Plasticity-Induced Effects of Theta Burst Transcranial Ultrasound Stimulation in Parkinson's Disease.

BACKGROUND: Low-intensity transcranial ultrasound stimulation (TUS) is a noninvasive brain stimulation (NIBS) technique with high spatial specificity. Previous studies showed that TUS delivered in a theta burst pattern (tbTUS) increased motor cortex (MI) excitability up to 30 minutes due to long-term potentiation (LTP)-like plasticity. Studies using other forms of NIBS suggested that cortical plasticity may be impaired in patients with Parkinson's disease (PD). OBJECTIVE: The aim was to investigate the neurophysiological effects of tbTUS in PD patients off and on dopaminergic medications compared to healthy controls. METHODS: We studied 20 moderately affected PD patients in on and off dopaminergic medication states (7 with and 13 without dyskinesia) and 17 age-matched healthy controls in a case-controlled study. tbTUS was applied for 80 seconds to the MI. Motor-evoked potentials (MEP), short-interval intracortical inhibition (SICI), and short-interval intracortical facilitation (SICF) were recorded at baseline, and at 5 minutes (T5), T30, and T60 after tbTUS. Motor Unified Parkinson's Disease Rating Scale (mUPDRS) was measured at baseline and T60. RESULTS: tbTUS significantly increased MEP amplitude at T30 compared to baseline in controls and in PD patients on but not in PD patients off medications. SICI was reduced in PD off medications compared to controls. tbTUS did not change in SICI or SICF. The bradykinesia subscore of mUPDRS was reduced at T60 compared to baseline in PD on but not in the off medication state. The presence of dyskinesia did not affect tbTUS-induced plasticity. CONCLUSIONS: tbTUS-induced LTP plasticity is impaired in PD patients off medications and is restored by dopaminergic medications. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Visual and vestibular integration in Parkinson's disease while walking.

Postural control requires effective sensory integration. People with Parkinson's disease (PD) are reported to have impaired visual and vestibular perception. While self-motion perception is a key aspect of locomotion, visual-vestibular integration has not been directly characterized in people with PD during gait. We compared the ability of people with PD and healthy older adults (OA) to integrate multi-sensory information during straight-line walking in response to visual and vestibular perturbations, using continuous translations of the visual surround and galvanic vestibular stimulation within a virtual reality environment. We measured their endpoint deviations from midline and changes in gait parameters. We found that people with PD deviated more than OA when walking in a dark environment but did not show differences in deviations when walking in a virtual room with visual information. With visual and vestibular perturbations, people with PD did not differ from OA in endpoint deviations nor variabilities. However, people with PD did not adopt a more cautious gait when GVS was applied in a virtual room, unlike OA. Overall, we showed that people with mild PD did not perform worse than OA but did show differences in gait patterns, suggesting that visual-vestibular integration is relatively preserved during gait in PD.

Long-Term Recording of Subthalamic Aperiodic Activities and Beta Bursts in Parkinson's Disease.

BACKGROUND: Local field potentials (LFPs) represent the summation of periodic (oscillations) and aperiodic (fractal) signals. Although previous studies showed changes in beta band oscillations and burst characteristics of the subthalamic nucleus (STN) in Parkinson's disease (PD), how aperiodic activity in the STN is related to PD pathophysiology is unknown. OBJECTIVES: The study aimed to characterize the long-term effects of STN-deep brain stimulation (DBS) and dopaminergic medications on aperiodic activities and beta bursts. METHODS: A total of 10 patients with PD participated in this longitudinal study. Simultaneous bilateral STN-LFP recordings were conducted in six separate visits during a period of 18 months using the Activa PC + S device in the off and on dopaminergic medication states. We used irregular-resampling auto-spectral analysis to separate oscillations and aperiodic components (exponent and offset) in the power spectrum of STN-LFP signals in beta band. RESULTS: Our results revealed a systematic increase in both the exponent and the offset of the aperiodic spectrum over 18 months following the DBS implantation, independent of the dopaminergic medication state of patients with PD. In contrast, beta burst durations and amplitudes were stable over time and were suppressed by dopaminergic medications. CONCLUSIONS: These findings indicate that oscillations and aperiodic activities reflect at least partially distinct yet complementary neural mechanisms, which should be considered in the design of robust biomarkers to optimize adaptive DBS. Given the link between increased gamma-aminobutyric acidergic (GABAergic) transmission and higher aperiodic activity, our findings suggest that long-term STN-DBS may relate to increased inhibition in the basal ganglia. © 2022 International Parkinson and Movement Disorder Society.

Human Studies of Transcranial Ultrasound neuromodulation: A systematic review of effectiveness and safety.

BACKGROUND: Transcranial ultrasound stimulation (TUS) is gaining traction as a safe and non-invasive technique in human studies. There has been a rapid increase in TUS human studies in recent years, with more than half of studies to date published after 2020. This rapid growth in the relevant body of literature necessitates comprehensive reviews to update clinicians and researchers. OBJECTIVE: The aim of this work is to review human studies with an emphasis on TUS devices, sonication parameters, outcome measures, results, and adverse effects, as well as highlight future directions of investigation. METHODS: A systematic review was conducted by searching the Web of Science and PubMed databases on January 12, 2022. Human studies of TUS were included. RESULTS: A total of 35 studies were identified using focused/unfocused ultrasound devices. A total of 677 subjects belonging to diverse cohorts (i.e., healthy, chronic pain, dementia, epilepsy, traumatic brain injury, depression) were enrolled. The stimulation effects vary in a sonication parameter-dependant fashion. Clinical, neurophysiological, radiological and histological outcome measures were assessed. No severe adverse effects were reported in any of the studies surveyed. Mild symptoms were observed in 3.4% (14/425) of the subjects, including headache, mood deterioration, scalp heating, cognitive problems, neck pain, muscle twitches, anxiety, sleepiness and pruritis. CONCLUSIONS: Although increasingly being used, TUS is still in its early phases. TUS can change short-term brain excitability and connectivity, induce long-term plasticity, and modulate behavior. New techniques should be used to further elucidate its underlying mechanisms and identify its application in novel populations.

Induction of Human Motor Cortex Plasticity by Theta Burst Transcranial Ultrasound Stimulation.

OBJECTIVE: Transcranial ultrasound stimulation (TUS) is a promising noninvasive brain stimulation technique with advantages of high spatial precision and ability to target deep brain regions. This study aimed to develop a TUS protocol to effectively induce brain plasticity in human subjects. METHODS: An 80-second train of theta burst patterned TUS (tbTUS), regularly patterned TUS (rTUS) with the same sonication duration, and sham tbTUS was delivered to the motor cortex in healthy subjects. Transcranial magnetic stimulation (TMS) was used to examine changes in corticospinal excitability, intracortical inhibition and facilitation, and the site of plasticity induction. The effects of motor cortical tbTUS on a visuomotor task and the effects of occipital cortex tbTUS on motor cortical excitability were also tested. RESULTS: The tbTUS produced consistent increase in corticospinal excitability for at least 30 minutes, whereas rTUS and sham tbTUS produced no significant change. tbTUS decreased short-interval intracortical inhibition and increased intracortical facilitation. The effects of TMS in different current directions suggested that the site of the plastic changes was within the motor cortex. tbTUS to the occipital cortex did not change motor cortical excitability. Motor cortical tbTUS shortened movement time in a visuomotor task. INTERPRETATION: tbTUS is a novel and efficient paradigm to induce cortical plasticity in humans. It has the potential to be developed for neuromodulation treatment for neurological and psychiatric disorders, and to advance neuroscience research. ANN NEUROL 2022;91:238-252.

Time course of the effects of low-intensity transcranial ultrasound on the excitability of ipsilateral and contralateral human primary motor cortex.

Low-intensity transcranial ultrasound stimulation (TUS) is a promising non-invasive brain stimulation technique that can modulate the excitability of cortical and deep brain structures with a high degree of focality. Previous human studies showed that TUS decreases motor cortex (M1) excitability measured by transcranial magnetic stimulation (TMS), but whether the effects appear beyond sonication and whether TUS affects the excitability of other interconnected cortical areas is not known. The time course of M1 TUS on ipsilateral and contralateral M1 excitability was investigated in 22 healthy human subjects via TMS-induced motor-evoked potentials. With sonication duration of 500 ms, we found suppression of M1 excitability from 10 ms before to 20 ms after the end of sonication, and the effects were stronger with blocked design compared to interleaved design. There was no significant effect on contralateral M1 excitability. Using ex-vivo measurements, we showed that the ultrasound transducer did not affect the magnitude or time course of the TMS-induced electromagnetic field. We conclude that the online-suppressive effects of TUS on ipsilateral M1 cortical excitability slightly outlast the sonication but did not produce long-lasting effects. The absence of contralateral effects may suggest that there are little tonic interhemispheric interactions in the resting state, or the intensity of TUS was too low to induce transcallosal inhibition.

Cerebellar tDCS Alters the Perception of Optic Flow.

Studies have shown that the cerebellar vermis is involved in the perception of motion. However, it is unclear how the cerebellum influences motion perception. tDCS is a non-invasive brain stimulation technique that can reduce (through cathodal stimulation) or increase neuronal excitability (through anodal stimulation). To explore the nature of the cerebellar involvement on large-field global motion perception (i.e., optic flow-like motion), we applied tDCS on the cerebellar midline while participants performed an optic flow motion discrimination task. Our results show that anodal tDCS improves discrimination threshold for optic flow perception, but only for left-right motion in contrast to up-down motion discrimination. This result was evident within the first 10 min of stimulation and was also found post-stimulation. Cathodal stimulation did not have any significant effects on performance in any direction. The results show that discrimination of optic flow can be improved with tDCS of the cerebellar midline and provide further support for the role of the human midline cerebellum in the perception of optic flow.

Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behavior.

Low-intensity transcranial ultrasound (TUS) can non-invasively modulate human neural activity. We investigated how different fundamental sonication parameters influence the effects of TUS on the motor cortex (M1) of 16 healthy subjects by probing cortico-cortical excitability and behavior. A low-intensity 500 kHz TUS transducer was coupled to a transcranial magnetic stimulation (TMS) coil. TMS was delivered 10 ms before the end of TUS to the left M1 hotspot of the first dorsal interosseous muscle. Varying acoustic parameters (pulse repetition frequency, duty cycle, and sonication duration) on motor-evoked potential amplitude were examined. Paired-pulse measures of cortical inhibition and facilitation, and performance on a visuomotor task was also assessed. TUS safely suppressed TMS-elicited motor cortical activity, with longer sonication durations and shorter duty cycles when delivered in a blocked paradigm. TUS increased GABAA-mediated short-interval intracortical inhibition and decreased reaction time on visuomotor task but not when controlled with TUS at near-somatosensory threshold intensity.

The contribution of nonrigid motion and shape information to object perception in pigeons and humans.

The ability to perceive and recognize objects is essential to many animals, including humans. Until recently, models of object recognition have primarily focused on static cues, such as shape, but more recent research is beginning to show that motion plays an important role in object perception. Most studies have focused on rigid motion, a type of motion most often associated with inanimate objects. In contrast, nonrigid motion is often associated with biological motion and is therefore ecologically important to visually dependent animals. In this study, we examined the relative contribution of nonrigid motion and shape to object perception in humans and pigeons, two species that rely extensively on vision. Using a parametric morphing technique to systematically vary nonrigid motion and three-dimensional shape information, we found that both humans and pigeons were able to rely solely on either shape or nonrigid motion information to identify complex objects when one of the two cues was degraded. Humans and pigeons also showed similar 80% accuracy thresholds when the information from both shape and motion cues were degraded. We argue that the use of nonrigid motion for object perception is evolutionarily important and should be considered in general theories of vision at least with respect to visually sophisticated animals.

Sensitivity of the avian motion system to light and dark stimuli.

Global motion perception is important for mobile organisms. In laterally eyed birds, global motion appears to be processed in the entopallium, a neural structure that is part of the tectofugal pathway. Electrophysiological research has shown that motion selective cells in the entopallium are most responsive to small dark moving targets. Here, we investigated whether this bias toward dark targets of entopallial cells is mirrored by perceptual performance in a motion detection task in pigeons. We measured the detection thresholds of pigeons using random dot stimuli that consisted of either black or white dots on a gray background. We found that thresholds were significantly lower when using black dots as opposed to white dots. This heightened sensitivity is also noted in the learning rates of the pigeons. That is, we found that the pigeons learned the detection task significantly faster when the stimuli consisted of black dots. We believe that our results have important implications for the understanding of the functional role of the entopallium and the ON and OFF pathways in the avian motion system.

Re-evaluating birds' ability to detect Glass patterns.

Glass patterns (GPs) are static stimuli that consist of randomly positioned dot-pairs that are spatially integrated to create the perception of a global form. However, when multiple independently generated static GPs are presented sequentially (termed 'dynamic' GP), observers report a percept of coherent motion, and data show an improvement in sensitivity. This increased sensitivity has been attributed to a summation of the form signals provided by the individual GPs. In Experiment 1, we tested whether pigeons also show a heightened sensitivity to dynamic GPs. Our results show that pigeons are significantly better at learning to discriminate dynamic GPs from noise compared with static GPs. However, in contrast to previous research, we found that pigeons did not perform well enough with our static GPs to extract sensitivity measurements. In Experiment 2, we compared our static GPs to those that have been used previously. We show that the difference in the comparison noise patterns is important. We used dipole noise patterns, while previous studies used uniform noise patterns that differ in mean dot spacing to the S+. We argue that prior findings from the use of GPs in pigeons should be re-evaluated using dynamic GP stimuli with noise that consist of dipoles.

Temporal summation of global form signals in dynamic Glass patterns.

The ability to perceive complex objects in the environment requires that the visual system integrate local form information into global shapes. Glass patterns (GPs) are stimuli that are commonly used to study this integration process. GPs consist of randomly positioned dot-pairs oriented in a coherent way to create a global form. When multiple GPs are presented sequentially, observers report a percept of illusory coherent motion and have lower detection thresholds relative to a single presentation GPs. The percept of illusory motion has been attributed to the visual system interpreting the dot-pairs in GPs as motion streaks. However, it remains unclear why dynamic GPs are detected at lower thresholds than static GPs. Two main differences exist between static and dynamic GPs: (a) dynamic GPs contain multiple presentations of global form signals compared to a single presentation in static GPs and (b) dynamic GPs have a greater temporal frequency than static GPs. Here we investigated which of these two factors contributed to the heightened sensitivities for dynamic GPs. We systematically varied the number of unique GPs and the rate at which each unique frame is presented (i.e., temporal frequency). The results show that, within the range of temporal frequency used, the primary influence on detection thresholds was the number of unique frames. These results suggest that the improved detection sensitivities can be driven by a mechanism of temporal summation of global form.

Perception of complex motion in humans and pigeons (Columba livia).

In the primate visual system, local motion signals are pooled to create a global motion percept. Like primates, many birds are highly dependent on vision for their survival, yet relatively little is known about motion perception in birds. We used random-dot stimuli to investigate pigeons' ability to detect complex motion (radial, rotation, and spiral) compared to humans. Our human participants had a significantly lower threshold for rotational and radial motion when compared to spiral motion. The data from the pigeons, however, showed that the pigeons were most sensitive to rotational motion and least sensitive to radial motion, while sensitivity for spiral motion was intermediate. We followed up the pigeon results with an investigation of the effect of display aperture shape for rotational motion and velocity gradient for radial motion. We found no effect of shape of the aperture on thresholds, but did observe that radial motion containing accelerating dots improved thresholds. However, this improvement did not reach the thresholds levels observed for rotational motion. In sum, our experiments demonstrate that the pooling mechanism in the pigeon motion system is most efficient for rotation.

Use of geometric properties of landmark arrays for reorientation relative to remote cities and local objects.

Five experiments investigated how human adults use landmark arrays in the immediate environment to reorient relative to the local environment and relative to remote cities. Participants learned targets' directions with the presence of a proximal 4 poles forming a rectangular shape and an array of more distal poles forming a rectangular shape. Then participants were disoriented and pointed to targets with the presence of the proximal poles or the distal poles. Participants' orientation was estimated by the mean of their pointing error across targets. The targets could be 7 objects in the immediate local environment in which the poles were located or 7 cities around Edmonton (Alberta, Canada) where the experiments occurred. The directions of the 7 cities could be learned from reading a map first and then from pointing to the cities when the poles were presented. The directions of the 7 cities could also be learned from viewing labels of cities moving back and forth in the specific direction in the immediate local environment in which the poles were located. The shape of the array of the distal poles varied in salience by changing the number of poles on each edge of the rectangle (2 vs. 34). The results showed that participants regained their orientation relative to local objects using the distal poles with 2 poles on each edge; participants could not reorient relative to cities using the distal pole array with 2 poles on each edge but could reorient relative to cities using the distal pole array with 34 poles on each edge. These results indicate that use of cues in reorientation depends not only on the cue salience but also on which environment people need to reorient to.

Perception of dynamic glass patterns.

In the mammalian brain, form and motion are processed through two distinct pathways at early stages of visual processing. However, recent evidence suggests that these two pathways may interact. Here we used dynamic Glass patterns, which have been previously shown to create the perception of coherent motion in humans, despite containing no motion coherence. Glass patterns are static stimuli that consist of randomly positioned dot pairs that are integrated spatially to create the perception of a global form, whereas dynamic Glass patterns consist of several independently generated static Glass patterns presented sequentially. In the current study, we measured the detection threshold of five types of dynamic Glass patterns and compared the rank order of the detection thresholds with those found for static Glass patterns and real motion patterns (using random dot stimuli). With both the static Glass patterns and dynamic Glass patterns, detection thresholds were lowest for concentric and radial patterns and highest for horizontal patterns. We also found that vertical patterns were better detected than horizontal patterns, consistent with prior evidence of a "horizontal effect" in the perception of natural scene images. With real motion, detection thresholds were equivalent across all patterns, with the exception of higher thresholds for spiral patterns. Our results suggest that dynamic Glass patterns are processed primarily as form prior to input into the motion system.