What is the effect of benzodiazepines on deep brain activity? A study in pediatric patients with dystonia.

Introduction: Benzodiazepines (BDZs) are commonly used to treat the symptoms of movement disorders; however, deep brain stimulation (DBS) has become a popular treatment for these disorders. Previous studies have investigated the effects of BDZ on cortical activity, no data are currently available on their effects on deep brain regions, nor on these regions' responses to DBS. How the BDZ affects the thalamus and basal ganglia in dystonia patients remains unknown. Methods: DBS recordings were performed in ventral oralis anterior/posterior (VoaVop), ventral intermediate (VIM) and ventral anterior (VA) thalamic subnuclei, as well as globus pallidus interna (GPi) and subthalamic nucleus (STN). Evoked potentials (EP) and frequency domain analysis were performed to determine the BDZ effect on neural activities compared to the control condition (off-BDZ). Three male pediatric patients with dystonia treated with BDZ and undergoing depth electrode evaluation for clinical targeting were recruited for the study. Stimulation was administered at 25 and 55 Hz frequencies and recordings were simultaneously gathered through pairs of externalized stereoelectroencephalography (sEEG) electrodes. EP amplitude and the effect of stimulation on the frequency spectrum of activity were compared at baseline and following clinical administration of BDZ. Results: Frequency analysis showed consistent reductions in activity during BDZ treatment in all studied brain regions for all patients. Evoked potential (EP) analysis showed increased subthalamic nucleus (STN) EP amplitude and decreased ventral intermediate (VIM) and STN EP amplitude during BDZ treatment. Interpretation: BDZs reduce thalamic and basal ganglia activity in multiple regions and alter the efficacy of transmission between these regions. While the mechanism is unknown our results confirm the known widespread effects of this class of medications and identify specific areas within the motor system that are directly affected.

Globus pallidus internus activity increases during voluntary movement in children with dystonia.

The rate model of basal ganglia function predicts that muscle activity in dystonia is due to disinhibition of thalamus resulting from decreased inhibitory input from pallidum. We seek to test this hypothesis in children with dyskinetic cerebral palsy undergoing evaluation for deep brain stimulation (DBS) to analyze movement-related activity in different brain regions. The results revealed prominent beta-band frequency peaks in the globus pallidus interna (GPi), ventral oralis anterior/posterior (VoaVop) subnuclei of the thalamus, and subthalamic nucleus (STN) during movement but not at rest. Connectivity analysis indicated stronger coupling between STN-VoaVop and STN-GPi compared to GPi-STN. These findings contradict the hypothesis of decreased thalamic inhibition in dystonia, suggesting that abnormal patterns of inhibition and disinhibition, rather than reduced GPi activity, contribute to the disorder. Additionally, the study implies that correcting abnormalities in GPi function may explain the effectiveness of DBS targeting the STN and GPi in treating dystonia.

Increased movement-related signals in both basal ganglia and cerebellar output pathways in two children with dystonia.

The contribution of different brain regions to movement abnormalities in children with dystonia is unknown. Three awake subjects undergoing depth electrode implantation for assessments of potential deep brain recording targets performed a rhythmic figure-8 drawing task. Two subjects had dystonia, one was undergoing testing for treatment of Tourette Syndrome and had neither dystonia nor abnormal movements during testing. Movement-related signals were evaluated by determining the magnitude of task-related frequency components. Brain signals were recorded in globus pallidus internus (GPi), the ventral oralis anterior/posterior (VoaVop) and the ventral intermediate (Vim) nuclei of the thalamus. In comparison to the subject without dystonia, both children with dystonia showed increased task-related activity in GPi and Vim. This finding is consistent with a role of both basal ganglia and cerebellar outputs in the pathogenesis of dystonia. Our results further suggest that frequency analysis of brain recordings during cyclic movements may be a useful tool for analysis of the presence of movement-related signals in various brain regions.

High-fidelity transmission of high-frequency burst stimuli from peripheral nerve to thalamic nuclei in children with dystonia.

High-frequency peripheral nerve stimulation has emerged as a noninvasive alternative to thalamic deep brain stimulation for some patients with essential tremor. It is not known whether such techniques might be effective for movement disorders in children, nor is the mechanism and transmission of the peripheral stimuli to central brain structures understood. This study was designed to investigate the fidelity of transmission from peripheral nerves to thalamic nuclei in children with dystonia undergoing deep brain stimulation surgery. The ventralis intermediate (VIM) thalamus nuclei showed a robust evoked response to peripheral high-frequency burst stimulation, with a greatest response magnitude to intra-burst frequencies between 50 and 100 Hz, and reliable but smaller responses up to 170 Hz. The earliest response occurred at 12-15 ms following stimulation onset, suggesting rapid high-fidelity transmission between peripheral nerve and thalamic nuclei. A high-bandwidth, low-latency transmission path from peripheral nerve to VIM thalamus is consistent with the importance of rapid and accurate sensory information for the control of coordination and movement via the cerebello-thalamo-cortical pathway. Our results suggest the possibility of non-invasive modulation of thalamic activity in children with dystonia, and therefore the possibility that a subset of children could have beneficial clinical response without the need for invasive deep brain stimulation.

Diffuse optical tomography to measure functional changes during motor tasks: a motor imagery study.

The present work shows the spatial reliability of the diffuse optical tomography (DOT) system in a group of healthy subjects during a motor imagery task. Prior to imagery task performance, the subjects executed a motor task based on the finger to thumb opposition for motor training, and to corroborate the DOT spatial localization during the motor execution. DOT technology and data treatment allows us to distinguish oxy- and deoxyhemoglobin at the cerebral gyri level unlike the cerebral activations provided by fMRI series that were processed using different approaches. Here we show the DOT reliability showing functional activations at the cerebral gyri level during motor execution and motor imagery, which provide subtler cerebral activations than the motor execution. These results will allow the use of the DOT system as a monitoring device in a brain computer interface.

Evoked Potentials During Peripheral Stimulation Confirm Electrode Location in Thalamic Subnuclei in Children With Secondary Dystonia.

Deep brain stimulation is an elective surgical intervention that improves the function and quality of life in children with dystonia and other movement disorders. Both basal ganglia and thalamic nuclei have been found to be relevant targets for treatment of dystonia in children, including the ventral intermediate nucleus of the thalamus, in which stimulation can control dystonic spasms. Electrophysiological confirmation of correct electrode location within the ventralis intermediate nucleus is thus important for the success of the surgical outcome. The present work shows the evoked potentials response during contralateral median-nerve stimulation at the wrist at low frequency (9 Hz) provides physiological evidence of the electrode's localization within the thalamus. We show the correlation between evoked potentials and magnetic resonance imaging (MRI) and computed tomography (CT) in 14 children undergoing implantation of deep brain stimulation electrodes for secondary dystonia. High fidelity and reproducibility of our results provides a new approach to ensure the electrode localization in the thalamic subnuclei.

Neurofunctional correlates of eye to hand motor transfer.

This work investigates the transfer of motor learning from the eye to the hand and its neural correlates by using functional magnetic resonance imaging (fMRI) and a sensorimotor task consisting of the continuous tracking of a virtual target. In pretraining evaluation, all the participants (experimental and control group) performed the tracking task inside an MRI scanner using their right hand and a joystick. After which, the experimental group practiced an eye-controlled version of the task for 5 days using an eye tracking system outside the MRI environment. Post-training evaluation was done 1 week after the first scanning session, where all the participants were scanned again while repeating the manual pretraining task. Behavioral results show that the training in the eye-controlled task produced a better performance not only in the eye-controlled modality (motor learning) but also in the hand-controlled modality (motor transfer). Neural results indicate that eye to hand motor transfer is supported by the motor cortex, the basal ganglia and the cerebellum, which is consistent with previous research focused on other effectors. These results may be of interest in neurorehabilitation to activate the motor systems and help in the recovery of motor functions in stroke or movement disorder patients.

Visual inputs decrease brain activity in frontal areas during silent lipreading.

AIM: The aim of the present work is to analyze the modulation of the brain activity within the areas involved in lipreading when an additional visual stimulus is included. METHODS: The experiment consisted of two fMRI runs (lipreading_only and lipreading+picture) where two conditions were considered in each one (oral speech sentences condition [OSS] and oral speech syllables condition [OSSY]). RESULTS: During lipreading-only, higher activity in the left middle temporal gyrus (MTG) was identified for OSS than OSSY; during lipreading+picture, apart from the left MTG, higher activity was also present in the supplementary motor area (SMA), the left precentral gyrus (PreCG) and the left inferior frontal gyrus (IFG). The comparison between these two runs revealed higher activity for lipreading-only in the SMA and the left IFG. CONCLUSION: The presence of a visual reference during a lipreading task leads to a decrease in activity in frontal areas.

Is it necessary to show virtual limbs in action observation neurorehabilitation systems?

INTRODUCTION: Action observation neurorehabilitation systems are usually based on the observation of a virtual limb performing different kinds of actions. In this way, the activity in the frontoparietal Mirror Neuron System is enhanced, which can be helpful to rehabilitate stroke patients. However, the presence of limbs in such systems might not be necessary to produce mirror activity, for example, frontoparietal mirror activity can be produced just by the observation of virtual tool movements. The objective of this work was to explore to what point the presence of a virtual limb impacts the Mirror Neuron System activity in neurorehabilitation systems. METHODS: The study was conducted by using an action observation neurorehabilitation task during a functional magnetic resonance imaging (fMRI) experiment with healthy volunteers and comparing two action observation conditions that: 1 - included or 2 - did not include a virtual limb. RESULTS: It was found that activity in the Mirror Neuron System was similar during both conditions (i.e. virtual limb present or absent). CONCLUSIONS: These results open up the possibility of using new tasks that do not include virtual limbs in action observation neurorehabilitation environments, which can give more freedom to develop such systems.

The relationship between amplitude of low frequency fluctuations and gray matter volume of the mirror neuron system: Differences between low disability multiple sclerosis patients and healthy controls.

The study of the relationship between function and structure of the brain could be particularly interesting in neurodegenerative diseases like multiple sclerosis (MS). The aim of the present work is to identify differences of the amplitude of low frequency fluctuations (ALFF) in the mirror neuron system (MNS) between MS patients and healthy controls and to study the relationship between ALFF and the gray matter volume (GMV) of the regions that belong to the MNS. Relapsing-remitting MS patients with minor disability were compared to healthy controls (HC) using resting-state functional magnetic resonance imaging (fMRI), anatomic T1 weighted images and diffusion tensor imaging (DTI). Region of interest (ROI) analyses was performed in the MNS regions. A decrease of ALFF in MS patients was observed in the left inferior frontal gyrus (IFG). Furthermore, a correlation between ALFF in the IFG and the GMV of the left inferior parietal lobule (IPL) was identified. This relationship was different for MS patients than for HC, which may be associated with changes in diffusivity measures which were impaired in MS patients. MS patients with low disability may show ALFF differences in the MNS without clinical correspondence. This functional difference may be associated with cortical and subcortical changes related to the disease.

Comparing diffuse optical tomography and functional magnetic resonance imaging signals during a cognitive task: pilot study.

Diffuse optical tomography (DOT) measures concentration changes in both oxy- and deoxyhemoglobin providing three-dimensional images of local brain activations. A pilot study, which compares both DOT and functional magnetic resonance imaging (fMRI) volumes through t-maps given by canonical statistical parametric mapping (SPM) processing for both data modalities, is presented. The DOT series were processed using a method that is based on a Bayesian filter application on raw DOT data to remove physiological changes and minimum description length application index to select a number of singular values, which reduce the data dimensionality during image reconstruction and adaptation of DOT volume series to normalized standard space. Therefore, statistical analysis is performed with canonical SPM software in the same way as fMRI analysis is done, accepting DOT volumes as if they were fMRI volumes. The results show the reproducibility and ruggedness of the method to process DOT series on group analysis using cognitive paradigms on the prefrontal cortex. Difficulties such as the fact that scalp-brain distances vary between subjects or cerebral activations are difficult to reproduce due to strategies used by the subjects to solve arithmetic problems are considered. T-images given by fMRI and DOT volume series analyzed in SPM show that at the functional level, both DOT and fMRI measures detect the same areas, although DOT provides complementary information to fMRI signals about cerebral activity.

The Mirror Neuron System in Relapsing Remitting Multiple Sclerosis Patients with Low Disability.

To study the visuospatial/visuoperceptive function using a mirror neuron system (MNS) based approach in multiple sclerosis (MS) patients and a healthy control group. Two task-based fMRIs (an execution task and an observation task) and one resting-fMRI were performed in a group of MS patients (n = 24) and a group of healthy controls (n = 15). The execution and observation tasks consisted of the performance or observation of the index-thumb opposition task. Statistical parametric mapping approaches were used to identify differences in the brain activity and functional connectivity (FC) of the MNS between MS patients and healthy controls. Furthermore, visuospatial and visuoperceptive evaluation was performed by a neuropsychologist on all the participants. No global differences between groups were identified when the activity during both the execution and the observation conditions was tested. Nevertheless, differences in FC maps were identified: healthy controls showed higher connectivity between the MNS regions (between the inferior parietal lobule and the inferior frontal gyrus bilaterally) than MS patients. The absence of differences between the studied groups may be the consequence of the selection of a cohort of MS patients with low disability and with no recent relapse. However, the presence of a decrease in functional connectivity within the MNS in MS patients could indicate the presence of subclinical disability in MNS functioning, not measurable by neuropsychological tests.

The mirror neuron system also rests.

The mirror neuron system (MNS) is a brain network that has been associated with the understanding of the actions performed by others. The main areas of the brain that are considered as belonging to the MNS are the rostral part of the inferior parietal lobe (IPL) and the inferior frontal gyrus (IFG). Many studies have tried to focus on the relationship between the regions belonging to the MNS, but a little consideration has been given to the study of the MNS in resting conditions. In the present experiment, the MNS has been studied by two fMRI modalities (task-based fMRI and resting-fMRI) and three analytical procedures [task-block comparison, functional connectivity (FC), and independent component analysis (ICA)]. The task-fMRI with block design showed a mirror activity located in the rostral IPL. The coordinates of this local maximum voxel were defined as a region of interest (ROI) for an FC analysis of the resting-fMRI. This analysis revealed the existence of a functional connectivity within regions forming the core of MNS network and also with other regions with mirror properties. Finally, resting-state fMRI ICA showed the same functional network, although it was more restricted to the core MNS regions. To the best of our knowledge, this is the first study that approaches the MNS using the resting-state fMRI analysis using independent component analysis and functional connectivity at the same time.