exhibited developmental shortening of action potential waveforms that was experience independent. Thus, we dissected experience-dependent and -independent developmental maturation processes of surviving and eliminated presynaptic terminals during neuronal circuit refinement.

Intracranial Pressure During the Development of Renovascular Hypertension.

[Figure: see text].

Brainstem local microglia induce whisker map plasticity in the thalamus after peripheral nerve injury.

Whisker deafferentation in mice disrupts topographic connectivity from the brainstem to the thalamic ventral posteromedial nucleus (VPM), which represents whisker map, by recruiting "ectopic" axons carrying non-whisker information in VPM. However, mechanisms inducing this plasticity remain largely unknown. Here, we show the role of region-specific microglia in the brainstem principal trigeminal nucleus (Pr5), a whisker sensory-recipient region, in VPM whisker map plasticity. Systemic or local manipulation of microglial activity reveals that microglia in Pr5, but not in VPM, are necessary and sufficient for recruiting ectopic axons in VPM. Deafferentation causes membrane hyperexcitability of Pr5 neurons dependent on microglia. Inactivation of Pr5 neurons abolishes this somatotopic reorganization in VPM. Additionally, microglial depletion prevents deafferentation-induced ectopic mechanical hypersensitivity. Our results indicate that local microglia in the brainstem induce peripheral nerve injury-induced plasticity of map organization in the thalamus and suggest that microglia are potential therapeutic targets for peripheral nerve injury-induced mechanical hypersensitivity.

Combination targeting of subthalamic nucleus and ventral intermediate thalamic nucleus with a single trajectory in deep brain stimulation for tremor-dominant Parkinson's disease.

Deep brain stimulation (DBS) has traditionally been used to target the subthalamic nucleus (STN) or globus pallidus internus (GPi) to treat Parkinson's disease (PD) and the ventral intermediate thalamic nucleus (VIM) to treat essential tremor (ET). Recent case reports have described targeting both the STN and VIM with a single trajectory and electrode to treat patients with tremor-dominant PD, yet outcome data for this procedure remains sparse. Our objective is to determine the safety and efficacy of combination STN-VIM DBS. We conducted a single-center retrospective case series of all patients who underwent combined STN-VIM DBS. Demographic, perioperative, and outcome data, including Unified Parkinson Disease Rating Scale-III (UPDRS) and tremor scores (OFF-medication), and levodopa equivalent daily dose (LEDD), were collected and analyzed. Nineteen patients underwent this procedure. Patients were 89% male and 11% female, with a mean age of 63.6 years. Mean preoperative UPDRS was 24.1, and LEDD was 811.8. At a mean follow-up of 33.8 months, UPDRS and LEDD decreased by an average of 9.2 (38.2%) and 326.3 (40.2%), respectively. Tremor scores decreased by 4.9 (59.0%), and 58% were able to decrease total medication burden. One patient developed transient left-sided weakness, yielding a complication rate of 5.3%. Combined targeting of STN and VIM thalamus via a single frontal trajectory for tremor-dominant Parkinson's Disease results in similar UPDRS outcomes to STN DBS and improved control of tremor symptoms. Larger multicenter studies are necessary to validate this as the optimal DBS target for tremor-dominant PD.

Imaging the response to deep brain stimulation in rodent using functional ultrasound.

In this study, we explored the feasibility of using functional ultrasound (fUS) imaging to visualize cerebral activation associated with thalamic deep brain stimulation (DBS), in rodents. The ventrolateral (VL) thalamus was stimulated using electrical pulses of low and high frequencies of 10 and 100 Hz, respectively, and multiple voltages (1-7 V) and pulse widths (50-1500 µs). The fUS imaging demonstrated DBS-evoked activation of cerebral cortex based on changes of cerebral blood volume, specifically at the primary motor cortex (PMC). Low frequency stimulation (LFS) demonstrated significantly higher PMC activation compared to higher frequency stimulation (HFS), at intensities (5-7 V). Whereas, at lower intensities (1-3 V), only HFS demonstrated visible PMC activation. Further, LFS-evoked cerebral activation was was primarily located at the PMC. Our data presents the functionality and feasibility of fUS imaging as an investigational tool to identify brain areas associated with DBS. This preliminary study is an important stepping stone towards conducting real-time functional ultrasound imaging of DBS in awake and behaving animal models, which is of significant interest to the community for studying motor-related disorders.

Orientation-selective and directional deep brain stimulation in swine assessed by functional MRI at 3T.

Functional MRI (fMRI) has become an important tool for probing network-level effects of deep brain stimulation (DBS). Previous DBS-fMRI studies have shown that electrical stimulation of the ventrolateral (VL) thalamus can modulate sensorimotor cortices in a frequency and amplitude dependent manner. Here, we investigated, using a swine animal model, how the direction and orientation of the electric field, induced by VL-thalamus DBS, affects activity in the sensorimotor cortex. Adult swine underwent implantation of a novel 16-electrode (4 rows x 4 columns) directional DBS lead in the VL thalamus. A within-subject design was used to compare fMRI responses for (1) directional stimulation consisting of monopolar stimulation in four radial directions around the DBS lead, and (2) orientation-selective stimulation where an electric field dipole was rotated 0°-360° around a quadrangle of electrodes. Functional responses were quantified in the premotor, primary motor, and somatosensory cortices. High frequency electrical stimulation through leads implanted in the VL thalamus induced directional tuning in cortical response patterns to varying degrees depending on DBS lead position. Orientation-selective stimulation showed maximal functional response when the electric field was oriented approximately parallel to the DBS lead, which is consistent with known axonal orientations of the cortico-thalamocortical pathway. These results demonstrate that directional and orientation-selective stimulation paradigms in the VL thalamus can tune network-level modulation patterns in the sensorimotor cortex, which may have translational utility in improving functional outcomes of DBS therapy.

A ventrolateral medulla-midline thalamic circuit for hypoglycemic feeding.

Marked deficits in glucose availability, or glucoprivation, elicit organism-wide counter-regulatory responses whose purpose is to restore glucose homeostasis. However, while catecholamine neurons of the ventrolateral medulla (VLMCA) are thought to orchestrate these responses, the circuit and cellular mechanisms underlying specific counter-regulatory responses are largely unknown. Here, we combined anatomical, imaging, optogenetic and behavioral approaches to interrogate the circuit mechanisms by which VLMCA neurons orchestrate glucoprivation-induced food seeking behavior. Using these approaches, we found that VLMCA neurons form functional connections with nucleus accumbens (NAc)-projecting neurons of the posterior portion of the paraventricular nucleus of the thalamus (pPVT). Importantly, optogenetic manipulations revealed that while activation of VLMCA projections to the pPVT was sufficient to elicit robust feeding behavior in well fed mice, inhibition of VLMCA-pPVT communication significantly impaired glucoprivation-induced feeding while leaving other major counterregulatory responses intact. Collectively our findings identify the VLMCA-pPVT-NAc pathway as a previously-neglected node selectively controlling glucoprivation-induced food seeking. Moreover, by identifying the ventrolateral medulla as a direct source of metabolic information to the midline thalamus, our results support a growing body of literature on the role of the PVT in homeostatic regulation.

Neural activity during a simple reaching task in macaques is counter to gating and rebound in basal ganglia-thalamic communication.

Task-related activity in the ventral thalamus, a major target of basal ganglia output, is often assumed to be permitted or triggered by changes in basal ganglia activity through gating- or rebound-like mechanisms. To test those hypotheses, we sampled single-unit activity from connected basal ganglia output and thalamic nuclei (globus pallidus-internus [GPi] and ventrolateral anterior nucleus [VLa]) in monkeys performing a reaching task. Rate increases were the most common peri-movement change in both nuclei. Moreover, peri-movement changes generally began earlier in VLa than in GPi. Simultaneously recorded GPi-VLa pairs rarely showed short-time-scale spike-to-spike correlations or slow across-trials covariations, and both were equally positive and negative. Finally, spontaneous GPi bursts and pauses were both followed by small, slow reductions in VLa rate. These results appear incompatible with standard gating and rebound models. Still, gating or rebound may be possible in other physiological situations: simulations show how GPi-VLa communication can scale with GPi synchrony and GPi-to-VLa convergence, illuminating how synchrony of basal ganglia output during motor learning or in pathological conditions may render this pathway effective. Thus, in the healthy state, basal ganglia-thalamic communication during learned movement is more subtle than expected, with changes in firing rates possibly being dominated by a common external source.

Anatomically segregated basal ganglia pathways allow parallel behavioral modulation.

In the basal ganglia (BG), anatomically segregated and topographically organized feedforward circuits are thought to modulate multiple behaviors in parallel. Although topographically arranged BG circuits have been described, the extent to which these relationships are maintained across the BG output nuclei and in downstream targets is unclear. Here, using focal trans-synaptic anterograde tracing, we show that the motor-action-related topographical organization of the striatum is preserved in all BG output nuclei. The topography is also maintained downstream of the BG and in multiple parallel closed loops that provide striatal input. Furthermore, focal activation of two distinct striatal regions induces either licking or turning, consistent with their respective anatomical targets of projection outside of the BG. Our results confirm the parallel model of BG function and suggest that the integration and competition of information relating to different behavior occur largely outside of the BG.

Frequency-dependent spike-pattern changes in motor cortex during thalamic deep brain stimulation.

The cerebellar-receiving area of the motor thalamus is the primary anatomical target for treating essential tremor with deep brain stimulation (DBS). Although neuroimaging studies have shown that higher stimulation frequencies in this target correlate with increased cortical metabolic activity, less is known about the cellular-level functional changes that occur in the primary motor cortex (M1) with thalamic stimulation and how these changes depend on the frequency of DBS. In this study, we used a preclinical animal model of DBS to collect single-unit spike recordings in M1 before, during, and after DBS targeting the cerebellar-receiving area of the motor thalamus (VPLo, nucleus ventralis posterior lateralis pars oralis). The effects of VPLo-DBS on M1 spike rates, interspike interval entropy, and peristimulus phase-locking were compared across stimulus pulse train frequencies ranging from 10 to 130 Hz. Although VPLo-DBS modulated the spike rates of 20-50% of individual M1 cells in a frequency-dependent manner, the population-level average spike rate only weakly depended on stimulation frequency. In contrast, the population-level entropy measure showed a pronounced decrease with high-frequency stimulation, caused by a subpopulation of cells that exhibited strong phase-locking and general spike-pattern regularization. Contrarily, low-frequency stimulation induced an entropy increase (spike-pattern disordering) in a relatively large portion of the recorded population, which diminished with higher stimulation frequencies. These results also suggest that changes in phase-locking and spike-pattern entropy are not necessarily equivalent pattern phenomena, but rather that they should both be weighed when quantifying stimulation-induced spike-pattern changes.NEW & NOTEWORTHY The network mechanisms of thalamic deep brain stimulation (DBS) are not well understood at the cellular level. This study investigated the neuronal firing rate and pattern changes in the motor cortex resulting from stimulation of the cerebellar-receiving area of the motor thalamus. We showed that there is a nonintuitive relationship between general entropy-based spike-pattern measures and phase-locked regularization to DBS.

Effect of Cycling Thalamosubthalamic Stimulation on Tremor Habituation and Rebound in Parkinson Disease.

BACKGROUND: Deep brain stimulation is an effective treatment for severe tremor in essential tremor and Parkinson disease (PD). However, progressive loss of the beneficial effects of deep brain stimulation may occur due to several factors. CASE DESCRIPTION: We assessed the effects of different temporal patterns of cycling stimulation in the posterior subthalamic area, subthalamic nucleus, and the ventral intermediate nucleus of the thalamus in 3 PD patients with early decline of tremor suppression associated with severe tremor rebound. CONCLUSIONS: Certain temporal patterns of cycling (10 seconds on/1 second off or 30 seconds on/5 seconds off, soft start off) were useful for treating tremor habituation and rebound and showed long-term tremor suppression. Cycling stimulation may prevent tremor habituation in PD patients with severe tremor rebound.