Modulation of Cerebellar Oscillations with Subthalamic Stimulation in Patients with Parkinson's Disease.

Background: Deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) has emerged as a potent treatment for alleviating motor symptoms in Parkinson's disease (PD). Despite its effectiveness, the impact of high frequency STN-DBS on cerebellar oscillations remains unclear, posing an intriguing challenge for neural modulation. Given the direct and indirect connections between the STN and cerebellum, we investigated whether STN-DBS affects cerebellar oscillations. Objective: To observe the effects of STN-DBS on cerebellar oscillations in patients with PD. Methods: We recruited 15 PD patients receiving STN-DBS. Electroencephalographic (EEG) signals were recorded from cerebellar regions during resting-state conditions in both the OFF-DBS and STN-DBS conditions. Our analyses centered on spectral features, particularly theta and beta oscillations, guided by prior research and correlation tests to investigate the relationship between oscillatory changes and motor symptom severity. Results: In the mid-cerebellar (Cbz) region, we observed a significant increase in the relative power in all frequency bands, including theta and beta oscillations during STN-DBS, showing the global effect of DBS. Importantly, the correlation results indicated significant associations between mid-cerebellar (Cbz) beta power during the OFF condition and motor severity, which were not evident during STN-DBS. Interestingly, correlations between beta power and motor severity were not observed at the mid-occipital (Oz) and mid-frontal (Cz) regions. Notably, signal similarity analyses demonstrated no evidence of volume conduction effects between the mid-cerebellar (Cbz) and nearby mid-occipital (Oz) regions. Conclusions: While these findings provide valuable insights into the complex interplay between STN-DBS and neural oscillations, further research is essential to decipher their precise functional significance and clinical implications. Understanding these intricacies may contribute to the optimization of DBS therapies for PD.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for reducing motor symptoms in Parkinson's disease (PD). However, its effects on brain activity, specifically in the cerebellum, are not well understood. This study aimed to investigate how STN-DBS affects cerebellar brain waves in PD patients. We recruited 15 PD patients undergoing STN-DBS and recorded their brain activity including cerebellar region using EEG. We compared the brain wave patterns during periods when the DBS was turned OFF and when it was turned ON, focusing on specific brain wave frequencies (theta and beta). The results showed a significant increase in brain wave power across all frequencies in the mid-cerebellar region during STN-DBS. Additionally, there was a strong link between beta power in the cerebellum and motor symptom severity when DBS was OFF, which was not present when DBS was ON. This relationship was specific to the cerebellum and not found in other brain regions. The findings suggest that STN-DBS significantly alters cerebellar brain activity and that these changes are related to improvements in motor symptoms. However, more research is needed to fully understand the functional significance and potential clinical applications of these findings for optimizing DBS treatment in PD patients.

Water and brain function: effects of hydration status on neurostimulation with transcranial magnetic stimulation.

Neurostimulation/neurorecording are tools to study, diagnose, and treat neurological/psychiatric conditions. Both techniques depend on volume conduction between scalp and excitable brain tissue. Here, we examine how neurostimulation with transcranial magnetic stimulation (TMS) is affected by hydration status, a physiological variable that can influence the volume of fluid spaces/cells, excitability, and cellular/global brain functioning. Normal healthy adult participants (32, 9 males) had common motor TMS measures taken in a repeated-measures design from dehydrated (12-h overnight fast/thirst) and rehydrated (identical dehydration protocol followed by rehydration with 1 L water in 1 h) testing days. The target region was left primary motor cortex hand area. Response at the target muscle was recorded with electromyography. Urinalysis confirmed hydration status. Motor hotspot shifted in half of participants. Motor threshold decreased in rehydration, indicating increased excitability. Even after redosing/relocalizing TMS to the new threshold/hotspot, rehydration still showed evidence of increased excitability: recruitment curve measures generally shifted upward and the glutamate-dependent paired-pulse protocol, short intracortical facilitation (SICF), was increased. Short intracortical inhibition (SICI), long intracortical inhibition (LICI), long intracortical facilitation (LICF), and cortical silent period (CSP) were relatively unaffected. The hydration perturbations were mild/subclinical based on the magnitude/speed and urinalysis. Motor TMS measures showed evidence of expected physiological changes of osmotic challenges. Rehydration showed signs of macroscopic and microscopic volume changes including decreased scalp-cortex distance (brain closer to stimulator) and astrocyte swelling-induced glutamate release. Hydration may be a source of variability affecting any techniques dependent on brain volumes/volume conduction. These concepts are important for researchers/clinicians using such techniques or dealing with the wide variety of disease processes involving water balance.NEW & NOTEWORTHY Hydration status can affect brain volumes and excitability, which should affect techniques dependent on electrical volume conduction, including neurostimulation/recording. We test the previously unknown effects of hydration on neurostimulation with TMS and briefly review relevant physiology of hydration. Rehydration showed lower motor threshold, shifted motor hotspot, and generally larger responses even after compensating for threshold/hotspot changes. This is important for clinical and research applications of neurostimulation/neurorecording and the many clinical disorders related to water balance.

Left anterior supramarginal gyrus activity during tool use action observation after extensive tool use training.

The advanced use of complex tools is considered a primary characteristic of human evolution and technological advancement. However, questions remain regarding whether humans possess unique underlying brain networks that support advanced tool-using abilities. Specifically, previous studies have demonstrated the presence of a structurally and functionally unique region in the left anterior supramarginal gyrus (aSMG), that is consistently active during tool use action observation. This region has been proposed as a primary hub for integrating semantic and technical information to form action plans with tools. However, it is still largely unknown how tool use motor learning affects left aSMG activation or connectivity with other brain regions. To address this, participants with little experience using chopsticks observed an experimenter using chopsticks to perform a novel task while undergoing two functional magnetic resonance imaging (fMRI) scans. Between the scans, participants underwent four weeks of behavioral training where they learned to use chopsticks and achieve proficiency in the observed task. Results demonstrated a significant change in effective connectivity between the left aSMG and the left anterior intraparietal sulcus (aIPS), a region involved in object affordances and planning grasping actions. These findings suggest that during unfamiliar tool use, the left aSMG integrates semantic and technical information to communicate with regions involved with grasp selection, such as the aIPS. This communication then allows appropriate grasps to be planned based on the physical properties of the objects involved and their potential interactions.

Effects of Very Low- and High-Frequency Subthalamic Stimulation on Motor Cortical Oscillations During Rhythmic Lower-Limb Movements in Parkinson's Disease Patients.

BACKGROUND: Standard high-frequency deep brain stimulation (HF-DBS) at the subthalamic nucleus (STN) is less effective for lower-limb motor dysfunctions in Parkinson's disease (PD) patients. However, the effects of very low frequency (VLF; 4 Hz)-DBS on lower-limb movement and motor cortical oscillations have not been compared. OBJECTIVE: To compare the effects of VLF-DBS and HF-DBS at the STN on a lower-limb pedaling motor task and motor cortical oscillations in patients with PD and with and without freezing of gait (FOG). METHODS: Thirteen PD patients with bilateral STN-DBS performed a cue-triggered lower-limb pedaling motor task with electroencephalography (EEG) in OFF-DBS, VLF-DBS (4 Hz), and HF-DBS (120-175 Hz) states. We performed spectral analysis on the preparatory signals and compared GO-cue-triggered theta and movement-related beta oscillations over motor cortical regions across DBS conditions in PD patients and subgroups (PDFOG-and PDFOG+). RESULTS: Both VLF-DBS and HF-DBS decreased the linear speed of the pedaling task in PD, and HF-DBS decreased speed in both PDFOG-and PDFOG+. Preparatory theta and beta activities were increased with both stimulation frequencies. Both DBS frequencies increased motor cortical theta activity during pedaling movement in PD patients, but this increase was only observed in the PDFOG + group. Beta activity was not significantly different from OFF-DBS at either frequency regardless of FOG status. CONCLUSION: Results suggest that VL and HF DBS may induce similar effects on lower-limb kinematics by impairing movement speed and modulating motor cortical oscillations in the lower frequency band.

Sensorimotor control of object manipulation following middle cerebral artery (MCA) stroke.

Methods for assessing the loss of hand function post-stroke examine limited aspects of motor performance and are not sensitive to subtle changes that can cause deficits in everyday object manipulation tasks. Efficiently lifting an object entails a prediction of required forces based on intrinsic features of the object (sensorimotor integration), short-term updates in the forces required to lift objects that are poorly predicted (sensorimotor memory), as well as the ability to modulate distal fingertip forces, which are not measured by existing assessment tools used in clinics for both diagnostic and rehabilitative purposes. The presented research examined these three components of skilled object manipulation in 60 chronic, unilateral middle cerebral artery stroke participants. Performance was compared to age-matched control participants, and linear regressions were used to predict performance based on clinical scores. Most post-stroke participants performed below control levels in at least one of the tasks. Post-stroke participants presented with combinations of deficits in each of the tasks performed, regardless of the hemisphere damaged by the stroke. Surprisingly, the ability to modulate distal forces was impaired in those patients with damage ipsilateral (right hemisphere) to the hand being used. Sensorimotor integration was also impaired in patients with right hemisphere damage, though they performed at control levels in later lifts, whereas left-hemisphere-damaged patients did not. Lastly, during a task requiring sensorimotor memory, neither patient group performed outside of control ranges on initial lifts, with patients with right hemisphere damage showing impaired performance in later lifts suggesting they were unable to learn the mapping novel mapping of color and mass of the objects. The presented research demonstrates unilateral MCA stroke patients can have deficits in one or more components required for the successful manipulation of hand-held objects and that skillful object lifting requires intact bilateral systems. Further, this information may be used in future studies to aid efforts that target rehabilitation regimens to a stroke survivor's specific pattern of deficits.

Cerebellar oscillatory dysfunction during lower-limb movement in Parkinson's disease with freezing of gait.

Studies have demonstrated dysfunctional connectivity between the cortico-basal ganglia and cerebellar networks in Parkinson's disease (PD). These networks are critical for appropriate motor and cognitive functions, specifically to control gait and postural tasks in PD. Our recent reports have shown abnormal cerebellar oscillations during rest, motor, and cognitive tasks in people with PD compared to healthy individuals, however, the role of cerebellar oscillations in people with PD and freezing of gait (PDFOG+) during lower-limb movements has not been examined. Here, we evaluated cerebellar oscillations using electroencephalography (EEG) electrodes during cue-triggered lower-limb pedaling movement in 13 PDFOG+, 13 PDFOG-, and 13 age-matched healthy subjects. We focused analyses on the mid-cerebellar Cbz as well as lateral cerebellar Cb1 and Cb2 electrodes. PDFOG+ performed the pedaling movement with reduced linear speed and higher variation compared to healthy subjects. PDFOG+ exhibited attenuated theta power during pedaling motor tasks in the mid-cerebellar location compared to PDFOG- or healthy subjects. Cbz theta power was also associated with FOG severity. No significant differences between groups were seen in Cbz beta power. In the lateral cerebellar electrodes, lower theta power was seen between PDFOG+ and healthy subjects. Our cerebellar EEG data demonstrate the occurrence of reduced theta oscillations in PDFOG+ during lower-limb movement and suggest a potential cerebellar biosignature for neurostimulation therapy to improve gait dysfunctions.

Functional Connectivity in Patients With Parkinson's Disease and Freezing of Gait Using Resting-State EEG and Graph Theory.

BACKGROUND: Although many studies have shown abnormalities in brain structure and function in people with Parkinson's disease (PD), we still have a poor understanding of how brain structure and function relates to freezing of gait (FOG). Graph theory analysis of electroencephalography (EEG) can explore the relationship between brain network structure and gait function in PD. METHODS: Scalp EEG signals of 83 PD (42 PDFOG+ and 41 PDFOG-) and 42 healthy controls were recorded in an eyes-opened resting-state. The phase lag index was calculated for each electrode pair in different frequency bands, but we focused our analysis on the theta-band and performed global analyses along with nodal analyses over a midfrontal channel. The resulting connectivity matrices were converted to weighted graphs, whose structure was characterized using strength and clustering coefficient measurements, our main outcomes. RESULTS: We observed increased global strength and increased global clustering coefficient in people with PD compared to healthy controls in the theta-band, though no differences were observed in midfrontal nodal strength and midfrontal clustering coefficient. Furthermore, no differences in global nor midfrontal nodal strength nor global clustering coefficients were observed between PDFOG+ and PDFOG- in the theta-band. However, PDFOG+ exhibited a significantly diminished midfrontal nodal clustering coefficient in the theta-band compared to PDFOG-. Furthermore, FOG scores were negatively correlated with midfrontal nodal clustering coefficient in the theta-band. CONCLUSION: The present findings support the involvement of midfrontal theta oscillations in FOG symptoms in PD and the sensitivity of graph metrics to characterize functional networks in PDFOG+.

Interval timing and midfrontal delta oscillations are impaired in Parkinson's disease patients with freezing of gait.

Gait abnormalities and cognitive dysfunction are common in patients with Parkinson's disease (PD) and get worse with disease progression. Recent evidence has suggested a strong relationship between gait abnormalities and cognitive dysfunction in PD patients and impaired cognitive control could be one of the causes for abnormal gait patterns. However, the pathophysiological mechanisms of cognitive dysfunction in PD patients with gait problems are unclear. Here, we collected scalp electroencephalography (EEG) signals during a 7-s interval timing task to investigate the cortical mechanisms of cognitive dysfunction in PD patients with (PDFOG +, n = 34) and without (PDFOG-, n = 37) freezing of gait, as well as control subjects (n = 37). Results showed that the PDFOG + group exhibited the lowest maximum response density at around 7 s compared to PDFOG- and control groups, and this response density peak correlated with gait abnormalities as measured by FOG scores. EEG data demonstrated that PDFOG + had decreased midfrontal delta-band power at the onset of the target cue, which was also correlated with maximum response density and FOG scores. In addition, our classifier performed better at discriminating PDFOG + from PDFOG- and controls with an area under the curve of 0.93 when midfrontal delta power was chosen as a feature. These findings suggest that abnormal midfrontal activity in PDFOG + is related to cognitive dysfunction and describe the mechanistic relationship between cognitive and gait functions in PDFOG + . Overall, these results could advance the development of novel biosignatures and brain stimulation approaches for PDFOG + .

Resting-State Low-Frequency Cerebellar Oscillations Can Be Abnormal in Parkinson's Disease.

Recent anatomical studies have shown connections between the basal ganglia and the cerebellum. The basal ganglia and cerebellum are major subcortical structures that influence motor and cognitive functions. Recent neuroimaging and animal studies have suggested the role of the cerebellum in the pathophysiology of Parkinson's disease. However, the role of cerebellar oscillations in PD has not been studied. Here, we recruited 75 PD and 39 healthy control subjects to collect cerebellar EEG during a resting-state condition. We followed the recently published protocols to collect cerebellar oscillations. Relative spectral power was computed in the delta, theta, beta, and gamma frequency bands. Further, we performed classifier methods to differentiate PD subjects from controls. We observed significantly increased theta-band (4-7 Hz) relative power in the cerebellar electrodes in PD subjects compared to controls. We also found differences in different frequency bands between mid-cerebellar and nearby mid-occipital EEG signals. Classification analysis using mid-cerebellar theta relative power showed differentiation between PD and control groups. Our results demonstrate that in addition to established cortical and basal ganglia oscillations, abnormal cerebellar oscillations in the theta-band may also participate in the underlying pathophysiology of PD. We suggest that low-frequency cerebellar oscillations may be a potential target for non-invasive neuromodulation to improve PD symptoms.

Cortical and Cerebellar Oscillatory Responses to Postural Instability in Parkinson's Disease.

Introduction: Posture and balance dysfunctions critically impair activities of daily living of patients with progressing Parkinson's disease (PD). However, the neural mechanisms underlying postural instability in PD are poorly understood, and specific therapies are lacking. Previous electrophysiological studies have shown distinct cortical oscillations with a significant contribution of the cerebellum during postural control tasks in healthy individuals. Methods: We investigated cortical and mid-cerebellar oscillatory activity via electroencephalography (EEG) during a postural control task in 10 PD patients with postural instability (PDPI+), 11 PD patients without postural instability (PDPI-), and 15 age-matched healthy control participants. Relative spectral power was analyzed in the theta (4-7 Hz) and beta (13-30 Hz) frequency bands. Results: Time-dependent postural measurements computed by accelerometer signals showed poor performance in PDPI+ participants. EEG results revealed that theta power was profoundly lower in mid-frontal and mid-cerebellar regions during the postural control task in PDPI+, compared to PDPI- and control participants. In addition, theta power was correlated with postural control performance in PD subjects. No significant changes in beta power were observed. Additionally, oscillatory changes during the postural control task differed from the resting state. Conclusion: This study underlines the involvement of mid-frontal and mid-cerebellar regions in postural stability during a balance task and emphasizes the important role of theta oscillations therein for postural control in PD.

Altered Cerebellar Oscillations in Parkinson's Disease Patients during Cognitive and Motor Tasks.

Structural and functional abnormalities in the cerebellar region have been shown in patients with Parkinson's disease (PD). Since the cerebellar region has been associated with cognitive and lower-limb motor functions, it is imperative to study cerebellar oscillations in PD. Here, we evaluated cerebellar electroencephalography (EEG) during cognitive processing and lower-limb motor performances in PD. Cortical and cerebellar EEG were collected from 74 PD patients and 37 healthy control subjects during a 7-second interval timing task, 26 PD patients and 13 controls during a lower-limb pedaling task, and 23 PD patients during eyes-open/closed resting conditions. Analyses were focused on the mid-cerebellar Cbz electrode and further compared to the mid-occipital Oz and mid-frontal Cz electrodes. Increased alpha-band power was observed during the eyes-closed resting-state condition over Oz, but no change in alpha power was observed over Cbz. PD patients showed higher dispersion when performing the 7-second interval timing cognitive task and executed the pedaling motor task with reduced speed compared to controls. PD patients exhibited attenuated cue-triggered theta-band power over Cbz during both the interval timing and pedaling motor tasks. Connectivity measures between Cbz and Cz showed theta-band differences, but only during the pedaling motor task. Cbz oscillatory activity also differed from Oz across multiple frequency bands in both groups during both tasks. Our cerebellar EEG data along with previous magnetoencephalography and animal model studies clearly show alterations in cerebellar oscillations during cognitive and motor processing in PD.

Getting a handle on virtual tools: An examination of the neuronal activity associated with virtual tool use.

Tool use is associated with three visual streams-dorso-dorsal, ventro-dorsal, and ventral visual streams. These streams are involved in processing online motor planning, action semantics, and tool semantics features, respectively. Little is known about the way in which the brain represents virtual tools. To directly assess this question, a virtual tool paradigm was created that provided the ability to manipulate tool components in isolation of one another. During functional magnetic resonance imaging (fMRI), adult participants performed a series of virtual tool manipulation tasks in which vision and movement kinematics of the tool were manipulated. Reaction time and hand movement direction were monitored while the tasks were performed. Functional imaging revealed that activity within all three visual streams was present, in a similar pattern to what would be expected with physical tool use. However, a previously unreported network of right-hemisphere activity was found including right inferior parietal lobule, middle and superior temporal gyri and supramarginal gyrus - regions well known to be associated with tool processing within the left hemisphere. These results provide evidence that both virtual and physical tools are processed within the same brain regions, though virtual tools recruit bilateral tool processing regions to a greater extent than physical tools.